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Pharmacology

for
Physiotherapy
Pharmacology
for
Physiotherapy
Second Edition

Padmaja Udaykumar
Professor and Head
Department of Pharmacology
Fr Muller Medical College
Mangalore, Karnataka, India

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Pharmacology for Physiotherapy


© 2011, Padmaja Udaykumar

All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or
transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise,
without the prior written permission of the author and the publisher.
This book has been published in good faith that the material provided by author is original. Every
effort is made to ensure accuracy of material, but the publisher, printer and author will not be held
responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled
under Delhi jurisdiction only.

First Edition : 2004


Second Edition : 2011

ISBN 978-93-80704-67-8

Typeset at JPBMP typesetting unit


Printed at
Dedicated to
My dear students
Foreword

Textbook is the most important companion, tool and light of a learning student to lead him, to shape
him, enlighten him to perfect himself in the chosen subject of his studies. So it should be reader
friendly, descriptive and analytical, to reach those goals, to fit into the mind of the learner. It should
also be tailored to the needs of the student to pass his examination, which also is one of the primary
goals of a student.

Pharmacology to many, including me, is one of the tough subjects, to learn amongst the medical
curriculum. Most of the textbooks in pharmacology have been written, tailored to the needs of a
medical student. Dr Padmaja Udaykumar in her own inimitable style has penned this textbook fully
looking into the needs of a physiotherapy student. Physiotherapy is one of the most dynamic fields in
medicine today to put back the patient to his physical perfection and the student ought to know the
pharmacodynamics of the musculoskeletal and neurovascular systems. This book has met all these
goals and I find it useful to an orthopedic and physical medicine postgraduate student as well.

I have known Dr Padmaja for many years. Her tenacity of purpose, vision and enthusiasm has
culminated in yet another masterpiece. She is a source of inspiration to the younger generation for
academic excellence.

I am sure this textbook will be of immense help to its user and I strongly recommend it, especially
to physiotherapy students.

With best wishes

Dr M Shantharam Shetty
Vice-Chancellor and Professor of Orthopaedics
KS Hegde Medical Academy, Nitte University
Mangalore, Karnataka, India
Preface to the Second Edition

The expansion of pharmacology in the last few years has been phenomenal. Basic knowledge of
commonly used drugs is essential for all those who are involved in patient care. The depth of
pharmacology knowledge required for physiotherapists has now been better understood. This has
prompted changes in syllabus in several universities for physiotherapy. To keep pace with these
changes, this edition has been published. In this edition, several new topics relating to muscle nerve
pathophysiology and geriatric pharmacology have been added as required by the syllabus of some
universities and unnecessary information has been pruned. The book has been tailored to the needs of
physiotherapy students.

Any feedback may please be mailed to padmajaudaykumar@gmail.com.

Padmaja Udaykumar
Preface to the First Edition

Pharmacology is a science that is rapidly growing. Basic knowledge of pharmacology is required for
all those who deal with patients. Since there is no standard textbook meant exclusively for
physiotherapy students, they are faced with the hardship of having to refer medical pharmacology
books. Such volume and depth of pharmacology is unnecessary for physiotherapists and also difficult
to comprehend. Hence this book is written to make pharmacology simple for physiotherapy students.
The presentation has been simple so that the students easily understand the subject. Guidelines of the
University syllabus has been followed. More importance has been given for topics like analgesics,
skeletal muscle relaxants and other musculoskeletal disorders which are emphasized for physiotherapy
students. Syllabuses of some universities have recommended topics like ‘drugs and exercise’,
‘vasoconstrictors and vasodilators’ for physiotherapy students. They have also been discussed briefly.

I hope this book reduces the burden of students in learning pharmacology.

Padmaja Udaykumar
Acknowledgments

I am extremely grateful to Dr M Shantharam Shetty, Vice-Chancellor and Professor of Orthopedics, KS


Hegde Medical Academy, Nitte University, Mangalore, for writing Foreword to this book.

I am sincerely thankful to the management of Fr Muller Medical College, Director–Fr Patrick


Rodrigues, Administrator– Fr Dennis D’Sa, Chief of Medical Services–Dr B Sanjeev Rai, and Dean
Dr Jaya Prakash Alva for their encouragement and support.

I wish to place on record my sincere thanks to Dr Annappa Kulal for his suggestions. I am thankful
to my colleagues Dr Princy Palatty, Dr Prasanna Lakshmi, Dr Vijayalakshmi, Dr Raghvendra Baliga,
and Dr Chandrashekhar, Dr Manohar Revankar and Ms Rojin for their encouragement.

I owe a special note of thanks to my husband Prof Udaykumar K for his constant encouragement
and valuable suggestions, which made this work possible.

I also wish to thankfully acknowledge the prompt and meticulous work of M/s Jaypee Brothers
Medical Publishers (P) Ltd, New Delhi.
Contents

1. General Pharmacology ......................................................................................... 1


• Introduction and sources of drugs ............................................................................................ 1
• Routes of drug administration .................................................................................................. 2
• Pharmacokinetics ........................................................................................................................ 8
• Pharmacodynamics .................................................................................................................. 18
• Adverse drug reactions ............................................................................................................26
• Drug interactions .......................................................................................................................28
• Gene therapy .............................................................................................................................. 29

2. Autonomic Nervous System .............................................................................. 30


• Introduction to autonomic pharmacology ............................................................................30
• Cholinergic system .................................................................................................................... 31
• Anticholinergic drugs ............................................................................................................... 39
• Adrenergic system .....................................................................................................................41
• Adrenergic drugs (Sympathomimetics) .................................................................................42
• Adrenergic antagonists ............................................................................................................47

3. Musculoskeletal System ..................................................................................... 51


• Skeletal muscle relaxants .........................................................................................................51
• Drugs used in the treatment of local muscle spasm ............................................................. 55
• Drugs used in other musculoskeletal diseases ...................................................................... 56
• Agents used in the prevention and treatment of osteoporosis .......................................... 56
• Drugs used in the treatment of immunological
and inflammatory neuromuscular diseases ......................................................................... 56
• Drugs and exercise .....................................................................................................................60

4. Drugs Acting on the Kidney ............................................................................... 62


• Diuretics ......................................................................................................................................63
• Antidiuretics .............................................................................................................................. 66

5. Cardiovascular System and Blood .................................................................... 67


• Cardiac glycosides and treatment of cardiac failure ...........................................................67
• Antiarrhythmic drugs ..............................................................................................................71
• Drugs used in the treatment of angina pectoris .................................................................... 74
• Antihypertensive drugs ...........................................................................................................77
xvi Pharmacology for Physiotherapy

• Pharmacotherapy of shock ...................................................................................................... 83


• Plasma expanders ...................................................................................................................... 83
• Vasoactive drugs .......................................................................................................................84
• Cerebral ischemia ...................................................................................................................... 84
• Drugs used in treatment of peripheral vascular diseases ................................................... 85
• Hypolipidemic drugs ................................................................................................................87
• Drugs used in the disorders of coagulation ........................................................................... 88
• Hematinics .................................................................................................................................. 94

6. Central Nervous System..................................................................................... 97


• General anesthetics ...................................................................................................................97
• Local anesthetics ..................................................................................................................... 101
• Sedative hypnotics ................................................................................................................. 106
• Alcohols .................................................................................................................................... 110
• Antiepileptics .......................................................................................................................... 111
• Drugs used in parkinsonism ................................................................................................. 116
• Opioid analgesics and antagonists ...................................................................................... 118
• Nonsteroidal anti-inflammatory drugs (NSAIDs) ............................................................ 126
• Drugs used in rheumatoid arthritis and gout .................................................................... 134
• Drugs used in psychiatric disorders—antipsychotics,
antidepressants and antianxiety agents ............................................................................. 139
• Antidepressants ...................................................................................................................... 142
• CNS stimulants ....................................................................................................................... 145

7. Autacoids ........................................................................................................... 147


• Histamine and antihistamines ............................................................................................. 147
• 5-Hydroxytryptamine, ergot alkaloids, angiotensin and kinins .................................... 150
• Eicosanoids .............................................................................................................................. 152

8. Respiratory System .......................................................................................... 155


• Drugs used in the treatment of bronchial asthma ............................................................ 155
• Drugs used in the treatment of cough ................................................................................. 158

9. Gastrointestinal Tract ....................................................................................... 161


• Drugs used in peptic ulcer ..................................................................................................... 161
• Prokinetic agents ..................................................................................................................... 165
• Emetics and antiemetics ........................................................................................................ 165
• Drugs used in the Treatment of Constipation .................................................................... 167
• Drugs used in the Treatment of Diarrhea ........................................................................... 169
Contents xvii

10. Hormones .......................................................................................................... 172


• Hypothalamus and anterior pituitary hormones ............................................................. 172
• Thyroid hormones and antithyroid drugs ......................................................................... 175
• Insulin and oral hypoglycemics ........................................................................................... 177
• Corticosteroids ........................................................................................................................ 182
• Estrogens, progestins and oral contraceptives .................................................................. 188
• Androgens and anabolic steroids ........................................................................................ 193
• Agents affecting bone mineral turnover ............................................................................. 196

11. Chemotherapy ................................................................................................... 200


• General considerations .......................................................................................................... 200
• Sulfonamides ........................................................................................................................... 206
• Cotrimoxazole ......................................................................................................................... 207
• Quinolones ............................................................................................................................... 208
• Beta-lactam antibiotics .......................................................................................................... 209
• Broad-spectrum antibiotics .................................................................................................. 215
• Aminoglycosides ..................................................................................................................... 217
• Macrolides and other antibacterial agents ......................................................................... 219
• Chemotherapy of urinary tract infections ......................................................................... 222
• Chemotherapy of tuberculosis ............................................................................................. 223
• Chemotherapy of leprosy ...................................................................................................... 226
• Antifungal drugs ..................................................................................................................... 227
• Antiviral drugs ....................................................................................................................... 229
• Chemotherapy of malaria ..................................................................................................... 232
• Antiamoebic drugs ................................................................................................................. 234
• Drugs used leishmaniasis and trypanosomiasis ............................................................... 235
• Anthelmintics .......................................................................................................................... 236
• Cancer chemotherapy ............................................................................................................ 238
• Immunosuppressants and immunostimulants ................................................................. 242
• Vaccines and antisera ............................................................................................................ 245

12. Geriatric Pharmacology ................................................................................... 247


• Pharmacokinetic changes ...................................................................................................... 248
• Pharmacodynamic changes .................................................................................................. 249
• Adverse reactions in the elderly .......................................................................................... 249

Index ................................................................................................................................................ 251


General
Pharmacology

• INTRODUCTION AND SOURCES OF DRUGS


• ROUTES OF DRUG ADMINISTRATION
• PHARMACOKINETICS
• PHARMACODYNAMICS
• ADVERSE DRUG REACTIONS
• DRUG INTERACTIONS
• GENE THERAPY

INTRODUCTION AND SOURCES OF DRUGS like’ and dilution enhances the action of drugs.
Thus, several systems of therapeutics were
Pharmacology is the science that deals with the introduced, of which only few survived. The basic
study of drugs and their interaction with the living reason for failure of many systems is that man’s
systems. concepts about diseases were incorrect and
Early man recognized the benefits and toxic baseless in those days. By the end of the 17th
effects of many plants and animal products. century the importance of experimentation and
India’s earliest pharmacological writings are from observation became clear and many physicians
the ‘Vedas.’ An ancient Indian physician Charaka applied these to the traditional drugs. Francois
and then Sushruta and Vagbhata described many Magendie and Claude-Bernard popularized the
herbal preparations included in ‘Ayurveda’ use of animal experiments to understand the
(meaning the science of life). James Gregory effects of drugs. The development of physiology
recommended harsh and dangerous remedies like also helped in the better understanding of
blood-letting, emetics and purgatives to be used pharmacology. The last century has seen a rapid
until the symptoms of the disease subsided (such growth of the subject with new concepts and
remedies often resulted in fatality). This was called techniques being introduced.
‘Allopathy’ meaning the other suffering. This
word, still being used for the modern system of
DEFINITIONS
medicine, is a misnomer. To counter this system,
Hannemann introduced the system of Homoeo- The word pharmacology is derived from the Greek
pathy meaning similar suffering in the early 19th word—Pharmacon meaning an active principle or
century. The principles of this include ‘like cures drug and logos meaning a discourse or study.
2 Pharmacology for Physiotherapy

Drug (Drogue—a dry herb in French) is a substance SOURCES OF DRUGS


used in the diagnosis, prevention or treatment of
The sources of drugs could be natural or synthetic.
a disease. WHO definition—“A Drug is any
substance or product that is used or intended to
be used to modify or explore physiological systems Natural Sources
or pathological states for the benefit of the Drugs can be obtained from:
recipient.” 1. Plants, e.g. atropine, morphine, quinine, and
Pharmacodynamics is the study of the effects of digoxin.
the drugs on the body and their mechanisms of 2. Animals, e.g. insulin, heparin, gonado-
action, i.e. what the drug does to the body. trophins and antitoxic sera.
3. Minerals, e.g. magnesium sulphate, alumi-
Pharmacokinetics is the study of the absorption,
nium hydroxide, iron, sulphur and radio-
distribution, metabolism and excretion of drugs,
active isotopes.
i.e. what the body does to the drug (in Greek
4. Microorganisms—antibacterial agents are
Kinesis = movement).
obtained from some bacteria and fungi. We
Therapeutics deals with the use of drugs in the thus have penicillin, cephalosporins, tetra-
prevention and treatment of diseases. cyclines and other antibiotics.
5. Human—some drugs are obtained from
Toxicology deals with the adverse effects of drugs
human beings, e.g. immunoglobulins from
and also the study of poisons, i.e. detection,
blood, growth hormone from anterior
prevention and treatment of poisonings
pituitary and chorionic gonadotrophins
(Toxicon = poison in Greek).
from the urine of pregnant women.
Chemotherapy is the use of chemicals for the
treatment of infections. The term now also includes Synthetic
the use of chemical compounds to treat
malignancies. Most drugs are now synthesized, e.g. quinolones,
omeprazole.
Pharmacopoeia (In Greek Pharmacon = drug;
Many drugs are obtained by cell cultures, e.g.
poeia=to make) is the official publication con-
urokinase from cultured human kidney cells.
taining a list of drugs and medicinal preparations
Some are now produced by recombinant DNA
approved for use, their formula and other
technology, e.g. human insulin, tissue plasmi-
information needed to prepare a drug; their
nogen activator.
physical properties, tests for their identity, purity
and potency. Each country may follow its own
pharmacopoeia to guide its physicians and ROUTES OF DRUG ADMINISTRATION
pharmacists. We thus have the Indian Pharma-
Drugs may be administered by various routes. The
copoeia (IP), the British Pharmacopoeia (BP) and
choice of the route in a given patient depends on
the United States Pharmacopoeia (USP). The list
the properties of the drug and the patient’s
is revised at regular periods to delete old useless
requirements. A knowledge of the advantages and
drugs and to include newly introduced ones.
disadvantages of the different routes of adminis-
Pharmacy is the science of identification, tration is essential.
compounding and dispensing of drugs. It also The routes can be broadly divided into:
includes collection, isolation, purification, • Enteral
synthesis and standardization of medicinal • Parenteral
substances. • Local.
General Pharmacology 3

ENTERAL ROUTE (ORAL INGESTION) minimizes chances of the drug getting into larynx
or behind the epiglottis. Recumbent patient
This is the most common, oldest and safest route
should not be given drugs orally as some drugs
of drug administration. The large surface area of
may remain in the esophagus due to the absence
the gastrointestinal tract, the mixing of its contents
of gravitational force which facilitates the passage
and the differences in pH at different parts of the
of the drug into the stomach. Such drugs can
gut facilitate effective absorption of the drugs given
damage the esophageal mucosa, e.g. iron salts,
orally. However, the acid and enzymes secreted
tetracyclines.
in the gut and the biochemical activity of the
bacterial flora of the gut can destroy some drugs
Enteric Coated Tablets
before they are absorbed.
Some tablets are coated with substances like
Advantages cellulose-acetate, phthalate, gluten, etc. which are
1. Safest route. not digested by the gastric acid but get disinte-
2. Most convenient. grated in the alkaline juices of the intestine. This
3. Most economical. will:
4. Drugs can be self-administered. 1. Prevent gastric irritation.
5. Non-invasive route. 2. Avoid destruction of the drug by the stomach.
Disadvantages 3. Provide higher concentration of the drug in
1. Onset of action is slower as absorption needs the small intestine.
time. 4. Retard the absorption, and thereby prolong
2. Irritant and unpalatable drugs cannot be the duration of action. But if the coating is
administered. inappropriate, the tablet may be expelled
3. Some drugs may not be absorbed due to certain without being absorbed at all. Similarly,
physical characteristics, e.g. streptomycin. controlled-release or sustained-release
4. Irritation to the gastrointestinal tract may lead preparations are designed to prolong the rate
to vomiting. of absorption and thereby the duration of
5. There may be irregularities in absorption. action of drugs. This is useful for short-acting
6. Some drugs may be destroyed by gastric juices, drugs.
e.g. insulin. Advantages
7. Cannot be given to unconscious and unco- • Frequency of administration may be reduced.
operative patients. • Therapeutic concentration may be maintained
8. Some drugs may undergo extensive first pass specially when nocturnal symptoms are to be
metabolism in the liver. treated.
To overcome some of the disadvantages,
Disadvantages
irritants are given in capsules, while bitter drugs
• There may be ‘failure of the preparation’
are given as sugar coated tablets. Sometimes drugs
resulting in release of the entire amount of the
are coated with substances like synthetic resins,
drug in a short-time leading to toxicity.
gums, sugar, coloring and flavoring agents
• It is more expensive.
making them more acceptable.
Certain precautions are to be taken during oral
PARENTERAL ROUTE
administration of drugs—capsules and tablets
should be swallowed with a glass of water with Routes of administration other than the enteral
the patient in upright posture either sitting or stan- (intestinal) route are known as parenteral routes.
ding. This facilitates passage of the tablet into the Here the drugs are directly delivered into tissue
stomach and its rapid dissolution. It also fluids or blood.
4 Pharmacology for Physiotherapy

Advantages can be enhanced by the addition of the enzyme


• Action is more rapid and predictable than oral hyaluronidase.
administration.
Disadvantages
• These routes can be employed in an
• As SC tissue is richly supplied by nerves,
unconscious or uncooperative patient.
irritant drugs can cause severe pain. Hence
• Gastric irritants can be given parenterally and
such drugs cannot be injected.
therefore irritation to the gastrointestinal tract
• In shock, absorption is not dependable
can be avoided.
because of vasoconstriction.
• It can be used in patients with vomiting or
• Repeated injections at the same site can cause
those unable to swallow.
lipoatrophy resulting in erratic absorption.
• Digestion by the gastric and intestinal juices
and the first pass metabolism are avoided. Hypodermoclysis is the SC administration of large
Therefore, in emergencies parenteral routes are volumes of saline employed in pediatric practice.
very useful routes of drug administration as the
Drugs can also be administered subcu-
action is rapid and predictable and are useful in
taneously as:
unconscious patients.
1. Dermojet In this method, a high velocity jet of
Disadvantages drug solution is projected from a fine orifice
• Asepsis must be maintained. using a gun. The solution gets deposited in
• Injections may be painful. the SC tissue from where it is absorbed. As
• More expensive, less safe and inconvenient. needle is not required, this method is painless.
• Injury to nerves and other tissues may occur. It is suitable for vaccines.
2. Pellet implantation Small pellets packed with
Parenteral routes include: drugs are implanted subcutaneously. The
1. Injections. drug is slowly released for weeks or months to
2. Inhalation. provide constant blood levels, e.g. testosterone.
3. Transdermal route. 3. Sialistic implants The drug is packed in sialistic
4. Transmucosal route. tubes and implanted subcutaneously. The
drug gets absorbed over months to provide
INJECTIONS constant blood levels, e.g. hormones and
contraceptives. The empty non-biodegradable
Intradermal
implant has to be removed.
The drug is injected into the layers of the skin
raising a bleb, e.g. BCG vaccine, tests for allergy or Intramuscular (IM)
by multiple punctures of the epidermis through a
drop of the drug, e.g. smallpox vaccine. Only a Aqueous solution of the drug is injected into one
small quantity can be administered by this route of the large skeletal muscles—deltoid, triceps,
and it may be painful. gluteus or rectus femoris. As the muscles are
vascular, absorption is rapid and quite uniform.
Drugs are absorbed faster from the deltoid region
Subcutaneous (SC) Injection
than gluteal region especially in women. The
Here the drug is deposited in the SC tissue, e.g. volume of injection should not exceed 10 ml. For
insulin, heparin. As this tissue is less vascular, infants, rectus femoris is used instead of gluteus
absorption is slow and largely uniform making which is not well-developed till the child starts
the drug long-acting. It is reliable and patients walking. If the drug is injected as an oily solution,
can be trained for self-administration. Absorption absorption is slow and steady.
General Pharmacology 5

Advantages rate can be increased—specially for short-


• Intramuscular route is reliable. acting drugs.
• Absorption is rapid.
• Soluble substances, mild irritants, depot Disadvantages
preparations, suspensions and colloids can • Once injected into the vein, the drug cannot be
be injected by this route. withdrawn.
• Irritation of the veins may cause thrombo-
Disadvantages phlebitis.
• Intramuscular injection may be painful and • Extravazation of some drugs may cause severe
may even result in an abscess. irritation and sloughing.
• Nerve injury should be avoided near a nerve, • Only aqueous solutions can be given IV but
irritant solutions can damage the nerve if not suspensions, oily solutions and depot
injected. preparations.
• Self medication is difficult.
Intravenous (IV)
Intraperitoneal
Here, the drug is injected into one of the superficial
veins so that it directly reaches the circulation and Peritoneum offers a large surface area for absorp-
is immediately available for action. tion. Fluids are injected intraperitoneally in
infants. This route is also used for peritoneal
Drugs can be given IV as:
dialysis.
1. A bolus—where an initial large dose is
given, e.g. heparin. The drug is dissolved Intrathecal
in a suitable amount of the vehicle and
Drugs can be injected into the subarachnoid space
injected slowly.
for action on the CNS, e.g. spinal anesthetics. Some
2. Slowly—over 15-20 minutes, e.g. amino-
antibiotics and corticosteroids are also injected
phylline.
by this route to produce high local concentrations.
3. Slow infusion—when constant plasma
Strict aseptic precautions are a must.
concentrations are required, e.g. oxytocin
Drugs are also given extradurally. Morphine
in labor or when large volumes have to be
can be given epidurally to produce analgesia.
given, e.g. dextrose, saline. Generally about
one liter of solution is infused over 3 to 4 Intra-articular
hours. But the patients condition dictates
Drugs are injected directly into a joint for the treat-
the rate of infusion.
ment of arthritis and other diseases of the joints.
Advantages Strict aseptic precautions are required, e.g.
• Most useful route in emergencies as the drug hydrocortisone in rheumatoid arthritis.
is immediately available for action.
Intra-arterial
• Provides predictable blood concentrations
with 100 percent bioavailability. Here drug is injected directly into the arteries. It is
• Large volumes of solutions can be given. used only in the treatment of (i) peripheral
• Irritants can be given by this route as they get vascular diseases, (ii) local malignancies and
quickly diluted in the blood. (iii) diagnostic studies like angiograms.
• Rapid dose adjustments are possible—if
unwanted effects occur, infusion can be Intramedullary
stopped; if higher levels are required, infusion Injection into a bone marrow—now rarely used.
6 Pharmacology for Physiotherapy

INHALATION application. The drug slowly diffuses through the


membrane and percutaneous absorption takes
Volatile liquids and gases are given by inhalation,
place. The rate of absorption is constant and
e.g. general anesthetics. In addition, drugs can be
predictable. Highly potent and short acting drugs
administered as solid particles, i.e. solutions of
are suitable for use in such systems.
drugs can be atomized and the fine droplets are
Sites of application are chest, abdomen, upper
inhaled as aerosol, e.g. salbutamol. These inhaled
arm, back or mastoid region, e.g. hyoscine,
drugs and vapors may act on the pulmonary
nitroglycerine, fentanyl transdermal patches.
epithelium and mucous membranes of the
respiratory tract and are also absorbed through Advantages
these membranes. • Duration of action is prolonged
Advantages • Provides constant plasma drug levels
• Almost instantaneous absorption of the drug • Patient compliance is good.
is achieved because of the large suface area of Inunction This route where a drug rubbed into the
the lungs. skin gets absorbed to produce systemic effects is
• In pulmonary diseases, it serves almost as a called inunction.
local route as the drug is delivered at the
Iontophoresis In this procedure, galvanic current
desired site making it more effective and less
is used for bringing about penetration of lipid
harmful.
insoluble drugs into the deeper tissues where its
• First pass metabolism is avoided.
action is required, e.g. Salicylates.
• Blood levels of volatile anesthetics can be
conveniently controlled as their absorption Jet injection As absorption of drug occurs across
and excretion through the lungs are governed the layers of the skin, dermojet may also be
by the laws of gases. considered as a form of transdermal drug
administration (description on page 4).
Disadvantages
• Irritant gases may enhance pulmonary
TRANSMUCOSAL
secretions-should be avoided.
• This is an important route of entry of certain Drugs are absorbed across the mucous mem-
drugs of abuse. branes. Transmucosal administration includes
sublingual, nasal and rectal routes.
TRANSDERMAL
Sublingual
Highly lipid soluble drugs can be applied over
the skin for slow and prolonged absorption, e.g. Here, the tablet or pellet containing the drug is
nitroglycerine ointment in angina pectoris. placed under the tongue. It dissolves in the saliva
Adhesive units, inunction, iontophoresis and jet and the drug is absorbed across the sublingual
injection are some forms of transdermal drug mucosa, e.g. nitroglycerine, nifedipine,
delivery. buprenorphine.
Adhesive units (transdermal therapeutic systems) Advantages
are adhesive patches of different sizes and shapes • Absorption is rapid—within minutes the drug
made to suit the area of application. The drug is reaches the circulation.
held in a reservoir between an outer layer and a • First pass metabolism is avoided.
porous membrane. This membrane is smeared • After the desired effect is obtained, the drug
with an adhesive to hold on to the area of can be spat out to avoid the unwanted effects.
General Pharmacology 7

Disadvantage Evacuant enema In order to empty the bowel,


Buccal ulceration can occur. about 600 ml of soap water is administered per
rectally. Water distends and thus stimulates the
Nasal rectum while soap lubricates. Enema is given prior
to surgeries, obstetric procedures and radiological
Drugs can be administered through nasal route
examination of the gut.
either for systemic absorption or for local effects,
Retention enema The drug is administered
e.g.
with about 100 ml of fluids and is retained in the
• Oxytocin spray is used for systemic absorption.
rectum for local action, e.g. prednisolone enema
• For local effect
in ulcerative colitis.
– Decongestant nasal drops, e.g. oxymeta-
zoline;
– Budesonide nasal spray for allergic rhinitis. TOPICAL
Drugs may be applied on the skin for local action
Rectal as ointment, cream, gel, powder, paste, etc. Drugs
Rectum has a rich blood supply and drugs can may also be applied on the mucous membrane as
cross the rectal mucosa to be absorbed for systemic in the eyes, ears and nose, as ointment, drops and
effects. Drugs absorbed from the upper part of the sprays. Drugs may be administered as suppository
rectum are carried by the superior hemorrhoidal for rectum, bougie for urethra and pessary and
vein to the portal circulation (can undergo first douche for vagina. Pessaries are oval shaped
pass metabolism), while that absorbed from the tablets to be placed in the vagina to provide high
local concentrations of the drug at the site, e.g.
lower part of the rectum is carried by the middle
antifungal pessaries in vaginal candidiasis.
and inferior hemorrhoidal veins to the systemic
circulation.
Special Drug Delivery Systems
Some irritant drugs are given per rectally as
suppositories: In order to improve drug delivery, to prolong
Advantages duration of action and thereby improve patient
• Gastric irritation is avoided. compliance, special drug delivery systems are
• Can be administered by unskilled persons. being tried. Drug targeting, i.e. to deliver drugs at
• Useful in geriatric patients and others with the site where it is required to act is also being
vomiting and those unable to swallow. aimed at, especially for anticancer drugs. Some
such systems are ocusert, progestasert, trans-
Disadvantages
dermal adhesive units, prodrugs, osmotic pumps,
• Irritation of the rectum can occur.
computerized pumps and methods using
• Absorption may be irregular and unpredic-
monoclonal antibodies and liposomes as carriers.
table.
• Drugs like—indomethacin, chlorpromazine, Ocusert systems are thin elliptical units that
diazepam and paraldehyde can be given contain the drug in a reservoir which slowly
rectally. releases the drug through a membrane by
diffusion at a steady rate, e.g. pilocarpine ocusert
Drugs may also be given by this route as
used in glaucoma is placed under the lid and can
enema.
deliver pilocarpine for 7 days.
Enema is the administration of a drug in a
liquid form into the rectum. Enema may be Progestasert is inserted into the uterus where it
evacuant or retention enema. delivers progesterone constantly for over one year.
8 Pharmacology for Physiotherapy

Transdermal Adhesive Units (See page 6). site-specific delivery of drugs may be possible with
the help of liposomes.
Prodrug is an inactive form of the drug which gets
metabolized to the active derivative in the body. A
prodrug may overcome some of the disadvantages PHARMACOKINETICS
of the conventional forms of drug administration, Pharmacokinetics is the study of the absorption,
e.g. dopamine does not cross the BBB; levodopa, a distribution, metabolism and excretion of drugs,
prodrug crosses the BBB and is then converted i.e. the movement of the drugs into, within and
to dopamine in the CNS. Prodrugs may also be out of the body. For a drug to produce its specific
used to have longer duration of action, e.g. response, it should be present in adequate
Bacampicillin (a prodrug of ampicillin) is longer concentrations at the site of action. This depends
acting. on various factors apart from the dose. Once the
drug is administered, it is absorbed, i.e. enters the
Osmotic pumps are small tablet shaped units blood, is distributed to different parts of the body,
consisting of the drug and an osmotic substance reaches the site of action, is metabolized and
placed in two chambers. The osmotic layer swells excreted (Fig. 1.1). All these processes involve
and pushes the drug slowly out of a small hole. passage of the drug molecules across various
Iron and prazosin are available in this form. barriers—like the intestinal epithelium, cell memb-
rane, renal filtering membrane, capillary barrier
Computerized miniature pumps: These are
and so on. To cross these barriers the drug has to
programmed to release drugs at a definite rate
cross the cell membrane or pass in-between the
either continuously as in case of insulin or
epithelial or endothelial cells.
intermittently in pulses as in case of GnRH.
The cell membrane/biological membrane is
Various methods of drug targeting are tried
made up of two layers of phospholipids with
especially for anticancer drugs to reduce toxicity.
intermingled protein molecules (Fig. 1.2). All lipid
Monoclonal antibodies against the tumor specific soluble substances get dissolved in the cell
antigens are used to deliver anticancer drugs to membrane and readily permeate into the cells. The
specific tumor cells. junctions between epithelial or endothelial cells
have pores through which small water-soluble
Liposomes are phospholipids suspended in molecules can pass. Movement of some specific
aqueous vehicles to form minute vesicles. Drugs substances is regulated by special carrier proteins.
encapsulated in liposomes are taken up mainly The passage of drugs across biological
by the reticuloendothelial cells of the liver and membranes involves processes like passive
are also concentrated in malignant tumors. Thus, (filtration, diffusion) and active transport.

Fig. 1.1: Schematic representation of movement of drug in the body


General Pharmacology 9

Fig. 1.2: Cell/biological membrane (schematic)

Mechanisms of Transport of Drug Across occurs in the direction of the concentration


Biological Membranes gradient. The carrier facilitates diffusion and is
Passive Carrier-mediated Endocytosis highly specific for the substance, e.g. uptake of
transfer transport glucose by cells, vitamin B12 from intestines.
— Simple — Active
diffusion transport Endocytosis
— Filtration — Facilitated
diffusion Endocytosis is the process where small droplets
are engulfed by the cell. Some proteins are taken
up by this process (like pinocytosis in amoeba).
Passive Transfer
The drug moves across the membrane without any ABSORPTION
need for energy either by simple diffusion in the Absorption is defined as the passage of the drug
direction of its concentration gradient, i.e. from from the site of administration into the circulation.
higher concentration to a lower concentration or For a drug to reach its site of action, it must pass
by filtration through aqueous pores in the through various membranes depending on the
membrane. Most drugs are absorbed by simple route of administration. Absorption occurs by one
diffusion. of the processes described above, i.e. passive
diffusion or carrier-mediated transport. Except for
Carrier-mediated Transport intravenous route, rate and extent of absorption
by all other routes of administration is influenced
Active transport is the transfer of drugs against a
by several factors (Fig. 1.3). They are:
concentration gradient and needs energy. It is
1. Disintegration and dissolution time The
carried by a specific carrier protein. Only drugs
drug taken orally should break up into indivi-
related to natural metabolites are transported by
dual particles (disintegrate) to be absorbed.
this process, e.g. levodopa, iron, amino acids.
It then has to dissolve in the gastrointestinal
Facilitated diffusion is a unique form of carrier fluids. In case of drugs given subcutaneously
transport which differs from active transport in or intramuscularly, the drug molecules have
that it is not energy dependent and the movement to dissolve in the tissue fluids. Liquids are
10 Pharmacology for Physiotherapy

Fig. 1.3: Factors affecting absorption of drugs

absorbed faster than solids. Delay in should be kept large, e.g. anthelmintics like
disintegration and dissolution as with poorly bephenium hydroxynaphthoate.
water-soluble drugs like aspirin, result in 4. Lipid solubility Lipid soluble drugs are
delayed absorption. absorbed faster and better by dissolving in
2. Formulation Pharmaceutical preparations the phospholipids of the cell membrane.
are formulated to produce desired 5. pH and ionization Ionized drugs are poorly
absorption. Inert substances used with drugs absorbed while unionized drugs are lipid
as diluents like starch and lactose may soluble and are well absorbed. Most drugs
sometimes interfere with absorption. are weak electrolytes and ionise according
3. Particle size Small particle size is important to pH. Thus acidic drugs remain unionized
for better absorption of drugs. Drugs like in acidic medium of the stomach and are
corticosteroids, griseofulvin, digoxin, aspirin rapidly absorbed, e.g. aspirin, barbiturates.
and tolbutamide are better absorbed when Basic drugs are unionized when they reach
given as small particles. On the other hand, the alkaline medium of intestine from where
when a drug has to act on the gut and its they are rapidly absorbed, e.g. pethidine,
absorption is not desired, then particle size ephedrine.
General Pharmacology 11

Strong acids and bases are highly ionized glycerine, propranolol, salbutamol. But for drugs
and therefore poorly absorbed, e.g. strepto- that undergo extensive first pass metabolism, the
mycin. route of administration has to be changed, e.g.
6. Area and vascularity of the absorbing isoprenaline, hydrocortisone, insulin.
surface: The larger the area of absorbing
First pass metabolism
surface and more the vascularity—better is
• is metabolism of a drug during its first passage
the absorption. Thus most drugs are
through gut wall and liver
absorbed from small intestine because it has
• reduces bioavailability
a large surface area for absorption and good
vascularity. • extent of metabolism depends on the drug and
7. Gastrointestinal motility: individuals
Gastric emptying time—if gastric emptying is • consequences:
faster, the passage of the drug to the intestines — dose has to be increased for some drugs like
is quicker and hence absorption is faster. propranolol
— route has to be changed for some others like
Intestinal motility—when highly increased as
hydrocortisone
in diarrheas, drug absorption is reduced.
8. Presence of food: In the stomach delays • Examples: morphine, chlorpromazine, nitro-
glycerine, verapamil, testosterone, insulin,
gastric emptying, dilutes the drug and delays
lignocaine
absorption. Drugs may form complexes with
food constituents and such complexes are
poorly absorbed, e.g. tetracyclines chelate Bioavailability
calcium present in food. Moreover, certain Bioavailability is the fraction of the drug that
drugs like ampicillin, roxithromycin and reaches the systemic circulation following
rifampicin are well-absorbed only on empty administration by any route. Thus for a drug given
stomach. intravenously, the bioavailability is 100 percent.
9. Metabolism: Some drugs may be degraded On IM/SC injection, drugs are almost completely
in the GI tract, e.g. nitroglycerine, insulin. absorbed while by oral route, bioavailability may
Such drugs should be given by alternate be low due to incomplete absorption and first pass
routes. metabolism. Infact all the factors which influence
10. Diseases of the gut like malabsorption and the absorption of a drug also alter bioavailability.
achlorhydria result in reduced absorption of
drugs. Bioequivalence
First pass metabolism is the metabolism of a Comparison of bioavailability of different
drug during its passage from the site of absorption formulations of the same drug is the study of
to the systemic circulation. It is also called bioequivalence. Often oral formulations con-
presystemic metabolism or first pass effect and is taining the same amount of a drug from different
an important feature of oral route of administ- manufacturers may result in different plasma
ration. Drugs given orally may be metabolized in concentrations, i.e. there is no bioequivalence.
the gut wall and in the liver before reaching the Such differences occur with poorly soluble, slowly
systemic circulation. The extent of first pass absorbed drugs mainly due to differences in the
metabolism differs from drug to drug and among rate of disintegration and dissolution. Variation
individuals, from partial to total inactivation. in bioavailability (nonequivalence) can result in
When it is partial, it can be compensated by giving toxicity or therapeutic failure in drugs that have
higher dose of the particular drug, e.g. nitro- low safety margin like digoxin and drugs that need
12 Pharmacology for Physiotherapy

precise dose adjustment like anticoagulants and example, indomethacin displaces warfarin
corticosteroids. For such drugs, in a given patient, from protein binding sites leading to increased
the preparations from a single manufacturer warfarin levels.
should be used. 5. Chronic renal failure and chronic liver disease
result in hypoalbuminemia with reduced
DISTRIBUTION
protein binding of drugs.
After a drug reaches the systemic circulation, it
Some highly protein bound drugs
gets distributed to other tissues. It should cross
several barriers before reaching the site of action. Warfarin Tolbutamide Phenytoin
Like absorption, distribution also involves the Frusemide Clofibrate Sulfonamides
same processes, i.e. filtration, diffusion and Diazepam Salicylates Phenylbutazone
Indomethacin
specialized transport. Various factors determine
the rate and extent of distribution, viz lipid solu-
bility, ionization, blood flow and binding to Tissue Binding
plasma proteins and cellular proteins. Unionized
lipid soluble drugs are widely distributed Some drugs get bound to certain tissue consti-
throughout the body. tuents because of special affinity for them. Tissue
binding delays elimination and thus prolongs
Plasma Protein Binding duration of action of the drug. For example, lipid
soluble drugs are bound to adipose tissue. Tissue
On reaching the circulation most drugs bind to binding also serves as a reservoir of the drug.
plasma proteins; acidic drugs bind mainly
albumin and basic drugs to alpha-acid glyco- Redistribution
protein. The free or unbound fraction of the drug
When highly lipid soluble drugs are given intra-
is the only form available for action, metabolism
venously or by inhalation, they get rapidly
and excretion while the protein bound form serves
distributed into highly perfused tissues like brain,
as a reservoir. The extent of protein binding varies
heart and kidney. But soon they get redistributed
with each drug, e.g. warfarin is 99 percent and
into less vascular tissues like the muscle and fat
morphine is 35 percent protein bound while
resulting in termination of the action of these
binding of ethosuximide and lithium is 0 percent,
drugs. The best example is the intravenous
i.e. they are totally free.
anesthetic thiopental sodium which induces
anesthesia in 10-20 seconds but the effect stops in
Clinical Significance of Plasma Protein Binding
5-15 minutes due to redistribution.
1. Only free fraction is available for action,
metabolism and excretion. When the free drug Blood-brain Barrier (BBB)
levels fall, bound drug is released.
The endothelial cells of the brain capillaries lack
2. Protein binding serves as a store (reservoir) of
intercellular pores and instead have tight
the drug and the drug is released when free
junctions. Moreover, glial cells envelope the
drug levels fall. capillaries and together these form the BBB. Only
3. Protein binding prolongs duration of action lipid soluble, unionized drugs can cross this BBB.
of the drug. During inflammation of the meninges, the barrier
4. Many drugs may compete for the same binding becomes more permeable to drugs, e.g. penicillin
sites. Thus one drug may displace another from readily penetrates during meningitis. The barrier
the binding sites resulting in toxicity. For is weak at some areas like chemoreceptor triggor
General Pharmacology 13

zone (CTZ), posterior pituitary and parts of hypo- are easily excreted through the kidneys. Some
thalamus and allows some compounds to diffuse. drugs may be excreted largely unchanged in the
urine, e.g. frusemide, atenolol.
Placental Barrier
Site
Lipid soluble, unionized drugs readily cross the
placenta while lipid insoluble drugs cross to a The most important organ of biotransformation is
much lesser extent. Thus drugs taken by the mother the liver. But drugs are also metabolized by the
can cause several unwanted effects in the fetus. kidney, gut mucosa, lungs, blood and skin.

Volume of Distribution (Vd) Result of Biotransformation


Apparent volume of distribution is defined as the volume Though biotransformation generally inactivates
necessary to accommodate the entire amount of the the drug, some drugs may be converted to active
drug, if the concentration throughout the body were or more active metabolites (Table 1.1).
equal to that in plasma. It relates the amount of the When the metabolite is active, the duration of
drug in the body to the concentration of the drug in action gets prolonged. Prodrug is an inactive drug
plasma. It is calculated as which gets converted into an active form in the
Amount of drug in the body body (Table 1.1).
Vd = ________________________________
Plasma concentration
ACTIVE DRUG
For example, if the dose of a drug given is 500 mg
and attains a uniform concentration of 10 mg in the Metabolism
body, its Vd = 50 liters. Inactive → active → INACTIVATION ← active ← Active
The knowledge of Vd of drugs is clinically drug metabolite metabolite drug
important in the treatment of poisoning. Drugs (Prodrug) (Prolongs
with large Vd like pethidine are not easily removed duration
of action)
by hemodialysis.
Enzymes in Biotransformation
BIOTRANSFORMATION (Metabolism)
The biotransformation reactions are catalyzed by
Biotransformation is the process of biochemical
alteration of the drug in the body. Body treats most specific enzymes located either in the liver
drugs as foreign substances and tries to inactivate microsomes (microsomal enzymes) or in the
and eliminate them by various biochemical cytoplasm and mitochondria of the liver cells and
reactions. These processes convert the drugs into also in the plasma and other tissues (non-
more polar, water-soluble compounds so that they microsomal enzymes).

TABLE 1.1: Result of biotransformation


Active drug to Active drug to active Inactive drug to active
inactive metabolite metabolite metabolite (prodrug)
e.g. Morphine e.g. Primidone → e.g. Levodopa →
Chloramphenicol Phenobarbitone Dopamine
Digitoxin → Digoxin Prednisone → Prednisolone
Diazepam → Oxazepam Enalapril → Enalaprilat
14 Pharmacology for Physiotherapy

The chemical reactions of biotransformation enzymes can be enhanced by certain drugs and
can take place in two phases (Fig. 1.4). environmental pollutants. This is called enzyme
1. Phase I (Non-synthetic reactions) induction and this process speeds up the meta-
2. Phase II (Synthetic reactions). bolism of the inducing drug itself and other drugs
metabolized by the microsomal enzymes, e.g.
Phase I reactions convert the drug to a more polar phenobarbitone, rifampicin, alcohol, cigarette
metabolite by oxidation, reduction or hydrolysis. smoke, DDT, griseofulvin, carbamazepine and
Oxidation reactions are the most important phenytoin are some enzyme inducers.
metabolizing reactions, mostly catalyzed by Enzyme induction can result in drug inter-
mono-oxygenases present in the liver. If the actions when drugs are given together because
metabolite is not sufficiently polar to be excreted, one drug may enhance the metabolism of the other
they undergo phase II reactions. drug resulting in therapeutic failure.

Phase II reactions are conjugation reactions Therapeutic application of enzyme induction


where water-soluble substances present in the Neonates are deficient in both microsomal and
nonmicrosomal enzymes. Hence their capacity to
body like glucuronic acid, sulfuric acid,
conjugate bilirubin is low which results in
glutathione or an amino acid, combine with the
jaundice. Administration of phenobarbitone—an
drug or its phase I metabolite to form a highly enzyme inducer, helps in rapid clearance of the
polar compound. This is inactive and gets readily jaundice in them by enhancing bilirubin
excreted by the kidneys. Large molecules are conjugation.
excreted through the bile. Thus, phase II reactions
invariably inactivate the drug. Enzyme Inhibition
Glucuronide conjugation is the most
Some drugs like cimetidine and ketoconazole
common type of metabolic reaction (Table 1.2). inhibit cytochrome P450 enzyme activity. Hence,
metabolism of other drugs get reduced and can
Enzyme Induction result in toxicity. Therefore, enzyme inhibition by
Microsomal enzymes are present in the micro- drugs is also the basis of several drug interactions.
somes of the liver cells. The synthesis of these Chloramphenicol, cimetidine, erythromycin,

Fig. 1.4: Phases in metabolism of drugs. A drug may be excreted as phase I


metabolite or as phase II metabolite. Some drugs may be excreted as such
General Pharmacology 15

TABLE 1.2: Important drug biotransformation reactions


Reactions Examples of drugs
Oxidation Phenytoin, diazepam, ibuprofen,
Amphetamine, chlorpromazine, dapsone
Reduction Chloramphenicol, halothane
Hydrolysis Pethidine, procaine
Conjugation reactions
Glucuronide conjugation Chloramphenicol, morphine
Acetylation Sulfonamides, isoniazid
Methylation Adrenaline, histamine
Glutathione conjugation Paracetamol
Sulfate conjugation Paracetamol, steroids

ketoconazole, ciprofloxacin and verapamil are Drugs may compete for the same transport system
some enzyme inhibitors. resulting in prolongation of action of each other,
e.g. penicillin and probenecid.
EXCRETION
Passive tubular reabsorption: Passive diffusion
Drugs are excreted from the body after being of drug molecules can occur in either direction in
converted to water-soluble metabolites while some the renal tubules depending on the drug
are directly eliminated without metabolism. The concentration, lipid solubility and pH. As highly
major organs of excretion are the kidneys, the lipid soluble drugs are largely reabsorbed, their
intestines, the biliary system and the lungs. Drugs excretion is slow. Acidic drugs get ionized in
are also excreted in small amounts in the saliva, alkaline urine and are easily excreted while bases
sweat and milk. are excreted faster in acidic urine. This property
Renal Excretion is useful in the treatment of poisoning. In
poisoning with acidic drugs like salicylates and
Kidney is the most important route of drug barbiturates, forced alkaline diuresis (Diuretic +
excretion. The three processes involved in the sodium bicarbonate + IV fluids) is employed to
elimination of drugs through kidneys are hasten drug excretion. Similarly, elimination of
glomerular filtration, active tubular secretion and basic drugs like quinine and amphetamine is
passive tubular reabsorption. enhanced by forced acid diuresis.
Glomerular filtration: The rate of filtration through Fecal and Biliary Excretion
the glomerulus depends on GFR, concentration
of free drug in the plasma and its molecular weight. Unabsorbed portion of the orally administered
Ionized drugs of low molecular weight (< 10,000) drugs are eliminated through the faeces. Liver
are easily filtered through the glomerular transfers acids, bases and unionized molecules
membrane. into bile by specific acid transport processes. Some
drugs may get reabsorbed in the lower portion of
Active tubular secretion: Cells of the proximal the gut and are carried back to the liver. Such
tubules actively secrete acids and bases by two recycling is called enterohepatic circulation and it
transport systems. Thus, acids like penicillin, prolongs the duration of action of the drug;
salicylic acid, probenecid, frusemide; bases like examples are chloramphenicol, tetracycline, oral
amphetamine and histamine are so excreted. contraceptives and erythromycin.
16 Pharmacology for Physiotherapy

Pulmonary Excretion body is metabolized/eliminated per unit time.


The lungs are the main route of elimination for The metabolic enzymes get saturated and
gases and volatile liquids viz general anesthetics hence with increase in dose, the plasma drug
and alcohol. This also has legal implications in level increases disproportionately resulting in
medicolegal practice. toxicity.
Some drugs like phenytoin and warfarin are
Other Routes of Excretion eliminated by both processes, i.e. by first order
Small amounts of some drugs are eliminated initially and by zero order at higher concent-
through the sweat and saliva. Excretion in saliva rations.
may result in a unique taste of some drugs, e.g.
metronidazole and phenytoin. Drugs like iodide, Plasma Half-life
rifampicin and heavy metals are excreted through and Steady State Concentration
sweat. Plasma half-life (t½) is the time taken for the
The excretion of drugs in the milk is in small plasma concentration of a drug to be reduced to
amounts and is of no significance to the mother. half its value (Fig. 1.5). Four to five half-lives are
But, for the suckling infant, it may be sometimes required for the complete elimination of a drug.
important especially because of the infant’s Each drug has its own t½ and is an important
immature metabolic and excretory mechanisms. pharmacokinetic parameter that guides the dosing
Though most drugs can be taken by the mother regimen. It helps in calculating loading and
without significant toxicity to the child, there are maintenance doses of a drug. It also indicates the
a few exceptions (Table 1.3). duration of action of a drug.
TABLE 1.3: Example of drugs that could be toxic Biological half-life is the time required for total
to the suckling infant when taken by the mother
amount of the drug in the body to be reduced to
Sulphasalazine Doxepin half.
Theophylline Amiodarone
Anticancer drugs Primidone Biological effect half-life is the time required for
Salicylates Ethosuximide the biological effect of the drug to reduce to half.
Chloramphenicol Phenobarbitone In some drugs like propranolol, the pharmaco-
Nalidixic acid Phenothiazines logical effect of the drug may last much longer, i.e.
Nitrofurantoin β-blockers
even after its plasma levels fall. In such drugs,
Drugs are metabolized/eliminated from the biological effect half life gives an idea of the
body by: duration of action of the drug.
1. First-order kinetics In first order kinetics, a If a drug is administered repeatedly at short
intervals before complete elimination, the drug
constant fraction of the drug is metabolized/
accumulates in the body and reaches a ‘state’ at
eliminated per unit time. Most drugs follow
which the rate of elimination equals the rate of
first order kinetics and the rate of metabolism/
administration. This is known as the ‘Steady-state’
excretion is dependant on their concentration or plateau level (Fig. 1.6). After attaining this level,
(exponential) in the body. It also holds good the plasma concentration fluctuates around an
for absorption of drugs. average steady level. It takes 4-5 half-lives for
2. Zero order kinetics (Saturation kinetics) Here the plasma concentration to reach the plateau
a constant amount of the drug present in the level.
General Pharmacology 17

Fig. 1.5: Plasma concentration-time curve following intravenous dose. Plasma t½ = 4 hours

Fig. 1.6: Drug accumulation and attainment of steady state concentration on oral administration

DRUG DOSAGE Fixed dose: In case of reasonably safe drugs, a


fixed dose of the drug is suitable for most patients,
Depending on the patient’s requirements and the
e.g. analgesics like paracetamol—500 mg to
characteristics of the drug, drug dosage can be of
1000 mg 6 hourly is the usual adult dose.
the following kinds:
18 Pharmacology for Physiotherapy

Individualized dose: For some drugs especially PHARMACODYNAMICS


the ones with low safety margin, the dose has to
be ‘tailored’ to the needs of each patient, e.g. Pharmacodynamics is the study of actions of the
anticonvulsants, antiarrhythmic drugs. drugs on the body and their mechanisms of action,
i.e. to know what drugs do and how they do it.
Loading dose: In situations when rapid action
Drugs produce their effects by interacting with
is needed, a loading/bolus dose of the drug is
the physiological systems of the organisms. By
given at the beginning of the treatment. A loading
such interaction, drugs merely modify the rate of
dose is a single large dose or a series of quickly
functions of the various systems. But they cannot
repeated doses given to rapidly attain target
bring about qualitative changes, i.e. they cannot
concentration, e.g. heparin given as 5000 IU bolus
change the basic functions of any physiological
dose. Once the target level is reached, a maintenance
system. Thus drugs act by:
dose is sufficient to maintain the drug level and to
1. Stimulation
balance the elimination.
2. Depression
The disadvantage with the loading dose is that
3. Irritation
the patient is rapidly exposed to high concent-
4. Replacement
rations of the drug which may result in toxicity.
5. Anti-infective or cytotoxic action
6. Modification of the immune status.
Therapeutic Drug Monitoring
The response to a drug depends on the plasma Stimulation
concentration attained in the patient. In some
Stimulation is the increase in activity of the
situations it may be necessary to monitor treatment
specialized cells, e.g. adrenaline stimulates the
by measuring plasma drug concentrations. Such
heart.
situations are:
1. While using drugs with low safety margin—
Depression
to avoid therapeutic failure, e.g. digoxin,
theophylline, lithium. Depression is the decrease in activity of the
2. To reduce the risk of toxicity, e.g. amino- specialized cells, e.g. quinidine depresses the
glycosides. heart; barbiturates depress the central nervous
3. To treat poisoning. system. Some drugs may stimulate one system and
depress another, e.g. morphine depresses the CNS
METHODS OF PROLONGING DRUG ACTION but stimulates the vagus.
(TABLE 1.4)
In several situations it may be desirable to use Irritation
long-acting drugs. But when such drugs are not This can occur on all types of tissues in the body
available, the duration of action of the available and may result in inflammation, corrosion and
drugs may be prolonged. necrosis of cells.
The duration of action of drugs can be
prolonged by interfering with the pharmaco-
Replacement
kinetic processes, i.e. by
1. Slowing absorption. Drugs may be used for replacement when there is
2. Using a more plasma protein bound derivative. deficiency of natural substances like hormones,
3. Inhibiting metabolism. metabolites or nutrients, e.g. insulin in diabetes
4. Delaying excretion. mellitus, iron in anemia, vitamin C in scurvy.
General Pharmacology 19

TABLE 1.4: Methods of prolonging duration of action of drugs


Processes Methods Examples
ABSORPTION
Oral Sustained release preparation,
coating with resins, etc. Iron, deriphylline
Parenteral 1. Reducing solubility Procaine + Penicillin
— Oily suspension Depot progestins
2. Altering particle size Insulin zinc suspension as large crystals
that are slowly absorbed
3. Pellet implantation DOCA
— Sialistic capsules Testosterone
4. Reduction in vascularity Adrenaline +
of the absorbing surface lignocaine (vasoconstrictor)
5. Combining with protein Protamine + zinc + insulin
6. Chemical alteration
— Esterification Estrogen
Testosterone
Dermal Transdermal adhesive patches, Scopolamine
Ointments Nitroglycerine
Ocuserts (Transmucosal)—used in eye Pilocarpine
DISTRIBUTION Choosing more protein bound Sulfonamides-like
member of the group sulfamethoxypyridazine
METABOLISM Inhibiting the metabolizing Physostigmine prolongs the action
enzyme cholinesterase of acetylcholine
By inhibiting enzyme peptidase Cilastatin—prolongs action of imipenem
in renal tubular cells
EXCRETION Competition for same Probenecid prolongs the action of
transport system penicillin and ampicillin
— for renal tubular secretion

Anti-infective and Cytotoxic Action ion channels. Drugs may act on the cell membrane,
inside or outside the cell to produce their effect.
Drugs may act by specifically destroying infective
Drugs may act by one or more complex mecha-
organisms, e.g. penicillins, or by cytotoxic effect
nisms of action. Some of them are yet to be
on cancer cells, e.g. anticancer drugs.
understood. But the fundamental mechanisms of
drug action may be:
Modification of Immune Status
Vaccines and sera act by improving our immunity Through Receptors
while immunosuppressants act by depressing Drugs may act by interacting with specific
immunity, e.g. glucocorticoids. receptors in the body (see below).

MECHANISMS OF DRUG ACTION Through Enzymes and Pumps


Most drugs produce their effects by binding to Drugs may act by inhibition of various enzymes,
specific target proteins like receptors, enzymes and thus altering the enzyme-mediated reactions, e.g.
20 Pharmacology for Physiotherapy

allopurinol inhibits the enzyme xanthine oxidase; Agonist: An agonist is a substance that binds to
acetazolamide inhibits carbonic anhydrase. the receptor and produces a response. It has
Membrane pumps like H+ K+ ATPase, Na+ K+ affinity and intrinsic activity.
ATPase may be inhibited by drugs, e.g.
Antagonist: An antagonist is a substance that
omeprazole, digoxin.
binds to the receptor and prevents the action of
agonist on the receptor. It has affinity but no
Through Ion Channels
intrinsic activity.
Drugs may interfere with the movement of ions
Partial agonist binds to the receptor but has low
across specific channels, e.g. calcium channel
intrinsic activity.
blockers, potassium channel openers.
Ligand is a molecule which binds selectively to a
Physical Action specific receptor.
The action of a drug could result from its physical Last three decades have seen an explosion in
properties like: our knowledge of the receptors. Various receptors
Adsorption – Activated charcoal in poisoning have been identified, isolated and extensively
Mass of the drug – Bulk laxatives like psyllium, bran studied.
Osmotic property – Osmotic diuretics—Mannitol
Site: The receptors may be present in the cell
– Osmotic purgatives—Magne-
membrane, in the cytoplasm or on the nucleus.
sium sulphate
Radioactivity – 131I Nature of receptors: Receptors are proteins.
Radio-opacity – Barium sulphate contrast media.
Synthesis and life-span: Receptor proteins are
Chemical Interaction synthesized by the cells. They have a definite life
Drugs may act by chemical reaction. span after which the receptors are degraded by
Antacids – neutralise gastric acids the cell and new receptors are synthesized.
Oxidising agents – like potassium permanganate -
germicidal Functions of Receptors
Chelating agents – bind heavy metals making them The two functions of receptors are:
nontoxic. 1. Recognition and binding of the ligand
2. Propagation of the message.
Altering Metabolic Processes
For the above function, the receptor has two
Drugs like antimicrobials alter the metabolic sites (domains):
pathway in the microorganisms resulting in i. A ligand binding site—the site to bind the drug
destruction of the microorganism, e.g. molecule
sulfonamides interfere with bacterial folic acid ii. An effector site—which undergoes a change
synthesis. to propagate the message.
Drug-receptor interaction has been considered
Receptor to be similar to ‘lock and key’ relationship where
A receptor is a site on the cell with which an the drug specifically fits into the particular
agonist binds to bring about a change, e.g. receptor (lock) like a key. Interaction of the agonist
histamine receptor, α and β adrenergic receptors. with the receptor brings about changes in the
receptor which in turn conveys the signal to the
Affinity is the ability of a drug to bind to a receptor.
effector system. The final response is brought
Intrinsic activity or efficacy is the ability of a drug about by the effector system through second
to produce a response after binding to the receptor. messengers. The agonist itself is the first
General Pharmacology 21

messenger. The entire process involves a chain of response curve (DRC). Initially the extent of
events triggered by drug receptor interaction. response increases with increase in dose till the
maximum response is reached. After the
Receptor Families maximum effect has been obtained, further
increase in doses does not increase the response.
Four families (types) of cell surface receptors are
If the dose is plotted on a logarithmic scale, the
identified. The receptor families are:
curve becomes sigmoid or ‘S’ shaped (Fig. 1.7).
1. Ion channels
2. G-protein coupled receptors
Drug Potency and Maximal Efficacy
3. Enzymatic receptors
4. Nuclear receptors (receptors that regulate gene The amount of drug required to produce a
transcription). response indicates the potency. For example,
1 mg of bumetanide produces the same diuresis
Receptor Regulation as 50 mg of frusemide. Thus, bumetanide is more
potent than frusemide. In Figure 1.8, drugs A and
The number of receptors (density) and their
B are more potent than drugs C and D, drug A
sensitivity can be altered in many situations.
being the most potent and drug D—the least
Denervation or prolonged deprivation of the
potent. Hence higher doses of drugs C and D are
agonist or constant action of the antagonist all
to be administered as compared to drugs A and B.
result in an increase in the number and sensitivity
Generally potency is of little clinical significance
of the receptors. This phenomenon is called ‘up
unless very large doses of the drug needs to be
regulation.’
given due to low potency.
Prolonged use of a β adrenergic antagonist like
propranolol results in up regulation of β Maximal efficacy: Efficacy indicates the
adrenergic receptors. maximum response that can be produced by a
On the other hand, continued stimulation of drug, e.g. frusemide produces powerful diuresis,
the receptors causes desensitization and a not produced by any dose of amiloride. In Figure
decrease in the number of receptors—known as 1.8, drugs B and C are more efficacious than drugs
‘down regulation’ of the receptors. A and D. Drug A is more potent but less efficacious
than drugs B and C. Such differences in efficacy
Clinical importance of receptor regulation: After
are of great clinical importance.
prolonged administration, a receptor antagonist
should always be tapered. For example, if propra- Therapeutic index: The dose response curves
nolol—a β adrenoceptor blocker is suddenly for different actions of a drug could be different.
withdrawn after long-term use, it precipitates Thus salbutamol may have one DRC for
angina due to upregulation of β receptors. bronchodilation and another for tachycardia. The
Constant use of β adrenergic agonists in distance between beneficial effect DRC and
bronchial asthma results in reduced therapeutic unwanted effect DRC indicates the safety margin
response due to down regulation of β2 receptors. of the drug (Fig. 1.9).

Dose Response Relationship Median lethal dose (LD50) is the dose which is
lethal to 50 percent of animals of the test
The response to different doses of a drug can be population.
plotted on a graph to obtain the Dose Response
Curve. Median effective dose (ED50) is the dose that
The clinical response to the increasing dose of produces a desired effect in 50 percent of the test
the drug is defined by the shape of the dose population.
22 Pharmacology for Physiotherapy

Fig. 1.9: The distance between curves A and B


indicates safety margin of the drug. The greater the
Fig. 1.7: Log dose response curve distance, more selective is the drug

Therapeutic index (TI) is the ratio of the • TI varies from species to species
median lethal dose to the median effective dose. • For a drug to be considered reasonably safe,
it’s TI must be > 1
LD50
Therapeutic index = ___________ • Penicillin has a high TI while lithium and
ED50 digoxin have low TI.
It gives an idea about the safety of the drug.
• The higher the therapeutic index, the safer Drug Synergism and Antagonism
is the drug When two or more drugs are given concurrently
the effect may be additive, synergistic or
antagonistic.

Additive Effect
The effect of two or more drugs get added up and
the total effect is equal to the sum of their
individual actions.
Examples are ephedrine with theophylline in
bronchial asthma; nitrous oxide and ether as
general anesthetics.

Synergism
When the action of one drug is enhanced or
facilitated by another drug, the combination is
Fig. 1.8: Dose response curves of four drugs showing synergistic. In Greek, ergon = work; syn = with.
different potencies and maximal efficacies. Drug A is Here, the total effect of the combination is greater
more potent but less efficacious than B and C. Drug D than the sum of their independent effects. It is often
is less potent and less efficacious than drugs B and C called ‘potentiation’ or ‘supra-additive’ effect.
General Pharmacology 23

Examples are — acetylcholine + physostigmine


levodopa + carbidopa.

Antagonism
One drug opposing or inhibiting the action of
another is antagonism. Based on the mechanisms,
antagonism can be:
• Chemical antagonism
• Physiological antagonism
• Antagonism at the receptor level
— Reversible (Competitive)
— Irreversible
• Non-competitive antagonism. Fig. 1.10: Dose response curves of an agonist: (A) in
the absence of competitive antagonist; (B) in the
Chemical antagonism: Two substances interact presence of increasing doses of a competitive
chemically to result in inactivation of the effect, antagonist
e.g. chelating agents inactivate heavy metals like
lead and mercury to form inactive complexes;
Irreversible antagonism: The antagonist binds
antacids like aluminium hydroxide neutralize
firmly by covalent bonds to the receptor. Thus it
gastric acid.
blocks the action of the agonist and the blockade
Physiological antagonism: Two drugs act at cannot be overcome by increasing the dose of the
different sites to produce opposing effects. For agonist and hence it is irreversible antagonism,
example, histamine acts on H2 receptors to e.g. adrenaline and phenoxybenzamine at alpha
produce bronchospasm and hypotension while adrenergic receptors (Fig. 1.11).
adrenaline reverses these effects by acting on
adrenergic receptors.
Insulin and glucagon have opposite effects on
the blood sugar level.
Antagonism at the receptor level: The antagonist
inhibits the binding of the agonist to the receptor.
Such antagonism may be reversible or irreversible.
Reversible or competitive antagonism: The
agonist and antagonist compete for the same
receptor. By increasing the concentration of the
agonist, the antagonism can be overcome. It is thus
reversible antagonism. Acetylcholine and atropine
compete for the muscarinic receptors. The
antagonism can be overcome by increasing the
concentration of acetylcholine at the receptor. Fig. 1.11: Dose response curves of an agonist:
d-tubocurarine and acetylcholine compete for the (A) in the absence of antagonist. (B1), (B2) and (B3) in
nicotinic receptors at the neuromuscular junction the presence of increasing doses of an irreversible
(Fig. 1.10). antagonist
24 Pharmacology for Physiotherapy

Noncompetitive antagonism: The antagonist In the elderly, the capacity of the liver and
blocks at the level of receptor-effector linkage. For kidney to handle the drug is reduced and are
example, verapamil blocks the cardiac calcium more susceptible to adverse effects. Hence
channels and inhibits the entry of Ca++ during lower doses are recommended, e.g. elderly are
depolarization. It thereby antagonises the effect at a higher risk of ototoxicity and
of cardiac stimulants like isoprenaline and nephrotoxicity by streptomycin.
adrenaline.
3. Sex: The hormonal effects and smaller body
FACTORS THAT MODIFY size may influence drug response in women.
THE EFFECTS OF DRUGS Special care is necessary while prescribing for
pregnant and lactating women and during
The same dose of a drug can produce different menstruation.
degrees of response in different patients and even
in the same patient under different situations. 4. Species and race: Response to drugs may
Various factors modify the response to a drug. vary with species and race. For example,
They are: rabbits are resistant to atropine. Then it
becomes difficult to extrapolate the results of
1. Body weight: The recommended dose is
animal experiments. Blacks need higher doses
calculated for medium built persons. For the
of atropine to produce mydriasis.
obese and underweight persons, the dose has
to be calculated individually. Though body 5. Diet and environment: Food interferes with
surface area is a better parameter for more the absorption of many drugs. For example,
accurate calculation of the dose, it is incon- tetracyclines form complexes with calcium
venient and hence not generally used. present in the food and are poorly absorbed.
Formula: Polycyclic hydrocarbons present in
cigarette smoke may induce microsomal
Body weight (kg)
Dose = _________________________ × average adult dose enzymes resulting in enhanced metabolism of
70 some drugs.
2. Age: The pharmacokinetics of many drugs
6. Route of administration: Occasionally route
change with age resulting in altered response
of administration may modify the pharmaco-
in extremes of age. In the newborn, the liver
dynamic response, e.g. magnesium sulfate
and kidneys are not fully mature to handle the
given orally is a purgative. But given IV it
drugs, e.g. chloramphenicol can produce grey
causes CNS depression and has anti-
baby syndrome. The blood-brain barrier is not
convulsant effects. Applied topically (poultice),
well-formed and drugs can easily reach the
it reduces local edema. Hypertonic magne-
brain. The gastric acidity is low, intestinal
sium sulfate retention enema reduces
motility is slow, skin is delicate and permeable
intracranial tension.
to drugs applied topically. Hence calculation
of the appropriate dose, depending on body 7. Genetic factors: Variations in an individual’s
weight is important to avoid toxicity. Also response to drugs could be genetically
pharmacodynamic differences could exist, e.g. mediated. Pharmacogenetics is concerned
barbiturates which produce sedation in adults with the genetically mediated variations in
may produce excitation in children. drug responses. The differences in response is
Formula for calculation of dose for children most commonly due to variations in the
Young’s formula amount of drug metabolizing enzymes since
Age (years) the production of these enzymes are
Child’s dose = __________________ × Adult dose
Age + 12 genetically controlled.
General Pharmacology 25

Examples of liver and kidneys. These may result in


a. Acetylation of drugs: The rate of drug cumulation and toxicity of drugs like
acetylation differs among individuals who propranolol and lignocaine.
may be fast or slow acetylators, e.g. INH, • Renal dysfunction: Drugs mainly excreted
sulfonamides and hydralazine are through kidneys are likely to accumulate
acetylated. Slow acetylators treated with and cause toxicity, e.g. Streptomycin,
hydralazine are more likely to develop amphotericin B—Dose of such drugs need
lupus erythematosus. to be reduced.
b. Atypical pseudocholinesterase: Succinyl- 10. Repeated dosing can result in
choline is metabolized by pseudo- • Cumulation
cholinesterase. Some people inherit • Tolerance
atypical pseudocholinesterase and they • Tachyphylaxis.
develop a prolonged apnea due to
Cumulation: Drugs like digoxin which are slowly
succinylcholine.
eliminated may cumulate resulting in toxicity.
c. G6PD deficiency: Primaquine, sulphones
and quinolones can cause hemolysis in Tolerance: Tolerance is the requirement of higher
such people. doses of a drug to produce a given response.
d. Malignant hyperthermia: Halothane and Tolerance may be natural or acquired.
succinylcholine can trigger malignant Natural tolerance: The species/race shows less
hyperthermia in some genetically sensitivity to the drug, e.g. rabbits show tolerance
predisposed individuals. to atropine; Black race are tolerant to mydriatics.
Acquired tolerance: develops on repeated
8. Dose: It is fascinating that the response to a
administration of a drug. The patient who was
drug may be modified by the dose adminis-
initially responsive becomes tolerant, e.g. barbitu-
tered. Generally as the dose is increased, the
rates, opioids, nitrites produce tolerance.
magnitude of the response also increases
Tolerance may develop to some actions of the
proportionately till the ‘maximum’ is reached.
drug and not to others, e.g. morphine—tolerance
Further increases in doses may with some
develops to analgesic and euphoric effects of
drugs produce effects opposite to their lower- morphine but not to its constipating and miotic
dose effect, e.g. (i) in myasthenia gravis, effects.
neostigmine enhances muscle power in Barbiturates—tolerance develops to sedative
therapeutic doses, but in high doses it causes but not antiepileptic effects of barbiturates.
muscle paralysis, (ii) physiological doses of
vitamin D promotes calcification while Mechanisms: The mechanisms of development
hypervitaminosis D leads to decalcification. of tolerance could be:
9. Diseases: Presence of certain diseases can Pharmacokinetic: Changes in absorption,
influence drug responses, e.g. distribution, metabolism and excretion of drugs
• Malabsorption: Drugs are poorly absorbed. may result in reduced concentration of the drug
• Liver diseases: Rate of drug metabolism is at the site of action and is also known as
reduced due to dysfunction of hepatocytes. dispositional tolerance, e.g. barbiturates induce
Also protein binding is reduced due to low microsomal enzymes and enhance their own
serum albumin. metabolism.
• Cardiac diseases: In CCF, there is edema of Pharmacodynamic: Changes in the target tissue,
the gut mucosa and decreased perfusion may make it less responsive to the drug. It is also
26 Pharmacology for Physiotherapy

called functional tolerance. It could be due to down In fact all forms of treatment including
regulation of receptors as in opioids or due to physiotherapy and surgery have placebo effect.
compensatory mechanisms of the body, e.g. Substances used as placebo include lactose,
blunting of response to some antihypertensives some vitamins, minerals and distilled water
due to salt and water retention. injections.
Cross tolerance is the development of tolerance 12. Presence of other drugs: When two or more
to pharmacologically related drugs, i.e. to drugs drugs are used together, one of them can alter
belonging to a particular group. Thus chronic the response of the other resulting in drug
alcoholics also show tolerance to barbiturates and interactions (see Drug Interactions page 28).
general anesthetics.
ADVERSE DRUG REACTIONS
Tachyphylaxis is the rapid development of
tolerance. When some drugs are administered All drugs can produce unwanted effects. WHO
repeatedly at short intervals, tolerance develops has defined an adverse drug reaction as “any
rapidly and is known as tachyphylaxis or acute response to a drug that is noxious and unintended
tolerance, e.g. ephedrine, amphetamine, tyramine and that occurs at doses used in man for
and 5-hydroxytryptamine. This is thought to be prophylaxis, diagnosis or therapy.”
due to depletion of noradrenaline stores as the All drugs can cause adverse effects. Some
above drugs act by displacing noradrenaline from patients are more likely to develop adverse effects
the sympathetic nerve endings. Other mechanisms to drugs.
involved may be slow dissociation of the drug
from the receptor thereby blocking the receptor. 1. Side Effects
Thus ephedrine given repeatedly in bronchial Side effects are unwanted effects of a drug that are
asthma may not give the desired response. extension of pharmacological effects and are seen
with the therapeutic dose of the drug. They are
11. Psychological factor: The doctor patient predictable, common and can occur in all people,
relationship influences the response to a drug e.g. hypoglycemia due to insulin; hypokalemia
often to a large extent by acting on the patient’s following frusemide.
psychology. The patients confidence in the
doctor may itself be sufficient to relieve a 2. Toxic Effects
suffering, particularly the psychosomatic
Toxic effects are seen with higher doses of the drug
disorders. This can be substantiated by the fact
and can be serious, e.g. morphine causes
that large number of patients respond to
respiratory depression in overdosage.
placebo. Placebo is the inert dosage form with
no specific biological activity but only 3. Intolerance
resembles the actual preparation in
Drug intolerance is the inability of a person to
appearance. Placebo = ‘I shall be pleasing’ (in
tolerate a drug and is unpredictable. Patients show
Latin).
exaggerated response to even small doses of the
Placebo medicines are used in:
drug, e.g. vestibular dysfunction after a single dose
1. Clinical trials as a control
of streptomycin seen in some patients. Intolerance
2. To benefit or please a patient psycho-
could also be qualitative, e.g. idiosyncrasy and
logically when he does not actually require
allergic reactions.
an active drug as in mild psychosomatic
disorders and in chronic incurable Idiosyncrasy is a genetically determined abnormal
diseases. reaction to a drug, e.g. primaquine and
General Pharmacology 27

sulfonamides induce hemolysis in patients with antibody complexes activate the complement
G6PD deficiency; some patients show excitement system resulting in cytolysis causing thrombo-
with barbiturates. In addition, some responses like cytopenia, agranulocytosis and aplastic anemia.
chloramphenicol-induced agranulocytosis,
where no definite genetic background is known, Type III (Arthus) reactions: The antigen binds to
are also included under idiosyncrasy. In some circulating antibodies and the complexes are
cases the person may be highly sensitive even to deposited on the vessel wall where it initiates the
low doses of a drug or highly insensitive even to inflammatory response resulting in vasculitis.
high doses of the drug. Rashes, fever, arthralgia, lymphadenopathy,
serum sickness and Steven-Johnson’s syndrome
Allergic reactions to drugs are immunologically- are some of the manifestations of arthus type
mediated reactions which are not related to the reaction.
therapeutic effects of the drug. The drug or its
metabolite acts as an antigen to induce antibody Type IV (Delayed hypersensitivity) reactions
formation. Subsequent exposure to the drug may are mediated by T-lymphocytes and macro-
result in allergic reactions. The manifestations of phages. The antigen reacts with receptors on
allergy are seen mainly on the target organs viz. T-lymphocytes which produce lymphokines
skin, respiratory tract, gastrointestinal tract, blood leading to a local allergic reaction, e.g. contact
and blood vessels. dermatitis.

Types of Allergic Reactions 4. Iatrogenic Diseases (Physician Induced)


and their Mechanisms These are drug induced diseases. Even after the
drug is withdrawn toxic effects can persist, e.g.
Drugs can induce both types of allergic reactions
isoniazid induced hepatitis; chloroquine induced
viz humoral and cell-mediated immunity.
retinopathy.
Mechanism involved in type I, II and III are
humoral while type IV is by cell-mediated
5. Drug Dependence
immunity.
Drugs that influence the behavior and mood are
Type I (Anaphylactic) reaction: Certain drugs
often misused to obtain their pleasurable effects.
induce the synthesis of IgE antibodies which are
Repeated use of such drugs result in dependence.
fixed to the mast cells. On subsequent exposure,
Several words like drug abuse, addiction and
the antigen-antibody complexes cause
dependence are used confusingly. Drug
degranulation of mast cells releasing the
dependence is a state of compulsive use of drugs
mediators of inflammation like histamine,
in spite of the knowledge of risks associated with
leukotrienes, prostaglandins and platelet-
its use. It is also referred to as drug addiction.
activating factor. These are responsible for the
Dependence could be ‘psychologic’ or ‘physical’
characteristic signs and symptoms of anaphylaxis
dependence. Psychologic dependence is
like bronchospasm, laryngeal edema and
compulsive drug-seeking behavior to obtain its
hypotension which could be fatal. Allergy
pleasurable effects, e.g. cigarette smoking.
develops within minutes and is called immediate
Physical dependence is said to be present
hypersensitivity reaction, e.g. penicillins. Skin
when withdrawal of the drug produces adverse
tests may predict this type of reactions.
symptoms. The body undergoes physiological
Type II (Cytolytic) reactions: The drug binds to a changes to adapt itself to the continued presence
protein and together they act as antigen and of the drug in the body. Stopping the drug results
induce the formation of antibodies. The antigen in ‘withdrawal syndrome.’ The symptoms of
28 Pharmacology for Physiotherapy

withdrawal syndrome are disturbing and the 8. Other Adverse Drug Reactions
person then craves for the drug, e.g. alcohol, Drugs can also damage various organ systems.
opioids and barbiturates.
Mild degree of physical dependence is seen in Organ system affected Examples
people who drink too much of coffee.
1. Hepatotoxicity Isoniazid, pyrazinamide,
paracetamol,
6. Teratogenicity chlorpromazine,
Teratogenicity is the ability of a drug to cause fetal 6-Mercaptopurine,
abnormalities when administered to the pregnant halothane, ethanol,
phenylbutazone
lady. Teratos in Greek means monster. The seda-
tive-thalidomide taken during early pregnancy for 2. Nephrotoxicity Analgesics,
aminoglycosides,
relief from morning sickness resulted in thousands
cyclosporine, cisplatin,
of babies being born with phocomelia (seal limbs).
cephelexin, penicillamine,
This thalidomide disaster (1958-61) opened the gold salts
eyes of various nations and made it mandatory to
3. Ototoxicity Aminoglycosides,
impose strict teratogenicity tests before a new drug frusemide
is approved for use.
4. Ocular toxicity Chloroquine, ethambutol
Depending on the stage of pregnancy during
5. Gastrointestinal Opioids, broad spectrum
which the teratogen is administered, it can
systems antibiotics
produce various abnormalities.
6. Cardiovascular Digoxin, doxorubicin
i. Conception — Usually resistant to
system
to 16 days teratogenic effects.
7. Respiratory system Aspirin, bleomycin,
If affected, abortion occurs.
busulfan, amiodarone,
ii. Period of — Most vulnerable period; methotrexate
organogenesis major physical
8. Musculoskeletal Corticosteroids, heparin
(17 to 55 days abnormalities occur. system
of gestation)
9. Behavioral toxicity Corticosteroids, reserpine
iii. Fetal period — Period of growth and
10. Neurological INH, haloperidol,
—56 days development—hence
system ethambutol, quinine,
onwards developmental and func- doxorubicin vincristine
tional abnormalities
11. Dermatological Doxycycline,
result. toxicity sulfonamides
Therefore, in general drugs should be avoided
12. Electrolyte Diuretics,
during pregnancy especially in the first trimester. disturbances mineralocorticoids
The type of malformation also depends on the
13. Hematological Chloramphenicol,
drug, e.g. thalidomide causes phocomelia; tetra- toxicity sulfonamides
cyclines cause deformed teeth; sodium valproate
14. Endocrine disorders Methyldopa, oral
causes spina bifida. contraceptives

7. Carcinogenicity and Mutagenicity


DRUG INTERACTIONS
Some drugs can cause cancers and genetic
abnormalities. For example anticancer drugs can Definition: Drug interaction is the alteration in
themselves be carcinogenic; other examples are the duration or magnitude of the pharmacological
radioactive isotopes and some hormones. effects of one drug by another drug.
General Pharmacology 29

When two or more drugs are given con- carbamazepine and rifampicin are enzyme
currently, the response may be greater or lesser inducers while chloramphenicol and cimetidine
than the sum of their individual effects. Such are some enzyme inhibitors.
responses may be beneficial or harmful. For
example a combination of drugs is used in Excretion: When drugs compete for the same renal
hypertension—hydralazine + propranolol for tubular transport system, they prolong each others
their beneficial interaction. But unwanted drug duration of action, e.g. penicillin and probenecid.
interactions may result in severe toxicity. Such 2. Pharmacodynamic mechanisms: Drugs acting
interactions can be avoided by adequate on the same receptors or physiological systems
knowledge of their mechanisms and by judicious result in additive, synergistic or antagonistic
use of drugs. effects. Many clinically important drug interac-
tions have this basis. Atropine opposes the effects
Site: Drug interaction can occur:
of physostigmine; naloxone antagonises
i. In vitro in the syringe before administration—
morphine; antihypertensive effects of β blockers
mixing of drugs in syringes can cause
are reduced by ephedrine or other vasoconstrictors
chemical or physical interactions—such
in cold remedies.
drug combinations are incompatible in
solution, e.g. penicillin and gentamicin
should never be mixed in the same syringe. GENE THERAPY
ii. In vivo, i.e. in the body after administration.
Gene therapy is the replacement of defective gene
Pharmacological basis of drug interactions: by the insertion of a normal, functional gene. Gene
The two major mechanisms of drug interactions transfer may be done to replace a missing or
include pharmacokinetic and pharmacodynamic defective gene or provide extra-copies of a
mechanisms. normally expressed gene. Gene therapy is aimed
at genetically correcting the defect in the affected
1. Pharmacokinetic mechanisms: Alteration in part of the body. Unlike all other drugs which
the extent or duration of response may be only alter the rate of normal cell functions, gene
produced by influencing absorption, distribution, therapy can confer new functions to the cell.
metabolism or excretion of one drug by another. Gene transfer requires the use of vectors to
deliver the DNA material, such as:
Absorption of drugs from the gut may be affected
i. Viral vectors like retroviral vectors and
by:
adenoviral vectors.
i. Binding—Tetracyclines chelate iron and
ii. Liposomes.
antacids resulting in reduced absorption
ii. Altering gastric pH Therapeutic applications of gene therapy: Gene
iii. Altering GI motility. therapy is at present a developing area. Though
originally it was seen as a remedy for inherited
Distribution: Competition for plasma protein or
single gene defects, gene therapy has now found
tissue binding results in displacement inter-
to be useful in several acquired disorders. The
actions, e.g. warfarin is displaced by
principle applications are in the treatment of
phenylbutazone from protein binding sites.
cancer, cardiovascular diseases, atherosclerosis,
Metabolism: Enzyme induction and inhibition of immunodeficiency disorders—particularly AIDS;
metabolism can both result in drug interactions anemia, Alzheimer’s disease and many infectious
(see page 14), e.g. phenytoin, phenobarbitone, diseases.
Autonomic
Nervous System

• INTRODUCTION TO AUTONOMIC PHARMACOLOGY


• CHOLINERGIC SYSTEM
• ANTICHOLINERGIC DRUGS
• ADRENERGIC SYSTEM
• ADRENERGIC DRUGS (SYMPATHOMIMETICS)
• ADRENERGIC ANTAGONISTS

INTRODUCTION TO AUTONOMIC heart, the smooth muscles, the glands and the
PHARMACOLOGY viscera and controls the functions of these organs.
The centers for autonomic reflexes are present
The nervous system is divided (Fig. 2.1) into in the hypothalamus, medulla and spinal cord.
central and peripheral nervous systems. The Hypothalamus coordinates the autonomic
peripheral nervous system consists of autonomic activity.
and somatic nervous systems. The ANS consists of 2 major divisions—the
The autonomic nervous system (ANS) (Fig. 2.2) sympathetic and the parasympathetic (Fig. 2.3).
is not under voluntary control and therefore was Most of the viscera have both sympathetic and
so named by Langley (Autos = self, nomos = parasympathetic innervation. The two divisions
governing—in Greek). The ANS innervates the have opposing effects and normally their effects

Fig. 2.1: Nervous system


Autonomic Nervous System 31

Fig. 2.2: Structures under the control of autonomic nervous system

are in a state of equilibrium. The prime function of The autonomic efferent is divided into
the sympathetic system is to help the person to sympathetic and parasympathetic divisions. The
adjust to stress and prepare the body for fight or parasympathetic efferents are carried through the
flight reactions, while the parasympathetic mainly craniosacral outflow. The sympathetic efferents
participates in tissue building reactions. Man can extend from the first thoracic to second or third
still survive without sympathetic system but not lumbar segments (T1-L3 ) of the spinal cord.
without parasympathetic. Adrenal medulla is also considered as
sympathetic ganglia and differs from the other
Autonomic innervation (Fig. 2.4): The autonomic
sympathetic ganglion in that the principal
afferents are carried in visceral nerves through
catecholamine that is released is adrenaline.
nonmyelinated fibers. For example, the para-
sympathetic afferents are carried by the 9th and Neurotransmitters: For the transmission of an
10th cranial nerves. The autonomic efferent impulse across a synapse, a neurohumoral
innervation consists of a myelinated pregang- transmitter substance is released into the synaptic
lionic fiber which synapses with the axon of a cleft. In the ANS, the neurotransmitters released
nonmyelinated postganglionic fiber. The post- are acetylcholine, noradrenaline, dopamine and
ganglionic fiber in turn forms a junction with the in adrenal medulla, it is adrenaline.
receptors of the organs supplied by it. The
junction between the pre and postganglionic fibers CHOLINERGIC SYSTEM
is called a ganglion and that between the post-
ganglionic fibers and the receptors is the Acetylcholine (ACh) an ester of choline, is an
neuroeffector junction. The traveling of an impulse important neurotransmitter of the ANS. The
along the nerve fiber is known as conduction while nerves that synthesize, store and release ACh are
its passage across a synapse is known as called ‘cholinergic.’ Acetylcholine is released in
transmission. response to cholinergic stimulation.
32
Pharmacology for Physiotherapy

Fig. 2.3: Drugs acting on sympathetic and parasympathetic nervous system


Few examples have been given
Autonomic Nervous System 33

The sites of release of acetylcholine are


(Fig. 2.5):
1. Ganglia—All the preganglionic fibers of ANS,
i.e. at both the sympathetic and parasympa-
thetic ganglia.
2. The postganglionic parasympathetic nerve
endings.
3. Sweat glands—The sympathetic post-
ganglionic nerve endings supplying the sweat
glands.
4. Skeletal muscles—somatic nerve endings
supplying skeletal muscles.
5. Adrenal medulla.
6. CNS—brain and spinal cord.
Synthesis of ACh: Acetylcholine is synthesized
from acetyl-CoA and choline, catalyzed by the
enzyme choline acetyltransferase. This ACh is
stored in small oval vesicles in the cholinergic
nerve terminals.
Transmission of an impulse: When an action
Fig. 2.4: Autonomic innervation potential reaches the presynaptic membrane,

Fig. 2.5: Sites of release of neurotransmitters—acetylcholine and


noradrenaline in the peripheral nervous system
34 Pharmacology for Physiotherapy

ACh is released into the synaptic cleft (Fig. 2.6). TABLE 2.1: Subtypes and location
This ACh binds to and activates the choli- of cholinergic receptors
nergic receptor on the postsynaptic membrane Subtypes Location
leading to the depolarization of this membrane.
Thus the impulse is transmitted across the Muscarinic M1 Autonomic ganglia,
gastric glands, CNS
synapse.
ACh released into the synaptic cleft is rapidly M2 Heart, nerves, smooth
destroyed by the acetylcholinesterase (AChE) muscles
enzyme. Then the postsynaptic membrane is M3 Glands, smooth muscles
repolarized. M4 CNS
Cholinesterases: Acetylcholine is hydrolyzed to M5 CNS
choline and acetic acid by the enzymes
Nicotinic Nm Neuromuscular junction
cholinesterases. Two types of AChE are present:
1. True cholinesterase—at neurons, ganglia and Nn Autonomic ganglia
neuromuscular junction. Adrenal medulla, CNS
2. Pseudocholinesterase—in plasma, liver and
other organs. receptors are identified (Table 2.1). Nm receptors
Cholinergic receptors: There are two classes of are present at the skeletal muscle end plate and
cholinergic receptors—muscarinic and nicotinic. Nn receptors at the autonomic ganglia and adrenal
Muscarinic receptors are present in the heart, medulla.
smooth muscles, glands, eyes and CNS. Five
subtypes of muscarinic receptors, M1-M5 are CHOLINERGIC DRUGS
recognized (Table 2.1). Cholinergic drugs are chemicals that act at the
Nicotinic receptors are present in the same site as acetylcholine and thereby mimic its
neuromuscular junction, autonomic ganglia and actions. They are therefore called parasympatho-
adrenal medulla. Two subtypes of nicotinic mimetics or cholinomimetics.

Fig. 2.6: Cholinergic transmission—schematic representation


Autonomic Nervous System 35

Cholinergic drugs may be classified as: Urinary bladder—detrusor contracts and


1. Esters of choline: Acetylcholine, methacho- trigonal sphincter relaxes—promotes voiding
line, carbachol, bethanechol. of urine.
2. Cholinomimetic alkaloids: Pilocarpine, Bronchial smooth muscle—contracts resulting in
muscarine. bronchospasm.
3. Anticholinesterases 4. Secretory glands: Acetylcholine enhances
Reversible—Neostigmine, physostigmine the secretions of all glands; salivary, lacrimal,
Irreversible—Organophosphorus compounds. nasopharyngeal, tracheobronchial, gastric
and intestinal secretions are increased.
PHARMACOLOGICAL ACTIONS Sweating is also increased. Enhanced
OF ACETYLCHOLINE bronchial secretions and bronchospasm result
Acetylcholine is taken as the prototype of para- in severe dyspnea.
sympathomimetic drugs. Acetylcholine produces 5. Eye: Acetylcholine brings about constriction
its actions by binding to muscarinic and nicotinic of pupil (miosis) by contracting the circular
receptors. muscles of the iris. It improves drainage of
aqueous humor and reduced intraocular
Muscarinic Actions pressure. Ciliary muscle contracts resulting in
Muscarinic actions resemble the actions of the spasm of accommodation.
alkaloid muscarine found in some mushrooms.
Nicotinic Actions
1. Heart: The action of ACh is similar to that of
vagal stimulation. It reduces the heart rate and These effects resemble the actions of the alkaloid
force of contraction. In larger doses, AV nicotine.
conduction is depressed. 1. NMJ: ACh brings about contraction of skeletal
2. Blood vessels: ACh relaxes the vascular muscles. Large doses cause persistent
smooth muscles and dilates the blood vessels depolarization of skeletal muscles resulting
of the skin and mucous membrane. The BP in paralysis.
falls due to a fall in total peripheral resistance. 2. Autonomic ganglia: ACh stimulates sympa-
3. Smooth muscle: ACh increases the tone of thetic and parasympathetic ganglia and the
all other smooth muscles. adrenal medulla.
Gastrointestinal tract—tone and peristalsis is 3. CNS: ACh is a neurotransmitter at several sites
enhanced, sphincters are relaxed, resulting in in the CNS.
rapid forward propulsion of intestinal The important actions of acetylcholine are
contents. summarized in Table 2.2.

TABLE 2.2: Actions of acetylcholine


CVS — ↓ HR ↓ BP
Non-vascular smooth muscle — contraction, ↑ gut peristalsis, promotes urine voiding, bronchospasm
Glands — ↑ secretion
Eye — miosis, spasm of accommodation, ↓ intraocular pressure
NMJ — muscle contraction
Ganglia — stimulation
36 Pharmacology for Physiotherapy

Uses: Acetylcholine is destroyed in the gut when Glaucoma is an eye disease characterized by
given orally. On intravenous administration, it is increased intraocular pressure. If untreated,
rapidly metabolized by pseudocholinesterases in irreversible damage can occur, because optic
the plasma and by true cholinesterase at the site nerve degenerates due to constant increase in
of action. Therefore it is not used therapeutically. pressure and this leads to permanent
Among the choline esters, methacholine is rarely blindness. Glaucoma is of two types:
used. Carbachol is used in glaucoma. Bethanechol i. Acute congestive/narrow angle glau-
may be used in some cases of postoperative coma—In this, iris blocks the drainage of
paralytic ileus and urinary retention. aqueous humor at the canal of Schlemn
leading to increased intraocular pressure
CHOLINOMIMETIC ALKALOIDS (Fig. 2.7). It needs immediate treatment.
Pilocarpine is an alkaloid obtained from the leaves ii.Chronic simple/open angle glaucoma—
of Pilocarpus microphyllus. Like ACh it stimulates onset is slow; needs long-term treatment.
cholinergic receptors, but its muscarinic actions Surgery is the preferred option.
are prominent. Drugs used in glaucoma are summarized in
Its actions on the eye are important—when Table 2.3.
applied to the eye it causes miosis, spasm of 2. Pilocarpine eye drops are also used alternately
accommodation and a fall in intraocular pressure with mydriatics like homatropine to break the
(IOP). It also increases sweat (diaphoretic) and adhesions between the iris and the lens.
salivary secretions (sialogogue). 3. Pilocarpine can be used to overcome dryness
of mouth that is seen following radiation of
Adverse effects: When used as eye drops, burning
head and neck.
senzation and painful spasm of accommodation
can occur.
ANTICHOLINESTERASES
Uses Anticholinesterases (antiChEs) or cholinesterase
1. Pilocarpine is used in glaucoma (0.5-4% eye inhibitors are drugs which inhibit the
drops). Pilocarpine ocusert is a special drug enzyme cholinesterase. As their structure
delivery system that can deliver pilocarpine resembles that of ACh, they bind to AChEs and
constantly for 7 days. inactivate them.

Fig. 2.7: Schematic diagram showing pathway for the drainage of aqueous humor
Autonomic Nervous System 37

TABLE 2.3: Drugs used in glaucoma


Drugs Routes Mechanisms
Cholinomimetics
Pilocarpine, carbachol Topical Miosis
Physostigmine, echothiophate Topical ↑drainage of aqueous humor
Alpha adrenergic agonists
Adrenaline Topical ↑drainage of aqueous humor
Dipivefrin Topical
β blockers
Timolol Topical ↓ aqueous secretion
Diuretics
Acetazolamide Oral ↓ aqueous secretion
Prostaglandin analogs latanoprost, bimatoprost Topical ↑ drainage of aqueous humor

Acetylcholine Edrophonium is rapid and short-acting. It is used


↓ AChE ← AntiChE in myasthenia gravis, snake bite and in curare
Choline + Acetic acid poisoning.
Thus ACh is not hydrolyzed and it accumu-
Uses of Anticholinesterases
lates. The actions of these drugs are due to this
1. As a miotic: Physostigmine causes miosis,
accumulated ACh. Hence the actions are similar spasm of accommodation and a ↓ IOP. It is
to cholinergic agonists. used:
Anticholinesterases may be: a. in glaucoma—can be used with pilocar-
1. Reversible: Physostigmine, neostigmine, pine for better effect.
pyridostigmine, rivastigmine, donepezil, b. alternately with a mydriatic to break the
edrophonium. adhesions between the iris and the lens.
2. Irreversible: Organophosphates— 2. Myasthenia gravis: Myasthesia gravis is a
malathion, sumithion, toxic nerve gases, chronic autoimmune disease characterized by
echothiophate. progressive weakness with rapid and easy
Physostigmine is an alkaloid obtained from the fatiguability of the skeletal muscles. Anti-
plant Physostigma venenosum. It is a tertiary bodies to nicotinic receptors are formed which
ammonium compound—hence has better destroy these receptors, resulting in a decrease
penetration into tissues and also crosses the BBB. in the number of these receptors at the
It is available as 0.1-1 percent eye drops. It is used neuromuscular junction (NMJ). Edrophonium
in glaucoma and in atropine poisoning. Its use in is used for the diagnosis. Anticholinesterases
glaucoma can cause browache, and on long-term bring about improvement in muscle strength.
use retinal detachment and cataract. Neostigmine (15 mg tab 6 hourly) or pyrido-
stigmine or a combination of these two may be
Neostigmine is a synthetic quaternary ammo- given. In addition to its antiChE activity,
nium compound—poorly absorbed from the gut; neostigmine directly stimulates the nicotinic
it does not cross the BBB. It is used in myasthenia receptors and increases the amount of ACh
gravis and postoperative paralytic ileus and atony released during each nerve impulse. AntiChEs
of the urinary bladder. enhance ACh levels at the NMJ by preventing
38 Pharmacology for Physiotherapy

the destruction of ACh. They thus increase the 6. Cobra bite: Cobra venom, a neurotoxin causes
force of contraction and improve muscle power skeletal muscle paralysis. Specific treatment
by more frequent activation of the existing is antivenom. Intravenous edrophonium
nicotinic receptors. In advanced disease, prevents respiratory paralysis.
anticholinesterases are not effective because 7. Alzheimer’s disease: Rivastigmine and
the available nicotinic receptors are very few. donepezil are tried.
Factors like infection, surgery and stress
can result in severe muscle weakness called – Irreversible Anticholinesterases
myasthenic crisis. But severe weakness may
Organophosphorus compounds are powerful
also result from an excess dose of an inhibitors of AChE enzyme; binding with the
anticholinesterase drug (flaccid paralysis due enzyme is permanent—by covalent bonds.
to more of acetylcholine) called ‘cholinergic Actions are similar to ACh as ACh accumulates in
crisis’. These two crises can be differentiated the tissues. Organophosphates are highly lipid
by 2 mg IV edrophonium—the patient soluble and hence are absorbed from all routes
immediately improves if it is myasthenic crisis including intact skin.
but the weakness worsens if it is cholinergic
crisis. Treatment of cholinergic crisis is with Uses
atropine while myasthenic crisis requires a
Glaucoma—echothiophate eye drops are some-
higher dose of an alternative anticholinergic
times used in glaucoma.
drug.
Other drugs used in myasthenia gravis
Organophosphorus Poisoning
are—glucocorticoids—they inhibit the
production of antibodies to the nicotinic As organophosphates are used as agricultural
receptors. These are used when anti- and domestic insecticides, poisoning from
cholinesterases alone are not adequate. them is quite common. Poisoning may be
Immunosuppressants—Azathioprine and occupational—as while spraying insecticides,
cyclosporine can be used as alternatives to accidental or suicidal. Symptoms include
prednisolone in advanced myasthenia gravis. muscarinic, nicotinic and central effects; vomiting,
They inhibit the production of antinicotinic abdominal cramps, diarrhea, miosis, sweating,
receptor antibodies. increased salivary, tracheobronchial and gastric
3. Poisoning due to anticholinergic drugs: secretions and bronchospasm; hypotension,
Physostigmine is used in atropine poisoning muscular twitchings, weakness, convulsions and
and in toxicity due to other drugs with coma. Death is due to respiratory paralysis.
anticholinergic activity like phenothiazines, Treatment
tricyclic antidepressants and antihistamines. 1. If poisoning is through skin—remove clothing
4. Curare poisoning: Skeletal muscle paralysis and wash the skin with soap and water; if
caused by curare can be antagonized by consumed by oral route—gastric lavage is
AntiChEs. Edrophonium is preferred for its given.
fast action. But, neostigmine has a better 2. Maintain BP and patent airway.
capacity to antagonize the effects of curare 3. Drug of choice is atropine (2 mg IV every 10
because of which it is preferred in severe minutes till pupil dilates) because it blocks the
poisoning. muscarinic receptors and thereby antagonises
5. Postoperative paralytic ileus and urinary retention: the muscarinic effects of organophosphorus
Neostigmine may be useful. compounds.
Autonomic Nervous System 39

4. Cholinesterase reactivators—pralidoxime, Bronchi—atropine causes bronchodilatation.


obidoxime. These compounds combine with Urinary bladder—relaxes urinary bladder and
cholinesterase-organophosphate complex, may cause urinary retention.
release the binding and set free AChE enzyme. 4. Eye—On local instillation, atropine produces
They should be given within a few hours (< 24 mydriasis by blocking the muscarinic
hrs) after poisoning, preferably immediately receptors in the sphincter pupillae. The ciliary
because the complex undergoes ‘ageing’ and muscle is paralyzed resulting in cycloplegia
then the enzyme cannot be released. or paralysis of accommodation. Because of
mydriasis, the iris may block the drainage of
ANTICHOLINERGIC DRUGS aqueous humor—IOP increases and may
precipitate glaucoma in some patients.
Anticholinergic drugs are agents which block the 5. CNS—In higher doses atropine stimulates the
effects of ACh on cholinergic receptors but CNS resulting in restlessness, disorientation,
conventionally antimuscarinic drugs, i.e. drugs hallucinations and delirium. In contrast,
which block only muscarinic receptors are referred scopolamine produces sedation and
to as anticholinergic drugs. They are also called drowsiness.
cholinergic blocking or parasympatholytic drugs.
Pharmacokinetics: Atropine and hyoscine are
Drugs that block the nicotinic receptors are
well-absorbed, cross the BBB and are metabolized
ganglion blockers and neuromuscular blockers.
in the liver.
Anticholinergic drugs include atropine and
related drugs—atropine is the prototype. Adverse effects are common but not serious and
Atropine is obtained from the plant Atropa include blurring of vision, dry mouth, dysphagia,
belladonna. Atropine and scopolamine (hyoscine) dry skin, fever, constipation and urinary
are the belladonna alkaloids. They compete with retention. Skin rashes may appear. High doses
acetylcholine for muscarinic receptors and block cause palpitation, flushing, restlessness, delirium,
these receptors—they are muscarinic antagonists. hallucinations, psychosis, convulsions and coma.
Poisoning is treated with IV physostigmine.
Actions
Uses of Belladonna Alkaloids
The actions of atropine and scopolamine are
1. As antispasmodic: In diarrhea and dysentry,
similar except that atropine is a CNS stimulant
atropine relieves abdominal pain.
while scopolamine is a CNS depressant and
– In renal and biliary colic—atropine is used
causes sedation.
with morphine (see page 121).
1. CVS—Atropine increases heart rate. In large
– Nocturnal enuresis in children and in
doses, vasodilation and hypotension occurs.
paraplegia atropine reduces urinary
2. Secretions—Atropine reduces all secretions
frequency.
except milk. Lacrimal, salivary, naso-
pharyngeal, tracheobronchial and gastric 2. As mydriatric and cycloplegic:
secretions are decreased. Sweating is also – Diagnostic for testing error of refraction and
reduced. fundoscopic examination of the eye.
3. Smooth muscle – Therapeutic: To provide rest to the iris in
GIT—↓ tone and motility and relieves spasm iritis, iridocyclitis and keratitis.
→ may result in constipation. Mydriatics are used alternately with
Biliary tract—smooth muscles are relaxed; miotics to break the adhesions between the
biliary spasm is relieved. iris and the lens.
40 Pharmacology for Physiotherapy

3. As preanesthetic medication: When administered ATROPINE SUBSTITUTES


30 minutes before anesthesia, atropine reduces
Belladonna alkaloids lack selectivity and exert a
salivary and respiratory secretions. This will
wide range of effects—producing many side
prevent the development of laryngospasm. It
effects. Hence, several synthetic and semisynthetic
also prevents bradycardia during surgery. Its
derivatives with selective action were introduced
bronchodilator action is of additional value.
(Table 2.4).
Glycopyrrolate an atropine substitute, is most
• Mydriasis and cycloplegia produced by
commonly used for this purpose.
atropine lasts for 7-10 days. The derivatives
4. In organophosphorus poisoning: Atropine is life have a shorter action (6-24 hours); some can
saving in OP poisoning and is also useful in selectively produce either mydriasis or
mushroom poisoning. cycloplegia and these can also be used in
5. Heart block: Atropine can be used to overcome atropine intolerance.
bradycardia and partial heart block due to its • Spasmolytics are used in colics, gastritis and
vagolytic properties. peptic ulcer.
6. In bronchial asthma, peptic ulcer and parkinsonism: • Pirenzepine and telenzapine are selective M1-
Atropine derivatives are preferred over blockers—inhibit gastric secretion at doses
atropine—see below. that do not affect other functions and has been
7. Motion sickness: Hyoscine given 30 minutes tried in peptic ulcer.
before the journey prevents travelling sickness. • When used in bronchial asthma, atropine
Transdermal hyoscine patches are available thickens bronchial secretions and interferes
to be applied behind the ear for a prolonged with the movement of cilia and thus favors
action. formation of mucus plugs. Ipratropium
bromide is a bronchodilator that does not affect
8. Hyoscine can also be used during labor to
mucociliary activity. When given as
produce sedation and amnesia. It can be used
inhalation, it produces no systemic side effects
for lie detection because of these properties.
because of poor absorption. It is used in
Drug interactions: When anticholinergics are bronchial asthma and chronic obstructive
given with other drugs that also have anti- pulmonary disease (COPD).
cholinergic property like antihistaminics, • Benztropine, benzhexol and trihexyphenidyl
phenothiazines, tricyclic antidepressants—side are the derivatives used in drug induced
effects get added up. parkinsonism.

TABLE 2.4: Atropine substitutes


1. Derivatives used on the eye Homatropine, eucatropine, cyclopentolate, tropicamide
2. Antispasmodics Atropine methonitrate
Propantheline methantheline
Oxyphenonium, glycopyrrolate
3. Derivatives used in peptic ulcer Pirenzepine, telenzepine
4. Derivatives used in bronchial asthma Ipratropium bromide
5. Antiparkinsonian drugs Benzhexol, benztropine, trihexyphenidyl
6. Preanesthetic medication Glycopyrrolate
7. Urinary disorders Dicyclomine, tolterodine
Autonomic Nervous System 41

• Urinary disorders — Reduce urinary urgency The sympathetic postganglionic nerve fibers
and frequency. Therefore anticholinergics are that synthesize, store and release NA are called
used in urinary disorders, urologic surgeries adrenergic. Noradrenaline is stored in small
and in nocturnal enuresis in children. vesicles in the adrenergic nerve terminals. In
• Glycopyrrolate is used in preanesthetic response to nerve impulse, NA is released into
medication as it is an antisialogogue. It does the synaptic cleft by a process of exocytosis. This
not cross the blood brain barrier and therefore NA binds to adrenergic receptors located on the
has no CNS effects. postsynaptic membrane to produce the response
(Fig 2.9). A small portion of NA is metabolized by
ADRENERGIC SYSTEM the enzyme COMT. But a large portion (nearly
80%) is taken back into the nerve terminals by an
The prime function of the adrenergic or active transport process termed uptake 1, which
sympathetic nervous system is to help the human is responsible for termination of action of NA. Of
beings to adjust to stress and prepare the body for this, a fraction is metabolized by MAO and the
fight or flight reactions. When exposed to stress, remaining NA is then transferred to the storage
the heart rate and stroke volume increase with the vesicles. Some part of NA released into the
resultant increase in CO. The blood is shifted from
the skin, gut, kidney and glands to the heart,
skeletal muscles, brain and lungs, as these organs
need more blood during stress. Pupils and bronchi
are dilated and sweating is increased. Blood
glucose increases by glycogenolysis.
Neurotransmitters of the sympathetic system
are noradrenaline (NA, norepinephrine) and
dopamine (DA). Adrenaline (epinephrine) is the
major hormone secreted by the adrenal medulla.
Synthesis of catecholamines: The 3 cate-
cholamines—NA, adrenaline and DA are
synthesized from the amino acid tyrosine (Fig. 2.8). Fig. 2.8: Biosynthesis of catecholamines

Fig. 2.9: Synthesis, storage, release and metabolism of noradrenaline


42 Pharmacology for Physiotherapy

synaptic cleft penetrates into the effector cells and ADRENERGIC DRUGS (Sympathomimetics)
is known as uptake 2.
Sympathomimetics are drugs whose actions
Adrenergic receptors Alquist classified mimic that of sympathetic stimulation. They may
adrenergic receptors into 2 types—α and β. With be classified in various ways.
the availability of newer, synthetic, selective
I. Chemical classification—based on
drugs, these are further classified into sub-
presence/absence of catechol nucleus
divisions. We now know α1 α2, β1, β2 and β3
1. Catecholamines Noradrenaline (NA),
adrenergic receptors.
Adrenaline,
The stimulation of α receptors mainly produces
Dopamine (DA),
excitatory effects (exception-GIT); β stimulation
Isoprenaline
causes mainly inhibitory effects (exception- heart).
(Synthetic)
The characteristics of these receptors are given in
Table 2.5. α 2 receptors are located on the 2. Non-catecholamines Ephedrine,
presynaptic membrane. When the concentration Amphetamine
of NA reaches adequate levels, these presynaptic II. Depending on the mode of action
α2 receptors are stimulated and inhibit the further 1. Directly acting by interacting with
release of NA. Thus α2 receptors exert a negative sympathomimetics adrenergic receptors
feed back on NA release. α2 receptors are also — NA, isoprenaline,
present postsynaptically in pancreatic islets, dopamine,
platelets and brain. adrenaline

TABLE 2.5: Characteristics of adrenergic receptors


Receptor type Selective agonist Selective antagonist Location Response
α1 Phenylephrine Prazosin Vascular smooth muscle Contraction
Gut Relaxation
Genitourinary Contraction
smooth muscle
Liver Glycogenolysis
α2 Clonidine Yohimbine Pancreatic β cells ↓ Insulin release
Platelets Aggregation
Nerve terminals ↓ NE release
β1 Dobutamine Metoprolol Heart ↑ Force of contraction,
Atenolol heart-rate, AV
conduction velocity
β2 Salbutamol Butoxamine Smooth muscle— Relaxation
vascular, bronchial,
gut and genitourinary
β3 — — Adipose tissue Lipolysis
Autonomic Nervous System 43

2. Indirectly acting by releasing NA from rate, force of contraction, cardiac output and
sympathomimetics nerve terminals— conduction velocity. The work done and the
Amphetamine, resultant O2 consumption of the heart is increased.
Tyramine
Blood vessels and BP: Blood vessels of skin
3. Mixed action amines both direct and and mucous membrane are constricted (α1) and
indirect actions:
that of skeletal muscles are dilated (β2 ) by
Ephedrine,
adrenaline.
Methoxamine
Moderate doses given IV produce a rapid
III. Therapeutic or clinical classification increase in BP followed by a fall— a biphasic
1. Vasopressors Noradrenaline, response. The rise in BP is due to α1 mediated
Dopamine, vasoconstriction. Action on β receptors is more
Methoxamine, persistent and as the action on alpha receptors
Metaraminol wears off, the action on β receptors gets unmasked
2. Cardiac stimulants Adrenaline, resulting in ↓ BP. Sir Henry Dale demonstrated
Dopamine, that when α receptors are blocked (with alpha
Dobutamine, blockers—ergot alkaloids), adrenaline produces
Isoprenaline, only a fall in BP and this is named after him as
Ephedrine Dale’s vasomotor reversal (or Dale’s pheno-
3. CNS stimulants Amphetamine, menon).
Ephedrine Noradrenaline is mainly an alpha agonist and
4. Bronchodilators Adrenaline, brings about a rise in BP.
Isoprenaline, Other vascular beds: Adrenaline causes renal
Salbutamol, vasoconstriction resulting in fall in renal blood
Terbutaline, flow; it also causes pulmonary and mesenteric
Salmeterol vasoconstriction.
5. Nasal decongestants Ephedrine, Cerebral and coronary blood flow is enhanced.
Pseudoephedrine,
Phenyl- 2. Smooth Muscles
propanolamine, Bronchi: Adrenaline is a powerful bronchodilator
Phenylephrine, and a weak respiratory stimulant. Pulmonary
Oxymetazoline, vasoconstriction relieves bronchial congestion.
Xylometazoline All these result in an increase in vital capacity.
6. Appetite suppres- Fenfluramine, Uterus: Nonpregnant uterus—contracts
sants (anorectics) Dexfenfluramine Last month of pregnancy—relaxes.
7. Uterine relaxants Salbutamol, Gut: Smooth muscle is relaxed—but weak and
Terbutaline, transient action.
Isoxuprine, ritodrine
Splenic capsule: Contracts resulting in the release
ACTIONS of RBCs into the circulation.
Pilomotor muscles of the hair follicle: Contraction.
1. Cardiovascular System
Bladder: Detrusor is relaxed while trigonal
Heart: Adrenaline is a powerful cardiac stimulant. sphincter is contracted thereby increasing the
Acting through β1 receptors, it increases the heart holding capacity of the bladder.
44 Pharmacology for Physiotherapy

3. Eye Uses of Adrenaline


Adrenaline causes mydriasis due to contraction 1. Anaphylactic shock: Adrenaline is the drug
of the radial muscles of the iris (α1); it also reduces of choice (0.3-0.5 ml of 1:1000 solution). It
intraocular pressure. promptly reverses hypotension, laryngeal
edema and bronchospasm and is life saving
4. Metabolic Effects in anaphylactic shock. IM route is preferred
Adrenaline increases the blood sugar level by as absorption by SC route is not reliable in
enhancing hepatic glycogenolysis. It also inhibits shock.
insulin release. It acts on β3 receptors in the 2. Cardiac arrest: Sudden cardiac arrest due to
adipocytes to increase the breakdown of drowning, electrocution, etc. are treated with
triglycerides. intracardiac adrenaline.
3. Control of hemorrhage: Adrenaline in 1:
5. Skeletal Muscles 10,000 to 1 : 20,000 concentration is used as a
Catecholamines facilitate neuromuscular topical hemostatic to control bleeding from
transmission by action on both α and β receptors— skin and mucous membrane. Bleeding stops
they enhance the amount of ACh released. due to vasoconstriction. Adrenaline packs are
used.
Pharmacokinetics: As catecholamines are 4. With local anesthetics: (see page 105) Injected
rapidly inactivated in the gut and the liver they with LA, adrenaline produces vaso-
are not given orally. Adrenaline and NA are constriction and reduces the rate of absorption
metabolized by COMT and MAO. of LA. By this it prolongs the action and reduces
Adrenaline Noradrenaline systemic toxicity of LA. 1: 10,000 to 1: 2,00,000
COMT COMT adrenaline is used.
Metanephrine Normetanephrine 5. Acute bronchial asthma: SC/inhalation
adrenaline produces bronchodilation (see
page 156).
Vanilyl mandelic acid (VMA) 6. Glaucoma: Adrenaline ↓ IOP and can be used
in glaucoma.
Excreted in urine
Noradrenaline: Can be used in shock to increase
Adverse reactions: Anxiety, palpitation, weak- BP—but it is very rarely used.
ness, tremors, pallor, dizziness, restlessness and Isoprenaline (Isoproterenol, isopropylarterenol)
throbbing headache may follow adrenaline/NA is a synthetic catecholamine with predominantly
administration. In patients with ischaemic heart β receptor stimulant action and negligible α
disease, both adrenaline and NA can precipitate actions. It has cardiac stimulant and smooth
anginal pain. Rapid IV injection can cause sudden muscle relaxant properties. Due to vasodilation
sharp rise in BP which may precipitate BP falls; it is a potent bronchodilator. Adverse
arrthythmias, subarachnoid hemorrhage or effects include palpitation, angina, headache and
hemiplegia. flushing.
Preparations: Adrenaline 1:1000, 1:10,000 and Isoprenaline is used in heart block and shock
for its cardiac stimulant actions. It can be used in
1:1,00,000 solutions are available for injection.
bronchial asthma (page 156).
Adrenaline is given SC/IM; intracardiac in emer-
gencies. Adrenaline aerosol for inhalation and 2 Dopamine is the precursor of NA. It acts on
percent ophthalmic solution are also available. the dopaminergic and adrenergic receptors.
Autonomic Nervous System 45

It is a central neurotransmitter. Low doses Uses


stimulate vascular D 1 receptors in renal, 1. Bronchial asthma: Ephedrine is useful in mild,
mesenteric and coronary beds causing chronic bronchial asthma (see page 156) but it
vasodilatation in these vessels. Higher doses is not preferred.
cause cardiac stimulation through β1 receptors 2. Nasal decongestion: Nasal drops of ephedrine
and in high doses α1 receptors are activated are used. Pseudoephedrine—an isomer of
resulting in vasoconstriction and ↑ BP. ephedrine is used orally for decongestion.
3. Mydriasis: Ephedrine eyedrops are used to
Adverse effects: Nausea, vomiting, palpitation, produce mydriasis without cycloplegia.
angina, sudden ↑ in BP may occur. 4. Hypotension: For prevention and treatment
of hypotension during spinal anesthesia—IM
Uses: DA is used in the treatment of shock—
ephedrine is used.
cardiogenic, hypovolemic and septic shock. It is
5. Narcolepsy is a condition with an irresistable
specially useful when there is renal dysfunction
desire and tendency to sleep. As ephedrine is
and low cardiac output.
a CNS stimulant, it is useful in narcolepsy.
Dobutamine a derivative of dopamine, is a 6. Nocturnal enuresis (Bed wetting) in children
relatively selective β1 agonist. Though it also may be treated with ephedrine as it increases
activates α receptors, in therapeutic doses the only the holding capacity of the bladder. Drugs
dominant action is an increase in the force of should be used only when non-pharmaco-
contraction of the heart without a significant logical measures have failed.
increase in the heart rate. Thus, it is used in
Amphetamine is a synthetic compound with
patients with CCF or acute myocardial infarction
actions similar to ephedrine, tachyphylaxis can
or following cardiac surgery when there may be
occur on repeated use. Amphetamine is a potent
heart failure.
CNS stimulant; it produces increased mental and
Non-catecholamines are devoid of catechol physical activity, alertness, increased con-
nucleus, they act both by direct stimulation of centration and attention span, elation, euphoria
adrenergic receptors and indirectly by releasing and increased capacity to work. It also increases
NA. In contrast to catecholamines, they are initiative and self confidence, postpones fatigue
effective orally, relatively resistant to MAO and and improves physical performance (temporarily)
therefore are longer-acting; they cross the blood- as seen in athletes. All these properties make
brain barrier and have CNS effects. amphetamine a drug of dependence and abuse.
Higher doses produce confusion, delirium and
Ephedrine is an alkaloid obtained from the plants
hallucinations. The effects may be reversed with
of the genus Ephedra. It acts by direct stimulation
overdosage.
of α and β receptors and indirectly through release
of NA. Repeated administration at short intervals Respiration: Amphetamine stimulates respi-
result in tachyphylaxis. Ephedrine ↑ BP by peri- ration—analeptic.
pheral vasoconstriction and by increasing the Depression of appetite: Acting on the feeding
cardiac output. Like adrenaline it relaxes smooth center in the hypothalamus, amphetamine
muscles; it is a CNS stimulant and produces reduces hunger and suppresses appetite.
insomnia, restlessness, anxiety, tremors and Amphetamine also has weak anticonvulsant
increased mental activity. property.
Adverse effects include sleeplessness, tremors Adverse effects include restlessness, tremors,
and difficulty in micturition. insomnia, palpitation, anxiety, confusion and
46 Pharmacology for Physiotherapy

hallucinations. Prolonged use may precipitate Phenylephrine is a selective α1 stimulant; it is also


psychosis. a nasal decongestant. Reflex bradycardia is
High doses cause angina, delirium, prominent. It produces mydriasis without
arrhythmias, hypertension, acute psychosis, coma cycloplegia.
and death due to convulsions.
Methoxamine has actions similar to phenyleph-
Dependence: Amphetamine causes psychologic rine.
dependence.
Uses NASAL DECONGESTANTS
1. Attention deficit hyperactivity disorder (ADHD) Nasal decongestants are α agonists which relieve
in children is characterized by decreased congestion due to vasoconstriction.
ability to concentrate and hold attention, They may be used:
aggressive behavior and hyperactivity; 1. Orally Ephedrine, pseudoephedrine
Amphetamine increases attention span in 2. Topically Oxymetazoline, xylometa-
such children and improves performance in zoline, naphazoline,
school. phenylephrine, mephen-
2. Narcolepsy: Amphetamine is preferred over teramine, metaraminol
ephedrine.
• Irritation and after congestion are
3. Obesity: Though appetite is suppressed, due
disadvantages
to risk of dependence and other side effects,
• On prolonged use nasal decongestants
amphetamine should not be used for this
may cause atrophy of the mucosa due
purpose.
to intense vasoconstriction.
4. Epilepsy: Amphetamine can be used as an
adjuvant and to counter the sedation due to Uses: Rhinitis in upper respiratory infection,
antiepileptics. allergic and vasomotor rhinitis, sinusitis and
VASOPRESSORS blocked eustachian tubes—nasal decongestants
afford symptomatic relief.
These are α1 agonists and include metaraminol,
mephenteramine, phenylephrine and methoxa-
SELECTIVE β 2 STIMULANTS
mine. They increase the BP by increasing total
peripheral resistance (TPR) or cardiac output (CO) Selective β2 stimulants include orciprenaline,
or both. They are given parenterally with constant salbutamol, terbutaline and salmeterol. These are
monitoring of BP. Tachyphylaxis may develop. smooth muscle relaxants which produce
bronchodilatation, vasodilation and uterine
Uses: Vasopressors are used to raise the BP in
relaxation without significant cardiac stimulation.
hypotension as seen in cardiogenic or neurogenic
They can be given by inhalation and are used in:
shock and during spinal anesthesia.
i. Bronchial asthma (see chapter 8)
Metaraminol is an alpha stimulant and also acts ii. As uterine relaxants to delay premature
indirectly by NA release. CO is increased. It is labor.
also a nasal decongestant.
Side effects include muscle tremors, palpitation and
Mephenteramine acts on both α and β receptors to arrhythmias.
↑ TPR, ↑ CO and thereby raises BP. It is orally Isoxuprine is a selective β receptor stimulant
effective. Pressor effect is accompanied by used as uterine relaxant in premature labor,
bradycardia. threatened abortion and dysmenorrhea.
Autonomic Nervous System 47

ANORECTIC AGENTS (ANOREXIANTS) Selective α1-blockade—results in hypotension


without significant tachycardia.
Though amphetamine suppresses appetite, it is
not recommended for the treatment of obesity Selective α2-blockade—↑ ↑ NA release resulting in
due to its central stimulant effects. Many hypertension.
amphetamine-like drugs which suppress appetite α-blockade also results in miosis and nasal
but lack significant CNS stimulant effects are now stuffiness. α-blockade in the bladder and prostate
available. They are fenfluramine, dexfenfluramine, leads to decreased resistance to the flow of urine.
mazindol, phenylpropanolamine and others.
Adverse effects of α-blockers—postural hypoten-
Adverse effects include risk of abuse, drowsiness
sion, palpitation, nasal stuffiness, miosis and
and depression because of which they are only
impaired ejaculation which may result in
used for short periods as adjuncts to other
impotence.
measures.
Classification
ADRENERGIC ANTAGONISTS
1. Non-selective
Adrenergic blockers bind to the adrenergic a. Non-competitive Phenoxybenzamine
receptors and prevent the action of adrenergic blocker
drugs. They may block alpha or beta receptors or b. Competitive Ergot alkaloids
both. blockers (ergotamine),
Tolazoline,
ALPHA ADRENERGIC BLOCKING AGENTS Phentolamine,
Alpha receptor antagonists block the adrenergic Chlorpromazine
responses mediated through alpha adrenergic 2. Selective
receptors. Some of them have selectivity for α1 or a. α1-blockers Prazosin, terazosin
α2 receptors.
b. α2-blocker Yohimbine
Actions Phenoxybenzamine binds covalently to alpha
receptors causing irreversible blockade. Given IV,
The important effects of α receptor stimulation
blood pressure gradually falls and is associated
are α 1 mediated vasoconstriction and α 2 -
with tachycardia. The action lasts for 3-4 days.
(presynaptic) receptor mediated inhibition of NA
release. The result of blockade of these alpha Ergot alkaloids like ergotamine, ergotoxine and
receptors by α-antagonists is hypotension with their derivatives are competitive α antagonists and
tachycardia. This effect is due to: the blockade is of short duration.
i. α 1-blockade—inhibits vasoconstriction--
Phentolamine and tolazoline are imidazoline
leading to vasodilation and thereby ↓ BP.
derivatives. They are competitive α-blockers. In
This fall in BP is opposed by the baroreceptor
addition they also block 5-HT receptors, stimulate
reflexes which tend to ↑ heart rate and
gut motility and ↑ gastric secretion. Hence they
cardiac output.
can cause vomiting and diarrhea in addition to
ii. α2-blockade—enhances release of NA which
the effects of α-blockade.
stimulates β receptors (α are already blocked)
β1 stimulation in heart results in tachycardia Prazosin is a potent, highly selective, α1-blocker
and ↑ cardiac output. with 1000 times greater affinity for α1 receptors.
48 Pharmacology for Physiotherapy

Arterioles are dilated more than veins resulting urethra reduce resistance to urine outflow.
in hypotension. There is no significant tachycardia Prazosin is useful in patients who cannot be
(as α2 receptors are spared there is no ↑ in NA operated upon.
release).
It is orally effective and is metabolized in the BETA ADRENERGIC BLOCKING AGENTS
liver.
β-blockers are drugs that block the actions of
Adverse effects—First dose phenomenon—1 hour catecholamines mediated through the β receptors.
after the initial dose, marked postural hypotension
occurs which may lead to fainting. To avoid this, Classification
prazosin should be started with a low dose and 1. Non-selective: Propranolol, nadolol, timolol,
taken at bed time. sotalol.
2. Cardioselective (β 1): Metoprolol, atenolol,
Terazosin is longer-acting and can be given once
acebutolol, esmolol.
daily.
3. Partial agonists: Pindolol, oxprenolol.
Yohimbine is a relatively selective α2-blocker 4. With additional alpha blocking property:
which increases BP and heart rate due to ↑ NA Labetalol, carvedilol.
release. It causes congestion of genitals for which
it is used to treat psychogenic impotence. It is also Pharmacological Actions
claimed to be an aphrodisiac (drug that increases 1. CVS: β-blockers decrease heart rate, force of
sexual desire) though the effect is only psycho- contraction and cardiac output. Blood
logical. pressure falls. The effect is more pronounced
in presence of increased sympathetic tone than
Uses of α-blockers in a normal situation.
1. Hypertension—Selective α 1 -blockers like AV conduction is delayed. Myocardial oxygen
prazosin are used in the treatment of hyper- requirement is reduced due to reduced cardiac
tension (page 81). Phenoxybenzamine or work.
phentolamine can be used in hypertensive High doses produce membrane-stabilizing
crisis. activity like quinidine, causing direct
2. Pheochromocytoma is an adrenal medullary depression of the heart.
tumor which secretes large amounts of 2. Exercise: β-blockers prevent the increase in
catecholamines resulting in hypertension. The heart rate and force of contraction which are
tumor has to be removed surgically. brought about by exercise. β-blockers may also
Phenoxybenzamine and phentolamine are reduce the work capacity. These effects are less
used for the preoperative management of the prominent with β1 selective agents. This is
patient and during the operation. Inoperable because blockade of β2 receptors prevents the
cases are put on long-term treatment with increase in blood flow to the skeletal muscles
phenoxybenzamine. during exercise. β-blockers improve exercise
3. Peripheral vascular diseases like Raynaud’s tolerance in patients with angina.
phenomenon may be benefited by α-blockers 3. Respiratory tract: Blockade of β2 receptors in
which afford symptomatic relief. the bronchial smooth muscle causes increase
4. Congestive cardiac failure—Because of its in airway resistance—may precipitate acute
vasodilator action, prazosin is useful in CCF. attacks in asthmatics.
But ACE inhibitors are preferred. 4. Eye: Many β-blockers reduce intraocular
5. Benign prostatic hypertrophy (BPH)—Blockade pressure by decreased secretion of aqueous
of α1 receptors in the bladder, prostate and humor.
Autonomic Nervous System 49

5. Metabolic: β-antagonists block lipolysis and 2. Propranolol + verapamil—since both cause


glycogenolysis induced by sympathetic myocardiac depression, profound depression
stimulation. Plasma triglycerides may increase may result. Hence the combination should be
and HDL levels decrease in some patients. avoided.

Pharmacokinetics Cardioselective β -blockers, e.g. Atenolol,


metoprolol, esmolol.
Though well absorbed on oral administration,
These drugs:
some β-blockers like propranolol undergo
• Selectively block β1 receptors, β2-blockade
extensive first pass metabolism. Most of them have
is weak
short t½ and are metabolized in the liver.
• Bronchospasm is less/negligible
• Inhibition of glycogenolysis is lower—
Adverse Reactions
hence safer in diabetics
1. Bradycardia is common. • Exercise performance impaired to a lesser
2. CCF—In patients with impaired cardiac degree
function, sympathetic activity supports the • Reduced chances of peripheral vascular
heart. β-blockade eliminates this and may disease
result in CCF. • Atenolol is long-acting—given once daily
3. Cold extremities especially in patients with • Esmolol is very short-acting and can be
peripheral vascular disease may occur. given intravenously in emergencies.
4. β-blockers can precipitate acute asthmatic
Partial agonists—Pindolol, oxprenolol.
attacks and is contraindicated in asthmatics.
These have intrinsic sympathomimetic activity
5. CNS—Sedation, depression and rarely
due to their partial β-agonistic property. As a
hallucinations can follow the use of β-blockers.
result, bradycardia and myocardiac depression
6. Metabolic effects—Weakness, ↓ exercise
are less marked. They are therefore preferred in
capacity may be seen due to its metabolic
patients with low cardiac reserve or those who
effects.
are likely to have severe bradycardia.
7. Abrupt withdrawal of β-blockers after
prolonged use can cause rebound hyper- Uses of β-blockers
tension and precipitate anginal attacks. This
1. Hypertension: β-blockers are useful in the
is due to up-regulation of β receptors. Hence
treatment of mild to moderate hypertension.
β-blockers should be gradually withdrawn
A β-blocker can be used alone or with other
over many weeks.
antihypertensives (page 80).
2. Angina pectoris: β-blockers are useful in the
Some Important Drug Interactions
prophylaxis of exertional angina. Both the
1. Propanol + insulin—when diabetics on severity and frequency are reduced (page 76).
insulin also receive propranolol: 3. Cardiac arrhythmias: β-blockers are useful
i. β-blockade masks tachycardia which is in the treatment of both ventricular and
the first warning signal of hypoglycemia. supraventricular arrhythmias (page 73).
ii. β-blockade delays the recovery from 4. Myocardial infarction: IV β-blockers in acute
hypoglycemia by preventing glyco- MI may limit the size of the infarct.
genolysis induced by sympathetic stimu- In patients who have recovered from MI,
lation. This may be avoided by using a long-term treatment with β-blockers prolongs
β1-selective blocker. survival.
50 Pharmacology for Physiotherapy

5. Obstructive cardiomyopathy: β-blockers are other symptoms of sympathetic overactivity


found to be beneficial. are alleviated.
6. Pheochromocytoma: Propranolol is given
with α-blockers before surgery to control Alpha and Beta-adrenergic Blockers
hypertension.
7. Thyrotoxicosis: Propranolol controls Labetalol: Blocks both α1 and β (β1 and β 2)
palpitation, tremors and affords symptomatic receptors. It is a competitive antagonist. Heart rate,
relief in thyrotoxicosis. contractility, AV conduction and BP fall. Blood
8. Glaucoma: Timolol is used topically in open flow to the limbs increases.
angle glaucoma.
9. Prophylaxis of migraine: Propranolol Side effects include postural hypotension, GI
reduces frequency and severity of migraine disturbances and other effects of alpha and β-
headache; used for prophylaxis. blockade.
10. Anxiety: Propranolol prevents the acute Uses: Labetalol is used in hypertensive emer-
panic symptoms seen in public speaking, gencies and pheochromocytoma.
examination and other such anxiety-provo-
king situations. Performance in musicians Carvedilol and medroxalol also block both alpha
can be improved. Tremors, tachycardia and and beta receptors.
Musculoskeletal
System

• SKELETAL MUSCLE RELAXANTS


• DRUGS USED IN THE TREATMENT OF LOCAL MUSCLE SPASM
• DRUGS USED IN THE OTHER MUSCULOSKELETAL DISEASES
• AGENTS USED IN THE PREVENTION AND TREATMENT OF OSTEOPOROSIS
• DRUGS USED IN THE TREATMENT OF IMMUNOLOGICAL AND INFLAMMATORY
NEUROMUSCULAR DISEASES
• DRUGS AND EXERCISE

SKELETAL MUSCLE RELAXANTS Depolarizing blockers—Succinylcholine,


Decamethonium
Skeletal muscle relaxants (SMR) are drugs that 2. Drugs acting centrally—Diazepam, Baclofen,
reduce the muscle tone either by acting Mephenesin, Tizanidine
peripherally at the neuromuscular junction 3. Drugs acting directly on the muscle—
(neuromuscular blockers) or centrally in the Dantrolene.
cerebrospinal axis or directly on the contractile
mechanism. They reduce the spasticity in a variety PERIPHERALLY ACTING SKELETAL
of neurological conditions and are also useful in MUSCLE RELAXANTS
surgeries. Neuromuscular Blockers (NMB)
Competitive Blockers
CLASSIFICATION
Curare was used by the South American Indians
1. Drugs acting peripherally at the NMJ as arrow poison for hunting wild animals because
Competitive blockers—d-Tubocurarine, curare paralyzed the animals. On extensive
Non-depolarizing Pancuronium, research, the active principle from curare,
agents Alcuronium, tubocurarine was identified. d-tubocurarine
Rocuronium, (d-Tc) is the dextrorotatory quaternary ammonium
Atracurium, alkaloid obtained from the plant Chondrodendron
Mivacurium, tomentosum and plants of the Strychnos species (l-
Doxacurium, tubocurarine is less potent). Several synthetic
Pipecurium, agents have been developed. All these are
Vecuronium, quaternary ammonium compounds, because of
Rapacuronium, which they are not well absorbed and are quickly
Gallamine excreted.
52 Pharmacology for Physiotherapy

Fig. 3.1: d-Tc molecules bind to nicotinic receptors and prevent the binding of ACh on these receptors

Mechanism of Action Pharmacokinetics


Non-depolarizing blockers bind to nicotinic d-Tc is a quaternary ammonium compound—
receptors on the motor end plate and block the hence not absorbed orally. It is given either IM or
actions of acetylcholine by competitive blockade IV.
(Fig. 3.1). These compounds slowly dissociate from
Adverse Reactions
the receptors and transmission is gradually
restored. Thus, their action is reversible. 1. Respiratory paralysis and prolonged apnea.
It should be treated with artificial ventilation.
Pharmacological Actions Neostigmine reverses the skeletal muscle
paralysis.
Skeletal muscle: On parenteral administration, 2. Hypotension due to ganglion blockade and
tubocurarine initially causes muscular weakness histamine release.
followed by flaccid paralysis. Small muscles of 3. Flushing and bronchospasm due to histamine
the eyes and fingers are the first to be affected, release by d-Tc; this is not seen with newer
followed by those of the limbs, neck and trunk. agents.
Later the intercostal muscles and finally the
diaphragm are paralyzed and respiration stops.
Consciousness is not affected throughout. TABLE 3.1: Duration of action of competitive
Recovery occurs in the reverse order, i.e. the neuromuscular blockers
diaphragm is the first to recover. The effect lasts Drug Duration (min)
for 30-60 minutes (Table 3.1).
Tubocurarine 35-60
Autonomic ganglia: In high doses tubocurarine Gallamine 35-60
can block autonomic ganglia and adrenal Pancuronium 35-80
medulla resulting in hypotension. Doxacurium 90-120
Atracurium 20-35
Histamine release: Tubocurarine can cause Vecuronium 20-35
histamine release the mast cells from leading to Mivacurium 12-18
bronchospasm, increased salivary, tracheo- Pipecuronium 80-100
bronchial and gastric secretions and this also Rapacuronium 15-30
Rocuronium 30-60
contributes to hypotension.
Musculoskeletal System 53

Synthetic Competitive Blockers depolarizes the skeletal muscle membrane. But,


Pancuronium, atracurium, vecuronium, galla- unlike ACh, it is destroyed very slowly by pseudo-
mine, doxacurium, mivacurium, pipecuronium, cholinesterase. Thus continued presence of the
rapacuronium, rocuronium (Table 3.1) are drug causes persistent depolarization resulting
synthetic competitive blockers. Tubocurarine, in flaccid paralysis. This is phase I block. In high
doxacurium and gallamine have a slow onset doses SCh produces a dual block—initial
(4-5 minutes) but long duration of action; depolarizing block followed by non-depolarizing
pancuronium, vecuronium, atracurium and block. The membrane gets slowly repolarized but
mivacurium have intermediate onset (2-4 minutes) cannot be depolarized again. The mechanism of
while rapacuronium and rocuronium have fast this phase II block is not clearly known.
onset of action (1-2 minutes). The synthetic
compounds have the following advantages over Pharmacological Actions
tubocurarine. Skeletal muscle On intravenous administration
• Less/no histamine release. onset of action is very rapid—within 1 minute.
• Do not block autonomic ganglia hence cause Initial transient muscular fasciculations and
less hypotension twitchings, mostly in the chest and abdominal
• Spontaneous recovery takes place with most regions are followed by skeletal muscle paralysis.
of these drugs. The fasciculations are maximum in 2 minutes and
• Some are more potent than tubocurarine. subside in 5 minutes. It is due to stimulation of
• Atracurium can be safely used in patients with the muscle fibers by a discharge of action
renal impairment because it is degraded by potentials in them. SCh is a short-acting muscle
plasma esterases and does not depend on the relaxant and the effect lasts for 5-10 minutes.
kidney for elimination. Hence it has to be given continuously as an
• The newer agents rapacuronium and infusion for longer effect.
rocuronium have a rapid onset of action.
Hence they can be used as alternatives to CVS Initially hypotension and bradycardia may
succinylcholine (SCh) for muscle relaxation result from stimulation of the nicotinic receptors
before endotracheal intubation. in vagal ganglia. This is followed by tachycardia
• Rocuronium does not cause hypotension, and hypertension due to stimulation of sympa-
tachycardia and is fast acting. thetic ganglia. Higher doses can cause cardiac
Tubocurarine causes histamine release, arrhythmias. SCh can also cause histamine
ganglion blockade (resulting in hypotension) and release if injected rapidly.
its muscle relaxant effect needs to be reversed with Other effects SCh can cause hyperkalemia as it
drugs. Hence tubocurarine is not used now. The triggers the release of K + from the cells by
synthetic compounds are preferred. increasing the permeability to cations. It can also
cause a transient increase in intraocular pressure.
Depolarizing Blockers
Succinylcholine (SCh, Suxamethonium) is a Pharmacokinetics
quaternary ammonium compound with the SCh is rapidly hydrolyzed by pseudocholi-
structure resembling two molecules of nesterases—hence it is short-acting (about 5
acetylcholine joined together. minutes). Some people (1 in 2000) have an abnor-
mal pseudocholinesterase, a hereditary defect;
Mechanism of Action
SCh does not get metabolized and even the usual
The neuromuscular effects of SCh are like those of dose results in prolonged apnea and paralysis
ACh. SCh reacts with nicotinic receptors and which may last for several hours. Artificial
54 Pharmacology for Physiotherapy

ventilation and fresh blood transfusion are endotracheal intubation. SMRs are also useful
needed. in laryngoscopy, bronchoscopy, eso-
phagoscopy and in orthopedic procedures like
Adverse Reactions reduction of fractures and dislocations.
2. In electroconvulsive therapy SMRs protect the
Postoperative muscle pain is a common adverse
patient from convulsions and trauma during
effect of SCh. It may be due to the damage to muscle
ECT.
fibers that occurs during initial fasciculations.
3. In spastic disorders SMRs are used to overcome
Hyperkalemia: This may result in cardiac arrest in the spasm of tetanus, athetosis and status
patients with burns and nerve injuries. epilepticus.
Cardiac arrhythmias: SCh can cause cardiac
CENTRALLY ACTING MUSCLE RELAXANTS
arrhythmias.
These drugs act on higher centers and cause
Malignant hyperthermia: It is a rare genetically
muscle relaxation without loss of consciousness.
determined condition where there is a sudden
They also have sedative properties.
increase in body temperature and severe muscle
spasm due to release of intracellular Ca++ from
Mechanism of Action
the sarcoplasmic reticulum. Certain drugs like
halothane, isoflurane and succinylcholine can Centrally acting muscle relaxants depress the
trigger this process which can be fatal. Combi- spinal polysynaptic reflexes. These reflexes
nation of halothane and SCh is the most common maintain the muscle tone. By depressing these
triggering factor. Intravenous dantrolene is life- spinal reflexes, centrally acting SMRs reduce the
saving in malignant hyperthermia. Oxygen muscle tone.
inhalation and immediate cooling of the body also
help. Diazepam has useful antispastic activity. It can
be used in relieving muscle spasm of almost any
Drug Interactions origin including local muscle trauma (see page
107).
1. General anesthetics augment the action of
SMRs. Baclofen is an analog of the inhibitory
2. Anticholinesterases like neostigmine—reverse neurotransmitter GABA. It is a GABA agonist—it
the action of competitive blockers. depresses the monosynaptic and polysynaptic
3. Aminoglycosides and calcium channel reflexes in the spinal cord. It relieves painful
blockers potentiate the action of SMRs. spasms including flexor and extensor spasms
and may also improve bladder and bowel
Uses of Peripherally Acting functions in patients with spinal lesions. Normal
Skeletal Muscle Relaxants tendon reflexes and voluntary muscle power are
not affected. Baclofen is generally given orally.
Inappropriate use of peripherally acting SMRs
Side effects are drowsiness, weakness and
can be fatal. Hence they should be given only by
ataxia. Baclofen should be gradually withdrawn
qualified anesthetists or adequately trained
after prolonged use.
doctors.
1. Adjuvant to anesthesia Adequate muscle Mephenesin is not preferred due to its side effects.
relaxation is essential during surgeries. A number of related drugs like carisoprodol,
Skeletal muscle relaxants are used as methocarbamol, chlorzoxazone are used in acute
adjuvants to general anesthesia. Short-acting muscle spasm caused by local trauma. All of them
SMRs like succinylcholine is used during also cause sedation.
Musculoskeletal System 55

Tizanidine is a congener of clonidine. It is a central hepatotoxicity. Liver function tests should be done
α2 agonist like clonidine. It increases presynaptic to look for hepatotoxicity.
inhibition of motor neurons and reduces muscle
spasms. Adverse effects include drowsiness, Uses
weakness, hypotension and dry mouth. Dantrolene is used in spastic disorders and
Tizanidine is used in the treatment of spasticity malignant hyperthermia (page 54, 99). Dantrolene
due to stroke, multiple sclerosis and amyotropic prevents the release of Ca++ from the sarcoplasmic
lateral sclerosis. reticulum and relieves muscle spasm in malig-
nant hyperthermia.
Other centrally acting spasmolytic agents
include riluzole, gabapentin and progabide.
Riluzole has both presynaptic and postsynaptic DRUGS USED IN THE TREATMENT OF
effects. It inhibits glutamate release in the CNS. It LOCAL MUSCLE SPASM
is well tolerated with minor adverse effects like Several agents are used for the treatment of
nausea and diarrhea. It is used to reduce spasticity local muscle spasms which may result from
in amyotropic lateral sclerosis. injury or strain. Cyclobenzaprine, metaxalone,
carisoprodol, chlorzoxazone, meprobamate, and
Uses of Centrally Acting Muscle Relaxants methocarbamol are some of them. They have the
following common features:
1. Musculoskeletal disorders like muscle strains,
• All these drugs act by depressing spinal
sprains, myalgias, torticollis, cervical root
polysynaptic reflexes.
syndromes, herniated disc syndromes, low
• Common adverse reactions include
backache, dislocations, arthritis, fibrositis and
drowsiness and dizziness.
bursitis all cause painful muscle spasms.
• Cyclobenzaprine has anticholinergic effects
Muscle relaxants are used with analgesics in
and can therefore cause dryness of mouth,
these. drowsiness and dizziness.
2. Spastic neurological disorders like cerebral palsy, • Many of them are available in combination
multiple sclerosis, poliomyelitis, hemiplegia with NSAIDs.
and quadriplegia are treated with diazepam • NSAIDs are equally or more effective in
or baclofen. relieving muscle spasms.
3. Tetanus Diazepam is given IV.
4. ECT Diazepam is given along with periphe- Botulinum toxin is produced by the anerobic
rally acting SMRs. bacterium Clostridium botulinum. The toxin
5. Orthopedic procedures like fracture reduction inhibits the release of acetylcholine at the
may be done after administering diazepam. cholinergic synapses resulting in flaccid paralysis
of skeletal muscles.
Botulinum toxin is useful (local injection) in
Directly Acting Muscle Relaxants
the treatment of dystonias, including sports or
Dantrolene directly affects the skeletal muscle writer’s cramps, muscle spasms, tremors, cerebral
contractile mechanism. It inhibits the muscle palsy and in rigidity seen in extrapyramidal
contraction by preventing the calcium release from disorders. It is commonly used to relieve
the sarcoplasmic reticulum. blepharospasm. Botulinum toxin is also gaining
Adverse effects include drowsiness, dizziness, popularity in cosmetic therapy to remove facial
fatigue, muscle weakness, diarrhoea and rarely lines by local injection.
56 Pharmacology for Physiotherapy

DRUGS USED IN OTHER • Tetany Hypocalcemia results in tetany


MUSCULOSKELETAL DISEASES and increased neuromuscular excitability.
Calcium salts should be given orally or in
1. Osteomalacia and rickets—Vitamin D more severe cases intravenously (see page 197).
deficiency results in osteomalacia. Vitamin D
(see page 197) is used for the prevention and
AGENTS USED IN THE PREVENTION AND
treatment of osteomalacia.
TREATMENT OF OSTEOPOROSIS
2. Paget’s disease—is due to abnormal
osteoclastic activity which results in altered Drugs may be used either to prevent bone
bone architecture. NSAIDs, calcitonin and resorption or promote bone formation or a
bisphosphonates are used. Analgesics reduce combination of both in the prevention and
pain while calcitonin and bisphosphonates treatment of osteoporosis. These agents reduce the
reduce bone resorption. risk of fractures in patients with osteoporosis.
3. Osteoarthritis—NSAIDs and glucocorticoids
Drugs that prevent bone resorption are:
are used (see page 58).
• Calcium (↑BMD)
4. Drugs used in spasticity—Spasticity is due
• Vitamin D (↑absorption of calcium)
to hypertonic contraction of the skeletal
• Estrogens (prevents osteoporosis)
muscles. Spasticity is seen in cerebral palsy,
• Raloxifene—selective estrogen receptor
stroke and multiple sclerosis. Drugs used in
modulator a SERM (↑BMD)
spasticity include baclofen, diazepam and
• Calcitonin (prevents bone resorption, ↑BMD*)
dantrolene.
• Bisphosphonates (↓bone resorption, ↑BMD*)
5. Other muscular disorders—Some muscular
disorders like congenital myotonia, Lambert- *BMD (Bone mineral density)
Eaton syndrome, McCardle syndrome and Drugs that promote bone formation
tetany are due to impaired neuromuscular • Fluoride (in small doses ↑osteoblastic activity
transmission. →↑bone mass — but generally not preferred)
• Congenital myotonia is characterized by • Testosterone (in hypogonadal men)
violent muscle spasm, which results from • Anabolic steroids (in postmenopausal
irritability of the muscle fiber membrane. women)
Membrane stabilizing agents like phenytoin • PTH analogs are being tried.
and quinine are found to be useful in this
condition. Bisphosphonates are used to inhibit bone
• Lambert-Eaton syndrome is characterized by resorption (see page 199).
muscular weakness and easy fatiguability. It
is associated with some cancers like lung DRUGS USED IN THE TREATMENT OF
cancer. Physical exercise and calcium are IMMUNOLOGICAL AND INFLAMMATORY
found to be useful in improving muscle power. NEUROMUSCULAR DISEASES
• McCardle syndrome in some people, glycogen
1. Idiopathic Inflammatory Myopathies
cannot be converted to glucose in the muscle
due to an enzyme deficiency. Hence after some Inflammatory myopathies (IM) are inflammatory
exercise such persons develop severe muscle disorders of the skeletal muscle characterized by
weakness, stiffness and pain. It can be treated symmetric muscle weakness of proximal muscles
with large doses of glucose or by adrenaline of the limbs and rarely neck and pharyngeal
injection, which releases glucose from the liver. muscles. These could be accompanied by
Musculoskeletal System 57

polymyositis and dermatomyositis. The etiology active exercises should be encouraged. Training
is not known but toxins and infections may be the use of inspiratory muscles can be of benefit for
involved. Inclusion body myositis is a type of patients with inspiratory muscle weakness.
inflammatory myopathy with frequent episodes Other facilitatory measures like grip bars,
of distal muscle weakness. In biopsy of the raised toilet seats, walking aids can also be of help.
muscle, unique inclusions are seen in the muscle.
Treatment is to suppress inflammation. 2. Demyelinating Disease
Drugs used are:
Demyelinating disease could be acute inflam-
• Glucocorticoids
matory demyelinating polyneuropathy [Guillian
• Immunosuppressive agents
Barre (GB) Syndrome] or Chronic Inflammatory
• Hormone replacement therapy in postmeno-
Demyelinating disease.
pausal women
Acute demyelinating disease is a motor
• Physiotherapy.
neuropathy which develops over 1-4 weeks after
Glucocorticoids are the first line drugs because respiratory infection or diarrhea. Microorganisms
they suppress inflammation. Prednisolone is commonly involved are Campylobacter jejunum and
started in the dose of 1-2 mg/kg/day in 2-3 cytomegalovirus. Cell mediated immune response
divided doses. A gradual improvement in grip is directed at the myelin protein of the spinal roots
strength may be noticed. However, this condition and cranial nerves. This results in the release of
is slow to respond and some may take as long as inflammatory mediators viz cytokines which
3 months. Once the response is established, a block nerve conduction and complement mediated
lower maintenance dose is effective to prevent destruction of the myelin sheath and associated
axon.
steroid – induced osteoporosis. Daily dietary
Clinical features include prodromal symptoms
supplements of calcium and vitamin D should be
with headache, vomiting, fever, pain in the back
given, guided by screening of bone mineral
and limbs. After a few days, the stage of paralysis
density.
begins with distal paresthias, rapidly ascending
Immunosuppressive agents – Patients who do muscle weakness, facial and bulbar weakness,
not respond to steroids or poorly tolerate steroids (ophthalmoplegia) and in some patients weakness
may be put on immunosuppressive agents. of the respiratory muscles. Involvement of head
Azathioprine, methotrexate, mercaptopurine, and neck muscles causes dysphagia. Sensory
cyclophosphamide and cyclosporin are all found symptoms with pain, tingling and numbness of
to be effective. Immunoglobulins given intra- the limbs, tenderness in the muscles, cranial nerve
venously appear to be useful in patients not paralysis, depressed or loss of reflexes and
responding to the above measures. sometimes urinary retention are also seen.
Nerve conduction studies done in the first few
Hormone Replacement Therapy – Postmeno- days show prolonged distal motor latencies in
pausal women may need hormone replacement the limbs, prolonged F wave latencies and action
therapy (see page 191). potential amplitudes are small. Later stages show
slowing of nerve conduction which indicates
Physiotherapy plays a vital role in the treatment. demyelination.
Patients should be advised bed rest during periods By about 3 weeks, quadriparesis and respi-
of active inflammation. A daily exercise program ratory paralysis may develop. However majority
should be designed to include passive stretching. recover with minor residual neurological
This avoids muscle contractures. Reasonable symptoms.
58 Pharmacology for Physiotherapy

Treatment of articular cartilage and simultaneous


• Analgesics like paracetamol or ibuprofen and proliferation of new bone. Pain is due to low grade
hot packs for pain. inflammation of the joints resulting from abnormal
• Regular respiratory monitoring-assisted wearing out of the cartilage and a decrease in
respiration if required. synovial fluid. The word osteoarthritis is derived
• Glucocorticoids may be tried in patients with from the Greek words ‘osteo’ meaning ‘of the bone’
severe weakness or bulbar involvement – but and ‘arthritis’ meaning joint. However,
not shown to be useful by studies. inflammatory changes in the synovium are
• Physiotherapy-early active and passive usually minor. Though both men and women are
movements. affected, OA is more severe in older women.
• In more severe cases plasma exchange may be Osteoarthritis with no known etiology is called
needed. primary and when the cause for degenerative joint
• Intravenous immunoglobulin therapy may be changes can be identified, it is known as
given to shorten the course of illness. secondary osteoarthritis. Genetic predisposition
is known particularly in primary osteoarthritis.
Acute axonal polyneuropathy – is an axonal
variant of GB syndrome with antibodies to Symptoms
peripheral nerve gangliosides. It could also result
from exposure to certain drugs and toxins. Pain in the joints is the most common symptom.
The joints affected may be those of the spine, hip,
Miller-Fisher syndrome – is a variant of Guillian knees and hand – usually only one of these joints
Barre syndrome with ataxia, areflexia and is involved. Onset of symptoms is gradual with
ophthalmoplegia. sharp pain with the use of the joint. As the disease
Chronic inflammatory demyelinating poly- progresses, the joint movement becomes restricted,
neuropathy – develops over months (usually two joints become stiff and the associated muscles go
months) or years. It could be due to an aberrant into spasm. There may be effusions into the joint,
immune response leading to chronic GB syndrome the surrounding muscles atrophy and the related
or hereditary type. Several abnormal gene types ligaments may become lax. This associated muscle
have been shown to result in hereditary demyeli- wasting is an important indicator of the duration
nating peripheral neuropathies (known as Charcot and progress of the disease. ‘Crepitus’ may be felt
– Marie Tooth (CMT) disease). This condition is or heard when the joint is touched or moved.
characterized by distal wasting, i.e. the legs
resemble an inverted champagne bottle or the legs Treatment
of a ‘stork’. The pathological changes in the joint are largely
Chronic inflammatory demyelinating peripheral irreversible. Hence the aim of treatment is to reduce
neuropathy manifests as progressive generalized the pain and improve joint function. Analgesics
neuropathy with predominantly motor symptoms. like paracetamol help most patients. If the pain is
Treatment is with immunosuppressants, plasma severe, antiinflammatory doses of NSAIDs like
exchange and immunoglobulins. ibuprofen, diclofenac or piroxicam may be needed.
Chronic axonal polyneuropathy may be However, these are not to be used for long periods
caused by drugs and toxins. because of the risk of gastric ulceration, renal
impairment and fluid retention.
3. Osteoarthritis
Local – Intra-articular or periarticular injection
Osteoarthritis (OA, osteoarthrosis) is a degene- of a glucocorticoid can relieve pain particularly
rative joint disease characterized by degeneration in the knee. Intra-articular injection of hyaluronan
Musculoskeletal System 59

or a local anesthetic like lignocaine can also afford (like knee braces when knee is affected) — all these
temporary symptomatic relief. Local application help in reducing morbidity to a large extent.
of a gel of a NSAID like diclofenac or ibuprofen
Surgery – If medical line of treatment is ineffective,
gel may be helpful and safe in most patients.
surgery to remove the damaged fragments or in
Though drugs like tramadol and opioids may
some cases joint replacement may be needed.
relieve pain in severe OA, they should be avoided
for the risk of dependence. Their use must be
4. Myasthenia Gravis (See page 37)
restricted only to patients with severely painful
joints and debilitating disease. 5. Systemic Lupus Erythematosus

Other Drug Supplements Systemic Lupus Erythematosus (SLE) is a chronic


autoimmune disease involving connective tissue
Several drugs have been tried : characterized by the presence of antibodies
1. Glucosaminoglycan, pentosan polyphos- leading to widespread tissue damage. Systemic
phate and hyaluronan - are shown to have a Lupus Erythematosus (SLE) is particularly
chondro - protective effect in the animals and common among Americans of African origin with
in “in vitro” experiments. Glucosamine is the a higher incidence in women (9:1).
precursor of glucosaminoglycan and The immune system regulation is impaired and
chondroitin is the most abundant gluco- the autoantibodies attack the host cells and tissue
saminoglycan in the cartilage. They help in resulting in inflammation and tissue damage.
the process of cartilage formation and repair. Though not clear, the etiology of immunologically
Dietary supplements of glucosamine and mediated tissue damage could be multifactorial
chondroitin sulphate have been tried in including genetic, environmental (like Sunrays)
patients with OA. They are thought to improve hormones and drugs. SLE is a multi-system
the symptoms and delay the disease connective tissue disease affecting joints, skin,
progression. However, clinical trials have not lungs, liver, heart, kidneys, blood vessels and
shown the combination of glucosamine and nervous system.
chondroitin to be anyway better than just Mucocutaneous manifestations include skin
placebo. rashes (classic malar rash or butterfly rash),
2. Omega – 3 – fatty acids – dietary supple- alopecia, livido reticularis, ulcers in the nose,
ments of omega – 3 – fatty acids from certain mouth and vagina. Most patients experience joints
marine fish have been tried in order to subdue pain with chronic inflammatory arthritis involving
the inflammatory process. small joints of the hand and wrist though other
3. Antioxidants – dietary supplements contain- joints may also be affected. However joint
ing Vitamin E are given for their antioxidant destruction is milder when compared to other
properties. types of arthritis. Migratory arthalgia with mild
4. Vitamin D supplementation is recommended morning stiffness and tenosynovitis may be
since many patients with OA have Vitamin D misdiagnosed as rheumatoid arthritis. However,
deficiency. unlike rheumatoid arthritis, joint deformities are
rare in SLE.
Non-Pharmacological Measures
Other features include anemia, lupus
Lifestyle modification to bring about a reduction glomerulonephritis with hematuria and
in weight, regular exercises and rest to the affected proteinuria; cardiorespiratory manifestations
joints, appropriate physiotherapy, relaxation resulting from inflammation of various parts
techniques, mechanical devices to support the joint leading to pericarditis, endocarditis, myocarditis,
60 Pharmacology for Physiotherapy

atherosclerosis, fibrosing alveolitis, lupus common musculoskeletal manifestations. It may


pneumonitis, pulmonary hypertension and be associated with pulmonary, gastrointestinal,
progressive dyspnea. renal and other complications.
SLE can also manifest with esophagitis with Decreased gastric motility, gastric ulcers,
pain during swallowing, malabsorption, lupus upper gastrointestinal bleeding, scleroderma renal
gastroenteritis, pancreatitis, hepatitis, cystitis and crisis with malignant hypertension, high renin
systemic vasculitis. levels, hematuria and proteinuria, pulmonary
manifestations with pulmonary hypertension and
Treatment in later stages pulmonary hemorrhage and
Most patients have mild disease and would pneumothorax can be seen.
respond to NSAIDs. Hydroxychloroquine,
glucocorticoids, immunosuppressants like metho- Treatment
trexate, azathioprine and cyclophosphamide may Depending on the organ/system involved,
be needed for more severe cases. treatment is initiated to control the symptoms.
Patients must be advised to avoid exposure to • Raynaud’s phenomenon is treated with
direct sun light, use sun protective clothing and vasodilators (See page 85). Joints pain and
sun block lotions containing sun protection factor myositis may be alleviated with NSAIDs.
25 – 50. Weight reduction is recommended in • Infected ulcers need antibiotics. Poor
overweight subjects. Patients who had earlier penetration of drugs through skin lesions
episodes of thrombosis should be put on life long makes it necessary for drugs to be given in
warfarin. higher doses and for longer periods. Patients
with severe ischemia and ulceration of the
6. Systemic Sclerosis (Scleroderma) digits may be benefited by prostaglandin
Systemic sclerosis is a chronic connective tissue analogs epoprostenol or iloprost.
disorder affecting the skin, internal organs and • Alveolitis, myositis and severe manifestations
vasculature with excessive deposits of collagen requiring immunosuppression may be treated
in the skin or other organs. It was earlier called with methotrexate, cyclosporine, cyclo-
scleroderma. The characteristic clinical features phosphamide or glucocorticoids. Scleroderma
include sclerodactyly with Raynaud’s pheno- renal crisis with acute renal failure and severe
menon. It is of two types – hypertension can be given an ACE inhibitor
1. Systemic type – the diffuse cutaneous systemic like enalapril.
• Maintenance of core body temperature is
sclerosis which is the severe form.
important to avoid Raynaud’s phenomenon.
2. Localized type – limited cutaneous systemic
sclerosis which is the localized type of the
disease. DRUGS AND EXERCISE
In the systemic form, most patients have
vascular symptoms – Raynaud’s phenomenon Effect of Exercise on the
can lead to painful ulcers on the fingers and toes Cardiorespiratory Function
known as digital ulcers. Calcinosis near the During exercise, oxygen consumption of the
elbows, knees and joints may restrict joint mobility skeletal muscle increases. Hence it requires more
particularly of the small joints. Arthralgia, oxygen supply. In order to meet this increased
morning stiffness, weakness and discomfort in demand, various changes take place in the
the muscles and flexor tenosynovitis are the cardiovascular and respiratory system. The heart
Musculoskeletal System 61

rate, force of contraction and thereby the cardiac sperm production and decreased fertility. Some
output increase; the respiratory rate, depth and cause gynecomastia, hepatotoxicity, an increase
thereby tidal volume increase. The blood vessels in serum cholesterol and psychological disorders.
of skeletal muscles are dilated which increases Androgens cause virilization in women.
blood supply as well as washes away the
metabolites formed. Bronchodilators Methylxanthines are broncho-
dilators (see page 156). The main compounds are
Drugs that Influence Exercise theophylline and caffeine. They are present in
coffee, tea and cocoa. Methylxanthines are CNS
Drugs like amphetamines, anabolic steroids, stimulants. They reduce fatigue, improve alertness
methylxanthines and cocaine improve exercise and physical performance. They are mild
performance while β-blockers decrease exercise psychomotor stimulants. They also bring about
tolerance. bronchodilation and cardiac stimulation which
add to their beneficial effects on exercise.
Amphetamine improves both mental and
physical performance (see page 45). It improves β-adrenergic agonists Adrenaline and selective
alertness and performance even in highly tiring β2 -agonists like salbutamol, terbutaline and
conditions. It postpones fatigue and brings about salmeterol are bronchodilators. Though their
a significant improvement in athletic performance bronchodilator effect may help better oxygenation
in sportsmen. Amphetamines are banned in during respiration, these drugs cause skeletal
sports. Amphetamine is also a drug of muscle tremors. The exact mechanism is not
dependence. known but they may act through β-receptors to
increase the discharge of muscle spindles. Clen-
Cocaine Like amphetamine, cocaine is a buterol is a β2-agonist used by sportsmen for its
psychomotor stimulant. It produces euphoria and anabolic effects.
increased motor activity. It inhibits the uptake of
catecholamines in the nerve terminals resulting Drugs that Decrease Exercise Tolerance
in increased sympathetic activity. Cocaine is a
drug of dependence and its long-term use results β-adrenergic blockers prevent the exercise induced
in various adverse effects. increase in heart rate and force of contraction. β-
blockers reduce the work capacity and impair
Anabolic steroids are androgens with selective exercise performance. The increase in blood flow
anabolic effects and lesser degree of androgenic to the skeletal muscle during exercise is reduced
effects. Anabolic steroids improve muscle strength. by β2 blockade. They also prevent the rise in blood
They are misused by athletes and are now banned glucose level brought about by catecholamines.
in them. But androgens can cause various side They may also increase airway resistance. By all
effects if used over a long-time including reduced these effects, β-blockers reduce exercise tolerance.
Drugs Acting
on the Kidney

• DIURETICS
• ANTIDIURETICS

DIURETICS AND ANTIDIURETIC DRUGS electrically neutral Na+ and Cl– transporter. This
transporter is blocked by thiazide diuretics.
Kidney, the excretory organ of our body serves
the important functions of excretion of waste
products, regulation of fluid volume and
electrolyte content of the extracellular fluid.

PHYSIOLOGY OF URINE FORMATION


Normally about 180 liters of fluid is filtered
everyday, of which 99% gets reabsorbed and about
1.5 liters of urine is formed. For simplification, the
nephron can be divided into four sites (Fig. 4.1).
Proximal tubule: Sodium bicarbonate, sodium
chloride, amino acids and glucose are reabsorbed
in the proximal tubule along with water by specific
transport mechanisms. Osmotic diuretics act here.
Henle’s loop: In the thin descending limb of the
loop of Henle, water is reabsorbed by osmotic
forces. Hence osmotic diuretics are acting here too.
The thick ascending limb actively reabsorbs
sodium chloride from the lumen (but is
impermeable to water) by Na+ /K+/2Cl – co- Fig. 4.1: Simplified diagram of a nephron showing
transporter. ‘Loop diuretics’ selectively block this sites of action of diuretics (1) Proximal tubule—
transporter. osmotic diuretics, mannitol, (2) Ascending limb of
Henle’s loop—loop diuretics, (3) Early distal tubule—
Distal convoluted tubule: In the early distal thiazides, (4) Distal tubule and collecting duct—K +
tubule, sodium chloride is reabsorbed by an sparing diuretics
Drugs Acting on the Kidney 63

Collecting tubule: In the late distal tubule and loop. They inhibit the Na+, K+, 2Cl–, co-transport
collecting duct, NaCl– is actively reabsorbed, in mechanism. As a large amount of NaCl – is
exchange for K+ and H+ to maintain the ionic absorbed in this segment, they are highly
balance-regulated by aldosterone. Absorption of efficacious. Diuretic response increases with dose
water is under the control of antidiuretic hormone and higher doses can cause dehydration (high
(ADH). ceiling of effect).
Loop diuretics also enhance the excretion of
DIURETICS K+, Ca++ and Mg++ (But Ca++ is reabsorbed in the
distal tubule—hence no hypocalcemia). They
Diuretic is an agent which increases urine and increase reabsorption of uric acid in the proximal
solute excretion. tubule. They also alter renal hemodynamics to
reduce fluid and electrolyte reabsorption in the
CLASSIFICATION proximal tubule.
1. High efficacy diuretics Furosemide, Frusemide (Furosemide) is a sulfonamide
(Loop diuretics) Bumetanide, derivative. It is the most popular loop diuretic.
Piretanide, Given intravenously it acts in 2-5 minutes, while
Ethacrynic acid, following oral use, it takes 20-40 minutes;
Torsemide duration of action is 3-6 hours.
2. Moderate efficacy diuretics IV furosemide relieves pulmonary congestion
Thiazides Benzothiadiazines and reduces left ventricular filling pressure by
like Chlorothiazide, causing venodilation in congestive heart failure
Hydro- and pulmonary edema.
chlorothiazide,
Pharmacokinetics Furosemide is rapidly absorbed
Polythiazide,
orally, highly bound to plasma proteins and
Bendro-
excreted by kidneys.
flumethiazide
Thiazide related agents Chlorthalidone, Bumetanide is a sulfonamide like frusemide but
Clopamide, is 40 times more potent. Bioavailability is 80% and
Indapamide, is better tolerated.
Metolazone,
Xipamide Ethacrynic acid is more likely to cause adverse
3. Low efficacy diuretics effects and hence is not commonly used.
Potassium sparing Triamterene,
Adverse Effects of Loop Diuretics
diuretics Amiloride,
1. Hypokalemia and metabolic alkalosis is dose
Spironolactone
dependent and can be corrected by K +
Carbonic anhydrase Acetazolamide
replacement and correction of hypovolemia.
inhibitors
2. Ototoxicity Loop diuretics cause hearing loss
Osmotic diuretics Mannitol, Urea,
by a toxic effect on the hair cells in the internal
Glycerol
ear—more common with ethacrynic acid. It is
Methylxanthines Theophylline
dose-related and generally reversible.
Concurrent use of other ototoxic drugs should
High efficacy or Loop Diuretics
be avoided.
Loop diuretics act by inhibiting NaCl– reabsorp- 3. Hyperuricemia may precipitate acute attacks of
tion in the thick ascending limb of the Henle’s gout.
64 Pharmacology for Physiotherapy

4. Hypocalcemia and hypomagnesemia After Pharmacokinetics


prolonged use this may result in osteoporosis.
Thiazides are well-absorbed orally and are rapid
5. Hyponatremia, dehydration and hypovolemia
acting. Duration varies from 6-48 hours. They are
should be treated with saline infusion.
excreted by the kidney.
6. Hyperglycemia and hyperlipidemia are mild in
therapeutic doses.
Adverse Effects
7. GIT disturbances like nausea, vomiting and
diarrhea are common with ethacrynic acid. Hypokalemia, metabolic alkalosis, hyperuricemia,
8. Allergic reactions like skin rashes are more hypovolemia, dehydration, hyponatremia,
common with sulfonamide derivatives. hypercalcemia, and hyperlipidemia are similar
to that seen with loop diuretics. Hyperglycemia
Uses induced by thiazides may precipitate diabetes
1. Edema Frusemide is highly effective for the mellitus probably by inhibition of insulin
relief of edema of all origins like cardiac, secretion. It is more common when long-acting
hepatic and renal edema. thiazides are used for a long time. Weakness,
• Acute pulmonary edema is relieved by IV fatigue and allergic reactions like rashes and
frusemide due to its immediate vasodilator photosensitivity can be seen.
effect and then by diuretic action.
• In cerebral edema, frusemide is used as an Uses
alternative to osmotic diuretics. 1. Hypertension Thiazides are the first line drugs
2. Forced diuresis In poisoning due to drugs like (see page 78).
barbiturates and salicylates, frusemide is used 2. Congestive heart failure Thiazides are the first
with IV fluids. line drugs in the management of edema due to
3. Hypertension with renal impairment may be mild to moderate CHF (see page 70).
treated with loop diuretics. 3. Edema Thiazides may be tried in hepatic or
4. Hypercalcemia and hyperkalemia Loop diuretics renal edema.
enhance the excretion of Ca++ and K+. But Na+ 4. Renal stones Hypercalciuria with renal stones
and Cl – should be replaced to avoid can be treated with thiazides which reduce
hyponatremia and hypochloremia. calcium excretion.
5. Diabetes insipidus Thiazides reduce plasma
Thiazides and Thiazide-like Diuretics volume and GFR and benefit such patients.
Chlorothiazide was the first thiazide to be
synthesized. All thiazides have a sulfonamide Potassium Sparing Diuretics
group. Spironolactone is an aldosterone antagonist. It
binds aldosterone receptors on distal tubule and
Actions collecting duct and competitively inhibits the
This group of drugs block Na+/Cl– co-transport action of aldosterone (aldosterone promotes Na+
in the early distal tubule (site 3). They also inhibit reabsorption and K+ secretion). As major amount
carbonic anhydrase activity. Thiazides also of Na+ is already reabsorbed in the proximal parts,
enhance excretion of Mg+ and K+ (in the distal spironolactone has low efficacy. Spironolactone
segments, Na+ in the lumen is exchanged for K+ also reduces K+ loss due to other diuretics.
which is then excreted). But they inhibit urinary It enhances the excretion of calcium by a direct
excretion of Ca++ and uric acid. action on the renal tubules.
Drugs Acting on the Kidney 65

Adverse effects include gynecomastia, Carbonic Anhydrase Inhibitors


drowsiness, hyperkalemia especially in renal
Carbonic anhydrase is an enzyme that catalyses
insufficiency; metabolic acidosis and skin rashes.
the formation of carbonic acid which spon-
Amiloride and triamterene are directly acting taneously ionizes to H+ and HCO3–. This HCO3–
agents which enhance Na+ excretion and reduce combines with Na+ and is reabsorbed.
K+ loss by acting on ion channels in the distal H2O + CO2 H2CO3
tubule and collecting duct. They block the Na+
H2CO3 H+ + HCO3–
transport through ion-channels in the luminal
membrane. Since K+ secretion is dependent on Na+ Carbonic anhydrase is present in the nephron,
entry, these drugs reduce K+ excretion. eyes, gastric mucosa, pancreas and other sites.
Adverse effects are gastrointestinal disturbances, Acetazolamide, inhibits the enzyme carbonic
hyperkalemia and metabolic acidosis. anhydrase and enhances the excretion of sodium,
potassium, bicarbonate and water. The loss of
Uses of potassium sparing diuretics
bicarbonate leads to metabolic acidosis.
1. With thiazides and loop diuretics to prevent
potassium loss. Other Actions
2. Edema In cirrhosis and renal edema where
aldosterone levels may be high. 1. Eye Bicarbonate and sodium ions are required
3. Hypertension Along with thiazides to avoid for the production of aqueous humor.
hypokalemia and for additive effect. Carbonic anhydrase inhibition results in
4. Primary or secondary aldosteronism Spirono- decreased formation of aqueous humor and
lactone is used. thereby reduces intraocular pressure.
2. Brain Bicarbonate is secreted into CSF and
Drug Interactions with Diuretics carbonic anhydrase inhibition reduces the
formation of CSF.
1. Frusemide and ethacrynic acid are highly
protein bound and may compete with drugs Adverse Effects
like warfarin and clofibrate for protein binding
sites. Metabolic acidosis, renal stones, hypokalemia,
2. Other ototoxic drugs like aminoglycosides drowsiness and allergic reactions can occur.
should not be used with loop diuretics to avoid
enhanced toxicity. Uses
3. Hypokalemia induced by diuretics enhance 1. Glaucoma—(see page 37)
digitalis toxicity. 2. To alkalinize the urine—as required in
4. NSAIDs blunt the effect of diuretics as they overdosage of acidic drugs.
cause salt and water retention to avoid 3. Metabolic alkalosis—acetazolamide enhances
enhanced toxicity. HCO–3 excretion.
5. Diuretics enhance lithium toxicity by reducing 4. Mountain sickness—In mountain climbers
renal excretion of lithium. who rapidly ascend great heights, severe
6. Other drugs that cause hyperkalemia (ACE pulmonary edema or cerebral edema may
inhibitors) and oral K + supplements occur. Acetazolamide may help by reducing
should be avoided with K+ sparing diuretics CSF formation.
because, together they can cause severe hyper- 5. Epilepsy—acetazolamide is used as an
kalemia. adjuvant as it increases the seizure threshold.
66 Pharmacology for Physiotherapy

Osmotic Diuretics synthesized in the supraoptic and para-


ventricular nuclei of the hypothalamus,
Mannitol is a pharmacologically inert substance.
transported along the hypothalamo-hypophyseal
When given IV (orally not absorbed), mannitol
tract to the posterior pituitary and it is stored there.
gets filtered by the glomerulus but not reabsorbed.
ADH is released in response to two stimuli—
It causes water to be retained in the kidney by
dehydration and rise in plasma osmolarity.
osmotic effect resulting in water diuresis. There is
also some loss of Na+.
Adverse effects are dehydration, ECF volume Actions
expansion, headache and allergic reactions. ADH acts on vasopressin receptors and enhances
water reabsorption, causes vasoconstriction and
Uses raises BP. It also acts on other smooth muscles to
1. To maintain urine volume in conditions like increase peristalsis in the gut and contracts the
shock. uterus.
2. To reduce intracranial and intraocular It is given parenterally as injection or as
pressure—following head injury and glau- intranasal spray.
coma respectively.
Adverse Effects
Glycerol is effective orally—reduces intraocular
and intracranial pressure. When used intranasally ADH can cause nasal
irritation, allergy, rhinitis and atrophy of the nasal
Methylxanthines like theophylline have mild
mucosa. Other effects include nausea, abdominal
diuretic effect.
cramps and backache (due to contractions of the
uterus).
NEWER DRUGS
Vasopressin antagonists – conivaptan, tolvaptan Uses
and lixivaptan inhibit the effects of ADH in the
collecting tubule to cause diuresis. They are useful 1. Diabetes insipidus of pituitary origin.
in hyponatremia and in patients with 2. Bleeding esophageal varices—ADH constricts
inappropriate secretion of ADH. mesenteric blood vessels and may help.
3. Before abdominal radiography—expels gases
from the bowel.
ANTIDIURETICS
4. Hemophilia—may release factor VIII.
Antidiuretics are drugs that reduce urine volume.
Thiazides Paradoxically thiazides reduce urine
These include
volume in diabetes insipidus of both pituitary and
1. Antidiuretic hormone (Vasopressin)
renal origin by an unknown mechanism.
2. Thiazide diuretics
3. Miscellaneous Chlorpropamide an oral hypoglycemic, sensi-
— Chlorpropamide tizes the kidney to ADH action.
— Carbamazepine.
Antidiuretic hormone (ADH) is secreted by Carbamazepine an antiepileptic, stimulates ADH
the posterior pituitary along with oxytocin. It is secretion.
Cardiovascular
System and Blood

• CARDIAC GLYCOSIDES AND TREATMENT OF CARDIAC FAILURE


• ANTIARRHYTHMIC DRUGS
• DRUGS USED IN THE TREATMENT OF ANGINA PECTORIS
• ANTIHYPERTENSIVE DRUGS
• PHARMACOTHERAPY OF SHOCK
• PLASMA EXPANDERS
• VASOACTIVE DRUGS
• CEREBRAL ISCHEMIA
• DRUGS USED IN THE TREATMENT OF PERIPHERAL VASCULAR DISEASES
• HYPOLIPIDEMIC DRUGS
• DRUGS USED IN THE DISORDERS OF COAGULATION
• HEMATINICS

CARDIAC GLYCOSIDES AND TREATMENT adequately contract and pump the blood out of
OF CARDIAC FAILURE the heart.
Cardiac action potential When a stimulus
The cardiac muscle is a specialized tissue with reaches the cardiac cell, specific ions move into
unique properties like excitability, contractility and out of the cell eliciting an action potential.
and automaticity. The myocardium has two types Such movement of ions across the cardiac cell may
of cells—the contracting cells and the conducting be divided into phases (Fig. 5.1).
cells. The contracting cells participate in the
Phase 0 is rapid depolarization of the cell
pumping action of the heart. SA node, AV node
membrane during which there is fast entry of
and His-Purkinje system comprise the
sodium ions into the cell through the sodium
conducting tissue of the heart. Parts of the
channels. This is followed by repolarization.
conducting tissue have the characteristic property
of automaticity. Automaticity is the ability of the Phase 1 is a short, initial, rapid repolarization
cell to generate electrical impulses spontaneously. due to efflux of potassium ions.
Normally the SA node acts as the pace maker. Phase 2 is a prolonged plateau phase due to slow
Excitability is the ability of the cell to undergo entry of calcium ions into the cell through the
depolarization in response to a stimulus. calcium channels. Cardiac cell differs from other
Contractility is the ability of the myocardium to cells in having this phase of action potential.
68 Pharmacology for Physiotherapy

is reduced and the cardiac output decreases. The


ventricles are not completely emptied resulting in
increased venous pressure in the pulmonary and
systemic circulation. This causes pulmonary
edema, dyspnea, liver enlargement and peripheral
edema. As a compensatory mechanism, there is
stimulation of the sympathetic system and renin
angiotensin system which help in maintaining
the cardiac output. The myocardium also
undergoes structural alterations like ventricular
hypertrophy and remodelling to adapt itself to
the stressful situation. These compensatory
changes maintain the cardiac output for
Fig. 5.1: Cardiac action potential phases 0-4: Phase sometime.
0—indicates rapid depolarization, Phases 1-3— Low output failure could result from ischemic
indicate repolarization, Phase 4—gradual depolari- heart disease, hypertension, valvular and
zation during diastole congenital heart diseases. High output failure
results from anemia, thyrotoxicosis, beriberi and
certain congenital heart diseases.
Phase 3 is a second period of rapid repolarization The drugs used in CCF include diuretics,
with potassium ions moving out of the cell. vasodilators and cardiac glycosides. The
Phase 4 is the resting phase during which pharmacology of cardiac glycosides has been
potassium ions return into the cell while sodium discussed first, followed by the role of other drugs
and calcium ions move out of it and the resting in CCF.
membrane potential is restored.
During phases 1 and 2, the cell does not CARDIAC GLYCOSIDES
depolarize in response to another impulse, i.e. it Cardiac glycosides are obtained from the plants
is in absolute refractory period. But during phases of the foxglove family. William Withering, an
3 and 4, the cell is in relative refractory period and English physician first described the clinical
may depolarize in response to a powerful impulse. effects of digitalis in CCF in 1785.
The cardiac output is determined by heart rate
and stroke volume. The stroke volume in turn Source Digitoxin is obtained from the leaves of
depends on the preload, afterload and Digitalis purpurea. From the leaves of Digitalis
contractility. Preload is the load on the heart due lanata, digitoxin and digoxin are derived and the
to the volume of blood reaching the left ventricle. seeds of Strophanthus gratus contain ouabain. They
It depends on the venous return. Afterload is the are all called cardiac glycosides but digoxin is the
resistance to the left ventricular ejection, i.e. the most commonly used of them because of its
total peripheral resistance. favorable pharmacokinetic properties. The word
digitalis is used to mean cardiac glycosides.
Congestive cardiac failure (CCF) is one of the
common causes of morbidity and mortality. In Chemistry The glycosides consist of an aglycon
congestive cardiac failure, the heart is unable to attached to sugars. The aglycon has pharmaco-
provide adequate blood supply to meet the body’s dynamic activity while sugars influence
oxygen demand. The pumping ability of the heart pharmacokinetic properties.
Cardiovascular System and Blood 69

Pharmacological Actions results in an increase in intracellular Na+ and Ca++.


Thus more calcium is available for contraction,
1. Cardiac actions: Digoxin is a cardiotonic
resulting in increased force and velocity of
drug. Cardiac glycosides increase the force of
contraction.
contraction of the heart—the stroke volume
increases and thereby the cardiac output. The Pharmacokinetics: Digoxin is well-absorbed
systole is shortened and the diastole is (Table 5.1). Presence of food in the stomach delays
prolonged which allows more rest to the heart. absorption. Bioavailability varies with different
The ventricles are more completely emptied manufacturers and because the safety margin is
because of more forceful contractions. Thus low, in any given patient, the preparations from
digoxin is a positive inotropic drug. the same manufacturer should be used.
The heart rate is reduced due to: Glycosides are cumulative drugs.
a. Increased vagal tone Adverse effects: Cardiac glycosides have a low
b. Decreased sympathetic overactivity due to safety margin and adverse effects are common.
improved circulation
Extracardiac: Anorexia, nausea, vomiting and
c. By a direct action on SA and AV nodes.
diarrhea are the first symptoms to appear.
Digitalis also produces the characteristic
Weakness, confusion, hallucinations, blurred
ECG changes. vision and gynecomastia can occur.
Blood pressure No significant effects in CCF Cardiac toxicity: Arrhythmias of any type
patients. including extrasystoles, bradycardia, pulses
Coronary circulation improves due to increased bigeminy and AV block, ventricular tachycardia
cardiac output and prolonged diastole during and fibrillation can be caused by cardiac
which the coronaries get filled better. glycosides. Hypokalemia enhances digitalis
toxicity.
2. Extracardiac actions
• Kidney—Diuresis occurs which relieves Treatment of toxicity
edema in CCF patients. • Stop digitalis
• CNS—High doses stimulate CTZ resulting • Oral or parenteral K+ supplements are given
in nausea and vomiting. • Ventricular arrhythmias are treated with IV
lignocaine or phenytoin
Mechanism of action: Cardiac glycosides inhibit • Bradycardia is treated with atropine and
the enzyme Na+/K+ ATPase—also called ‘sodium supraventricular arrhythmias with propra-
pump’ present on the cardiac myocytes. This nolol

TABLE 5.1: Pharmacokinetic properties of digoxin and digitoxin


Properties Digoxin Digitoxin
Absorption 40-60% 90-100%
Plasma protein binding 25% 95%
Onset of action 15-30 min 30-120 min
t½ 24-48 hr 5-7 days
Route of elimination Renal excretion Hepatic metabolism
Time for digitalization (without loading dose) 5-7 days 25-30 days
Daily dose (slow loading or maintenance) 0.125-0.5 mg 0.05-0.2 mg
Rapid digitalizing dose 0.5-0.75 mg 0.2-0.4 mg every
every 8 hours 3 doses 12 hours 3 doses
70 Pharmacology for Physiotherapy

TABLE 5.2: Drug interactions


Drugs that enhance digoxin toxicity
• Diuretics (due to hypokalemia), calcium
• Quinidine, verapamil, methyldopa—↑digoxin levels
Drugs that reduce digoxin levels
• Antacids, neomycin, metoclopramide—↓ absorption
• Rifampicin, phenobarbitone—hasten metabolism due to enzyme induction

• Antidigoxin immunotherapy that is anti- — Phosphodiesterase (PDE) inhibitors —


digoxin antibodies are now available (Table Amrinone, milrinone.
5.2). 1. Diuretics: High ceiling diuretics like frusemide
are used. They increase salt and water
Uses
excretion and reduce blood volume. By this
1. Congestive cardiac failure (see below) they reduce preload and venous pressure,
2. Cardiac arrhythmias improve cardiac performance and relieve
• Atrial fibrillation and atrial flutter— edema.
digoxin reduces the ventricular rate 2. Vasodilators reduce the mortality in patients
• Paroxysmal supraventricular tachycardia with cardiac failure. Vasodilators may be
(PSVT)—digoxin is an alternative to arteriolar or venular dilators or both.
verapamil. • Arteriolar dilators (↓after load)—hydrala-
zine relaxes arterial smooth muscles, thus
DRUGS USED IN CONGESTIVE reducing peripheral vascular resistance
CARDIAC FAILURE (↓afterload). As a result, the work load on
In congestive cardiac failure, the heart is unable the heart is reduced.
to provide adequate blood supply to meet the • Venodilators (↓preload)—nitrates-reduce
demand. The aim of treatment is to reduce the venous return to the heart (↓preload)
morbidity and mortality by restoring cardiac thus reducing the stretching of the
output and relieving congestion. ventricular walls and myocardial oxygen
requirements.
The drugs used in CCF include:
• Both arteriolar and venular dilators—ACE
1. Diuretics—frusemide
inhibitors, sodium nitroprusside, prazo-
2. Vasodilators—hydralazine, nitrates, ACE
sin, calcium channel blockers—these
inhibitors, sodium nitroprusside, prozosin,
reduce both preload and afterload.
calcium channel blockers
3. Positive inotropic agents Organic nitrates: Nitroglycerine and
— Digitalis (Table 5.3) isosorbide dinitrate are good vasodilators
— Beta adrenergic agonists–dobutamine, with a rapid and short action. They can be
dopamine, dopexamine used for short periods to decrease the

TABLE 5.3: Precautions and contraindications to digitalis therapy


• Hypokalemia—enhances toxicity
• MI, thyrotoxicosis patients—more prone to arrhythmias
• Acid base imbalance—prone to toxicity
Cardiovascular System and Blood 71

ventricular filling pressure in acute heart ANTIARRHYTHMIC DRUGS


failure. Nitroglycerine can be used IV in
acute CCF. Nitrates may be given in combi- Arrhythmia is an abnormality of the rate, rhythm
nation with hydralazine. or site of origin of the cardiac impulse or an
abnormality in the impulse conduction. Cardiac
Angiotensin converting enzyme inhibitors arrhythmias may be due to abnormal generation
(ACE-I) (page 78). or conduction of impulses. Factors like hypoxia,
ACE-I like captopril, enalapril, lisinopril and electrolyte disturbances, trauma, drugs and
ramipril act by autonomic influences can cause arrhythmias
i. Reduction of afterload Angiotensin II is a (Table 5.4).
powerful vasoconstrictor present in the
plasma in high concentrations in cardiac CLASSIFICATION
failure. ACE-inhibitors prevent the con-
Vaughan Williams classified antiarrhythmics as
version of angiotensin I to angiotensin II and
follows:
thereby reduce the afterload.
Class I. Sodium channel blockers
ii. Reduction of preload Aldosterone causes salt
A. Prolong repolarization
and water retention and increases plasma
— Quinidine, procainamide, disopyramide
volume. ACE-I prevent the formation of
B. Shorten repolarization
aldosterone (by reducing Ang-II) and thereby
— Lignocaine, mexiletine, phenytoin
reduce the preload.
C. Little effect on repolarization
iii. Reversing compensatory changes Angiotensin
— Encainide, flecainide
II formed locally in the myocardium is
Class II. β-adrenergic blockers
responsible for various undesirable
(reduce sympathetic tone)
compensatory changes like ventricular
— Propranolol, acebutolol, esmolol, etc.
hypertrophy and ventricular remodelling
Class III. K+ channel blockers
seen in CCF. ACE-I reverse these changes.
(Prolong repolarization)
ACE inhibitors are the most preferred drugs
— Amiodarone, sotalol, dofetilide, ibutilide
in chronic congestive cardiac failure.
Class IV. Ca++ channel blockers
3. Positive inotropic agents (Prolong conduction and refractoriness
specially in SA and AV nodes).
Digitalis: Mild to moderate cases of low output
— Verapamil, diltiazem.
failure are treated with diuretics and vasodilators
(ACE-inhibitors preferred). When patients are not
Sodium Channel Blockers
controlled by these, they may be put on digoxin.
Digoxin improves cardiac performance in the Class I A drugs
dilated, failing heart. If there is associated atrial Prevent inward sodium movement by blocking
fibrillation, digoxin is the preferred drug in such Na+ channels, depress phase-0 depolarization
patients. and prolong repolarization.
Other positive inotropic agents like dobuta-
mine, dopamine and dopexamine increase the Quinidine is the D-isomer of quinine obtained
force of contraction of the heart and increase from the cinchona bark. By blocking Na+ channels,
cardiac output. They are useful in acute heart it depresses all cardiac properties—automaticity,
failure. excitability, conduction velocity and prolongs
72 Pharmacology for Physiotherapy

TABLE 5.4: Choice of drugs in cardiac arrhythmias


Arrhythmia Cause Treatment
Sinus tachycardia ↑ sympathetic tone, fever, thyrotoxicosis • Treat the cause
• If severe—propranolol
Atrial extrasystoles Excess caffeine, nicotine, alcohol • Treat the cause
• Reassurance
• If severe—propranolol/disopyramide
Atrial flutter/fibrillation Rheumatic heart disease, • Cardioversion
cardiomyopathy, hypertension • Propranolol/quinidine/
disopyramide/digitalis
PSVT • Vagal maneuvers like carotid massage
• Verapamil/adenosine
• β-blockers
Ventricular ectopics Normal heart—benign; also in • β-blockers
cardiomyopathy, ischemic, • Lignocaine
digitalis induced
Ventricular tachycardia Organic heart disease and ventricular • Cardioversion
dysfunction, drug-induced • Lignocaine
Ventricular fibrillation Acute MI, organic heart disease, • Cardioversion
surgical trauma, drug-induced • Lignocaine
• Class I A drugs for prevention
Digitalis induced Digitalis toxicity • Phenytoin
tachyarrhythmias • Potassium
• Lignocaine
Sinus bradycardia • Atropine

repolarization: quinidine thus has membrane- sensitivity and idiosyncratic reactions can occur.
stabilizing activity, i.e. it inhibits the propagation Higher doses can cause cinchonism like quinine.
of the action potential.
Procainamide a derivative of the local anesthetic
Quinidine also has vagolytic and α-blocking
procaine has the advantages over quinidine that
properties. It is also a skeletal muscle relaxant.
it has weak anticholinergic properties and is not
Pharmacokinetics: Given orally quinidine is an α-blocker. It is better tolerated than quinidine.
rapidly absorbed, 90 percent bound to plasma Disopyramide has significant anticholinergic
proteins, metabolized in the liver and excreted in properties.
the urine.
Uses: Class I A drugs are useful in almost all
Adverse effects: Quinidine is not well-tolerated types of arrhythmias. They are used in atrial
due to adverse effects and may need to be stopped. fibrillation and atrial flutter and in ventricular
Quinidine itself can cause arrhythmias and heart arrhythmias. Because of the adverse effects,
block. Hence treatment should be monitored. quinidine is not preferred in arrhythmias but it
Hypotension, nausea, vomiting, diarrhea, hyper- can be used in malaria in place of quinine.
Cardiovascular System and Blood 73

Class I B Drugs Esmolol given intravenously is rapid and short-


acting and can be used to treat arrhythmias during
Class I B drugs block the sodium channels and
surgeries and other emergencies.
also shorten repolarization.
Sotalol a β-blocker also prolongs the action
Lignocaine suppresses the electrical activity of potential duration and is often preferred when a
the arrhythmogenic tissues while the normal β-blocker is needed.
tissues are not much affected. It is a local
anesthetic. Given orally lignocaine undergoes high Class III Drugs
first pass metabolism and has a short t½—hence
These drugs prolong the action potential duration
used parenterally. It may cause drowsiness,
and refractory period by blocking the potassium
hypotension, blurred vision, confusion and
channels.
convulsions. Lignocaine is used in the treatment
of ventricular arrhythmias, especially that caused Amiodarone is a powerful antiarrhythmic which
by acute myocardial infarction or open heart contains iodine in its structure. In addition to
surgery. prolonging action potential duration, it also blocks
β adrenergic receptors and sodium channels.
Phenytoin is an antiepileptic also useful in Amiodarone can cause various adverse effects
ventricular arrhythmias and digitalis induced like heart block, cardiac failure, hypotension,
arrhythmias. hypothyroidism, pulmonary fibrosis and
Mexiletine can be used orally; causes dose related hepatotoxicity. It is used only in resistant cases of
neurologic adverse effects including tremors and chronic ventricular arrhythmias and to prevent
blurred vision. Nausea is common. It is used as recurrence of atrial fibrillation and flutter.
an alternative to lignocaine in ventricular Dronadarone–an analog of amiodarone does not
arrhythmias. contain iodine atoms and therefore does not cause
the thyroid related side effects. It is longer acting
Class I C Drugs and is used in atrial fibrillation.
Class I C drugs like encainide and flecainide are Bretylium is an adrenergic neurone blocker used
the most potent sodium channel blockers. Because in resistant ventricular arrhythmias.
of the risk of cardiac arrest, sudden death and
other adverse effects, they are not commonly used. Class IV Drugs
They may be used only in severe ventricular
Calcium channel blockers inhibit the inward
arrhythmias.
movement of calcium resulting in reduced
contractility, automaticity and AV nodal conduc-
Class II Drugs
tion. Verapamil and diltiazem have prominent
β-blockers like propranolol exert antiarrhythmic cardiac effects.
effects due to blockade of cardiac β receptors (in Verapamil is used to terminate paroxysmal
high doses has membrane stabilizing activity). supraventricular tachycardia (PSVT). It is also
They depress myocardial contractility, auto- used to control ventricular rate in atrial flutter or
maticity and conduction velocity. fibrillation.
Propranolol is used in the treatment of supra-
Miscellaneous
ventricular arrhythmias especially those
associated with exercise, emotion or hyper- Adenosine is a purine nucleotide having rapid
thyroidism. and short antiarrhythmic action. Given IV it
74 Pharmacology for Physiotherapy

suppresses automaticity, AV conduction and Drugs are used to improve the balance between
dilates the coronaries. Adenosine is the drug of oxygen supply and demand either by increasing
choice for acute termination of paroxysmal oxygen supply to the myocardium (coronary
supraventricular tachycardias (PSVT). dilation) or by reducing the oxygen demand
Adverse effects are nausea, dyspnea, flushing (reducing preload/afterload/heart rate or all of
and headache but are of short duration. these).

DRUGS USED IN THE TREATMENT ANTIANGINAL DRUGS


OF ANGINA PECTORIS
1. Nitrates—Nitroglycerine, isosorbide dinitrate,
Angina pectoris is the symptom of ischemic heart isosorbide mononitrate, Penta erythritol
disease (IHD) characterized by sudden, severe, tetranitrate.
substernal discomfort or pain which may radiate 2. Calcium channel blockers—Verapamil,
to the left shoulder and along the flexor surface of diltiazem, amlodipine.
the left arm. Myocardial oxygen consumption is 3. β-blockers—Propranolol, atenolol, etc.
mainly determined by preload (venous return and 4. Potassium channel openers —Nicorandil
stretching of the heart), afterload (peripheral pinacidil, cromakalim.
arterial resistance) and heart rate. When the 5. Miscellaneous—Aspirin, trimetazidine.
oxygen supply to the myocardium is insufficient
for its needs, myocardial ischemia develops. Pain Nitrates
is due to accumulation of metabolites in the cardiac
muscle. Two forms of angina are: Nitrates are vasodilators (mainly venodilators).
1. Classical angina (stable angina, angina of effort) They are converted to nitric oxide which leads to
Pain is induced by exercise or emotion, both of relaxation of the vascular smooth muscles. Veno-
which increase myocardial oxygen demand. dilation reduces venous return to the heart thereby
As there is narrowing of the coronary arteries reducing preload. Arteriolar dilation reduces
due to atherosclerosis, they cannot dilate to vascular resistance thus decreasing afterload. As
increase the blood supply during exercise. both preload and afterload are reduced, work load
Hence there is imbalance between oxygen of the heart is decreased thereby reducing oxygen
supply and demand. requirement of the heart.
2. Variant or Prinzmetal’s angina occurs at rest and In variant angina, nitrates relieve vasospasm
is caused by spasm of the coronary artery. due to coronary vasodilation.

TABLE 5.5: Some nitrates used in angina pectoris


Drug Dose and route Duration of action
Nitroglycerine (GTN) 0.5 mg SL 15-40 min
(ANGISED) 5 mg oral 4-8 hr
2% Skin ointment applied 4-6 hr
1-2 inches on the precardial region
Isosorbide dinitrate 5-10 mg SL 20-40 min
(SORBITRATE) 10-20 mg oral 2-3 hr
Isosorbide mononitrate (ISMO) 10-20 mg oral 6-8 hr
SL — sublingual
Cardiovascular System and Blood 75

Nitrates also cause dilation of blood vessels leading to a fall in BP. Reflex tachycardia may
in the skin—resulting in flushing; dilatation of occur with some.
the meningeal vessels result in headache. 2. Heart: CCBs depress myocardial contractility,
Bronchial smooth muscles are also relaxed. reduce heart rate, cardiac work and
myocardial O2 consumption.
Adverse effects: Headache is common; flushing,
3. Coronary circulation: Coronary vasodilation
sweating, palpitation, weakness, postural
occurs, increasing coronary blood flow. Hence
hypotension and rashes can occur. Tolerance to
CCBs are useful in variant angina.
vascular effects develops on repeated long term
use. CCBs include:
Dihydropyridines: Nifedipine, nimodipine,
Uses nicardipine, amlodipine, felodipine, isradipine,
1. Angina: Sublingual nitroglycerine is the drug nitrendipine, nisoldipine.
of choice for acute anginal attacks. It relieves
Others: Verapamil, diltiazem.
pain in 3 minutes. If the pain is not relieved,
the dose may be repeated (up to 3 tablets in 15 Verapamil has prominent myocardiac depressant
minutes). actions. AV conduction is depressed and usually
Orally nitrates are also used for the bradycardia is seen. Hence it should not be
prophylaxis of angina. Nitroglycerine oint- combined with β-blockers. Fall in BP is mild as
ment may be applied over the chest. the vasodilator effect of verapamil is less potent.
2. Cardiac failure: Nitrates are useful due to their Adverse effects include constipation,
vasodilator property. bradycardia, heart block and hypotension. It may
3. Myocardial infarction: IV nitroglycerine is used precipitate CCF in patients with diseased heart.
by many physicians. Nifedipine a dihydropyridine, is a potent
4. Cyanide poisoning: Nitrates convert hemo- vasodilator and causes a significant fall in BP and
globin to methemoglobin which binds to evokes reflex tachycardia. Myocardiac depressant
cyanide, forming cyanmethemoglobin. It thus effect is weak. It can be given sublingually.
protects the important enzymes from binding Adverse effects are headache, flushing,
to cyanide. Amyl nitrite is preferred. Early palpitation, dizziness, fatigue, hypotension, leg
treatment is very important. cramps and ankle edema.
5. Antispasmodic: Nitrates relieve esophageal Other CCBs like amlodipine, felodipine,
spasm when taken sublingually before meals. nitrendipine and nicardipine are similar to
Nitrates also relieve biliary colic. nifedipine with some pharmacokinetic variations.
They have higher vascular selectivity. Nimodipine
Calcium Channel Blockers
selectively relaxes cerebral vasculature. Diltiazem
The depolarization of cardiac and vascular has less potent vasodilator effects but is a
smooth muscle cells depend on the entry of myocardiac depressant.
extracellular calcium into the cell through calcium
Pharmacokinetics: CCBs are well-absorbed but
channels. This calcium triggers the release of
undergo extensive first pass metabolism. They are
intracellular calcium from the sarcoplasmic
all highly plasma protein bound and are meta-
reticulum. All these calcium ions cause contrac-
bolized in the liver.
tion. Calcium channel blockers (CCB) inhibit the
entry of Ca++ by blocking the Ca++ channels. This
Uses of CCBs
results in the following actions:
1. Smooth muscle relaxation: Arteriolar dilatation 1. Ischemic heart diseases: CCBs, verapamil and
reducing peripheral vascular resistance, diltiazem are used in the treatment of stable
76 Pharmacology for Physiotherapy

angina. They are very effective in relieving the through nitric oxide to cause vasodilatation.
pain and spasm in vasospastic angina. Adverse effects are headache, flushing, dizziness
Verapamil is also useful in unstable angina. and hypotension. Nicorandil is used as an
2. Hypertension: Verapamil, nifedipine, amlodi- alternative to nitrates in the treatment of angina.
pine and diltiazem can be used. Nifedipine is It is used in the dose of 10-20 mg twice daily.
used sublingually in hypertensive crisis. Pinacidil is similar to nicorandil and is also useful
3. Arrhythmias: Verapamil is the drug of choice in hypertension. Minoxidil and diazoxide are K+
in PSVT. channel openers used in hypertension.
4. Peripheral vascular disease: Nifedipine is useful
in Raynaud’s disease due to its vasodilator Miscellaneous
effects.
5. Hypertrophic cardiomyopathy: Verapamil is Aspirin: Low dose aspirin is given for a long
used. period for its antiplatelet aggregatory property. It
6. Migraine: Verapamil can be used in the has been shown to prevent myocardial infarction
prophylaxis of migraine. in patients with angina.
7. Subarachnoid hemorrhage: Vasospasm that
Trimetazidine is a calcium channel blocker
follows subarachnoid hemorrhage is believed
claimed to have a protective effect on the ischemic
to be responsible for neurological defects. As
myocardium and to maintain left ventricular
nimodipine brings about cerebral vasodilation,
function. Trimetazidine belongs to a new class of
it is used to treat neurological deficits in
drugs that modulate the metabolism in the
patients with cerebral vasospasm.
myocardium. Trimetazidine inhibits the enzyme
8. Atherosclerosis: Dihydropyridines may slow
involved in fatty acid oxidation pathway in the
the progress of atherosclerosis.
myocardium. It also inhibits the cytotoxicity to
the myocardial cells. Trimetazidine thus protects
β-blockers the myocardium from ischemic damage. It is orally
β-blockers reduce the frequency and severity of effective and is well tolerated with occasional
attacks of exertional angina and are useful in the gastric irritation, fatigue and muscle cramps.
prevention of angina. Exercise, emotion and Trimetazidine is used as an add on drug along
similar situations increase sympathetic activity with other antianginal drugs in the treatment of
leading to increased heart-rate, force of contraction angina pectoris.
and BP, thereby increasing O2 consumption by
Ranolazine is a recently introduced trimetazidine
the heart. β-blockers prevent angina by blocking
derivative with a unique mechanism of action.
all these actions. They are used for the long-term
Ranolazine inhibits the late sodium current in the
prophylaxis of classical angina and may be
myocardium and prevents calcium overload in
combined with nitrates. β-blockers should always
the myocardium during ischemia. It thus reduces
be tapered after prolonged use. They are not useful
myocardial oxygen demand. Due to this cardio-
in variant angina.
protective properties, ranolazine is approved for
the prevention of angina as add on therapy in
Potassium Channel Openers
patients who do not respond to first line drugs.
Nicorandil is an arterial and venous dilator. Ranolazine in orally effective. It can cause
Opening of the K+ channels results in hyperpolari- weakness, postural hypotension, QT pro-
zation and therefore relaxation of the vascular longation, dizziness, headache and constipation.
smooth muscles. In addition nicorandil also acts Dose 500 mg sustained release tablets twice daily.
Cardiovascular System and Blood 77

Pharmacotherapy of Angina need hospitalization and rigorous treatment for


its prevention.
Acute attack: Sublingual nitroglycerine is the drug
of choice. If the pain does not subside in 5 minutes, Drugs used in unstable angina – aspirin, heparin
repeat the dose. After the relief of pain, the tablet and IV nitroglycerine may be used in unstable
should be discarded. angina. Long-term administration of β-blockers
Acute prophylaxis: Sublingual nitroglycerine given like atenolol or a CCB like verapamil is beneficial.
15 minutes before an exertion (e.g. walking uphill) Drugs used in myocardial infarction
can prevent the attack. The prophylactic effect Rupture of an atheromatus plaque in the coronary
lasts for 30 minutes. artery results in the formation of a thrombus which
blocks the artery leading to loss of blood supply
Chronic prophylaxis: Long-acting nitrates or β-
to the concerned part of the heart. This results in
blockers (preferred) or calcium channel blockers
acute myocardial infarction.
can be used. All are given orally.
Drugs used are:
If one drug is not effective, a combination of
• IV opioid analgesics like morphine/pethidine
drugs may be used.
to relieve pain and anxiety
• Thrombolytics like streptokinase to dissolve
Combinations of Drugs in Angina
the thrombus
1. Nitrates + β-blockers—very effective in • Aspirin for its antiplatelet aggregatory effect.
exertional angina. • Atenolol, ACE inhibitors and O2 inhalation
Reflex tachycardia due to nitrates is countered also help.
by β-blockers. Ventricular dilatation due to β-
blockers is opposed by nitrates. ANTIHYPERTENSIVE DRUGS
2. Nifedipine + β-blockers. The antianginal effects
Hypertension is an elevation of systolic and/or
are additive. Reflex tachycardia due to
diastolic BP above 140/90 mm of Hg. It is a
nifedipine is countered by β-blockers.
common cardiovascular condition. Hypertension
3. Nitrates + CCBs—nitrates decrease preload,
may be primary (essential) hypertension—where
CCBs reduce afterload and the combination
the cause is not known or secondary—when it is
reduces cardiac workload.
secondary to other conditions like renal,
4. CCBs + β-blockers + Nitrates—if the angina is
endocrine or vascular disorders.
not controlled by 2 drug combinations, 3 drugs
Based on the degree of severity, hypertension
can be used. Nitrates reduce preload, CCBs
can be graded as:
reduce afterload while β-blockers decrease
• Mild—diastole up to 104
heart rate. This combination is useful in severe
• Moderate—105-114
angina.
• Severe— more than 115.
Unstable angina includes: Blood pressure is determined by cardiac output
— Patients with exertional angina developing (CO) and total peripheral vascular resistance
angina at rest (PVR). Blood pressure is controlled by baroreceptor
— Severe, prolonged anginal attacks without reflexes acting through autonomic nervous system
ECG evidence of MI along with the renin-angiotensin-aldosterone
— Angina developing after myocardial infarc- system.
tion. Prolonged hypertension damages the blood
Such patients with unstable angina are at a vessels of the heart, brain and the kidneys and
high risk of developing MI or sudden death and may result in several complications like stroke,
78 Pharmacology for Physiotherapy

coronary artery disease or renal failure. Hence Diuretics enhance the excretion of sodium and
hypertension needs to be treated. water resulting in:
Antihypertensives act by influencing the BP 1. ↓ Plasma volume → ↓ cardiac output → ↓ BP
regulatory systems viz the autonomic system, 2. ↓ Body sodium → relaxation of vascular
renin-angiotensin system, calcium channels or smooth muscles (due to Na+ depletion) → ↓
sodium and water balance (plasma volume).
PVR → ↓ BP.
Restriction of dietary salt intake will reduce
CLASSIFICATION
the dose of the diuretic needed. Thiazides are the
1. Diuretics first-line antihypertensives. They may be
• Thiazides Hydrochlorothiazide, chlortha- combined with a K+ sparing diuretic to avoid hypo-
lidone, etc. kalemia. Thiazides may be used in combination
• Loop diuretics Frusemide
with other antihypertensives. Loop diuretics are
• K + Sparing diuretics Spironolactone,
used only in hypertension with chronic renal
amiloride, triamterene.
2. Drugs acting on renin angiotensin system failure or congestive heart failure.
• Angiotensin converting enzyme inhibitors
Captopril, enalapril, lisinopril, ramipril. Drugs Acting on Renin Angiotensin System
• Angiotensin II receptor antagonist 1. Angiotensin Converting
Losartan, candesartan, valsartan. Enzyme (ACE) Inhibitors
• Renin inhibitor Aliskiren.
3. Sympatholytics Angiotensin II is a powerful vasoconstrictor.
• Centrally acting drugs: Clonidine, methyl- Aldosterone also raises the BP by increasing the
dopa plasma volume (Fig. 5.2). ACE inhibitors prevent
• Ganglion blockers: Trimethaphan the formation of angiotensin II and (indirectly)
• Adrenergic neuron blockers: Guanithidine, aldosterone. There is vasodilation and decrease
reserpine in PVR resulting in ↓ BP. As ACE also degrades
• Adrenergic receptor blockers: bradykinin, ACE inhibitors raise the bradykinin
— β-blockers propranolol, atenolol, etc. levels which is a potent vasodilator. This also
— α-blockers prazosin contributes to the fall in BP.
• Mixed α and β blockers Labetalol. The blood flow to the kidneys, brain and heart
4. Vasodilators increases due to selective vasodilation and thus
• Arteriolar dilators: Hydralazine, minoxidil, maintains adequate blood supply to these vital
diazoxide organs.
• Arteriolar and venular dilators: Sodium Pharmacokinetics: ACE inhibitors are generally
nitroprusside well-absorbed. Except captopril and lisinopril, all
5. Ca++ channel blockers Verapamil, nifedipine, others are prodrugs. Duration of action varies
etc. (Table 5.6).

Diuretics (see Chapter 3) Adverse effects: ACE inhibitors are well-


tolerated. Adverse effects include persistent dry
The antihypertensive effect of diuretics is mild— cough (due to ↑ bradykinin levels), hyperkalemia,
BP falls by 15-20 mm Hg over 2-4 weeks. Diuretics alteration of taste sensation, skin rashes, hypo-
act as antihypertensives as follows. tension, headache, nausea, abdominal pain and
Cardiovascular System and Blood 79

Fig. 5.2: Renin-angiotensin system

blood disorders. Angioedema though rare can be 3. Myocardial infarction: ACE inhibitors started
severe. At the first sign of angioedema ACE within 24 hours and given for several weeks
inhibitors should be stopped. prevent the development of CCF and reduce
mortality.
Uses 2. Angiotensin II Receptor Antagonists
1. Hypertension: ACE inhibitors are useful in the Losartan is an angiotensin II receptor antagonist.
treatment of hypertension of all grades due to AT1 receptors present in vascular and myocardial
all causes. Addition of a diuretic potentiates tissue, brain, kidney and adrenal glomerular cells
their efficacy. They are presently the first line are blocked by losartan. Losartan relaxes vascular
antihypertensives. They are specially indi- smooth muscles, promotes salt and water
cated as antihypertensives in: excretion and reduces plasma volume. The
a. Patients with diabetes as ACE-I slow the advantage of AT II antagonists over ACE
development of nephropathy. inhibitors is that there is no increase in bradykinin
b. Renal diseases—ACE inhibitors slow the levels and its associated adverse effects like dry
progression. cough and angioedema.
c. Left ventricular hypertrophy—is gradually Adverse effects include hypotension and
reversed by ACE inhibitors. hyperkalemia. It is contraindicated in pregnancy
2. CCF: ACE inhibitors are the first line drugs. and lactation.

TABLE 5.6: Dose and duration of action of some commonly used ACE inhibitors
Drug Duration of action (in hrs) Daily dose in hypertension (mg)
Captopril 6-12 12.5-50 mg BD
Enalapril 24 2.5-20 mg OD
Lisinopril >24 5-40 mg OD
Ramipril 8-48 1.25-10 mg OD
80 Pharmacology for Physiotherapy

Uses: Losartan (50 mg OD) is used in the treatment norepinephrine which is an α2 agonist and acts
of hypertension in similar indications as that of like clonidine. Renin levels also fall. Left ventri-
ACE inhibitors. Others like candesertan and cular hypertrophy is reversed in about 12 weeks
valsartan can also be used. of treatment.
Adverse effects are sedation, dryness of mouth
3. Renin inhibitors: Aliskiren is a recently and nose, headache, postural hypotension, fluid
introduced direct renin inhibitor—blocks the retention and impotence.
effects of renin thereby reducing the blood
pressure. It can be used alone or with other drugs. Uses: It is used in mild to moderate hypertension
Dose 150-300 mg once daily. along with a diuretic.

SYMPATHOLYTICS Ganglion Blockers

Drugs Acting Centrally These drugs block both sympathetic and para-
sympathetic ganglia resulting in decreased
Clonidine is a selective α2 agonist. Stimulation of sympathetic tone and a fall in BP. But they produce
α2 receptors in the CNS (in the vasomotor center several side effects as they block both ganglia and
and hypothalamus), decreases central sympa- are not used now. Trimethaphan is the only
thetic outflow, blocks the release of noradrenaline ganglion blocker used intravenously to produce
from the nerve terminals leading to a fall in BP controlled hypotension during certain surgeries
and bradycardia. for its rapid and short action (15 minutes).
Adverse effects include drowsiness, dryness
of mouth, nose and eyes; parotid gland swelling Adrenergic Neuron Blockers
and pain, fluid retention, constipation and
impotence. Sudden withdrawal of clonidine will Guanethidine depletes the stores of noradrena-
lead to rebound hypertension, headache, tremors, line in the adrenergic neurons and also blocks its
sweating and tachycardia. Hence the dose should release. Because of the adverse effects like postural
be tapered. hypotension, diarrhea and sexual dysfunction, it
is not used.
Uses: Mild to moderate hypertension.
Reserpine is an alkaloid obtained from Rauwolfia
serpentina (Sarpagandhi) that grows in India. In
Other Uses
the neurons, it binds to the vesicles that store
1. In opioid withdrawal: Most withdrawal monoamines like noradrenaline, dopamine and
symptoms in opioid addicts are due to 5-HT and destroys these vesicles. It thus depletes
sympathetic overactivity and can be benefited the stores of these monoamines. Reserpine also
by treatment with clonidine. causes various side effects like drowsiness,
2. Diabetic neuropathy: Clonidine controls depression, parkinsonism, postural hypotension,
diarrhea by improving absorption of NaCl and edema and sexual dysfunction. Hence it is
water in the gut by stimulation of α2 receptors generally not preferred.
in the intestines.
3. With anesthetics: Clonidine given preoperatively Adrenergic Receptor Blockers
reduces the dose of the general anesthetic
needed due to its analgesic effects. β-blockers (see Chapter 2) are mild antihyper-
tensives. They reduce the BP due to a fall in the
α-methyl dopa—an analog of dopa, is a prodrug. cardiac output. They also lower plasma renin
It is metabolized in the body to α-methyl activity and have an additional central
Cardiovascular System and Blood 81

antihypertensive action. They are well-tolerated Vasodilators


and are of special value in patients who also have
Vasodilators relax the vascular smooth muscles
arrhythmias or angina. They are also suitable for
thus reducing BP due to decreased peripheral
combination with other antihypertensives. They
vascular resistance. Salt and water retention and
are thus the first line antihypertensive drugs in
reflex tachycardia are common with vasodilators.
mild to moderate hypertension. Atenolol is the
Vasodilators may be:
preferred β-blocker because of the advantages like
1. Arteriolar dilators—Hyralazine, minoxidil,
once a day dosing, absence of CNS side effects
diazoxide, calcium channel blockers.
and β1 selectivity. β-blockers should always be
2. Arteriolar and venular dilators—Sodium
tapered while withdrawing.
nitroprusside.
α-blockers (see Chapter 2) Prazosin is a selective Hydralazine is a directly acting arteriolar dilator.
α1-blocker; it dilates both arterioles and venules. The fall in BP is associated with tachycardia, renin
Peripheral vascular resistance is decreased release and fluid retention. Coronary, cerebral and
leading to a fall in BP with only mild tachycardia. renal blood flow are increased.
‘First dose phenomenon’ can be avoided by Adverse effects are headache, flushing, palpi-
starting with a low dose (0.5 mg) given at bed tation, salt and water retention. It may precipitate
time. Dose is gradually increased. Prazosin is used angina in some patients. Hypersensitivity
in mild to moderate hypertension; it may be reactions like serum sickness and lupus
combined with diuretics and β-blockers. erythematosus may occur.

α and β -blockers Labetalol blocks α1 and β Uses: Hydralazine is used with a β-blocker and/
receptors. It is used intravenously in the treatment or a diuretic in moderate to severe hypertension
of hypertension in pheochromocytoma and in not controlled by the first line drugs. It can be given
hypertensive emergencies. in hypertension in pregnancy.

TABLE 5.7: Dose and route of administration of some commonly used antihypertensives
Antihypertensives Daily doses Routes
Hydrochlorothiazide + 12.5-25 mg + Oral
Amiloride 1.25-2.5 mg daily
Clonidine 100-300 μg Oral
Methyldopa 250-500 mg q 6-12 hr Oral
Atenolol 25-100 mg OD Oral
Prazosin 2-20 mg daily Oral
Hydralazine 25-50 mg q 8-24 hr Oral
Diazoxide 50-100 mg every 5-10 min IV
Sodium nitroprusside 0.2-0.3 mg/min IV
Nifedipine 10 mg SL
5-20 mg q 8-12 hr Oral
Losartan 50 mg OD Oral
For ACE inhibitors see Table 5.6
82 Pharmacology for Physiotherapy

Minoxidil is a directly acting arteriolar dilator the arterioles resulting in reduced peripheral
used in severe hypertension not responding to vascular resistance. Nifedipine produces some
other drugs. It acts by opening K+ channels in reflex tachycardia while this is not seen with
smooth muscles. verapamil and diltiazem as they are cardiac
Minoxidil stimulates the growth of hair on depressants. Fluid retention is negligible unlike
prolonged use. Hence it is used topically (2% other arteriolar dilators.
solution) in alopecia. Young men with relative • CCBs are well-tolerated, and effective.
alopecia are more likely to respond. • Sublingual nifedipine used in hypertensive
emergencies effectively lowers BP in 10
Diazoxide is related to thiazide diuretics and is a minutes.
potent arteriolar dilator. It’s mechanism of action • CCBs are of special value in patients who also
is like minoxidil. It is used in hypertensive have angina.
emergencies where monitoring of infusion is not • Sustained release preparations or long acting
possible. Diazoxide has a long duration of action CCBs may be used for smoother control of BP.
(24 hours) and is suitable in such situations. • CCBs may be used in combination with other
antihypertensives in moderate to severe
Sodium nitroprusside is a rapidly acting
hypertension.
vasodilator and it relaxes both arterioles and
venules. Both peripheral resistance and cardiac Drug Interactions of Antihypertensives
output are reduced resulting in lower myocardial
oxygen consumption. Nitroprusside acts through 1. Sympathomimetics and tricyclic anti-
the release of nitric oxide which relaxes the depressants can antagonize the effects of
vascular smooth muscles. On IV administration, sympatholytics.
it is rapid (acts within 30 seconds) and short- 2. Antihistamines add to sedation produced by
acting (duration 3 minutes) allowing titration of clonidine and methyldopa.
the dose. This makes it suitable for use in hyper- 3. NSAIDs tend to cause salt and water retention
tensive emergencies with close monitoring. It and may blunt the effect of antihypertensives.
decomposes on exposure to light; the infusion
bottle and tubing should be covered with opaque Treatment of Hypertension
foil. Mild hypertension: Treatment is started with low
dose of a single drug—a thiazide diuretic or a β-
Adverse reactions are palpitation, sweating,
blocker. If the patient does not adequately respond
weakness, nausea, vomiting and in high doses
in 3-4 weeks, an ACE inhibitor or a calcium chan-
thiocyanate toxicity including psychosis.
nel blocker should be tried. If BP is not controlled
Uses by one drug, another should be added.
1. Nitroprusside is the drug of choice in hyper- Moderate hypertension: A combination of a
tensive emergencies. diuretic with a sympatholytic may be given. If
2. It is used in situations where short-term response is inadequate add a third drug.
reduction of myocardial workload is required Severe hypertension may be associated with
as in myocardial infarction. cardiac or renal disorder. A vasodilator with a
diuretic and a β-blocker is useful.
Calcium Channel Blockers
Hypertensive emergencies: Conditions like
Calcium channel blockers (CCBs) are another hypertensive encephalopathy and acute cardiac
important group of antihypertensives. They dilate failure due to hypertension require immediate
Cardiovascular System and Blood 83

reduction of BP. Parenteral drugs are preferred. hemorrhage, burns or dehydration—results in


IV sodium nitroprusside under close monitoring hypovolemic shock.
is the drug of choice (in some conditions BP should 2. Septic shock is precipitated by severe bacterial
be lowered gradually to avoid ischemia to vital infection. It may be due to release of bacterial
organs). IV esmolol, diazoxide and sublingual toxins.
nifedipine are alternatives. As soon as possible 3. Cardiogenic shock is due to failure of heart as a
switch over to oral drugs. pump as in myocardial infarction.
4. Anaphylactic shock Type I hypersensitivity
Hypertension in pregnancy: The drugs found safe
reaction causing release of massive amounts
are—methyldopa orally for maintenance and
of histamine which is triggered by antigen-
hydralazine (parenteral) for reduction of BP in
antibody reaction.
emergency. However they should be used only
5. Neurogenic shock is due to venous pooling as
after the first trimester. Cardio-selective β-blockers
following spinal anesthesia, abdominal or
(atenolol) can also be used.
testicular trauma.
Combination of antihypertensives: When it is
Shock of any type needs immediate treatment:
not possible to achieve adequate control of BP
a. The cause should be identified and treated
with a single drug, a combination may be used.
b. Maintain BP and plasma volume
Antihypertensives may also be combined to
c. Correct the acid base and electrolyte distur-
overcome the side effects of one another. This also
bances
allows use of lower doses of each drug.
d. Ensure adequate urine output.
Sympatholytics and vasodilators cause fluid
In shock due to myocardial infarction, IV
retention which can be overcome by adding a
morphine is the drug of choice to relieve pain
diuretic.
and anxiety. Thrombolytic therapy (see Chapter
Vasodilators like nifedipine and hydralazine
8) and oxygen inhalation should be started
evoke reflex tachycardia. This can be countered
immediately. Absolute bed rest, prevention of
by β-blockers, while propranolol may cause initial
arrhythmias and maintenance of cardiac output
rise in PVR which is countered by vasodilators.
are all important.
Combination of ACE inhibitors and diuretics
Septic shock should be treated with appro-
is synergistic.
priate antibiotics.
Non-pharmacological measures: Low salt diet, Anaphylactic shock—treatment—see page 44.
weight reduction, transidental meditation, all go
a long way in controlling the blood pressure. PLASMA EXPANDERS
Smoking and alcohol should be given up. These
measures also help in reducing the dose of the To restore the intravascular volume, the compo-
antihypertensive needed. nent lost should ideally be replaced like—plasma
in burns and blood after hemorrhage. But in
PHARMACOTHERAPY OF SHOCK emergency, immediate volume replacement is
important. In such situations plasma expanders
Shock is acute circulatory failure with underper- are used. These are high molecular weight
fusion of tissues. Symptoms of sympathetic substances which when infused IV exert oncotic
overactivity of tissues are generally seen—like pressure and remain in the body for a long time to
pallor, sweating, cold extremities and tachycardia. increase the volume of circulating fluid.
Shock may be: An ideal plasma expander should exert oncotic
1. Hypovolemic shock: Decreased fluid volume due pressure comparable to plasma, be long-acting,
to sudden loss of plasma or blood as in non-antigenic and pharmacologically inert.
84 Pharmacology for Physiotherapy

The plasma expanders used are dextran, Drugs


gelatin polymer, hydroxyethyl starches and α-agonists — adrenaline, ephedrine,
polyvinyl pyrrolidone. phenylephrine,
mephenteramine,
Dextrans (Dextran 70 mol. wt. 70,000 and dextran metaraminol methoxamine
40 mol. wt. 40,000) are commonly used. Allergic 5HT agonist— sumatriptan, ergot alkaloids.
reactions are common.
Vasodilators
Gelatin products have a mol. wt. of 30,000 and a
duration of action of 12 hours. Allergic reactions Endogenous—PGs, acetylcholine, nitric oxide
are rare. Drugs
ACE inhibitors—captopril, enalapril, ramipril,
Hydroxyethyl starch (Hetastarch) maintains etc.
blood volume for a long period and allergic
reactions are rare. Angiotensin II receptor
antagonists—losartan, candesartan, etc.
Polyvinyl pyrrolidone (PVP) is a synthetic Ca++ channel blockers—nifedipine, nimodipine,
polymer. It is not preferred due to various etc.
disadvantages like—it provokes histamine release α blockers—prozosin, phentolamine, phenoxy-
and interferes with blood grouping. benzamine
Nitrates—nitroglycerine, sodium nitro-
Uses of plasma expanders These are used as prusside
plasma substitutes in hypovolemic shock, burns K+ channel openers—minoxidil, cromakalim,
and extensive fluid loss—as an emergency nicorandil
measure to restore plasma volume. Others—hydralazine, theophylline.
Vasoconstrictors: In general vasoconstrictors
VASOACTIVE DRUGS
bring about a rise in blood pressure with
Drugs that affect the vascular smooth muscles are bradycardia. α1 agonists are used in hypotension
vasoactive drugs and include vasoconstrictors and topically as nasal decongestants.
and vasodilators. Vasodilators: In general the effects of vasodilators
Some prostaglandins, angiotensin and anti- include hypotension and reduced cardiac
diuretic hormone are natural vasoconstrictors workload. However, they may cause reflex
released in the body (endogenous). They are tachycardia. Adverse effects to vasodilators
released in hypotension and hypovolemia. Drugs generally include palpitation, flushing, dizziness,
that cause vasoconstriction are listed below. headache, hypotension and edema.
Vasodilators include natural vasodilators Vasodilators are used in the treatment of
released in the body like some prostaglandins, hypertension, angina pectoris, cardiac failure,
acetylcholine, nitric oxide and drugs like nitrates myocardial infarction and peripheral vascular
and others (see below). diseases.

Vasoconstrictors CEREBRAL ISCHEMIA


Endogenous Noradrenaline, PGs (TXA2) Stroke is due to sudden reduction of blood flow
Angiotensin, ADH, 5-HT for a brief period (few seconds to few minutes) in
Cardiovascular System and Blood 85

the brain which if continues for more than a few oral anticoagulants. However it carries the risk
minutes results in infarction of the brain tissue. of hemorrhage and the benefits have not been
Stroke results from focal ischemia of a part of the proved. Therefore routine heparin use is not
brain, or intracranial hemorrhage. Ischemia could recommended.
be due to a thrombus or embolus occluding a 4. Maintenance of airway, circulation and blood
blood vessel in the brain. Stroke is the commonest pressure are important in acute stroke, risk
cause of severe physical disability and about 50 factors if any like hypertension, uncontrolled
percent of patients who survive acute stroke suffer diabetes mellitus, hyperlipidemia should be
from physical disability. taken care of.
Risk factors include prolonged hypertension, 5. Rehabilitation includes physiotherapy,
diabetes mellitus, old age, heredity, hyper- speech therapy and if needed occupational
lipidemia, atherosclerosis and smoking. therapy.
Manifestations of stroke include hemiplegia 6. To reduce the risk of recurrence antiplatelet
which may be associated with signs of focal drugs should be continued for long-term.
cerebral dysfunction like aphasia, sensory loss Carotid angioplasty and stenting also prevent
and visual field defects. Transient ischemic attack restenosis.
is stroke which resolves in 24 hours. The cause
should be detected and efforts should be made to DRUGS USED IN TREATMENT OF
prevent its recurrence. PERIPHERAL VASCULAR DISEASES
Treatment of Ischemic Stroke Peripheral vascular diseases (PVD) result from
1. Thrombolytics—Though thrombolytics seem reduced blood supply to the lower limbs.
to be helpful in dissolving the clot and Reduction in blood supply may be due to organic
restoring the blood supply, it carries the risk occlusion (e.g. thrombus) or vasospasm.
of hemorrhagic transformation of the infarct Obstruction to the blood flow in the peripheral
which could be fatal. However, thrombolysis circulation due to any cause can result in ischemia
carried out within 3 hours of onset of stroke in of the area distal to it with its related consequences.
selected patients after ruling out hemorrhage Peripheral vascular diseases include
results in improvement. Intravenous infusion thromboangitis obliterans (TAO, Buerger’s
of recombinant tissue plasmogen activator is disease), Raynaud’s Phenomenon, frost bite,
started. Blood supply may also be restored by vascular complications of diabetes mellitus like
alternative methods like intra-arterial gangrene, leg and foot ulcers.
thrombolysis, mechanical dissolution or Drugs used in peripheral vascular diseases
removal of the clot. include:
2. Antiplatelet drugs—Low dose aspirin (300 1. Vasodilators
mg) should be started immediately if tPA is a. CCBs – nifedipine
not given. If thrombolytics are given, aspirin b. Adrenergic blockers – prazosin, tolazoline
may be started on the second day and should c. β adrenergic agonists – isosxuprine
be continued – alternatively, clopidogrel or 2. Anticoagulants and antiplatelet drugs –
ticlopidine can be used. Heparin, warfarin, aspirin, clopidogrel.
3. Anticoagulants—After ruling out hemorrhage 3. Other drugs:
by MRI, heparin is started intravenously to Hypolipidemics (Statins), pentoxiphylline,
prevent recurrence. Heparin is given for a week naftidofuryl oxalate, cilostazol, cyclandelate,
and then anticoagulation is continued with xanthinol nicotinate.
86 Pharmacology for Physiotherapy

Vasodilators are of no significant value in Dose: 400 mg 2-3 times a day with food.
obstructive peripheral vascular diseases because
Naftidofuryl oxalate is found to be useful in
they do not enhance the blood flow to the ischemic
peripheral vascular diseases like TAO and in
areas. Infact they may even harm such an area
cerebrovascular disorders. Though not a
because general vasodilation may shift the blood
vasodilator, it is said to improve the supply of
to other nonischemic areas described as ‘steal’
ATP to the skeletal muscles and reduce their lactate
syndrome. However, vasodilators may be used
levels—it is called a ‘metabolic enhancer’—thus
in vasospastic diseases like Raynaud’s
it improves performance in patients with TAO or
phenomenon. The strategy is to bring about
intermittent claudication where it increases the
dilation of the arterioles to allow better blood flow
walking distance. Naftidofuryl oxalate also blocks
to the limbs with minimum hypotension.
5HT 2 receptors and inhibits 5HT induced
• Calcium channel blockers – like nifedipine (See
vasoconstriction and platelet aggregation.
page 75) are good vasodilators and are
However, it is found to increase the blood flow
beneficial in patients with peripheral vascular
to the skin rather than the muscles. It has
diseases. Nifedipine is given in the dose 5 – 20
beneficial effects in the treatment of venous leg
mg thrice daily.
ulcers. Dose: 100 mg BD - TDS oral.
• Alpha adrenergic blockers – like prazosin (See
page 47) may be used in the dose of 0.5 mg Xanthinol nicotinate – both xanthine and
twice daily. nicotinic acid are vasodilators and xanthinol
• Beta adrenergic agonists like isosuxprine also nicotinate increases blood flow in several vascular
help to relieve symptoms. beds. Therefore it has been tried in cerebrovascular
insufficiency and peripheral vascular diseases.
Anticoagulants and antiplatelet drugs like
However clinically it is not proved to be useful.
heparin and warfarin prevent the formation of
clot. They are of value particularly in obstructive Dose: 300-600 mg TDS oral/300 mg IM/slow IV.
peripheral vascular disease. Aspirin 75 – 150 mg
Cilostazol is a phosphodiestrase III inhibitor. It
once a day or clopidogrel 10 mg twice daily may
has vasodilator and antiplatelet effects – improves
be used for this purpose.
pain free walking and maximum walking
Pentoxiphylline an analog of xanthine is a distance. It is used in the dose of 100 mg BD to be
phosphodiesterase inhibitor. It reduces the taken 30 minutes before breakfast and dinner. It
viscosity of the blood and enhances blood flow to can cause headache, diarrhea, dizziness and
the ischemic areas. It is also claimed to improve tachycardia and is contraindicated in heart
the flexibility of the RBCs – (called hemorrheo- failure.
logical action) resulting in an improvement of
Thromboangitis obliterans: Atheroma of the
microcirculation and is devoid of steal pheno-
peripheral arteries results in reduced blood supply
menon. It potentiates the action of anticoagulants.
to the concerned part—usually lower limbs.
Uses: Pentoxiphylline is used in transient Historically, localized inflammatory changes can
ischemic attacks, nonhemorrhagic stroke, chronic be seen in the walls of the arteries and veins
cerebrovascular insufficiency, trophic leg ulcers, leading to thrombosis. Initially there is pain in
gangrene, intermittent claudication (which could the legs on walking (intermittent claudication) but
be due to diabetes, atherosclerosis or inflammatory later pain even at rest while in severe cases there
vascular disease). Pentoxiphylline is also used in could be gangrene of the feet and legs.
AIDS patients with increased TNF (because The goal is to prevent pain, arrest progression
pentoxiphylline can inhibit the production of of the disease and decrease the risk of cardio-
TNFα) and to improve sperm motility. vascular and cerebrovascular events. Patients
Cardiovascular System and Blood 87

should first stop smoking. Hyperlipidemia if any Hypolipidemics


should be corrected. Vasodilators may be tried.
1. HMG CoA reductase inhibitors—Lovastatin,
Night cramps – quinine has been tried in a
simvastatin, pravastatin
low dose of 200 mg at night to relieve night cramps.
2. Fibric acids—Gemfibrozil, clofibrate,
Surgical treatment is the preferred option.
fenofibrate
Angioplasty of iliac or superficial femoral arteries
3. Bile acid binding resins—Cholestyramine,
(with stent placement) is often effective. Other
colestipol
options include arterial bypass grafting or 4. Antioxidant—Probucol
endarterectomy and lastly amputation of the leg 5. Miscellaneous—Nicotinic acid, neomycin,
in severe cases. ezetimibe.
Raynaud’s phenomenon is a vasospastic HMG CoA Reductase Inhibitors (Statins)
disorder. A vasodilator like nifedipine, topical
nitroglycerine, indoramin, prazosin or slow Hydroxymethylglutaryl-CoA (HMG-CoA) is the
infusion of prostacyclin (epoprostenol) help to rate controlling enzyme in the biosynthesis of
relieve symptoms. Regular exercises to improve cholesterol. Lovastatin and its congeners are
blood supply to the muscles may help. Because β competitive inhibitors of the enzyme HMG-CoA
blockers can worsen PVD including Raynaud’s reductase. They lower plasma LDL cholesterol and
triglycerides. The concentration of HDL-
phenomenon (due to reduced cardiac output), they
cholesterol (the protective lipoprotein) increases
should be avoided in these patients. Exposure to
by 10 percent.
cold should also be avoided.
Pharmacokinetics: Statins are well absorbed when
HYPOLIPIDEMIC DRUGS given orally but may undergo extensive first pass
metabolism in the liver. Simvastatin is a prodrug
Hyperlipoproteinemias (HPL) are conditions in converted to its active metabolite in the liver.
which the concentration of cholesterol or
Adverse effects include gastrointestinal distur-
triglyceride (TG) carrying lipoproteins in the
bances, headache, insomnia, rashes and angio-
plasma is elevated above normal (Table 5.8). When
edema.
the lipoproteins increase, the development of
Treatment with statins can cause hepato-
atherosclerosis is faster and is a risk factor for
toxicity though not very common. Serum trans-
myocardial infarction. LDL is the primary carrier aminases may be elevated on prolonged therapy.
of cholesterol while VLDL is the carrier of Patients should be watched for hepatotoxicity
triglycerides. Along with reduction of body weight while on statins. All statins can cause myopathy
and low cholesterol diet, hypolipidemic drugs (with myalgia and weakness), rhabdomyolysis
may be given in patients with hyperlipopro- though the incidence is low (<0.1-0.1%).
teinemias. Concurrent use of other drugs that also cause
myopathy including fibrates and niacin should
be avoided.
TABLE 5.8: Plasma lipid levels (mg/dl)
Statins are contraindicated in pregnancy and
lactation as they are not proved to be safe in them.
Grade Total cholesterol Triglycerides
Uses (Table 5.9)
Normal < 200 < 200
1. Statins are used in patients with MI, angina,
Borderline 200-240 200-400
stroke and transient ischemic attacks to lower
High > 240 > 400
cholesterol levels.
88 Pharmacology for Physiotherapy

TABLE 5.9: Choice of hypolipidemics Ezetimibe


Elevated TG levels Gemfibrozil Ezetimibe is a recently developed drug which
Elevated LDL cholesterol Lovastatin; adjuvant- selectively inhibits the absorption of cholesterol
binding resins/nicotinic and other phytosterols by enterocytes. Ezetimibe
acid and its metabolite concentrate in the brush border
Elevated TG + cholesterol Lovastatin + Gemfibrozil of the small intestine and interfere with the
absorption of cholesterol by inhibiting a specific
transport protein NPCILI which takes up
cholesterol from intestinal lumen. As a result there
2. HMG CoA reductase inhibitors are the first is a decrease in hepatic cholesterol leading to
line drugs for hyperlipidemias both for familial increased clearance of cholesterol from the
and secondary hyperlipidemias as in diabetes plasma. The plasma LDL cholesterol decreases
mellitus. by 15-20 percent with a marginal increase in HDL
Fibric acids enhance the activity of the enzyme cholesterol.
lipoprotein lipase which degrades VLDL resulting Ezetimibe also blocks the reabsorption of
in lowering of triglycerides. They also increase cholesterol excreted in the bile. The effects are
HDL levels. Gemfibrozil is the drug of choice in synergistic with statins and the combination can
patients with increased TG levels. bring about a significant (up to 60%) decrease in
LDL cholesterol level.
Adverse effects include GI upset, skin rashes, Ezetimibe undergoes glucuronide conju-
headache, muscle cramps and blurred vision. gation, enterohepatic circulation and is largely
Bile acid binding resins bind bile acids in the excreted through the gut. It is well tolerated and
intestine and increase their excretion. Bile acids with available data, can occasionally cause
are required for intestinal absorption of reversible hepatic dysfunction and myositis. It has
cholesterol. Plasma cholesterol and LDL levels fall. a long half-life-given 10 mg once daily.
Bile acid binding resins are unpleasant to take; Ezetimibe may be used as monotherapy in
they may cause GI upset, constipation and piles. patients with mild hypercholesterolemia or in
They also bind many drugs in the intestines combination with a low dose of statins in patients
thereby reducing their absorption. who have not had adequate response with statins
alone. It may also be used in patients with
Antioxidant phytosteloremia.
Probucol is a synthetic antioxidant which lowers
plasma cholesterol, LDL and HDL levels. It is used DRUGS USED IN THE DISORDERS
with other hypolipidemics. OF COAGULATION

Miscellaneous Hemostasis is the spontaneous arrest of bleeding


from the damaged blood vessels. In the process,
Nicotinic acid—a B group vitamin, inhibits
complex interactions take place between the
lipolysis and increases lipoprotein lipase activity
injured vessel wall, platelets and clotting factors.
resulting in lowering of TGs and LDL levels. It
When there is any injury, there is local
reduces the synthesis of VLDL.
vasoconstriction and platelets stick to one
Neomycin forms insoluble complexes with bile another. A clot forms on this with the help of
acids in the intestines and thus lowers cholesterol fibrin forming a plug which temporarily stops
levels. bleeding.
Cardiovascular System and Blood 89

Clotting factors are proteins synthesized by • Low mol. wt. heparins—Enoxaporin,


the liver. Several proteins interact to form the clot dalteparin, reviparin, nadreparin,
(Fig. 5.3). tinzaparin
• Synthetic heparin derivatives—
Anticoagulants Fondaparinux
• Direct thrombin inhibitors—Hirudin,
Anticoagulants are drugs that reduce the
argatroban.
coagulability of the blood.
B. Slow acting—Oral anticoagulants
• Coumarin derivatives: Bishydroxy-
Classification
coumarin, warfarin sodium, nicouma-
1. Anticoagulants used in vivo lone
A. Fast acting • Indandione derivatives: Phenindione,
• Heparin diphenadione.
• Heparinoids—Heparan sulphate, 2. Anticoagulants used in vitro
dextran sulphate Heparin, citrates, oxalates and sodium edetate.

Fig. 5.3: Major reactions of blood coagulation


90 Pharmacology for Physiotherapy

Heparin was discovered by McLean, a medical treatment of deep vein thrombosis and pulmonary
student in 1916. It was named ‘heparin’ as it was embolism.
first extracted from the liver. It is found in the mast
Direct thrombin inhibitors like argatroban have
cells of the liver, lungs and intestinal mucosa.
a rapid onset of action and predictable absorption;
Heparin is the strongest acid in the body.
frequent monitoring of anticoagulant therapy
Actions: Heparin is a powerful anticoagulant is not needed. Hence they are the preferred
that acts instantaneously both in vivo and in vitro. anticoagulants in several conditions.
Mechanism of action: Heparin activates plasma Synthetic heparin derivative fondaparinux is
antithrombin III which binds to the clotting factors longer acting, risk of thrombocytopenia is less and
and inactivates them. Clotting time is prolonged. does not require frequent monitoring.
Pharmacokinetics: Heparin is not effective Heparin antagonist Protamine sulphate is a
orally. It is given IV or SC. Treatment is monitored protein obtained from the sperm of certain fish.
by the clotting time. Heparin is metabolized by Given intravenously, it neutralizes heparin and
heparinase in the liver. acts as heparin antagonist in heparin overdosage.
Adverse reactions
ORAL ANTICOAGULANTS
1. Bleeding is the most common, major adverse
effect of heparin. Careful monitoring and dose Bishydroxycoumarin was the first oral anti-
control will prevent this to a great extent. coagulant to be identified in North America. Many
2. Hypersensitivity reactions—for commercial use related compounds were then developed and are
heparin is obtained from bovine lung or also being used as rat poisons.
porcine intestine. Because of its animal origin
Mechanism of action: Oral anticoagulants
allergic reactions are quite common.
prevent the synthesis of vitamin K dependent
3. Thrombocytopenia—Heparin induced platelet
clotting factors (factors II, III, IX and X) in the liver.
aggregation and formation of anti-platelet
The onset of action is slow; it develops over
antibodies can both result in thrombocyto-
1-3 days because oral anticoagulants do not
penia. Hepain should be stopped immediately
destroy the already circulating clotting factors.
at the first sign of thrombocytopenia.
Prothrombin time (PT) is measured to monitor the
4. Alopecia is reversible.
treatment. It takes 5-7 days for PT to return to
5. Osteoporosis—on long-term use.
normal after stopping oral anticoagulants.
Contraindications to Heparin Therapy Pharmacokinetics: Warfarin is completely
Bleeding disorders, thrombocytopenia, hemo- absorbed orally and is 99 percent bound to plasma
philia, severe hypertension, intracranial proteins.
hemorrhage, cirrhosis, ulcers in the gut, renal Adverse effects
failure and neurosurgery. 1. Hemorrhage is the main adverse effect.
Low molecular weight (LMW) heparins e.g., Bleeding in the intestines, brain, nose and
Enoxaparin and dalteparin are LMW heparins gums can occur.
which have longer action, lower risk of Treatment—depends on the severity:
thrombocytopenia as well as lower risk of bleeding a. Stop the anticoagulant.
when compared to standard heparin prepa- b. Fresh blood transfusion is given to supply
rations. They are used for the prevention and the clotting factors.
Cardiovascular System and Blood 91

c. Antidote—The specific antidote is vitamin Uses of anticoagulants: Anticoagulants can


K 1 oxide which allows synthesis of prevent extension of the thrombus but cannot
clotting factors. But the response to vitamin destroy the existing clots. Heparin has rapid and
K1 oxide needs several hours. Hence in short-action which makes it suitable for initiating
emergency, fresh whole blood is treatment while warfarin is suitable for long-term
necessary to counter the effects of oral maintenance due to its slow and prolonged action
anticoagulants. and convenience of oral use.
2. Other adverse effects include allergic 1. Venous thrombosis and pulmonary embolism—
reactions, gastrointestinal disturbances and anticoagulants prevent extension of thrombus
teratogenicity. and recurrence of embolism.
2. Postoperative, post-stroke patients; bedridden
Factors influencing oral anticoagulant activity patients due to leg fractures and other causes—
Factors enhancing activity Factors reducing activity who cannot be ambulant for several months—
anticoagulants prevent venous thrombosis
Poor diet, bowel disease, Pregnancy—there is and pulmonary embolism in such patients.
liver disease and chronic increased synthesis 3. Rheumatic heart disease—anticoagulants
alcoholism—result in of clotting factors
prevent embolism.
vitamin K deficiency Hypothyroidism—there
4. Unstable angina—heparin reduces the risk of
is reduced degradation
myocardial infarction in patients with unstable
of clotting factors.
angina.
5. Vascular surgery, artificial heart valves and
Drug Interactions hemodialysis—anticoagulants prevent
thromboembolism.
Many drugs increase warfarin action
1. Drugs that inhibit platelet function—NSAIDs Contraindications to anticoagulant therapy
like aspirin increase the risk of bleeding. • Bleeding disorders including thrombo-
2. Drugs that inhibit hepatic drug metabolism cytopenia
like cimetidine, chloramphenicol and • Severe hypertension
metronidazole enhance plasma levels of • Malignancies
warfarin. • Bacterial endocarditis
3. Drugs that displace warfarin from plasma • Liver and kidney diseases.
protein binding sites like NSAIDs enhance
plasma levels.
THROMBOLYTICS (Fibrinolytics)
4. Drugs like broad spectrum antibiotics inhibit
gut flora thus decreasing vitamin K synthesis. Thrombolytics lyse or dissolve the clot or thrombi
Some drugs reduce the effect of oral anticoagulants. by activating the natural fibrinolytic system.
Tissue
1. Drugs that enhance the metabolism of oral plasminogen Fibrin
anticoagulants—microsomal enzyme indu- Plasminogen Plasmin ↓
cers like barbiturates, rifampicin, griseofulvin activator Fibrin degradation
products
enhance the metabolism of oral anticoagulants.
When these drugs are suddenly withdrawn, Plasminogen circulates in the plasma and also
excess anticoagulant activity may result in some of it is bound to fibrin. Tissue plasminogen
hemorrhages. activator (tPA) activates plasminogen which is
2. Drugs that increase the synthesis of clotting converted to plasmin. Plasmin degrades fibrin
factors—oral contraceptives. thereby dissolving the clot. Thrombolytic agents
92 Pharmacology for Physiotherapy

are streptokinase, urokinase, alteplase, duteplse, ANTIFIBRINOLYTICS


teneteplase, and reteplase anistreplase. All are
Antifibrinolytics inhibit plasminogen activation
expensive drugs.
and thus prevent fibrinolysis.
Streptokinase obtained from β-hemolytic Epsilon aminocaproic acid (EACA) and its
streptococci activates plasminogen. Anti- analogue tranexemic acid are antifibrinolytics.
streptococcal antibodies present in the blood due Tranexemic acid can be given by oral, topical and
to previous streptococcal infections inactivate a intravenous routes.
large amount of streptokinase. Allergic reactions
are common. Uses
Tranexemic acid is used in:
Urokinase is an enzyme prepared from cultures a. Over dosage of fibrinolytics.
of human kidney cells (it was first isolated from b. Menorrhagia, postpartum hemorrhage.
human urine—hence the name). It activates c. After cardiac surgeries including cardio-
plasminogen. It is more expensive than pulmonary bypass.
streptokinase. d. Bleeding peptic ulcer.
Tissue plasminogen activator (tPA) prefe- e. Following dental procedures to prevent
rentially activates plasminogen that is bound to bleeding in patients with hemophilia as a
fibrin which means circulating plasminogen is mouth wash.
largely spared. f. After prostate surgery, tonsillectomy.
g. Epistaxis, bleeding from eye injury.
Alteplase is tPA produced by recombinant DNA h. Hereditary angioedema-this rare condition is
technology. It is very expensive. associated with plasmin induced uncontrolled
Reteplase is modified human tPA obtained by activation of the complement system.
genetic engineering. It has less bleeding tendency
ANTIPLATELET DRUGS
when compared to other fibrinolytics.
Many newer fibrinolytics like duteplase, Platelets form the initial plug at the site of vascular
reteplase, anistreplase and tenecteplase are injury and are also involved in the formation of
available. They are all similar to alteplase with atherosclerosis. By inhibiting the platelet function,
minor differences. thrombosis and atherosclerotic vascular disease
can be largely prevented.
Adverse effects of thrombolytics: Bleeding is Antiplatelet drugs or drugs interfering with
the major toxicity of all thrombolytics. platelet function are aspirin, dipyridamole,
Hypotension and fever can occur. Allergic sulphinpyrazone and ticlopidine.
reactions are common with streptokinase. Antiplatelet drugs include—
Uses 1. PG synthesis inhibitors — Aspirin
1. Acute myocardial infarction—Intravenous 2. Phosphodiesterase inhibitor — Dipyridamol
thrombolytics reduce the morality rate in acute 3. ADP antagonists — Ticlopidine, clopidogrel
MI. 4. Glycoprotein IIb/IIIa receptor antagonists —
2. Deep vein thrombosis and large pulmonary Abciximab, eptifibatide, tirofiban.
emboli are also treated with fibrinolytics. 5. Others — Prostaglandin I2.
Contraindications to thrombolytic therapy Aspirin (See chapter 27) — ThromboxaneA2
• Recent surgery, injury, gastrointestinal promotes platelet aggregation. Aspirin inactivates
bleeding, stroke cyclo-oxygenase (COX) and thereby inhibits the
• Severe hypertension synthesis of thromboxane A2 even in low doses
• Bleeding disorders. (75 mg/day). The COX inhibition is irreversible
Cardiovascular System and Blood 93

and the effect lasts for 7 to 10 days-till fresh Eptifibatide and tirofiban are peptides given
platelets are formed. Aspirin is the most as IV infusion. They are short acting and are tried
commonly used antiplatelet drug. in unstable angina and myocardial infarction.
Dipyridamole is a phosphodiesterase inhibitor
Others
which interferes with platelet function by
increasing platelet cyclic AMP levels. It is used Epoprostenol (PGI2) can be used during hemo-
along with aspirin for the prophylaxis of dialysis to prevent platelet aggregation as an
thromboemboli in patients with prosthetic heart alternative to heparin.
valves.
Uses of Antiplatelet Drugs
ADP Antagonists 1. Myocardial infarction—Aspirin with
Ticlopidine ADP binds to receptors on platelets thrombolytics improve survival in acute MI.
to bring about platelet aggregation. Ticlopidine is Long-term treatment with aspirin reduces
a prodrug. Its active metabolite blocks ADP reinfarction in post-MI patients.
receptors and prevents platelet aggregation. Onset 2. Unstable angina and stable angina pectoris-
of action is slow (7-11 days) and the antiplatelet Aspirin reduces the risk of acute MI.
effect remains for some days even after stopping Clopidogrel may be added to aspirin in
the drug. Dose — 250 mg twice daily. unstable angina.
Adverse effects include dyspepsia, diarrhea, 3. In patients with prosthetic heart valves,
bleeding and leukopenia. It is used in patients valvular heart disease, coronary artery bypass
who cannot tolerate aspirin. surgery–long-term use of low dose aspirin is
recommended.
Clopidogrel has structural similarity to 4. Cerebral thrombosis and TIA—In patients
ticlopidine with similar mechanism of action. Like with transient ischemic attacks aspirin
ticlopidine it is a prodrug and the active metabolite reduces the incidence of stroke and mortality.
blocks ADP receptors. Its actions are additive with In cerebral thrombosis aspirin prevents
aspirin as the mechanisms are different. Toxicity recurrence.
is milder with lesser incidence of leukopenia and 5. Atrial fibrillation—If oral anticoagulants can
thrombocytopenia. not be given, aspirin is useful.
Clopidogrel is used as an alternative when
aspirin cannot be used. It can also be used with COAGULANTS
aspirin for additive effects.
Coagulants are drugs that promote coagulation
Glycoprotein IIb/IIIa receptor antagonists (procoagulants) and control bleeding. They are
Fibrinogen and Von Willebrand afactor bind to also called hemostatics. They may be used locally
glycoprotein IIb/IIIA receptors on the platelets and or systemically. Local hemostatics are called
mediate the action of platelet agonists like styptics. Physical methods like application of
thrombin, collagen and TXA2. Drugs that block pressure, tourniquet or ice can control bleeding.
these receptors inhibit platelet aggregation
Styptics are local hemostatics that are used on
induced by all platelet agonists.
bleeding sites like tooth socket. They are:
Abciximab is a monoclonal antibody which binds 1. Adrenaline: Sterile cotton soaked in 1:10,000
glycoprotein IIb/IIIA receptors and inhibits solution of adrenaline is commonly used in
platelet aggregation. It can cause bleeding and tooth sockets and as nasal packs for epistaxis.
allergic reactions. It is used in patients undergoing Adrenaline arrests bleeding by vasoconstric-
coronary angioplasty. tion.
94 Pharmacology for Physiotherapy

2. Thrombin powder is dusted over the bleeding HEMATINICS


surface following skin grafting. It is obtained
from bovine plasma. Hematinics are compounds required in the
3. Fibrin obtained from human plasma is formation of blood and are employed in the
available as sheets. It is used for covering or treatment of anemias. Iron, vitamin B12 and folic
packing bleeding surfaces. acid are essential for normal erythropoiesis.
4. Gelatin foam is porous spongy gelatin used with
thrombin to control bleeding from wounds. It IRON
gets completely absorbed in 4 to 6 weeks and Iron is essential for hemoglobin production. It is
can be left in place after suturing of the wound. also present in myoglobin, the cytochromes and
5. Thromboplastin powder is used in surgery as a other enzymes. Total body iron is about 2.5 to 5
styptic. grams.
6. Astringents like tannic acid are used on
Daily requirement of iron
bleeding gums.
Adult male 0.5-1 mg
Adult female 1-2 mg
COAGULANTS USED SYSTEMICALLY Pregnancy and lactation 3-5 mg

Vitamin K
Dietary sources of iron: Food that is rich in iron
Vitamin K is a fat-soluble vitamin essential for the are liver, egg yolk, meat, fish, chicken, spinach,
biosynthesis of clotting factors (factors II, VII, IX dry fruits, wheat and apple.
and X by the liver).
Absorption: The average Indian diet provides
about 10-20 mg of iron. Ten percent of this iron is
Uses absorbed. It is mostly absorbed from the upper
1. Vitamin K deficiency. gut in the ferrous form. During deficiency,
2. Newborn babies lack intestinal flora and have absorption is better.
low levels of prothrombin and other clotting Factors that influence iron absorption
factors. Routine administration of vitamin K—
Ascorbic Antacids,
1 mg IM prevents hemorrhagic disease of the acid, amino phosphates,
newborn. acids, meat, Increase phytates, Decrease
3. Oral anticoagulant toxicity. ↑gastric absorption tetracyclines, absorption
acidity presence of
Other Coagulants food in the
stomach
Fresh plasma or whole blood is useful in most
coagulation disorders as it contains all the clotting Transport and distribution: Iron is transported
factors. Other concentrated plasma fractions like with the help of a glycoprotein transferrin and
fibrinogen, factors VIII, II, VII, IX and X are stored as ferritin and hemosiderin, in liver, spleen
available for the treatment of specific deficiencies. and bone marrow.
Snake venoms: Some venoms like Russels viper
Preparations of Iron
venom stimulate thrombokinase and promote
coagulation. Iron can be given both orally and parenterally.
Cardiovascular System and Blood 95

Oral iron preparations tion, cardiovascular collapse and coma.


1. Ferrous sulphate—200 mg tab Immediate diagnosis and treatment are important
2. Ferrous fumarate—200 mg tab as death may occur in 6-12 hr.
3. Ferrous gluconate—300 mg tab
4. Ferrous succinate—100 mg Treatment
5. Iron calcium complex—5% iron
• Stomach wash with sodium bicarbonate
6. Ferric ammonium citrate—45 mg.
solution.
• Ferrous salts are better absorbed than ferric
• Desferrioxamine is the antidote.
salts and are cheaper.
• Correction of acidosis and shock.
• Expensive preparations of iron with
vitamins, liver extract, amino acids, etc. are
Uses of Iron
available but have no clear advantages.
• Dose Ferrous sulphate 3-4 tablets daily. 1. Iron deficiency anemia. The cause for iron
deficiency should be identified. Treatment
Adverse effects of oral iron: Epigastric pain, should be continued depending on the
nausea, vomiting, gastritis, metallic taste, consti- response for 3-6 months to replenish the iron
pation (due to astringent effect) or diarrhea stores.
(irritant effect) are the usual adverse effects. Liquid 2. Iron is given in conditions with increased iron
preparations of iron cause staining of the teeth. requirement as in pregnancy, infancy and pro-
fessional blood donors.
Parenteral iron: Iron is given parenterally only
in some situations. Intramuscular injection of iron
VITAMIN B12 AND FOLIC ACID
is given deep IM. Intravenous iron is given slowly
over 5-10 minutes or as infusion after a test dose. Vitamin B12 and folic acid are water soluble
Iron dextran can be given IM and IV. Iron sorbitol vitamins, belonging to the B-complex group. They
citric acid is given IM. are essential for normal DNA synthesis. Their
deficiency leads to impaired DNA synthesis and
Indications for parenteral iron
abnormal maturation of RBCs and other rapidly
1. When oral iron is not tolerated
dividing cells. This results in megaloblastic
2. Failure of absorption—as in malabsorption,
anemia, characterized by the presence of red cell
chronic bowel disease
precursors in the blood and bone marrow. Other
3. When patients do not take regularly
manifestations of deficiency include glossitis,
4. Severe deficiency with bleeding.
stomatitis and malabsorption; neurological
manifestations can also result.
Adverse Effects of Parenteral Iron
Local: Pain at the site of injection and pigmentation Vitamin B12
of the skin.
Vitamin B12 (Cyanocobalamin) is synthesized by
Systemic: Fever, headache, joints pain, palpitation, microorganisms. Liver, fish, egg yolk, meat, cheese
and rarely anaphylaxis. and pulses are the dietary sources of B12.
Acute iron poisoning is common in infants Vitamin B12 or extrinsic factor is absorbed with
and children in whom about 10 tablets (1-2 g) can the help of intrinsic factor, a protein secreted by
be lethal. Manifestations include vomiting, the stomach. It is carried in the plasma by B12
abdominal pain, hematemesis, bloody diarrhea, binding proteins called transcobalamin and is
shock, drowsiness, cyanosis, acidosis, dehydra- stored in the liver. Requirement: Table 5.10.
96 Pharmacology for Physiotherapy

TABLE 5.10: Daily requirement of Deficiency


vitamin B12 and folic acid
Folate deficiency may be due to dietary folate
Adults Pregnancy and lactation deficiency, malabsorption and other diseases of
Vitamin B12 1-3 μg 3-5 μg the small intestine or drug induced. Phenytoin,
Folic acid 50-100 μg 200-400 μg phenobarbitone, oral contraceptives, methotrexate
and trimethoprim can induce folate deficiency.
Increased requirement as in growing children,
Deficiency pregnancy and lactation can also cause
deficiency. Manifestations include megaloblastic
B12 deficiency may be due to: anemia, glossitis, diarrhea and weakness.
1. Pernicious anemia: There is deficiency of
intrinsic factor resulting in failure of B12 Uses
absorption.
2. Other causes: Chronic gastritis, malabsorption 1. Megaloblastic anemia due to folate as well as
and fish tapeworm infestation (consumes B12). B12 deficiency—folic acid is given orally along
with vitamin B12.
Uses 2. In pregnancy lactation, infancy and other
situations with increased requirement of folic
1. Vitamin B 12 deficiency—prevention and acid.
treatment of megaloblastic anemia due to B12
deficiency. HEMATOPOIETIC GROWTH FACTORS
2. Vitamin B12 neuropathies like subacute com-
bined degeneration respond to vitamin B12. These are glycoprotein hormones that regulate
erythropoiesis. Erythropoietin, granulocyte
Folic Acid colony-stimulating factor (G-CSF), granulocyte
macrophage colony-stimulating factor (GM-CSF)
Folic acid was first isolated from spinach and are the hematopoietic growth factors available for
therefore named as folic acid (from leaf). clinical use. They are useful in the prevention and
Dietary source: Green vegetables, liver, yeast, egg, treatment of anemia and neutropenia in AIDS,
milk and some fruits. Prolonged cooking with aplastic anemia, following cancer chemotherapy
spices destroys folic acid. and bone marrow transplantation.
Central Nervous
System

• GENERAL ANESTHETICS
• LOCAL ANESTHETICS
• SEDATIVE HYPNOTICS
• ALCOHOLS
• ANTIEPILEPTICS
• DRUGS USED IN PARKINSONISM
• OPIOID ANALGESICS AND ANTAGONISTS
• NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
• DRUGS USED IN RHEUMATOID ARTHRITIS AND GOUT
• DRUGS USED IN PSYCHIATRIC DISORDERS—ANTIPSYCHOTICS, ANTIDEPRESSANTS
AND ANTIANXIETY AGENTS
• ANTIDEPRESSANTS
• CNS STIMULANTS

GENERAL ANESTHETICS Ideal anesthetic should be pleasant, non-


irritating, provide adequate analgesia, immobility
General anesthetics are agents that bring about and muscle relaxation; should be non-
reversible loss of sensation and consciousness. inflammable and administration should be easy
Before 1846, alcohol, opium, packing a limb with and controllable and have a wide margin of safety.
ice and concussion, i.e. making the patient Induction and recovery should be smooth and
unconscious by a blow on the head were used to should not affect cardiovascular functions. It
relieve surgical pain. Dr Horace Wells a dentist, should be inexpensive.
tried to demonstrate the effect of nitrous oxide as Classification
an anesthetic in 1844 but was unsuccessful as he
I. Inhalational
removed the gas bag too early. Dr William Morton A. Gases – Nitrous oxide,
who was present at the demonstration, worked cyclopropane
on it and in 1846 demonstrated ether anesthesia B. Liquids – Ether, halothane,
successfully. Since then several anesthetics have enflurane, isoflurane,
been synthesized over the decades. methoxyflurane
98 Pharmacology for Physiotherapy

II. Intravenous 4. It is a bronchodilator.


A. Inducing agents – Thiopentone sodium, 5. Provides full muscle relaxation in deep
methohexitone, anesthesia.
propofol, etomidate 6. Does not sensitize the heart to adrenaline.
B. Dissociative – Ketamine 7. Easy to administer because complicated
anesthesia equipment is not necessary.
C. Neuro- – Fentanyl + Droperidol 8. Inexpensive.
leptanalgesia
D. Benzodiazepines – Diazepam, lorazepam, Disadvantages
midazolam. 1. It is inflammable—hence diathermy is
contraindicated.
INHALATIONAL ANESTHETICS 2. Induction is slow and unpleasant.
3. It is irritating and therefore enhances
Nitrous oxide is a gas with a slightly sweetish respiratory secretions.
odor. It produces light anesthesia without 4. Postoperative nausea and vomiting are
significant depression of respiration or vasomotor frequent.
center. 5. Recovery is slow.
Advantages
Status in anesthesia: Ether is now not preferred
1. Strong analgesic.
because of flammability and irritant property. But
2. Induction is rapid and smooth.
it is still used in developing countries like India
3. It is non-irritating and non-inflammable.
because it is cheap, easy to administer (by open
4. Recovery is rapid.
drop method) and relatively safe.
5. Postoperative nausea is not significant.
6. Has little effect on respiration and cardio- Halothane is a colorless volatile liquid with a
vascular functions, hence ideal for combi- sweet odor. It is non-irritant and non-inflammable.
nation.
7. It is non-toxiedemaver, kidney and brain and Advantages
is quickly removed from lungs. 1. Potent, non-inflammable anesthetic.
2. Induction is smooth and rapid—in 2-5
Disadvantages
minutes anesthesia can be produced.
1. It is less potent and should be used with other
3. Non-irritant—therefore does not increase
agents.
salivary or bronchial secretions.
2. Poor muscle relaxant.
4. Recovery is rapid.
Status in anesthesia: Nitrous oxide is used as an 5. Postoperative nausea and vomiting is of low
adjuvant to other anesthetics. It is used along with incidence.
oxygen (30%).
Disadvantages
Ether is a colorless volatile liquid. It is highly 1. Not a good analgesic; not a muscle relaxant.
inflammable; vapors are irritating. 2. Halothane is a direct cardiac depressant.
Advantages Cardiac output and BP start falling and heart
1. Potent and reliable anesthetic. rate may decrease. It sensitizes the heart to
2. Good analgesic. the actions of adrenaline.
3. Effect on cardiovascular and respiratory 3. It also causes some respiratory depression.
functions are not significant; reflexes are 4. Severe hepatitis which may be fatal occurs
well-maintained. rarely.
Central Nervous System 99

5. Malignant hyperthermia—a genetically onset of action and anesthesia is maintained by


determined reaction occurs rarely. an inhalational agent.
Succinylcholine accentuates this effect of
halothane. It is due to intracellular release of INDUCING AGENTS
calcium which causes muscle contraction
Thiopentone sodium is an ultrashort-acting
and increased heat production. It is treated
barbiturate which when administered IV, rapidly
with dantrolene.
induces anesthesia without analgesia.
6. Expensive.
On IV injection it produces unconsciousness
Status in anesthesia: Halothane is one of the most in 20-30 sec. It is highly lipid soluble; duration of
popular anesthetics. Analgesics and muscle action is 4-7 minutes. It gets rapidly redistributed
relaxants are used along with it. Non-flam- in the body tissues.
mability, non-irritant property, rapid induction
Advantages: Quick onset of action; induction is
and recovery has made halothane an important
smooth, rapid and pleasant.
and preferred anesthetic—most widely used.
Disadvantages: Not a good analgesic nor muscle
Enflurane and isoflurane are similar to halothane
relaxant. Thiopentone sodium cannot be used
except that:
alone as the dose required results in respiratory
1. They are safer regarding the liver toxicity.
and circulatory depression.
2. They do not sensitize the heart to adrenaline.
Isoflurane is extensively used in European Uses: For induction of anesthesia prior to
countries. administration of inhalational anesthetics.
Desflurane and sevoflurane are newer agents Precautions: Equipment for resuscitation should
which allow very rapid induction and recovery. be kept ready.
But they too have some disadvantages. Desflurane
Adverse effects include respiratory depression,
is pungent—may induce coughing and sometimes
hypotension and hiccoughs.
laryngospasm. A special vaporizer is required for
its administration. Sevoflurane is chemically Methohexitone is similar to thiopentone but is
unstable. A metabolite of sevoflurane may cause more potent.
renal damage. If these disadvantages of
Propofol is an oily liquid; quick induction (30
sevoflurane could be overcome, we may have
sec) and recovery (4 min) is possible from a single
found an ideal anesthetic.
dose. It is used for induction and maintenance for
Oxygen in anesthesia: Oxygen should be added short procedures of up to 1 hour duration.
routinely to inhalational agents to protect against
hypoxia (especially when halothane is used). DISSOCIATIVE ANESTHESIA
When O2 is not available, ether is the safest agent
Ketamine is a phencyclidine derivative. In
for maintenance of anesthesia.
anesthetic doses it produces a trance-like state
known as dissociative anesthesia characterized by
INTRAVENOUS ANESTHETICS
intense analgesia, immobility, amnesia (loss of
Intravenous anesthetics allow an extremely memory) and a feeling of dissociation from ones
rapid induction because the blood concentration own body and surroundings. Ketamine hydro-
can be raised rapidly—in one arm-brain chloride given 1-2 mg/kg slow IV or 10 mg/kg IM
circulation (~ 11 sec) there is loss of consciousness. produces dissociative anesthesia within 3-5 min
These are used for induction because of the rapid which lasts for 10-15 min after a single injection.
100 Pharmacology for Physiotherapy

Amnesia lasts for 1-2 hr. Premedication with symptoms may be seen—due to droperidol. It is
atropine is needed. Return to consciousness is employed for endoscopies, burn dressing,
gradual. Delirium may be accompanied. If angiographies and other diagnostic and minor
diazepam is administered pre and postopera- surgical procedures.
tively, delirium can be avoided. Heart rate, CO
Neuroleptanesthesia : Addition of 65 percent N2O
and BP are increased due to sympathetic stimu-
+ 35 percent O2 to the above combination produces
lation.
neuroleptanesthesia.
Advantages
• Provides profound analgesia and can be used BENZODIAZEPINES
as a single agent for minor procedures.
Benzodiazepines like diazepam, lorazepam and
• Respiration is not depressed, does not induce
midazolam are used to induce or supplement
hypotension.
anesthesia. They cause sedation, amnesia and
• Less likely to induce vomiting.
reduce anxiety which are beneficial in such
• Pharyngeal and laryngeal reflexes are only
patients. BZD may be employed alone in pro-
slightly affected.
cedures like endoscopies, reduction of fractures,
• It is particularly useful in children and poor-
cardiac catheterization and cardioversion. IV
risk patients and also in asthmatic patients
midazolam is particularly preferred as it is faster
since it does not induce bronchospasm.
and shorter-acting, more potent and does not cause
Disadvantages pain or irritation at the injection sites. BZDs are
• Hallucinations and involuntary movements also used as preanesthetic medication.
may occur during recovery.
• May be dangerous in hypertensives as it raises PREANESTHETIC MEDICATION
the BP.
Prior to anesthesia, certain drugs are administered
Contraindications: Hypertension, CCF, cerebral in order to make anesthesia safer and more
hemorrhage, increased intracranial tension, pleasant and is known as preanesthetic medi-
psychiatric disorders and pregnancy before term. cation. It is given in order to:
1. Decrease anxiety.
NEUROLEPTANALGESIA 2. Provide amnesia for the preoperative period.
3. Relieve preoperative pain if present.
A combination of fentanyl and droperidol is used.
4. Make anesthesia safer.
Fentanyl is a short-acting (30-50 min) and potent 5. Reduce side effects of anesthetics.
opioid analgesic (page 124). 6. Reduce gastric acidity.
To achieve the above purpose, more than one
Droperidol is a rapidly acting, potent neuroleptic
drug is required. An informative, supportive,
related to haloperidol.
preoperative visit by the anesthesiologist is very
When the combination is given IV, a state of
much essential.
‘neuroleptanalgesia’ is produced. This is charac-
terized by calmness, psychic indifference and Sedative hypnotics: Antianxiety agents like
intense analgesia without loss of consciousness. benzodiazepines are used extensively as
It lasts for 30-40 min. Fentanyl 0.05 mg + preanesthetic medication. They reduce anxiety
droperidol 2.5 mg/ml—4 to 6 ml is infused IV and produce sedation. Diazepam 5-10 mg is given
over 10 min. Patient is drowsy but cooperative. orally. It also produces amnesia. Barbiturates are
Respiratory depression is present. There is a slight not preferred due to the disadvantages like
fall in BP and HR. During recovery extrapyramidal respiratory depression.
Central Nervous System 101

Antihistamines have sedative, antiemetic and postoperative constipation and urinary retention;
anticholinergic properties and are useful, e.g. precipitate asthma and delay recovery from
promethazine. anesthesia.
Antiemetics: Metoclopramide, domperidone or Balanced anesthesia: Since it is not possible to
ondansetron may be used. Antihistamines with achieve ideal anesthesia with a single drug,
antiemetic properties may also be used for this multiple drugs are employed—preanesthetic
purpose. medication, IV anesthetics for induction,
inhalational agents for maintenance, oxygen,
Anticholinergic drugs: Some irritant anesthetics skeletal muscle relaxants and analgesics to attain
like ether increase the salivary and respiratory balanced anesthesia.
secretions. The secretions from the oral cavity may
enter into the larynx causing various problems LOCAL ANESTHETICS
including laryngospasm and aspiration
pneumonia. Hence we need drugs that reduce Local anesthetics (LAs) are drugs that block nerve
these secretions. But we now have less irritant conduction when applied locally to nerve tissue
anesthetics and secretions are less of a problem. in appropriate concentrations. Their action is
Atropine, scopolamine or glycopyrrolate can be completely reversible. They act on every type of
used. They nerve fiber and can cause both sensory and motor
• Reduce the secretions. paralysis in the innervated area. They act on
• Prevent bradycardia due to vagal stimulation. axons, cell body, dendrites, synapses and other
• Prevent laryngospasm which is due to excitable membranes that utilize sodium channels
excessive secretions. as the primary means of action potential genera-
Scopolamine produces more sedation. Glyco- tion.
pyrrolate is a derivative of atropine. As compared Cocaine was the first agent to be isolated by
to atropine glycopyrrolate is longer acting, and is Niemann in 1860. Inspite of its addiction poten-
less likely to cause significant tachycardia. It also tial, cocaine was used for 30 years as a surface
produces less sedation than scopolamine. anesthetic. In an effort made to improve the
properties of cocaine, procaine was synthesized
Drugs that reduce acidity: H 2 blockers like in 1905. It ruled the field for the next 50 years. In
ranitidine decrease gastric acid secretion and are 1943, lignocaine was synthesized and it con-
given on the night before surgery. Decrease in tinues to dominate the field of local anesthetics
gastric secretions reduces the damage to lungs if till today.
aspiration occurs when the patient is on Classification of local anesthetics (LAs) based
anesthesia. on the route of administration and duration of
action—
Gastrokinetic agents: Metoclopramide is a
dopamine antagonist that promotes gastro- I. Injectable
intestinal motility and increases the tone of 1. Short-acting — Procaine,
esophageal end of the stomach. This speeds up chloroprocaine
gastric emptying. The combination of an H2 2. Intermediate-acting — Lignocaine, prilocaine
blocker + metoclopramide provides best protection 3. Long-acting — Tetracaine
against aspiration. (amethocaine),
bupivacaine
Opioids: Like morphine and pethidine reduce — Dibucaine
anxiety and apprehension, provide analgesia and (cinchocaine),
reduce the dose of the anesthetic required. But they ropivacaine,
depress respiration and may cause hypotension, etidocaine.
102 Pharmacology for Physiotherapy

II. Surface — Lignocaine, cocaine, 2. Reduces systemic toxicity of LAs since the
anesthetics tetracaine, benzocaine, absorption rate is reduced and as it gets
oxethazaine, absorbed, it gets metabolized.
dibucaine, dyclonine
SYSTEMIC ACTIONS
Depending on the linking chain in their
structure, LAs can be classified as: Depending on the concentration attained in the
Ester linked – Cocaine, procaine, tetracaine, plasma, any LA can produce systemic effects. LAs
benzocaine, chloroprocaine interfere with the function of all organs in which
Amide linked – Lignocaine (lidocaine), conduction or transmission of impulses occur.
mepivacaine, bupivacaine, Thus CNS, autonomic ganglia, NMJ and all
etidocaine, prilocaine and muscles are affected.
ropivacaine.
CNS: Local anesthetics depress the inhibition from
MECHANISM OF ACTION the cerebral cortex. This loss of inhibition results
in unopposed excitatory activity which is
Local anesthetics prevent the generation and the manifested as restlessness, tremors and may
conduction of nerve impulses. The primary proceed to convulsions. This central stimulation
mechanism of action is blockade of voltage-gated is followed by generalized CNS depression and
sodium channels. death may result from respiratory failure.
Local anesthetics directly interact with specific
sites on the voltage-sensitive Na+ channels and CVS: The primary site of action is the myo-
gradually raise the threshold for excitation. With cardium—lignocaine decreases excitability,
increasing concentration, impulse conduction conduction rate and force of contraction (quinidine
slows, rate of rise of action potential (AP) declines, like effects). It also causes arteriolar dilatation.
AP amplitude decreases and finally the ability to Since procaine is short-acting, procainamide is
generate an AP is abolished. These result from used as an antiarrhythmic. Bupivacaine is more
binding of LA to more and more sodium channels. cardiotoxic than other LAs.
Thus, it prevents the generation of an AP and its
Smooth muscle: LAs depress contractions in the
conduction.
intact bowel. They alsededemascular and
Small nerve fibers are more susceptible as they
bronchial smooth muscles.
present a greater surface area per unit volume.
Thus, smaller fibers are blocked first—autonomic
PHARMACOKINETICS
fibers are blocked first followed by sensory fibers
conducting pain, temperature sense, then touch, Local anesthetics are rapidly absorbed from the
pressure and vibration sensations in the same mucous membranes and abraded skin. Rate of
order. Sensory and motor fibers are equally absorption is dependent on the vascularity of the
sensitive. Non-myelinated fibers are blocked more area. Thus, vasoconstriction decreases the
readily than the myelinated when they are of absorption. Toxicity depends on the balance
smaller diameter. between absorption and metabolism, i.e. if it gets
Addition of a vasoconstrictor like adrenaline metabolized as it gets absorbed, then toxicity is
(1:1,00,000 to 1: 2,00,000) or phenylephrine less. Ester-linked LAs are rapidly hydrolyzed by
(1:20,000): plasma pseudocholinesterase and in the liver.
1. Prolongs the duration of action of LAs by Amide linked LAs are metabolized by the
slowing the rate of absorption from the site liver. They undergo extensive first pass
of administration. metabolism.
Central Nervous System 103

ADVERSE EFFECTS (Table 6.1) 2. Bupivacaine HCl—Widely used. But it can


1. Hypersensitivity reactions—Skin rashes, cause more cardiotoxicity than others.
dermatitis, asthma or rarely Injection 0.25-0.5 percent with or without
anaphyledeedemae reactions are more adrenaline.
common with ester type of drugs. Intradermal 3. Ropivacaine—Is similar to bupivacaine
sensitivity test should be done before using except that it is less cardiotoxic.
these drugs. Moreover, allergy is most often 4. Chloroprocaine HCl—Potency is twice that
due to the preservative methylparaben. of procaine and its toxicity is lower because
Preparations that do not contain this of its more rapid metabolism.
preservative are now available. 5. Etidocaine HCl—Its analgesic action lasts
2. CNS—Dizziness, auditory and visual 2-3 times longer. It is used for epidural and
disturbances, mental confusion, disorien- all types of infiltration and regional anes-
tation, anxiety, muscle tremors, convulsions thesia.
and respiratory failure can result from large 6. Mepivacaine—Action is more rapid in onset
doses. Intravenous diazepam controls and more prolonged than that of lignocaine.
convulsions. Infact, these can be prevented
7. Prilocaine HCl—Onset of action and
by preanesthetic administration of diaze-
duration are longer. Because of it’s toxicity,
pam, especially if large doses are to be used.
its use is restricted to dental procedures.
3. CVS—Hypotension, bradycardia, arrhyth-
mias may be encountered. Rarely cardiac 8. Cocaine—Produces euphoria and is a drug
arrest can occur. of dependence and abuse. It is a surface
4. Local irritation—Can be seen with bupi- anesthetic. It is a protoplasmic poison and
vacaine. Wound healing may be delayed. hence cannot be injected. Cocaine is not
preferred now due to toxicity.
TABLE 6.1: Adverse effects of local anesthetics 9. Procaine—Was widely used once. But is
CNS : Dizziness, confusion, anxiety, now replaced by other agents. It is
tremors, occasionally convulsions hydrolyzed to PABA which interferes with
and respiratory depression sulfonamides. It is rapidly absorbed
CVS : Hypotension, bradycardia, following parenteral administration. It is
arrhythmias ineffective when applied topically—thus not
Hypersensitivity : Rashes, dermatitis, asthma, rarely useful as a surface anesthetic.
reactions anaphylaxis 10. Tetracaine—Is a PABA derivative and is 10
times more toxic and more active than
INDIVIDUAL COMPOUNDS procaine. It is used on the eye as 0.5 percent
drops, ointments 0.5 percent and cream 1
A. INJECTABLE (Table 6.2) percent for topical use. 0.25 to 0.5 percent
1. Lignocaine—Most widely used LA. It is injection is used for spinal anesthesia.
faster and longer-acting. Action is seen in 3
B. LOCAL ANESTHETICS USED
minutes for nerve block. It is useful for all
ONLY ON THE EYE
types of blocks. In contrast to other LAs,
lignocaine causes drowsiness and mental Benoxinate HCl—Within 60 seconds of
clouding. administration it produces corneal anesthesia
Xylocaine 4 percent topical solution, 2 enough to perform tonometry.
percent jelly, 5 percent ointment, 1 percent Proparacaine HCl—Produces little or no initial
and 2 percent injection, 5 percent for spinal irritation—0.5 percent ophthalmic solution is
anesthesia. used.
104 Pharmacology for Physiotherapy

TABLE 6.2: Preparations and uses of some local anesthetics


Drug Preparation Uses
1. Tetracaine 1-2% ointment, eye Topical, spinal anesthesia
drops, cream, powder
2. Lignocaine 2-4% drops, spray, jelly, Topical, infiltration, nerve block, spinal,
ointment, cream, 1-10% Inj epidural and IV regional anesthesia
3. Benzocaine 1-2% dusting powder, 5% Topical anesthesia
suppository, cream, gels,
ointments, 20% spray
4. Oxethazaine 0.2% suspension Topical anesthesia (used in peptic ulcer)
5. Prilocaine 5% cream, 4% Inj Topical, nerve block anesthesia
6. Dibucaine 0.5-1% cream Topical anesthesia
7. Mepivacaine 1-3% Inj Nerve block, epidural anesthesia
8. Bupivacaine 0.25-0.75% Inj Infiltration, nerve block,
spinal, epidural anesthesia
9. Ropivacaine 2-10% Inj Infiltration, nerve block,
spinal, epidural anesthesia
10. Etidocaine 1% Inj Epidural anesthesia

C. LOCAL ANESTHETICS USED ON 1. Surface anesthesia: Anesthesia of mucous


THE SKIN AND MUCOUS MEMBRANES membrane of the eyes, nose, mouth,
Local anesthetics used on the skin and mucous tracheobronchial tree, esophagus and
membranes are lignocaine, dibucaine, dyclonine genitourinary tract can be produced by direct
hydrochloride and pramoxine hydrochloride. application of the anesthetic solution.
These drugs are effective when used topically in Tetracaine 2 percent, lignocaine 2-10 percent
the symptomatic relief of anal and genital pruritus, are most often used. Phenylephrine (but not
poison ivy rashes, acute and chronic dermatoses. adrenaline) produces vasoconstriction on
Dibucaine is the most potent, most toxic and topical application and prolongs the duration
longest-acting LA. It is available as cream and of action. Anesthesia is entirely superficial and
ointment. does not extend to submucosal structures. But
LAs are absorbed from mucous membranes
D. POORLY SOLUBLE ANESTHETIC and may result in systemic toxicity. Local
These are too slowly absorbed to be toxic. They anesthetics can also be used on abraded skin.
can be applied to wounds directly and ulcerated Surface anesthesia is useful in the eye for
surfaces as they produce sustained anesthetic tonometry, surgery, nasal lesions, stomatitis,
effect, e.g. benzocaine. sore throat, tonsillectomy, endoscopies,
intubation, gastric ulcer, burns and
USES OF LOCAL ANESTHETICS proctoscopy. Proparacaine is used on the eye
for surface anesthesia.
Local anesthesia is the loss of sensation without
the loss of consciousness or impairment of central 2. Infiltration anesthesia: Injection of a local
control of vital functions. Depending on the site anesthetic solution directly into the tissue can
and technique of administration, LA can be: be (i) superficial—only into the skin, or (ii) into
Central Nervous System 105

deeper structures including intra-abdominal Onset of action is within 3 minutes with


organs. Duration of anesthesia can be lignocaine. Duration depends on lipid
increased by adrenaline (1:2,00,000). Adrena- solubility and protein binding. Anesthesia by
line should not be used (i) around end arteries nerve block lasts longer than by field block or
to avoid necrosis, and (ii) intradermally to infiltration techniques. Nerve blocks are done
avoid sloughing. Drugs used are lignocaine, for tooth extraction, operations on the eyes,
procaine, bupivacaine. limbs and in neuralgias.
Advantage: By using infiltration anesthesia, it 5. Spinal anesthesia (SA): Local anesthetic
is possible to provide anesthesia without solution is injected into the subarachnoid
disturbing normal body activities. space between L2-3 and L3-4. The drug acts
Disadvantage: Large amounts of the anesthetic on nerve roots. Lower abdomen and lower
is required in major surgeries which may result limbs are anesthetized and paralyzed. The
in systemic toxicity. level of anesthesia can be altered by changing
Uses: For minor procedures like incisions, the volume of injection, specific gravity of the
drainage of an abscess, excision, etc. solution and posture of the patient. Level of
sympathetic block produced is 2 segments
3. Field block: Subcutaneous injection of a LA higher and motor paralysis is 2 segments
solution proximal to the site to be anesthetized, lower than sensory or cutaneous anesthesia.
interrupts nerve transmission in the region Duration depends on the concentration, dose
distal to the injection. Sites such as forearm, and the drug itself.
scalp, anterior abdominal wall and lower
limbs are used for field block. Knowledge of Advantages: Safer, provides good analgesia and
the neuroanatomy of the area is essential. muscle relaxation and there is no loss of
Advantages: Lesser dose can be used to provide consciousness. In cardiac, pulmonary and
a greater area of anesthesia. renal diseases, SA may be preferred over
general anesthesia whenever possible.
4. Nerve block: Injection of a solution of a LA
around individual peripheral nerves or nerve Uses: Surgical procedures on the lower limb,
plexuses produces larger areas of anesthesia pelvis, lower abdomen, obstetric procedures,
with a smaller amount of the drug than the cesarean section and other operations are done
above techniques. Anesthesia starts a few on spinal anesthesia.
centimeters distal to the injection. Complications of SA
Nerve block anesthesia is useful for: 1. Hypotension and bradycardia due to
1. Blocks of brachial plexus for procedures on sympathetic blockade.
the arm (distal to deltoid). 2. Respiratory paralysis—hypotension and
2. Intercostal nerve blocks to anesthetize ischemia of the respiratory center results
anterior abdominal wall. in respiratory failure. Due to paralysis of
3. Cervical plexus block for surgery of the neck. the abdominal muscles, cough reflex is less
4. Sciatic and femoral nerve blocks for effective resulting in stasis of respiratory
surgeries distal to the knee. secretions → respiratory infections.
5. Blocks of nerves at wrist and ankle. 3. Headache due to seepage of CSF, can be
6. Radial and ulnar nerve block at the elbow. treated with analgesics.
7. Sensory cranial nerve blocks. 4. Cauda equina syndrome is uncommon—
8. Facial and lingual nerve blocks. control over bladder and bowel sphincters
9. Inferior alveolar nerve block for extraction is lost because of damage to nerve roots.
of lower jaw teeth. 5. Infection—resulting in meningitis.
106 Pharmacology for Physiotherapy

6. Nausea and vomiting—premedication can Sleep can be classified into two types depend-
be given to prevent this. ing on the physiological characteristics.
1. NREM (Non-rapid eye movement) sleep.
6. Epidural anesthesia: LA is injected into the
2. REM (Rapid eye movement) sleep.
spinal extradural space and it acts on the nerve
Throughout the night, NREM and REM sleep
roots. It is technically more difficult and
cycles repeat alternately for brief periods.
comparatively larger volumes of the anesthetic
Approximately one-third of our life is spent in
are needed.
sleep.
Advantages
1. Sensory blockade is 4-5 segments higher CLASSIFICATION
than motor blockade. This is useful in 1. Benzodiazepines
childbirth, as the mother has no labor pain Long-acting Diazepam,
and can still cooperate in the process of labor chlordiazepoxide,
and is conscious throughout. flurazepam, chlorazepate.
2. As there is no risk of injecting into SA space, Short-acting Temazepam, lorazepam,
there are no chances of infection. triazolam, midazolam,
nitrazepam, clonazepam,
7. Intravenous regional anesthesia: This type alprazolam
of anesthesia is useful for rapid anestheti- 2. Barbiturates Phenobarbitone,
zation of an extremity. A rubber bandage is mephobarbitone, secobarbi-
used to force the blood out of the limb (veins) tone, pentobarbitone,
and a tourniquet is applied to prevent the re- thiopentone, hexobarbitone
entry of the blood. A dilute solution of the local 3. Newer agents Zolpidem, zopiclone,
anesthetic is then injected intravenously. It eszopiclone, zaleplon
diffuses into extravascular tissues. Onset of 4. Miscellaneous Paraldehyde, chloral
anesthesia is in 2 minutes. Because of the pain hydrate, glutethimide.
produced by the tourniquet, this type of
anesthesia is used for procedures lasting less BENZODIAZEPINES (BZD)
than one hour. About 25 percent of the drug Chlordiazepoxide was the first BZD to be
enters into the systemic circulation. This type introduced into clinical medicine in 1961 and
of anesthesia is commonly used on the upper since then thousands of BZDs have been
limbs though it can also be used on the legs synthesized of which 35 are now in clinical use.
and the thighs.
Pharmacological Actions
SEDATIVE HYPNOTICS The most important actions of BZDs are on the
CNS and include—
Sedative is a drug that produces a calming or 1. Sedation and hypnosis.
quietening effect and reduces excitement. It may 2. Reduction in anxiety.
cause drowsiness. Hypnotic is a drug that induces 3. Muscle relaxation.
sleep resembling natural sleep. Both sedation and 4. Anticonvulsant effects.
hypnosis may be considered as different grades Sedation and hypnosis: BZDs hasten the onset
of CNS depression. All human beings need sleep. of sleep and increase the duration of sleep. The
Insomnia is sleeplessness. Since centuries man quality of sleep resembles natural sleep more
has sought the help of drugs and other remedies closely when compared to other hypnotics.
for insomnia. Tolerance develops to this effect gradually.
Central Nervous System 107

Anxiolytic or antianxiety effects: BZDs reduce impaired motor coordination such as driving
anxiety and aggression and thus produce a skills—therefore, while on BZDs driving should
calming effect. be avoided.
In some patients it may cause irritability and
Muscle relaxant action: BZDs reduce muscle tone
anxiety.
by a central action. Generally anxiety is associated
with an increased muscle tone and may be Tolerance and dependence: Both tolerance and risk
responsible for aches and pains in these patients. of dependence are less with BZDs as compared to
The muscle relaxation by BZDs adds to its barbiturates. Patients develop tolerance to the
beneficial effects in such patients. sedative effects. If BZDs are suddenly stopped after
Anticonvulsant effects: BZDs have anticonvulsant long-term administration, withdrawal symptoms
properties (see page 114). like anxiety, sleeplessness, irritability and
sweating can occur.
Mechanism of Action
Uses of BZDs
BZDs bind to the BZD receptors and enhance the
effect of GABA—the inhibitory neurotransmitter. 1. Insomnia: BZDs are the agents of choice in
treatment of insomina.
BZDs as hypnotics—when compared to barbiturates: 2. In anxiety states: BZDs are the most
1. BZDs induce sleep which more closely commonly used anxiolytics for the treatment
resembles natural sleep and has less of anxiety states and anxiety neuroses.
hangover. 3. As anticonvulsants: IV diazepam is the drug
2. In hypnotic doses they do not affect respiration of choice in the treatment of status
or cardiovascular functions. epilepticus. Clonazepam is used with other
3. BZDs have a higher safety margin and are antiepileptic drugs.
safer than barbiturates even in overdoses. The 4. Muscle relaxant: BZDs are centrally acting
respiratory depression in overdoses is milder. muscle relaxants used in chronic muscle
4. In case of BZD overdosage, a specific BZD spasm and spasticity.
antagonist—flumazenil can be used to reverse 5. As preaneshetic medication BZDs are useful
the symptoms. for their sedation and amnesia, anxiolytic
5. BZDs do not cause microsomal enzyme effects.
induction and therefore do not alter the blood 6. As an anesthetic intravenous diazepam or
levels of other drugs. midazolam may be used for short surgical
6. BZDs have lower abuse liability. procedures and to supplement general
Because of the above reasons, BZDs are the anesthetics.
most preferred sedative hypnotics. 7. During alcohol withdrawal: BZDs are useful
in patients during withdrawal of alcohol or
Pharmacokinetics
other sedative-hypnotics.
There are significant pharmacokinetic differences
among BZDs due to their difference in lipid Flumazenil is a BZD receptor antagonist which
solubility. competes with BZDs for the receptor and reverses
all the actions of BZDs.
Adverse Effects
Uses
BZDs are generally well tolerated. The common
side effects include drowsiness, confusion, 1. To reverse BZD sedation/anesthesia
amnesia, lethargy, ataxia, day time sedation and 2. In BZD overdosage.
108 Pharmacology for Physiotherapy

BARBITURATES Skeletal muscles: Higher doses of barbiturates


Barbiturates are derivatives of barbituric acid and depress the excitability of the neuromuscular
were the largest group of hypnotics in clinical use junction.
until the 1960s.
PHARMACOKINETICS
Classification
Barbiturates are well-absorbed and widely
Barbiturates can be classified based on their distributed in the body. Barbiturates are meta-
duration of action as: bolized in the liver. They are hepatic microsomal
Long-acting Phenobarbitone, enzyme inducers. The metabolites are excreted in
mephobarbitone the urine.
Short-acting Pentobarbitone, butobarbitone
Ultrashort-acting Thiopentone, hexobarbitone, ADVERSE REACTIONS
methohexitone
Hangover may be accompanied by nausea,
Mechanism of Action vomiting, vertigo and diarrhea. Changes of mood,
impaired judgement and fine motor skills may be
Barbiturates bind to GABA receptors and enhance seen. Respiratory depression and hypersensitivity
the inhibitory activity of GABA. reactions are common.

PHARMACOLOGICAL ACTIONS Tolerance and dependence: On repeated


administration, tolerance develops to the effects
CNS:
of barbiturates.
Sedation: Barbiturates cause sedation and induce
Development of dependence to barbiturates
sleep. They reduce anxiety and impair memory.
make them one of the drugs of abuse. Withdrawal
They can produce euphoria and are drugs of
symptoms include anxiety, restlessness, abdo-
addiction while some people may experience
minal cramps, hallucinations, delirium and
dysphoria. Barbiturates produce hyperalgesia
convulsions.
(increased sensitivity to pain). Therefore
barbiturates, when given as hypnotics for a patient Acute barbiturate poisoning: In acute barbiturate
in pain may be more troublesome than being of poisoning, there is respiratory depression,
any benefit. hypotension and shock. It can be fatal. There is no
Anesthesia: In higher doses barbiturates produce specific antidote for treatment. Stomach wash,
general anesthesia. The ultra short-acting forced alkaline diuresis and hemodialysis should
barbiturates like thiopentone sodium are used be done.
intravenously for this effect.
Uses: Because of respiratory depression and risk
Anticonvulsant effects: All barbiturates have of abuse, barbiturates are generally not preferred.
anticonvulsant action. Phenobarbitone is used in 1. Sedation and hypnosis: Benzodiazepines are
the treatment of epilepsy. preferred to barbiturates as sedative hypnotics.
2. Anesthesia: Thiopentone sodium is used IV for
Respiratory system: Barbiturates depress the
the induction of general anesthesia.
respiration.
3. Preanesthetic medication: Barbiturates were used
Cardiovascular system: Barbiturates cause mild earlier for the sedative-hypnotic property, but
hypotension. are not preferred now.
Central Nervous System 109

4. Antiepileptic: Phenobarbitone is used as an the liver both by microsomal and non-microsomal


antiepileptic (page 113). enzymes. It has the advantages that withdrawal
5. Neonatal jaundice: Phenobarbitone is a micro- symptoms are very mild after stopping it and no
somal enzyme inducer. It enhances the tolerance develops. It has rapid onset but short
production of the enzyme required for meta- duration of action. No significant side effects are
bolism and excretion of bilirubin. It therefore reported in therapeutic doses.
helps in the clearance of jaundice in the
neonates. Uses
Because zaleplon has a rapid onset of action, it is
NEWER AGENTS
useful in patients who require a long time to fall
The newer agents zolpidem, zopiclone, asleep (long sleep latency). Duration of sleep is
eszopiclone and zaleplon are hypnotics. not much prolonged with zaleplon.
• They are not BZDs but produce their effects by
binding to the GABAA receptors and facilitate Zopiclone
the inhibitory actions of GABA.
Zopiclone is another new hypnotic. Its actions
• The modification of sleep pattern is negligible
resemble those of BZDs. Zopiclone binds to the
in therapeutic doses.
GABAA receptor and potentiate the effects of
• The risk of dependence and tolerance is lower
GABA. It does not suppress REM sleep and
than with BZDs.
prolongs deep sleep.
• These newer agents are used for short periods
to treat insomnia. Adverse effects include dryness of mouth,
• They are all rapid and short acting agents and metallic taste; higher doses can cause impaired
produce minimum hangover. psychomotor performance.
• Their actions are blocked by flumazenil. Eszopiclone is an isomer of zopiclone.
• They are selective hypnotics—do not produce
anesthesia, are not muscle relaxants or
MISCELLANEOUS
anticonvulsants.
Chloral hydrate is used as an alternative to BZD.
Zolpidem It has a bad taste and is an irritant—causes nausea
and vomiting. It produces hypnosis without
Zolpidem is a good hypnotic but has weak
affecting respiratory and cardiovascular
anticonvulsant, anxiolytic and muscle relaxant
functions. Not preferred now.
effects.
Zolpidem does not suppress deep sleep and Paraldehyde is a colorless, transparent,
the suppression of REM sleep is negligible. It is pungent, inflammable liquid. It is an irritant and
short acting (t½-2 hrs) but the effects on sleep can dissolve plastic—cannot be given by a plastic
continue for a longer time even after stopping syringe. It is a good hypnotic causing little
zolpidem. The duration of sleep is 8 hrs after a hangover. It can be given rectally, intramuscularly
single dose. or orally.
Adverse effects include dizziness and diarrhea. It also has anticonvulsant properties.

Zaleplon Uses
Zaleplon is rapidly absorbed from the gut and 1. As an anticonvulsant.
has a short t½ of about 1 hour. It is metabolized in 2. Hypnotic—rarely used.
110 Pharmacology for Physiotherapy

ALCOHOLS 2. Bed sores: When rubbed onto the skin, alcohol


hardens the skin and prevents bed sores.
ETHYL ALCOHOL (Ethanol) 3. Alcoholic sponges are used for reduction of
Ethyl alcohol is manufactured by fermentation of body temperature in fevers.
sugars. It is a colorless, volatile, inflammable 4. Appetite stimulant: About 50 ml of 6-10 percent
liquid. The ethanol content of various alcoholic alcohol given before meals is an appetite
beverages ranges from 4-55 percent. stimulant.
5. Neuralgias: In severe neuralgias like
Actions trigeminal neuralgia, injection of alcohol
1. Local: On topical application, ethanol around the nerve causes permanent loss of
evaporates quickly and has a cooling effect. It transmission and relieves pain.
is an astringent—precipitates surface proteins 6. In methanol poisoning (discussed ahead).
and hardens the skin. 40-50 percent alcohol is
rubefacient and counter irritant. Alcohol is Disulfiram
also an antiseptic. At 70 percent, it has Disulfiram inhibits the enzyme aldehyde
maximum antiseptic properties which dehydrogenase. If alcohol is consumed after taking
decrease above that. It is not effective against disulfiram, acetaldehyde accumulates and within
spores. few minutes it can produce flushing, throbbing
2. CNS: Alcohol is a CNS depressant. Small headache, nausea, vomiting, sweating, hypo-
doses cause euphoria, relief of anxiety and loss tension and confusion called the antabuse
of social inhibitions. Moderate doses impair reaction. The effect lasts for 7-14 days after
muscular coordination and visual acuity stopping disulfiram. The reactions can sometimes
making driving dangerous. With higher doses be very severe and therefore treatment should be
mental clouding, impaired judgment, given in a hospital.
drowsiness and loss of self control result. High Other drugs that cause antabuse reaction are
doses cause coma. Death is due to respiratory metronidazole, chlorpropamide, tolbutamide,
depression. griseofulvin, cephalosporins and phenyl-
Alcohol may precipitate convulsions in butazone.
epileptics. Tolerance develops on long-term use. Contraindications: Patients with liver disease,
Chronic consumption of moderate amounts patients physically dependent on alcohol.
of alcohol results in accumulation of fat in the
liver, liver enlargement, followed by fatty METHYL ALCOHOL
degeneration and cirrhosis. (Methanol, Wood Alcohol)
Alcohol induces microsomal enzymes.
Methanol is used to denature ethyl alcohol.
Other effects: Alcohol causes vasodilation in the Ingestion results in methanol poisoning.
skin causing warmth. But this increases heat loss
and should not be used in cold weather. Alcohol Alcohol
also increases gastric secretion. It is an appetizer. Methanol Formaldehyde
Low doses taken over a long-time increases HDL dehydrogenase
and lowers LDL cholesterol. Alcohol is a diuretic Aldehyde
(↓ADH secretion). Food value is 7 calories/gram. Formic acid
dehydrogenase
Uses Toxic effects are due to formic acid. Mani-
1. Antiseptic: 70 percent alcohol is applied festations are vomiting, headache, vertigo, severe
topically. abdominal pain, hypotension, delirium, acidosis
Central Nervous System 111

and coma. Formic acid has affinity for optic nerve Simple partial seizures: The symptoms depend
and causes retinal damage resulting in blindness. on the site that is affected in the cortex, e.g. if the
Death is due to respiratory failure. motor cortex representing the right thumb is
involved, there is recurrent contractions of the
Treatment right thumb. If the sensory area representing the
left palm is involved, there is numbness or
1. Correction of acidosis: As acidosis hastens
paresthesia of the left palm. This type of seizures
retinal damage, immediate correction of
last for 20-60 seconds.
acidosis with IV sodium bicarbonate
infusion helps in preventing blindness. Complex partial seizures: This is characterized
2. Patient should be kept in a dark room to by purposeless movements like lipsmaking, hand
protect the eyes. wringing or swallowing that lasts for 30 sec to 2
3. Gastric lavage should be given. minutes. Consciousness is impaired.
4. BP and ventilation should be maintained.
5. Ethyl alcohol is given as infusion. It Generalized seizures They may be:
competes with methanol for alcohol dehydro-
genase, slows the metabolism of methanol Absence seizures (petitmal): In this, there is
and thus prevents the formation of toxic sudden onset of impaired consciousness and the
metabolites. person is staring. He stops all activities and the
episode lasts for a short period usually less than
30 seconds.
ANTIEPILEPTICS
Myoclonic seizures: They involve a sudden, brief,
Epilepsy is a common neurological abnormality shock-like contraction of muscles. It may be limited
that affects about 0.5-1 percent of the population. to a part of the body or may affect the whole body.
Epilepsy is a chronic disorder characterized by
recurrent seizures often accompanied by episodes Atonic seizures (Drop attacks): They are
of unconsciousness and/or amnesia. It is a characterized by sudden loss of postural tone and
disorder of brain function. Convulsions are the head may drop for a few seconds or the person
involuntary, violent spasms series of jerking or may drop to the ground for no reason.
prolonged contractions of the skeletal muscles. Tonic-clonic seizures (Grandmal epilepsy): This
Seizure is an alteration in behavior because is characterized by sudden loss of consciousness
of abnormal firing of some brain neurons. In most followed by sustained contraction of muscles
of the cases, the cause is not known. It may be due throughout the body (known as tonic phase),
to various reasons including trauma during birth lasting for 1 minute and then, a series of jerks, i.e.
process, head injury, childhood fevers, brain periods of muscle contraction alternating with
tumors, meningitis or drug induced (e.g. periods of relaxation (clonic phase) lasting for 2-4
chlorpromazine, methylxanthines). minutes follow. CNS depression then occurs and
Seizures have been classified into partial and the person goes into sleep. Injury may occur during
generalized seizures. the convulsive episode. The episode of tonic clonic
seizures may be preceded by ‘aura’.
Partial seizures are classified as simple partial
in which there is no impairment of consciousness Status epilepticus: This is continuous or repeated
and complex partial seizures with impairment of seizures of any variety without recovery of
consciousness. consciousness between the attacks.
112 Pharmacology for Physiotherapy

Classification of Antiepileptic Drugs kinetics as the dose increases. Therefore,


monitoring of plasma concentration is useful.
Hydantoins Phenytoin, mephenytoin
Phenytoin is an enzyme inducer.
Barbiturates Phenobarbitone,
mephobarbitone Adverse Effects
Deoxybarbiturate Primidone
Adverse effects depend on the dose, duration and
Iminostilbene Carbamazepine route.
Succinimide Ethosuximide 1. Nausea, vomiting, epigastric pain, anorexia.
GABA transaminase Valproic acid, vigabatrin 2. Nystagmus, diplopia, ataxia are common.
inhibitors 3. Gingival hyperplasia is more common in
children on prolonged use.
Benzodiazepines Diazepam, Clonazepam,
4. Peripheral neuropathy.
Lorazepam, Clorazepate
5. Endocrine i. Hirsutism, acne, coarsening of
Miscellaneous Gabapentin, lamotrigine, facial features.
tiagabine, vigabatrin, ii. Hyperglycemia—as pheny-
topiramate, felbamate, toin inhibits insulin release.
levetiracetam, zonisamide, iii. ↓ release of ADH.
acetazolamide, lacosamide, iv. Osteomalacia, hypocalcemia
amphetamine. due to altered metabolism of
vitamin D and inhibition of
PHENYTOIN (Diphenylhydantoin) intestinal absorption of Ca.++
Phenytoin was synthesized in 1908, but its Phenytoin also reduces target
anticonvulsant property was discovered only in tissue sensitivity to vitamin D.
1938. 6. Hypersensitivity—rashes, systemic lupus
erythematosus, hepatic necrosis, lymph-
Pharmacological Actions adenopathy and neutropenia.
7. Megaloblastic anemia—as phenytoin
CNS: Phenytoin has good antiseizure activity. It decreases absorption and increases excretion
is one of the most effective drugs against of folates.
generalized tonic-clonic seizures and partial 8. Teratogenicity—when taken by the pregnant
seizures. lady, phenytoin produces fetal hydantoin
syndrome characterized by hypoplastic
Mechanism of Action phalanges, cleft palate, harelip and micro-
Phenytoin causes blockade of the sodium chan- cephaly in the offspring.
nels and stabilizes the neuronal membrane. It Toxic doses—cerebellar and vestibular effects
inhibits the generation of repetitive action are prominent; drowsiness, delirium, confusion,
potentials. hallucinations, altered behavior and coma follow.

Pharmacokinetics Uses
Phenytoin is poorly water-soluble—hence absorp- 1. Generalized tonic-clonic seizures and partial
tion is slow. Phenytoin is 90 percent bound to seizures (not useful in absence seizures).
plasma proteins. It is metabolized in the liver 2. Status epilepticus—phenytoin is used by
initially by first order and later by zero order slow IV injection.
Central Nervous System 113

3. Trigeminal neuralgia—as an alternative to similar to phenytoin, i.e. it blocks sodium


carbamazepine. channels.
4. Cardiac arrhythmias—Phenytoin is useful Carbamazepine is also useful in the treatment
in digitalis induced arrhythmias. of trigeminal neuralgia (severe pain along the
distribution of the trigeminal nerve) and
Drug Interactions glossopharyngeal neuralgia.
• Phenytoin is an enzyme inducer. Given with Carbamazepine is also found to be beneficial
phenobarbitone, both increase each other's in mood disorders.
metabolism. Also phenobarbitone competi- Pharmacokinetics: Absorption is slow and
tively inhibits phenytoin metabolism. erratic; has a t½ of 10-20 hours. It is a microsomal
• Carbamazepine and phenytoin enhance each enzyme inducer.
other’s metabolism.
• Valproate displaces protein bound pheny- Adverse effects: Drowsiness, vertigo, ataxia,
toin and produce phenytoin toxicity. diplopia, blurring of vision, nausea, vomiting and
• Cimetidine and chloramphenicol inhibit the dizziness are common. Driving is dangerous for
metabolism of phenytoin resulting in toxicity. patients on carbamazepine. Hypersensitivity reac-
• Antacids ↓ absorption of phenytoin. tions—like skin rashes may occur. Hematological
toxicity includes leukopenia, thrombocytopenia
PHENOBARBITONE (page 108) and rarely agranulocytosis and aplastic anemia.
Phenobarbitone was the first effective antiepileptic It is a teratogen.
drug to be introduced in 1912. It is still used as an
antiepileptic. Uses

Antiepileptic actions: Phenobarbitone has 1. Generalized tonic clonic seizures (grand mal
specific antiepileptic activity and raises the epilepsy).
seizure threshold. Primidone which is rarely used 2. Simple and complex partial seizures—
now is metabolized to phenobarbitone. especially temporal lobe epilepsy.
3. Trigeminal neuralgia and glossopharyngeal
Mechanism of action: Barbiturates enhance the neuralgia—carbamazepine is the drug of
inhibitory activity of GABA in the CNS. choice for these neuralgias and has to be
Pharmacokinetics: Oral absorption of given for several months.
phenobarbitone is slow but complete. It is a 4. Bipolar mood disorder—carbamazepine is
microsomal enzyme inducer. used as an alternative to other antidepres-
sants.
Uses: Phenobarbitone is one of the widely used
antiepileptic because of its efficacy and low cost. ETHOSUXIMIDE
It is used in:
1. Generalized tonic-clonic seizures. Ethosuximide is the primary agent for absence
2. Partial seizures. seizures. It raises the seizure threshold.
3. In neonatal jaundice (see page 14) Mechanism of action: Ethosuximide reduces the
calcium currents (T-currents) in the thalamic
CARBAMAZEPINE neurons.
Carbamazepine is closely related to imipramine.
Pharmacokinetics: Absorption is complete on
Antiseizure activity: Carbamazepine has good administration of oral dosage forms. It is
antiseizure activity. It’s mechanism of action is metabolized in the liver.
114 Pharmacology for Physiotherapy

Adverse effects: The most common adverse Valproate is also useful as a mood stabilizer
effects are nausea, vomiting, epigastric pain, in bipolar mood disorder.
gastric irritation and anorexia. These can be
avoided by starting with a low dose and gradually BENZODIAZEPINES
increasing it. CNS effects like drowsiness, fatigue,
Benzodiazepines have useful anticonvulsant
lethargy, euphoria, dizziness, headache and
properties. Diazepam is the drug of choice in
hiccough are dose-related effects. Hypersensitivity
status epilepticus. Clonazepam is a potent
reactions like rashes, urticaria, leukopenia,
antiepileptic useful in absence and myoclonic
thrombocytopenia or pancytopenia have been
seizures. But tolerance develops to its antiepileptic
reported.
effects. Clobazam causes less sedation and is
Uses: Ethosuximide is the drug of choice for effective in most types of epilepsies.
absence seizures.
NEWER ANTIEPILEPTICS
VALPROIC ACID Gabapentin is a highly lipid soluble analog of
Valproic acid (salt→sodium valproate) is a very GABA which was designed to cross the BBB. It is
effective antiepileptic drug useful in many types effective in tonic clonic seizures. Its exact
of epilepsies including absence seizures, partial mechanism of action is not known, but it does not
and generalized tonic-clonic seizures. act directly on GABA receptors. It is well tolerated
and does not influence the plasma concentrations
Mechanism of action: Valproic acid acts by of other antiepileptics.
multiple mechanisms. Adverse effects include ataxia, fatigue,
1. It enhances the level of GABA by: drowsiness and dizziness. Tolerance develops to
i. Increasing the synthesis of GABA—by these effects in 1-2 weeks. Gabapentin is used in
increased activity of GABA synthetase combination with other antiepileptic drugs, as an
enzyme. add on drug in partial seizures. It is also used in
ii. Decreasing the metabolism of GABA—by migraine, neuropathic pain and in bipolar mood
inhibiting GABA transaminase enzyme. disorder.
2. Like phenytoin, it blocks the sodium channels.
Pregabalin is a prodrug, which is more potent
3. Like ethosuximide, it suppresses the calcium
than gabapentin.
‘T’ currents in the hypothalamus.
Lamotrigine has a broad spectrum of
Adverse effects: Gastrointestinal symptoms like antiepileptic activity. It inhibits the sodium
nausea, vomiting, epigastric distress occur channels and also inhibits the release of the
initially. Tremors, sedation, ataxia, rashes and excitatory amino acids like glutamate. It is
alopecia are rare. Valproic acid can cause completely absorbed from the gut. Lamotrigine
fulminant hepatitis—though rare can be fatal. may cause skin rashes, nausea, ataxia and
Hence careful monitoring of liver functions is dizziness. It is used either alone or with other
mandatory. Valproic acid is teratogenic, it can drugs in partial and generalized seizures.
cause neural tube defects.
Vigabatrin is a GABA analog which acts by
Uses: Useful in partial and generalized seizures. irreversibly inhibiting the enzyme GABA
Valproic acid is particularly useful in absence transaminase thereby raising brain GABA levels.
seizures. In patients with both absence seizures It can cause depression in some patients.
and generalized tonic-clonic attacks, valproate is Vigabatrin is useful in patients not responding to
the drug of choice. other antiepileptics.
Central Nervous System 115

Levetiracetam a pyrrolidine, is effective against Lacosamide has been recently introduced for the
partial and secondarily generalized seizures. Its treatment of partial seizures. It acts on the sodium
mechanism of action is not known. It is not an channels, is completely absorbed when given
enzyme inducer - no related drug interactions. orally and can cause headache, nausea, dizziness
Levetiracetam can be used as an add-on drug in and blurred vision. It can be used as add-on drug
refractory partial seizures. in partial seizures in patients above 16 years of
age.
Tiagabine
• Newer antiepileptics include gabapentin,
Tiagabine a GABA analog, inhibits the reuptake pregabalin, lamotrigine, vigabatrin,
of GABA into neurons and thereby enhances levetiracetam, tiagabine, topiramate,
extracellular GABA levels. It may cause felbamate, zonisamde and locosamide.
drowsiness and dizziness. Tiagabine can be used • Gabapentin, vigabatrin and lamotrigine act
as add-on drug for refractory partial seizures. by influencing GABA.
• Lamotrigine, topiramate and zonisamide act
Topiramate a monosaccharide, acts by multiple on sodium channels.
mechanisms. It blocks the sodium channels, • The newer antiepileptics are indicated as add
enhances GABA receptor currents, blocks AMPA on drugs in refractory epilepsies.
receptors (glutamate receptor). It is effective in
partial and generalized seizures. Topiramate can
be used as add-on therapy in refractory epilepsy. Treatment of Epilepsies (Table 6.3)

Felbamate an analogue of meprobamate is found Most patients with epilepsy require prolonged
to have good antiepileptic action. It blocks the treatment, side effects from antiepileptics are
NMDA receptors in addition to weak sodium respected because of the long duration of treatment
channel blocking effect. But felbamate can needed.
sometimes cause serious adverse effects like
Febrile convulsions: Two to four percent of
aplastic anemia and hepatitis because of which it
children experience convulsions during fever; of
is employed only in refractory epilepsy.
them 2-3 percent become epileptics. Treatment is
Zonisamide a sulfonamide derivative acts by controversial. Children < 18 months developing
inhibiting the T type Ca++ currents and also by febrile convulsions, those with neurological
blocking Na+ channels. It is well tolerated and is abnormalities and those with seizures lasting for
indicated in refractory partial seizures. > 15 minutes, complex seizures—all these have

TABLE 6.3: Choice of antiseizure drugs

Types of epilepsy Preferred drugs

1. Generalized tonic-clonic and simple partial seizures Carbamazepine, phenytoin


2. Absence seizures Ethosuximide, valproic acid
3. Tonic-clonic + absence seizures Valproic acid
4. Complex partial seizures Carbamazepine, phenytoin, valproic acid
5. Febrile convulsions Diazepam
6. Status epilepticus Diazepam, phenytoin, general anesthesia
116 Pharmacology for Physiotherapy

greater risk of recurrence. Diazepam (0.5 mg/kg) CLASSIFICATION


given orally or rectally at the onset of fever prevents
1. Drugs that increase dopamine levels
convulsions. Timely use of paracetamol and tepid
i. Dopamine precursor: Levodopa.
sponging prevents high fever. If convulsions occur,
ii. Drugs that release dopamine: Amantadine.
diazepam rectally or intravenously can be used.
iii. Dopaminergic agonists: Bromocryptine,
Status epilepticus: It is a neurological emergency lisuride, ropinirole, pramipexole.
which may be fatal. Diazepam IV (5-10 mg every iv. Inhibit dopamine metabolism
10-15 minutes up to 30 mg) is the drug of choice. a. MAO inhibitors—Selegiline.
Phenytoin given intravenously takes 15-20 b. COMT inhibitors—Tolcapone, enta-
minutes to act. Some prefer to combine diazepam capone.
and phenytoin. If seizures continue—general 2. Drugs influencing cholinergic system
i. Central anticholinergics: Benztropine,
anesthesia is the last resort. Airway maintenance
benzhexol, biperidine, trihexyphenidyl.
is important. After the control of seizures, long-
ii. Antihistamines: Diphenhydramine, orphena-
term antiepileptic therapy is needed.
drine, promethazine.
In pregnancy—antiepileptics should be conti-
nued in pregnancy because abrupt disconti- LEVODOPA
nuation increases the risk of status epilepticus Though parkinsonism is due to dopamine
which is hazardous to the fetus. deficiency, dopamine is of no therapeutic value
because it does not cross the blood-brain barrier.
DRUGS USED IN PARKINSONISM Levodopa is a prodrug which is converted to
dopamine in the body. It crosses the BBB and is
Parkinsonism is a chronic, progressive, motor taken up by the surviving nigrostriatal neurons.
disorder characterized by rigidity, tremors and dopa decarboxylase
___________________________
bradykinesia. Other symptoms include excessive Levodopa → Dopamine
salivation, abnormalities of posture and gait, Antiparkinsonian effect: On administration of
seborrhea and mood changes. It was described by levodopa, there is an overall improvement in the
James Parkinson in 1817 and is therefore named patient as all the symptoms subside.
after him.
The incidence is about 1 percent of population Other actions:
above 65 years of age. It is usually idiopathic in • CTZ—Dopamine stimulates the chemo-
origin but can also be drug induced. In idiopathic receptor triggor zone to induce vomiting.
parkinsonism, there is degeneration of • CVS—Large amounts of levodopa converted
nigrostriatal neurons in the basal ganglia resulting to dopamine in the periphery causes postural
in dopamine deficiency. The balance between hypotension and tachycardia—dopamine is
inhibitory dopaminergic neurons and excitatory a catecholamine.
Endocrine—Dopamine suppresses the pro-
cholinergic neurons is disturbed.
lactin secretion.
Antiparkinsonian drugs can only help to reduce
the symptoms and improve the quality of life. The Pharmacokinetics: Levodopa is rapidly
two strategies in the treatment are (i) to enhance absorbed. Presence of food delays absorption. It
dopamine activity (ii) to depress cholinergic undergoes first pass metabolism in the gut and
overactivity. the liver. Its t½ is 1-2 hours.
Central Nervous System 117

Adverse reactions: As large amounts (95%) of Amantadine is an antiviral drug. It enhances the
levodopa is converted to dopamine in the release of DA in the brain and diminishes the re-
periphery, several adverse effects are expected. uptake of DA. The response starts early and its
Nausea, vomiting, postural hypotension, adverse effects are minor. Large doses produce
tachycardia and occasionally arrhythmias can insomnia, dizziness, vomiting, postural hypo-
occur. Tolerance develops to these effects after tension, hallucinations, ankle edema and livido
sometime. Behavioral effects like anxiety, reticularis.
depression, hallucinations and sometimes Amantadine is used in mild cases of
psychosis can occur. parkinsonism. It can also be used along with
Abnormal involuntary movements like facial tics, levodopa.
grimacing, choreoathetoid movements of the limbs Dopamine receptor agonists: Bromocriptine and
may develop after a few months of use and require pergolide are ergot derivatives having dopamine
reduction in the dose of levodopa. agonistic activity. The newer agents ropinirole
Fluctuation in response to levodopa can occur and pramipexole are selective D2 agonists, are
after 2-5 years of use—known as ‘on-off’ better tolerated, quickly attain therapeutic levels
phenomenon—where the patient has alternately and adverse effects are milder except that they
good response and severe disease. may cause some sleep disorders.
Dopamine agonists are all longer acting
Uses: Levodopa is the most effective drug in because of which they are useful in the treatment
idiopathic parkinsonism but is not useful in drug of ‘on-off’ phenomenon.
induced parkinsonism. Adverse effects include nausea, vomiting,
Drug interactions hallucinations and skin eruptions. Ergot
1. Pyridoxine enhances the peripheral derivatives can cause postural hypotension and
decarboxylation of levodopa and thus ‘first dose phenomenon’—that is sudden
reduces its availability to the CNS. cardiovascular collapse.
2. Phenothiazines, metoclopramide and DA agonists are used:
reserpine are DA antagonists. They reverse 1. In the treatment of ‘on-off’ phenomenon.
the effects of levodopa. 2. As alternatives in the initial treatment of
Carbidopa and benserazide are peripheral dopa parkinsonism.
decarboxylase inhibitors. When carbidopa or
Lisuride and pergolide are similar to bromocriptine.
benserazide are given with levodopa, they prevent
the formation of dopamine in the periphery. They
Drugs that Inhibit DA Metabolism
do not cross the BBB and hence allow levodopa to
reach the CNS. The combination is synergistic and Selegiline (Deprenyl) is a selective MAO-B
therefore levodopa is always given with inhibitor. MAO-B is present in DA containing
carbidopa/benserazide. regions of the CNS. Selegiline prolongs the action
of levodopa by preventing its destruction.
Advantages of combining carbidopa/benserazide—
Selegiline may delay the progression of
with levodopa.
parkinsonism.
1. Dose of L-dopa can be reduced by 75 percent.
Adverse effects include nausea, postural
2. Response to L-dopa appears earlier.
hypotension, confusion and hallucinations.
3. Side effects like vomiting and tachycardia are
largely reduced. Uses: Mild cases of parkinsonism are started on
4. Pyridoxine does not interfere with treatment. selegiline. It is also used along with levodopa.
118 Pharmacology for Physiotherapy

COMT inhibitors—tolcapone and entacapone somatic pain. It is usually caused by inflammation


inhibit the peripheral metabolism of levodopa and is well-defined or sharp pain.
thereby increasing its bioavailability. Tolcapone Pain arising from the viscera is vague, dull-
crosses the BBB and enhances the availability of aching type, difficult to pinpoint to one site and is
levodopa in the brain. known as visceral pain. It may be accompanied
Adverse effects are nausea, orthostatic hypo- by autonomic responses like sweating, nausea and
tension, confusion and hallucinations. Tolcapone hypotension. It may be due to spasm, ischemia or
can also cause hepatotoxicity. inflammation.
When pain is referred to a cutaneous area
Anticholinergics: The cholinergic overactivity is which receives nerve supply from the same spinal
overcome by anticholinergics. Tremors, seborrhea segment as that of the affected viscera, it is known
and sialorrhea are reduced more than rigidity. as referred pain, e.g. cardiac pain referred to the
Atropine derivatives like benzhexol, benztropine, left arm.
trihexyphenidyl are used. Antihistamines are Pain consists of 2 components—the original
useful in parkinsonism because of their anti- ‘sensation’ and the ‘reaction’ to it. The original
cholinergic properties. Atropine-like side effects sensation is carried by the afferent nerve fibers
such as dry mouth, constipation, blurred vision and is the same in all. The reaction component
may be encountered. differs widely from one person to another.
Uses: Anticholinergics are used as (i) adjunct to Analgesic is a drug which relieves pain without
levodopa, (ii) drugs of choice in drug-induced loss of consciousness. Analgesics only afford
parkinsonism. symptomatic relief from pain without affecting the
cause.
Drug induced parkinsonism: Drugs like
Analgesics are of 2 classes:
reserpine, metoclopramide and phenothiazines
• Opioid or morphine type of analgesics
can induce parkinsonism. Reserpine depletes
(Narcotic analgesics).
catecholamine stores, metoclopramide and
• Non-opioid or aspirin type of analgesics
phenothiazines are dopamine antagonists.
(NSAIDs).
Treatment: Withdrawal of the parkinsonism
inducing drug usually reverses the symptoms. OPIOID ANALGESICS
When drugs are needed, one of the anti- Opium is the dark brown gummy substance
cholinergics are effective. obtained from the poppy capsule (Papaver
somniferum). On incising the unripe seed capsule,
OPIOID ANALGESICS AND ANTAGONISTS a milky juice comes out which turns brown on
drying and this is crude opium. Opium is the Greek
Pain or algesia is an unpleasant sensation. It name for juice. Opium has been in use since 4000
cannot be easily defined. Pain is a warning signal BC. It was used both for medicinal and recreational
and indicates that there is some impairment in purposes as it causes euphoria. By 18th century,
the body. It is the most important symptom that opium smoking had become quite popular in
brings the patient to the doctor or physiotherapist Europe. It was Serturner who isolated a pure opium
and demands immediate relief. Prompt relief of alkaloid in 1806. He named it Morphine after
pain instills enormous confidence in the patient Morpheus, the Greek God of dreams. As the
regarding the doctors treating ability. research progressed, opium was found to contain
Pain arising from the skin and integumental 20 alkaloids. By around 19th century, the pure
structures, muscles, bones and joints is known as opium alkaloids were available for therapeutic
Central Nervous System 119

use. But because they were equally abused, efforts receptors are abundant in the CNS and other
were made to isolate the analgesic property, i.e. to tissues. The opioid receptors are mu (μ) kappa (κ)
obtain an opioid that is only analgesic and has and delta (δ). It is found that there are 3 families of
no euphoric effects. In the process, various endogenous opioid peptides released in the body
agonists, antagonists and partial agonists were viz enkephalins, endorphins and dynorphins. This
synthesized. ’Opioid’ is the term used for drugs indicates that we have a natural system in the
with morphine-like actions. They were earlier body that releases various opioid peptides in
called narcotic analgesics. response to pain.
Most pharmacological effects of opioids
CLASSIFICATION including analgesia, sedation, euphoria, respi-
ratory depression, miosis and constipation are all
1. Agonists: Natural opium alkaloids, e.g.
due to stimulation of µ (mu) opioid receptors.
Morphine, codeine, synthetic opioids, e.g.
Pethidine, methadone.
Pharmacological Actions
2. Antagonists: Naloxone, naltrexone, nalmefene.
3. Mixed agonist-antagonists: Pentazocine, Central nervous system
nalbuphine, butorphanol, buprenorphine, 1. Analgesia: Morphine is a potent analgesic
nalorpine. and relieves pain without loss of conscious-
ness. Dull aching visceral pain is relieved better
Chemically the opium alkaloids
than sharp pricking pain. In higher doses it
can be grouped into
relieves even the severe pain as that of biliary
1. The phenanthrene group: Morphine, codeine, colic. Morphine alters both the perception and
thebaine. reaction to pain. It raises the pain threshold
2. The benzylisoquinoline group: Papaverine, and thus increases the capacity to tolerate
noscapine, narcine. pain. Further it alters the emotional reaction
Opioids can also be classified to pain.
depending on their source as Euphoria and sedation contribute to its
analgesic effects.
1. Natural opium alkaloids: Morphine, codeine,
2. Euphoria, sedation and hypnosis: Morphine
noscapine.
produces a feeling of well-being termed
2. Semisynthetic derivatives: Heroin, oxymor-
euphoria. It is this effect which makes it an
phone, pholcodeine.
important drug of abuse. Rapid intravenous
3. Synthetic opioids: Pethidine, fentanyl,
injection of morphine produces a warm
diphenoxylate, loperamide, methadone,
flushing of the skin and an immensely
dextropropoxyphene and tramadol.
pleasurable sensation in the lower abdomen
Morphine is the most important alkaloid of
lasting for about 45 seconds and is known as
opium. Many new opioids with actions similar to
‘high’, ‘rush’ or ‘kick’. The person loses
morphine have been synthesized. But none of
rational thinking and is lost in colorful day
them are superior to morphine as an analgesic.
dreams. It also produces drowsiness, a calming
Morphine is discussed as the prototype of the
effect, inability to concentrate, feeling of
group.
detachment and indifference to surroundings.
But the effects of morphine may not be
Mechanism of Action pleasurable in all. A person has to learn to
Morphine and other opioids produce their effects experience its pleasurable effects. It may
by acting on specific opioid receptors. These produce dysphoria in some.
120 Pharmacology for Physiotherapy

3. Respiration: Morphine produces significant spasms of the intestine. The tone of the sphincters
respiratory depression. It directly depresses is increased leading to spasm. The intestinal
the respiratory center in the brainstem. This motility is markedly diminished. Thus, reduced
action is dose dependent. Death from secretions and motility result in marked
morphine poisoning is almost always due to constipation.
respiratory arrest.
Sedation and indifference to surroundings Other Smooth Muscles
add to the respiratory depression.
Biliary tract: Morphine causes spasm of the
4. Cough center: It directly depresses the cough
sphincter of Oddi and may cause biliary colic.
center and thereby suppresses cough.
5. Nausea and emesis: Morphine directly Urinary bladder and ureter: Tone and contractions
stimulates the chemoreceptor trigger zone of the ureter is increased; tone of external sphincter
(CTZ) in the medulla causing nausea and and volume of the bladder are increased. Opioids
vomiting. In higher doses it depresses the inhibit urinary voiding reflex. All these result in
vomiting center and hence there is no vomiting urinary retention especially in elderly male with
in poisoning. Therefore, emetics should not be prostatic hypertrophy.
tried in poisoning.
Bronchi: Morphine causes release of histamine
6. Pupils: Morphine produces constriction of
from the mast cells leading to bronchoconstriction.
pupil. In higher doses a characteristic pinpoint
This can be dangerous in asthmatics.
pupil is seen by a central effect.
7. Vagus: Morphine stimulates vagal center
Neuroendocrine Effects
causing bradycardia.
8. Heat regulation: Opioids act on heat-regulat- Morphine inhibits the release of gonadotrophin-
ing center and body temperature falls slightly. releasing hormone and CRF.
9. Excitatory effect: In high doses opioids
produce convulsions. They may increase the Pharmacokinetics
excitability of the spinal cord.
Given orally, absorption of morphine is slow and
Cardiovascular system: In therapeutic doses, incomplete and undergoes extensive first pass
morphine produces hypotension by direct metabolism. Bioavailability is 20 to 40 percent.
peripheral vasodilatation. Given subcutaneously, onset of action is within
In higher doses it causes depression of the 15-20 min, duration of action is 3-5 hr. Morphine
vasomotor center and also brings about histamine is metabolized in the liver by glucuronide
release, both causing a fall in BP. Postural conjugation.
hypotension and fainting may occur.
Adverse Effects
GIT: Opioids decrease the motility of the gut.
Morphine can produce a wide range of adverse
Stomach: Gastric motility is decreased and gastric
effects like-nausea, vomiting, dizziness, mental
acid secretion is reduced. Opioids increase the
clouding, respiratory depression, constipation,
tone of the antrum and first part of the duodenum
dysphoria, urinary retention and hypotension.
which also result in delayed emptying by as much
Allergic reactions including skin rashes,
as 12 hours.
pruritus and wheal at the site of injection and
Intestines: Morphine reduces all intestinal rarely anaphylaxis may be seen. This is because
secretions, delays digestion of food in the small morphine liberates histamine. It is a drug of
intestine; resting tone is increased. There can be dependence.
Central Nervous System 121

Tolerance and dependence: Repeated vomiting and fever. Tincture of opium is started
administration of morphine results in the and gradually withdrawn.
development of tolerance to some of its effects
including respiratory depression, analgesia, Management of Addiction
sedation and euphoriant effects and other CNS Morphine is slowly withdrawn over several days
depressant effects. Constipation and miosis show and oral methadone is given.
no tolerance. Though lethal dose of morphine is Advantages of methadone administration are:
about 250 mg, addicts can tolerate morphine in 1. Methadone is effective orally and by this route
grams. An addict needs progressively higher no ‘kick’ is experienced.
doses to get his ‘kick’ or ‘rush’. Patients in pain 2. It is more potent, long-acting and prevents
can also tolerate a higher dose of morphine. Cross- withdrawal symptoms.
tolerance is seen among different opioids. The dose is adjusted based on the degree of
Opium has been a drug of addiction for many dependence. Methadone is then slowly with-
centuries. Its ability to produce euphoria makes it drawn.
a drug of addiction. Opioids produce both Most addicts can be completely withdrawn
psychological and physical dependence. Sudden from opioids in about 10 days though mild
withdrawal of opioids or administration of opioid withdrawal symptoms still remain. Symptoms like
antagonists produce significant withdrawal insomnia, malaise, restlessness, irritability,
symptoms in such dependent individuals. fatigue and GI hyperactivity may last up to several
Manifestations are lacrimation, sweating, months.
yawning, anxiety, apprehension, restlessness, Clonidine a central α2 agonist can suppress
running nose and tremors—seen 8-12 hr after the some of the autonomic withdrawal symptoms like
last dose. The person craves for the drug. As the anxiety, nausea, vomiting and diarrhea. It is given
syndrome progresses, fever, insomnia, abdominal for 7-10 days and withdrawn over 3-4 days. Night
colic, severe sneezing, violent yawning, diarrhea, time sedation with a hypnotic is helpful.
blurring of vision due to mydriasis, hypertension,
Uses of Morphine
severe dehydration, gooseflesh, palpitation and
cardiovascular collapse can occur. There is severe Dose: Morphine 10 to 20 mg IM/SC; 20 mg tab
weakness, depression and irritability. Goose flesh (ethyl morphine) is now available for oral use.
is due to pilomotor activity; skin resembles that of 1. Analgesic: Morphine is one of the most potent
a plucked turkey. Hence the word ‘cold turkey’ is analgesics available. It provides symptomatic
used for sudden withdrawal. Abdominal cramps, relief of pain without affecting the underlying
pain in the bones and muscles of the back and disease. It is an excellent analgesic for severely
limbs are also characteristic. painful conditions such as acute myocardial
Withdrawal symptoms are generally not fatal. infarction, fractures, burns, pulmonary
Administration of a suitable opioid, dramatically embolism, terminal stages of cancer, acute
and completely reverses the symptoms of pericarditis, spontaneous pneumothorax and
withdrawal. Without treatment, symptoms postoperative pain. In excruciating pain,
disappear in 7-10 days. morphine can be given IV.
In myocardial infarction, morphine
Withdrawal in the newborn: Babies born to mothers relieves pain and thereby anxiety. As a result
who were addicts prior to delivery—will also be reflex sympathetic stimulation is reduced.
dependent. Withdrawal symptoms seen are • Morphine is given with atropine to relieve
irritability, excessive crying, tremors, frantic renal and biliary colic. Atropine relieves
suckling of fists, diarrhea, sneezing, yawning, spasm.
122 Pharmacology for Physiotherapy

• Since opiate receptors are present in the 6. Special anesthesia:


spinal cord, epidural morphine can be used • High doses of morphine can be used IV to
to produce epidural analgesia. There is no produce general anesthesia
interference with motor function or • Neuroleptanalgesia—fentanyl an opioid,
autonomic changes and no systemic can be used to produce neuroleptanalgesia
adverse effects. with the neuroleptic droperidol (page 140)
• Obstetric analgesia: Pethidine is preferred • Morphine can be used epidurally for the
to morphine for this condition. relief of postoperative and chronic pain.
• Opioids can be given to control pain of 7. Sedative: Morphine relieves anxiety in
cancers. threatened abortion without affecting uterine
• But opioids should not be freely used in motility. It is an useful sedative in the presence
case of other chronic pain because of the of pain.
risk of addiction.
2. As preanesthetic medication: Morphine and Acute morphine poisoning may be accidental,
pethidine are commonly used as preanesthetic suicidal or homicidal. Lethal dose in non-addicts
medication. They reduce anxiety, provide is about 250 mg but addicts can tolerate grams of
analgesia, allow smoother induction and morphine. Signs and symptoms include respi-
reduce the dose of the anesthetic required. But ratory depression with shallow breathing, pin
they have certain disadvantages: point pupils, hypotension, shock, cyanosis,
• Opioids depress respiration. flaccidity, stupor, hypothermia, coma and death
• Morphine may cause bronchospasm and due to respiratory failure and pulmonary edema.
is dangerous in patients with poor
respiratory reserve. Treatment
• They cause vasomotor depression.
1. Positive pressure respiration.
• They may induce vomiting.
2. Maintenance of BP.
• Postoperative urinary retention and
3. Gastric lavage with potassium permanganate
constipation may be troublesome.
to remove unabsorbed drug.
3. Acute left ventricular failure: Morphine 4. Specific antidote is naloxone—0.4-0.8 mg IV
relieves the dyspnea of LVF and pulmonary repeated every 10-15 min.
edema. The mechanism is not clear. The relief
may be due to: Precautions and Contraindications
i. Reduction in the work of the heart due to
decreased anxiety. Reduced anxiety 1. Avoid opioids in patients with respiratory
decreases sympathetic stimulation which insufficiency—COPD; it should also be
inturn decreases cardiac work. avoided in infants.
ii. Cardiovascular effects like decreased PVR 2. An attack of bronchial asthma can be
reduces the cardiac workload. precipitated by morphine.
3. Head injury—morphine is contraindicated
4. Diarrhea: Opioids are effective for the because:
symptomatic treatment of diarrhoea. Synthetic i. Morphine increases CSF pressure.
opioids—diphenoxylate and loperamide are ii. Causes respiratory depression.
preferred as antidiarrheals. iii. Vomiting, miosis and mental clouding
5. Cough: Codeine and noscapine are the produced by morphine makes it difficult
preferred opioids for this purpose. But now to treat head injuries.
many nonaddictive antitussives are available 4. In hypovolemic shock, morphine further
for the treatment of cough. decreases the BP.
Central Nervous System 123

5. Opioids potentiate CNS depressants–avoid Pholcodeine is structurally related to opioids


concurrent use of CNS depressants. and is an effective antitussive. It has a long half-
6. Undiagnosed acute abdomen—morphine life and therefore can be given once a day.
relieves pain, may cause vomiting and
Dextromethorphan has no analgesic or
constipation. All these may interfere with the
addictive properties. It acts centrally as an
diagnosis. Hence it can be administered only
antitussive. Toxicity is very low; extremely high
after the diagnosis is made.
doses cause CNS depression. Antitussive dose:
7. In the elderly respiratory depression can be
10-30 mg, 3-4 times a day.
significant; opioids can also cause urinary
retention in men with prostatic hypertrophy–
PETHIDINE (MEPERIDINE)
hence they should be used cautiously in the
elderly. Pethidine is a derivative of morphine. Many of its
actions resemble that of morphine. When
OTHER OPIOIDS compared to morphine:
• Pethidine is 1/10th as potent as morphine (100
Codeine is a naturally occurring opium alkaloid.
mg pethidine = 10 mg morphine). However,
Codeine depresses the cough center even in low
as an analgesic pethidine is equal to morphine.
doses. It is effective orally and is well-absorbed.
• The onset of action is more rapid and duration
It is less potent (one-sixth) than morphine as
of action is shorter.
an analgesic (60 mg codeine = 10 mg morphine).
• It produces corneal anesthesia.
It produces less respiratory depression and is
• It is not a good antitussive.
less constipating. Codeine has less addiction
• It is less constipating.
liability and less chances of tolerance. It is well
• In some patients, it may cause dysphoria.
absorbed on oral administration.
• In toxic doses, pethidine sometimes produces
Hence codeine is used as an antitussive.
CNS stimulation and convulsions instead of
Duration of action is 4-6 hr. Constipation is the
sedation.
most common side effect.
Adverse effects are similar to morphine except
Uses: Codeine is a commonly used antitussive. that constipation and urinary retention are less
It is also available in combination with common.
paracetamol for analgesia. It is to be given at
bedtime (CODOPLUS → Codeine 30 mg + Uses
Paracetamol 500 mg).
Dose: 25-100 mg IM/SC is the analgesic dose.
Papaverine is devoid of opioid and analgesic
activity. In pain: Pethidine is used as an analgesic in
visceral pain and also for other indications of
Noscapine is a naturally occurring opium morphine. Because of efficacy and less spasmo-
alkaloid. In therapeutic doses, it has no other genic effect, it is preferred to morphine.
actions on the CNS except for antitussive effects.
During labor: Given during labor, pethidine
Hence it has no disadvantages of opioids. Dose:
produces less respiratory depression in the
15-30 mg—3-4 times a day. Noscapine is highly
newborn when compared to morphine and is
effective and safe. The only adverse effect is
therefore preferred to morphine for obstetric
nausea. It is used as a cough suppressant.
analgesia.
Several other centrally acting antitussives
have been synthesized including, pholcodeine Preanesthetic medication: Pethidine can also be
and dextromethorphan. used as preanesthetic medication.
124 Pharmacology for Physiotherapy

Derivatives of Pethidine Uses


Fentanyl is a pethidine congener. It is about 80 1. In opioid dependence: In morphine addicts oral
times more potent than morphine as an analgesic methadone is given and morphine is stopped.
and is faster acting. It is used in combination with Methadone prevents withdrawal symptoms
droperidol, a neuroleptic agent to produce ‘neuro- in them (see page 121).
leptanalgesia.’ The combination is given IV to 2. Opioid maintenance: Gradually increasing
produce sedation and intense analgesia without doses of methadone is given orally to produce
loss of consciousness. This state is maintained a high degree of tolerance. Such subjects do
for 30-40 minutes as both have rapid and short not experience the pleasurable effects of IV
action. morphine, because of tolerance, i.e. opioids are
A fixed dose combination is available with 0.05 not pleasurable in them and they give up the
mg fentanyl + 2.5 mg droperidol per ml. 5 ml is the habit.
dose used IV over 10 minutes. Patient is drowsy 3. Methadone can also be used as an analgesic.
but responds to commands. Dextropropoxyphene is a congener of
i. Neuroleptoanalgesia is useful for short methadone. It binds to the opioid receptors and
surgical procedures especially in ‘poor risk’ produces effects similar to morphine. It is less
patients. constipating and is orally effective. But dextro-
ii. Epidural fentanyl is used for postoperative propoxyphene is an irritant when given
and obstetric analgesia. parenterally. Large doses cause CNS stimulation.
iii. Fentanyl is also used for chronic pain. It also has abuse potential.
Transdermal patches of fentanyl are
available. Uses: Used in mild to moderate pain. It is
Other derivatives of pethidine alfentanil, marketed in combination with aspirin.
sufentanil and ramifentanil are similar to fentanyl. Dextropropoxyphene 32 mg + aspirin 600 mg.
Tramadol is a recently developed synthetic
Methadone a synthetic opioid, has actions analgesic. It is a weak opioid agonist. In addition
similar to morphine. It’s main features are: it inhibits the re-uptake of noradrenaline and
• It is an effective analgesic. serotonin in the CNS. The mechanism of action is
• It is effective by oral route. not clear.
• It has a long duration of action and therefore Adverse effects include drowsiness, dryness
effectively suppresses withdrawal symptoms of mouth and nausea. It is a drug of dependence.
in addicts. It may precipitate seizures.
Methadone is about 90 percent bound to Tramadol is used in acute and chronic pain,
plasma proteins; it is firmly bound to proteins in like postoperative pain and neuralgias.
various tissues, including brain. After repeated
administration, it accumulates in tissues. When MIXED AGONISTS AND ANTAGONISTS
administration is stopped, it is slowly released
They include—pentazocine, nalbuphine, bupre-
from these binding sites. Hence, its withdrawal
norphine, butarphanol and nalorphine.
symptoms are mild. As euphoric effects are less
intense, abuse potential is less. Tolerance develops Pentazocine: In an attempt to develop an
more slowly. Even in addicts, withdrawal analgesic with less risk of addiction and low
symptoms are gradual in onset, less intense, but adverse effects, pentazocine was developed.
prolonged. Pentazocine it is a κ receptor agonist.
Central Nervous System 125

• CNS effects of pentazocine are similar to Dose: 0.3-0.6 mg SC, IM or sublingual (oral not
morphine. Euphoria is seen only in low doses. available).
With higher doses—dysphoria can occur due
Uses: Chronic pain like terminal cancer.
to κ receptor stimulation.
• Sedation and respiratory depression are less. Butorphanol is similar to pentazocine.
• It has weak antagonistic properties at μ
Nalorphine is also an agonist-antagonist. At low
receptors.
doses, it is a good analgesic. But it causes
• Tolerance and dependance develop on
dysphoria (κ agonist) and respiratory depression
repeated use.
even in low doses. Hence it cannot be used as an
• CVS—in contrast to morphine, pentazocine
analgesic. At high doses it acts as an antagonist
causes ↑BP and ↑heart rate and thereby
and counters all the actions of opioids.
increases cardiac work. It is therefore not
suitable in MI. Uses: Nalorphine may be used in acute opioid
• Biliary spasm and constipation are less severe. poisoning. It can also be used for the diagnosis of
• Pentazocine can be given both orally and opioid addiction.
parenterally. It undergoes first pass
metabolism. OPIOID ANTAGONISTS
• Dose 50-100 mg oral; 30-60 mg IM (FORTWIN).
Naloxone is a pure antagonist—acts as a
Adverse effects: Sedation, sweating, dizziness, competitive antagonist to all types of opioid
nausea, dysphoria with anxiety, nightmares and receptors. In normal individuals, it does not
hallucinations, which are unpleasant are seen produce any significant actions. But in opium
above 60 mg. As it is an irritant, IM injection can addicts, given IV, it promptly antagonizes all the
be painful and cause sterile abscesses. actions of morphine including respiratory
depression and sedation and precipitates
Uses: Pentazocine is a commonly used opioid withdrawal syndrome. It also blocks the action of
analgesic especially in postoperative and chronic endogenous opioid peptides—endorphins,
pain—abuse liability is less than morphine. enkephalins and dynorphins. It blocks the
Nalbuphine is an agonist-antagonist—like penta- analgesia produced by placebo and acupuncture.
zocine. It is a good analgesic. Though it produces This suggests that endogenous opioid peptides
respiratory depression like morphine, it has a are responsible for analgesia by these methods.
ceiling effect at 30 mg, i.e. an increase in dose Given orally it undergoes first pass metabolism
beyond 30 mg does not increase respiratory and is metabolized by the liver. Duration of action
depression further. Higher doses produce is 3-4 hours.
dysphoria.
Uses
Uses: As analgesic—10-20 mg IM.
1. Naloxone is the drug of choice for morphine
Buprenorphine is a highly lipid soluble synthetic overdosage.
opioid. It is a partial μ agonist, 25 times as potent 2. It is also used to reverse neonatal asphyxia
as morphine. Though onset of action is slow, due to opioids used in the mother during labor.
duration of analgesia is long. Other CNS effects 3. Naloxone can also be used for the diagnosis
are similar to morphine while respiratory depres- of opioid dependence—it precipitates
sion is less. Patients exhibit lower degree of withdrawal in addicts.
tolerance and dependence liability. Withdrawal 4. Hypotension seen during shock could be due
syndrome appears late and is mild. to endogenous opioids released during such
126 Pharmacology for Physiotherapy

stress. Naloxone has been found to be During inflammation, arachidonic acid


beneficial in reversing such hypotension. liberated from membrane phospholipids is
converted to prostaglandins (PGs), catalyzed
Naltrexone is another pure opioid antagonist. It
by the enzyme cyclo-oxygenase. These prosta-
is:
glandins produce hyperalgesia—they sensitize
• Orally effective.
the nerve endings to pain and other mediators of
• Has a longer duration of action of 1-2 days.
inflammation like bradykinin and histamine.
Naltrexone is used for ‘opioid blockade’
NSAIDs inhibit the PG synthesis by inhibiting
therapy in post addicts so that even if such persons
the enzyme cyclo-oxygenase.
take an opioid, they do not experience the
pleasurable effects and therefore lose the liking
CLASSIFICATION
for opioids.
Alcohol craving is also reduced by naltrexone A. Nonselective Cox Inhibitors
and is used to prevent relapse of heavy drinking.
1. Salicylic acid derivatives—Aspirin, sodium
Nalmefene is an orally effective and longer acting salicylate, diflunisal.
opioid antagonist. It has better bioavailability than 2. Para-aminophenol derivatives—Para-
naltrexone and is used in opioid overdosage. cetamol.
3. Pyrazolone derivatives—Phenylbutazone,
NONSTEROIDAL ANTI-INFLAMMATORY azapropazone.
DRUGS (NSAIDs) 4. Indole acetic acid derivatives—Indo-
methacin, sulindac.
NSAIDs are aspirin-type or non-opioid analgesics. 5. Arylacetic acid derivatives—Diclofenac,
In addition they have anti-inflammatory, ketorolac, tolmetin.
antipyretic and uricosuric properties—without 6. Propionic acid derivatives—Ibuprofen,
addiction liability. fenoprofen, carprofen, naproxen, ketoprofen,
The medicinal effects of the bark of the willow oxaprozin.
tree has been known since centuries. The active 7. Anthranilic acids (Fenamates)—Flufenamic
principle ‘salicin’ was isolated from the willow acid, mefenamic acid, enfenamic acid.
bark. This salicin is converted to glucose and 8. Oxicams—Piroxicam, tenoxicam.
salicylic acid in the body. In 1875, sodium 9. Alkanones—Nabumetone.
salicylate was first used in the treatment of
rheumatic fever. After its anti-inflammatory and B. Selective Cox-2 Inhibitors
uricosuric properties were established, efforts were Nimesulide, celecoxib, rofecoxib, etoricoxib.
made to synthesize derivatives which were less
expensive. Now they have replaced the natural SALICYLATES
ones in the market.
Salicylates are salts of salicylic acid, e.g. methyl
Mechanism of Action salicylate, sodium salicylate, acetyl salicylic acid
(aspirin). Aspirin is taken as the prototype.
Phospholipids

NSAIDs Phospholipase A2 PHARMACOLOGICAL ACTIONS


Arachidonic acid 1. Analgesia: Aspirin is a good analgesic and
relieves pain of inflammatory origin without
Cyclo-oxygenase Lipoxygenase euphoria. Pain originating from the integu-
mental structures like muscles, bones, joints,
Prostaglandins Leukotrienes
and pain in connective tissues is relieved. But
Central Nervous System 127

in vague visceral pain, aspirin is relatively respiratory center. Salicylates also directly
ineffective. stimulate the medullary respiratory center.
The pain is relieved without euphoria and Both these actions increase the rate and depth
hypnosis. Hence there is no development of of respiration. These effects are dose depen-
tolerance and dependance. But aspirin is a dent.
weak analgesic when compared to morphine. As a result of this stimulation of respiration,
plasma CO2 is washed out leading to respi-
2. Antipyretic action: In fever, salicylates bring
ratory alkalosis. With toxic doses, the
down the temperature to normal level. But, in
respiratory center is depressed leading to
normal individuals, there is no change in
respiratory failure.
temperature.
In fever, pyrogen—a protein, circulates in 5. Acid-base and electrolyte balance: In anti-
the body and this increases the synthesis of inflammatory doses, salicylates produce
PGs in the hypothalamus, thereby raising its significant respiratory stimulation so that CO2
temperature set point. The thermostatic is washed out resulting in respiratory
mechanism in the hypothalamus is thus alkalosis; pH becomes alkaline. This is
disturbed. Aspirin inhibits PG synthesis in the compensated by increased excretion of HCO3–
hypothalamus and resets the thermostat at the in urine.
normal level bringing down the temperature. With toxic doses, salicylates depress the
Enhanced sweating and cutaneous respiratory center directly. As a result, CO2
vasodilatation promote heat loss and assist in accumulates, plasma CO2 level rises and pH
the antipyretic action. decreases, i.e. there is acidosis.
Toxic doses also depress vasomotor
3. Anti-inflammatory action: At higher doses of center. This vasomotor depression impairs
4-6 gm/day, aspirin acts as an anti-inflam- renal function resulting in accumulation of
matory agent. Signs of inflammation like strong acids of metabolic origin like lactic,
tenderness, swelling, erythema and pain are pyruvic and acetoacetic acids.
all reduced or suppressed. But, the progression The above effects are accompanied by
of the disease in rheumatoid arthritis, rheu- dehydration due to:
matic fever or osteoarthritis is not affected. • Water lost in urine with HCO3–, Na+ and K+
Once again the mechanism of action is PG • Increased sweating
synthesis inhibition—PGs present in inflam- • Water lost during hyperventilation.
matory tissue are responsible for edema, Thus high doses cause severe dehydration
erythema and pain. In addition, aspirin also with acidosis.
interferes with the formation of chemical medi-
6. Metabolic effects: Salicylates enhance the
ators of the kallikrein system. As a result, it
cellular metabolism. More of O2 is used and
decreases the adherence of granulocytes to the
more CO2 is produced, especially in skeletal
damaged vasculature, stabilizes lysomes and
muscles—leading to increased heat produc-
decreases the migration of the polymorpho-
tion. Glucose utilization is increased leading
nuclear leukocytes and macrophages into the
to mild hypoglycemia.
site of inflammation.
In toxic doses, hyperpyrexia, increased
4. Respiration: In therapeutic doses of 4-6 g/ protein catabolism, negative nitrogen balance
day—salicylates increase consumption of and hyperglycemia (due to central sympathetic
oxygen by skeletal muscles. As a result there stimulation which increases adrenaline levels)
is ↑CO2 production. The ↑CO2 stimulates can occur.
128 Pharmacology for Physiotherapy

7. Gastrointestinal tract: Aspirin is a gastric cannot synthesize cyclooxygenase and fresh


irritant. Irritation of the gastric mucosa leads platelets have to be formed to restore TXA2
to epigastric distress, nausea and vomiting. activity.
Aspirin also stimulates the CTZ to produce 12. Local effects: Salicylic acid when applied
vomiting. locally is a keratolytic. It also has mild
Gastric erosion, ulceration and GI bleeding antiseptic and fungistatic properties. Salicylic
can occur particularly in higher doses. acid is also an irritant for the broken skin.
Mechanism: Salicylates increase gastric acid
PHARMACOKINETICS
secretion and suppress the protective effect of
prostaglandins by inhibiting their synthesis Salicylates are absorbed from the stomach and
(we know that PGs increase mucous the upper small intestine. But aspirin as such is
production in the stomach and protect from poorly soluble, hence not well-absorbed. When
ulceration). administered as microfine particles, absorption
In addition it decreases platelet aggregation increases. Thus particle size, pH of the GIT,
which also increases the tendency to bleed. solubility of the preparation and presence of food
in the stomach influence the absorption.
8. CVS: In therapeutic doses no significant
Salicylic acid and methylsalicylate are
cardiovascular effects are seen. In toxic doses
absorbed from the intact skin. They are extensively
it depresses the VMC and thus depresses the
bound to plasma proteins. Aspirin is broken
circulation.
down in the liver, plasma and other tissues to
9. Immunological effects: In higher doses, release salicylic acid which is the active form.
salicylates suppress several antigen-antibody Plasma t½ of aspirin is 3-5 hours. Salicylates are
reactions. It inhibits antibody production, Ag- excreted in the urine.
Ab aggregation and antigen induced release
of histamine. These effects might also help in ADVERSE EFFECTS
rheumatic fever.
1. Nausea, epigastric distress, vomiting, erosive
10. Uric acid excretion: Uric acid is excreted by gastritis, peptic ulcer, increased occult blood
secretion from the distal tubules. In a dose of loss in stools are common.
1-2 gm/day, aspirin increases plasma urate 2. Allergic reactions are manifested as rashes,
levels because it inhibits urate secretion by the urticaria, angio-edema, and asthma especially
distal tubules. in those with a history of allergies.
Large doses of > 5 gm/day increase urate 3. Salicylates can cause hemolysis in patients
excretion because it inhibits reabsorption of with G6PD deficiency.
urate by the proximal tubule causing 4. Nephrotoxicity: Almost all NSAIDs can cause
uricosuria. But, its uricosuric effect cannot be nephrotoxicity after long-term use.
used for treatment of gout because high doses 5. Hepatotoxicity can also occur.
are required and such doses result in many 6. Reye’s syndrome: seen in children is a form of
adverse effects. hepatic dysfunction which may be fatal. It
11. Blood: Even in small doses aspirin inhibits develops a few days after a viral infection
TXA2 synthesis by platelets. It therefore especially influenza and varicella. An
interferes with platelet aggregation and increased incidence of this syndrome has been
prolongs the bleeding time. Even a single dose noted when aspirin is used to treat fever. Hence
can irreversibly inhibit TXA2 synthesis in the aspirin is contraindicated in children with
platelets. Because platelets have no nuclei, they viral fever.
Central Nervous System 129

7. Pregnancy and infancy: Aspirin when taken in frusemide is given along with IV fluids.
full term pregnancy delays the onset of labor Sodium bicarbonate make salicylates water
due to inhibition of PG synthesis (PGs play an soluble and increases their excretion through
important role in the initiation of labor). kidneys.
Premature closure of ductus arteriosus may
occur in the fetus resulting in portal hyper- Precautions and Contraindications
tension. It can also increase postpartum
bleeding due to inhibition of platelet aggre- Peptic ulcer, liver diseases, bleeding tendencies,
gation. children suffering from viral fever and pregnancy
8. Salicylism: Prolonged administration of are contraindications for the use of salicylates.
salicylates as in the treatment of rheumatoid Treatment with NSAIDs should be stopped one
arthritis may lead to chronic salicylate week before any surgery.
intoxication termed ‘Salicylism’. The syn-
drome is characterized by headache, vertigo, Preparations
dizziness, tinnitus, vomiting, mental con- Preparations and dosage of salicylates (Table 6.4).
fusion, diarrhea, sweating, difficulty in
hearing, thirst and dehydration. These USES
symptoms are reversible on withdrawal of
1. As analgesic for headache, backache,
salicylates.
myalgias, arthralgias, neuralgias, toothache
Acute salicylate intoxication: Poisoning may be and dysmenorrhea. The NSAIDs are beneficial
accidental or suicidal. It is more common in in a variety of painful conditions of integu-
children, 15-30 g is the fatal dose of aspirin. mental origin.
2. Fever: NSAIDs are useful for the symptomatic
Symptoms and signs: Dehydration, hyperpyrexia, relief of fever.
GI irritation, vomiting, sometimes hematemesis, 3. For inflammatory conditions: Aspirin is effective
acid-base imbalance, restlessness, delirium, in a number of inflammatory conditions such
hallucinations, metabolic acidosis, tremors, as arthritis and fibromyositis.
convulsions, coma and death due to respiratory
4. Acute rheumatic fever: In a dose of 4-6 g/day,
failure and cardiovascular collapse.
aspirin brings about a dramatic relief of signs
Treatment is symptomatic and includes:
and symptoms in 24 to 48 hr. The dose is
1. Stomach wash lavage to eliminate unabsorbed
reduced after 4-7 days and maintenance doses
drugs.
of 2-3 g/day are given for 2-3 weeks.
2. IV fluids to correct acid-base imbalance and
5. Rheumatoid arthritis: Aspirin relieves pain,
dehydration.
reduces swelling and redness of joints in
3. Temperature is brought down by external
rheumatoid arthritis. Joint mobility improves,
cooling with alcohol or cold water sponges.
fever subsides, and there is a reduction in
4. If there is bleeding, blood transfusion and
morning stiffness. But NSAIDs do not alter the
vitamin K are needed.
progress of the disease. The relief is only
5. The IV fluids should contain Na+, K+, HCO3–
symptomatic.
and glucose (to treat hypokalemia and
acidosis). Dose: 4-6 g/day in 4-6 divided doses.
6. In severe cases, forced alkaline diuresis with 6. Osteoarthritis: It provides symptomatic relief
sodium bicarbonate and a diuretic like in osteoarthritis.
130 Pharmacology for Physiotherapy

TABLE 6.4: Preparations and dosage of salicylates

Drug Preparation Dose

Aspirin 300, 350 tab (ASABUF); Analgesic—300-600 mg every 6-8 hr


DISPRIN Anti-inflammatory—4-6 gm/day
(Apirin 350 mg and Antiplatelet effects—75-300 mg/day
Calcium carbonate 105 mg)
Sodium salicylate 325, 650 mg tablets 325-650 mg every 4-8 hr
Salicylic acid 2 percent ointment;
Whitfield’s ointment- For topical use
– Salicylic acid 3 percent
– Benzoic acid 6 percent
Methylsalicylate Ointment/liniment for topical use As counter irritant
(Oil of wintergreen)
Diflunisal 250, 500 mg tab (DOLOBID) 250 mg every 8-12 hr

7. Postmyocardial infarction and post-stroke: as an anti-inflammatory agent but is a poor


Aspirin in a low dose inhibits platelet antipyretic due to poor penetration into CNS.
aggregation and by this it may prevent Gastrointestinal and antiplatelet effects are less
reinfarction. It also decreases the incidence of intense than aspirin. Side effects are fewer.
transient ischemic attacks (TIA) and stroke in
Uses: Osteoarthritis, strain and sprains. Initial
such patients.
dose 500-1000 mg followed by 250 mg twice or
8. Miscellaneous uses thrice daily.
i. To delay labor—since PGs are involved in
the initiation of labor, aspirin delays labor PARA-AMINOPHENOL DERIVATIVES
due to PG synthesis inhibition.
ii. Patent ductus arteriosus—Aspirin may Paracetamol (acetaminophen): Phenacetin was
bring about closure of PDA in the newborn. the first drug used in this group. But, due to severe
adverse effects it is now banned.
9. Local: Salicylic acid is used as a keratolytic,
Paracetamol, a metabolite of phenacetin is
fungistatic and mild antiseptic. Methyl-
found to be safer and effective.
salicylate is a counter-irritant used in myalgias.
Actions: Paracetamol has analgesic, good
DRUG INTERACTIONS antipyretic and weak anti-inflammatory proper-
ties. Due to weak PG inhibitory activity in the peri-
• Salicylates compete for protein binding sites
phery, it has poor anti-inflammatory actions.
and displace other drugs resulting in toxicity
Paracetamol is active on cyclo-oxygenase in
with warfarin, heparin, naproxen, phenytoin
the brain because of which it acts as an antipyretic.
and sulfonylureas.
In the presence of peroxides which are present at
• Inhibition of platelet aggregation may increase
the site of inflammation, paracetamol has poor
the risk of bleeding with oral anticoagulants.
ability to inhibit cyclo-oxygenase. It is therefore a
Diflunisal is a derivative of salicylic acid. poor anti-inflammatory agent. It does not stimulate
Diflunisal is 3-4 times more potent than aspirin respiration, has no actions on acid-base balance,
Central Nervous System 131

cellular metabolism, cardiovascular system and PYRAZOLON DERIVATIVES


platelet function; it is not an uricosuric agent and
Phenylbutazone has good anti-inflammatory
gastric irritation is mild.
activity, but has poorer analgesic and antipyretic
Pharmacokinetics: Paracetamol is well-absorbed effects. It is an uricosuric agent.
orally, 30 percent protein bound; metabolized by Phenylbutazone causes retention of Na+ and
the hepatic microsomal enzymes: by glucuronide water. Thus, after 1-2 weeks of use edema results.
and glutathione conjugation. It can also precipitate congestive cardiac failure.
Adverse effects: In antipyretic doses, paracetamol Pharmacokinetics: Completely absorbed orally;
is safe and well-tolerated. Nausea and rashes may IM injection is not recommended because its
occur. But when large doses are taken, acute absorption is slow as it binds to local tissue
paracetamol poisoning results. Children are more proteins and also causes local tissue damage. It is
susceptible because their ability to conjugate by 98 percent bound to plasma proteins; t½ is 60
glucuronidation is poor. 10-15 gm in adults cause hours.
serious toxicity. Symptoms are—nausea, vomiting,
Dose: 100-200 mg, BD. Small doses may be given
anorexia and abdominal pain during first 24 hrs.
3-4 times a day to avoid gastric irritation.
Paracetamol is hepatotoxic and causes severe
hepatic damage. Manifestations are seen within
Adverse Effects
2-4 days and include increased serum transa-
minases, jaundice, liver tenderness and prolonged • Phenylbutazone is more toxic than aspirin and
prothrombin time which may progress to liver is poorly tolerated—dyspepsia, epigastric
failure in some patients. Hepatic lesions are distress, nausea, vomiting, peptic ulceration
reversible when promptly treated. and diarrhea may occur. Edema and CCF can
Nephrotoxicity may result in acute renal occur.
failure in some. • Hypersensitivity reactions like rashes, serum
sickness, stomatitis, hepatitis, nephritis,
Mechanism: A small portion of paracetamol is
dermatitis and jaundice can occur. Phenyl-
metabolized to a toxic compound—N-acetyl-
butazone may cause serious hematological
benzoquinone-imine which is destroyed generally
complications such as bone marrow
by conjugation with glutathione. But when large
depression, aplastic anemia, agranulocytosis
doses of paracetamol are taken, hepatic
and thrombocytopenia.
glutathione gets used up and the levels of toxic
• It may inhibit iodine uptake by thyroid
compound increase. It causes hepatic necrosis.
resulting in hypothyroidism and goiter on
Chronic alcoholics and infants are more prone
long-term use.
to hepatotoxicity.
• CNS effects like insomnia, vertigo, optic
Treatment: Stomach wash is given. Activated neuritis, blurring of vision and convulsions
charcoal prevents further absorption. Antidote is may be encountered.
N-acetylcysteine which is more effective when Because of its toxicity, phenylbutazone is
given early. withdrawn from the market in many western
countries.
Uses
Uses
• Paracetamol is used as an analgesic in painful
conditions like toothache, headache and 1. Rheumatoid arthritis.
myalgia. 2. Ankylosing spondylitis.
• As an antipyretic in fevers. 3. Osteoarthritis.
132 Pharmacology for Physiotherapy

4. Gout—phenylbutazone produces satisfactory • Ankylosing spondylitis.


relief from pain and inflammation in acute • Psoriatic arthritis.
attacks. • For closure of patent ductus arteriosus in the
5. Other musculoskeletal disorders. newborn.
Azapropazone is structurally related to phenyl- Sulindac has weaker analgesic, antipyretic and
butazone but is less likely to cause agranulo- anti-inflammatory actions but is less toxic. Does
cytosis; t½ is 12-16 hr. not antagonize the diuretic and antihypertensive
Metamizol is a potent analgesic and antipyretic, actions of thiazides. It may be used as an alter-
but poor anti-inflammatory agent and has no native drug for inflammatory conditions.
uricosuric properties (ANALGIN, NOVALGIN) Diclofenac is an analgesic, antipyretic and anti-
500 mg 3-4 times a day. It offers no advantages inflammatory agent. It’s tissue penetrability is
over aspirin. Not recommended in children up to good and attains good concentration in synovial
6 years. fluid which is maintained for a long time. Adverse
Propiphenazone is similar to metamizol. effects are mild.
Dose: 300-600 mg 3-4 times a day (SARIDON). Dose: 50 mg BD–TDS. Gel is available for topical
application (INAC GEL). Ophthalmic preparation
INDOLE ACETIC ACID DERIVATIVES is available for use in postoperative pain.
Indomethacin is a potent anti-inflammatory
agent, antipyretic and good analgesic. It is well- Uses
absorbed, 90 percent bound to plasma proteins; 1. Treatment of chronic inflammatory conditions
t½—4-6 hr. like rheumatoid arthritis and osteoarthritis.
Dose: 25-50 mg BD-TDS. 2. Acute musculoskeletal pain.
3. Postoperatively for relief of pain and
Adverse effects are high: Gastrointestinal
inflammation.
irritation with nausea, gastrointestinal bleeding,
vomiting, diarrhea and peptic ulcers can occur. Ketorolac: Another PG synthesis inhibitor having
good analgesic and anti-inflammatory properties.
CNS effects include headache, dizziness, ataxia,
It is used to relieve postoperative pain. It is mostly
confusion, hallucinations, depression and
used parenterally though it can also be given
psychosis.
orally.
Hypersensitivity reactions like skin rashes,
leukopenia, and asthma are common. It can also
cause bleeding due to decreased platelet PROPIONIC ACID DERIVATIVES
aggregation and edema due to salt and water Ibuprofen is better tolerated than aspirin.
retention. Analgesic, antipyretic and anti-inflammatory
Drug interactions: Indomethacin blunts the diuretic efficacy is slightly lower than aspirin. It is 99
action of furosemide and the antihypertensive percent bound to plasma proteins.
action of thiazides, furosemide, β-blockers and
Adverse effects are milder and the incidence is
ACE inhibitors by causing salt and water
lower. Nausea, vomiting, gastric discomfort, CNS
retention.
effects, hypersensitivity reactions, fluid retention
Uses are all similar but less severe.
• Rheumatoid arthritis. Dose: Ibuprofen—400-800 mg TDS (BRUFEN);
• Gout. Ibuprofen + paracetamol (COMBIFLAM).
Central Nervous System 133

Uses SELECTIVE COX-2 INHIBITORS


1. As an analgesic in painful conditions. Celecoxib and rofecoxib—both diaryl substi-
2. In fever. tuted compounds are highly selective COX-2
3. Soft tissue injuries, fractures, following tooth inhibitors. They have good anti-inflammatory,
extraction, to relieve postoperative pain, analgesic and antipyretic properties but do not
dysmenorrhea and osteoarthritis. affect platelet aggregation.
4. Gout. They are better tolerated because of milder
Other propionic acid derivatives like feno- gastric irritation (due to COX-2 selectivity) - but
profen, ketoprofen, carprofen and naproxen are more long term studies are needed. Both celecoxib
similar to ibuprofen in actions. Oxaprozin is long and rofecoxib can cause hypertension and edema
acting and given once daily. which can be troublesome in patients with
cardiovascular problems. They can be used in
ANTHRANILIC ACID DERIVATIVES acute painful conditions like postoperative pain,
dysmenorrhea and dental pain as well as in
Fenamates are analgesic, antipyretic, anti- osteoarthritis and rheumatoid arthritis.
inflammatory drugs with less efficacy, and are
more toxic; contraindicated in children. They Dose
should not be used for more than one week.
Celecoxib—anti-inflammatory - 100-200 mg once
Though they can be used as analgesics they are
or twice daily.
not preferred.
Rofecoxib—analgesic - 50 mg daily Anti-inflam-
matory - 12.5-25 mg daily.
OXICAMS
Nimesulide a sulfonamide, compound is a weak
Piroxicam is an oxicam derivative. It is long- inhibitor of PG synthesis with a higher affinity
acting, has good anti-inflammatory, analgesic and for COX-2 than COX-1. It inhibits leukocyte
antipyretic activity. No clinically significant drug function, prevents the release of mediators and in
interactions are seen; better tolerated as it is less addition has antihistaminic and antiallergic
ulcerogenic. Dose 20 mg OD. It is long-acting. properties. Nimesulide has analgesic, antipyretic
Piroxicam is used for rheumatoid arthritis, and anti-inflammatory actions like other NSAIDs.
osteoarthritis, ankylosing spondylitis, acute Nimesulide is well-absorbed orally, exten-
musculoskeletal pain and postoperative pain. sively bound to plasma proteins and has a t½ of 3
Meloxicam, pivoxicam and tenoxicam are hours. It is excreted by the kidney.
other oxicams with action and adverse effects
similar to piroxicam. Dose: 50-100 mg BD.
Adverse effects are generally mild; they are
ALKANONES nausea, epigastric pain, rashes, drowsiness and
dizziness. But it can cause serious hepatotoxicity
Nabumetone is an anti-inflammatory agent with
because of which it is now banned in most
significant efficacy in rheumatoid arthritis and
countries.
osteoarthritis. It has a relatively low incidence of
side effects, it is comparatively less ulcerogenic. Uses: Nimesulide was used in headache,
Nabumetone is a prodrug and also selectively toothache, myalgia, dysmenorrhea, sinusitis, post-
inhibits COX-2 due to these, nabumetone causes operative pain and arthritis. It is beneficial in
less gastric irritation. patients who develop bronchospasm with other
It is used in rheumatoid and osteoarthritis. NSAIDs.
134 Pharmacology for Physiotherapy

ANTAGONISTS OF LEUKOTRIENE Nonsteroidal Anti-inflammatory


SYNTHESIS AND LEUKOTRIENE RECEPTORS Drugs (NSAIDs)
Zileuton, docebenone, piriprost—Some of them Nonsteroidal anti-inflammatory drugs are the first
inhibit 5-lipoxygenase and thereby prevent the line drugs in rheumatoid arthritis. NSAIDs afford
synthesis of leukotrienes, while others act as symptomatic relief but do not modify the course
competitive antagonists of LT receptor. They are of the disease (Table 6.5).
useful in asthma and other inflammatory con-
ditions.
Disease Modifying Drugs (DMDs)
Adverse effects: Dyspepsia, diarrhea and
headache. Disease modifying drugs are also called disease
modifying anti-rheumatic drugs (DMARDs). These
Drugs that block both cyclo-oxygenase and
are the second line drugs and are reserved for
lipoxygenase are tenidap, diclofenac and
patients with progressive disease who do not
indomethacin. Tenidap also blocks interleukin-1
obtain satisfactory relief from NSAIDs. They are
formation.
capable of arresting the progress of the disease
DRUGS USED IN RHEUMATOID and inducing remission in these patients. Recent
ARTHRITIS AND GOUT studies have shown that RA causes significant
systemic effects that shorten life expectancy. This
Rheumatoid arthritis (RA) is a chronic,
has renewed interest in the use of DMDs in RA.
progressive, autoimmune, inflammatory disease,
The effects of these drugs may take 6 weeks to 6
mainly affecting the joints and the periarticular
months to become evident and are therefore called
tissues. The antigen-antibody complexes trigger
slow-acting anti-rheumatic drugs (SAARDs).
the pathological process. Mediators of inflam-
mation released in the joints initiate the Gold salts were introduced for the treatment of
inflammatory process. The earliest lesion is RA in 1920s, but only in 1960s their beneficial
vasculitis, followed by synovial edema and effects were clearly shown. They are considered
infiltration with inflammatory cells. There is local
to be the most effective agents for arresting the
synthesis of prostaglandins and leukotrienes.
disease process.
Prostaglandins cause vasodilation and pain. The
On treatment, a gradual reduction of the signs
inflammatory cells release lysosomal enzymes
and symptoms are seen. It brings about a decrease
which cause damage to bones and cartilage.
in the rheumatoid factor and immunoglobulins.
Drugs Used in the Treatment of Rheumatoid
Arthritis Mechanism of action is not exactly known. But
1. NSAIDs gold depresses cell-mediated immunity (CMI).
2. DMDs — Gold, d-penicilla- Gold salts concentrate in tissues rich in mono-
mine, chloroquine nuclear phagocytes, selectively accumulate in the
and hydroxy- lysosomes of synovial cells and other macro-
chloroquine, phages in the inflamed synovium. They alter the
sulphasalazine, structure and functions of the macrophages,
abatacept TNF depress their migration and phagocytic activity.
blocking drugs They also inhibit lysosomal enzyme activity. Thus
3. Immunosuppressants — Methotrexate, gold salts depress CMI.
cyclophospha-
mide, azathioprine, Preparations: Aurothiomalate sodium and
leflunomide auronofin are given orally, aurothioglucose is
4. Adjuvants — Glucocorticoids. given parenterally.
TABLE 6.5: Properties of some commonly used NSAIDs

Drugs Properties Advantages Uses

Aspirin Good analgesic, antipyretic, Antiplatelet activity even As analgesic—headache backache,


anti-inflammatory and in low doses; powerful neuralgias, dysmenorrhea; pyrexia,
uricosuric agent anti-inflammatory rheumatic fever, rheumatic, psoriatic and
activity osteoarthritis, for anti-platelet activity in
post-stroke and post-MI; closure of PDA;
to delay labor
Paracetamol Good analgesic, antipyretic Less gastric irritation As analgesic; in fever
but poor anti-inflammatory
Diclofenac Analgesic, antipyretic, Good concentration in Chronic inflammatory conditions;
anti-inflammatory synovial fluid; adverse rheumatoid arthritis, osteoarthritis,
effects mild acute musculoskeletal pain
and postoperative pain
Piroxicam Analgesic, antipyretic, Long-acting (given once a day), Arthritis, musculoskeletal pain,
anti-inflammatory less ulcerogenic, better tolerated postoperative pain
Phenylbutazone Good anti-inflammatory; poor Powerful anti-inflammatory Rheumatoid and osteoarthritis; gout,
analgesic, antipyretic; salt and agent ankylosing spondylitis
water retention causes edema;
more toxic than aspirin
Indomethacin Good analgesic, anti- Potent anti- Rheumatoid, psoriatic and
inflammatory and antipyretic inflammatory osteoarthritis, gout, ankylosing
but toxicity is high and analgesic spondylitis, closure of PDA
Ibuprofen Analgesic, anti-inflammatory, Adverse effects As analgesic in painful conditions, anti-
antipyretic-all actions milder-therefore pyretic, soft tissue injuries, fractures, post-
milder than aspirin better tolerated operative pain, arthritis and gout
Central Nervous System
135
136 Pharmacology for Physiotherapy

Adverse effects: Treatment with gold is aplastic anemia, a variety of autoimmune diseases
associated with several adverse effects and only including lupus erythematosus, thyroiditis and
60 percent of patients remain on treatment at the hemolytic anemia. Anorexia, nausea, vomiting,
end of 2 years. loss of taste perception and alopecia may also be
seen.
Adverse effects include:
1. On skin and mucous membrane: Dermatitis, Chloroquine and hydroxychloroquine: These
pruritus, stomatitis, pharyngitis, glossitis, antimalarial drugs are found to be useful in mild
gastritis, colitis and vaginitis. A grey blue non-erosive rheumatoid arthritis. They induce
pigmentation on exposed parts of the skin may remission in 50 percent of patients. They are less
be seen. effective but are better tolerated than gold.
2. Renal toxicity: Hematuria, glomerulonephritis. Mechanism of action is not exactly understood
3. Nervous system: Encephalitis, peripheral but they are known to depress cell-mediated
neuritis. immunity.
4. Liver: Hepatitis, cholestatic jaundice.
Toxicity: Chloroquine and hydroxychloroquine
5. Blood: Thrombocytopenia, leukopenia,
accumulate in tissues leading to toxicity. The most
agranulocytosis, aplastic anemia.
significant side effect is the retinal damage on
6. CVS: Postural hypotension.
long-term use. This toxicity is less common and
7. Lungs: Pulmonary fibrosis.
reversible with hydroxychloroquine which is
Contraindications: Kidney, liver and skin diseases; therefore preferred over chloroquine in
pregnancy and blood dyscrasias. rheumatoid arthritis. Every 3 months eyes should
be tested. Other adverse effects include myopathy,
Uses neuropathy and irritable bowel syndrome.
1. Rheumatoid arthritis—gold is used in active Dose: Hydroxychloroquine 400 mg/day for 4-6
arthritis that progresses even after treatment weeks; maintenance dose is 200 mg/day.
with an adequate course of NSAIDs, rest and
physiotherapy. In most patients gold salts Sulphasalazine is a compound of sulphapyridine
arrest the progression of the disease, improve and 5-amino salicylic acid. In the colon,
grip strength, reduce morning stiffness and sulphasalazine is split by the bacterial action and
prevent involvement of unaffected joints. sulphapyridine gets absorbed. This has anti-
Gold is also beneficial in: inflammatory actions though the mechanism is
2. Juvenile rheumatoid arthritis. not known. Adverse effects include gastrointestinal
3. Psoriatic arthritis. upset and skin rashes.
4. Pemphigus. Abatacept inhibits T cell activation and can be
5. Lupus erythematosus. used alone or with other drugs as an I.V. infusion.
d-penicillamine is an analog of the amino acid There is a clinical improvement but can increase
cysteine and a metabolite of penicillin. It is a the risk of infection particularly upper respiratory
chelating agent that chelates copper. Its actions infection.
and toxicities are similar to gold but is less
TNF blocking agents: Cytokines, particularly
effective than gold. Hence it is not preferred. It is
tumor necrosis factor (TNF) plays an important
used as an alternative to gold in early, mild and
role in the process of inflammation. TNF produced
non-erosive disease.
by macrophages and activated T cells, acts through
Adverse effects include drug fever, skin rashes, TNF receptors to stimulate the release of other
proteinuria, leukopenia, thrombocytopenia, cytokines. TNF blocking drugs are found to be
Central Nervous System 137

useful in rheumatoid arthritis. Infliximab is a immunosuppressant activity. They produce


monoclonal antibody which specifically binds to prompt and dramatic relief of symptoms but do
human TNF. When given in combination with not stop the progress of the disease. However, long-
methotrexate, it slows the progression of term use of these drugs leads to several adverse
rheumatoid arthritis. It is given intravenously. effects. Moreover, on withdrawal of gluco-
Adverse effects of the combination include corticoids, there may be an exacerbation of the
increased susceptibility to upper respiratory disease. Therefore glucocorticoids are used as
infections, nausea, headache, cough, sinusitis and adjuvants. They may be used to treat exacer-
skin rashes. Antinuclear and anti-DNA antibodies bations. Low dose long-term treatment with
may develop. prednisolone is used in some patients (5-10 mg/
Etanercept is a recombinant fusion protein day).
that binds to TNF molecules. It is given subcu- Intra-articular corticosteroids are helpful to
taneously and is found to slow the progression of relieve pain in severely inflamed joints.
the disease in rheumatoid arthritis patients. It is
also found to be useful in psoriatic and juvenile Immunoadsorption Apheresis
arthritis. Etanercept can be given with metho- Extracorporeal immunoadsorption of plasma for
trexate and the combination has a better effect. the removal of IgG-containing immunocomplexes
Pain, itching and allergic reactions at the site has been approved for the treatment of moderate
of injection, anti-etanercept antibodies and anti- to severe rheumatoid arthritis. The duration of
DNA antibodies have been detected. benefit varies from few months to several years.
Adverse effects are mild and tolerable.
Immunosuppressants
Immunosuppressants are cytotoxic drugs and are Diet and Inflammation
reserved for patients having seriously crippling Clinical studies have shown that when patients
disease with reversible lesions after conventional of rheumatoid arthritis are given a diet rich in
therapy has failed. Among the immuno- unsaturated fatty acids (such as marine fish), there
suppressants, methotrexate is the best tolerated is a decrease in morning stiffness, pain and
and most commonly used. Toxicity includes swelling of the joints. Unsaturated fatty acids
nausea, mucosal ulcers, bone marrow suppres- compete with arachidonic acid for uptake and
sion and hepatotoxicity. Weekly regimens of low metabolism and their metabolic products are only
oral doses are better tolerated. weak inflammatory mediators when compared to
Leflunomide is a prodrug. The active metabolite the products of arachidonic acid metabolism.
inhibits autoimmune T cell proliferation and Adequate consumption of marine fish should be
production of autoantibodies by B cells. recommended. For people who do not eat fish,
Leflunomide is orally effective, and has a long t½ eicosapentaenoic acid 1-4 g/day may be given as
of 5-40 days. Adverse effects include diarrhea and tablets. It serves as an adjuvant.
raised hepatic enzymes.
Leflunomide is used with methotrexate in Pharmacotherapy of Gout
rheumatoid arthritis patients who are not Gout is a familial metabolic disorder characterized
responding to methotrexate alone. by recurrent episodes of acute arthritis due to
deposits of monosodium urate in the joints and
Corticosteroids cartilage. There is an inherent abnormality of
Detailed pharmacology is discussed in chapter purine metabolism resulting in overproduction
10. Glucocorticoids have anti-inflammatory and of uric acid—a major end product of purine
138 Pharmacology for Physiotherapy

metabolism. As uric acid is poorly water soluble, Adverse effects are dose related. Nausea,
it gets precipitated—especially at low pH and vomiting, diarrhea and abdominal pain are the
deposited in the cartilages of joints and ears, earliest side effects and may be avoided by giving
subcutaneous tissues, bursae and sometimes in colchicine intravenously. Anemia, leukopenia and
kidneys. An acute attack of gout occurs as an alopecia may be seen. In high doses hemorrhagic
inflammatory reaction to crystals of sodium urate gastroenteritis, nephrotoxicity, CNS depression,
deposited in the joint tissue. There is infiltration muscular paralysis and respiratory failure can
of granulocytes which phagocytize the urate occur.
crystals and release a glycoprotein that causes
joint destruction. The joint becomes red, swollen, Uses
tender and extremely painful.
1. Acute gout—colchicine 1 mg orally initially
Secondary hyperuricemia may be drug
followed by 0.5 mg every 2-3 hours relieves
induced or may occur in lymphomas and
pain and swelling within 12 hours. But
leukemias. Gout may also be due to decreased
diarrhea limits its use.
excretion of uric acid.
2. Prophylaxis—Colchicine may also be used for
Strategies in the treatment of gout is either to
the prophylaxis of recurrent episodes of gouty
decrease the biosynthesis of uric acid or enhance
arthritis.
the excretion of uric acid.
NSAIDs afford symptomatic relief in the treatment
Drugs Used in Gout of gout. Indomethacin is the most commonly used
agent in acute gout. Piroxicam, naproxen and other
In acute gout: Colchicine,
newer NSAIDs are also used. They relieve an
NSAIDs.
acute attack in 12-24 hours and are better tolerated
In chronic gout: Uric acid synthesis Allopurinol
than colchicine. But NSAIDs are not recom-
inhibitor
mended for long-term use due to their toxicity.
Uricosuric drugs Probenecid,
Sulphin- Allopurinol is an analog of hypoxanthine and
pyrazone. inhibits the biosynthesis of uric acid.
Colchicine is an alkaloid of Colchicum autumnale. Mechanism of action: Purine nucleotides are
It is a unique anti-inflammatory agent effective degraded to hypoxanthine. Uric acid is produced
only against gouty arthritis. It is not an analgesic. as shown in Figure 6.1. Allopurinol and its
metabolite alloxanthine both inhibit the enzyme
Actions: In gout, colchicine is highly effective in
xanthine oxidase and thereby prevent the
acute attacks and it dramatically relieves pain
synthesis of uric acid. The plasma concentration
within a few hours.
of uric acid is reduced.
Mechanism of action: Colchicine inhibits the
migration of granulocytes into the inflamed area
and the release of glycoprotein by them.
Other actions: Colchicine binds to microtubules
and arrests cell division in metaphase. It increases
gut motility by neurogenic stimulation.
Pharmacokinetics: Colchicine is rapidly absorbed
orally, metabolized in the liver and undergoes
enterohepatic circulation. Fig. 6.1: Biosynthesis of uric acid
Central Nervous System 139

Pharmacokinetics: Allopurinol is 80 percent adverse effects similar to probenecid. It is used in


absorbed orally; t½ of allopurinol is 2-3 hr; t½ of chronic gout in an initial dose of 200 mg/day and
alloxanthine is 24 hours. gradually increased to 400-800 mg/day.
Adverse effects are mild. Hypersensitivity
reactions include fever and rashes. Gastro- DRUGS USED IN PSYCHIATRIC
intestinal irritation, headache, nausea and DISORDERS—ANTIPSYCHOTICS,
dizziness may occur. ANTIDEPRESSANTS AND
Attacks of acute gouty arthritis may be seen ANTIANXIETY AGENTS
frequently during the initial months of treatment
with allopurinol. Since ages, man has sought the help of drugs to
modify behavior, mood and emotion. Psycho-
Drug interactions: The anticancer drugs—6- active drugs were used both for recreational
mercaptopurine and azathioprine are meta- purposes and for the treatment of mental illnesses
bolized by xanthine oxidase. Hence when (Psyche = mind).
allopurinol is used concurrently the dose of these In 1931 Sen and Bose showed that Rawolfia
anticancer drugs should be reduced. serpentina is useful in the treatment of insanity.
Uses: Allopurinol is used in chronic gout and ECT was introduced in 1937 for the treatment of
secondary hyperuricemia. Initial dose is 100 mg/ depression. In 1950 chlorpromazine was
day and may be gradually increased to 300 mg/ synthesized in France and its usefulness in
day depending on the response. Colchicine or an psychiatric patients was demonstrated in 1952.
NSAID should be given during the first few weeks During the second half of the twentieth century,
of allopurinol therapy to prevent the acute attacks extensive research has been carried out in
of gouty arthritis. On treatment with allopurinol, psychopharmacology and we now have several
tophi are gradually resorbed and the formation of useful drugs in this branch of pharmacology.
renal stones are prevented. In patients with large Psychiatric conditions are broadly divided
tophaceous deposits, both allopurinol and into psychoses, neuroses and personality
uricosuric drugs can be given. disorders.
Uricosuric Drugs Psychoses are the more severe psychiatric
Probenecid is an organic acid developed to disorders of the three and involve a marked
inhibit the renal tubular secretion of penicillin in impairment of behavior, inability to think
order to prolong its action. coherently, and to comprehend reality. Patients
Probenecid blocks tubular reabsorption of uric have no ‘insight’ into these abnormalities.
acid and thereby promotes its excretion. It is well- Psychoses could be due to:
absorbed and well-tolerated. Adverse effects i. An organic cause, i.e. there is a definable toxic,
include gastrointestinal irritation and skin rashes. metabolic or pathological change—as
Large amounts of water should be given to prevent following head injury.
the formation of renal stones. ii. Functional or idiopathic disorders—where
Probenecid is indicated in chronic gout and there is no definable cause like in
secondary hyperuricemia. It is started with 500 schizophrenia, paranoia and affective
mg once a day and gradually increased to 1 g/
disorders.
day. Probenecid may also precipitate acute attacks
of gout due to fluctuating urate levels. Schizophrenia (split mind) affects about 1 percent
Sulphinpyrazone: A pyrazolone derivative is of population, starts in an early age and is highly
another uricosuric drug which has actions and incapacitating. It is characterized by delusions,
140 Pharmacology for Physiotherapy

hallucinations, irrational conclusions, inter- Chlorpromazine (CPZ)


pretations and withdrawal from social contacts.
Patients with chronic schizophrenia have Pharmacological Actions
shrinkage of the brain. CNS: Behavioral effects—in normal subjects CPZ
reduces motor activity, produces drowsiness and
Neuroses are the milder forms of psychiatric
indifference to surroundings. In psychotic
disorders and include anxiety, mood changes,
agitated patients, it reduces aggression, initiative
panic disorders, obsessions, irrational fears and and motor activity, relieves anxiety and brings
reactive depression as seen following tragedies. about emotional quietening and drowsiness. It
Personality disorders include paranoid, normalizes the sleep disturbances characteristic
schizoid, histrionic, avoidant, antisocial and of psychoses.
obsessive compulsive personality types.
Drugs used in psychiatric illnesses may be Other CNS Actions
grouped as: 1. Cortex: CPZ lowers seizure threshold and
1. Antipsychotics or neuroleptics—used in can precipitate convulsions in untreated
psychoses. epileptics.
2. Antidepressants or psychotropic drugs—used in 2. Hypothalamus: CPZ decreases gonado-
affective disorders. trophin secretion and may result in amenorr-
3. Antianxiety drugs. hea in women. It increases the secretion of
Neuroleptic is a drug that reduces initiative, prolactin resulting in galactorrhea and
brings about emotional quietening and induces gynecomastia.
drowsiness. Tranquilliser is a drug that brings 3. Basal ganglia: CPZ acts as a dopamine
about tranquillity by calming, soothing and antagonist and therefore results in extra-
quietening effects. This is the older terminology. pyramidal motor symptoms (drug induced
Neuroleptics or antipsychotics were called ‘major parkinsonism).
traquillisers’ and antianxiety drugs were called 4. Brainstem: Vasomotor reflexes are depressed
‘minor tranquillisers’. These terminologies are no leading to a fall in BP.
longer used. 5. CTZ: Neuroleptics block the dopamine (DA)
receptors in the CTZ and thereby act as
ANTIPSYCHOTICS (NEUROLEPTICS) antiemetics.
Classification Autonomic nervous system: The actions on the
1. Classical/typical neuroleptics ANS are complex. CPZ is an alpha blocker. The
a. Phenothiazines—Chlorpromazine, triflu- alpha blocking potency varies with each neuro-
promazine, thioridazine, mesoridazine, leptic. CPZ also has anticholinergic properties
trifluoperazine, fluphenazine. which leads to side effects like dryness of mouth,
b. Butyrophenones—Haloperidol, droperidol, blurred vision, reduced sweating, decreased
trifluperidol. gastric motility, constipation and urinary
c. Thioxanthenes—Thiothixene, chlorpro- retention. The degree of anticholinergic activity
thixene. also varies with each drug.
2. Atypical neuroleptics—Clozapine, olanza- CVS: Neuroleptics produce orthostatic hypo-
pine, risperidone, quetiapine, ziprasidone, tension due to alpha blockade action and reflex
aripiprazole. tachycardia. CPZ also has a direct myocardiac
3. Miscellaneous—Reserpine. depressant effect like quinidine.
Central Nervous System 141

Local anesthetic: CPZ has local anesthetic intramuscularly and the response is seen in 24
properties—but is not used for the purpose since hours. In chronic psychosis it takes 2-3 weeks of
it is an irritant. treatment to obtain the response.
1. Psychiatric conditions: Psychoses including
Kidney: CPZ depresses ADH secretion and has
schizophrenia and organic brain syndromes
weak diuretic effects.
like delirium and dementia all respond to
Tolerance develops to the sedative and
antipsychotics.
hypotensive actions while no tolerance is seen to
2. Nausea, vomiting: CPZ is a good antiemetic and
the antipsychotic actions.
is used in vomiting due to radiation sickness
Pharmacokinetics: CPZ is incompletely and drug induced vomiting.
absorbed following oral administration and also 3. Hiccough: CPZ can control intractable
undergoes significant first pass metabolism hiccough though the mechanism of action is
(bioavailability is 30%). It is highly protein bound; not known.
has a t½ of 20 to 24 hr and is therefore given once 4. Other neuropsychiatric syndromes: Neuroleptics
a day. are useful in the treatment of several syndromes
with psychiatric features like psychoses
Adverse reactions: Antipsychotics have a high associated with chronic alcoholism, mania,
therapeutic index and are fairly safe drugs. bipolar mood disorders and Huntington’s
1. Cardiovascular and autonomic effects— disease.
postural hypotension, palpitation, blurred
vision, dry mouth, constipation, nasal
Atypical Antipsychotics
stuffiness and urinary retention.
2. CNS effects—drowsiness and mental con- Atypical antipsychotics have the following
fusion, a variety of neurological syndromes advantages over conventional antipsychotics:
involving the extrapyramidal system includ- 1. Very low incidence of extrapyramidal side
ing parkinsonism, dyskinesias, dystonias, effects.
akathesia, perioral tremors and malignant 2. Sedation is low.
neuroleptic syndrome are troublesome side 3. No endocrine side effects, i.e. no galactorrhea
effects. and gynecomastia.
3. Endocrine disturbances—gynecomastia, 4. They are effective in patients not responding
amenorrhea and galactorrhea. to conventional antipsychotics.
4. Hypersensitivity reactions—jaundice,
agranulocytosis and skin rashes. Clozapine: In addition to blocking DA receptors,
clozapine also blocks 5-HT2, α adrenergic and
Drug interactions: Neuroleptics enhance the muscarinic receptors. Clozapine is an effective
sedative effects of CNS depressants, and the effects antipsychotic.
of anticholinergic drugs and alpha blockers. When
combined with these groups of drugs, the effects Disadvantage: May cause agranulocytosis in some
may be additive. patients which can be fatal. Hence use should be
Neuroleptics inhibit the actions of dopamine restricted to patients who are not responding to
agonists and L-dopa. other drugs. Clozapine can also cause sedation,
weight gain and hypotension.
Uses Olanzepine: It has the advantage that it causes
Neuroleptics are given orally (chlorpromazine no EPS dysfunction and no agranulocytosis has
100-800 mg). In acute psychosis they may be given been reported.
142 Pharmacology for Physiotherapy

Risperidone: It blocks serotonin and dopamine after 2-3 weeks of treatment, elevation of mood
receptors and is a commonly used antipsychotic. occurs; the patient shows more interest in the
surroundings and the sleep pattern becomes
Advantages
normal.
1. At low doses no EPS dysfunction.
Mechanism of action: TCAs block the reuptake
2. Low sedation.
of amines (noradrenaline or 5-HT) into the
presynaptic terminal, and thereby prolong
ANTIDEPRESSANTS their action on the receptors. Thus they
potentiate amine neurotransmission in the
Affective disorders are a group of psychoses
CNS.
associated with changes of mood, i.e. depression
and mania. 2. CVS : Postural hypotension and tachycardia
(due to blockade of α 1 adrenergic and
Depression is a common psychiatric disorder and muscarinic receptors) can be severe in
could be: overdosage.
1. Reactive: Due to distressing circumstances in
3. ANS: TCAs have anticholinergic properties
life.
and cause dry mouth, blurred vision, consti-
2. Endogenous: Major depression due to a
pation and urinary retention.
biochemical abnormality in the brain.
3. Bipolar mood disorder: Mania and depres-
Pharmacokinetics
sion occur alternately causing cyclic mood
swings. TCAs are rapidly absorbed, highly protein bound
Endogenous depression is thought to be due and metabolized in the liver. They have a long t½
to deficiency of monoamine activity (NA, 5-HT) and can be given once daily.
in the CNS.
Adverse Effects
Drugs Used in Affective Disorders
Sedation, postural hypotension, tachycardia,
Classification sweating and anticholinergic side effects like dry
mouth, constipation, blurred vision and urinary
1. Tricyclic antidepressants (TCA)—Imipramine,
retention are relatively common. TCA may
desipramine, amitriptyline, nortriptyline
precipitate convulsions in epileptics; may cause
doxepin.
hallucinations and mania in some patients. Many
2. Selective serotonin (5-HT) reuptake inhibitors
TCAs may also cause weight gain due to increased
(SSRI)—Fluoxetine, fluoxamine, paroxetine,
appetite.
citalopram, sertraline, venlafaxine.
3. Monoamine oxidase (MAO) inhibitors— Acute toxicity is manifested by (mimic symptoms
Phenelzine, tranylcypromine. of atropine poisoning) delirium, excitement,
4. Atypical antidepressants—Trazodone, nefazo- hypotension, convulsions, fever, arrhythmias,
done, bupropion, mianserine. respiratory depression and coma.

Tricyclic Antidepressants Treatment


Pharmacological Actions Physostigmine is given to overcome atropine-like
1. CNS: In normal subjects, TCA cause effects; sodium bicarbonate for acidosis, phenytoin
dizziness, drowsiness, confusion and for seizures and arrhythmias—with other
difficulty in thinking. In depressed patients, supportive measures.
Central Nervous System 143

Tolerance and dependence—tolerance develops inhibition of MAO by drugs, tyramine escapes


gradually to the sedative and anticholinergic metabolism and displaces NA from nerve
effects over 2-3 weeks. endings leading to hypertension. Similar
Following long-term treatment, TCAs should interaction with SSRI can result in severe
be gradually withdrawn as withdrawal hypertension (serotonin syndrome).
symptoms like headache, anxiety and chills can • Because of the side effects and drug
occur due to physical dependence. interactions, MAO inhibitors are not the
preferred antidepressants.
Drug Interactions
1. Tricyclics potentiate sympathomimetics— Atypical antidepressants: Trazodone, bupro-
even small amounts of adrenaline used with pion, mianserin.
local anesthetics can cause serious hyper-
tension. Advantages
2. Highly protein bound drugs like phenytoin, • Fewer side effects—particularly sedation and
aspirin and phenylbutazone displace TCAs anticholinergic effects.
from binding sites resulting in toxicity. • Safer in overdose.
3. TCAs potentiate the effects of alcohol and other • Effective in patients not responding to TCA.
CNS depressants.
Selective serotonin reuptake inhibitors (SSRI): Uses of Antidepressants
Fluoxetine, fluoxamine, paroxetine, citalopram, 1. Endogenous depression: Antidepressants are
sertraline, venlafaxine. used over a long period. The response appears
Antidepressant actions are similar to TCA but after 2-3 weeks of treatment. The choice of the
differ as follows: antidepressant depends on the side effects and
• Low cardiovascular side effects. patient factors like age. In severe depression
• Anticholinergic side effects are less. with suicidal tendencies, electroconvulsive
• Less sedation. therapy (ECT) is given.
• Preferred in elderly. 2. Panic attacks: Post-traumatic stress disorders
• Safer in overdose. and other anxiety disorders—all respond to
• Fluoxetine is the most commonly used SSRI. antidepressants (acute episodes of anxiety are
MAO inhibitors: Tranylcypromine, phenelzine: known as panic attacks).
• Irreversibly inhibit the enzyme MAO inhibitors 3. Obsessive compulsive disorders: SSRIs and
and enhance neuronal levels of noradrenaline, clomipramine are effective.
dopamine and 5-HT. 4. Nocturnal enuresis in children may be treated
• Antidepressant actions develop slowly over with antidepressants only when other
weeks of treatment. measures fail and drugs are to be given.
• Side effects are hypotension, weight gain, CNS 5. Psychosomatic disorders: Newer antidipressants
stimulation and atropine-like effects. are tried in fibromyalgia, irritable bowel
• They interact with many drugs and food. syndrome, chronic fatigue, tics, migraine and
• Patients on MAOI taking tyramine containing sleep apnea.
foods like cheese, beer, wines, yeast, buttermilk 6. Other indications: Attention deficit hyper-
and fish—develop severe hypertension and is activity disorder, chronic pain and chronic
known as cheese reaction. Tyramine is normally alcoholism—may result in depression—
metabolized by MAO in the gut wall. On antidepressants are tried.
144 Pharmacology for Physiotherapy

MOOD STABILIZERS Drug Interactions


Lithium is a monovalent cation. On prophylactic 1. Diuretics enhance Na+ loss and lithium
use in bipolar mood disorder (manic-depressive absorption from the kidney. This increases
illness), lithium acts as a mood stabilizer. It plasma lithium levels resulting in toxicity.
prevents swings of mood and thus reduces both 2. NSAIDs ↓ lithium elimination and enhance
the depressive and manic phases of the illness. toxicity.
Given in acute mania, it gradually suppresses the
episode over weeks. Uses

The Mechanism of Action 1. Prophylaxis of bipolar mood disorder—


episodes of mania and depression are reduced.
The mechanism of action of lithium is complex 2. Acute mania—since the response to lithium is
and not fully understood. It inhibits the synthesis
slow, neuroleptics are preferred.
of second messengers IP3 and DAG and thereby
3. Other uses—lithium is tried in recurrent
blocks the respective receptor-mediated effects.
neuropsychiatric disorders, hyperthyroidism
This is the most accepted mechanism of action.
and inappropriate ADH secretion syndrome.
Pharmacokinetics Other mood stabilizers: Because of difficulty in
Lithium is a small ion and mimics the role of using lithium, other drugs are being tried.
sodium in excitable tissues. Given orally it is well- Carbamazepine and sodium valproate are found
absorbed. It is filtered at the glomerulus but to be useful, less toxic alternatives.
reabsorbed like sodium. Steady state concentration
is reached in 5-6 days. Since safety margin is ANTIANXIETY DRUGS (ANXIOLYTICS)
narrow, plasma lithium concentration needs to
be monitored. Anxiety is tension or apprehension which is a
normal response to certain situations in life. It is a
Adverse Effects universal human emotion. But when it becomes
excessive and disproportionate to the situation, it
Lithium is a drug of low therapeutic index and
side effects are common. Nausea, vomiting, mild becomes disabling and needs treatment.
diarrhea, thirst and polyuria occur initially in
most patients. As the plasma concentration rises, Classification
hypothyroidism, CNS effects like coarse tremors, Benzodiazepines: Diazepam, chlordiazepoxide,
drowsiness, giddiness, confusion, ataxia, blurred lorazepam, alprazolam.
vision and nystagmus are seen. In severe
overdosage, delirium, muscle twitchings, convul- 5-HT agonist-antagonists: Buspirone, gepirone,
sions, arrhythmias and renal failure develop. ipsapirone.
β-blockers: Propranolol.
Precautions
Others: Meprobamate, hydroxyzine.
1. Minimum effective dose should be used.
2. Patients should always use the same Benzodiazepines (page 106) have good
formulation. antianxiety actions and are the most commonly
3. Patients should be aware of the first symptom used drugs for anxiety. They are CNS depressants.
of toxicity. Alprazolam in addition has antidepressant
4. Lithium is contraindicated in pregnancy. properties.
Central Nervous System 145

Buspirone is an azapirone with good anxiolytic reduced. They have a low safety margin and may
properties. It is a selective 5-HT1A partial agonist produce convulsions.
and a weak D2 antagonist. It is useful in mild to
moderate anxiety. Antianxiety effect develops Doxapram: It appears to act mainly on the
slowly over 2 weeks. Unlike diazepam, it is not a brainstem and spinal cord and increase the
muscle relaxant, not an anticonvulsant, does not activity of respiratory and vasomotor centers.
produce significant sedation, tolerance or Adverse effects are nausea, cough, restlessness,
dependence and is not useful in panic attacks. hypertension, tachycardia, arrhythmias and
Buspirone is rapidly absorbed and metabo- convulsions.
lized in the liver.
Uses
Dose: 5-15 mg OD or TDS.
1. Doxapram is occasionally used IV as an
Side effects are mild including headache,
analeptic in acute respiratory failure.
dizziness, nausea and rarely restlessness.
2. Apnea in premature infants not responding
β-blockers (page 48) In patients with prominent to theophylline.
autonomic symptoms of anxiety like tremors,
palpitation and hypertension, propranolol may Nikethamide is not used because of the risk of
be useful. β-blockers are also useful in anxiety convulsions.
inducing states like public speaking and stage Psychomotor stimulants: Amphetamine and
performance. They can be used as adjuvants to
dextroamphetamine are sympathomimetic drugs
benzodiazepines.
(Chapter 2).
Meprobamate has anxiolytic property but is not
Cocaine is a CNS stimulant, produces euphoria
preferred now as it is less effective and causes
and is a drug of abuse. It is also a local anesthetic
high sedation.
(page 101).
Hydroxyzine is an antihistaminic with anxioly-
tic actions. But due to high sedation it is not Methylxanthines: Caffeine, theophylline and
preferred. theobromine are the naturally occurring xanthine
alkaloids. The beverages—coffee contains caffeine;
tea contains theophylline and caffeine; cocoa has
CNS STIMULANTS
caffeine and theobromine. Caffeine and theo-
Drugs that have a predominantly stimulant effect phylline are CNS stimulants. They bring about
on the CNS may be broadly divided into: an increase in mental alertness, a reduction of
1. Respiratory stimulants: Doxapram, niketha- fatigue produce a sense of well being and improve
mide. motor activity and performance, with a clearer
2. Psychomotor stimulants: Amphetamine, cocaine flow of thought. Caffeine stimulates the respi-
and methylxanthines. ratory center. Higher doses produce irritability,
3. Convulsants: Leptazol, strychnine. nervousness, restlessness, insomnia, excitement,
and headache. High doses can result in
Respiratory stimulants are also called convulsions.
analeptics. These drugs stimulate respiration and
are sometimes used to treat respiratory failure. CVS: Methylxanthines increase the force of
Though they may bring about temporary contraction of the myocardium and increase the
improvement in respiration, the mortality is not heart rate and therefore increase the cardiac output.
146 Pharmacology for Physiotherapy

But, they also produce peripheral vasodilatation Uses


which tends to decrease the BP. The changes in
i. Headache: Because of the effect of caffeine on
BP are therefore not consistent. Caffeine causes
cerebral blood vessels, it is combined with
vasoconstriction of cerebral blood vessels. ergotamine for the relief of migraine
Kidneys: The xanthines have a diuretic effect and headache. Caffeine is also combined with
thereby increase the urine output. aspirin/paracetamol for the treatment of
headache.
Smooth muscle: Xanthines cause relaxation of ii. Bronchial asthma: Theophylline is used in the
smooth muscles especially the bronchial smooth treatment of bronchial asthma.
muscle (page 156).
Nootropics are drugs that improve memory and
Skeletal muscle: Xanthines enhance the power of cognition (cognition enhancers).
muscle contraction and thereby increase the Piracetam – described as a ‘nootropic agent’ is
capacity to do muscular work by both a central thought to protect cerebral cortex from hypoxia
stimulant effect and the peripheral actions. and improve learning and memory. In higher
doses it also inhibits platelet aggregation. Adverse
GI tract: Xanthines increase the secretion of acid
effects include insomnia, weight-gain, nervous-
and pepsin in the stomach and are gastric irritants.
ness, depression and gastrointestinal distur-
Adverse effects include nervousness, insomnia, bances.
tremors, tachycardia, hypotension, arrhythmias, It has been tried in dementia, myoclonus, stroke
headache, gastritis, nausea, vomiting, epigastric and other cerebrovascular accidents; alcoholism,
pain and diuresis. High doses produce convul- behavioral disorders and learning problems in
sions. Tolerance develops after sometime. children and in vertigo. The beneficial effects in
Habituation to caffeine is common. all these is not proved.
Autacoids

• HISTAMINE AND ANTIHISTAMINES


• 5-HYDROXYTRYPTAMINE, ERGOT ALKALOIDS, ANGIOTENSIN AND KININS
• EICOSANOIDS

Autacoids are substances formed in various inactive form. Histamine found in brain serves as
tissues, have complex physiologic and pathologic a neurotransmitter. Degranulation of the mast
actions and act locally at the site of synthesis. They cells release histamine which is quickly degraded
have a brief action and are destroyed locally. at the site.
Hence they are called local hormones and differ
from true hormones which are produced by Mechanism of Action
specific cells and reach their target tissues through Histamine produces its effects by acting on the
circulation. The word autacoid is derived from histamine receptors. Three subtypes are known.
Greek: autos-self akos-remedy. Histamine, 5- • H1—present in lungs, gut, blood vessels, nerve
hydroxytryptamine (serotonin), endogenous endings and brain.
peptides like bradykinin and angiotensin; • H2—stomach (gastric glands), heart, blood
prostaglandins and leukotrienes are autacoids. vessels and brain.
• H3—CNS.
HISTAMINE AND ANTIHISTAMINES
Actions
HISTAMINE
1. CVS: Histamine dilates small blood vessels
Histamine (tissue amine) (Histos = tissue) is a resulting in hypotension accompanied by
biogenic amine formed in many tissues. It is also reflex tachycardia. Cerebral blood vessels
found in the venoms of bees, wasps and other dilate—producing severe throbbing head-
stinging secretions. ache.
Synthesis, storage, distribution and degradation Triple response: Intradermal injection of
In humans, histamine is formed from the amino histamine elicits triple response comprising
acid histidine. Large amounts are found in the of:
lungs, skin and intestines. Histamine is stored in i. Red spot at the site (flush)—due to local
the granules of the mast cells and basophils in an capillary dilation.
148 Pharmacology for Physiotherapy

AUTACOIDS AND THEIR ANTAGONISTS

HISTAMINE 5-HT OR SEROTONIN ANGIOTENSIN


(H1 H2) (5-HT 1-7) (AT1, AT2)
H1 blockers Agonists Blockers
• Diphenhydramine • Sumatriptan • Losartan
• Chlorpheniramine • Buspirone
• Cetirizine, loratadine ACE inhibitors
• Dexfenfluramine
• Captopril
H2 blockers Blockers • Enalapril
• Ranitidine • Cyproheptadine • Ramipril
• Famotidine • Ketanserin
• Roxatidine • Ondensetran

PROSTAGLANDINS KININS (B1 B2) LEUKOTRIENES


Antagonists
Analogs Synthesis • Bradykinin • Moutelukast
• Misoprostol inhibitors • Kallidin • Zafirlukast
• Dinoprostone • Aspirin • Antagonists are Lipoxygenase
• Carboprost • Indomethacin being developed Inhibitors
• Paracetamol • Zileuton

Some autacoids with examples of agonists and antagonists. Receptor types are given in brackets

ii. Flare—redness surrounding the ‘flush’ due Adverse reactions include hypotension,
to arteriolar dilatation. flushing, tachycardia, headache, wheal, broncho-
iii. Wheal—local edema due to the escape of fluid spasm and diarrhea.
from the capillaries.
This response is accompanied by pain and Uses
itching. Histamine is of no therapeutic value. It is
2. Smooth muscle: Histamine causes contrac- occasionally used in some diagnostic tests like to
tion of the nonvascular smooth muscles. Thus test the acid secreting ability of the stomach,
bronchospasm and increased intestinal moti- diagnosis of pheochromocytoma, and to test for
lity are produced. bronchial hyperreactivity.
3. Glands: Histamine is a powerful stimulant of Histamine Substitutes
the gastric acid secretion-acts through H2
Betazole is a H2 agonist and can be used in gastric
receptors (Chapter 9). It also stimulates pepsin
function tests. Betahistine is a H1 agonist used to
and intrinsic factor secretion.
control vertigo in Meniere’s disease.
4. CNS: Histamine functions as a neuro-
transmitter in the CNS. ANTIHISTAMINES
5. Nerve endings: Histamine stimulates sensory Histamine antagonists can be H1 receptor blockers
nerve endings causing pain and itching. and H2 receptor blockers.
Autacoids 149

Drugs that competitively block H1 histamine 2. Sedation: Antihistamines cause CNS


receptors are conventionally called the depression; sedation, dizziness, inability to
antihistamines. H2 blockers are used in the concentrate and disturbances of coordination
treatment of peptic ulcer (see page 163). are common. Alcohol and other CNS depres-
sants potentiate this action. Some patients
Classification of H1 Blockers may experience CNS stimulation resulting in
tremors, restlessness and insomnia.
Sedative: Diphenhydramine, dimenhydrinate, 3. Antimotion sickness effects: Several anti-
promethazine. histamines prevent motion sickness and
Less sedative: Pheniramine, chlorpheniramine, vomiting due to other labyrinthine distur-
cyclizine, meclizine, buclizine, mepyramine, bances. Some of them also control vomiting of
tripelennamine. pregnancy.
4. Antiparkinsonian effects: Some of them suppress
Newer non-sedative: Terfenadine, astemizole, tremors, rigidity and sialorrhea probably due
loratadine, desloratadine, cetirizine. to their anticholinergic properties.
5. Anticholinergic actions: Many of the H1 blockers
Actions have anticholinergic property.
6. Other actions: Antihistamines also have local
1. Blockade of actions of histamine: H1 receptor
anesthetic effects in high doses. Some of them
antagonists block the actions of histamine on
also block α1 adrenergic and 5-HT receptors.
H 1 receptors. They block the histamine
induced effects on smooth muscles of the gut, Pharmacokinetics: Antihistamines are well-
bronchi, blood vessels and triple response. absorbed, widely distributed in the body,

TABLE 7.1: Dose and preparations of some antihistamines

Antihistamine Route Trade name

Diphenhydramine HCl Oral IM Benadryl cap, syr


Dimenhydrinate Oral, IM Dramamine tab, syr inj
Promethazine Oral, IM Phenergan tab, syr, inj
Promethazine Oral Avomine tab
chlortheophyllinate
Pheniramine maleate Oral, IM Avil tab, syr, inj
Chlorpheniramine Oral, IM Zeet tab, syr, inj
Cyclizine HCl Oral Marezine tab
Meclizine HCl Oral Ancolan tab
Buclizine Oral Longifene tab, syr
Cinnarizine Oral Stugeron tab
Nonsedative (II generation) antihistamines
Terfenadine Oral Trexyl tab, syr
Astemizole Oral Astelong, tab, syr
Loratadine Oral Lorfast, tab, syr
Desloratadine Oral Deslor tab
Cetirizine Oral Alerid, tab, syr
150 Pharmacology for Physiotherapy

metabolized in the liver and are excreted in the 4. Antiemetic: Promethazine is used to prevent
urine. Route of administration and preparations drug induced and postoperative vomiting. It
are given in Table 7.1. has also been used in ‘morning sickness.’
5. Preanesthetic medication: For its sedative,
Adverse reactions are mild and on continued
anticholinergic and antiemetic properties,
use tolerance develops.
promethazine has been used as preanesthetic
Sedation, dizziness, motor incoordination,
medication.
inability to concentrate make driving dangerous
6. Hypnotic: The sedative antihistamines are
while on antihistamines. Anticholinergic effects
sometimes used to induce sleep. Hydroxizine
like dryness of mouth, blurred vision, constipa-
has been used as an anxiolytic.
tion and urinary retention may be troublesome.
7. Parkinsonism: Some of them are useful in drug
Epigastric distress and headache can also occur.
induced parkinsonism due to their anti-
Many of them are teratogenic.
cholinergic action.
Newer non-sedative antihistamines also called 8. Cough due to postnasal drip can be controlled
second generation antihistamines have the by antihistamines like diphenhydramine.
following advantages over classical antihista-
mines: 5-HYDROXYTRYPTAMINE, ERGOT
• No sedation because they poorly cross the
ALKALOIDS, ANGIOTENSIN AND KININS
blood-brain barrier.
• No anticholinergic side effects as these are
5-HYDROXYTRYPTAMINE
pure H1 blockers and do not block cholinergic
receptors. 5-Hydroxytryptamine (serotonin) is of great
• Some of them like astemizole are long-acting. pharmacological interest. It is found in various
However, the therapeutic indications of these plant and animal tissues. In human body, 5-HT is
agents are limited to allergic disorders like allergic present in the intestines, platelets and brain. It is
rhinitis and chronic urticaria. They are more synthesized from the amino acid tryptophan and
expensive. Terfenadine can very rarely cause fatal stored in granules. It is degraded mainly by
ventricular arrhythmias; erythromycin and monoamine oxidase (MAO).
ketoconazole potentiate this cardiotoxicity.
5-HT Receptors: The actions of serotonin are
Uses mediated through its receptors. Seven types of 5-
HT receptors (5-HT1-7) with further subtypes of 5-
1. Allergic reactions: Antihistamines are useful for
HT1 and 5-HT2 receptors are presently known.
the prevention and treatment of symptoms of
Many receptor selective agonists and antagonists
allergic reactions. They are effective in allergic
are being developed.
rhinitis, conjunctivitis, hay fever, urticaria,
pruritus, some allergic skin rashes and
Actions
pollinosis.
2. Common cold: Antihistamines reduce 1. CVS: The action on blood vessels is complex.
rhinorrhea and afford symptomatic relief in Large vessels are constricted while arterioles
common cold. dilate. A characteristic triphasic response is
3. Motion sickness: Given 30-60 minutes before seen on blood pressure following IV injection.
journey, antihistamines prevent motion Initial fall in BP in followed by a rise and
sickness. They are also useful in treating then fall.
vertigo of Meniere’s disease and other vesti- 2. GI tract: 5-HT increases gastrointestinal
bular disturbances. Cinnarizine is preferred. motility and contraction resulting in diarrhea.
Autacoids 151

3. Other actions: Weak bronchoconstriction, ‘ergotism’ manifested as gangrene of hands and


platelet aggregation; stimulation of sensory feet, hallucinations and other CNS effects.
nerve endings—causes pain if injected into the Natural ergot alkaloids include ergometrine,
skin. 5-HT is a neurotransmitter in the CNS. ergotamine and ergotoxine. The semisynthetic
dehydrogenated derivatives are also available.
Physiological and pathophysiological role: 5-HT
is postulated to be having a role in peristalsis, Actions: Ergot alkaloids have agonist, partial
vomiting, platelet aggregation, homoeostasis and agonist and antagonistic actions at 5-HT and
inflammation. It is also thought to initiate the alpha adrenergic receptors and agonistic actions
vasoconstriction in migraine. at CNS dopamine receptors. Thus their actions
are complex. Some of them are powerful hallu-
Drugs acting on 5-HT receptors: Serotonin has no
cinogens, e.g. lysergic acid diethylamide (LSD).
therapeutic uses. However its receptor agonists
They cause stimulation of smooth muscles—some
and antagonists have been used in various
mainly vascular smooth muscles and others
conditions.
mainly uterine smooth muscles. The vasoconstric-
tor effect is responsible for gangrene.
Serotonin Agonists
Adverse effects like nausea, vomiting and
Sumatriptan—a 5-HT1D agonist is effective in the
diarrhea are common. Prolonged use results in
treatment of acute migraine and cluster headache.
gangrene due to persistent vasospasm.
Given at the onset of an attack, sumatriptan
relieves headache and also suppresses nausea and
Uses (Table 7.2)
vomiting of migrane. It is short-acting.
1. Migraine.
Other Agonists 2. Postpartum hemorrhage—ergometrine is used
for the prevention and treatment.
Buspirone (see page 144) is a 5-HT1A agonist-
antagonist used as an antianxiety agent.
TABLE 7.2: Serotonin agonists, antagonists
Dexfenfluramine (see page 47) is used as an and their therapeutic uses
appetite suppressant.
Uses
Serotonin Antagonists AGONISTS
Cyproheptadine blocks 5-HT2, H1 histamine and Sumatriptan • Acute migraine
• Cluster headache
cholinergic receptors. It increases appetite and is
used to promote weight gain especially in children. Buspirone Anxiolytic
Dexfenfluramine Appetite suppressant
Ketanserin blocks 5-HT2 receptors and anta-
gonizes vasoconstriction and platelet aggregation ANTAGONISTS
promoted by 5-HT. It is used in hypertension. Cyproheptadine • Appetite stimulant
• Carcinoid tumors
Ondansetron is a 5-HT3 antagonist (see page 167)
Ketanserin Hypertension
used in the prevention and treatment of vomiting.
Many other drugs including some anti- Ondansetron Antiemetic
histamines also block serotonin receptors. ERGOT ALKALOIDS
Ergotamine Acute attack of migraine
ERGOT ALKALOIDS
Ergometrine Postpartum hemorrhage
Ergot alkaloids are produced by a fungus Claviceps Methysergide Prophylaxis of migraine
purpurea. Consumption of such grains results in
152 Pharmacology for Physiotherapy

Drugs Used in the Treatment of Migraine KININS


Migraine is a common disorder characterized by Kinins are vasodilator peptides formed from the
severe, throbbing, unilateral, headache often precursor kininogen by the action of the enzymes
associated with nausea, vomiting and fatigue called kallikreins. The most important of kinins is
lasting for several hours. In the classical migraine, bradykinin.
a brief ‘aura’ of visual disturbances occurs prior Kinins are potent vasodilators and cause a brief
to the headache. An attack is triggered by factors fall in BP. They stimulate contraction of other
like stress, anxiety, excitement, food (like chocolate smooth muscles—thus they induce bronchospasm
and cheese) and hormonal changes. These in asthmatics, slow contraction of intestines
triggering factors stimulate the release of vaso- (Brady= slow) and uterus. Kinins mediate inflam-
active substances from nerve endings which are mation, and stimulate the pain nerve endings.
responsible for the events that follow. However Kinins produce their actions by acting through B1
the exact pathophysiology is not understood and and B2 receptors.
several hypotheses have been put forward. Drugs affecting the kallikrein-kinin system—
Aspirin, paracetamol or other NSAIDs, B1 and B2 antagonists are now being developed.
ergotamine and sumatriptan are effective in acute
attacks. Drug should be taken at the initiation of EICOSANOIDS
an attack.
When the attacks are frequent and severe, Eicosanoids are 20-carbon (eicosa referring to the
prophylaxis is needed. Drugs used for the 20-C atoms) unsaturated fatty acids derived
prophylaxis are: propranolol, flunarizine, mainly from arachidonic acid in the cell walls.
cyproheptadine and amytriptyline. The principal eicosanoids are the prostaglandins
(PG), the thromboxanes (TX), and the leukotrienes
ANGIOTENSIN (LT).

Angiotensins are peptides synthesized from the Biosynthesis


precursor angiotensinogen. Angiotensin II, the
most potent angiotensin, acts through angiotensin Eicosanoids are synthesized locally in most
receptors (AT1 and AT2) present on the tissues. tissues from arachidonic acid. The pathway for
synthesis is shown in Figure 7.1.
Actions The cyclo-oxygenase (COX) pathway
generates PGs and TXs while lipoxygenase (LOX)
Angiotensin II causes vasoconstriction resulting pathway generates LTs. There are 2 cyclo-
in increased blood pressure. It stimulates the oxygenase isozymes viz. COX-1 and COX-2.
synthesis of aldosterone by the adrenal cortex Eicosanoids produced by COX-1 mainly take part
which increases sodium reabsorption by the in physiological functions while those produced
kidneys. By these actions, renin-angiotensin by COX-2 result in inflammatory and pathological
system regulates the fluid and electrolyte balance changes.
and blood pressure.
Inhibitors of ACE and blockers of angiotensin
PROSTAGLANDINS AND THROMBOXANES
II receptors are now used in the treatment of
hypertension, congestive heart failure and other In 1930s it was found that human semen contains
conditions that are due to excess of angiotensin II a substance that contracts uterine smooth muscle.
activity (see Chapter 4). As this substance was thought to originate in the
Autacoids 153

and PGF2α are used. They are also used


with mifepristone to ensure complete
expulsion of the products of conception.
b. Facilitation of labor: As alternative to
oxytocics in patients with renal failure.
c. Cervical priming: Intravaginal PGE2 is used.
d. Postpartum hemorrhage: Intramuscular
PGF 2α is used as an alternative to
ergometrine.
2. Gastrointestinal: Peptic ulcer PGE1 (miso-
prostol) and PGE2 (enprostil) are used for the
prevention of peptic ulcer in patients on high
dose NSAIDs.
3. Cardiovascular
a. Patent ductus arteriosus: Patency of fetal
ductus arteriosus depends on local PG
synthesis. In neonates with some
congenital heart diseases, patency of the
Fig. 7.1: Biosynthesis of eicosanoids ductus arteriosus is maintained with PGs
until surgery is done.
prostate, they called it ‘Prostaglandin’. But it was b. To prevent platelet aggregation during
later found to be produced in many tissues. hemodialysis.
4. Other uses: PGs are used in pulmonary
Actions hypertension and some peripheral vascular
The eicosanoids act through their specific diseases. They can also be used in open angle
receptors present on the tissues. glaucoma to lower intraocular pressure.
CVS: Prostacycline causes vasodilation while
TXA2 causes vasoconstriction. PGE2 and PGF2α LEUKOTRIENES
are weak cardiac stimulants. Leukotrienes (LT) are products of arachidonic acid
Other actions: PGs (TXA2 , PGF2α) contract metabolism synthesized by the lipoxygenase
gastrointestinal and bronchial smooth muscles. pathway and are found in the lungs, platelets,
TXA2 induces platelet aggregation while PGI2 mast cells and white blood cells. (‘Leuko’—
inhibits it. PGE2 and PGF2α contract uterus. PGs because they are found in white cells; ‘trienes’—
also stimulate bone turnover and sensitize the they contain triene system of double bonds). LTA4
nerve endings to pain. is the precursor from which LTB4, LTC4, LTD4,
LTE4 and LTF4 are derived. LTC4, LTD4 and LTE4
Adverse effects depend on the type of PG, dose
are together known as slow reacting substances
and route. Diarrhea, nausea, vomiting, fever,
(SRS-A) of anaphylaxis. The LTs produce their
hypotension and pain due to uterine contractions
effects through specific receptors.
are common.

Uses Actions
1. Gynecological and obstetrical Leukotrienes cause vasoconstriction, increase
a. Abortion For I and II trimester abortion and vascular permeability leading to edema, increase
ripening of cervix during abortion, PGE2 airway mucous secretion and are potent
154 Pharmacology for Physiotherapy

bronchiolar spasmogens. Given subcutaneously PLATELET ACTIVATING FACTOR (PAF)


they cause wheal and flare. Leukotrienes have a
role in inflammation including rheumatoid PAF is an important mediator in acute and
arthritis, psoriasis and ulcerative colitis. They also chronic, allergic and inflammatory phenomena.
contribute to bronchial hyper-responsiveness in PAF is released from inflammatory cells and acts
bronchial asthma. on specific receptors. It causes local vasodilatation
Drugs that inhibit lipoxygenase and thus resulting in edema, hyperalgesia and wheal for-
block the synthesis of leukotrienes are under mation. It is a potent chemotaxin for leukocytes
investigation in the treatment of bronchial and a spasmogen on bronchial and intestinal
asthma. smooth muscles. It is a mediator of inflammation.
Respiratory
System

• DRUGS USED IN THE TREATMENT OF BRONCHIAL ASTHMA


• DRUGS USED IN THE TREATMENT OF COUGH

DRUGS USED IN THE TREATMENT c. Anticholinergics: Ipratropium bromide,


OF BRONCHIAL ASTHMA atropine, tiotropium bromide.
Bronchial asthma is characterized by dyspnea 2. Anti-inflammatory agents
and wheeze due to increased resistance to the flow a. Systemic: Glucocorticoids, hydrocortisone,
of air through the bronchi. Bronchospasm, prednisolone.
mucosal congestion and edema result in increased b. Inhalational: Beclomethasone, budesonide,
flunisolide, triamcinolone.
airway resistance. The bronchial smooth muscle
is hyperresponsive to various stimuli like dust, 3. Mast cell stabilizers
allergens, cold air, infection and drugs. These Disodium cromoglycate, nedocromil,
trigger factors—trigger an acute attack. Antigen- Ketotifen.
antibody interaction on the surface of mast cells 4. Leukotriene receptor antagonists
cause (Fig. 8.1): Montelukast, zafirlukast.
i. Degranulation of mast cells releasing stored 5. Anti IgE antibody
mediators of inflammation. Omalizumab.
ii. Synthesis of other inflammatory mediators
Sympathomimetic Drugs (see page 42)
which are responsible for bronchospasm,
mucosal congestion and edema. Inflammation These drugs are potent bronchodilators. They
is the primary pathology. stimulate β 2 receptors in bronchial smooth
muscles resulting in increased cAMP levels. This
Classification increased cAMP leads to bronchodilatation. The
increased cAMP in mast cells inhibit the release
1. Bronchodilators
of inflammatory mediators. They also reduce
a. Sympathomimetics: Salbutamol, terbutaline,
bronchial secretions and congestion (by acting on
salmeterol, isoprenaline adrenaline,
α receptors).
ephedrine.
b. Methylxanthines: Theophylline, amino- Salbutamol and terbutaline are selective β2
phylline. agonists. Given by inhalation, they are fastest-
156 Pharmacology for Physiotherapy

acute attacks) but the effect remains for 12 hours.


It is therefore used for long-term maintenance and
for prevention of nocturnal asthmatic attacks.
Newer agents like fenoterol, formoterol
bambuterol, pirbuterol are similar to salbutamol.

Others
Adrenaline, ephedrine and isoprenaline are
nonselective β receptor stimulants. Though
adrenaline and isoprenaline produce prompt
bronchodilation, they are not preferred due to the
risk of adverse effects.
Ephedrine produces bronchodilation but is
slow in onset. Because of low efficacy, side effects
and availability of better drugs, ephedrine is not
preferred.
Methylxanthines (page 145)
Theophylline and its derivatives like aminophylline
are good bronchodilators.

Fig. 8.1: Immediate and late responses of Mechanism of action: Phosphodiesterase (PDE)
mast cell activation by antigen is the enzyme that degrades cyclic AMP.
Methylxanthines inhibit PDE and thereby
enhance cAMP levels which brings about
bronchodilation. cAMP also inhibits the release
acting bronchodilators with peak effect in 10 of mediators of inflammation.
minutes. The action lasts for 6 hours. Adverse
effects to β2 agonists include muscle tremors, cAMP
palpitation and nervousness. ↓ PDE ← Methylxanthines
Selective β2 agonists are the most commonly 5’AMP
used bronchodilators as they are the most effective, Aminophylline is given intravenously, slowly
fast-acting, convenient and relatively safe in acute attacks of asthma not responding to β2
bronchodilators. They are available as metered agonists. In an acute attack, drugs given by
dose inhalers, nebulizers and also tablets for oral inhalation may sometimes fail to reach the
use. The proper technique in using the inhaler bronchioles because of severe bronchospasm.
should be taught. ‘Spacers’ can be used in children Intravenous aminophylline may then be tried. 250
and adults who cannot follow the right technique mg aminophylline should be injected slow IV over
of inhalation. 15-20 minutes. Rapid IV injection may cause
Oral β2 agonists have higher adverse effects collapse and death due to hypotension and
and are used only in small children who cannot arrhythmias. Convulsions can also occur and
use inhalers and have occasional wheezing (1-4 should be carefully watched for.
mg 6 hourly).
Adverse effects: Theophylline is a drug of low
Salmeterol is a long-acting selective β2 agonist. therapeutic index. Gastric irritation, vomiting,
The onset of action is slow (hence not useful in insomnia, tremors, diuresis, palpitation, and
Respiratory System 157

hypotension are quite common. Higher doses because of the small dose required. But they are
cause restlessness, delirium, convulsions and not effective in acute attacks and are only of
arrhythmias. Children may develop behavioral prophylactic value. They prevent episodes of acute
abnormalities on prolonged use—should be asthma and bronchial hyperreactivity and
avoided in children. effectively control symptoms. The effect develops
after 1 week of treatment.
Status in bronchial asthma: Theophylline is a
Side effects of inhaled steroids include
second line drug in bronchial asthma.
hoarseness of voice, sore throat and oropharyn-
1. Chronic asthma: Oral theophylline can be used geal candidiasis. Rinsing the mouth and throat
to control mild to moderate asthma. with water after each use can reduce the incidence
Etophylline + 80% theophylline (Deriphylline) of candidiasis and sore throat. No HPA axis
injections (IM) are used to relieve acute attacks. suppression is seen in the recommended doses.
2. Acute severe asthma (status asthmaticus): Beclomethasone dipropionate, budesonide,
Intravenous aminophylline is tried when flunisolide and triamcinolone are used as inhalers.
sympathomimetics fail to relieve broncho-
Dose: Beclomethasone: BECLATE INHALER 50,
spasm—but are found to be less effective.
100 and 200 μg per metered dose → 1-2 Puffs 3-4
3. Apnea in premature infants. times a day.
Anticholinergics (see Chapter 2)—relax bronchial Use of Glucocorticoids in Asthma
smooth muscles but response is slower than
sympathomimetics. Ipratropium bromide is given 1. Acute exacerbation: A short course (5-7 days) of
by inhalation and its actions are largely limited to oral prednisolone is given in addition to β2
the respiratory tract. It is more effective in chronic agonists.
bronchitis. It is safe and well-tolerated. 2. Chronic asthma: Beclomethasone/Budesonide
inhalation for a long period as prophylaxis.
Uses 3. Status asthmaticus: IV hydrocortisone
hemisuccinate followed by oral prednisolone.
1. As an adjunct to β2 agonists.
2. As a bronchodilator in some cases of chronic MAST CELL STABILIZERS
bronchitis.
Cromolyn sodium (disodium cromoglycate) was
synthesized in 1965.
ANTI-INFLAMMATORY DRUGS
Mechanism of action: Cromolyn inhibits the
Glucocorticoids: Since inflammation is the degranulation of mast cells and thereby inhibits
primary pathology in bronchial asthma, anti- the release of mediators of inflammation. It thus
inflammatory agents afford significant benefit. prevents bronchospasm and inflammation
Mechanism of action: Steroids are not broncho- following exposure to allergens. It is therefore used
dilators. They suppress the inflammatory for prophylaxis. It is not a bronchodilator — hence
response to antigen-antibody reaction and thereby not useful in acute episodes.
reduce mucosal edema and hyperirritability. They Cromolyn sodium is used as an inhaler; it
restore response to β2 agonists if tolerance has takes 2-4 weeks of treatment for the beneficial
developed. Oral prednisolone is commonly used. effects to develop.
Adverse effects are rare. Throat irritation,
Inhaled steroids: The use of inhalational steroids cough and sometimes bronchospasm can occur
largely minimizes the adverse effects of steroids on inhalation due to the fine powder.
158 Pharmacology for Physiotherapy

Uses Treatment of Asthma


1. Prophylaxis of bronchial asthma—Cromolyn Mild asthma—Inhaled β2 stimulants.
sodium is used over a long period—2 puffs—
3-4 times daily reduces the frequency and Moderate asthma—Regular prophylaxis with
severity of episodes of acute asthma. Young cromoglycate. If symptoms persist—inhaled
patients are more likely to be benefitted. It is steroids for prophylaxis. Acute episodes are
used prophylactically and not useful in acute managed with inhaled β2 agonists.
bronchospasm. Severe asthma
2. Allergic rhinitis—Prophylactic nasal spray is a. Regular inhaled steroids.
used. b. Inhaled β2 agonists 3-4 times a day.
3. Allergic conjunctivitis—Eyedrops are used c. Oral steroids may be considered.
prophylactically. d. Additional inhaled ipratropium bromide or
Nedocromil is similar to cromolyn sodium in its oral theophylline may be given.
actions and uses. It is given twice daily. Status asthmaticus or acute severe asthma is
an acute exacerbation. It is a medical emergency;
Ketotifen is an antihistaminic with actions like
may be triggered by an acute respiratory infection,
cromolyn sodium. It inhibits airway inflammation
abrupt withdrawal of steroids, drugs, allergens
but it is not a bronchodilator. It is given orally.
or emotional stress.
Beneficial effects are seen after 6-12 weeks of use.
It is used for the prophylaxis of bronchial asthma Treatment
and other allergic disorders like allergic rhinitis 1. Nebulization of β2 agonist and ipratropium
and conjunctivitis. Drowsiness and dry mouth alternately—every 30 minutes. Additional
are common side effects. salbutamol injection (IM/SC) may be given.
Severe tachycardia should be watched for.
Leukotriene Receptor Antagonists 2. Hydrocortisone hemisuccinate IV followed by
Leukotrienes are important mediators of inflam- a course of oral prednisolone.
mation. They cause bronchospasm and increase 3. Oxygen inhalation.
respiratory mucus secretion and mediate 4. Antibiotics.
inflammation. Zafirlukast and montelukast block 5. IV fluids to correct dehydration.
the leukotriene receptors and antagonise the 6. Aminophylline 250 mg slow IV over 15-20
effects of leukotrienes-reduce mucosal edema and minutes may be given carefully—watch for
relieve bronchospasm. They can cause headache, adverse effects.
rashes and gastrointestinal disturbances. They 7. Artificial ventilation may be required in
may be used as alternatives to other drugs in mild extreme cases.
to moderate asthama.
Omalizumab is a monoclonal antibody against DRUGS USED IN THE
IgE antibodies. It binds to IgE antibodies and TREATMENT OF COUGH
prevents the development of allergic response.
Omalizumab is given subcutaneously once in 2-4 Cough is a protective reflex that removes the
weeks for prophylaxis in moderate to severe irritant matter and secretions from the respiratory
asthmatics. It is expensive. tract. It could be due to infection, allergy, pleural
Respiratory System 159

diseases and malignancy. Since it is a protective 2. Pharyngeal Demulcents


mechanism, undue suppression of cough can
These drugs increase the flow of saliva which
cause more harm than benefit. Only in some
produces a soothing effect on the pharyngeal
conditions as in dry annoying cough, it may serve mucosa (demulcere = to caress soothingly—in
no useful purpose. In such situations, antitussives Latin) and reduce afferent impulses arising from
or cough suppressants may be used. Antitussives the irritated mucosa. Dry cough due to irritation
only provide symptomatic relief and do not alter of the pharyngeal mucosa is relieved. Candy sugar
the cause. or a few drops of lemon also serve this purpose.

ANTITUSSIVES
3. Expectorants
1. Central cough Codeine, noscapine, dextro-
Expectorants (Latin—expectorate = to drive from
suppressants methorphan, antihistamines,
the chest) increase the production of respiratory
benzonatate.
tract secretions which cover the irritated mucosa.
2. Pharyngeal Lozenges, cough drops,
As the secretions now become thin and less viscid,
demulcents linctuses
they can be easily coughed out. Expectorants may
3. Expectorants Potassium iodide, guaiphe-
increase the secretions directly or reflexly.
nesin, ammonium chloride,
ipecacuanha Direct stimulants: Volatile oils like eucalyptus oil;
4. Bronchodilators Salbutamol, terbutaline creosotes, alcohol, cidar wood oil—when
5. Mucolytics Bromhexine, ambroxol, administered by inhalation with steam can
acetylcysteine, carbocysteine. increase respiratory secretions.

1. Central Cough Suppressants Reflex expectorants are given orally, they are gastric
irritants and reflexly increase respiratory
Central cough suppressants act by inhibiting secretions.
cough center in the medulla.
Potassium iodide acts both directly and reflexly.
Codeine is a good antitussive with less addiction Ipecacuanha is an emetic. In sub-emetic doses it
liability; nausea, constipation and drowsiness are is used as an expectorant.
common. Dose: 10-15 mg every 6 hours (page 123).
Noscapine is a potent antitussive; no other CNS 4. Bronchodilators
effects are prominent in therapeutic doses. Nausea
Bronchodilators like salbutamol and terbutaline
is the only occasional side effect. Dose: 15-30 mg
relieve cough that is resulting from bronchospasm.
every 6 hours.
The antitussive preparations generally have a
Dextromethorphan and pholcodeine are synthetic combination of a central cough suppressant, an
opioid derivatives with antitussive actions like expectorant, an antihistaminic and sometimes a
codeine but with less side effects. Pholcodeine is bronchodilator and a mucolytic agent.
longer-acting—given twice daily.
Benzonatate is chemically related to the local 5. Mucolytics
anesthetic procaine. It acts on the cough receptors Normally the respiratory mucus is watery. The
in the lungs and also has a central effect. It is given glycoproteins in the mucus are linked by
orally. disulphide bonds to form polymers making it
Antihistamines are useful in cough due to allergy slimy. In respiratory diseases, the glycoproteins
except that due to bronchial asthma. form larger polymers with plasma proteins present
160 Pharmacology for Physiotherapy

in the exudate and the secretions become thick Carbocysteine is similar to acetylcysteine and is
and viscid. Mucolytics liquefy the sputum making used orally.
it less viscid so that it can be easily expectorated.
Pancreatic dornase—deoxyribonucleoprotein is
Bromhexine obtained from the plant Adhatoda a major component of the purulent respiratory tract
vasica is a good mucolytic. It depolymerizes the secretions. Pancreatic dornase is a deoxy-
mucopolysaccharides in the mucus. It is given ribonuclease obtained from the bovine pancreas.
orally (8-16 mg thrice daily). Side effects are It breaks the deoxyribonucleic acid (DNA) into
minor—may cause rhinorrhea. smaller parts thus making the secretions thin and
less viscid. It is administered by inhalation.
Ambroxol is a metabolite of bromhexine with
actions similar to it. Ambroxol may be given orally Pancreatic dornase can cause allergic
by inhalation. It can be used as an alternative to reactions.
bromhexine. Steam inhalation offers an effective and
inexpensive alternative to drugs. In presence of
Acetylcysteine opens disulfide bonds in the
dehydration, just rehydrating the patient is found
mucoproteins of the sputum reducing its visco-
to be beneficial.
sity. It is given by aerosol. Side effects are common
and hence not preferred.
Gastrointestinal
Tract

• DRUGS USED IN PEPTIC ULCER


• PROKINETIC AGENTS
• EMETICS AND ANTIEMETICS
• DRUGS USED IN THE TREATMENT OF CONSTIPATION
• DRUGS USED IN THE TREATMENT OF DIARRHEA

DRUGS USED IN PEPTIC ULCER 2. Drugs that reduce gastric acid secretion
a. H2 receptor blockers—Cimetidine, rani-
Acid-peptic disease is common in the present days tidine, famotidine, roxatidine, nizatidine.
that are full of tension and anxiety. Peptic ulcer b. Proton pump inhibitors (PPIs)—
results from an imbalance between acid-pepsin Omeprazole, lansoprazole, pantoprazole,
secretion and mucosal defense. The factors that rabeprazole.
protect the mucosa are its ability to secrete mucous, c. Muscarinic antagonists—Pirenzepine.
bicarbonate and prostaglandins. Gastric acid 3. Ulcer protectives: Sucralfate, bismuth com-
secretion is controlled by three pathways—vagus pounds.
(ACh), gastrin and local release of histamine— 4. Other drugs: Carbenoxolone, cisapride,
each acting through its own receptors (Fig. 9.1). prostaglandins.
Histamine acts through H2 receptors on parietal
cells while acetylcholine through M1 muscarinic ANTACIDS
and gastrin through G receptors on the parietal
Antacids are basic substances. Given orally they
cells. These activate H+ K+ ATPase (proton pump)
neutralize the gastric acid and raise the pH of
on the parietal cells resulting in the secretion of
gastric contents. Peptic activity is also reduced
H+ into the gastric lumen. This combines with Cl–
because, pepsin is active only above pH 4.
(drawn from plasma) and HCl is secreted.
Antacids are of 2 types:
1. Systemic Sodium bicarbonate
Classification
2. Nonsystemic Aluminium hydroxide, mag-
1. Drugs that neutralize gastric acid: Antacids— nesium trisilicate, magnesium
MgOH2, Al(OH)3 hydroxide, calcium carbonate.
162 Pharmacology for Physiotherapy

absorption resulting in hypophosphatemia on


prolonged use.
Magnesium salts: The action is quick and
prolonged. Rebound acidity is mild. Magnesium
salts are osmotic purgatives and the dose used as
antacids may cause mild diarrhea.
Calcium carbonate acts quickly and has
prolonged action but liberates CO2 which may
cause discomfort. It may also cause constipation
and hypercalcemia.
Antacids are given in combination to obtain
Fig. 9.1: Regulation of gastric secretion: M— maximum effects with least adverse effects as
Muscarinic receptor (M2/3); G—Gastrin receptors; follows.
H2—Histamine H2 receptor 1. Quick and prolonged effect—Fast-acting
[Mg(OH)2] and slow acting [Al(OH)3] are
combined.
Systemic Antacids 2. Neutralizing side effects—Magnesium salts
cause diarrhea while aluminium salts are
Sodium bicarbonate is rapid but short-acting. CO2
constipating—combination neutralizes each
that is released in the stomach escapes as
other’s side effects.
eructation. Sodium bicarbonate gets absorbed from
3. Gastric emptying—Magnesium salts hasten
the intestines leading to systemic alkalosis. There
while aluminium salts delay gastric emptying.
is ‘rebound’ hyperacidity as gastrin levels
All antacid tablets should be chewed and
increase due to raised gastric pH. Sodium load
swallowed as they do not disintegrate well in the
may increase. It is not preferred because of the
stomach. Gels are more effective than tablets. One
above disadvantages.
dose given 1 hr after food neutralizes the acid for
Sodium bicarbonate is used with other
2 hours (Table 9.1).
antacids in peptic ulcer. Other uses are to
alkalinize the urine in poisoning and to treat
TABLE 9.1: Some antacid
metabolic acidosis. combination preparations
Non-systemic Antacids Brand name Combination
Non-systemic antacids are insoluble compounds
that react in the stomach with HCl to form a chloride 1. GELUSIL Aluminium hydroxide gel +
liquid, tablet Magnesium trisilicate
salt and water. They are not absorbed.
2. DIGENE Magnesium hydroxide +
Aluminium hydroxide is slow acting. Food further gel, tablet Aluminium hydroxide gel
slows it’s neutralizing capacity. It is also an + carboxymethyl cellulose sodium
astringent and demulcent—forms a protective + Methylpolysiloxane
coating over the ulcers. The aluminium ions relax
the smooth muscles resulting in delayed gastric
emptying and constipation. Aluminium Uses: Antacids are used in hyperacidity, peptic
hydroxide binds phosphate and prevents its ulcer and reflux esophagitis.
Gastrointestinal Tract 163

Drug interactions: Antacids form complexes with Famotidine is similar to but more potent than
iron, tetracyclines, digoxin, ranitidine, ranitidine. Headache and rashes can occur.
fluoroquinolones, sulfonamides and antimus-
carinic drugs. To avoid these, antacids should be Roxatidine is similar to ranitidine but is more
taken 2 hours before or 2 hours after other drugs. potent and longer-acting.
H2 receptor blockers: Cimetidine, ranitidine,
famotidine, roxatidine. Uses of H2 Blockers
These drugs bind to H 2 receptors and H2 blockers are used in the treatment of:
competitively inhibit the action of histamine on 1. Peptic uler—H2 blockers bring about rapid
H2 receptors and thereby reduce gastric secretion. relief from pain and ulcers heal in 6-8 weeks
Both volume and acidity of basal, nocturnal and of treatment.
food induced secretion are reduced. They can
2. Gastritis and non ulcer dyspepsia—respond
cause 90 percent reduction in gastric secretion by
to H2 blockers.
a single dose. Gastrin induced HCl secretion and
3. GERD—H2 blockers are alternatives to PPIs.
pepsin is also reduced. Due to these actions,
4. Preanesthetic medication—to reduce gastric
healing of peptic ulcers is faster.
acid secretion and prevent damage to the
Pharmacokinetics: H2 blockers are well-absorbed. respiratory mucosa if aspiration occurs during
Cimetidine acts for 5-8 hours, ranitidine and surgery.
famotidine for 12 hours. 5. Zollinger Ellison syndrome—High doses of
Adverse effects: The H2 blockers are well- H2 blockers are used as alternatives to PPIs.
tolerated with minor side effects like dizziness, Ranitidine is the most preferred. It is given
diarrhea, muscle pain and headache. Because the for 4-8 weeks (300 mg daily) in peptic ulcers. It
H2 receptors do not have any significant functions may be continued for 6 months to prevent
in other tissues except stomach, H2 receptor recurrence.
blockers are fairly selective and thereby safe drugs.
Cimetidine has antiandrogenic actions, it Proton Pump Inhibitors
increases plasma prolactin levels and inhibits
oestrogen metabolism in the liver. On prolonged Omeprazole is the most commonly used proton
use it may result in gynecomastia, impotence and pump (PP) inhibitor.
loss of libido. CNS effects include confusion, Mechanism of action: The parietal cells of the
delirium and hallucinations in the elderly. stomach secrete H+ with the help of an enzyme
Headache, dizziness, rashes and diarrhea can H +K+ ATPase (proton pump) present in the
result. Cimetidine inhibits microsomal enzymes plasma membrane. This is the final step in gastric
and interferes with the metabolism of many drugs.
acid secretion. Proton pump inhibitors specifically
Ranitidine is the preferred H2 blocker as it has inhibit this H+ K+ ATPase enzyme and thereby
several advantages over cimetidine. Ranitidine is inhibit gastric secretion. Omeprazole is a prodrug,
more potent, longer acting, has no antiandrogenic gets activated in the acidic environment of the
effects, no CNS effects as it does not cross BBB stomach and a single dose can totally inhibit
and does not inhibit microsomal enzymes gastric secretion. Acid secretion starts only after
significantly. Only adverse effects are headache new H+K+ATPase enzyme is synthesized. Ulcer
and dizziness. heals rapidly even in resistant cases.
164 Pharmacology for Physiotherapy

Omeprazole Ulcer Protectives


Sucralfate: In acidic medium (pH < 4), sucralfate
Sulfenic acid polymerizes to form a sticky, viscid gel which
firmly sticks to the base of the ulcers. It remains
there for over 6 hours acting as a physical block
Sulfenamide and prevents contact with acid and pepsin. It also
Bind ⊕ Covalent bond stimulates the PG synthesis in gastric mucosa. It
+ + thus promotes healing by protecting the ulcer.
H K ATPase
Sucralfate is not absorbed and is well-tolerated.
One tablet is given 1 hr before each meal and
↓ Gastric acid secretion one at bed time for 4-8 weeks and then it is
continued for 6 months to prevent recurrence.
Adverse effects: Omeprazole is well-tolerated. Side effects are rare and include constipation
Prolonged acid suppression may allow bacterial and dryness of mouth.
over growth in the stomach. Dizziness, headache,
Drug Interactions
arthralgia, nausea and rashes are rare.
• Sucralfate needs acidic pH for activation.
Long term administration may result in:
Hence antacids should not be given with it.
• Vitamin B12 deficiency due to its reduced
• Sucralfate adsorbs and interferes with the
absorption.
absorption of tetracyclines, digoxin, phenytoin
• ↑ gastrin levels.
and cimetidine.
• Atrophic changes in the stomach—have been
noticed after 3-4 years of use. Bismuth salts: Colloidal bismuth subcitrate on
oral administration forms complexes with
Uses: Omeprazole is used in peptic ulcers (20-40 proteins in the ulcer base and forms a protective
mg daily) and severe gastroesophageal reflux coating over the gastric mucosa. It also inhibits
(GERD) that is not responding to H2 blockers. the growth of H. pylori on gastric mucosa and
Ulcers heal fast and pain is relieved. It is given for stimulates the mucus production and PG
4-8 weeks. It is also used in H.pylori treatment synthesis. By these actions it promotes ulcer
regimen and in Zollinger Ellison syndrome. healing in 4-8 weeks. It may cause constipation
Lansoprazole is similar to omeprazole but is and black stools.
longer-acting.
Other Drugs
Pantoprazole is more acid stable and an I.V.
formulation is also available. Carbenoxolone: On ingestion carbenoxolone
alters the composition of mucous so that it sticks
Rabeprazole has the fastest onset of action but is to gastric mucosa to protect the ulcer base. It also
short acting. inhibits pepsin activity and prolongs the life of
prostaglandins. Because of its steroid like effects,
Anticholinergics: Though atropine reduces
it causes salt and water retention. It is therefore
gastric secretion, the dose needed results in several
not preferred.
adverse effects. A derivative of atropine—
pirenzepine selectively blocks muscarinic (M1) Prostaglandins: PGE2 and PGI2 synthesized by
receptors present in the stomach and inhibits the gastric mucosa inhibits gastric secretion,
gastric secretion without much side effects. It also enhances mucous production and exerts a
inhibits the secretion of gastrin, mucus and protective effect. PG analogs misoprostol and
bicarbonate. It is used as an adjuvant. enprostil are of special value in preventing drug
Gastrointestinal Tract 165

induced (e.g. NSAIDs) gastric ulceration. Diarrhea occur on long-term use due to blockade of
and muscle cramps are common. dopamine receptors.

Treatment of H. pylori Infection Uses


Infection with H. pylori is associated with 1. Reflux esophagitis—‘heart burn’ due to reflux
gastroduodenal disease including gastritis and of acid into the esophagus is benefited by
peptic ulcer. It is also thought to be responsible prokinetic agents.
for recurrence of peptic ulcer disease. Eradication 2. As antiemetics—in postoperative period and
of H. pylori along with reduction of acid secretion vomiting due to anticancer drugs.
has shown to reduce the relapse rate. 3. As preanesthetic medication to promote gastric
Various combination regimens are tried with emptying before induction of general anes-
clarithromycin, amoxicillin or tetracycline; thesia in emergency.
metronidazole and omeprazole for 1-2 weeks. 4. In endoscopy—to assist passage of tubes into
One regimen: Clarithromycin 250 mg BD + the duodenum.
metronidazole 400 mg BD + omeprazole 20 mg
Domperidone is similar to metoclopramide except
BD—for one week.
that it does not cross the blood-brain barrier and
hence does not cause extrapyramidal side effects.
PROKINETIC AGENTS Side effects include headache, dryness of mouth,
diarrhea and rashes.
Drugs that enhance gastroduodenal motility and Domperidone can be used in place of
hasten gastric emptying are called prokinetic metoclopramide.
agents. Metoclopramide, domperidone, cisapride
Cisapride enhances gastric motility by promoting
and mosapride are some prokinetic agents.
the release of acetylcholine in the gut wall. It also
promotes colonic motility which may result in
Metoclopramide
diarrhea. It was used in reflux esophagitis but it
Actions GIT—Metoclopramide promotes forward is now banned drug due to adverse effects.
movement of contents of the upper GI tract, speeds
Gastroesophageal reflux disease (GERD) Reflux
up gastric emptying, prevents reflux esophagitis
of acidic gastric contents into the esophagus
and also slightly increases intestinal peristalsis.
results in ‘heart burn’ due to esophagitis. Based
CNS: Metoclopramide acts as an antiemetic by its on severity, it may be treated with antacids,
actions on the CTZ and by speeding up gastric metoclopramide or drugs that reduce acid
emptying. secretion like ranitidine and proton pump
inhibitors. Omeprazole is the most effective agent.
Mechanism of action: Metoclopramide acts
Avoiding—heavy meals, late night dinner,
• by blocking the dopamine receptors in the gut.
smoking and alcohol—all help.
• by enhancing acetylcholine release from the
cholinergic neurons in the gut.
• by blocking the D2 receptors in the CT2— EMETICS AND ANTIEMETICS
responsible for antiemetic actions.
Stimulation of the vomiting center in the medulla
Adverse effects are sedation, dystonia and oblongata results in vomiting. The vomiting center
diarrhea; gynecomastia, galactorrhea and receives afferents from the chemoreceptor trigger
parkinsonism (extrapyramidal symptoms) can zone (CTZ), vestibular apparatus, GI tract and
166 Pharmacology for Physiotherapy

centers in the brain. CTZ is not protected by the Dopamine D2 Antagonists


blood-brain barrier and is stimulated by various
Metoclopramide acts centrally by blocking
drugs, chemicals and radiation.
dopamine D2 receptors in the CTZ. It increases
Emetics are drugs that produce vomiting. When the tone of the lower esophageal sphincter and
a noxious substance is swallowed, vomiting has enhances gastric peristalsis. It is used in nausea
to be induced. Mustard powder (1 teaspoon) with and vomiting due to gastrointestinal disorders,
water or hypertonic salt solution can evoke migraine, in postoperative period and vomiting
vomiting. due to anticancer drugs and radiotherapy.
Apomorphine is a derivative of morphine. Given
Domperidone acts like metoclopramide with fewer
SC/IM, it produces vomiting in 5-10 minutes. It
side effects.
acts by stimulating the CTZ.
Ipecacuanha contains an alkaloid emetine. Given Antimuscarinics
as a syrup (15- 20 ml), it produces vomiting in 15
Hyosine (see Chapter 2) is very effective in motion
minutes. It is safe even in children.
sickness. Motion sickness or travelling sickness
Antiemetics—vomiting is a protective mechanism is due to overstimulation of the vestibular
which tries to eliminate the unwanted harmful apparatus along with psychological and environ-
material from the stomach. But in some situations, mental factors. Taken 30 minutes before journey,
vomiting may not serve any useful purpose and hyoscine (0.4-0.6 mg oral) acts for 6 hours and the
may only be troublesome. In such circumstances, dose should be repeated if the journey is longer
vomiting needs to be suppressed. than that. A transdermal patch delivers hyoscine
constantly over 3 days and is to be applied behind
Classification the ear. Sedation and dry mouth are common side
1. Dopamine D2 antagonists—prokinetics: Meto- effects.
clopramide, domperidone. Dicyclomine is used to control vomiting in
2. Antimuscarinics: Hyoscine, H1 antihistamines morning sickness and motion sickness (Table 9.2).
like cyclizine, promethazine, diphenhydra-
mine. H1 antihistamines (see Chapter 7) like pro-
3. 5HT3 antagonists: Ondansetron, granisetron, methazine, diphenhydramine, cyclizine and
dolasetron, tropisetron. cinnarizine have anticholinergic properties. They
4. Neuroleptics: Chlorpromazine, prochlorpera- may act both centrally and on the GI tract. They
zine, haloperidol. are useful in motion sickness and postoperative
5. Other agents: Cisapride, corticosteroids. vomiting.

TABLE 9.2: Preferred drugs for vomiting due to various causes

Conditions Drugs

Motion sickness Hyoscine, cyclizine, promethazine, cinnarizine


Vomiting due to cytotoxic drugs Ondansetron + Dexamethasone
Vomiting due to other drugs Chlorpromazine, metoclopramide
Postoperative vomiting Ondansetron, metoclopramide
Vomiting in pregnancy Dicyclomine, pyridoxine, cyclizine, meclizine, metoclopramide
Gastrointestinal Tract 167

5-HT3 Antagonists are used for prevention of chemotherapy-induced


vomiting in combination with other drugs
Ondansetron 5-hydroxytryptamine released in
the gut is an important transmitter of emesis.
DRUGS USED IN THE
Ondansetron blocks 5 HT3 receptors in the GI tract
TREATMENT OF CONSTIPATION
and CTZ and prevents vomiting. It is a powerful
antiemetic and can be given orally or intravenously
Purgatives
(4-8 mg). It is specially useful to control vomiting
induced by anticancer drugs or radiotherapy. It is Purgatives are drugs that promote defecation. They
also useful in postoperative vomiting and other are also called laxatives and cathartics. Laxatives
drug induced vomiting. have milder action while cathartics or purgatives
have more powerful action.
Adverse effects—All 5HT3 antagonists are well
tolerated with minor adverse effects like headache,
Classification
constipation, abdominal discomfort and rashes.
1. Bulk laxatives Bran, plantago seeds,
Granisetron is more potent than ondansetron as agar, methylcellulose,
an antiemetic. ispaghula husk
2. Fecal softeners Docusate sodium, liquid
Neuroleptics (page 140) paraffin (emollients)
Neuroleptics block D2-receptors in the CTZ and 3. Osmotic purgatives Magnesium sulphate,
are useful in vomiting due to most causes except magnesium hydroxide,
motion sickness. Sedation and extrapyramidal sodium sulphate,
symptoms are the common side effects. lactulose
Prochlorperazine is mainly used as an antiemetic 4. Stimulant purgatives Phenolphthalein,
in vomiting and is also effective in vertigo bisacodyl, castor oil,
associated with vomiting. anthraquinones—
Cascara sagrada, senna.
Other Antiemetics
Bulk Laxatives
Corticosteroids are used as adjuvants along
with other antiemetics like ondansetron or Bulk laxatives include vegetable fiber and other
metoclopramide. substances that are not digested but increase the
volume of intestinal contents forming a large, soft,
Newer Drugs solid stool. Dietary fiber consists of cell walls and
other parts of fruits and vegetables that are
Dronabinol—a cannabinoid acts as an antiemetic
unabsorbable. Adding fiber to the diet is a safe
by stimulation of cannabinoid receptors in the
and natural way of treating constipation in
vomiting center. It is used in combination with
persons who are on low-fiber diet. Bran is the
other antiemetics for prevention of anticancer
residue left when flour is made from cereals and
drugs-induced vomiting.
contains 40 percent fiber—but is unpalatable.
Neurokinin receptor antagonists—Aprepitant Ispaghula and plantago seeds contain natural
and fosaprepitant bind to neurokinin receptors mucilage which absorbs water to form a
in the area postrema and act as antiemetics. They gelatinous mass and are more palatable than bran.
168 Pharmacology for Physiotherapy

Methylcellulose is a semisynthetic derivative of When cascara sagrada and senna (source:


cellulose. Adequate water should be taken along plants) are given orally, active anthraquinones
with bulk laxatives. are liberated in the intestines which stimulate the
myenteric plexus in the colon. Evacuation takes
Fecal Softeners 6-8 hr. Long-term use causes melanotic pigmen-
tation of the colon.
Docusate sodium (dioctyl sodium sulphosucci-
nate) softens feces by lowering the surface tension Phenolphthalein
of the intestinal contents. This allows more water
to be retained in the feces which becomes soft. Phenolphthalein an indicator, acts on the colon
after 6 to 8 hours to produce soft, semiliquid stools.
Liquid paraffin is a mineral oil that is not digested. It undergoes enterohepatic circulation which
It lubricates and softens feces. It is unpalatable; prolongs its actions. Allergic reactions including
aspiration may cause lipoid pneumonia; it may pink colored skin eruptions and colic limit it’s
leak out of the anus causing discomfort. Hence use.
not preferred.
Bisacodyl
Osmotic Purgatives Bisacodyl related to phenolphthalein is converted
Osmotic purgatives are solutes that are not to the active metabolite in the intestines. It can be
absorbed in the intestine, osmotically retain water given orally (5 mg) but usually is used as rectal
and increase the bulk of intestinal contents. They suppositories (10 mg) which results in defecation
increase peristalsis and expel a fluid stool. in 15-30 minutes. It is safe except that prolonged
Magnesium hydroxide, magnesium sulphate, use may cause local inflammation.
sodium potassium tartrate, sodium sulphate and
phosphate are some inorganic salts used as Castor Oil
osmotic or saline purgatives. They are used to Castor oil is hydrolyzed in the upper small
prepare the bowel before surgery and in food intestine to ricinoleic acid which is a local irritant
poisoning. and increases intestinal motility. It is a powerful
and one of the oldest purgatives. Stool is
Lactulose is a synthetic disaccharide that is not
semiliquid and is accompanied by gripping. It is
absorbed, holds water and acts as an osmotic
not preferred.
purgative. Flatulence and cramps may be
accompanied. In the colon, lactulose is fermented
Opioid Antagonists
to lactic and acetic acids which inhibit the growth
of ammonia-producing bacteria in the colon. It Opioid induced constipation can be troublesome
also inhibits the absorption of ammonia by in cancer patients and other terminally ill patients
lowering pH and thus lowers blood ammonia who are receiving opioids for pain relief.
levels. It is used in hepatic coma for this effect Methylnaltrexone and alvimopan are opioid
(hepatic coma is worsened by ammonia). antagonists which block the opioid receptors in
the gut. They do not cross the BBB and therefore
Stimulant Purgatives do not antagonize the analgesic effects of opioids.
Stimulant purgatives increase intestinal motility
Enema
and increase the secretion of water and
electrolytes by the mucosa. They may cause Enema produces defecation by softening stools
abdominal cramps. and distending the bowel. Evacuant enema is
Gastrointestinal Tract 169

used to prepare the gut for surgery, endoscopy DRUGS USED IN THE
and radiological examination (see page 7). TREATMENT OF DIARRHEA

Use of Laxatives in Constipation Diarrhea is the frequent passage of liquid stools.


It can be due to a variety of causes like infection,
Fiber rich diet, adequate fluid intake and physical toxins, anxiety and drugs. Acute diarrhea is one
activity are the best measures to prevent and treat of the major causes of death in infants specially in
mild constipation. If these measures are the developing countries. Death is due to dehydra-
inadequate, a laxative may be given (see Table tion.
9.3). In diarrhea, there is an increase in motility and
secretions in the gut with absorption of water and
Drug Induced Constipation electrolytes. Hence the approaches in the treatment
Drugs like anticholinergics, NSAIDs, opioids, of diarrhea include:
clonidine, iron, calcium channel blockers and 1. Replacement of fluid and electrolytes.
antihistamines can cause constipation. When 2. Treatment of the cause.
withdrawal of the causative drug is not possible, 3. Antidiarrheal agents.
a laxative may be used. Correction of fluid and electrolyte distur-
bances can be life saving in most cases especially
Laxative Abuse infants. Oral rehydration with sodium chloride,
glucose and water is useful. In the ileum, glucose
Habitual use of laxatives, especially stimulant increases sodium absorption and water follows.
laxatives may lead to various gastrointestinal Oral rehydration powders are available. They are
disturbances like irritable bowel syndrome, to be mixed with water and given in small
loss of electrolytes, loss of calcium in the stool amounts every 15-20 minutes for mild to moderate
and malabsorption. Misconceptions regarding cases. In severe degrees of dehydration, prompt
bowel habits should be cleared. The patient intravenous rehydration is necessary (Table 9.4).
should be convinced that normal bowel habits
may vary between 3 motions daily and 2 motions Treatment of the cause: Acute diarrhea could
per week. often be due to viral, bacterial or protozoal

TABLE 9.3: Choice of purgatives

Conditions Preferred laxative

1. Functional constipation Increasing dietary fiber and adequate fluid intake


2. Elderly patients Increasing dietary fiber and adequate fluid intake
3. Pregnancy dietary fiber
4. To avoid straining at stools—as in hernia, piles, Bulk laxatives or fecal softeners
fissure, cardiovascular diseases like
myocardial infarction
5. Irritable bowel syndrome—chronic constipation Bulk laxatives
6. Food or drug poisoning Osmotic purgatives
7. Bowel preparation before surgery, endoscopy Bisacodyl, osmotic purgatives
and radiological examination
170 Pharmacology for Physiotherapy

infection. The pathogen should be identified Super ORS—The content of ORS is modified to
whenever possible and treated accordingly. reduce the frequency and severity of diarrhea.
Amino acids are added which could promote
TABLE 9.4: Composition of oral sodium absorption. However they are expensive
rehydration salt/solution (ORS) and the benefit provided is marginal. Studies have
NaCl– — 3.5 gm
shown that boiled rice powder 40-50 g/L is a good
– and simple glucose supplement. Since the rice also
KCl — 1.5 gm
has some proteins (7%), it is a source of amino
Sodium citrate — 2.9 gm
acids which stimulates the absorption of salt and
Glucose — 20 gm water. The starch content adds to the calories. Rice
To be dissolved in 1 liter of boiled and cooled water is easily available, relatively inexpensive and has
good efficacy—rice based ORS may be preferred
WHO–ORS New Formula particularly in developing countries. Wheat, maize
or potato may be used instead of rice.
Standard ORS has Na+ 90 m M, Cl–80 mM, citrate
10 mM and glucose 110 mM making up a total of Antidiarrheal drugs provide symptomatic relief
310 mosm/L. Extensive research sponsored by and include adsorbents and antimotility drugs.
WHO has shown that ORS with lower osmolality
Adsorbents include kaolin, pectin, chalk and
has improved efficacy with a 30 percent reduction
activated charcoal. These adsorb intestinal toxins
in the incidence of vomiting and stool volume.
and microorganisms by coating them.
WHO and UNICEF have therefore recommended
new modified ORS solution with 245 mosm/L
osmolarity in place of the standard preparation Antimotility Drugs (Table 9.5)
with a decreased concentration of sodium and Codeine an opium alkaloid, stimulates the opioid
glucose. The only disadvantage is that it can cause receptors on the gastrointestinal smooth muscles
hyponatremia in adults suffering from cholera.
to reduce peristalsis. This delays passage of
The contents are as follows: intestinal contents and facilitates absorption of
New formula water. Nausea and vomiting may occur.
NaCl : 2.6 gm
Diphenoxylate is an opioid related to pethidine.
KCl : 1.5 gm
It is given with a small dose of atropine in order to
Trisodium citrate : 2.9 gm
discourage abuse. In therapeutic doses CNS effects
Glucose : 13.5 gm
are not prominent-hence no risk of abuse. It is used
Water : 1L
only in diarrheas. Nausea, drowsiness and
Total osmolarity : 245 mOsm/L
abdominal pain may occur.

TABLE 9.5: Antimotility drugs—some preparations and dosage


Drugs Trade names Doses

Diphenoxylate 2.5 mg LOMOTIL 2-4 tablets stat; 1 every 6 hr


+
Atropine 0.025 mg
Loperamide LOPESTAL 4 mg stat; 2 mg every 6 hr
Gastrointestinal Tract 171

Loperamide is an opiate. It has selective action and are useful in some diarrheas. They promote
on GI tract with additional antisecretory action. the growth of saccharolytic flora and alter the gut
CNS effects are negligible. It is less sedating, less pH so that the growth of pathogenic micro
addicting and is the most commonly used organisms is inhibited. They are called
antimotility drug. Its low solubility in water ‘probiotics’ and are found to be useful in reducing
discourages abuse by injection. Loperamide may the incidence of antibiotic induced diarrhea.
cause nausea, vomiting and abdominal cramps. Curds and buttermilk are cheaper alternatives.
Loperamide use has resulted in paralytic ileus Antispasmodics: Atropine derivatives like
and several fatalities are reported in children. propantheline and dicyclomine relax gastro-
Hence loperamide is contraindicated in children intestinal smooth muscles and relieve abdominal
below 4 years of age. colics.
Antimotility drugs are used for symptomatic
treatment of non-infective diarrheas and for Traveller’s diarrhea: Infection is the most
traveller’s diarrhea (as adjuvant). common cause of traveller’s diarrhea and should
be treated with suitable antimicrobials. Oral
rehydration salts and loperamide may also be
Other Drugs
used.
Lactobacillus acidophilus and lactobacillus
sporogenes are available as powders and tablets
Hormones

• HYPOTHALAMUS AND ANTERIOR PITUITARY HORMONES


• THYROID HORMONES AND ANTITHYROID DRUGS
• INSULIN AND ORAL HYPOGLYCEMICS
• CORTICOSTEROIDS
• ESTROGENS, PROGESTINS AND ORAL CONTRACEPTIVES
• ANDROGENS AND ANABOLIC STEROIDS
• AGENTS AFFECTING BONE MINERAL TURNOVER

HYPOTHALAMUS AND ANTERIOR synthetic analog of somatostatin which is longer-


PITUITARY HORMONES acting and useful in acromegaly and some
hormone secreting tumors.
The pituitary gland, under the influence of the
Thyrotrophin releasing hormone (TRH)
hypothalamus secretes many hormones which
secreted by the hypothalamus stimulates the
either control the secretion of other glands or
release of TSH from the anterior pituitary.
directly act on the target tissues. These are peptides
and act by binding to specific receptors present Corticotrophin releasing factor (CRF) releases
on the target cells (Table 10.1). ACTH and β-endorphins from the anterior pitui-
tary. It is used in diagnostic tests in Cushing’s
HYPOTHALAMIC HORMONES disease.
Gonadotrophin-releasing hormone (GnRH,
Growth hormone releasing hormone stimulates LHRH, Gonadorelin)—secreted in a pulsatile
anterior pituitary to secrete growth hormone. manner, regulates the secretion of gonado-
Sermorelin is an analog of GHRH used in trophins—FSH and LH. It is used in diagnostic
diagnostic tests of growth hormone deficiency. tests in hypogonadism. Pulsatile administration
Somatostatin is growth hormone release- of GnRH is used in infertility and delayed puberty.
inhibiting hormone present in the hypothalamus, Continuous administration inhibits gonado-
parts of the CNS, pancreas and in gastrointestinal trophin secretion and is used in prostatic cancers.
tract. It inhibits the secretion of GH, TSH, prolactin, GnRH analog leuprolide is used in prostatic
insulin, glucagon and gastrointestinal secretions. cancer and some gynecological conditions like
But it is very short-acting. Octreotide is the uterine fibroids and endometriosis.
Hormones 173

TABLE 10.1: Hormones secreted by the hypothalamus and anterior pituitary and their chief functions

Hypothalamic hormone Anterior pituitary hormone Chief actions

1. a. Growth hormone releasing hormone (GHRH) Growth hormone (GH) Regulates growth
b. Growth hormone release-inhibiting hormone
(somatostatin) (GHRIH) Inhibits GH release
2. Corticotropin releasing factor (CRF) Corticotrophin (ACTH) Stimulates adrenal cortex to
secrete glucocorticoids,
mineralocorticoids and androgens
3. Thyrotropin–releasing hormone (TRH) Thyroid-stimulating hormone Stimulates release of T3 and T4
(TSH, Thyrotrophin)
4. Gonadotrophin releasing • Follicle stimulating Stimulates growth of ovum and
hormone (GnRH, gonadorelin) hormone (FSH) graafian follicle in the female
• Luteinizing hormone and gametogenesis in the
(LH) or (ICSH) male; stimulates ovulation in
females and regulates
testosterone secretion in males
5. Prolactin–releasing factor Prolactin (PRL) Development of
breast and lactation
6. Prolactin-release inhibiting factor — Inhibits prolactin-release

ANTERIOR PITUITARY HORMONES burns and AIDS. It is liable for abuse in athletes
to promote growth.
Growth hormone (GH) a peptide, stimulates the
growth of all organs except brain and eye. It Corticotrophin (Adrenocorticotrophic hormone,
increases the uptake of amino acids by the tissues, ACTH) controls the synthesis and release of
promotes protein synthesis and positive nitrogen glucocorticoids, mineralocorticoids, and andro-
balance. It causes lipolysis and reduces glucose gens from the adrenal cortex (Fig. 10.1). It is used
uptake by skeletal muscles. It brings about linear in the diagnosis of adrenocortical insufficiency.
growth. These anabolic actions are mediated by
Thyroid-stimulating hormone (TSH, Thyrotro-
somatomedins or insulin-like growth factors (IGF)
pin): Thyrotropin stimulates the production and
produced in the liver.
secretion of thyroid hormones and thus regulates
The secretion of growth hormone is regulated
thyroid function. It is used to increase the uptake
by GHRH and somatostatin (GHRIH).
of radioactive iodine in thyroid carcinoma.
GH deficiency in children results in dwarfism
while excessive production results in gigantism Gonadotrophins: Follicle stimulating hormone
in children and acromegaly in adults. (FSH) and luteinizing hormone (LH)—produced
by the anterior pituitary regulate gonadal function.
Uses They stimulate follicular development in women
and also stimulate ovarian steroidogenesis
• GH deficiency: Replacement therapy with GH
(estrogens and progesterone synthesis). In men
in deficient children brings about normal
they promote spermatogenesis.
growth. It can also be used in GH deficient
adults. Uses ‘Menotropins’ is the combination of FSH
• Other conditions: GH has been tried in chronic and LH obtained from urine of postmenopausal
renal failure and in catabolic states like severe women. It is used in (Table 10.2):
174 Pharmacology for Physiotherapy

HORMONES AND RELATED DRUGS

HYPOTHALAMIC

Releasing hormones
• TRH
• CRH (CRF)
• GnRH analog—Leuprolide
• PRIH
• MSH-RH
Inhibiting hormones
• PIH
• Somatostatin, (GHRIH)
• MSH-IH

PITUITARY THYROID
Anterior pituitary Hormones Antithyroid drugs
• Growth hormone • T3 Propylthiouracil
Antagonist • T4 Carbimazole
• Octreotide Methimazole
• TSH
Iodides
• ACTH
• FSH I131
• LH
• PL • Calcitonin
• MSH
Posterior pituitary
• Oxytocin
• ADH

PARATHYROID PANCREAS
Insulin
Parathormone Glucagon

ADRENAL GONADS
Cortex
Glucocorticoids Sex hormones Antagonists
• Hydrocortisone • Estrogens – • Tamoxifen
• Prednisolone • Clomiphene
• Beclomethasone • Progestins – • Mifepristone
Mineralocorticoids • Androgens – • Flutamide
• Aldosterone
Sex hormones
Medulla Few examples have been
Adrenaline, noradrenaline given for each group
Hormones 175

TABLE 10.2: Uses of hypothalamic and anterior pituitary hormones and their analogs
Hypothalamic hormone Uses
Sermorelin Diagnosis of GH deficiency
Octreotide Acromegaly, hormone secreting tumors
TRH Diagnosis of thyroid disorders
CRF Diagnostic tests in Cushing’s disease and hypothalamic-pituitary function
GnRH (gonadorelin) Diagnostic tests of hypogonadism
Leuprolide Prostatic cancer, uterine fibroids
Anterior pituitary hormone
Growth hormone GH deficiency, chronic renal failure, burns
Corticotropin Diagnosis of adrenocortical insufficiency
Thyrotropin Test for thyroid functions
Gonadotropins FSH-LH deficiency, undescended testis, amenorrhea, infertility

1. Gonadotropin deficiency in males. THYROID HORMONES


2. Undescended testis. AND ANTITHYROID DRUGS
3. Amenorrhea and infertility.
4. In vitro fertilization—to time the ovulation. Thyroxine (T4) and triiodothyronine (T3) are the
hormones secreted by the thyroid gland (for
Prolactin: This peptide hormone promotes the calcitonin see page 199). T 4 is a less active
growth and development of breast during precursor of T3.
pregnancy. It stimulates milk production along
Synthesis, storage and secretion: The thyroid
with other hormones like estrogens and progestins.
hormones are synthesized and stored in the
Deficiency results in lactation failure while excess
thyroid follicles. The principle source of iodine is
prolactin results in galactorrhea.
diet. The main steps involved in the synthesis of
Regulation of secretion—suckling is the
thyroid hormones are as follows:
principal stimulus for prolactin secretion.
1. Uptake of plasma iodide by thyroid cells by an
Suckling stimulates the release of prolactin-relea-
active transport process.
sing factor from hypothalamus. Estrogens and
2. Oxidation of iodide to I+ (iodinium ions) by a
dopamine antagonists also stimulate prolactin-
peroxidase enzyme with the help of hydrogen
release. Prolactin is not used clinically.
peroxide. These combine with tyrosine
Dopamine agonists like bromocriptine inhibit
residues of thyroglobulin (TG) to form
prolactin-release.
monoiodotyrosine (MIT) and diiodotyrosine
Bromocriptine is an ergot derivative with (DIT).
dopamine agonistic properties. 3. Coupling: Pairs of MIT and DIT are coupled to
Bromocriptine is used form T 3 and T 4 catalyzed by the same
1. To suppress lactation and breast engorgement peroxidase enzyme.
after delivery (like in stillbirth) and following 4. Storage: Thyroglobulin containing iodinated
abortion. tyrosine residues are stored in the follicles.
2. In galactorrhea—due to excess prolactin. The hormones T4 and T3 are released into the
3. Prolactin secreting tumors. circulation and the secretion is regulated by TSH
4. Parkinsonism—bromocriptine is used with secreted by the anterior pituitary and TRH from
levodopa. the hypothalamus. In the peripheral tissues, most
176 Pharmacology for Physiotherapy

of the secreted T4 is converted to T3 which is the hyperthyroidism, diffuse goiter and IgG anti-
active hormone. Both T4 and T3 are extensively bodies that activate TSH receptors. Antithyroid
bound to plasma proteins. The free hormone is drugs may act by interfering with the synthesis,
metabolized in the liver and excreted in the bile. release or actions of thyroid hormones.
The t½ of T4 is 6-7 days and that of T3 is 1-2 days.
Drugs used in hyperthyroidism
T3 is 3-5 times more potent than T4 and acts faster.
1. Antithyroid drugs: Thionamides—Propylthiou-
Actions: Thyroid hormones are essential for racil, methimazole, carbimazole.
normal growth, development, function and 2. Iodine: Iodides and radioactive iodine.
maintenance of all body tissues. Congenital Thionamides act by inhibiting the synthesis of
deficiency results in cretinism. Thyroid hormones thyroid hormones. Propylthiouracil also inhibits
have important metabolic functions—they peripheral conversion of T4 to T3. T3 and T4 levels
increase metabolic rate, enhance carbohydrate and fall. Large doses may stimulate release of TSH
protein metabolism and stimulate lipolysis. They resulting in thyroid enlargement. Carbimazole is
facilitate erythropoiesis, are essential for normal commonly used as it is more potent and long-
functioning of the CNS (mental retardation is seen acting. Adverse effects are allergic reactions,
in cretinism), skeletal muscles, cardiovascular jaundice, headache and rarely granulocytopenia.
system, reproductive system and gastrointestinal
system (hypothyroid patients are constipated Uses: Hyperthyroidism—antithyroid drugs are
while hyperthyroid have diarrhea). used in hyperthyroidism.
a. Graves’ disease or diffuse toxic goiter needs long
Uses: Both thyroxine and triiodothyronine term (1-15 yrs) treatment with antithyroid
(leothyronine) are available and are given orally. drugs.
1. Replacement therapy: b. Toxic nodular goiter:—As an alternative—
• In cretinism, treatment should be started when surgery cannot be done as in case of the
immediately to avoid mental retardation. elderly patients.
Replacement should be continued lifelong. c. Preoperatively—Hyperthyroid patients are
• Hypothyroidism in adults can be reversed made euthyroid with antithyroid drugs and
by appropriate treatment. then operated.
• Myxedema coma is a medical emergency. IV Iodides inhibit the release of thyroid hormones
thyroxine or liothyronine should be given and in thyrotoxic patients the symptoms subside
with prophylactic corticosteroids to avoid in 1-2 days. The gland becomes firm, less vascular
adrenal insufficiency. and shrinks in size over a period of 10-14 days.
2. Non-toxic goiter: T4 suppresses TSH production These effects are transient and decrease after 15
and the goiter regresses. days.
3. Thyroid carcinoma: T4 induces temporary
Adverse effects include allergic reactions like
remission. It is used after surgery.
skin rashes, conjunctivitis, swelling of the lips and
4. Miscellaneous: Thyroxine is tried in refractory
salivary glands, fever and lymphadenopathy.
anemias, infertility and non-healing ulcers.
Chronic overdose can cause iodism with metallic
taste, excessive salivation, lacrimation, running
Hyperthyroidism and Antithyroid Drugs
nose, sore throat, cough and rashes.
Hyperthyroidism is due to an excess of circulating
thyroid hormones and could be due to various Uses
causes. Graves’ disease, an autoimmune disorder, 1. Preoperative preparation for thyroidectomy:
is the most common cause. It is characterized by Iodine is started just 10 days prior to surgery
Hormones 177

to make the thyroid gland firm and less metabolism of carbohydrates, lipids and proteins.
vascular. It is a common condition affecting 1-2 percent of
2. Severe thyrotoxicosis: Iodides act rapidly to population and has a strong hereditary tendency.
reduce the release of thyroid hormones. Diabetes mellitus can be of 2 types.
3. Prophylaxis: Iodide or iodate is added to salt
Type I: Insulin dependent diabetes mellitus
used in cooking to prevent endemic goiter.
(IDDM) is an autoimmune disorder where
4. Antiseptic
antibodies destroy the β cells of the islets of
5. Expectorant: Used in cough.
Langerhans. It usually occurs in young children
Radioactive iodine 131I given orally as a solution and adolescents (hence called juvenile onset
is rapidly absorbed and is concentrated by the diabetes mellitus).
thyroid in the follicles. It emits β rays which Type II: Non-insulin dependent diabetes mellitus
penetrate only 0.5 mm to 2 mm of the tissue so (NIDDM) is of maturity onset. Most patients are
that it destroys only the thyroid tissue without obese. There is both reduced sensitivity of tissues
damaging the surrounding structures. to insulin and impaired regulation of insulin
It is used in the treatment of hyperthyroidism secretion.
and in thyroid carcinoma. Small dose is also used
for diagnostic purpose in thyroid function tests. INSULIN
Advantages of 131I are that administration is
simple and convenient; surgery and its associated In 1921 Banting and Best obtained insulin in the
risks can be avoided. The disadvantages are (i) form of pancreatic extract. In 1922 the extract
the long time (3 months) taken for maximum containing insulin was first used on a 14 years
response, and (ii) the risk of hypothyroidism. old boy suffering from severe diabetes mellitus
with excellent response. Insulin was then purified
β-adrenergic blockers: Many of the symptoms in a few years.
of hyperthyroidism are of sympathetic overactivity
as there is increased tissue sensitivity to Chemistry, synthesis and secretion: Natural
catecholamines in hyperthyroidism. β adrenergic insulin is a polypeptide synthesized from the
blockers like propranolol relieve symptoms like precursor proinsulin. Human insulin differs from
palpitation, tremors, nervousness, sweating and bovine insulin by 3 amino acids and from porcine
myopathy. They only afford symptomatic relief insulin by 1 amino acid. Hence porcine insulin is
and are used as adjuvants. closer to human insulin. It is stored in granules in
the β islet cells of the pancreas. Normal pancreas
Ionic inhibitors interfere with the concentration releases about 50 units of insulin everyday. The
of iodine by the thyroid gland. Thiocyanate and secretion is regulated by factors like food,
perchlorate inhibit the organification of iodine but hormones and autonomic nervous system. The
are not used now due to the adverse effects. Ciga- islets of Langerhans are composed of 4 types of
rette smoking, sodium nitroprusside and certain cells—β cells secrete insulin, α(A) cells glucagon,
food items like cabbage increase the concentration δ(D) cells somatostatin and P cells secrete
of thiocyanate in the blood and may result in pancreatic polypeptide.
hypothyroidism. Insulin is metabolized in the liver, kidney and
muscle.
INSULIN AND ORAL HYPOGLYCEMICS
Actions of Insulin
Diabetes mellitus is a chronic metabolic disorder 1. Carbohydrate metabolism: Insulin stimulates
characterized by hyperglycemia and altered the uptake and metabolism of glucose in the
178 Pharmacology for Physiotherapy

peripheral tissues especially skeletal muscles 3. Lipodystrophy: Atrophy of the subcutaneous


and fat. fat at the site of injection may be due to immune
It inhibits glucose production in the liver response to contaminating proteins. It is rare
by inhibiting gluconeogenesis and glyco- with purified preparations. Insulin absorption
genolysis. may be irregular. Lipodystrophy can be
By the above actions, insulin lowers the prevented by using different sites for injection.
blood glucose concentration. 4. Edema: Some severe diabetics develop edema
2. Lipid metabolism: Insulin inhibits lipolysis which is self-limiting.
in adipose tissue and promotes the synthesis
of triglycerides. In diabetes, large amounts of Preparations of Insulin
fat are broken down. The free fatty acids so Insulin preparations differ in their source and
formed are converted by the liver to acetyl CoA duration of action. Conventional preparations are
and then ketone bodies. This results in obtained from bovine (cattle) and porcine (pig)
ketonemia and ketonuria. pancreas. They may be short, intermediate or long-
Insulin indirectly enhances lipoprotein acting (Table 10.3). All preparations are given SC.
lipase activity resulting in increased clearance Only regular (plane) insulin can be given IV in
of VLDL and chylomicrons. In insulin emergencies. Insulins are destroyed when given
deficiency, there is hypertriglyceridemia. orally. Doses are expressed as units.
3. Protein metabolism: Insulin facilitates amino Mixtures of short-acting and intermediate/
acid uptake and protein synthesis and inhibits long-acting preparations are given for a rapid
protein break down—anabolic effect. onset and long duration of action.
In diabetes, there is increased catabolic effect Disadvantages of the conventional prepa-
and negative nitrogen balance. rations are that:
i. They are allergenic because of the impurities
Mechanism of action: Insulin binds to specific
(1%) and their animal source.
receptors present on the surface of the target cells
ii. They are not very stable.
and produces its effects.
Hence highly purified preparations are now
Side effects made available which have advantages of being
1. Hypoglycemia is the most common compli- less antigenic, more stable, lesser chances of
cation of insulin therapy. It may be due to a insulin resistance and lipodystrophy. But they are
large dose of insulin, inappropriate time of all expensive.
insulin administration, unusually small meal
Highly purified insulins: Insulins are purified
or vigorous exercise. Symptoms—sweating,
by more developed purification techniques like
palpitation, tremors, blurred vision, weakness,
gel filtration and ion-exchange chromatography.
hunger and confusion. Severe hypoglycemia
As a result the contaminating protein content is
may result in convulsions and coma.
negligible. They have the following advantages:
Treatment: Glucose or fruit juice like orange
— They are less allergenic
juice can be given orally or in severe cases IV
— More stable
glucose promptly reverses the symptoms.
— Less chances of resistance
2. Allergy: This is due to the contaminating
— Less chances of lipodystrophy.
proteins in the insulin preparation. Urticaria,
angiedema and rarely anaphylaxis can occur. Human insulins are produced by recombinant
It is rare with purified preparations and with DNA technology. Human proinsulin gene is
human insulin. introduced into E.coli, cultured and proinsulin is
Hormones 179

TABLE 10.3: Preparations of insulin

Preparation Onset Duration

RAPID AND SHORT-ACTING (hr) (hr)


Regular (Plane, soluble) 0.5-1 8
Semilente (amorphous insulin zinc suspension) 1 14
Insulin lispro 0.25 3-5
Insulin aspart 0.25 3-5
INTERMEDIATE-ACTING
Lente ( Insulin zinc suspension) 2 24
NPH (Neutral protamine hagedorn) or Isophane insulin 2 24
LONG-ACTING
Ultra lente (crystalline insulin zinc suspension) 6 36
PZI (Protamine zinc insulin) 6 36
Insulin glargine 2-5 18-24
Insulin detemir 1-2 6-24

Highly purified insulins and human insulin are also available as regular and lente preparations

extracted. This is modified to get human insulin. Insulin delivery devices have been designed which
It can also be obtained by enzymatic treatment of make insulin administration more convenient.
porcine insulin. Human insulin is available as Portable pen injectors are small pen-size devices
regular, NPH, lente and ultralente preparations. containing multiple doses of insulin and
Human insulin is less immunogenic and is retractable needles. They can be carried to the
absorbed more rapidly; dose needed is lesser (10%). place of work and while travelling. Insulin pumps
It is more expensive. deliver appropriate doses of insulin on the basis
Indications for highly purified/human insulins: of self monitored blood glucose results. The set is
1. Allergy to conventional preparations. inserted subcutaneously.
2. Insulin resistance. Alternative routes of insulin delivery have been
3. Lipodystrophy at the site of injection. tried—inhaled insulin and insulin nasal spray
4. Pregnancy. are being evaluated for use.

Insulin analogs with favorable pharmacokinetic


Drug Interactions
properties have been synthesized. Insulin lispro,
aspart and glulisine are rapid and fast acting 1. β adrenergic blockers mask tachycardia, the
insulin analogs. They are absorbed 3 times faster important warning symptom of hypoglycemia.
than human insulin and therefore can be given They also prolong hypoglycemia by inhibiting
subcutaneously just 10 minutes before food; compensatory mechanisms acting through β2
chances of hypoglycemia are less with insulin
receptors.
analogs.
2. Salicylates precipitate hypoglycemia by
Insulin glargine and insulin detemir are long- enhancing insulin secretion and β cell
acting analog which act for 24 hours. sensitivity to glucose.
180 Pharmacology for Physiotherapy

Uses of Insulin Mechanism of action: Sulfonylureas reduce the


1. Diabetes mellitus blood glucose level by:
2. Burns—In patients with severe burns, insulin 1. Stimulating the release of insulin from the
may be given with glucose to reduce the loss pancreatic β cells.
of nitrogen and potassium. 2. Increasing the sensitivity of the peripheral
3. Hyperkalemia—Insulin-glucose drip may be tissues to insulin.
tried. 3. Increasing the number of insulin receptors.
4. Anorexia nervosa—Insulin increases the 4. Suppressing hepatic gluconeogenesis.
appetite in such patients. Sulfonylureas bind to receptors on pancreatic
β cells, cause depolarization and Ca++ influx
Oral Hypoglycemic Drugs leading to increased insulin secretion. Thus some
functional β cells are essential for their action.
The main disadvantage of insulin is the need for
injection. The advent of oral hypoglycemics came Pharmacokinetics: Sulfonylureas are well-
as a boon to millions of NIDDM patients with absorbed orally, extensively bound to plasma
early and mild diabetes. Sulfonylureas were the proteins, metabolized in the liver and some are
first oral antidiabetics (OAD) to be made available excreted in the urine. Hence they should be
in 1950s. We now have many oral hypoglycemics. avoided in patients with renal or liver dysfunction.
Adverse effects: Second-generation agents have
Classification fewer adverse effects. Hypoglycemia is the most
1. Sulfonylureas common adverse effect, least with tolbutamide due
I generation – Tolbutamide, to short t½ and low potency.
chlorpropamide, Nausea, vomiting, jaundice, and allergic
acetohexamide, reactions can occur. Patients on sulfonylureas
tolazamide may have an increase in the rate of cardiovascular
II generation – Glibenclamide, death. However this is still controversial and
glipizide, gliclazide sulfonylureas continue to be used.
2. Biguanides – Phenformin, metformin Drug interactions
3. Meglitinides – Repaglinide, I. Drugs that augment hypoglycemic effect.
nateglinide • NSAIDs, warfarin, sulfonamides—
displace sulfonylureas from protein
4. Thiazolidinediones – Troglitazone,
binding sites.
rosiglitazone,
• Alcohol, chloramphenicol, cimetidine—
pioglitazone
inhibit metabolism.
5. Alpha glucosidase – Acarbose, miglitol II. Drugs that decrease the action of sulfonylureas
inhibitors • Diuretics and corticosteroids—↑ blood
6. Newer drugs – Pramlintide, exenatide, glucose levels.
sitagliptin
Biguanides
Sulfonylureas Biguanides lower blood glucose level by insulin-
A sulfonamide derivative used for its antibacterial like effects on the tissues. Mechanism of action is
effects in typhoid patients produced hypo- not clear. They
glycemia. This observation led to the development • Suppress hepatic gluconeogenesis.
of sulfonylureas. • Inhibit glucose absorption from the intestines.
Hormones 181

• Stimulate peripheral uptake of glucose in in the intestines and reduce the absorption of
tissues in the presence of insulin. carbohydrates. They also inhibit the digestion of
Phenformin is not used therapeutically as it carbohydrates. Adverse effects include diarrhea,
causes lactic acidosis. Metformin is safer with flatulence and abdominal distension. They can
lower incidence of lactic acidosis. It does not cause be used with other antidiabetics.
hypoglycemia since it is an euglycemic agent. Newer drugs: Pramlintide (amylin analog) and
exenatide (GLP-1 analog) suppress glucagon
Biguanides
release, delay gastric emptying and suppress
• Have insulin-like effects
• Do not cause hypoglycemia
appetite. Sitagliptin (DDP-4 inhibitor) increases
• Weight reduction—due to anorexia insulin secretion and decreases glucagon levels.
• Nausea, diarrhea, metallic taste are transient They may be used with other antidiabetic drugs.
• Preferred in obese diabetics either alone or with
sulfonylureas Treatment of Diabetes Mellitus
• Contraindicated in renal, hepatic and cardiac The aim of treatment is to keep the blood sugar
diseases. within normal limits and prevent complications
of diabetes. In IDDM, insulin is the only treatment.
Adverse effects: Nausea, diarrhea, and metallic
Mild NIDDM may be controlled by diet, exercise
taste are self-limiting. Rarely lactic acidosis can
and weight reduction. When not controlled, an
occur. Anorexia is advantageous as it helps in
oral hypoglycemic should be given. Most NIDDM
reducing body weight. Long term use may interfere
patients may require insulin sometime later in life.
with vitamin B12 absorption.
Meglitinides Repaglinide and nateglinide Status of oral antidiabetics: Uncomplicated
increase the release of insulin by acting on NIDDM patients not controlled by diet and
pancreatic β-cells. They are well tolerated with exercise are given OAD. Mild NIDDM patients
minor adverse effects like hypersensitivity with recent onset diabetes, age above 40 years at
reactions, hypoglycemia and gastrointestinal the onset of diabetes, obese with fasting blood
disturbances. Meglitinides may be used either sugar < 200 mg/dl are candidates for oral
alone or with biguanides in NIDDM patients. hypoglycemics. They are convenient to use.
Sulfonylureas are preferred, but when blood sugar
Thiazolidinediones (TZDs) increase glucose is not adequately controlled, metformin can be
transport into muscle and adipose tissue and added. Metformin has the advantages of reducing
reduce hepatic glucose output. They may cause appetite and being euglycemic. In conditions like
edema, weight gain and anemia. Liver function stress, surgery or in any of the complications of
should be monitored. TZDs may be used with diabetes, insulin should be used (Table 10.4). In
other antidiabetics. some patients, insulin may be given along with
α -glucosidase inhibitors: Acarbose and sulphonylureas because the latter increase the
miglitol inhibit the enzyme α-glucosidase present tissue sensitivity to insulin.

TABLE 10.4: Preparations of some oral antidiabetics

Drug Dose Duration of action

Tolbutamide (RASTINON) 500 mg q 8-12 h 6-8 hr


Chlorpropamide (DIABINESE) 250-500 mg q24 h 36-48 hr
Glibenclamide (DAONIL, EUGLUCON) 5 mg q 12-24 h 18-24 hr
Metformin (GLYCIPHAGE) 500 mg q 12-24 h 6-8 hr
182 Pharmacology for Physiotherapy

Insulin is effective in all types of diabetes mellitus. CORTICOSTEROIDS


The dose should be adjusted as per the needs of
each patient—guided by blood sugar levels. Corticosteroids are hormones produced in the
cortex of the adrenal gland. They are gluco-
Insulin resistance is said to be present when the corticoids, mineralocorticoids and a small amount
insulin requirement is increased to > 200 U/day of androgens. Cortisol is the major glucocorticoid
(many consider >100 U/day). It is due to the while aldosterone is the major mineralocorticoid.
antibodies to insulin which partly neutralize it. The secretion of adrenal cortex is under the control
This is rare with purified preparations and human of ACTH secreted by the anterior pituitary and
insulin. Hence in presence of resistance, it is this is in turn regulated by CRF (Fig. 10.1). This is
necessary to change over to highly purified/ termed hypothalamic-pituitary-adrenal axis.
human insulin.
Treatment of diabetic ketoacidosis: Keto- STRUCTURE AND SYNTHESIS
acidosis may be precipitated by infection, trauma The corticosteroids have a steroid (cyclopentano-
or stress and is more common in IDDM patients. perhydrophenanthrene) ring. They are synthe-
Acidosis, dehydration, electrolyte imbalance, sized in the adrenal cortex from cholesterol
impaired consciousness, and hyperventilation are (Fig. 10.2) under the influence of ACTH.
the common features seen. Treatment is with Every day about 10-20 mg of hydrocortisone
regular (plane) insulin by continuous IV infusion. (maximum in the early morning) and 0.125 mg of
Fluid and electrolyte replacement are important. aldosterone are secreted. They are also released
in response to stress.
GLUCAGON
Glucagon is synthesized in the alpha (α) cells of ACTIONS
the pancreatic islets of Langerhans; like insulin, Glucocorticoid Actions
the secretion of glucagon is regulated by
nutrients—chiefly glucose, paracrine hormones 1. Metabolic effects: Carbohydrate, protein and
and autonomic nervous system. Fasting fat metabolism—Glucocorticoids promote
stimulates glucagon secretion. It is degraded in gluconeogenesis and glycogen deposition in
the liver, kidney and plasma. the liver and inhibit peripheral utilization of
glucose resulting in increased blood glucose
Actions: Glucagon increases blood glucose level levels. They enhance protein breakdown and
by glycogenolysis and gluconeogenesis in the liver. nitrogen is excreted leading to negative
It evokes insulin release. It mobilizes stored fat nitrogen balance. Glucocorticoids are catabolic
and carbohydrates. Glucagon increases heart rate hormones.
and force of contraction. It also relaxes the They promote lipolysis and redistribution
intestinal smooth muscles. of fat takes place—fat is mobilized from
extremities and deposited over the face, neck
Uses and shoulder and excess glucocorticoid
1. Severe hypoglycemia—glucagon can be used activity results in symptoms which are
in the emergency treatment of severe hypo- described as ‘moon face’, ‘fish mouth’ and
glycemia due to insulin. ‘buffalo hump’.
2. Diagnostic uses—for diagnosis of IDDM. 2. Anti-inflammatory and immunosuppressive
3. Radiology of the bowel—because glucagon effects: Glucocorticoids suppress the deve-
relaxes intestines. lopment of inflammatory response to all types
Hormones 183

of stimuli. They inhibit both early and late


manifestations of inflammation. Inhibition of
late response like capillary proliferation,
collagen deposition, fibroblastic activity and
scar formation may delay wound healing. They
inhibit migration and depress the function of
the leukocytes and macrophages including the
release of chemical mediators. The ability of
these cells to respond to antigens is decreased.
In addition glucocorticoids also reduce the
synthesis of prostaglandins and leukotrienes
by inhibiting phospholipase A2.
Glucocorticoids thus suppress cell-
mediated immunity, prevent manifestations of
allergy and prevent homograft rejection. Large
doses also inhibit antibody production.
3. Other actions
• Glucocorticoids reduce capillary permea-
bility, maintain the tone of arterioles and
have a positive inotropic effect. Prolonged
use can cause hypertension.
• They are essential for normal muscular
activity.
• They are required for normal functioning
of the central nervous system. Deficiency
results in apathy and depression while
large doses result in restlessness, anxiety
and sometimes psychosis.
Fig. 10.1: Hypothalamopituitary-adrenal axis
• GIT—Glucocorticoids enhance the secre-
regulation of synthesis and secretion of adrenal
tion of gastric acid and pepsin in the
corticosteroids
stomach.

Fig. 10.2: Synthesis of adrenal steroids


184 Pharmacology for Physiotherapy

• Calcium metabolism—Glucocorticoids PHARMACOKINETICS


inhibit absorption and enhance the renal Most glucocorticoids are well-absorbed orally.
excretion of calcium—they antagonize the Hydrocortisone undergoes high first pass
effect of vitamin D on calcium absorption. metabolism. It is 95 percent bound to plasma
Bone resorption takes place. proteins—transcortin. Glucocorticoids are
• Formed elements of blood—gluco- metabolized by microsomal enzymes in the liver
corticoids have a lympholytic effect and and are excreted by the kidneys. The t½ varies
this effect is very prominent in lymphomas. with each agent and we have short, intermediate
They also increase the number of platelets and long-acting agents (Table 10.6).
and RBCs.
• They are essential for maintaining normal Topical Preparations
GFR. Several glucocorticoid preparations are available
4. Mineralocorticoid action: Glucocorticoids for topical use as creams, ointments, nasal and
have a weak mineralocorticoid action—cause eyedrops. Some of them also contain antibiotics
some salt and water retention and potassium (Table 10.7).
• Hydrocortisone, the chief natural gluco-
excretion. Some synthetic glucocorticoids are
corticoid is used orally and parenterally; in
devoid of this activity (Table 10.5).
emergencies it is used intravenously.
• Prednisolone has potent glucocorticoid with
MECHANISM OF ACTION
mild mineralocorticoid activity. It is the most
Corticosteroids bind to specific receptors in the commonly used preparation.
cytoplasm, the drug-receptor complex is • Prednisone is a prodrug converted to
transported into the nucleus where it binds to prednisolone in the liver.
specific sites on DNA and regulates the synthesis • Methylprednisolone is similar to prednisolone
of new proteins that bring about the effects of and is used as retention enema and for high
glucocorticoids. dose pulse therapy.

TABLE 10.5: Relative potency of some corticosteroids

Drug Glucocorticoid activity Mineralocorticoid activity Equivalent dose

Short-acting (8-12 hr)


Hydrocortisone 1 1 20 mg
Cortisone 0.8 0.8 25 mg
Intermediate-acting (18-36 hr)
Prednisolone 4 0.8 5 mg
Methylprednisolone 5 0.5 4 mg
Triamcinolone 5 0 4 mg
Fludrocortisone 10 125 2 mg
Long-acting (36-54 hr)
Paramethasone 10 0 2 mg
Dexamethasone 25 0 0.75 mg
Betamethasone 30 0 0.6 mg
Fludrocortisone 10 125
Hormones 185

TABLE 10.6: Preparations and dose of some commonly used glucocorticoids

Glucocorticoid Trade name Daily dose

Hydrocortisone hemisuccinate Efcorlin 30-100 mg IV, IM inj


Prednisolone Wysolone 5-60 mg oral, 10-40 mg IM
Methylprednisolone acetate Solvmedrol 4-32 mg
Triamcinolone Kenacort 4-20 mg
Dexamethasone Dexoma 0.5-5 mg oral, 4-20 mg IV/IM
Betamethasone Betnesol 0.5-5 mg oral, 4-20 mg IM/IV

TABLE 10.7: Some topical glucocorticoid preparations

Hydrocortisone (Lycortin oint) 1 percent


Triamcinolone (Ledercort acetonide oint) 0.1 percent
Dexamethasone (Decadron cream) 0.1 percent
Flucinolone acetamide (Flucort oint) 0.025 percent
Betamethasone (Betnovate oint, cream) 0.025 percent
Beclomethasone dipropionate (Beclate cream) 0.025 percent
Clobetasol propionate (Tenovate cream) 0.05 percent

• Triamcinolone, dexamethasone, betametha- 1. Cushing’s syndrome with characteristic


sone have no mineralocorticoid activity and appearance of moon face, buffalo hump,
have selective, potent glucocorticoid effects. truncal obesity, muscle wasting, thinning of
the limbs and skin, easy bruising, purple
Inhalation steroids striae and acne.
Beclomethasone 50 μg, 100 μg 2. Hyperglycemia and sometimes diabetes
(Beclate inhaler) 200 μg/metered dose mellitus may be precipitated.
Budesonide 200 μg/metered dose 3. Susceptibility to infection is increased and the
(Budecort) severity of any infection may be more because
Fluticasone 25, 50, 150 μg/metered dose of immunosuppression. Opportunistic
(Flohale) infections may occur. Previously dormant
tuberculosis may become active.
4. Osteoporosis especially of the vertebrae is
Adverse effects of glucocorticoids: Adverse more common in the elderly.
effects of glucocorticoids (Fig. 10.3) are dependent 5. Avascular necrosis of the bone due to restriction
on the dose, duration of therapy and the relative of blood flow through bone capillaries may
potency of additional mineralocorticoid effects. cause pain and restriction of movement.
Whenever possible, they should be used topically Growth in children may be suppressed.
to avoid systemic effects. Single doses are harmless 6. Peptic ulceration may sometimes occur on
while short courses are well-tolerated. Prolonged prolonged therapy especially when other
use is associated with toxicity. Adverse effects ulcergenic drugs (e.g. NSAIDs) are used
include: concurrently.
186 Pharmacology for Physiotherapy

Fig. 10.3: Adverse effects of glucocorticoids

7. Mental disturbances like euphoria, psychosis proper drug history. If the patient has
or depression can occur with high doses. received long-term steroids within previous
8. Cataract and glaucoma may follow long-term six months, prophylactic hydrocortisone
use of glucocorticoids even as eyedrops. should be administered to avoid shock. Two
9. Delayed wound healing—Steroids may delay weeks of use of > 20 mg hydrocortisone/day
wound healing. needs tapering of the dose.
10. Other effects include raized intracranial In order to minimize HPA axis suppres-
pressure, convulsions, hypercoagulability of sion, (i) lowest effective dose of a glucocorticoid
the blood and menstrual disorders. for the shortest possible period should be used,
11. HPA axis suppression depends on the dose, (ii) the drug should be given in a single
duration and time of administration. After morning dose, (iii) administration on alternate
prolonged steroid therapy, adrenal cortex days is found to be associated with least/no
gradually atrophies due to feedback inhibi- HPA axis suppression and whenever
tion. If steroid administration is suddenly possible this measure should be followed,
especially when long-term steroids are
stopped, acute adrenal insufficiency results.
needed.
Hence after prolonged administration,
12. Mineralocorticoid effects including salt and
steroids should be tapered before withdrawal
water retention, edema, hypokalemia
to allow HPA axis to recover. Prior to surgery and hypertension are rare with selective
or general anesthesia, it is advisable to elicit glucocorticoids.
Hormones 187

Uses severe cases low dose oral prednisolone


is indicated.
I. Replacement therapy
7. Collagen diseases like polyarthritis nodosa,
A. Acute adrenal insufficiency is an emergency
lupus erythematosus, polymyositis,
condition that could be precipitated by an
Wegener’s granulomatosis and other
infection or sudden withdrawal of steroids.
rheumatoid disorders respond to gluco-
Intravenous hydrocortisone hemisuccinate
corticoids.
100 mg bolus followed by infusion is given
8. Eye diseases: Allergic conjunctivitis, uveitis,
immediately. Correction of fluid and electro-
optic neuritis and other inflammatory condi-
lyte balance are important.
tions are treated with steroids. In ocular
B. Chronic adrenal insufficiency (Addison’s
infections, steroids are contraindicated.
disease). Oral hydrocortisone 20-40 mg daily
9. Renal diseases like nephrotic syndrome are
is given. Some patients may need additional
treated with steroids.
fludrocortisone (a mineralocorticoid).
10. Skin diseases: Atopic dermatitis, seborrheic
II. Pharmacotherapy: Glucocorticoids have been dermatitis, inflammatory dermatoses and
used in a variety of nonendocrine conditions other local skin conditions are treated with
where they may even be life saving. topical steroids. Systemic steroids are life
1. Rheumatoid arthritis: In progressive disease saving in pemphigus.
steroids are given with NSAIDs. If 1-2 joints 11. Gastrointestinal diseases: Mild inflammatory
are involved, intraarticular injections are bowel diseases like ulcerative colitis are
preferred. They suppress inflammation and treated with steroid enema while severe cases
benefit such patients. need oral prednisolone.
2. Osteoarthritis: Steroids are given as intra- 12. Liver diseases: Steroids are useful in
articular injections. conditions like chronic active hepatitis and
3. Rheumatic carditis: Severely ill-patients with alcoholic hepatitis.
fever and carditis but not responding 13. Hematologic disorders like purpura and
adequately to NSAIDs require gluco- hemolytic anemia having immunological
corticoids. etiology respond to steroids.
4. Acute gout: When treatment with NSAIDs 14. Cerebral edema: Large doses of dexametha-
have not been successful, prednisolone is sone is given.
used as an adjuvant. 15. Malignancies: Because of their lympholytic
5. Allergic conditions like angioneurotic edema, effects, steroids are used in the treatment
hay fever, serum sickness, contact dermatitis, of acute lymphocytic leukemia and
urticaria, drug reactions and anaphylaxis— lymphomas—as a component of combination
steroids are indicated. Steroids are slow chemotherapy. Steroids are used for rapid
acting and in less severe cases, anti- symptomatic relief in other cancers like
histamines should be preferred. breast cancer.
6. Bronchial asthma 16. Lung diseases: Apart from bronchial asthma,
• Acute exacerbations—a short course of steroids are used in other diseases like
prednisolone. aspiration pneumonia and prevention of
• Status asthmaticus—intravenous hydro- infant respiratory distress syndrome.
cortisone hemisuccinate. 17. Organ transplantation: For prevention and
• Chronic asthma—steroids are used as treatment of graft rejection, high doses of
supplement to bronchodilators. Inhala- prednisolone are started at the time of surgery
tional steroids are used and in more with immunosuppressive agents.
188 Pharmacology for Physiotherapy

Contraindications to glucocorticoid therapy


The hypothalamus releases the GnRH in
Steroids should be used with caution in: pulses which stimulates the release of FSH and
1. Peptic ulcer 6. Psychoses LH from the anterior pituitary. At the beginning
2. Hypertension 7. Epilepsy of each cycle, a number of follicles in the ovary
3. Infections 8. CCF begin to enlarge in response to FSH. After 5-6 days,
4. Diabetes mellitus 9. Glaucoma one of the follicles begins to develop more rapidly.
5. Osteoporosis 10. Renal failure The granulosa cells of this follicle multiply and
under the influence of LH, synthesize estrogens.
MINERALOCORTICOIDS This estrogen inhibits FSH release, resulting in
regression of the smaller follicles. Just before the
The most important natural mineralocorticoid is midcycle, the estrogen secretion reaches a peak,
aldosterone which is synthesized in zona stimulating a brief surge in FSH and LH levels
glomerulosa of the adrenal cortex. Small amounts which results in ovulation by around the 14th
of desoxycorticosterone is also released. day of the cycle (Fig. 10.4).
Actions: Mineralocorticoids promote sodium and
water retention by distal renal tubules with loss ESTROGENS
of potassium. They act by binding to the mineralo- The estrogens are produced by the ovaries,
corticoid receptor. placenta and in small amounts by the adrenals
Adverse effects include weight gain, edema, and testes. During the first part of the menstrual
hypertension and hypokalemia. cycle, estrogens are produced by the theca cells in
the ovarian follicle and after ovulation—by the
Fludrocortisone has predominantly mineralo- granulosa cells of the corpus luteum. The major
corticoid properties and is used for replacement estrogens are estradiol, estrone and estriol.
therapy in aldosterone deficiency as in Addison’s Estradiol is converted to estrone and estriol by the
disease. Although aldosterone is the principle liver and other tissues.
natural mineralocorticoid, it is not used thera-
peutically since it is not effective orally. Natural estrogens: Estrogens, estradiol, estrone,
estriol.
Inhibitors of Adrenal Steroids Synthesis Synthetic estrogens: Ethinyl estradiol, stilboestrol
Metyrapone, trilastane, aminoglutethimide and and mestranol.
ketoconazole: These drugs inhibit the synthesis
of adrenal steroids by inhibiting certain enzymes
involved in steroid synthesis. They are used in
Cushing’s syndrome and some prostatic and
breast cancers.

ESTROGENS, PROGESTINS
AND ORAL CONTRACEPTIVES

PHYSIOLOGIC CONSIDERATION
At puberty, the ovary begins its cyclic function
called menstrual cycle which stretches over 30-40
years characterized by regular episodes of uterine Fig. 10.4: Regulation of secretion
bleeding. of gonadal hormones
Hormones 189

Actions: Estrogens are required for— Uses


1. The normal maturation of the female repro-
1. Replacement therapy: In primary hypo-
ductive tract.
gonadism—an estrogen started at 11-13 years
2. Development of secondary sexual characters
of age stimulates the development of secondary
in the female.
sexual characters and menstruation.
3. Stimulation of preovulatory endometrium.
2. Postmenopausal syndrome: Due to decreased
4. Metabolic effects—estrogens inhibit the
estrogen production at menopause, hot
resorption of bone and maintain the bone mass.
flushes, anxiety, fatigue, sweating, muscle and
They promote the fusion of epiphyses.
joints pain are common. Other longer-lasting
5. Estrogens are important for the maintenance
changes including osteoporosis, genital
of normal structure of the skin and blood
atrophy, skin changes, increased risk of
vessels in women.
cardiovascular disease and psychological
6. Estrogens decrease plasma LDL cholesterol
disturbances may be seen. Estrogens given in
and raise HDL cholesterol and triglycerides.
low doses is highly effective in reversing most
7. Effect on blood coagulation—estrogens
of the changes.
enhance the coagulability of the blood.
3. Senile vaginitis is common in elderly women
Pharmacokinetics: Natural estrogens are due to estrogen withdrawal from ovary.
metabolized rapidly in the gut—hence are not Estrogen cream is used topically.
effective orally; they have a short t½. All estrogens 4. Osteoporosis: In postmenopausal osteoporosis,
get absorbed through the skin and mucous estrogens restore calcium balance and need to
membrane. They are largely bound to plasma be given for a long time.
proteins. Synthetic estrogens are orally effective 5. Oral contraceptives Estrogens are used (page
and are long-acting. 192).
6. Dysmenorrhea: Estrogens combined with
Adverse effects: Nausea, breast tenderness, progestins suppress ovulation and such
migraine headaches, hyperpigmentation, anovulatory cycles are painless. Estrogens are
hypertension and cholestasis may be seen. In men used only in severe dysmenorrhea.
gynecomastia and feminization can occur. 7. Dysfunctional uterine bleeding: Estrogens are
used along with progesterone.
Cancers: Increased incidence of endometrial and 8. Carcinoma prostate is an androgen dependent
breast cancers are reported on long-term estrogen tumor. Estrogens antagonize the action of
therapy. androgens, suppress androgen production
and are useful for palliative therapy.
Teratogenic: When given to a pregnant lady,
estrogens may cause the following teratogenic Contraindications: Estrogen dependent tumors,
effects: liver disease, thromboembolic disorders.
• In female child—increased risk of vaginal and
cervical cancers. Selective Estrogen Receptor Modulators
• In male child—genital abnormalities. (SERMs) and Antiestrogens
Preparations: Estrogens are available for oral and Tamoxifen was earlier considered to be an
parenteral use. A transdermal patch for cyclic estrogen antagonist—but now it is understood
estrogen therapy is also available. that it acts as an agonist-antagonist or partial
190 Pharmacology for Physiotherapy

agonist depending on the site. Raloxifene, Adverse effects include hot flushes, leg cramps
tamoxifen and ormeloxifene have actions similar and an increased risk of deep vein thrombosis
to tamoxifen and are all termed selective estrogen and pulmonary embolism. Raloxifene is indicated
receptor modulators (SERMs). SERMs bind to for the prevention of post-menopausal osteo-
estrogen receptors and have tissue-selective porosis.
estrogenic activities i.e.:
• They have agonistic effects on bone, lipid PROGESTINS
metabolism, brain and liver. Progesterone is the natural progestin synthesized
• Antagonists at breast, pituitary and in the ovary and placenta. It is also synthesized
endometrium. by the testis and adrenals where it acts as a
• Partial agonist at genitourinary epithelium, precursor of various steroid hormones (see under
bone remodeling and cholesterol metabolism. corticosteroids).
Tamoxifen is given orally. Side effects include
hot flushes, nausea, vomiting, vaginal bleeding Progestins
and skin rashes. Natural Progesterone
Tamoxifen is used in advanced breast cancer Synthetic Medroxyprogesterone acetate
in postmenopausal women with estrogen Allylestrenol
receptor-positive tumors. Megestrol
Norethisterone acetate
Clomiphene citrate binds to the estrogen recep-
Lynestrenol
tors and acts as a competitive inhibitor of
Norgestimate
endogenous estrogens. Like tamoxifen, it is also a
partial agonist. Clomiphene opposes the negative
Actions
feedback of endogenous estrogens on the hypo-
thalamopituitary axis resulting in increased 1. Uterus: The secretory changes in the uterine
gonadotropin secretion and thereby induces endometrium like increased tortuosity of the
ovulation. glands are due to progesterone. In pregnancy,
decidual changes in the endometrium take
Side effects include ovarian hyperstimulation place under the influence of progesterone.
resulting in multiple pregnancy, ovarian cysts, Progesterone is very important for the
hot flushes, headache and skin rashes. maintenance of pregnancy (Progestin = favors
Uses pregnancy).
2. Cervix: The watery secretion of the cervix is
1. Infertility: Clomiphene citrate is used to induce
changed to a thick scanty secretion by
ovulation in infertility due to ovarian
progesterone.
disorders.
3. Vagina: Vaginal epithelium changes to that
2. In vitro fertilization: Clomiphene induced
seen in pregnancy by the influence of
ovulation is also useful in in vitro fertilization.
progesterone.
Raloxifene acts as an estrogen receptor agonist 4. Breast: Along with estrogen, progesterone is
in the bone. In women with postmenopausal responsible for the development of the
osteoporosis, raloxifene has antiresorptive effects secretory apparatus in the breast and prepares
on the bone. It reduces bone loss and may even the gland for lactation.
help to gain bone mass. Raloxifene also lowers 5. Body temperature: Increase in the body
LDL. It acts as an estrogen antagonist in the breast temperature by 1°C that is seen during luteal
cancer. Raloxifene does not stimulate the uterine phase which begins at ovulation is due to
endometrial proliferation. progesterone.
Hormones 191

Adverse effects: Headache, breast engorgement, facilitates expulsion of the blastocyst. If given
rise in body temperature, edema, acne and mood during the follicular phase—it also delays
swings may be seen. Progesterone is teratogenic. ovulation.
Mifepristone also binds to glucocorticoid
Uses receptors.
1. Contraception (see below).
2. Hormone replacement therapy (HRT): Progestins Uses
are combined with estrogens in HRT of 1. Termination of pregnancy: Early pregnancy up
postmenopausal women. Estrogen adminis- to 9 weeks can be terminated with a single
tration increases the risk of endometrial oral dose—600 mg of mifepristone followed
cancer—supplementing it with progestin 48 hr later by a prostaglandin to increase
counters this risk. uterine contractions and facilitate expulsion
3. Ovarian suppression: Progestins are used to of the blastocyst.
suppress ovulation in dysmenorrhea, Adverse effects include heavy bleeding,
endometriosis, dysfunctional uterine bleeding nausea and abdominal pain.
(DUB) and premenstrual syndrome. 2. Postcoital contraceptive: Mifepristone prevents
4. Threatened or habitual abortion: Efficacy in such implantation when given within 72 hr after
patients is not proved. coitus.
5. Endometrial carcinoma: Progestins are used as Regular use of mifepristone in late luteal phase
a palliative measure in cases with metastasis. acts as a contraceptive.

Therapeutic uses of estrogens and progestins


HORMONAL CONTRACEPTIVES
Estrogens Progestins
1. HRT 1. HRT
Millions of women around the world use
— Primary 2. Contraception hormonal contraceptives making them one of the
hypogonadism 3. Dysmenorrhea most widely prescribed drugs. When properly
— Postmenopausal 4. DUB used, they are the most effective spacing methods
syndrome 5. Endometriosis of contraception. Hormonal contraceptives have
2. Contraceptive 6. Premenstrual syndrome greatly contributed to the control of population
3. Senile vaginitis 7. Endometrial cancer throughout the world.
4. Osteoporosis
5. Carcinoma prostate Oral Pills Depot preparations
6. DUB 1. Combined-pill 1. Injectables
7. Dysmenorrhea 2. Mini-pill 2. Subcutaneous implants
3. Postcoital pill
ANTIPROGESTINS
Combined pill contains low doses of an estrogen
Mifepristone binds to the progesterone receptor
and a progestin. They are highly efficacious
and blocks the actions of progesterone. When
(success rate 98%).
given in early pregnancy—abortion occurs.
Ethinyloestradiol or mestranol are the
Mechanism: Mifepristone blocks the progesterone estrogens used. Newer progestins like desogestrel
receptors in the uterus and thereby causes and norgestimate cause least side effects. The pill
decidual breakdown; blastocyst gets detached, is started on the 5th day of the menstrual cycle,
HCG and progesterone secretions fall. This in turn taken daily for 21 days followed by a gap of 7
increases prostaglandin levels and stimulates days during which bleeding occurs. This is
uterine contractions. It also softens the cervix and monophasic regimen.
192 Pharmacology for Physiotherapy

Oral contraceptives are also available as lesser side effects reported. Two tablets should be
biphasic or triphasic preparations (Table 10.8). taken within 72 hours of coitus and repeated after
This reduces the amount of hormones needed and 12 hours has an efficacy of 90-98 percent. It is
more closely mimics menstrual cycles. advocated as an emergency method in situations
If a woman misses a pill, she should take 2 following rape or contraceptive failure. It prevents
pills the next day and continue the course. If more implantation.
than 2 pills are missed, then that course should Depot preparations are given as:
be withdrawn, should follow an alternative 1. Intramuscular injections of progesterone at
method of contraception for that particular cycle 3-6 months intervals, e.g. depot medroxy-
and restart the course of oral contraceptives on progesterone acetate (DMPA) (150-400 mg)
the 5th day of the next menstrual cycle. If the or Norethisterone enanthate (NET EN)
woman has conceived, the pregnancy should be (200 mg).
terminated because these hormones are 2. Subcutaneous implants—They are implanted
teratogenic. under the skin.
Mini-pill: A low dose progestin is taken daily Norplant capsules implanted subcutaneously in
without a gap. As estrogen is not used, its adverse the forearm or upper arm work for 5 years.
effects are also eliminated. But efficacy is lower, Disadvantages i. Amenorrhea is frequent.
menstrual cycles may be irregular and is therefore ii. Permanent sterility may occur.
not popular and not preferred.
Mechanism of action of oral contraceptives: The
Postcoital contraceptives: High dose of an combined pill blocks the release of gonado-
estrogen was used earlier. The combined pill is trophins from the pituitary and thereby inhibits
now preferred due to lower doses needed and ovulation.

TABLE 10.8: Oral contraceptive preparations

Regimen Estrogen Progestin Trade name

Monophasic Ethinyl estradiol 50 μg Norgestrel 0.5 mg Ovral-G


Ethinyl estradiol 30 μg Levonorgestrel 0.15 mg Ovral-L
Biphasic Ethinyl estradiol 35 μg Norethindrone —
0.5 mg (10 days)
1 mg (11 days)
Triphasic 6 days ethinyl estradiol Levonorgestrel 50 μg
30 μg; next 5 days Levonorgestrel 75 μg
Ethinyl estradiol 40 μg: Levonorgestrel 125 mg Triquilar
next 10 days
Ethinyl estradiol 30 μg
Mini-pill Nil Norgestrel 75 μg Ovrette
Postcoital pill Diethyl stilboestrol (25 mg/day for 5 days) — —
Or
Combined pill (2 stat and 2 after 12 hr)

Stat—at once
Hormones 193

Progestin only preparations make the cervical contraception is desired (The tablet should be
mucus thick and scanty and thereby inhibit sperm continued without withdrawing for menstrua-
penetration. They also inhibit tubal motility and tion).
delay ovum and sperm transport. Centchroman has the following advantages:
1. Success rate claimed is 97-99 percent.
Adverse effects: Headache, nausea, vomiting,
2. It is devoid of the side effects of hormonal
breast tenderness, amenorrhea and irregular
contraceptives.
menstrual cycles may be commonly seen. Weight
3. Long t½ allows once a week administration.
gain, acne, mood swings and hirsutism may
4. No teratogenicity, carcinogenicity or
occur. More severe side effects include—
mutagenicity reported.
cardiovascular effects—in women >35 years there
5. It is well tolerated.
is an increased risk of MI and venous thrombo-
Centchroman may cause prolongation of
embolism.
menstrual cycles in 10 percent of women. It may
Cancers: OCs may increase the incidence of cause ovarian enlargement and should be
cervical, breast and other cancers—but is avoided in polycystic ovaries. It should also be
controversial. avoided in renal and hepatic dysfunction,
Cholestatic jaundice and gallstones: Incidence may tuberculosis and in lactating mothers.
be higher.
ANDROGENS AND ANABOLIC STEROIDS
Contraindications to combined pill
• Thromboembolic and cerebrovascular disease Androgens are produced chiefly in the testis and
• Breast cancers small amounts in the adrenal cortex. In the
• Liver disease females, small amounts of androgens are
• OCs should be used with caution in diabetes, produced in the ovary and adrenal cortex.
hypertension, convulsive disorders, edema and Testosterone is the most important natural
CCF. androgen. In the adult male, 8-10 mg of testo-
sterone is produced daily. Secretion is regulated
Benefits of combined pills by gonadotrophins and GnRH.
1. Effective and convenient method of contra-
Physiological actions: In the male, testosterone
ception.
2. Reduced risk of ovarian and endometrial cancers.
is essential for the development of secondary
3. Reduced incidence of pelvic inflammatory disease sexual characters and sex organs. It is necessary
and ectopic pregnancy. for normal spermatogenesis and is important for
4. Menstrual benefits—loss menstrual blood less, maintaining sexual function in men. Testosterone
less iron-deficiency; premenstrual tension and promotes bone growth, enhances the muscle mass,
dysmenorrhea are less intense. protein synthesis and positive nitrogen balance—
has anabolic actions.
Centchroman a chroman derivative is a Mechanism of action is similar to other steroids.
nonsteroidal oral contraceptive developed by Androgens bind to androgen receptors on the
research institute (CDRI), Lucknow. It has anti- target cells, the complex moves to the nucleus
estrogenic and antiprogestogenic activity and may where it stimulates protein synthesis.
act by preventing implantation. Onset of action is
quick (< 60 minutes) and duration of action is 7 Adverse effects: Masculinization and acne in
days. Dosage (Saheli, Centron) 30 mg twice a week females, hepatotoxicity, increased libido and
for 3 months followed by once a week till precocious puberty can occur in young boys. With
194 Pharmacology for Physiotherapy

large doses, salt and water retention, suppression balance is corrected, appetite improves and
of spermatogenesis resulting in infertility can be there is a feeling of well being.
seen. Feminizing effects like gynecomastia in men 2. Senile osteoporosis: In elderly males respond by
can occur as some androgens are converted to formation of new bone tissue.
estrogens. 3. Growth stimulation in children: Anabolic
steroids promote linear growth in prepubertal
Uses boys. They may be used only for short periods—
but actual benefit on final height is not
1. Testicular failure: Androgen replacement established.
therapy in primary and secondary testicular 4. Other uses: Anabolic steroids are tried in
failure. chronic renal failure to reduce nitrogen load
2. Other uses: Androgens may be used in senile on the kidneys. They may benefit in refractory
osteoporosis and carcinoma of the breast in anemias with bone marrow failure.
premenopausal women. 5. Abuse in athletes: Anabolic steroids enjoy a
reputation for improving athletic performance.
ANABOLIC STEROIDS When combined with adequate exercise, the
muscle mass increases. But the dose used by
Anabolic steroids are synthetic androgens with athletes is very high and is associated with
higher anabolic and low androgenic activity. serious adverse effects like testicular atrophy,
These are believed to enhance protein synthesis sterility and gynecomastia in men and
and increase muscle mass. But with higher doses, virilizing effects in women; increased
the relative anabolic activity is lost and these drugs
aggressiveness, psychotic symptoms and
act like other androgens.
increased risk of coronary heart disease in both
Adverse effects are similar to those caused by sexes. Moreover, there is no evidence that
androgens. athletic performance improves. Hence the use
of anabolic steroids by athletes has been
Preparations of anabolic steroids banned and is medically not recommended.

Anabolic steroid Route Dose Trade name


Contraindications for the use of androgens.
1. Pregnancy.
Methandienone Oral 2-10 mg/day Pronabol 2. Carcinoma of prostate/breast in males.
Nandrolone IM 10-50 mg/wks Durabolin 3. Infants and children.
phenylpropionate 4. Renal/cardiac/liver disease.
Nandrolone IM 25 -100 mg/ Decadura-
decanoate 3 wks bolin ANTIANDROGENS
Ethylestrenol Oral 2-4 mg/day Orabolin Cyproterone acetate—a derivative of progeste-
Oxandrolone Oral 5-10 mg/day Anavar rone competitively binds to androgen receptors
Stanozolol Oral 2-10 mg/day Stromba and thus blocks the action of androgens. It also
has progestational activity.
Cyproterone is used to treat severe hyper-
Uses sexuality in males, in carcinoma prostate and in
female hirsutism.
1. Catabolic states: Anabolic steroids may benefit
patients following surgery, trauma, prolonged Flutamide is a potent competitive antagonist at
illness and debilitating conditions. Given androgen receptors. It is used in the treatment of
during convalescence, the negative nitrogen carcinoma prostate.
Hormones 195

Finasteride inhibits the enzyme 5-alpha DRUGS USED IN SEXUAL IMPOTENCE


reductase and thus inhibits the convertion of
Sexual impotence is the inability of a man to have
testosterone to its active metabolite dihydro-
satisfactory sexual intercourse due to inability to
testosterone which acts mainly in the male