PHARMACOLOGY

UNIT NOTES

Prepared by

Dr Zoran Pletikosa

July 2009
 CONTENTS

INTRODUCTION ...................................................................................................................................5
DRUG NAMES ...................................................................................................................................5
CONTROL OVER DRUG USE IN AUSTRALIA .............................................................................7
DRUG DEVELOPMENT....................................................................................................................9
SCHEDULING ..................................................................................................................................12
BASIC PRINCIPLES OF PHARMACOKINETICS.............................................................................14
DRUG ADMINISTRATION.............................................................................................................14
Oral................................................................................................................................................14
Sublingual ...................................................................................................................................14
Rectal............................................................................................................................................14
Topical application....................................................................................................................15
Parenteral administration........................................................................................................15
Bioavailability .............................................................................................................................16
DRUG METABOLISM (BIOTRANSFORMATION)......................................................................17
EXCRETION OF DRUGS ................................................................................................................20
MOLECULAR ASPECTS OF DRUG ACTION ..................................................................................23
RECEPTORS .....................................................................................................................................25
ION CHANNELS ..............................................................................................................................27
ENZYMES.........................................................................................................................................27
CARRIER PROTEINS ......................................................................................................................28
PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM .................................................31
CHOLINERGIC TRANSMISSION ..................................................................................................33
Acetylcholine receptors...........................................................................................................34
Muscarinic agonists .................................................................................................................35
Muscarinic antagonists ...........................................................................................................36
NORADRENERGIC TRANSMISSION ...........................................................................................38
Adrenergic receptors ...............................................................................................................38
Adrenoceptor agonists ............................................................................................................39
Adrenoceptor antagonists ......................................................................................................40
Drugs acting on noradrenergic nerve terminals ...............................................................42
PHARMACOLOGY OF THE HEART.................................................................................................45
DRUGS ACTING IN THE AUTONOMIC NERVOUS SYSTEM ..................................................46
CARDIAC GLYCOSIDES................................................................................................................46
ANTI-ANGINAL DRUGS ................................................................................................................47
Organic nitrates .........................................................................................................................49
β adrenoceptor antagonists (β blockers) ............................................................................49
Calcium antagonists.................................................................................................................50
PHARMACOLOGY OF THE VASCULAR SYSTEM........................................................................52
VASOCONSTRICTOR DRUGS.......................................................................................................52
VASODILATOR DRUGS.................................................................................................................53
Directly acting vasodilators....................................................................................................53
Indirectly acting vasodilators.................................................................................................54
Main uses of vasodilator drugs .............................................................................................54
TREATMENT OF HYPERTENSION ..............................................................................................56
TREATMENT OF HEART FAILURE .............................................................................................60
PHARMACOLOGY OF THE URINARY SYSTEM ...........................................................................61
DIURETICS.......................................................................................................................................62
Loop diuretics ............................................................................................................................62
Thiazides .....................................................................................................................................63
Potassium-sparing diuretics ..................................................................................................63
PHARMACOLOGY OF HAEMOSTASIS ...........................................................................................66
ANTICOAGULANTS .......................................................................................................................66
Oral anticoagulants ..................................................................................................................67
Injectable anticoagulants ........................................................................................................68
ANTIPLATELET DRUGS................................................................................................................68

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 FIBRINOLYTIC DRUGS .................................................................................................................69
CLINICAL USE OF DRUGS THAT AFFECT HAEMOSTASIS....................................................70
PHARMACOLOGY OF THE RESPIRATORY SYSTEM ..................................................................73
MANAGEMENT OF ASTHMA.......................................................................................................73
Bronchodilators (Relievers) ...................................................................................................74
Anti-inflammatory agents (Preventers) ...............................................................................75
MANAGEMENT OF COUGH..........................................................................................................79
Cough suppressants ................................................................................................................79
Mucolytic/expectorant medications .....................................................................................79
PHARMACOLOGY OF THE GASTROINTESTINAL TRACT.....................................................80
DRUGS USED IN TREATMENT OF PEPTIC ULCER ..................................................................81
H2 receptor antagonists...........................................................................................................81
Proton pump inhibitors............................................................................................................82
Antacids.......................................................................................................................................82
Drugs that protect the mucosa ..............................................................................................83
Anti-Helicobacter drugs ..........................................................................................................84
DRUGS USED IN TREATMENT OF NAUSEA AND VOMITING ..............................................86
DRUGS AFFECTING MOTILITY OF THE GASTROINTESTINAL TRACT..............................88
Laxatives .....................................................................................................................................88
Antidiarrhoeal drugs ................................................................................................................89
Antispasmodic drugs ...............................................................................................................90
PHARMACOLOGY OF THE ENDOCRINE SYSTEM ......................................................................91
DRUGS USED IN DIABETES MELLITUS.....................................................................................91
Insulin...........................................................................................................................................93
Oral hypoglycaemic drugs......................................................................................................94
Other hypoglycaemic drugs ...................................................................................................96
DRUGS USED IN THYROID DISORDERS ...................................................................................97
Drugs used in treatment of hyperthyroidism .....................................................................98
Drugs used in treatment of hypothyroidism ......................................................................99
DRUGS USED IN HYPERLIPIDAEMIA ......................................................................................101
PHARMACOLOGY OF THE REPRODUCTIVE SYSTEM .............................................................104
DRUGS USED FOR CONTRACEPTION......................................................................................104
The combined pill....................................................................................................................104
The progestogen-only preparations...................................................................................106
Emergency contraception.....................................................................................................107
POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY (HRT)...................................108
PHARMACOLOGY OF PAIN AND INFLAMMATION..................................................................110
OPIOID ANALGESIC DRUGS ......................................................................................................112
DRUGS FOR NEUROPATHIC PAIN............................................................................................116
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS...............................................................116
GLUCOCORTICOSTEROIDS .......................................................................................................124
ANTIRHEUMATIC DRUGS..........................................................................................................128
HISTAMINE ANTAGONISTS.......................................................................................................132
PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM .....................................................134
ANXIOLYTIC AND HYPNOTIC DRUGS....................................................................................134
Benzodiazepines .....................................................................................................................135
Novel anxiolytics and sedatives/hypnotics ......................................................................139
Selected antidepressants......................................................................................................139
Antihistamine sedatives ........................................................................................................139
NEUROLEPTIC DRUGS................................................................................................................140
DRUGS USED IN AFFECTIVE DISORDERS..............................................................................145
Selective serotonin reuptake inhibitors (SSRIs) .............................................................146
Tricyclic/tetracyclic antidepressants .................................................................................148
Monoamine oxidase inhibitors (MAOIs) ............................................................................149
Atypical neuroleptics .............................................................................................................151
Antimanic drugs ......................................................................................................................151
ANTIEPILEPTIC DRUGS ..............................................................................................................152
DRUGS USED IN PARKINSON’S DISEASE...............................................................................157
DRUGS USED IN ALZHEIMER’S DISEASE...............................................................................162
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 DRUGS USED IN MULTIPLE SCLEROSIS (MS) .......................................................................163
PHARMACOLOGY OF INFECTIOUS DISEASES ..........................................................................165
BASIC PRINCIPLES OF CHEMOTHERAPY...............................................................................165
ANTIBACTERIAL AGENTS .........................................................................................................169
Antibacterial drugs interfering with nucleic acid synthesis ........................................170
Antibacterial drugs affecting bacterial peptidoglycan synthesis...............................173
Antibacterial drugs affecting bacterial protein synthesis ............................................177
ANTIVIRAL DRUGS .....................................................................................................................180
ADVERSE DRUG REACTIONS........................................................................................................186
DOSE RELATED ADVERSE DRUG REACTIONS .....................................................................186
NON-DOSE RELATED ADVERSE REACTIONS .......................................................................187
DRUGS IN PREGNANCY .............................................................................................................189
DRUG INDEX.....................................................................................................................................190

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 INTRODUCTION

Pharmacology can be defined as the study of the manner in which drugs affect the function of
living systems. Drug is any synthetic or natural chemical substance used in the treatment,
prevention, or diagnosis of disease. Use of substances to cure disease is as old as human race.
Drugs have been the most widely used form of treatment in medicine. Initially all drugs were
natural products, mainly derived from plants, but in this century with advancements in
chemistry and chemical technology it became possible to manufacture active ingredients from
herbs and even develop new ones. Today majority of drugs are synthesised although many of
them still retain a natural core that has been chemically modified in order to increase efficacy,
reduce unwanted effects, improve absorption or slow down drug metabolism making a drug
more convenient for administration (e.g., once a day instead 4 times a day). Certain drugs do
not originate from nature at all and they are referred to as fully synthetic drugs.

DRUG NAMES

Drugs have three types of names:

• chemical name
• generic or non-proprietary name
• brand, trade or proprietary name

Chemical name constitutes a description of a drug using the terminology of chemistry, and
can be long and complex. Because of this complexity, chemical names are inappropriate for
everyday use. For example, few people would communicate using the chemical term N-
acetyl-para-aminophenol when a simpler generic name (paracetamol) or brand name (e.g.,
Panadol) could be used instead.

OH OH
OH

NH2 HN C=O

CH3
Phenol
(carbolic acid) Para-aminophenol N-acetyl-para-aminophenol

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Generic name of a drug is ‘invented’ by its manufacturer and approved by a local naming
authority. Each drug has only one generic name. The generic name is also known as the non-
proprietary name and is chemically ‘meaningless’. However, generic names are less complex
than chemical names but usually more complex than brand names.

Brand names, also known as proprietary, are the names under which a drug is marketed and
prescribed. Brand names are created by drug companies with the intention that the name be
easy for nurses, doctors, and consumers to recall and pronounce. When a pharmaceutical
company introduces a newly developed drug, it enjoys a monopoly on the sale of that drug
for a number of years, protected by a patent. Once the patent expires (after usually 15 years)
any other drug company may also then produce and market that same drug but under a
different brand name. Since any drug can be marketed in different formulations and by
multiple companies, the number of brand names that a drug can have is large. By way of
illustration, paracetamol is available as Panadol, Dymadon, Tylenol, Panamax, Paralgin,
Tempra and Parmol. However certain drugs are marketed under their generic names (e.g.,
Herron Paracetamol) because their manufacturers believe that their generic names are better
known than brand new brand names that would have to be invented. In most instances these
drugs are cheaper than equivalent brand names, while offering identical or almost identical
pharmacodynamics properties (action).

In almost all cases, the generic name for a drug is longer and more complicated than the
brand name, and thus more difficult to remember and pronounce. The only reason for this is
that pharmaceutical companies want consumers and prescribers to remember their brand
rather than the generic ones. However, the principal objection to brand names is their vast
number. Although a drug can have only one generic name, the number of brand names it can
have is unlimited. As the number of brand names for a single drug increases, the problem of
name recognition becomes progressively larger. Furthermore, brand names for the same
drugs can vary from country to country.

Do significant differences exist between different brands of the same drug? Examples can be
found in which different brands of the same drug are not therapeutically equivalent.
However, these examples are rare. In most cases, there is no significant difference among
preparations of a drug made by company A, company B, and company Z. Furthermore, it
should be noted that drugs marketed under generic names are chemically identical to those
marketed under brand names, and they are usually significantly cheaper. For example, the
medication present in tablets available generically as Diazepam is identical to that in tablets
marketed under the brand name Valium. In those cases in which drug preparations do differ
from one another, the differences are not in the chemical composition of the drugs
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themselves. Rather, differences concern either the rate or extent of drug absorption, which is
influenced by the manufacturing process, which is usually a carefully protected company
secret. Hence, even though brand A and brand B contain the same amount of the same drug,
these preparations may be absorbed slightly differently and, as a result, may produce
quantitatively different effects. Today very rarely such differences are large enough to be of
therapeutic significance.

Although generic names may be long, their important advantage is that each drug has only
one generic name. On the other hand, although brand names are easy to recall and pronounce,
many problems stem from the existence of multiple brand names for a single drug. Multiple
brand names can impede name recognition and can thereby promote medication errors and
miscommunication about drugs. Brand names for different drugs may sound similar leading
to mistakes in prescribing/dispensing (e.g., Alphamox-Amfamox, Anaprox-Aropax, Feldene-
Teldene). Clearly, generic names are preferable to brand names. In this text, generic names
are employed for routine discussion. Although brand names are presented (in square
brackets), they are not emphasised. We may eventually see the day when brand names are
abandoned and generic names are employed universally. Even then consumers would be able
to insist on their favourite brands (if they want) not by using brand names but referring to the
manufacturer (e.g., Glaxo SmithKline paracetamol instead of Panadol).

CONTROL OVER DRUG USE IN AUSTRALIA

A number of federal as well as state/territory acts and regulations deal with control of drugs.
Issues covered include categorisation of drugs, licensing, general restrictions and conditions,
prescribing, labeling, advertising, manufacturing, packing, storage, supply and administration
of drugs. Examples of such regulations/acts are:

• Commonwealth
ƒ Therapeutic Goods Act 1989
ƒ Therapeutic Goods Regulations 1990
ƒ Narcotic Drugs Act 1967
ƒ National Health Act 1953
• New South Wales
ƒ Poisons and Therapeutic Goods Act 1966
ƒ Poisons and Therapeutic Goods Regulations 1994

Government department in Australia that has responsibility for drug control is Department
of Health and Ageing. Therapeutic Goods Administration (TGA) is the main
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Commonwealth drug regulating authority in Australia (www.tga.gov.au). TGA maintains
Australian Register of Therapeutic Goods (ARTG) – official list of approved drugs,
remedies, supplements and medical devices (around 64,000 entries). A ‘therapeutic good’ is
broadly defined as “a good which is represented in any way to be, or is likely to be taken to
be, for therapeutic use” (medicines and therapeutic devices).

All medicines manufactured for supply in Australia must be listed or registered in the ARTG,
unless they are specifically exempt or excluded.

• Listed medicines are considered to be of lower risk than registered medicines; the
majority of listed medicines are self-selected by consumers and used for self-
treatment. Listed medicines are assessed by the TGA for quality and safety but not
efficacy; this means that the TGA has not evaluated them individually or requested
their evaluation to see if they work.

• Medicines assessed as having a higher level of risk must be registered (not listed).
The degree of assessment and regulation they undergo is rigorous and detailed, with
manufacturers being required to provide comprehensive safety, quality and efficacy
data. Registered medicines can be non-prescription (low risk for consumers) and
prescription (high risk for consumers).

Complementary medicines (also known as 'traditional' or 'alternative' medicines) may be

either listed or registered, depending on their ingredients and the claims made. Most
complementary medicines are listed in the ARTG and some are registered.

A number of committees with different portfolios exist within TGA:

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 • Australian Drug Evaluation Committee (ADEC) – expert body that evaluates and
gives recommendations to Minister for Health and Ageing in regard to approval of
new therapeutic goods

o Adverse Drug Reactions Advisory Committee (ADRAC) – subcommittee of

ADEC; collects and reviews reports of adverse reactions to medicines and
vaccines

• Complementary Medicines Evaluation Committee (CMEC) – provides advice to the

TGA’s Office of Complementary Medicines on whether a new complementary
substance or medicine should be permitted in the ARTG as a listed or registered
product

• Medical Device Evaluation Committee (MDEC) – provides medical and scientific

advice to TGA and the Minister on the safety, quality and performance of medical
devices supplied in Australia

• Medicines Evaluation Committee (MEC) – advises the TGA and the Minister on
matters relating to the inclusion of over-the-counter (OTC) medicines on ARTG

• Therapeutic Goods Committee (TGC) – expert committee which advises the TGA
and the Minister on adoption of therapeutic standards, requirements for
labeling/packaging and the manufacturing principles

DRUG DEVELOPMENT

Pharmaceutical industry is estimated to be worth worldwide $250 billion/year. Research and

development spending in pharmaceutical industry is enormous. For example the cost of
developing a new drug is estimated at $200-500 million. Drug companies need 1-2 new drugs
every 3-4 years to remain financially viable. On the other hand on average it takes more than
10 years to bring a newly discovered active compound to market.

Good Clinical Practice is internationally accepted standard for the designing, conducting,
recording and reporting of clinical trials. Some aspects of this document may be modified by
local regulatory agencies (TGA in Australia) to suit local conditions or culture. National
Health and Medical Research Council (NHMRC) issues guidelines for the conduct of
medical research and ethical matters related to health. NHMRC establishes Australian Health
Ethics Committee (AHEC) which issues guidelines for formation and work of Human
Research Ethics Committees (HREC).

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Primary responsibility for monitoring a clinical trial rests with:
• sponsor (company or institution which initiates, manages and finances clinical trial)
• institution in which the trial is being conducted and its HREC
• investigator (person responsible for the conduct of the clinical trial at a trial site; if
several investigators are involved then the leader of the team is called principal
investigator)

HREC is independent body constituted of medical professionals and non-medical members,

whose responsibility is to ensure the protection of the rights, safety & well-being of human
subjects involved in a trial. All HRECs must notify AHEC of their existence and give
assurances that they have been established and operate under AHEC’s guidelines. In
Australia HRECs have pivotal role in approving and overseeing clinical trials. Ethics
committees in Australia provide a combined ethical and scientific review process, which may
be supplemented on as-needed basis by external expert advice.

There are two schemes under which clinical trials involving therapeutic goods may be
conducted:
o Clinical Trial Exemption (CTX) Scheme
o Clinical Trial Notification (CTN) Scheme
CTN Scheme

• All material relating to the proposed trial is submitted directly to the HREC by the
researcher at the request of the sponsor
• TGA does not review any data relating to the clinical trial
• HREC is responsible for assessing the scientific validity of the trial design, the safety
and efficacy of the medicine and for approval of the trial protocol
• The final approval comes from the institution where it is to be conducted
(“Approving Authority”)
• When all parties have signed the CTN form it is sent to TGA

CTX Scheme

• Sponsor submits an application to conduct clinical trials to the TGA for evaluation
and comment
• TGA reviews the scientific information about the product and trial protocol provided
by the sponsor especially in relation to safety
• TGA may seek modifications of the proposed protocol if necessary
• When TGA is satisfied it gives written comments that need to be forwarded to HREC
at site at which the sponsor intends to conduct the trial
• HREC still needs to approve the trial

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The choice of which scheme to follow (CTN or CTX) lies firstly with the sponsor and then
with the ethics committee that reviews the protocol and provides advice Approving
Authority, which decides whether the trial is allowed to proceed. The determining factor for
an HREC is whether it has access to appropriate scientific and technical expertise in order to
assess the safety of the product. CTX Scheme is intended to assist HRECs when information
about a drug or device is limited, or further advice is required for some other reason, thus it is
easier for HREC to approve such trial.

Clinical trials on humans are onducted in three phases:

1. In phase 1 a new drug is given to a small number of healthy male volunteers to

determine the toxic dose when toxic/adverse effects start appearing by progressively
increasing the amount given to subjects.

2. In phase 2 the drug is given to around 100 patients who suffer from disease/condition
for whose treatment the drug is being developed. Here the new drug may be
compared with another drug (if it exists). The purpose of phase 2 studies is to verify
the efficacy of the new drug for the intended disorder and to determine the optimal
dose. Participants are also monitored for unwanted effects. Depending on results of
these studies, the drug may or may not proceed to the next phase.

3. Phase 3 studies may involve large number of participants (several hundred to several
thousand) and many physicians in several hospitals/facilities. These are full-scale
randomised controlled clinical trials designed to avoid bias. The purpose is to verify
results of phase 2 studies and uncover adverse effects that were not noticed on
relatively small number of patients that took part in phase 2 studies.

When enough data have been collected, all documentation is submitted to TGA in form of
new drug application (NDA). Australian Drug Evaluation Committee (ADEC) of the TGA
carries out application assessment and then advises the TGA whether the application should
be accepted or rejected. In the end the Minister signs the approval after recommendation by
the TGA. According to current law the Minister can decline to sign the approval (veto) but
he/she can not approve a new drug without TGA recommendation.

When a drug is released onto the market, monitoring continues. Phase 4 studies are ongoing
studies conducted after the drug is approved. These studies may be able to detect rare
unwanted effects and problems affecting certain subpopulation such as pregnant women,
children and elderly, who are usually excluded from previous phases. Reports from these
studies must be sent regularly to TGA, especially any unexpected unwanted effects, allergic
reaction or toxicity. Thus TGA continues to monitor safety and efficacy of drugs after
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 approval. In some instances the licence can be revoked and the drug can be taken off the
market.

SCHEDULING

The National Drugs and Poisons Schedule Committee recommends the classification of
drugs and poisons into categories called Schedules. Scheduling is a means of controlling their
availability to the public. The criteria for classification include toxicity, abuse potential,
safety and the actual need for the chemical. The Schedule can depend on the strength of a
substance. Some medications that are normally in Schedule 4 may also be in Schedule 3 in
smaller doses. There are also very strict labelling requirements for scheduled substances that
must be included on the package. Most drugs are scheduled 2, 3, 4 or 8. All recommendations
are contained in Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP).

Unscheduled substances are not considered to be poisons and therefore do not require control
by scheduling. Many therapeutic preparations are unscheduled substances such as most
antacids, contact lens products, infant milk formulas, vitamins and many herbal remedies.

The following table shows the Scheduling system in Australia/New Zealand

S Label Description Examples

UNUSED except in Victoria where it contains poisons of plant origin which can be dangerous to
health (currently some Traditional Chinese Medicine herbs); these are available only from registered
1
practitioners; may be extended to other states/territories in future after they adopt registration of
practitioners (also herbalists).
PHARMACEUTICAL SUBSTANCES
Cough and cold preparations,
Available to the public from pharmacies.
PHARMACY some antihistamines, analgesics,
2 A pharmacist’s advice is available if
MEDICINE worm tablets, antiinflammatory
required.
drugs, antifungal creams
Insulins, asthma aerosols, weak
Available to the public from a pharmacist
topical corticosteroids, some
PHARMACIST or medical/dental practitioner but without
3 preparations for gastro-
ONLY MEDICINE a need for prescription. These preparations
oesophageal reflux, topical
are located behind the counter.
antifungals for vaginal use
Supplied only under prescription from
PRESCRIPTION
4 medical/dental practitioner. These Most drugs
ONLY MEDICINE
preparations are stored in a dispensary.
AGRICULTURAL, DOMESTIC AND INDUSTRIAL SUBSTANCES

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 Substances with a low potential for
Household poisons including
causing harm, which can be minimised by
5 CAUTION cleaning alcohol, bleach,
the use of appropriate packaging and
ammonia
warning and safety direction on the label.
More dangerous than S5 with a moderate
Household and garden pesticides
6 POISON potential for causing harm. Extra storage
and solvents
and packaging controls are required.
Substances with a high potential for
causing harms at low exposure, and which
DANGEROUS require special precautions during Arsenic, cyanide, commercial
7
POISON manufacturing, handling, storage and use. pesticides
A permit is required to buy these
chemicals.
CONTROLLED DRUGS AND PROHIBITED SUBSTANCES
Prescription only substances that may
produce addiction or dependence.
Possession without authority is illegal.
Drugs must be stored in a locked cabinet,
and records kept for 3 years.
S8 drugs can be: non-restricted (most) and
restricted (mainly psychostimulant drugs
CONTROLLED for narcolepsy and attention deficit
8 Opioids and amphetamines
DRUG disorder)
A GP can only prescribe non-restricted
drugs for a limited number of patients.
For restricted drugs a doctor needs to be a
specialist, can only prescribe these
medications to a limited number of
patients and has to obtain a special
authority to prescribe for each patient.
Dangerous substances wit abuse potential
for which manufacturing, possession, sale Heroin and most recreational
PROHIBITED
9 or use is prohibited except in special drugs (except alcohol and
SUBSTANCES
circumstances (teaching, research or tobacco)
analytical use).

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 BASIC PRINCIPLES OF PHARMACOKINETICS

The branch of pharmacology concerned with what the body does to the drug is termed
pharmacokinetics and it encompasses processes of drug absorption, distribution and
elimination (metabolism and excretion). In order to produce effects drugs have to reach their
target tissue from the site of administration. Drugs can be administered via different routes.
The form in which the drug is administered such as tablet, syrup, drops and ointment are
known as formulations.

DRUG ADMINISTRATION

Oral

The great majority of drugs are taken by mouth and swallowed in form of tablets (discs
prepared by compressing a granulated drug powder with an appropriate amount of an inert
filler), enteric-coated tablets (coated with material that does not disintegrate in the acidic
conditions of the stomach but only in the alkaline conditions of the intestine), capsules (drug
powder enclosed in a hard gelatine case) or liquid preparations. Absorption of orally taken
medications occurs mainly in the gut as the stomach has a thick mucous layer and the time
that the drug remains there is usually short which contribute to minimal absorption across the
gastric mucosa.

Sublingual

Even though mucosa of the mouth is not ideal for absorption, some drugs (e.g., nitroglycerin)
may be applied directly into the oral cavity. In this way after absorption the drug will avoid
the portal circulation and the liver, which can be useful for drugs with a high degree of first-
pass metabolism in the liver. Additional advantage is that a rapid effect can usually be
achieved.

Rectal

This mode of administration is used either for drugs that are required to produce a local effect
(e.g., suppositories/creams for haemorrhoids) or to produce systemic effects (especially in

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small children who can not or refuse to take oral drugs, in unconscious patients, patients who
have difficulties swallowing or patients who experience nausea/vomiting). Similarly creams
or suppository-shaped medications known as pessaries are used for vaginal administration for
topical treatment.

Topical application

Drugs can be administered on various epithelial surfaces (e.g., skin, conjunctiva, nasal
mucosa, vaginal mucosa) for direct treatment of a local process (e.g., topical steroids,
antibiotics, antifungal preparations). The forms of drugs may be drops, sprays,
creams/ointments, gels and lotions. Occasionally transdermal administration may be utilised
for systemic effects. Since the skin due to its thick keratin layer is not very permeable, only
lipophilic (very lipid soluble) drugs can be successfully applied transdermally. The best
examples are patches with organic nitrates for treatment of angina, oestrogens for treatment
of menopausal symptoms, nicotine to help persons to stop smoking.

Parenteral administration

This refers to any method of drug administration that avoids the gastrointestinal tract. Even
though transdermal and intranasal administration are strictly speaking parenteral methods, the
use of this term is normally reserved for invasive modes of drugs administration, namely
injections. Parenteral administration is more reliable in terms of absorption which is always
almost complete.

Depending on type of drug an injection may be:

o Subcutaneous (convenient method that can be carried out by the patient e.g., insulin
is administered in this way)

o Intramuscular (slow release forms of drugs are given in this way to prolong
absorption and thus duration of action e.g., penicillin antibiotics, depot
glucocorticosteroids or antipsychotics)

o Intravenous (when immediate effect is needed e.g., life threatening cardiac

arrhythmia, diabetic ketoacidosis, or for drugs that are too corrosive and can not be
given in any other way e.g., certain anti-cancer drugs)

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Common abbreviations in prescription writing
• qhs = every night
• hs = at night
• qd = every day
• bid = twice a day
• tid = three times a day
• qid = four times a day
• qos = every night at bedtime
• ac = at meal time
• pc = after meal time
• po = orally
• prn = as needed

Bioavailability

Bioavailability is the fraction of a given dose of a drug that gains access to the systemic
circulation. Bioavailability is 100% following an intravenous injection, but drugs are usually
given orally and the proportion of the dose reaching the systemic circulation varies with
different drugs and also from patient to patient. Bioavailability depends greatly on the rate of
drug’s first-pass metabolism in the liver and absorption form the gastrointestinal system.
Some drugs show rapid first-pass hepatic metabolism after their absorption from the gut, and
thus poor oral bioavailability (e.g., nitroglycerine, propranolol, salbutamol, morphine,
adrenaline). With others bioavailability is low due to their low absorption from the gut (an
extreme example is etidronate used in management of osteoporosis which has a
bioavailability of only 0.5 %).

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Many drugs reversibly bind to plasma proteins such as albumin after being absorbed and
consequently a ratio exists between free and bound drug. Drugs vary in respect to their
affinity to bind plasma proteins. However only free, unbound fraction can produce
pharmacological effects; this fraction may be between 1% (e.g., Voltaren) and 99.9% (e.g.,
warfarin).
Excessive protein binding slows drug elimination from the body thus prolonging the drug
action. At the same time competition between drugs for protein binding may occur during
concurrent administration. This only rarely leads to clinically important interactions because,
while many drugs are significantly bound to proteins, they occupy only a small percentage of
binding sites, often less than 1%. An example of important interaction is between aspirin and
warfarin: aspirin will enhance the effect of warfarin if taken together. However, low
concentration of proteins (hypoproteinaemia) can increase the amount of free drugs leading to
an enhanced effect of a drug: e.g., in chronic liver disease

DRUG METABOLISM (BIOTRANSFORMATION)

After inducing certain pharmacological effect, most drugs undergo enzymatic modification of
their molecule, prior to their removal from the body. Only some drugs which are readily
water-soluble can be excreted largely unchanged. Two main objectives are achieved through
drug metabolism:
1. drugs are inactivated and their effect is terminated
2. drugs are converted into water-soluble compounds, suitable for excretion through the
urinary or hepatobiliary system, without significant reabsorption

Metabolic alteration of drug molecules involves two kinds of biochemical reactions, which
often occur sequentially, known as phase I and phase II reactions:

• Phase I reactions, such as oxidation (the most common), reduction, hydroxylation,

deamination and dealkylation involve mixed function oxidase system of enzymes located
on the smooth endoplasmatic reticulum, which includes cytochrome P-450 enzyme
complex (cytochrome P450, often abbreviated as CYP, is a superfamily of approximately
20 isoforms that catalyse monoxygenation). Three main families are involved in
metabolism of drugs in the liver are CYP1, CYP2 and CYP3. Five isoforms account for
90% of P450-mediated metabolism:

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17
 These reactions introduce a reactive polar chemical group (a ‘handle’) which is a point
of attack for conjugation enzymes. Phase I reaction have very variable effect on
pharmacological activity/toxicity of drugs. The formed intermediate products are
sometimes even more toxic then the original drug, which usually has no importance
since phase II reactions immediately follow and chemically transform these metabolites.
However, this may be an issue if phase II reactions become supersaturated, when toxic
damage of liver cells can occur (e.g., in intoxication with paracetamol).

• Phase II reactions: conjugation or attachment of a substituent group (e.g.,

glucoronidation with glucose-derived glucuronic acid, glycine conjugation, sulphation
etc.) usually form inactive, more water soluble and thus readily excretable products.

Both phase I and phase II reactions take place mainly in the liver, although drugs can to some
extent be metabolised in most cells of the body. Phase I reactions occur in the endoplasmatic
reticulum while phase II reactions occur in the cytosol. It should be noted that not all drugs
go through both phases of metabolism as many drugs that are already relatively well water-
soluble may undergo only phase I reactions before excretion.

Some drugs increase the amount and activity of drug-metabolising enzymes (enzyme
inducers) and accelerate removal of other drugs decreasing their effectiveness. Common
offenders are:
¾ antiepileptics such as carbamazepine and phenytoin
¾ antibiotic rifampicin (used mainly for tuberculosis)
¾ alcohol
¾ polycyclic aromatic hydrocarbons (in tobacco smoke, barbecued and smoked meats)

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18
 ¾ St. John’s wort (hypercicum) – a herb commonly used for its antidepressant
properties

Sometimes drugs can inhibit enzymes leading to accumulation of other drugs in the body
leading to increased, potentially toxic effects (enzyme inhibitors). Common examples are:
¾ cimetidine
¾ antibiotics erythromycin and ciprofloxacin
¾ antiarrhythmic drug amiodarone
¾ calcium channel blocker diltiazem
¾ antifungal drugs fluconazole
¾ antidepressant drug fluoxetine
¾ grape fruit

Many drugs can induce liver dysfunction or damage is some individuals thorugh various
mechanisms, which are often unclear. In most instances there are no clinical manifestations of
liver injury apart from abnormal liver function tests and perhaps fatty change (steatosis)
which could be seen on ultrasound. In more rare instances, especially in prolonged use of
large disease or with pre-existent liver disease, more serious liver damage which could
progress to liver failure can occur. Some of the drugs implicated are:
• paracetamol
• diclofenac (anti-inflammatory)
• amiodarone (antiarrhythmic)
• chlorpromazine (neuroleptic)
• quinolone antibiotics like ciprofloxacin
• erythromycin
• fluconazole (antifungal)
• isoniazid (used in TB)
• methyldopa (antihypertensive)
• statins (cholesterol lowering drugs)
• valproate (antiepileptic)
• methotraxate (immunosuppresive)
• oral contraceptives
• cocaine and ecstasy

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19
 Diagram showing two phases of drug metabolism

Phase 1 Phase 2

Drug Derivative Conjugate

Oxidation Conjugation
Hydroxylation
Dealkylation
Deamination

COOH COOH COOH OH

O OH
=

O−C−CH3 OH O HO

O
COOH

Acetylsalicylic acid Salicylic acid Glucuronide

(aspirin)

EXCRETION OF DRUGS

Excretion is defined as a process by which a drug or a metabolite is eliminated from the body
without further chemical change. The main routes by which drugs are removed from the body
are kidneys and hepato-biliary system. Excretion via the lungs occurs only with highly
volatile or gaseous agents (e.g., alcohol, inhalation anaesthetics). The great majority of drugs
leave the body in the urine. Most drugs passively cross the glomerular filtration membrane,
while some are actively secreted into the renal tubule (e.g., penicillins, cephalosporins,
diuretics). Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule, so are
not efficiently excreted in the urine, unless they are first conjugated in the liver. Several
important drugs are removed unchanged predominantly by renal excretion (e.g., frusemide,
gentamycin, methotrexate and digoxin), and are liable to cause toxicity in elderly persons and
patients with impaired renal function.

For most drugs, disappearance from the plasma follows an exponential time-course
characterised by the plasma half-life (t1/2). This is a time period required for drug plasma
concentration to be halved (e.g., for ampicillin 1-2 h, for diazepam 15-25 h).

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20
 C
o
n
c
e
n
t
r
a
t
i
o
n

Time

Such pattern of drug elimination means that the higher the blood concentration the faster is
elimination from the body (rate of the drug disappearance is proportional to the drug’s plasma
concentration). This is observed when metabolic and excretions pathways are unsaturated
(usually the case) and is called first order kinetics. In case of complete saturation of
elimination processes, the rate of elimination is constant regardless of blood concentration;
the time-concentration graph is linear (e.g., overdose). This is called zero order kinetics.

For example for ethanol if one consumes ≤ 8 g/hr, it follows first-order kinetics buut if
consumption ia > 8 g/hr, it will follow zero-order kinetics as the limited amount of enzymes
for metabolic processes become saturated by excess quantities of ethanol.

Plasma half-life values can be used to plan dosage regimen and choose a dosing interval that
does not produce excessively high peaks (toxic levels) and depressions (ineffective levels) in
drug concentration. Ideally in drug treatment, a steady-state plasma concentration is required
within the optimal and safe therapeutic range. This range is between minimum effective
concentration (mec) and maximum safe concentration (msc). It has been found that normally
it takes 4-5 t1/2 to reach thia steady state. For many drugs measurement of drugs plasma
concentrations proves very useful in fine-tuning the dosage (e.g., cardiac glycosides, certain
antiepileptic drugs).

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21
 Toxicity

Drug concentration in msc

Optimal range
(therapeutic window)

mec
blood

No effect

This diagram shows how a steady state conectration is reached with multiple
administrations of different doses of the same drug.

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22
 MOLECULAR ASPECTS OF DRUG ACTION

One of the basic facts of pharmacology is that drug molecules must interact with biological
compounds and/or biochemical reactions in the organism in order to produce a certain
pharmacological response in form of altered biochemistry or physiology. Pharmacodynamics
is a study of the biochemical and physiologic effects of drugs and their mechanism of action.

In rare instances drugs work by simple chemical reaction with their compound target. Such
drug is magnesium hydroxide (a component of many antacid preparations) which neutralises
gastric hydrochloric acid by the following chemical process

Mg(OH)2 + 2HCl ÅÆ MgCl2 + 2H2O

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23
However most drugs produce their effects by binding, usually to various protein molecules.
Such bond is almost always reversible and occurs via electrostatic forces such as hydrogen
bonds and van der Waals forces. Strength and duration of the bonding depends on number of
such bonds, which in turn depends on how complementary in shape the drug and the target
are. Only rarely the bond is unbreakable and covalent in type, which leads to permanent
change of the target (e.g., aspirin irreversibly blocks enzyme cyclo-oxygenase). Four kinds of
regulatory proteins are commonly involved as primary drug targets:
• enzymes
• carrier molecules
• ion channels
• receptors

Drugs must show a high degree of binding-site specificity in order to be clinically useful. This
specificity is the ability of a drug to combine with one particular type of target. However,
drugs are frequently unable to clearly distinguish between subtypes of their target proteins
and therefore are not always specific in their actions. As we will explain later the lack of
specificity is one of major mechanisms of unwanted effects. This is especially true for drugs
that act on receptors (e.g., adrenergic or cholinergic) and ion channels (e.g., calcium
channels). Even drugs that are very specific in therapeutic doses may loose their specificity
when the dose is increased for any reason (e.g., selective β2 agonists used as bronchodilators

in bronchial asthma may cause tachycardia by stimulating β1 receptors in the heart).

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24
 RECEPTORS

Many very important drugs act on receptors which are specific macromolecular components
found mainly on the cell membrane or sometimes in the cell cytoplasm or nucleus. All
receptors that exist in the organism have physiologic roles, and no receptor has been
specifically ‘allocated’ for drugs. When an endogenous mediator that can be a hormone,
neurotransmitter or other messenger combines with a receptor, cell function changes in some
way. Drugs that can bind and activate the receptor, thus mimicking the effect of certain
endogenous mediator, are termed agonists, while drugs that can combine with the receptor
without causing activation but antagonising the effect of endogenous mediator are known as
antagonists. A full agonist is a drug that when bound to a receptor produces 100% of the
maximum possible response. A partial agonist produces less than 100% of the maximum
possible response. Most antagonists are competitive and they bind receptors in reversible
fashion competiting with endogenous mediators.

Binding of drugs loosely obeys the law of mass action, which states that the rate of a
chemical reaction is proportional to the products of the concentrations of reactants. Translated
to a drug-receptor interaction, a pharmacological response is directly proportional to receptor
occupancy (number of receptors to which drug molecules have adhered). Receptor occupancy
depends on drug concentration in the fluid bathing the receptors, as well as affinity
(tendency) to bind receptors. Affinity largely depends on drugs’ molecular structure, how
well they are able to fit into their receptor. The higher the affinity of the drug for the receptor,
the lower is the concentration needed to produce a given effect. Once bound drugs initiate
changes which lead to pharmacological effects, and the ability to do this is known as efficacy.
Full agonists have efficacy of 1, partial agonists have efficacy between 0 and 1 while
antagonists have efficacy of 0.

Another important concept is potency which is related to the amount of a drug needed to
produce a certain effect. The relationship between efficacy and potency is illustrated by the
following example. If both drug A and drug B are able to reduce heart rate by 25% they have
the same efficacy. However to achieve that effect drug B needs to be given in 5 time greater
dose – drug B has lower potency that drug A.

The potency of a drug does not correlate reliably with efficacy or toxicity. There is simply no
basis for regarding a more potent drug as more effective, or more dangerous for that matter. It
is unfortunate that potency is used carelessly as a synonym for efficacy, but this practice is
not likely to change.

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25
In general, in clinical practice potency has little relevance; the drug is formulated in dosages
that are equipotent with competitors. Furthermore, it is extremely rare for a drug within a
given class to have efficacy greater than similar products. At equipotent doses, drugs within a
particular class are equally effective. However, there may be differences in the actual
frequency of unwanted effects or a particular patient's ability to tolerate the medication.

There are four main types of receptor, classified according to their molecular structure and
the nature of the receptor-effector linkage.

They are coupled directly to an ion channel and their activation leads to
ion channel opening and movement of ions through the cell membrane.
Depending on type of ion channel this ionic flux causes changes in
Type 1 resting membrane potential in form of hypopolarisation/depolarisation or
receptors
hyperpolarisation. An example of this type of receptor is the nicotinic
acetylcholine receptor found at neuromuscular junctions and autonomic
ganglia, which is coupled to sodium channels and is responsible for
quick depolarisation of the postsynaptic cell (muscle cell or ganglionic
neuron).

These are coupled to various second messengers such as cyclic

adenosine monophosphate (cAMP) via transduction G-proteins
(complex transmembrane GTP-binding proteins). Once formed second
messengers can cause ion channel opening/closing and changes in
Type 2
receptors resting membrane potential (excitatory or inhibitory), activation of
certain enzymes, increase of intracellular calcium or some other change
that alters cell function. Examples of this type of receptor are the
muscarinic acetylcholine receptor found in the parasympathetic nervous
system and all noradrenergic receptors found in the sympathetic nervous
system.

They are directly linked to effector enzymes (e.g., tyrosine kinase) which

Type 3 cause phosphorylation and activation of certain intracellular proteins

receptors (e.g., enzymes) and thus cellular effects. Examples are insulin receptor,
receptors for cytokines, and receptors for various growth factors that
stimulate cell growth and division.

These are the only receptors located inside the cell and not on the

_________________________________________________________________________________
26
 cellular membrane. The drug-receptor complex, after diffusion into the
Type 4 nucleus interacts with nuclear DNA and cellular effects are produced as
receptors
a result of increased protein synthesis which takes some time to be fully
developed. Examples are receptors for steroid hormones and thyroid
hormones.

ION CHANNELS

As explained earlier, some ion channels are directly linked to a receptor, and open only when
the receptor is occupied by an agonist (agonist gated channels). However, many other types
of ion channels known as voltage-gated also serve as direct targets for drug action. The most
common type of interaction involves a physical blocking of the channel by the drug molecule
which prevents the transfer of ions (e.g., calcium channel blocking drugs “plug” calcium
channels). Some drugs have ability to open ion channels and in that way enable movement of
ions along their concentration gradient (e.g., potassium channel opening drugs). Drugs that
interfere with ion channels produce their effects through changes in resting membrane
potential (hypopolarisation and hyperpolarisation).

ENZYMES

Many drugs are targeted on enzymes and the nature of their interaction can be different.

• Most commonly, the drug molecule is a substrate analogue (a substance that closely
resembles the real substrate in chemical structure but is functionally different) acts as a
competitive inhibitor of the enzyme by reversibly forming physical bonds with the
enzyme thus effectively blocking its active site (e.g., enalapril acting on angiotensin
converting enzyme, sulphonamides acting on dihydropteroate synthetase). Another type
of interaction is known as non-competitive inhibition when drugs, which bear no
resemblance to the normal substrate, form chemical bonds with a site distinct and often
remote from the active centre and in that way substantially change structure/function of
the enzyme (e.g., aspirin acting on cyclo-oxygenase, monoamine oxidase inhibitors
acting on monoamine oxidase). Since the enzyme is virtually destroyed in this way and
can not recover until more in produced, this mode of drug action is not commonly used in
practice, as it is very difficult to control and reverse.

• Another type of interaction involves the drug as a false substrate, where the drug
_________________________________________________________________________________
27
 molecules undergo enzyme-facilitated chemical transformation to form an abnormal
product which changes the normal physiology (the antihypertensive drug methyldopa
which enters the process of noradrenaline synthesis instead of dopa and causes
accumulation of methylnoradrenaline which is much less active than noradrenaline).

• Drugs may require enzymatic modification to convert them from an inactive form (the
pro-drug), to an active form (e.g., glucocorticoid prednisone to prednisolone, some
penicillin-derived antibiotics). This process can prolong the duration of action of a certain
drug making it easier to use (e.g., administration once a day). Such enzymatic
modification usually takes place in the liver.

CARRIER PROTEINS

The transport of ions and small organic molecules across cell membranes generally requires a
carrier protein of some kind, since the permeating molecules are often insufficiently lipid
soluble to penetrate lipid membranes on their own. The carrier proteins have a recognition
site that makes them specific for a particular permeating species, and it is not surprising that
these recognition sites can also be targets for drugs whose effect is to block the transport
system. Examples are tricyclic antidepressants which block noradrenaline uptake, selective
serotonine reuptake inhibitors (SSRIs) that are also antidepressants, cardiac glycosides block
Na+/K+ pump, omeprazole blocks proton pump in the gastric mucosa responsible for transport
of hydrochloric acid into the gastric lumen.

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28
 Diagram showing the types of drug targets

A. Receptors
Direct Ion channel opening

Agonist Enzyme activation/inhibiton

Transduction Ion channel modulation
mechanisms
DNA transcription

Antagonist No effect - endogenous mediator blocked

B. Ion channels

Blockers Permeation blocked

C. Enzymes
Normal reaction inhibited
Inhibitor

False substrate
Abnormal metabolite produced

Pro-drug
Active drug produced

D. Carriers

Normal transport

Inhibitor Transport blocked

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29
 Diagram showing the types of receptor-effector linkage

Direct control of Time scale

ion channel Miliseconds
R Cellular Example
Ions Hyperpolarisation effects Nicotinic
or depolarisation receptor

Change in
Ions Cellular
excitability
effects
G ⊕ or ∅
Time scale
R Seconds
G ⊕ or ∅ Calcium release Example
Muscarinic
E receptor
Indirect (G-protein) Second Protein
messengers phosphorylation
coupling via
second messangers (e.g., cAMP)
or ion channles Other

Time scale
Minutes
R/E
Protein Cellular Example
Direct control of phosphorylation effects Insulin
effector enzyme receptor

R Cellular Time scale

Nucleus Hours
effects
Example
Control of DNA R
mRNA Steroid
transcription receptor
synthesis
Protein
synthesis

LEGEND:

R receptor
G G-protein
E enzyme
R/E receptor-enzyme complex

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30
 PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system consists of three main anatomical divisions, sympathetic and
parasympathetic, and the enteric nervous system, that includes the intrinsic nerve plexuses of
the gastrointestinal tract, which is closely interconnected with the sympathetic and
parasympathetic systems. The autonomic nervous system is largely outside the influence of
voluntary control. The autonomic nervous system conveys all of the outputs from the central
nervous system to the rest of the body except for the motor innervation of skeletal muscle.
The enteric nervous system consists of neurons lying in the intramural plexuses of the
gastrointestinal tract (plexus myentericus and plexus submucosus). It receives inputs from
sympathetic and parasympathetic systems, but can to some extent act on its own to control
the motor and secretory functions of the intestine.

Sympathetic and parasympathetic systems are arranged in two-neuron pattern, consisting of

preganglionic neuron with cell body in CNS and postganglionic neuron with cell body in an
autonomic ganglion.

• Preganglionic neurons of the sympathetic nervous system are located in the lateral horns
of the spinal cord and extend their axons through the thoracic and lumbar spinal roots.
Sympathetic ganglia form two paravertebral chains, plus some midline prevertebral
ganglia. Axons of the postganglionic neurons start here and reach their target organs and
tissues in sympathetic nerves.

• The cell bodies of the preganglionic neurons of the parasympathetic division are located
in the nuclei of four cranial nerves – oculomotor (III), facial (VII), glossopharyngeal (IX)
and vagal (X) (cranial nerve outflow) and in the lateral grey horns of the second through
fourth sacral segments of the spinal cord (sacral outflow). The vagus nerve carries nearly
80% of the parasympathetic outflow. Parasympathetic preganglionic fibres make
synapses with postganglionic neurons in terminal (intramural) ganglia located very close
to or actually within the wall of a visceral organ.

Sympathetic and parasympathetic systems have opposing actions in some situations (e.g.,
control of heart rate, gastrointestinal smooth muscle), but not in others (e.g., salivary glands
are stimulated by both systems). Sympathetic activity increases in stress or so-called “E
situations” such as emergency, excitement, exercise and embarrassment (“fight-or-flight”
response) whereas parasympathetic activity predominates during satiation and repose (“rest
and digest”). The acronym “SLUD” can be used to remember the four main parasympathetic
responses: salivation (S), lacrimation (L), urination (U) and defecation (D).
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31
The principal transmitters in the autonomic system are acetylcholine (ACh) and
noradrenaline (NA). Preganglionic neurons in both systems are cholinergic, ganglionic
transmission occurs via nicotinic ACh receptors. Postganglionic parasympathetic neurons are
cholinergic, acting on muscarinic receptors in target organs. Postganglionic sympathetic
neurons are noradrenergic acting on adrenergic receptors.

Diagram showing transmitters in the peripheral nervous system

PERIPHERAL NERVOUS SYSTEM

ACh Skeletal Somatic efferent

(nic) muscle system
CENTRAL NERVOUS SYSTEM

ACh NA Target
(nic) (α/β) tissues
Sympathetic
system

ACh Adrenal
Adrenaline
(nic) medulla

ACh ACh Target Parasympatheti

(nic) (mus) tissues c

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32
 The most important effects of the autonomic nervous system

ORGAN SYMPATHETIC PARASYMPATHETIC

Heart Rate ↑, force ↑ (β1) Rate ↓, force ↓ (M2)
Arterioles (e.g., viscera
Constriction (α1) No effect
and skin)
Muscle arterioles and to
some extent those in the Dilation (β2) No effect
brain
Bronchial smooth Dilation by circulated
Constriction (M3)
muscle adrenaline (β2)
Bronchial glands No effect Secretion (M3)
GI tract and bladder
Motility decreased (α1, β1, β2) Motility increased (M3)
smooth muscle
Secretion (M3)
GI tract glands No effect
Gastric acid secretion (M1)

Uterus Relaxation (β2) No major effect

Eye pupil Dilation (α1) Constriction (M3)

Eye ciliary muscle Slight relaxation (β1) Contraction (M3)

Sweat glands Secretion (M3) No effect
Salivary glands Secretion (α1, β1) Secretion (M3)

Lacrimal glands No effect Secretion (M3)

CHOLINERGIC TRANSMISSION

ACh is synthesised from choline, which is taken in the neuron by carrier-mediated active
transport. Choline is first acetylated by the action of choline- acetyl transferase (CAT) and in
the presence of acetylCoA as a donor of acetyl groups. ACh is then accumulated and stored
inside synaptic vesicles through a carrier-mediated transport. ACh release from presynaptic
nerve terminals occurs by calcium-mediated exocytosis, triggered by an incoming
depolarisation wave. Released acetylcholine diffuses across the synaptic cleft to bind and
stimulate receptors on the postsynaptic cell.

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33
 CH3

HO – CH2 – CH2 – N – CH3 Choline

CH3

Acetyl CoA
Choline-acetyl
transferase

O CH3

CH3 – C – O – CH2 – CH2 – N – CH3 Acetylcholine

CH3

Acetylcholine receptors

Acetylcholine receptors (cholinoceptors) are divided into:

• Nicotinic receptors (they can be stimulated by nicotine), which are directly coupled to
cation channels and mediate fast excitatory synaptic transmission at the neuromuscular
junction, autonomic ganglia, in the adrenal medulla and at various sites in the CNS.
Binding of ACh to nicotinic receptors opens sodium channels, producing a rapid
depolarisation and thus activation of the target cell. There are two related types of
nicotinic receptors: neural located in autonomic ganglia and muscular located at
neuromuscular junctions.

• Muscarinic receptors (they can be stimulated by muscarine found in poisonous

mushroom Amanita muscaria), which are G-protein coupled receptors that mediate ACh
effects at all postganglionic parasympathetic synapses and also occur in many parts of the
CNS. Transmission mediated by muscarinic receptors is much slower in onset because it
works through G-proteins, and is probably responsible for modulation of cell function
rather then rapid cell activation. There are three main types of muscarinic receptors:

o M1 receptors stimulate gastric acid secretion, and can also be found in the brain
where they mediate higher cerebral functions such as thinking and memory
(reduction in number of cortical M1 receptors appears to play a role in dementias
such as Alzheimer disease)
o M2 receptors cause decrease in cardiac rate and force of contraction
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34
 o M3 receptors produce glandular secretion, contraction of visceral muscle and
vasodilation (via stimulation of nitric oxide release from vascular endothelium;
since blood vessels have no direct parasympathetic innervation physiological role
of this effect is uncertain)

ACh molecules remain bound to receptors for about 2 msec and are quickly hydrolysed
(broken down) by the enzyme acetylcholinesterase. In this way ACh action is terminated
until more is released from the nerve terminal. Inhibitors of this enzyme prolong the effect of
acetylcholine and have some value in management of Alzheimer’s disease (discussed later).

Drugs can influence cholinergic transmission by stimulating acetylcholine receptors

(cholinergic agonists) or by blocking acetylcholine receptors (cholinergic antagonists).
Because parasympathetic responses are mediated through muscarinic receptors clinically
useful cholinergic agonists and antagonists work only on muscarinic receptors and therefore
are more accurately called muscarinic agonists and antagonists.

Muscarinic agonists

Muscarinic agonists, as a group, are often referred to as parasympathomimetics because the

main effects that they produce resemble (mimic) those of parasympathetic stimulation.

Important compounds include betanechol [Urocarb] and pilocarpine [Pilocarpine, Isopto

Carpine]. Main effects of systemically given muscarinic agonists are: bradycardia and

vasodilation, leading to fall in blood pressure; contraction of visceral smooth muscle (gut,
bladder, bronchi); exocrine gland secretions (in the respiratory and gastrointestinal system),
ciliary muscle contraction and thus accommodation for near vision, constriction of the pupil.

Main use is in treatment of glaucoma (esp. pilocarpine) where topically applied muscarinic
agonists cause constriction of the pupil and thus stretching of the iris, which aids access of
the intraocular fluid to its drainage canal of Schlemm. This effect improves outflow of the
excessive fluid and decreases intraocular pressure. Systemic unwanted effects are almost non-
existent due to its local application. Betanechol can be used to stimulate contractions of the
bladder and intestines when there is inadequate nerve stimulation (e.g., after abdominal
surgery, after spinal injury or in multiple sclerosis). Because this drug is given systemically
unwanted effects (all other main effects except visceral smooth muscle contraction) are
common and may be troublesome. It is important to assess whether beneficial effects actually
outweigh unwanted effects as unwanted effects can not be avoided.

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35
 Muscarinic antagonists

Muscarinic antagonists are often referred to as parasympatholytics because they selectively

reduce or abolish the effects of parasympathetic stimulation. All of them are competitive
antagonists of acetylcholine at muscarinic receptors. All clinically useful muscarinic
antagonists show little or no selectivity for the different subtypes of muscarinic receptors,
which is responsible for many unwanted effects.

Most important compounds are atropine [Atropine Sulphate, Atropt], hyoscine [Buscopan,
Kwells, Setacol], propantheline [Pro-Banthine], mebeverine [Colese, Colofac], belladonna

extract (hyoscine, hyosciamine and atropine [Donnalix, Donnatab]), oxybutynin [Ditropan],

ipratropium [Atrovent, Apoven, Ipratrin] and tiotropium [Spiriva].

Main effects are: inhibition of gland secretions causing dry mouth (no salivation),
tachycardia, pupillary dilation and paralysis of accommodation causing sensitivity to light
and blurred vision respectively, relaxation of smooth muscle causing constipation and urinary
retention, inhibition of gastric acid secretion, CNS effects such as confusion, memory
impairment, and in large doses delusions and hallucinations. Other important effects are
suppression of nausea and vomiting (anti-emetic effect) and anti-parkinsonian effect
(discussed in section about Parkinson’s disease). Depending on treatment objective many of
these effects will be unwanted, but can not be avoided.

Clinical uses of muscarinic antagonists:

• Cardiovascular: treatment of sinus bradycardia (e.g., sometimes occurring after
myocardial infarction due to reflex activation of the parasympathetic system)
• Ophthalmic: in form of eye drops to dilate the pupil during eye examination (mydriasis)
to obtain better access to the retina
• Neurological: prevention of motion sickness and treatment of other forms of
nausea/vomiting, treatment of parkinsonism (especially to counteract Parkinson-like
movement disorders caused by antipsychotic drugs)
• Respiratory: asthma and COPD (ipratropium and tiotropium by inhalation), in
anaesthetic premedication to decrease bronchial secretion (general anaesthetics frequently
increase production of mucus in the lungs; during anaesthesia cough reflexes are
suppressed allowing mucus to accumulate)
• Gastrointestinal: to relax gastrointestinal and biliary smooth muscle (antispasmodic
action)

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36
 Diagram showing drugs acting on cholinergic transmission

Depolarisation
Choline

CAT
Choline
+
ACh Acetate
Voltage-gated
calcium channel

Ca2+
Ca2+ ⊕ AChE

∅
3

ACh 1
Na+ 2
⊕ ∅

NR MR G

⊕
Na+

Cell depolarisation Cellular effects

LEGEND:

ACh acetylcholine Drugs acting on cholinergic

CAT choline-acetyl transferase transmission:
AChE acetylcholine esterase 1. Muscarinic agonists
NR nicotinic receptor 2. Muscarinic antagonists
MR muscarinic receptor 3. Acetylcholinesterase inhibitors
G G-protein

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37
 NORADRENERGIC TRANSMISSION

Adrenergic receptors

The main pharmacological classification of adrenergic receptors (adrenoceptors) is into α and

β subtypes. There are two main α adrenoceptor subtypes (α1 and α2) and two β adrenoceptor

subtypes (β1 and β2). They all are G-protein coupled receptors, which produce effects through

second messengers. β receptors stimulate activity of enzyme adenylate cyclase and synthesis
of cAMP (cyclic adenosine monophosphate) from ATP, α1 receptors stimulate enzyme

phospholipase C and synthesis of InsP3 (inositol triphosphate), while α2 receptors inhibit

synthesis of cAMP.

The most important effects of receptor activation important in pharmacology are:

• α1 receptors; vasoconstriction

• α2 receptors; presynaptic inhibition of noradrenaline release (reduced synaptic

transmission)
• β1 receptors; increased cardiac rate and contractility

• β2 receptors; bronchodilation, muscle tremor, glycogenolysis and gluconeogenesis in the

liver

The main transmitter is noradrenaline, but in the adrenal medulla it is further converted to
adrenaline and released into the circulation. Because bronchial smooth muscle has no direct
sympathetic inervation, only circulating adrenaline can act on β2 receptors in the bronchial
smooth muscle to mediate bronchodilation. Noradrenaline and adrenaline differ to some
extent in their specificity for different adrenoceptors; roughly adrenaline is more effective on
β and noradrenaline on α.

The process of synthesis of noradrenaline and adrenaline goes through several steps:

1. Amino acid L-tyrosine is converted to dopa (dihydroxyphenylalanine) by tyrosine

hydroxylase
2. Dopa is converted to dopamine by dopa decarboxylase
3. Dopamine is converted to noradrenaline by dopamine β-hydroxylase, located in synaptic
vesicles
4. In the adrenal medulla, noradrenaline is converted to adrenaline by phenylethanolamine
N-methyl transferase

_________________________________________________________________________________
38
Noradrenaline is stored at high concentration in synaptic vesicles and released by calcium-
mediated exocytosis, triggered by a depolarisation wave spreading along the axon.
Transmitter action is terminated mainly by reuptake of noradrenaline into nerve terminals by
a specific amine pump (there is no significant metabolic degradation of noradrenaline in the
synaptic clefts) which is a relatively slow process. Tricyclic antidepressant drugs (discussed
later) block this uptake resulting in accumulation of noradrenaline in the synaptic cleft and its
prolonged and greater effect. Noradrenaline release is controlled by auto inhibitory feedback
mediated by α2 receptors. Drugs that stimulate these receptors (α2 adrenoceptor agonists) can
be useful in hypertension by decreasing noradrenaline release and thus noradrenaline
mediated vasoconstriction.

After entry into the nerve terminal noradrenaline is restored in the synaptic vesicles. When
the storage area is full any excess of noradrenaline is degraded by mitochondrial enzyme
monoamine oxidase (MAO). MAO is abundant in noradrenergic nerve terminals where it also
controls the amount of available noradrenaline by partially breaking down newly produced
noradrenaline, and consequently the releasable stores of noradrenaline are increased if the
enzyme is inhibited. Inhibitors of MAO have some value in the treatment of depression
(discussed later). Noradrenaline that has not been taken back into the nerve terminal is taken
by surrounding tissues and metabolised by enzyme catechol-O-methyl transferase (COMT).
The same enzyme also operates in the liver, where it is responsible for inactivation of
exogenous noradrenaline-related drugs (catecholamines).

Drugs that affect noradrenergic transmission can employ various strategies:

• acting directly on adrenoceptors, as agonists or antagonists
• modifying the synthesis, storage and release of noradrenaline
• interaction with neuronal uptake of released noradrenaline
• blocking enzymes which render noradrenaline inactive

Adrenoceptor agonists

Adrenoceptor agonists are usually referred to as sympathomimetics because their action

mimics the effect of sympathetic activation. Selective drugs exist for the four main
adrenoceptor subtypes α1, α2, β1 and β2.

1. Selective α1 agonists such as phenylephrine [eye drops Prefrin, nasal spray Nyal and in

oral combinations with other drugs (e.g., paracetamol and antihistamines) known as
Benatuss, Dimetapp, Demazin, Drixine, Prednefrin], oxymetazoline [Sinex, Dimetapp
_________________________________________________________________________________
39
 Nasal, Drixine Nasal] and xylometazoline [Otrivin] cause vasoconstriction and are used

for nasal decongestion. Naphazoline [Albalon, Murine Clear Eyes, Naphcon] is applied
topically for relief of allergic conjunctivitis, often combined with an antihistamine.
Common adverse effects of orally given preparations include hypertension, vision
problems (sensitivity to light), constipation and urinary retention.

2. Selective α2 agonists (clonidine [Catapres]) cause presynaptic inhibition of noradrenaline

release and may be useful in lowering elevated blood pressure.

3. Selective β1 agonists (isoprenaline [Isoprenaline, Isuprel], dobutamine [Dobutamine,

Dobutrex]) stimulate the heart and increase heart rate and cardiac contractility; they may

be given to treat cardiac arrest and bradycardia with serious haemodynamic impairment
(very low cardiac output). Common adverse effects include hypertension, tachycardia and
constipation.

4. Selective β2 agonists (salbutamol [Ventolin, Respolin], salmeterol [Serevent], terbutaline

[Bricanyl], eformoterol [Foradile, Oxis]) cause relaxation of bronchial smooth muscle

and are used in treatment of bronchial asthma. Common adverse effects are fine muscle
tremor (especially evident on the hands) and sometimes warm feeling caused by
vasodilation and increased blood flow through skeletal muscles. Although these drugs are
largely β2 selective, some residual β1 stimulation may produce tachycardia, especially in
larger doses.

Adrenoceptor antagonists

Adrenoceptor antagonists are commonly called sympatholytics. Most antagonists are α or

β adrenoceptor selective.

1. Selective α1 antagonists include prazosin [Minipress, Pressin] and terazosin [Hytrin]

which are used in treatment of hypertension because they reduce arteriolar and venous
tone (peripheral vascular resistance), leading to vasodilation. Tamsulosin [Flomax] has a
specific affinity to α1A-receptor subtype predominantly present in the human prostate that
maintains the tone of the prostatic smooth muscle. It is used to improve urine flow in
patients with benign prostatic hypertrophy (BPH). Systemic hypotension does not seem
to occur often.

2. β adrenoceptor antagonists also known as β blockers may be non-selective between β1

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40
 and β2 receptors (e.g., propranolol [Inderal, Deralin], pindolol [Visken], oxprenolol

[Corbeton], sotalol [Cardol, Solavert, Sotacor] and timolol [Timoptol]) and β1 selective

(atenolol [Tenormin, Tensig, Noten, Anselol, Atehexal], metoprolol [Betaloc,

Lopressor, Metohexal, Metrol, Minax], bisoprolol [Bicor] and esmolol [Breviblock]).

Because in most conditions that require treatment with β blockers inhibition of β2

receptors is undesirable, selective β1 antagonists are a better choice. All β adrenoceptor

antagonists decrease cardiac contractility and reduce oxygen demand of the myocardium,
which makes them useful in treatment/prevention of angina pectoris. They reduce blood
pressure by decreasing cardiac output and also by decreasing renin secretion in the
kidney (indirect vasodilation), and therefore can be used to treat hypertension (discussed
later). Sometimes they are used to treat anxiety because they can suppress muscle tremor
(only non-selective) and tachycardia which are commonly found in anxiety (affective
component is not altered though). Important unwanted effects are bradycardia and
worsening of present cardiac failure, cold extremities (due to reduction in cardiac output
and reflex peripheral vasoconstriction), dizziness, lethargy, increased gastrointestinal
motility and diarrhoea, insomnia, bad dreams and depression (through the block of
noradrenergic receptors in the CNS). Non-selective β blockers can also cause
bronchoconstriction in people with hyper-responsive airways (asthma is an absolute
contraindication), and hypoglycaemia due to decreased glycogen breakdown and
decreased gluconeogenesis in the liver.

Betaxolol [Betoptic, Betoquin] is a topic (eye drops) selective β1 antagonist that can

reduce production of intraocular fluid. It is used for lowering of intraocular pressure in

the treatment of ocular hypertension or chronic open angle glaucoma, alone or in
combination with other intraocular pressure lowering medication. Timolol [Timoptol]
and levobunolol [Betagan] are similar products but pharmacologically are non-selective
β antagonists.

3. α,β antagonists (labetalol [Trandate, Presolol] and carvedilol [Dilatrend, Kredex])

block both α1 and β1,2 receptors and are effective in lowering elevated blood pressure.
Their advantage over selective α1 antagonists is that due to blocking of β1 receptors in the
heart a drop in blood pressure is not followed by compensatory tachycardia.

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41
 Drugs acting on noradrenergic nerve terminals

This group comprises many drugs affecting the noradrenergic transmission at different levels.

• Methyldopa [Aldomet, Hydopa] affects the synthesis of noradrenaline giving rise to a

false transmitter (methylnoradrenaline) that accumulates in vesicles instead of
noradrenaline but has much weaker vasoconstricting action. Methyldopa may be used as
an antihypertensive agent, especially in pregnancy because it is safer than other
antihypertensives which may also have some effect on the baby.

• Indirectly acting sympathomimetics such as dexamphetamine [Dexamphetamine],

ephedrine [Ephedrine injection and nasal drops] and pseudoephedrine [in combination
with other drugs known as Actifed, Benadryl, Codral, Headclear, Sudafed, Lemsip
etc.] displace noradrenaline from vesicles, allowing it to escape from the nerve ending
and stimulate adrenoceptors on the postsynaptic cell. Ephedrine and pseudoephedrine are
commonly used to produce vasoconstriction in the nasal mucosa and consequently nasal
decongestion (‘cold and flu’ remedies and nasal drops/sprays). Oral preparations may
also have mild systemic effects in form of nervousness, difficulty sleeping, tremor,
increased heart rate (palpitations), cardiac contractility and blood pressure, headache and
constipation, and therefore should be taken with caution by patients with hypertension or
coronary heart disease. Dexamphetamine and related drug methylphenidate [Attenta,
Concerta] are used for treatment of hyperactivity in children (attention-deficit disorder),

but it is unclear how they produce their positive effects. Methamphetamine (‘speed’) and
tenamphetamine (‘ecstasy’ or MDMA) are amphetamine derivatives widely abused today
as ‘recreational’ drugs. They increase energy level, induce euphoria and alertness, reduce
fatigue, stimulate conversation and a sense of intimacy with others, which make them
popular for dance parties. These stimulant effects last for a few hours, and are followed
by depression and anxiety.

• Drugs that inhibit uptake of noradrenaline (and dopamine/serotonine) and thus enhance
its effects include cocaine (illegal recreational drug) and tricyclic antidepressant drugs
(discussed later). The effect of cocaine closely resembles that of amphetamine causing
euphoria, garrulousness, increased motor activity and a magnification of pleasure,
followed by depression and dysphoria. The duration of action of cocaine is much shorter
than that of amphetamine (30 minutes) and repeated administration is necessary for
maintenance of the effects.

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42
• Inhibitors of enzyme MAO that normally inactivates noradrenaline in noradrenergic nerve
terminals are used in depression (discussed later).

Diagram showing synthesis of dopamine, noradrenaline and

adrenaline

H H
C C NH2
Tyrosine
H COOH
HO

Tyrosine hydroxylase

H H
HO C C NH2 Dopa
H COOH
HO

Dopa decarboxylase

H H
HO C C NH2 Dopamine
H H
HO

Dopamine β-hydroxylase

H H
HO C C NH2
Noradrenaline
OH H
HO

Phenylethanolamine N-
methyl transferase

H H
HO C C NH Adrenaline
OH H CH3
HO

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43
 Diagram showing drugs acting on noradrenergic transmission

Depolarisation Tyrosine
8
Ca2+ NA synthesis ⊕
9 ∅
NA
Voltage-gated Metabolites
NA
calcium channel ⊕ Ca2+ 7
∅
cAMP MAO
ATP
⊕
AC
∅ 6
U ∅
α2
5 ⊕

2 NA 4
1 3
∅ ⊕ ⊕ ∅

G α1 β1,2 G

⊕ ⊕
Second messengers

NA

COMT
Cellular effects
Metabolites

LEGEND:

NA noradrenaline Drugs acting on noradrenergic

MAO monoamine oxidase transmission:
G G-protein 1. α1 antagonists (blockers)
U NA uptake mechanism 2. α1 agonists (stimulants)
AC Adenylate cyclase 3. β antagonists (blockers)
4. β agonists (stimulants)
5. α2 agonists (stimulants)
6. NA uptake inhibitors
7. MAO inhibitors
8. Indirectly acting sympathomimetics
9. Methyldopa

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44
 PHARMACOLOGY OF THE HEART

The mechanism of contraction is similar in cardiac and skeletal muscle: the electrical activity
(action potential) leads to mechanical response (contraction). The force with which a
myocardial cell contracts (contractility) when depolarised is directly proportional to the level
of free intracellular calcium, which is delivered from the extracellular fluid across the cell
membrane, via voltage-gated calcium channels in response to action potential, and from the
intracellular storage in sarcoplasmatic reticulum, again by the action potential.

Free intracellular calcium activates the contractile actin-myosin machinery, producing muscle
cell contraction. Calcium is eventually removed from the cytoplasm partly back into the
sarcoplasmatic reticulum (active process) and partly outside the cell via the exchange
counter-transport (antiport) in the cell membrane which expels calcium ions and brings in
sodium ions. The latter is a passive process driven by the sodium concentration gradient
+ +
which in turn is maintained by the action of energy dependant Na / K pump that removes
sodium from the cell. Because of this type of linkage the exchange process for calcium and
sodium is known as secondary active transport (sodium pump is primary active transport).

Cardiac work is also affected by extrinsic factors like after-load (the force that opposes
ejection of blood, roughly equivalent to systemic blood pressure, which is largely determined
by peripheral vascular resistance) and pre-load (the amount of blood returning into the heart
from the periphery measured as central venous pressure). In pathologic conditions cardiac
output (stroke volume multiplied by heart rate) may become insufficient to meet the
circulatory needs of the body (at rest or during exercise), and this is called heart failure. It
may be due to acute heart disease (myocardial infarction) or chronic heart disease
(cardiomyopathy, ischaemic heart disease, hypertensive heart disease) and may affect left
side, right side or both sides of the heart. The most common pathologic process affecting the
heart is atherosclerosis of arterial blood vessels that supply the heart (coronary arteries).
Atherosclerotic narrowing of the arteries leads to ischaemia (inadequate supply of blood to an
organ or tissue) clinically presenting as recurrent episodes of anginal pain or in more severe
forms myocardial infarction.

Drugs that have a major action on the heart can be divided into the following groups:
• Drugs that directly affect myocardial cells (drugs that interfere with autonomic
transmission and cardiac glycosides)
• Drugs that affect cardiac function indirectly, through actions elsewhere in the vascular
system (anti-anginal drugs organic nitrates, ACE inhibitors and angiotensin II antagonists

_________________________________________________________________________________
45
 used in treatment of heart failure)
• Calcium antagonists, which act both on the myocardium and on vascular smooth muscle

DRUGS ACTING IN THE AUTONOMIC NERVOUS SYSTEM

Sympathetic nervous system, acting through β1 adrenoceptors, increases heart rate (positive
chronotropic effect) and contractility (positive inotropic effect), but at the expense of
increased oxygen consumption. β1 adrenoceptors act by increasing cAMP formation, which
increases intracellular calcium level by opening calcium channels allowing more calcium ions
to enter the cell. As explained earlier β1 adrenoceptor agonists can be used to treat cardiac
arrest and bradycardia with serious haemodynamic impairment (cardiogenic shock).
However, they are not indicated in heart failure because cardiac muscle cells are too weak
(e.g., cardiomyopathy) or can not obtain enough oxygen for energy production (ischaemic
heart disease). On the other hand β1 adrenoceptor antagonists decrease cardiac rate and
contractility, decease cardiac output, reduce oxygen demand of the myocardium which make
them beneficial in angina pectoris and hypertension (discussed later). Due to their effect on
heart contraction they can worsen existing heart failure.

Parasympathetic nervous system, acting through M2 muscarinic receptors, causes cardiac

slowing (negative chronotropic effect) and decreased force of contraction (negative inotropic
effect). M2 muscarinic receptors, when stimulated, inhibit cAMP formation (opposite to β1
+
adrenoceptors), and also appear to open K channels leading to cell hyperpolarisation.
Muscarinic antagonists may be given to accelerate heart rate in serious sinus bradycardia that
can sometimes occur after myocardial infarction due to reflex activation of the
parasympathetic system.

CARDIAC GLYCOSIDES

Cardiac glycosides come from leaves of plants of the foxglove family (Digitalis Sp.), and
have been in use for many centuries as ‘cardiac tonics’. Their effectiveness in cardiac failure
+ + +
was first described in 1775! They act by inhibiting Na /K pump, binding the K site, thus
causing some accumulation of intracellular sodium. The block is ‘use-dependant’ and it
affects only sodium pumps in very active tissues such as the heart but not in others. This
effect leads to reduction of exchange of intracellular calcium for extracellular sodium, and as
a result more calcium is available to activate the myocardial actin-myosin contractile
_________________________________________________________________________________
46
apparatus. Therefore the main effect is increased force of contraction (positive inotropic
effect), boosting cardiac output. Additional effects are:
• decrease of sinoatrial node activity and conduction through the atrioventricular node by
enhancing parasympathetic effects (increased vagal discharge and sensitivity of the SA
and AV node to it); this leads to slowing down of the heart (negative chronotropic effect)
and increased diastolic filling time; this effect may also be useful in heart failure
associated with significant reflex tachycardia
• increase of ectopic pacemaker activity due to hypopolarisation of cardiac muscle cells
(arrhythmias are more likely to occur, especially in overdose); this is an important
unwanted effect

The most commonly used glycoside is digoxin [Lanoxin, Sigmaxin] and it may be given for:
• slowing ventricular rate in tachycardia
• treatment of heart failure in patients who remain symptomatic despite optimal use of
diuretics and angiotensin-converting enzyme inhibitors or angiotensin II antagonists,
which are the first line of treatment; here cardiac glycosides increase cardiac output and
reduce heart rate that has been excessively increased as a result of compensatory
activation of the sympathetic nervous system

Effects of cardiac glycosides are increased by hypokalaemia (low potassium levels) due to the
+ + +
less competition between K ions and glycosides for binding sites on Na /K ATPase. This
could lead to toxicity and is important if diuretics are also taken (this is common in heart
failure) because they tend to cause hypokalaemia (discussed later). Adverse effects include
nausea, vomiting (stimulation of chemoreceptor trigger zone in the brain), diarrhoea, cardiac
arrhythmias, and confusion, and they are especially apparent in overdose. Because of narrow
margin of safety and risk of toxicity, measurement of plasma digoxin concentration is
sometimes very useful in determining the optimal dose.

ANTI-ANGINAL DRUGS

Angina (Greek for choking) pectoris is the name for a clinical syndrome rather than a disease.
The term is used to describe a discomfort due to transient and moderate myocardial
ischaemia. It occurs when the coronary flow is insufficient to meet the heart’s demands for
oxygen, and it can be precipitated by any situation that causes an increase in cardiac output,
which is normally accomplished by increased cardiac contractility and rate: physical exertion

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47
(e.g., fast walking, climbing stairs), cold exposure, heavy meals, intense emotions.

Myocardial Myocardial
O2 supply O2 demand

In a normal heart the balance is maintained

Myocardial
O2 supply

Myocardial
O2 demand

In angina the demand for oxygen outweighs the supply

The discomfort of angina is not usually perceived as pain but as a sense of heaviness,
tightness or troublesome ache in the middle of the chest (‘like a band around the chest’),
usually induced by exertion and relieved by rest. This chest discomfort is often accompanied
by discomfort or numbness in the arms, more commonly left, even to the fingers. There may
be accompanied breathlessness and palpitation.

Anginal discomfort can be alleviated and the frequency of anginal attacks can be reduced by
use of organic nitrates, β adrenoceptor antagonists and calcium antagonists. The principal
effect of these drugs is a reduction in cardiac demands for oxygen. Significant increase in
blood (oxygen) supply can only be achieved through invasive surgical means such as balloon
angioplasty and bypass procedures.

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48
 Organic nitrates

Organic nitrates are powerful vasodilators, acting mainly on capacitance vessels (veins) to
reduce the return of blood to the heart (‘pre-load’), thereby reducing cardiac work. They
work by releasing in smooth muscle cells nitric oxide (NO), which then stimulates cGMP
(cyclic guanosine monophosphate) formation that in turn causes muscle relaxation and
vasodilation (discussed later). Organic nitrates may also produce some vasodilation of
coronary arteries which may improve ischaemia caused by spasm of coronary arteries (as
seen in so-called variant angina) but usually not in ischaemia associated with coronary
atherosclerosis.

The prototype of organic nitrates is nitroglycerin, also known as glyceryl trinitrate [Anginine,
Lycinate, Nitrostat] – tablets and [Nitrolingual Pumpspray] – sublingual spray.

Nitroglycerin is the most effective if taken sublingually (tablet or spray) shortly before
exertion or immediately when the pain is felt, when the improvement occurs in few minutes.
It may also be applied transdermally in form of patches that slowly release the active
ingredient over several hours [Nitro-Dur, Transiderm-Nitro, Minitran]. Isosorbide
mononitrate [Duride, Isomonit, Imtrate, Imdur, Monodur] and isorbide dinitrate [Isordil,
Sorbidin ] are longer-acting compounds given regularly by mouth in form of slow release

capsules to prevent attacks of angina. Because of the ability of all organic nitrates to relax
smooth muscle in general they can be beneficial in symptomatic relief of menstrual cramping
pain (dysmenorrhoea). There are no serious unwanted effects, although throbbing headache,
dizziness, light-headedness, facial flushing, postural hypotension (due to arteriolar dilation, if
larger doses are taken) and tachycardia may occur initially. These unwanted effects tend to
subside in time,

β adrenoceptor antagonists (β blockers)

By blocking β1 receptors in the heart these drugs reduce the heart rate and contractility and

thus cardiac output which leads to reduction of oxygen consumption of the heart. They are
used mostly for long-term prophylaxis of anginal pain. However, because β blocking drugs
decrease cardiac output and to some extent blood pressure, they may cause certain unwanted
effects such as bradycardia, dizziness, headache, lethargy, fatigue, poor effort tolerance, vivid
dreams, nightmares and depression due to blockage of β receptors in the CNS.

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49
 Calcium antagonists

Calcium antagonists (calcium channel blockers) act by preventing opening of voltage-gated

calcium channels during cell depolarisation. The main effect is on the heart and smooth
muscle, where inhibition of calcium entry is responsible for reduced contractility. Calcium
antagonists appear to be selective to a subtype of calcium channels found only in the heart
and smooth muscle as they don’t affect other calcium channels such as ones involved in
neurotransmitter release. Skeletal muscle cells are not affected because they don’t have
voltage gated calcium channels.

The main examples are: verapamil [Isoptin, Cordilox, Anpec], diltiazem [Cardizem, Dilzem,
Coras, Diltahexal, Vasocardol], nifedipine [Adalat, Nifehexal, Adefin, Addos, Nyefax],

nimodipine [Nimotop], felodipine [Plendil, Felodur], amlodipine [Norvasc, Amlo, Pervasc]

and lercanidipine [Zanidip]

Due to structural differences calcium antagonists have different selectivity between heart and
smooth muscle. For example verapamil is relatively cardioselective, diltiazem is intermediate
and nifedipine, felodipine, nimodipine and amlodipine are relatively smooth muscle selective.
A choice is made depending on whether effects on the heart or peripheral blood vessels are
needed. Effects on the heart are reduced contractility and thus reduced oxygen consumption,
and delayed atrio-ventricular conduction with slowing of the ventricles. Because of this they
may be useful in angina and atrial (also known as supraventricular) tachycardia with rapid
heart rate. Vasodilator effect is mainly on resistance vessels (arterioles), causing reduction in
after-load and fall in blood pressure, which is the rationale for their use in hypertension.
Calcium antagonists can relax other types of smooth muscle (biliary tract, urinary tract and
uterus) which may be useful in treating conditions such as biliary pain, urinary colic or
menstrual pain.

Unwanted effects are related to their action on the smooth muscle and heart and include
headache, flushing, constipation, difficulty in urination and ankle oedema (peripheral
vasodilation and leakage of fluid from blood vessels). There is a risk of causing cardiac
failure especially with verapamil and diltiazem in overdose. A caution is needed if calcium
antagonists are combined with β blockers as their additive effects may also precipitate cardiac
failure.

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50
 Diagram showing the main modes of action of drugs that
affect heart function

Ca2+ Ca2+ Na+ K+

Depolarisation 3 4
wave 2
⊕ ∅ ⊕ ∅ 1
∅
R E P
AC
⊕ G ATP
⊕
cAMP ATP
Na+ K+
2+
Ca
SR
Ca2+ excess

ATP required
Contraction Arrhythmia
Cell death
CARDIAC MUSCLE CELL

LEGEND:

AC adenylate cyclase enzyme

G G-protein
ATP adenosine triphosphate
cAMP cyclic adenosine monophosphate
R β1-adrenoceptor
P Na+/K+ pump (active transport)
E Na+/ Ca2+ counter transport
SR sarcoplasmatic reticulum
Drugs that affect heart function:
1. Cardiac glycosides
2. Calcium channel blockers
3. β1 adrenoceptor agonists
4. β1 adrenoceptor antagonists

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51
 PHARMACOLOGY OF THE VASCULAR SYSTEM

The walls of arteries and veins contain smooth muscle whose activity is controlled by the
sympathetic nervous system. α1 receptors mediate vasoconstriction in most arterioles and

veins, while β2 receptors cause vasodilation of arterioles in the brain and skeletal muscle. The
parasympathetic system has no regulatory function on blood vessels, except those supplying
erectile tissue (vasodilation).

Muscular arteries and arterioles are the main resistance vessels in the circulation, while veins
are capacitance vessels. In terms of cardiac function, therefore, arteries and arterioles
regulate the after-load (peripheral vascular resistance), while veins regulate the pre-load of
the ventricles (filling pressure).

Smooth muscle cell contraction is somewhat similar to heart muscle cell contraction and is
2+
initiated through the following sequence: rise in intracellular Ca Æ activation of calmodulin
Æ activation of enzyme myosin-kinase Æ phosphorylation of myosin Æ myosin-actin
interaction Æ contraction.

VASOCONSTRICTOR DRUGS

The most important vasoconstricting drugs are sympathomimetic amines, direct and indirect
(adrenaline, dopamine, ephedrine, pseudoephedrine, phenylephrine, oxymetazoline,
xylometazoline) which produce vasoconstriction by directly stimulating α1 adrenoceptors or

via released noradrenaline that acts on α1 receptors. The end result is release of intracellular
calcium from the endoplasmatic reticulum, secondary to receptor mediated inositol
triphosphate (InsP3) formation, as well as calcium entry through the cell membrane via

receptor-operated calcium channels. When given systemically α1 adrenoceptor agonists

constrict arteries, arterioles and veins, increasing peripheral resistance and systemic blood
pressure, reducing venous capacity and raising the central venous pressure.

Ergot alkaloids such as ergotamine derived from a fungus which contaminates rye grain have
similar effects acting as moderate agonists on α1 adrenoceptors. Ergotamine is available in

combination with caffeine which enhances its absorption from GIT [Cafergot].

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52
Dihydroergotamine [Dihydergot] is available as tables and injections.

Clinical uses of sympathomimetic amine vasoconstricting drugs are limited mainly to local
applications (e.g., nasal decongestion, co-administration with injectable local anaesthetics to
delay their removal from the administration site and thus prolong the duration of anaesthesia).
Ergotamine preparations are used to relieve pain (and nausea if combined with
antihistamines) in a migraine attack. While pathogenesis of migraine is still unclear,
ergotamine that causes vasoconstriction is beneficial in migraine episode (so-called
“abortive” effect) suggesting that intracranial vasodilation may play a role in this condition.
However, it shouldn’t be given to patients with hypertension, angina, history of heart attack
and peripheral vascular disease because some systemic vasoconstriction and increase in blood
pressure can not be avoided. Other abortive anti-migraine agents used for acute treatment are
serotonin 5-HT1B/1D agonists sumatriptan [Imigran, Suvalan], naratriptan [Naramig] and
zolmitriptan [Zomig]. It is believed that by stimulating serotonin receptors these drugs also
produce vasoconstriction of cerebral arteries, but they also have a number of other potential
modulatory effects on pain transmission in the brain.

VASODILATOR DRUGS

Vasodilators are a heterogenous group of drugs, and may be divided for convenience into
those that act directly on vascular smooth muscle and those that act indirectly by inhibiting
the action of a naturally occurring constrictor (noradrenaline or angiotensin II).

Directly acting vasodilators

• Calcium antagonists (nifedipine [Adalat, Nifehexal, Addos, Nyefax], nimodipine

[Nimotop], felodipine [Plendil, Felodur], amlodipine [Norvasc] and lercanidipine
[Zanidip]) act by blocking calcium entry through voltage-gated calcium channels in
response to depolarisation; they dilate both resistance and capacitance vessels.

• Organic nitrates (e.g., glyceryl trinitrate, isosorbide mono and dinitrates, also
nitroprusside [Sodium nitroprusside]), release nitric oxide and cause increased cGMP
formation, which opposes sympathetic nervous system-mediated muscle cell contraction
and thus lead to vasodilation.
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53
 Indirectly acting vasodilators

• Drugs that interfere with sympathetic transmission are α1 adrenoceptor antagonists such
as prazosin and terazosin (discussed earlier).

• Angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril [Alphapril, Auspril,

Enahexal, Enalabell, Renitec, Amprace], lisinopril [Prinivil, Fibsol, Zestril, Liprace,

Lisinobell], fosinopril [Monopril, Fosipril, Monace], quinapril [Acquin, Asig, Filpril,

Accupril], ramipril [Prilace, Tryazan, Tritace, Ramace], perindopril [Perindo, Coversyl],

trandolapril [Gopten, Odrik, Dolapril]) prevent conversion of angiotensin I to angiotensin

II that occurs mostly in the lung capillaries. A common unwanted effect of ACE
inhibitors is dry cough that may be caused by build up of bradykinin (ACE also
metabolises bradykinin). Due to decreased aldosterone secretion a small increase in
serum potassium is possible.

• Angiotensin II antagonists (also known as angiotensin receptor blockers) such as losartan

[Olmetec, Cozaar], irbesartan [Avapro, Karvea], candesartan [Atacand], eprosartan
[Teveten] and telmisartan [Micardis]) prevent angiotensin II from binding its target
receptors, and are the latest addition to this group of drugs. They do not cause cough,
probably because they do not prevent bradykinin degradation.

Main uses of vasodilator drugs

1. antihypertensive therapy (e.g., calcium antagonists, α1 antagonists, ACE inhibitors,

angiotensin II antagonists)

2. treatment of angina (e.g., organic nitrates, calcium antagonists) to reduce pre-load (filling
pressure) and to some extent after-load (vascular resistance), and thus cardiac work;
calcium antagonists also directly suppress cardiac contractility

3. treatment of cardiac failure (e.g., ACE inhibitors, angiotensin II antagonists) where

reduction in vascular resistance is supplemented by decreased secretion of aldosterone
and reduced sodium retention; ACE inhibitors and angiotensin II antagonists can block
inappropriate activation of the renin-angiotensin-aldosterone system in heart failure and
significantly improve survival

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54
 Diagram showing the main modes of action of vasodilator drugs

ENDOTHELIUM

Endothelin α1 agonists NO
Angiotensin II β2 agonists
Ca2+
1 2
∅ ∅
R AC
⊕
InsP3 ATP cAMP
NO
⊕ 3
⊕
SR ↑Ca2+ PKA
GC

Calmodulin Ca-calmodulin ∅ GTP cGMP

⊕ ⊕
MLCK
∅ PKG
Myosin Myosin-phosphate
+ ⊕
Actin Contraction
SMOOTH MUSCLE CELL

LEGEND:

AC adenylate cyclase enzyme

GC guanylate cyclase enzyme Drugs used for vasodilation:
cAMP cyclic adenosine monophosphate 1. α1 antagonists,
cGMP cyclic guanosine monophosphate angiotensin II antagonists
ATP adenosine triphosphate 2. Ca2+ channel blockers
GTP guanosine triphosphate 3. Organic nitrates
PKA cAMP dependant protein kinase
PKG cGMP dependant protein kinase
NO nitric oxide
MLCK myosin light chain kinase
InsP3 inositol triphosphate
SR sarcoplasmatic reticulum
R various (separate) receptors for:
- endothelin
- angiotensin II
- noradrenaline (α1)

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55
 TREATMENT OF HYPERTENSION

Hypertension is a common and usually progressive disorder, which, if not effectively treated,
results in a greatly increased probability of coronary heart disease, stroke and renal failure.
Until about 1950, there was no effective treatment, and the development of antihypertensive
drugs, which greatly increase life expectancy, has been a major therapeutic success story.

Hypertension is defined as an elevation of systolic and/or diastolic blood pressure above

generally accepted normal level of up to 140/90 mm Hg for adults. Suggested guidelines for
diagnosis of elevated blood pressure in adults are as follows:

• Stage 1 hypertension (mild) systolic 140-160 or diastolic 90-100

• Stage 2 hypertension (moderate) systolic 160-180 or diastolic 100-110
• Stage 3 hypertension (severe) systolic > 180 or diastolic > 110

Exercise, anxiety, discomfort and unfamiliar surroundings can all lead to a transient rise in
blood pressure, and measurements should be repeated when the patient is resting and relaxed.
For example office or white coat hypertension refers to blood pressure that is consistently
elevated in the physician’s surgery but normal when measured at home. Patients who have a
high blood pressure on first examination which subsequently settles with rest may not require
treatment but should be kept under review because they are more likely to develop sustained
hypertension. According to the guidelines, around 20% of adult population can be regarded
as hypertensive, though only a proportion of these will be diagnosed or receive treatment.

In about 5-10% of cases, hypertension can be shown to be a consequence of a specific disease

or abnormality, such as:
• Coarctation (narrowing) of the aorta
• Renal disease (chronic glomerulonephritis, chronic pyelonephritis, chronic renal failure,
renal artery stenosis)
• Endocrine disorders
o phaeochromocytoma (a benign tumour characterised by hypersecretion of
adrenaline and noradrenaline)
o Cushing’s syndrome (hypersecretion of glucocorticosteroids)
o Conn’s syndrome (hyperaldosteronism)
o acromegaly (hypersecretion of growth hormone)
o hyperthyroidism
• Excessive consumption of alcohol
• Drugs (oral contraceptives, corticosteroids, anabolic steroids)
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56
In the majority of patients with hypertension it is not possible to define a specific underlying
cause, and they are said to have primary or essential (idiopathic) hypertension. In 70% of
such patients another member of the family is affected. The main pathophysiologic
abnormality in primary hypertension appears to be increased peripheral vascular resistance,
although the exact mechanism of this is unclear and may well vary from one patient to
another.

After diagnosis of essential hypertension has been established, usually the first step is to
attempt to reduce blood pressure through lifestyle changes such as reduction of salt and
alcohol consumption, physical activity, stopping smoking, restriction of fat intake, relaxation
and stress management techniques etc. If these measures fail or are insufficient, drug therapy
should be considered. There are several drugs that can be used in treatment of hypertension
and the choice is influenced by the severity of hypertension, patient’s general condition, age,
associated conditions (e.g., angina), drug availability and cost, as well as unwanted effects.
Certain drugs can be taken in combinations (see the diagram).

• Thiazide diuretics (discussed later) seem to reduce blood pressure through a modest
reduction in plasma volume and a decrease in vascular reactivity (response to
sympathetic vasoconstricting stimuli), possibly mediated by shift in sodium from
intracellular to extracellular space (slight hyperpolarisation). One disadvantage of
thiazide diuretics may be erectile dysfunction in men which is fortunately reversible and
disappears as soon as diuretics are discontinued. As explained later thiazides may worsen
gout and type II diabetes, and should not be given to patients suffers from them.

• β adrenoceptors antagonists (β blockers) do not alter peripheral vascular resistance but

instead decrease heart rate and cardiac contractility, thus effectively reducing cardiac
output. In addition there is a drop in renin release from the kidneys (β1 receptors
stimulate renin secretion) that leads to vasodilation. Cardioselective β1 blockers are
preferable especially in asthmatics (non-selective β blockers may induce bronchospasm)
and diabetics on insulin where non-selective β blockers increase the likelihood of
exercise-induced hypoglycaemia because the normal adrenaline-induced release of
glucose from the liver is diminished (decreased glycogenolysis and gluconeogenesis).
Other common unwanted effects are fatigue, depression, cold extremities, insomnia with
bad dreams and sometimes erectile dysfunction in men. β blockers should be given with
caution in heart failure since they depress cardiac contractility (however in some cases of
heart failure with significant sympathetic heart stimulation β blockers can actually be

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57
 useful and prolong survival). Labetalol [Trandate, Presolol] and carvedilol [Dilatrend,
Kredex] block both α1 and β1,2 receptors and are also effective in hypertension.

• Calcium antagonists (calcium channel blockers) such as nifedipine [Adalat, Nifehexal,

Addos, Nyefax], nimodipine [Nimotop], felodipine [Plendil, Felodur], amlodipine

[Norvasc] and lercanidipine [Zanidip] are potent peripheral vasodilators and reduce
blood pressure by decreasing peripheral vascular resistance. In addition verapamil and
diltiazem slow the heart rate and have a negative inotropic effect on myocardial
contractility similar to β blockers, and consequently should not be prescribed in the
presence of heart failure.

• ACE inhibitors are vasodilators that reduce blood pressure by interfering with the
generation of angiotensin II from angiotensin I and are effective in most patients.
Angiotensin II is a potent vasoconstrictor (40 times more potent than noradrenaline in
raising blood pressure). While the mechanism through which ACE inhibitors lower blood
pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone
system, they appear to have an antihypertensive effect even in patients who do not have
elevated renin in blood. One explanation is that ACE inhibitors also inhibit the
breakdown of the potent vasodilator substance bradykinin. One of the advantages of these
drugs in the management of hypertension is their low adverse effect profile. A dry
irritating cough (probably caused by build up of bradykinin in the lungs) is the most
frequent unwanted effect of ACE inhibitors. Even this can be avoided when angiotensin
II antagonists are given instead, because these drugs block the action of angiotensin II
rather than its formation in the lungs. ACE inhibitors and angiotensin II antagonists are
least likely to cause sexual dysfunction in males, which makes them a popular choice for
hypertension. NSAIDs may reduce vasodilatatory effect of ACE inhibitors because
NSAIDs block the action of bradykinin (important vasodilator). ACE inhibitors and
angiotensin II blockers are contraindicated in pregnancy as they can produce fetal
hypotension and cause malformations

• α1 adrenoceptors antagonists cause vasodilation of arteries and veins leading to fall in

arterial pressure and central venous pressure. They are very effective drugs and their
unwanted effects are relatively mild including orthostatic hypotension, weakness and
sometimes reflex palpitations (tachycardia).

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58
 o Diagram showing the sites of action of antihypertensive drugs

Medulla
Baroreceptor oblongata (CC)
discharge

N1

Spinal cord
N2

1
NA NA ∅
4 (α1) ∅ 2 (β1)
∅
Peripheral Cardiac
resistance output
∅
3
Arterial ↑ Blood
pressure volume

5
Renal ∅ Sodium and
perfusion water

Aldosterone AG
∅
7 ∅
6 4
∅
Renin ACE (lungs)

Angiotensinogen Angiotensin I Angiotensin II

LEGEND:

NA noradrenaline Antihypertensive drugs:

ACE angiotensin-converting enzyme 1. β blockers
N1 preganglionic neuron 2. α1 blockers
N2 postganglionic neuron 3. Potassium channel
AG adrenal gland activators, calcium antagonists
CC cardiovascular centre 4. Angiotensin II antagonists
5. Diuretics
6. ACE inhibitors
7. Aldosterone antagonists
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59
 TREATMENT OF HEART FAILURE

Heart failure is characterised by inability of the heart to produce cardiac output appropriate to
circumstances. It is not a disease but a result of various diseases/processes affecting the heart
(eg. chronic hypertension, damaged valves, serious chronic bronchitis, cardiac ischaemia).
Consequences: reduced blood supply to tissues (ischaemia) and pooling of blood (congestion)
in peripheral tissues Æ increased hydrostatic pressure Æ swelling (oedema).
Heart failure can be:
• Right-sided heart failure: congestion and oedema of the legs, liver and GI tract
• Left-sided heart failure: pulmonary congestion and oedema

Important compensatory mechanismsactivated in heart failure:

• sympathetic nervous system that directly increases cardiac contractility and rate
• renin-angiotensin-aldosterone system with retention of sodium and water Æ
increased blood volume
They may help to improve the condition at the beginning, but will worsen the problem in the
long term.

Pharmacologic options for heart failure management:

• β blockers – even though they use appear counterproductive, in small doses they
prolong survival by reducing heart overstimulation by sympathetic fibres
• ACE inhibitors and angiotensin II antagonists – reduce inappropriate activation of
renin-angiotensin-aldosterone system in heart failure
• Diuretics – increase loss of sodium and water and thus reduce the degree of swelling
(oedema) – useful in congestive heart failure
• Digitalis – improves cardiac contractility and increases cardiac output (due to
potential toxicity and other issues it must be given cautiously – second line
treatment)

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60
 PHARMACOLOGY OF THE URINARY SYSTEM

The main function of the kidney is the excretion of waste products such as urea, uric acid and
creatinine. In the course of this activity, it fulfils another function, crucially important in
homeostasis - the regulation of the salt and electrolyte content and the volume of the extra-
cellular fluid. It also plays a part in acid-base balance by removing excess hydrogen (acids).

The main functional unit of the kidney is the nephron, which consists of glomerulus,
proximal convoluted tubule, loop of Henle, distal tubule and collecting duct. A conjunction
of afferent arteriole, efferent arteriole and distal convoluted tubule near the glomerulus
comprises the juxtaglomerular apparatus. At this site there are specialised cells in both the
afferent arteriole and in the tubule. The latter, termed macula densa cells, are able to respond
to changes in the rate of flow and the composition of tubule fluid, and are thought to control
renin release from the specialised granular renin-containing cells in the afferent arteriole.
Renin is involved in the generation of angiotensin I and II, the latter is a potent
vasoconstrictor.

All the constituents of the plasma, other than proteins, are filtered into the tubules but most
are reabsorbed back except waste products, excess of water and electrolytes. The main
+ +
primary active transport process for electrolytes throughout the tubules is Na /K -ATPase
(sodium pump), located in the basolateral membrane, which pumps sodium from the tubular
cell into the extracellular space. This action creates a concentration gradient for sodium
between the tubular fluid and intracellular fluid allowing the passage of sodium passively
through certain co-transport carriers. Since these carriers do not directly consume energy but
are linked to energy driven sodium pump, they are called secondary active transport. The
+ - +
most important carrier is Na /2Cl /K carrier that operates in the thick ascending limb and is
responsible for marked reabsorption of NaCl (the major factor responsible for hypertonicity
in the medulla). In the distal convoluted tubule there is moderate absorption of NaCl by an
+ -
Na /Cl carrier. Inhibition of these carriers effectively decreases NaCl absorption and
constitutes the mechanism of action of the most important diuretic drugs.
+ +
In the collecting tubules and ducts Na is absorbed through Na channels under the influence
of hormone aldosterone secreted by the adrenal gland. Aldosterone is a steroid hormone that
acts on cytoplasmatic receptors and induces synthesis of sodium pump molecules in the
+
basolateral membrane and a special protein, which increases the permeability of the Na
+ +
channels. K and H are secreted into the tubule in exchange for sodium, and rate of their
secretion is determined by the amount of sodium delivered to the collecting tubules

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61
(concentration gradient for sodium). This means that diuretic drugs will indirectly increase
loss of both potassium and hydrogen ions, therefore causing hypokalaemia and metabolic
alkalosis.

DIURETICS

Diuretics are drugs which increase the excretion of salt (NaCl) and water and thus increase
urine volume. Normally (e.g., in the absence of diuretics), less than 1% of filtered sodium is
excreted from the body. The main diuretics are:
• loop diuretics
• thiazides
• potassium-sparing diuretics

Loop diuretics

Loop diuretics are the most powerful of all diuretics, capable of causing 15-25% of sodium in
the filtrate to be excreted, and therefore are termed “high ceiling” diuretics. Loop diuretics act
+ - +
by inhibiting the Na /2Cl /K co-transporter in the thick ascending limb of loop of Henle.
+ -
Excretion of Na , Cl and accompanying water is increased which is useful in states of fluid
+
retention (oedema) in the body. The increased Na load in the late distal tubule and collecting
+ + +
tubule stimulates Na exchange with K and H , increasing their excretion and causing
hypokalaemia and metabolic alkalosis, which are the main unwanted effects. Low potassium
level in the blood leads to cell hyperpolarisation and thus muscle weakness, exhaustion,
constipation and sometimes irregular heartbeat (premature atrial and ventricular contractions).
The depletion of potassium must be compensated with food rich in potassium (not always
reliable), potassium supplements [Chlorvescent, Kay Ciel, Slow K, Span K, K-SR] or the
addition of potassium-sparing diuretics (see later). The most common clinical manifestations
of metabolic alkalosis are irritability and neuromuscular hyperexcitability (tetany,
paraesthesiae) caused by the reversible drop in plasma ionised calcium level. Large doses
may lead to dehydration and hypovolaemia with low blood pressure.

The main loop diuretics are frusemide [Lasix, Fruside, Uremide] and bumetanide [Burinex].
They are used in patients with salt and water overload and oedema due to chronic heart
failure (e.g., pulmonary and peripheral oedema), hepatic cirrhosis complicated by ascites and
nephrotic syndrome.

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62
 Thiazides

This group of drugs has a moderately powerful diuretic action. They act by inhibiting the
+ -
Na /Cl co-transporter in the early distal convoluted tubule, causing increased urine flow.
Hypokalaemia and metabolic alkalosis can occur in the same way as with loop diuretics.
Other unwanted effects are male erectile dysfunction (reversible on stopping the drug),
hypersensitivity reactions, hyperuricaemia that may precipitate gout (this is so because
thiazides are actively secreted into the proximal tubules where they compete with uric acid
for the same carrier mechanism), impairment of glucose tolerance (thiazides are
contraindicated in non-insulin dependant diabetes mellitus).

The main thiazide is hydrochlorothiazide [Dithiazide]. It often combined with:

• amiloride [Moduretic, Amizide]
• triamterene [Hydrene]
• ACE inhibitors quinapril [Accuretic], enalapril [Renitec Plus] and fosinopril
[Hyforil, Monoplus]
• angiotensin II antagonists candesartan [Atacand Plus], irbesartan [Avapro HCT,
Karvezide], eprosartan [Teveten Plus], telmisartan [Micardis Plus] and olmesartan

[Olmetec Plus]
Clinical uses are similar to loop diuretics, but they are also used in treatment of hypertension
as discussed earlier.

Potassium-sparing diuretics

These act in the collecting tubules by blocking the very mechanism responsible for
hypokalaemia when loop or thiazide diuretics are administered. Potassium-sparing diuretics
are very weak diuretics because only 2% of the total sodium resorption occurs in exchange
for potassium. These drugs work or by blocking the sodium channels controlled by
aldosterone (amiloride used in combination with) and triamterene (also in combination with
hydrochlorothiazide) or by acting as competitive antagonist at the aldosterone cytoplasmatic
receptor (spironolactone [Aldactone] and eplerenone [Inspra]).

If given alone they could cause hyperkalaemia, which can be dangerous (it is potentially
more serious than hypokalaemia) because it can lead to serious cardiac arrhythmias such as
ventricular extrasystoles, ventricular tachycardia or fibrillation. Other manifestations of
hyperkalaemia are nausea, vomiting, abdominal cramps and diarrhoea due to increased
_________________________________________________________________________________
63
gastrointestinal motility (high potassium causes hypopolarisation of cell membranes, making
cells more excitable). Spironolactone frequently causes gastrointestinal upsets (loss of
appetite, nausea, indigestion), irregular menstrual periods, gynaecomastia, erectile
dysfunction or diminished sexual drive (by acting on steroid receptors in other tissues). Due
to weak antiandrogenic properties spironolactone is frequently used to reduce hairiness
(hirsutism) associated with elevated androgen levels in patients with polycystic ovary
syndrome.

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64
 Diagram showing the sites of action of diuretic drugs

DISTAL TUBULE

Na+ Na+
Na+
P
1 ∅ C2 K+ K+
Cl- C1
-
Cl Cl-
Lumen Extracellular fluid

ASCENDING LIMB OF HENLE’S LOOP

Na+ Na+
Na+
P
2 ∅ C3 K +
K+

2Cl- C1
K+ K+ Cl- Cl-
Lumen Extracellular fluid

COLLECTING TUBULE
6
⊕
H2O H2O
Na+ Na+
Na+
∅ ⊕ 5 4
4 ∅ P ⊕
3
K+ K+ K+ ∅

H+ H+ CA H2O 5
H2CO3
CO2
HCO3- HCO3-

Lumen Extracellular fluid

LEGEND:

P sodium pump (Na+/K+ ATPase) Diuretic drugs and hormones:

-
C1 K+/Cl co-transporter 1. Thiazides
-
C2 Na+/Cl co-transporter 2. Loop diuretics
+ - +
C3 Na /2Cl /K co-transporter 3. Amiloride, triamterene
CA carbonic anhydrase enzyme 4. Aldosterone
passive diffusion 5. Spironolactone
6. Antidiuretic hormone (ADH)

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65
 PHARMACOLOGY OF HAEMOSTASIS

Haemostasis refers to a complex process that aims to stop blood loss from damaged vessels.
The main steps in this process are platelet adhesion/activation and blood coagulation (fibrin
formation). Thrombosis is an unwanted pathologic version of haemostasis and results from
inappropriate activation of the haemostatic mechanism within uninterrupted vascular system.
Thrombosis can develop both in venous and arterial circulation, although different
precipitating factors are involved.
1. Venous thrombosis is usually associated with stasis of blood (sluggish blood flow); a
venous thrombus has a small platelet component and a large component of fibrin and
erythrocytes. These thrombi are usually dark red.
2. Arterial thrombosis is usually associated with atherosclerosis, and the thrombus has a
large platelet component, but less erythrocytes, which accounts for its whitish-grey
appearance.
A portion of a thrombus may break away, travel as an embolus and lodge in another vessel,
causing ischaemia and even infarction.

The clotting mechanism consists of a cascade of enzymes and cofactors-factors I-XIII.

Inactive precursors are activated in series, each one giving rise to more of the next (chain
reaction). The last enzyme, thrombin, derived from prothrombin (II), converts soluble
fibrinogen (I) to an insoluble meshwork of fibrin in which blood cells are trapped, forming
the clot. Blood coagulation is controlled by:
• enzyme inhibitors, e.g., α2 globulin antithrombin III, which neutralises thrombin and other
activated enzymes in the cascade
• fibrinolytic process provided by plasmin, which is formed from plasminogen under the
action of tissue plasminogen activator (t-PA) released from endothelial cells, which breaks
down formed fibrin clots and prevents uncontrolled blood clotting

ANTICOAGULANTS

The drugs used to prevent unwanted coagulation (anticoagulants) may be oral and injectable.

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66
 Oral anticoagulants

These drugs are structurally similar to vitamin K, which is involved in synthesis of factors II,
VII, IX and X in the liver as a coenzyme. In this process vitamin K is reduced and before it
can be used again must be first oxidised into its active form.

Coagulation factor
synthesis

Active Inactive
Vitamin K Vitamin K

Epoxide reductase

Oral anticoagulants act as competitive inhibitors of enzyme epoxide reductase and in that way
reduce availability of active form of vitamin K in the liver. They act only in vivo and the
effect of these drugs takes several days to develop because of the time taken for degradation
of factors already produced.

Warfarin [Marevan, Coumadin] is the most important drug in this group. Warfarin is
eliminated in the liver by cytochrome-P450 enzyme system, and since it has relatively narrow
therapeutic window clinically important drug interactions are common. For example agents
which inhibit this enzymatic system slow down metabolism of warfarin (e.g., cimetidine,
chloramphenicol) and increase its effects. On the other hand drugs that cause induction of the
cytochrome-P450 enzymes in the liver increase the degradation of warfarin (e.g.,
carbamazepine) and attenuate its effect. Agents which impair platelet aggregation and platelet
function (e.g., aspirin) act synergistically with warfarin to amplify anti-coagulant effects. In
all these situations dose adjustments may be required.

Haemorrhage (especially into the bowel or the brain) is the main hazard and in order to
prevent this unwanted event prothrombin time should be monitored and maintained 2-4 times
of normal (normal range is 11-14 sec). As warfarin does not directly interfere with vitamin K,
vitamin K is an effective antidote in case of haemorrhagic episodes. Oral anticoagulants can
be teratogenic (not recommended in pregnancy, the risk of causing birth defects is
approximately 5%) and can cause liver damage though these effects are infrequent. Liver
function tests should be monitored.

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67
 Injectable anticoagulants

These agents act by binding and increasing action of the natural inhibitor of blood clotting
process antithrombin III, which inactivates thrombin (IIa) and factor Xa. The most important
example is heparin [Heparin, Calcihep], naturally occurring (produced by basophils, mast
cells and also found in endothelial cell membranes) highly acidic glycosaminoglycan
commercially derived from pig intestine or cow lung and can appear in various molecular
weights. Low-molecular-weight heparins (fragments of heparin) with slightly different
anticoagulant activity from the parent molecule, are now also available such as dalteparin
[Fragmin], danaparoid [Orgaran] and enoxaparin [Clexane]. It has been determined that the
activity of antithrombin III is increased 1000-fold when heparin is given. All of them are
given subcutaneously or intravenously (intramuscular injection can cause painful
haematoma), because they are not absorbed from the gastrointestinal tract due to their
electrical charge and thus lipid insolubility, and the onset of action is rapid.

Here the main hazard is also haemorrhage, which is treated by stopping therapy, and, if
necessary, giving a heparin antagonist protamine [Protamine Sulphate], an alkaline peptide
that forms an inactive complex with heparin. Anticoagulant effect of heparin can be
monitored by testing partial thromboplastin time, which should be increased by a factor of 2.
Prolonged use of heparin (6 months or more) can cause osteoporosis with spontaneous
fractures (the reason is unknown but formation of complexes with calcium in the bone may
be important). Warfarin is therefore a better choice for long-term treatment. Heparin can also
produce thrombocytopenia, which appears to be much less likely with low-molecular-weight
heparins (their main advantage over heparin). Various hypersensitivity reactions have been
reported.

ANTIPLATELET DRUGS

Normal vascular endothelium prevents platelet adhesion. Platelets adhere to diseased or

damaged areas and become activated, e.g., they change shape, exposing negatively charged
phospholipids and special glycoprotein receptors, and release various mediators such as
thromboxane A2 (TXA2), ADP, serotonin (5-HT), which stimulate other platelets to expose
the glycoprotein receptors on their surface and then aggregate. The mass of aggregated
platelets forms a plug which, together with vessel constriction, maintains haemostasis in
small vessels until the blood coagulation process is activated and the platelet plug reinforced
by fibrin.

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68
There are several drugs that can prevent platelet aggregation and activation:
• aspirin [Cardiprin, Cartia, Astrix 100] works by irreversibly blocking enzyme cyclo-
oxygenase (discussed later) in charge for synthesis of two important prostaglandins PGI2
and TXA2. The balance between prostacyclin PGI2 (an inhibitor of aggregation generated
by vascular endothelium) and TXA2 (a stimulant of aggregation generated by platelets) is
thus altered, since the endothelium can synthesise more cyclo-oxygenase enzyme but
platelets can not because they do not have nuclei and protein synthesis machinery. TXA2
synthesis only recovers when new platelets with new cyclo-oxygenase are formed. Other
NSAIDs produce reversible inhibition of cyclo-oxygenase and have minimal effect on
platelet aggregation. It is worth mentioning that prostacyclin production is controlled by
COX-2 while TXA2 production is controlled by COX-1. Because of this selective COX-2
inhibitors will change the balance between prostacyclin and TXA2 in favour of TXA2.
The net result is increased risk for thrombosis, especially in the presence of
atherosclerosis.
• dipyridamole [Persantin] is a phosphodiesterase inhibitor which slows down removal
and thus augments the activity of cAMP in platelets (cAMP inhibits platelet aggregation);
it acts best if combined with aspirin – such combination is Asasantin SR.
• ticlopidine [Ticlid, Tilodene] and related drug clopidogrel [Plavix, Iscover] are new
drugs that act by inhibiting the role of adenosine diphosphate (ADP) in platelet
aggregation
• tirofiban [Aggrastat] works by binding and blocking glycoprotein receptors IIb and IIIa
that are expressed on platelets’ surface during activation; as a result interlinking of
platelets is greatly reduced
• abciximab [ReoPro] is an artificially manufactured monoclonal antibody (mab =
monoclonal antibody) against glycoprotein receptors on platelet surface; it causes
inactivation of these receptors and consequently inhibition of platelet adhesion

FIBRINOLYTIC DRUGS

A fibrinolytic (thrombolytic) cascade is initiated concurrently with the coagulation cascade,

resulting in the formation of plasmin (fibrinolysin), an enzyme that digests fibrin and
dissolves the blood clot. Various fibrinolytic agents can promote the formation of plasmin
from its precursor plasminogen:
• streptokinase [Streptase] is extracted from cultures of β-haemolytic streptococci
bacteria

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69
• alteplase [Actilyse] and reteplase [Rapilysin] are genetically engineered tissue-type
plasminogen activators

Being a bacterial product streptokinase is antigenic and since most people have been exposed
to streptococci they posses antibodies that can neutralise streptokinase, thus necessitating
large doses to be given. For the same reason streptokinase can occasionally cause allergic
reactions (more likely after repetitive administration). Alteplase and reteplase are not
antigenic, and are also more efficient but more expensive. The main hazard for all fibrinolytic
agents is potentially serious bleeding, which may be treated by giving tranexemic acid
[Cyklokapron], which is an inhibitor of plasminogen activation and, if necessary, fresh
plasma or coagulation factors.

CLINICAL USE OF DRUGS THAT AFFECT HAEMOSTASIS

• Anticoagulants are used in treatment and prevention of venous thrombosis since the
underlying process is predominantly coagulation (fibrin formation) with only a small
component of platelet aggregation. Heparin is used for short-term action and warfarin for
prolonged therapy.

• Fibrinolytic agents plus aspirin are used in the therapy of acute myocardial infarction,
pulmonary embolism and ischaemic stroke (brain infarction). The sooner these are given
after onset the better because old thrombi are usually resistant to fibrinolysis. It should be
mentioned that stroke caused by brain haemorrhage is an absolute contraindication for this
treatment.

• Antiplatelet drugs are mainly used in prevention of arterial thrombosis in patients who
suffer from coronary heart disease (e.g., who have recovered from myocardial infarction
or have more troublesome or unstable angina which can progress to infarction) or cerebral
arterial disease (e.g., who have frequent transient ischaemic attacks or who had a stroke).
Recommended daily dose of aspirin is 100 mg which is insufficient to cause significant
gastrointestinal irritation. Ticlopidine and clopidogrel are slightly more effective and can
be used as alternatives, especially in patients with peptic ulcer disease, who may not
tolerate aspirin well. Tirofiban is given intravenously together with heparin to prevent
myocardial infarction in unstable angina. Abciximab is administered only intravenously to
patients undergoing percutaneous coronary interventions (e.g., balloon angioplasty, stent
placement, atherectomy) to prevent coronary thrombosis. It has been reported that for this
purpose abciximab is superior to other antiplatelet drugs.

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70
 Diagram showing sites of action of major antiplatelet drugs

Arachidonic
acid
1
∅
Cyclo-oxygenase

Prostacyclin Thromboxane A2
(endothelium) (platelets)

stimulates inhibits

Adenylate
cyclase

stimulates formation of
2
∅
Platelet cyclic Platelet
Phosphodiesterase block
AMP aggregation

4
3
Plain AMP ∅ ∅
(breakdown product ADP formation Receptor
of cAMP) expression

LEGEND:

Drugs affecting platelet activation and aggregation:

1. Aspirin
2. Dipyridamole
3. Ticlopidine, clopidogrel
4. Tirofiban, abciximab

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71
 Diagram of thrombus formation showing the coagulation
cascade, thrombolytic system and the action of drugs that modify
these systems

ARTERIAL WALL
Atherosclerotic
plaque
1
2
∅
∅
Activation of clotting factors
Platelet adhesion,
activation and aggregation ⊕ → formation of
prothrombinase (Xa+Va+Ca)

Antithrombin III ∅ Thrombin (IIa) Prothrombin (II)

⊕
3
⊕
∅
4
Fibrin → fibrin strands
Fibrinogen + trapped blood cells =
blood clot

5 6

Plasminogen
⊕ ∅ Plasmin
(profibrinolysin) (fibrinolysin) ⊕
⊕
Plasminogen activator: Fibrin degradation
tissue plasminogen activator (t-PA), products → blood clot
thrombin, dissolution
activated factor XII

LEGEND:

Drugs affecting the blood clotting process:

1. Oral anticoagulants
2. Antiplatelet drugs
3. Heparin
4. Protamine sulphate (antidote for heparin)
5. Fibrinolytic agents
6. Tranexemic acid (antidote for fibrinolytic agents)
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72
 PHARMACOLOGY OF THE RESPIRATORY SYSTEM

MANAGEMENT OF ASTHMA

Airflow through the bronchial system is tightly controlled by the autonomic nervous system
and various local chemical mediators. The parasympathetic nerves mediate bronchial
constriction and mucus secretion through an action on muscarinic M3 receptors. Sympathetic
nerves innervate only blood vessels causing constriction and thus indirectly inhibit oedema
formation and bronchial gland secretion. Circulating adrenaline released from the adrenal
gland when the sympathetic nervous system is activated acts on β2 receptors to relax the
airway smooth muscle (bronchodilation).

Asthma may be loosely defined as a syndrome in which there is recurrent reversible

obstruction of the airways in response to stimuli which are not directly noxious and which do
not affect non-asthmatic individuals. The asthmatic patient has intermittent attacks of mainly
expiratory dyspnoea (breathlessness), wheezing, and cough. Asthma occurs at all ages and it
has been estimated that 5-10% of adults and 10-20% of children suffer from it. When the
acute attack has an allergic basis the term extrinsic asthma is often used and this is the most
common type of asthma. When there is no obvious allergic basis for the disease it is called
intrinsic asthma and may be contributed by imbalance between the sympathetic and
parasympathetic system.

The main pathologic feature is chronic inflammatory changes in the airways, responsible for
bronchial hyper-responsiveness, which refers to abnormal sensitivity to various non-specific
stimuli (e.g., physical activity, cold weather, smoke or dust, strong scents etc.).

In many patients the asthmatic attack consists of two phases, which illustrate the
pathophysiology of the condition:
• an immediate phase on exposure to eliciting allergen characterised by mast cell
degranulation and release of various primary (already stored, such as histamine) and
secondary mediators (produced ‘on demand’, such as leukotrienes LTC4, LTD4, LTE4 and
prostaglandin PGD2) which are mainly responsible for early bronchospasm and mucosal
oedema.
• a later phase consisting of a special type of inflammation comprising vasodilation,
oedema, mucus secretion and bronchospasm initiated by inflammatory and chemotactic
mediators released from mast cells (LTB4, LTC4, LTD4, LTE4, PGD2 and platelet
activating factor PAF), as well as from eosinophils and neutrophils. It appears that certain

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73
 proteins released from eosinophils (major basic protein, eosinophil cationic protein) can
cause damage of bronchial epithelium making way for new allergen particles to reach the
mast cells. All of these changes may underlie bronchial hyper-responsiveness.

There are two categories of drugs used in management of asthma: bronchodilators and anti-
inflammatory agents. Bronchodilators are effective in reversing the bronchospasm in the
immediate phase, anti-inflammatory agents in inhibiting or preventing the inflammatory
components of both phases.

Bronchodilators (Relievers)

1. β2 adrenoceptors agonists

β2 agonists (stimulants) cause bronchodilation in a manner similar to relaxation of vascular

smooth muscle: increase in intracellular cAMP → activation of cAMP dependant protein

kinase → inhibition of myosin light chain kinase required for cell contraction → cell
relaxation. Main drugs in this category are salbutamol [Ventolin, Asmol, Airomir, Butamol,
Epaq], terbutaline [Bricanyl], salmeterol [Serevent] and eformoterol [Foradile, Oxis].

Salbutamol, eformoterol and salmeterol are more selective to β2 receptors than others, and
they are preferred because of low incidence of cardiovascular unwanted effects (mainly
increased heart rate, experienced as palpitations). However, they tend to loose their selectivity
when given in large doses and start stimulating β1 receptors in the heart as well. Salbutamol is
given by inhalation using a metered-dose inhaler (puffer); its effects start immediately and
last 3-5 h. Salbutamol can also be given orally (e.g., syrup for infants) and by intravenous
infusion in status asthmaticus. The most common adverse effect is muscle tremor (stimulation
of β2 receptors in muscles), vasodilation in muscles leading to feeling of warmth, and
occasionally due to more pronounced peripheral vasodilation there can be hypotension and
headache. Salmeterol has an advantage over salbutamol for it maintains the effect for 12
hours (important for control of overnight dyspnoea), but it is also more expensive.

2. Xanthine drugs

The mechanism of action of these drugs is probably inhibition of enzyme phosphodiesterase

normally responsible for inactivation of cAMP, which leads to build-up of cAMP (more
cAMP → more bronchodilation). It is then not surprising that pharmacological effects of
xanthines closely mirror the effects of β1,2 adrenoceptor stimulation as all β receptors are
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74
coupled to cAMP as a second messenger.

Main examples are theophylline which is in clinical use, and theobromine (in cocoa and tea)
and caffeine (coffee, cocoa, cola soft drinks) which are not used as drugs (caffeine and
theobromine are relatively weak bronchodilators). Theophylline has a narrow therapeutic
window; unwanted effects are dose related and include increase of heart rate and contractility,
arrhythmia, CNS stimulation leading to nervousness, agitation and tremor and gastrointestinal
disturbances (anorexia, nausea and vomiting). It is usually given intravenously by slow
infusion for status asthmaticus in form of theophylline-ethylene-diamine [Aminophylline], or
orally [Nuelin, Brondecon]. Theophylline is a second-line drug used as an alternative, or in
addition to steroids and other anti-asthmatic agents in patients whose asthma does not
respond adequately to β2 adrenoceptors agonists. In slow release forms it is a good choice for

prevention of nocturnal (night time) bronchospasm.

3. Muscarinic-receptor antagonists

The main compounds used specifically as bronchodilator are ipratropium [Atrovent, Aeron,
Ipratrin, Apoven, Ipravent] and tiotropium [Spiriva] (ipratropium combined with

salbutamol is available as Combivent). They relieve bronchial constriction and mucus

secretion caused by increased parasympathetic stimulation; this occurs particularly in asthma
produced by irritant stimuli (intrinsic asthma) and can occur in allergic asthma to some
extent. They bind to all muscarinic receptor subtypes (M1, M2 and M3), but bronchodilation is
linked to M3 receptors. They are given by aerosol inhalation, and in general they are safe and
well tolerated since absorption from the bronchial mucosa is minimal. Ipratropium/tiotropium
are relatively weak bronchodilators and they are usually used together with β2 adrenoceptors

agonists. Tiotropium is a bronchodilator of choice in chronic obstructive pulmonary disease

where β2 agonists show minimal relief.

Anti-inflammatory agents (Preventers)

1. Glucocorticoids

Glucocorticoids (corticosteroids) are not bronchodilators and instead they reduce the
inflammatory component in bronchial asthma, hence their value is in prophylaxis. The
mechanism of action involves decreased generation of PAF, prostaglandins, leukotrienes and
decreased activation of eosinophils and other inflammatory cells (discussed later). If given by

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75
inhalation (beclomethasone [Qvar], budesonide [Pulmicort], fluticasone [Flixotide],
ciclesonide [Alvesco]) systemic unwanted affects are rare, but oral thrush (candidiasis)
leading to voice problems (husky voice-dysphonia) can occur. This is caused by suppression
of non-specific defence mechanisms in the mucosa of the mouth, pharynx and larynx, and is
usually due to incorrect inhalation techniques. Such unwanted effect can be prevented or
relieved by having the patient use an adaptor-spacer or gargle with water after inhalation.

To increase convenience and compliance, inhaled corticosteroids can be combined with β2

agonists such as fluticasone + salmeterol [Seretide] and budesonide + eformoterol

[Symbicort].

More severe cases of asthma may require oral forms (prednisolone [Delta-Cortef,
Panafcortelone, Redipred], methylprednisolone [Medrol]) when a whole series of unwanted

effects can occur, depending on dose and duration of treatment (discussed later).
Hydrocortisone [Hysone, Nordicort] is administered intravenously in status asthmaticus,
which can sometimes be a life-saving measure.

2. Cromoglycate/nedocromil

Given prophylactically cromoglycate [Intal, Cromese] and nedocromil [Tilade] can prevent
both phases of asthma and reduce bronchial hyper-responsiveness in many but not all patients
(they are of no value in acute attacks). They are anti-inflammatory drugs of choice for asthma
in children (for some reason less effective in adults), but the effect may take few weeks to
mount.

The mechanism of action is uncertain; it appears that mast cell stabilisation through the
blockage of calcium influx plays some role. It is also possible that cromoglycate and
nedocromil can suppress exaggerated neuronal reflexes triggered by irritant agents, which
result in overproduction of spasmogenic neuropeptides. They are taken by inhalation in a
manner similar to salbutamol. Unwanted effects are minor respiratory tract irritation (cough
and mild bronchospasm initially that tend to disappear in time). Providing they are efficient
(this varies from one patient to another and can not be predicted) they are safer than steroids
for prolonged use.

3. Leukotriene antagonists

Leukotrienes, particularly LTC4, LTD4 and LTE4, are important inflammatory mediators
produced mainly by mast cells and eosinophils, that cause bronchial smooth muscle

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76
contraction, airway oedema and mucus secretion. It has been demonstrated that leukotrienes
are roughly 1000 times more potent than histamine in producing bronchoconstriction.
Leukotriene antagonists such as montelukast [Singulair] and zafirlukast [Accolate] reduce
the effects of leukotrienes by blocking specific leukotriene receptors on target cells.
Leukotriene antagonists have been shown to have strong anti-inflammatory properties and are
given regularly by mouth (one evening dose) in order to prevent asthmatic episodes. Some
clinical studies have shown that they are as effective as inhaled corticosteroids. In general
they are well tolerated with no significant unwanted effects reported so far (occasionally mild
headache and anorexia).

4. Anti-IgE strategies

By blocking IgE antibodies before they bind to mast cells it is possible to substantially reduce
the intensity of reaction to inhaled allergens and thus control symptoms of asthma.
Omalizumab [Xolair] is a monoclonal antibody designed to intercept and neutralise IgE. This
drug is given subcutaneously every fortnight or month to patients who have been found to
have high level of IgE in blood. The dose depends on this level. Unwanted effects are
virtually absent. The only disadvantage is currently high cost of such treatment.

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77
 Diagram showing the sites of action of antiasthmatic drugs

Mucus secretion ⊕
AG MBP, ECP

Bronchial epithelium Cross-linking

binding of two IgE
∅ Ca2+
7 4
∅
MC ⊕
↑Ca2+ Eo
∅ 5
5 MPL ∅
cAMP β2
∅ ⊕
PL PDE 1 Inflammation
AMP ∅
AA 3

LTB4, LTC4, LTD4 Oedema

Histamine ECF, NCF

∅
⊕ Hyper-responsiveness
6 PF
CA
2 1
M3
∅ ⊕ β2
LTr H1

Smooth Relaxation cAMP

Contraction cGMP 3
muscle
PDE ∅
AMP

LEGEND:

AG allergens in inhaled air

MC mast cell (mastocyte) Antiasthmatic drugs:
PDE phosphodiesterase (inactivates cAMP) 1. β2 adrenoceptors agonists
MPL membrane phospholipids 2. Muscarinic antagonists
AA arachidonic acid 3. Xanthines
LT leukotriene 4. Cromoglycate, nedocromil
LTr leukotriene receptor 5. Glucocorticoids
PF parasympathetic fibre 6. Leukotriene antagonists
ECF eosinophil chemotactic factor 7. Anti-IgE antibodies
NCF neutrophil chemotactic factor
Eo eosinophil
MBP major basic protein (toxic to mucosal cells)
ECP eosinophil cationic protein (toxic to mucosal cells)
CA circulating adrenaline (from the adrenal gland)

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78
 MANAGEMENT OF COUGH

Cough is a common sign of respiratory disease. It is essentially a protective reflex mechanism

intending to remove inhaled foreign materials and clear secretions from the airways. Cough
may be inappropriately activated by irritation of cough receptors caused by malignancy, or
dry cough caused by infection can be troublesome and painful. In situations like these cough
suppressants may be considered. However they are generally contraindicated in productive
cough, which may be encouraged by mucolytics/expectorants.

Cough suppressants

Cough suppressants (also called antitussive medications) act by poorly understood

mechanism in the hypothetical ‘cough centre’ in the medulla, producing its inhibition. All
narcotic analgesics produce suppression of cough in doses well below their analgesic doses
and cough suppressants are generally or narcotic themselves or closely related to them.
Examples are codeine [Actacode], dihydrocodeine [Parcodin, Rikodeine], pholcodine
[Actuss, Duro-Tuss, Linctus Tussinol, Logicin Cough Suppressant], dextrometorphan
[DHC, Actifed Dry, Benadryl Dry, Bisolvon Dry, Dexi-Tuss, Robitussin DM etc.] and
pentoxyverine [Nyal Cough Medicine, Vick’s Cough Syrup]. There is a great number of
various mixtures on the market (over the counter products) that contain cough suppressants
and other actives such as antihistamines, decongestants and even paracetamol. Like other
narcotic medications cough suppressants may produce nausea and occasionally vomiting,
drowsiness, sedation, and in prolonged use constipation.

Mucolytic/expectorant medications

These medications are claimed to reduce the viscosity of thick mucus assisting with its
clearance. They are generally indicated in productive ‘chesty’ cough. Examples of such
medications are bromhexine [Bisolvon], guaiphenesin [in Robitussin EX, Actifed Chesty,
Benadryl Chesty, Lemsip Chesty Cough Medicine etc.] and acetylcysteine [Mucomyst]. No

important unwanted effects have been reported with these drugs. However, most clinical
trials have not managed to demonstrate the claimed effectiveness of mucolytics, and their use
remains controversial. Like cough suppressants mucolytics are found in various combined
over the counter preparations.

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79
 PHARMACOLOGY OF THE GASTROINTESTINAL TRACT

The stomach secretes about two and a half litre of gastric juice daily. The principal exocrine
secretions are pepsin from the chief or peptic cells, and hydrochloric acid and intrinsic factor
(important in absorption of vitamin B12) from the parietal cells. The acid is secreted by so-
+ +
called proton-pump (K /H -ATPase) since hydrogen ions are essentially protons, while
mucus is released from the mucus secreting cells found amongst the surface cells throughout
gastric mucosa. The mucus forms a gel-like layer protecting the mucosa from the gastric
juice, and bicarbonates in the mucus neutralise the acid diffusing from the lumen.

The regulation of acid secretion from parietal cells is especially important in peptic ulcer and
constitutes a particular target for drug action. Gastric acid secretion is stimulated by:
• gastrin, a peptide hormone released from endocrine cells of the mucosa of the gastric
antrum, acting on gastrin receptors on parietal cells and histamine-containing cells (mast
cells).
• acetylcholine, a neurotransmitter released from the parasympathetic fibres, which
stimulates muscarinic receptors on the surface of the parietal cells and on the surface of
the mast cells
• histamine, a local hormone produced by mast cells, which lie close to the parietal cells,
acting on H2 receptors on parietal cells

On the other hand, locally produced prostaglandins PGE2 stimulates mucus and bicarbonate
secretion, and also increases mucosal blood flow to sweep away hydrogen ions that have
back-diffused into the mucosa from the lumen. It has been suggested that it can also directly
oppose secretion of gastric acid. Thus, 1st generation non-steroidal anti-inflammatory drugs
(such as aspirin), which non-selectively inhibit prostaglandin synthesis, will decrease the
protective effect of the barrier, and may predispose to and even cause peptic ulcer in patients
on long-term treatment (e.g., for rheumatoid arthritis).

Peptic ulcers are thought to arise due to an imbalance between:

• mucosal-damaging mechanisms (acid, pepsin) and
• mucosal-protecting mechanisms (mucus, bicarbonate, local synthesis of PGE2).

In some patients peptic ulcer develops as a result of long-term use of large doses of NSAIDs.
In others development of ulcers is linked to the presence of Helicobacter pylori, a gram-
negative bacillus, in their stomach. Helicobacter pylori infection is found in virtually all
patients with duodenal ulcers and more than 80% of those with gastric ulcers. However, it

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80
appears that only 15-20% of infected individuals eventually develop peptic ulcer, which
suggests that other factors also play some role. he bacteria live close to the epithelial cell
surface to some extent and enzymes, toxins and ammonia produced by strong urease activity
may damage the cells. H. pylori has an ability to stimulate gastrin production, which then
increases gastric acid synthesis. All of these, and probably other unknown factors, may in the
long run cause chronic gastritis and/or peptic ulcer. Furthermore, eradication of the bacillus
reduces the incidence of relapse by more than 90% and it is now recommended that treatment
of active peptic ulcers should include drugs that are active against H. pylori (certain
antibiotics).

DRUGS USED IN TREATMENT OF PEPTIC ULCER

H2 receptor antagonists

The introduction of the H2 receptor antagonists (H2 blockers) in the mid 1970s constituted a
major breakthrough in drug treatment of peptic ulcer. They are competitive inhibitors of
histamine at the H2 receptors, effectively inhibiting histamine-stimulated and decreasing
gastrin-stimulated and acetylcholine-stimulated acid secretion. Pepsin secretion and activity
also falls with the reduction in gastric acid production. Due to better understanding of
pathophysiology of peptic ulcer disease H2 blockers are no longer primary therapy when used
alone; they are frequently used as antisecretory drugs in anti-H. pylori regimens.

The drugs used are cimetidine [Tagamet, Magicul], ranitidine [Zantac, Ausran, Rani 2,
Renihexal, Ranoxyl, Ultac, Mylanta Ranitidine 12 hour, Gatrogel-Ranitidine, Gavilast 12

hour], nizatidine [Tazac, Nizac] and famotidine [Pepcidine, Pepzan, Pamacid, Amfamox,

Ausfam, Famohexal]; they are given orally although intramuscular and intravenous

preparations are also available.

Unwanted effects are rare and usually readily reversed on withdrawal of treatment. Diarrhoea,
dizziness, muscle pains and transient rashes have been reported. Cimetidine in large doses
can sometimes cause gynaecomastia (breast enlargement, painful breasts) in men and, rarely,
decrease in sexual function, due to its weak anti-androgenic effect. This may be seen when
cimetidine is used in treatment of Zollinger-Ellison syndrome, which is a rare
gastrin-secreting tumour of the pancreas that leads to overproduction of gastric acid and
multiple ulcers. Cimetidine also inhibits liver enzyme cytochrome P-450 and can slow down
the metabolism and thus potentiates the action of many drugs such as oral anticoagulants,
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81
antiepileptic drugs and tricyclic antidepressants, which can lead to clinically important
interactions. Other drugs in this group have no anti-androgenic effect and they are much less
likely to inhibit liver enzymes.

Proton pump inhibitors

+ +
Proton pump inhibitors block the K /H -ATPase, the terminal step in the acid secretory
pathway. It is believed that they chemically react with sulphydryl groups (-SH) associated
with the proton pump proteins, effectively causing their irreversible blockage. This is the
reason why despite relatively short plasma half-life of about 1 hour, a single daily dose
affects acid secretion for 2-3 days, until new proton pumps are produced in sufficient
numbers.

The main agents are omeprazole [Losec, Acimax, Meprazol, Omepral, Probitor], lansprazole
[Zoton], pantoprazole [Somac], rabeprazole [Pariet] and esomeprazole [Nexium], and these
drugs are key components of anti-H. pylori regimens.
Unwanted effects are mild and not common, but may include headache, diarrhoea and rashes,
sometimes dizziness, somnolence, mental confusion and pain in muscles and joints.

Antacids

Antacids provide temporary and symptomatic relief by neutralising gastric acid and thus
raising the gastric pH. This has the effect of inhibiting peptic activity, which practically
ceases at pH 5. Given in sufficient quantity 6-7 times a day for long enough they can produce
healing of peptic ulcers. Because such strict schedule is inconvenient for most patients,
antacids currently find their greatest application in the treatment of reflux oesophagitis with
heartburn (gastro-oesophageal reflux disease) and for symptomatic relief of simple
indigestion and heartburn caused by dietary and alcoholic excess, heavy smoking or anxiety
and nervousness.

Many patients self-medicate sodium bicarbonate (baking soda), which is the fastest acting
and most effective antacid. However, on reacting with acid in the stomach carbon dioxide gas
is liberated causing abdominal distension, belching, nausea, flatulence and ‘rebound’ increase
in acid production. The antacids in common use are salts of magnesium (e.g., magnesium
hydroxide, magnesium trisilicate and magnesium carbonate) and aluminium (usually

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82
aluminium hydroxide). Magnesium salts can cause diarrhoea and aluminium salts
constipation, so mixtures of these two are used to preserve normal bowel function. Several
antacid preparations have added simethicone that can reduce bloating and pressure in the
stomach and bowels by forcing individual gas bubbles to fuse into larges masses that are
easier to expel.

Numerous combined preparations are available such as Alu-Tab, Alugel, Gastrogel, Mylanta,
Gelucil, Simeco, Gaviscon, Almacarb, Dijene, Algicon. Liquid forms are probably more

effective than tablets. Apart from mild gastrointestinal disturbances, large doses of aluminium
antacids in the long run may have adverse effects on bones (osteoporosis), muscle and
probably on the CNS causing dementia. This is the reason why regular long term use of
antacids is not recommended.

Drugs that protect the mucosa

Some agents, termed “cytoprotective”, are said to enhance the mucosal protection
mechanisms and/or provide a physical barrier over the surface or the ulcer.

1. Sucralfate [Carafate] is a complex of aluminium hydroxide and sulphated sucrose, which

has been shown to form complex gels with mucus thereby providing additional protection to
the mucosa. It has no effect on acid output nor acidity in the stomach. The fact that it must be
given orally, four times daily before meals, makes it rather inconvenient and compliance is
low. Unwanted effects are few, the most common being mild constipation (in up to 15% of
patients).

3. Misoprostol [Cytotec] is a synthetic prostaglandin E that increases the secretion of mucus

and bicarbonate, and possibly inhibits gastric acid secretion. It is given orally and is used to
prevent the gastric damage that can occur with chronic use of 1st generation non-steroidal
anti-inflammatory drugs. Misoprostol is even available in combination with diclofenac
[Arthrotec] since diclofenac (separately available as Voltaren) is one of the most commonly
prescribed NSAIDs for chronic arthritis..
Unwanted effects of misoprostol are abdominal cramps, diarrhoea and stimulation of uterine
contractility that in pregnancy may even lead to miscarriage; therefore misoprostol is
absolutely contraindicated in pregnant women and should also be avoided in women of child
bearing age who are not on some form of contraception.

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83
 Anti-Helicobacter drugs

H. pylori bacteria are targeted with combination antibiotics. One of proton pump inhibitors is
added to help with healing process and reduce pain. The following preparations are given in
one week course with success rate of eradication of around 90%:
o omeprazole, amoxycillin and clarithromycin [Klacid Hp 7]
o esomeprazole, amoxycillin and clarithromycin [Nexium Hp 7]

These preparations are generally well tolerated. Failure to eradicate H. pylori are thought to
be mainly due to lack of compliance by the patient but also due to presence of resistant
bacteria (one more antibiotic may be needed in the repeated course).

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84
 Diagram showing the main modes of action of drugs used in
peptic ulcer

2 Blood vessel
∅ MAST CELL
M1R GR
Parasympathetic NSAIDs
nerve
Gastrin ∅
ACh

Histamine PGE2 AA
1
∅ 5
M1R H2R GR

HCO3- PGR PGR

MUCOUS
HCO3 -
H2CO3 ∅ ⊕ CELL
A HCO3-
⊕
Cl- CO2 H2O
- +
Cl K H+

PARIETAL CELL
S P
∅
2
∅
- + +
Cl K H 3

HCl ∅
4

LEGEND:
GR gastrin receptor
H2R histamine receptor type 2 Drugs used in peptic ulcer:
M1R muscarinic receptor type 1 1. H2 receptor antagonists
P proton pump 2. Proton pump inhibitors
S symport carrier for K+ and Cl- 3. Anti-Helicobacter agents
A antiport carrier for HCO3- and Cl- 4. Antacids
PGE2 prostaglandin E2 5. Prostaglandin analogues
AA arachidonic acid
NSAIDs non-steroidal anti-inflammatory drugs
PGR prostaglandin receptor

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85
 DRUGS USED IN TREATMENT OF NAUSEA AND VOMITING

The reflex of vomiting is controlled by:

• the vomiting centre, located in the medulla oblongata, which accepts input from the GI
tract, vestibular apparatus (inner ear), limbic system and the chemoreceptor trigger zone.
The vomiting centre projects to the vagal nerve and to the spinal motor neurones
supplying the abdominal smooth and striated muscle respectively.

• the chemoreceptor trigger zone, also located in the medulla, is sensitive to chemical
stimuli in blood such as endogenous toxins produced in chronic renal failure (uraemia),
chronic liver failure (e.g., advanced cirrhosis), radiation sickness and various drugs,
especially ones used in cancer treatment, because the chemoreceptor trigger zone is not
protected by the blood-brain barrier; impulses from here relay to the vomiting centre.

VOMITING

Efferent pathways

Vestibular Vomiting Chemoreceptor

apparatus centre trigger zone
H1 and ACh H1 and ACh D2 and 5-HT3
receptors receptors receptors

Afferent pathways

Pharynx
Stomach
Pylorus
Biliary tree
Intestines
5-HT3 receptors

Vomiting mechanism is very complex and still not fully understood. However it is known
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86
that the main neurotransmitters involved in the control of vomiting are acetylcholine acting
on muscarinic receptors, histamine acting on H1 receptors, serotonin (5-HT) acting on 5-HT3
receptors and dopamine acting on D2 receptors. Not surprisingly drugs that can reduce or
abolish the action of these transmitters can be useful in treatment of nausea and vomiting.

1. H1 receptor antagonists (antihistamines), better known for their use in symptomatic

relief of allergic reactions, are also useful in nausea and vomiting and are mostly used for
prevention of motion sickness and treatment of severe morning sickness of pregnancy
(pheniramine [Avil], promethazine [Avomine, Phenergan], dimenhydrinate [Dramamine]).
These antihistamines can cause drowsiness, which can sometimes be a problem.

2. Muscarinic antagonists are also recommended for motion sickness and the drug of
choice is hyoscine [Kwells, Travacalm]. The main unwanted actions are drowsiness, dry
mouth, blurred vision, constipation and urine retention, which are characteristic for all
muscarinic antagonists.

3. D2 receptor antagonists such as prochlorperazine [Stemetil, Stemzine] and

metoclopramide [Maxolon, Pramin] are used in treatment of vomiting caused by chronic

renal failure, biliary and renal colic, acute/chronic pancreatitis, migraine, unwanted
effects of anticancer drugs, serious gastroenteritis/food poisoning and severe morning
sickness of pregnancy if it is unbearable. These drugs are well tolerated in most patients
and unwanted effects are mild resembling those of muscarinic antagonists and
antihistamines (dry mouth, constipation, difficulty urinating, drowsiness, weakness,
blurred vision).

4. 5-HT3 receptor antagonists (also known as “the setrons”) are powerful anti-emetics and
are drugs of choice in serious vomiting caused by cytotoxic anticancer drugs,
postoperative vomiting and other serious pathology. The main examples are ondansetron
[Zofran, Ondaz], dolasetron [Anzemet], tropisetron [Navoban] and granisetron [Kytril].
They are very safe and well tolerated drugs with minimal unwanted effects. The main
disadvantage is relatively high cost.

5. Corticosteroids (e.g., dexamethasone [Dexamethasone, Sofradex], methylprednisolone

[Medrol, Solu-medrol]) act by unknown mechanism and are usually given together with
certain anticancer drugs to prevent nausea and vomiting (they are less efficient when
vomiting starts).

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 DRUGS AFFECTING MOTILITY OF THE GASTROINTESTINAL TRACT

These drugs may increase movements of the gastrointestinal tract (laxatives), or decrease the
motility of the gastro-intestinal smooth muscle (antidiarrhoeal drugs and antispasmodics)

Laxatives

The transit of food through the intestine may be accelerated by several different methods:

• By increasing the volume of non-absorbable solid residue with bulk laxatives. These
include cellulose (bran), methylcellulose [Cellulone], ispaghula [Fibogel], ispaghula husk
known as psyllium [Mucilax], psyllium + ispaghula [Metamucil] and certain plant gums
such as sterculia [Alvercol]. All of them are polysaccharide polymers, which are not
broken down by the normal processes of digestion in the upper part of the gastrointestinal
tract. They are mild laxatives and take several days to work but have no serious unwanted
effects. Bulk laxatives are the only laxatives suitable for long-term use.

• By increasing the water content with osmotic laxatives, such as magnesium salts (e.g.,
magnesium sulphate [Epsom]), lactulose [Duphalac, Genlac, Actilax, Lactocur, Lac-Dol]
(semisynthetic disaccharide composed of fructose and galactose, which is converted by
colonic bacteria into the lactic and acetic acids), sorbitol [Sorbilax] and macrogol
[Movicol]. Osmotic laxatives are mainly used to prepare patients for some diagnostic
bowel procedures (e.g., colonoscopy) by cleansing the bowel. Lactulose is also used in
treatment of hepatic encephalopathy in decompensated cirrhosis to accelerate bowel
emptying and thus eliminate colonic bacteria responsible for formation of protein-derived
toxins that are absorbed in blood. When the liver in unable to perform their degradation
they reach the brain leading to impairment of brain function and variety of neurological
and psychiatric phenomena.

• By altering the consistency of the faeces with faecal softeners (“wetting agents”) such as
docusate sodium [Coloxyl, Sennesoft] which act in a manner similar to a detergent and
produce softer faeces. They achieve this effect by breaking down surface tension and
allowing water to enter the faecal mass to soften and increase its bulk. Faecal softeners
are very weak laxatives if given alone, therefore they are usually combined with active
principles of senna (such combinations available as Soflax, Coloxyl with Senna etc).

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88
• By increasing motility and secretion with stimulant laxatives, such as preparations of
senna plant that contain anthraquinone glycosides with colon-specific stimulant action
[Senokot, Sennetabs, Bekunis etc], bisacodyl [Durolax, Bisalax, Lax-Tab] and
picosulphate sodium [Picolax, Pico-Prep, Durolax SP Drops]. It is believed that they act
by stimulating the myenteric plexus, resulting in increased muscle activity and thus
defecation. They are usually given orally and produce a laxative action within 8 hours.
These agents sometimes cause abdominal cramps and diarrhoea; prolonged use can lead
to atonic colon where the natural propulsive activity is diminished; now the only way to
achieve defecation is to take further amounts of laxatives (dependency state). That is why
stimulant laxatives should not be taken regularly for longer periods of time.

Antidiarrhoeal drugs

Diarrhoea is the too frequent passage of faeces that is too liquid. Diarrhoea is a symptom and
when possible the underlying disorder should be determined and appropriately treated. If
symptomatic treatment is warranted the following steps may be undertaken:

• maintenance of fluid and electrolyte balance by means of oral rehydration with

commercially available preparations of electrolytes and glucose [Gastrolyte, Hydralyte,
Repalyte]; if these are not available sport drinks such as Gatorade can be used, as well as

home-made solution of 1 tsp salt, 1 tsp baking soda, 4 tsp sugar in 1 L of water.

• use of anti-infective agents in case of proven bacterial or parasitic origin

• use of non-antimicrobial antidiarrhoeal agents to decrease motility of the GI tract, which

should be reserved for severe diarrhoea with serious dehydration

The main pharmacological agents which decrease motility are opioids (compounds related to
morphine) such as diphenoxylate + atropine [Lomotil, Lofenoxal] and loperamide [Imodium,
Gastro-Stop, Harmonise, Negastro, Diacare]. Loperamide is the most appropriate opioid

for local effects on the gut because it does not easily penetrate into the brain, therefore it has
few central actions and is unlikely to cause dependence. These drugs activate μ–receptors
(discussed later) on myenteric neurones and cause hyperpolarisation by increasing their
potassium conductance. This inhibits acetylcholine release from the myenteric plexus and
reduces bowel motility. All have unwanted effects in form of nausea, vomiting, sometimes
drowsiness and dizziness, therefore they should be used only for persistent diarrhoea leading
to serious dehydration.

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 Antispasmodic drugs

Antispasmodic drugs are used to relieve spasm in the gut and bowel cramps in irritable bowel
syndrome, diverticular disease (diverticulosis) and mild ulcerative colitis/Crohn’s disease.
Colicky pain associated with the passage of kidney stones or gallstones can be relieved when
these drugs are given with strong pain killers. The main antispasmodic drugs are muscarinic
receptor antagonists which decrease spasm of smooth muscle by inhibiting the
parasympathetic activity: propantheline [Pro-Banthine], hyoscine [Buscopan, Setacol],
oxybutynin [Ditropan], mebeverine [Colese, Colofac] and combined atropine + hyoscine +
hyoscyamine [Donnalix, Donnatab]. Unwanted effects are dry mouth, blurred vision, dry
skin, tachycardia, and difficulty with urination.

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 PHARMACOLOGY OF THE ENDOCRINE SYSTEM

DRUGS USED IN DIABETES MELLITUS

Insulin is a hormone secreted by the β-cells of the islets of Langerhans in the pancreas. Many
factors stimulate insulin secretion, but the main one is blood glucose concentration. Insulin is
a polypeptide (51 amino acids) consisting of two peptide chains connected by two disulphide
bridges (-S-S-). The β-cells posses K+ channels that are regulated by intracellular ATP (KATP
channels). When the blood glucose increases, more glucose enters the β-cells and its
metabolism results in an increase in intracellular ATP, which closes KATP channels. The
resulting depolarisation of the β-cells initiates influx of Ca2+ ions through voltage sensitive
Ca2+ channels and this triggers insulin release.

Na+ K+ KATP channel

Na+ ∅ K+
Depolarisation
Glucose ↑ATP
(no insulin ⊕
needed for
) Ca2+ Ca2+

⊕
β-CELL

Insulin

Insulin has essential metabolic actions as a fuel-storage hormone, and also affects cell growth
and differentiation. It decreases blood glucose by increasing glucose uptake, increasing
glycogen synthesis (glycogenesis), decreasing production of glucose from amino acids
(gluconeogenesis) and decreasing glycogen breakdown (glycogenolysis).

Insulin increases fatty acid synthesis and triglyceride formation in adipose tissue
(lipogenesis). It decreases lipolysis and causes lipogenesis in the liver. Insulin stimulates the
uptake of amino acids into muscle and increases protein synthesis. It also decreases protein
catabolism and the oxidation of amino acids, particularly in the liver.
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Insulin binds to a specific glycoprotein complex receptor on the surface of its target cells, and
insulin-receptor complex then enters the cell, where it is eventually destroyed by lysosomal
enzymes. The transduction mechanisms for the insulin response (e.g., the events than link
receptor-binding to the biological response) are still a matter of intensive research, but it
seems likely that several pathways are involved, probably through the process of alteration of
the state of key enzymes. Also, this ‘engulfment’ of the insulin-receptor complex seems to
underlie insulin resistance observed in obese patients with diabetes.

Diabetes mellitus is a chronic metabolic disorder in which there is high blood glucose
concentration (hyperglycaemia). The normal blood glucose is up to 6 mmol/L and diabetes is
diagnosed by a fasting plasma glucose >7.7 mmol/L. Hyperglycaemia occurs because the
liver and skeletal muscle cannot store glycogen and the tissues are unable to take up and
utilise glucose. When the renal threshold for glucose reabsorption is exceeded, glucose spills
over into the urine (glycosuria) and causes an osmotic diuresis (polyuria) which in turn
results in dehydration and increased fluid intake (polydipsia). Increased intake of food is
usually present (polyphagia).

Muscle wasting occurs in severe diabetes due to the fact that protein metabolism is deranged
and an excessive amount of protein is converted to carbohydrate. In the absence of insulin
and consequently impaired carbohydrate metabolism, energy can only be sourced from lipid
breakdown (lipolysis). Unfortunately not all tissues are capable of lipolysis but they can use
so-called ketone bodies (aceto-acetate, β-hydroxybutyrate and acetone) formed from fatty
acids in the liver (ketogenesis). When the rate of production exceeds that of removal by
peripheral tissues, then hyperketonaemia results with pH (ketoacidosis).

There are two main forms of diabetes:

• Type I (formerly insulin-dependent diabetes mellitus – IDDM, and juvenile onset diabetes)
which accounts for 10% of all diabetes cases. In Type I there is an absolute deficiency of
insulin, and unless insulin treatment is provided the patient will die with diabetic
ketoacidosis. Such patients are usually young and not obese when they first develop
symptoms.

• Type II (formerly non-insulin-dependent diabetes mellitus – IDDM, and maturity onset

diabetes) which is responsible for the remaining 90% of cases. In Type II there is both
insulin resistance (which precedes overt disease) and impaired insulin secretion. These
patients are usually obese (80 of them) and treatment is initially dietary although
supplementary oral hypoglycaemic drugs or insulin often become necessary.

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 Insulin

Insulin used to be extracted from porcine or bovine pancreas. Today there is only one bovine
insulin preparation available, and all others are human insulins. “Human” insulin is made by
microorganisms (E. coli or yeast Saccharomyces) modified through recombinant DNA
technology. It is usually given subcutaneously, sometimes in an emergency by intravenous
infusion. Human insulin is less immunogenic than animal insulin, which can evoke an
antibody response with insulin resistance and allergic reactions as consequences.

Several insulin analogues (amino acid sequence has been modified through amino acid
substitution) are also available:

1. Insulin lispro is achieved through a reversal of two amino acids (lysine and
proline) positions in a peptide sequence of the B chain - offers faster
subcutaneous absorption and onset of action

2. Insulin aspart is achieved through a substitution of the amino acid proline by

aspartic acid at position 28 on the B-chain - offers faster subcutaneous absorption
and onset of action

3. Insulin glargine is achieved by replacing amino acid asparagine at position A21

by glycine and addition of two arginines to C terminus of the B chain;
mechanism of prolonged action is low solubility at neutral body pH

4. Insulin detemir is achieved by addition of fatty acid myristic acid to lysine at

position B29; mechanism of prolonged action is thought to be both delayed
absorption and increased binding to plasma albumin.

There are three main types of insulin in regard to pharmacokinetics:

Fast, short acting Intermediate-acting Long acting

Start working after 30 min, Start working in 2-3 hours,

peak action in 2-4 hours,
duration of action 6-8 hours
(all figures shorter for insulin
analogues)
Given sc and iv
Start working in 4-6 hours,
peak action in 6-12 hours,
peak action in 12-24 hours,
duration of action 12-24
duration of action 24-36
hours
hours
Given sc, can be mixed with
Given sc
fast acting insulin

Human insulin [Actrapid, Isophane insulin Æ insulin Insulin detemir [Levemir]

Humulin R, Hypurin Neutral] bound to a protein protamine Insulin glargine [Lantus]

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Insulin lispro [Humalog] [Protaphane, Humulin NPH,
Insulin glulisine [Apidra] Hypurin Isophane, Mixtard]

Insulin aspart [NovoRapid]

Various regimes of insulin administration may be used. Intravenous infusion of soluble

insulin is used routinely in emergency treatment of diabetic ketoacidosis. A common regime
for type 1 patients, at least initially, is to inject a combination of short and intermediate-acting
insulins twice daily in various ratios depending on the patient, before breakfast and before the
evening meal. These pre-mixed preparations are marketed as Mixtard 50/50, Mixtard
30/70, Mixtard 15/85, Humulin 50/50, Humulin 30/70, Humulin 20/80, Humalog Mix25,

Humalog Mix50 (Humalog contains insulin lispro), NovoMix 30 (contains insulin aspart).

Several years after the onset of type 1 diabetes, residual insulin secretion typically ceases and
this regime is unable to maintain optimal glycaemic control. Insulin delivery should more
closely simulate the ‘normal’ pattern of insulin secretion; namely, continuous or ‘basal’
insulin levels (with long acting preparations) are required throughout the day, while brief
increases in insulin levels (‘boluses’ of short acting preparations) should coincide with the
ingestion of meals.

The main undesirable effect of insulin is hypoglycaemia, which is common and serious and
can result in substantial morbidity and death. It is due to insulin overdose, inadequate food
intake or unplanned strenuous exercise. Symptoms of hypoglycaemia are: weakness,
emptiness, hunger, diplopia (seeing in duplicate), blurring of vision, mental confusion,
abnormal behaviour (e.g., aggression, poor co-ordination), lassitude, somnolence, muscular
twitching, vomiting, coma. Allergy to insulin is unusual but may take the form of local (at
injection site) or systemic reactions (e.g., skin rash). In some instances repetitive
administration into site can produce lipodystrophy.

Oral hypoglycaemic drugs

Oral hypoglycaemic drugs are useful in treatment of NIDDM and only as a supplement to
dietary measures and weight loss. The main drugs in this category are:

• Metformin [Diaformin, Glucophage, Glucohexal, Glucomet, Diabex] belongs to groups

of biguanides and acts primarily to reduce hepatic glucose production by suppressing
gluconeogenesis. Peripherally, it also increases glucose uptake in peripheral tissues
provided some insulin is present (mechanism of action is still unclear but it may be
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94
 related to enhanced insulin-receptor binding). It does not increase appetite and is useful
in NIDDM patients who are obese and who fail to lose weight. Metformin may be used
together with sulphonylureas when these have ceased to work adequately (metformin and
glibenclamide are combined in Glucovance). Metformin is also often used with
thiazolidinediones (metformin + rosiglitazone = [Avandamet]). The main unwanted
effects are transient nausea, vomiting and diarrhoea, but not hypoglycaemia because
metformin does not increase insulin secretion like sulphonylureas.

• Sulphonylureas such as glibenclamide [Daonil, Glimel], glipizide [Minidiab, Melizide],

gliclazide [Diamicron, Glyade, Nidem] and glimepiride [Aylide, Amaryl, Diapride,
Dimirel] stimulate insulin release (insulin ‘secretagogues’ ) from the pancreatic islets by

closing KATP channels, causing depolarisation of the β-cells. These drugs are only
effective if β-cells are at least partially functional. Because sulfonylureas rely on a
preserved β-cell response, they are ineffective in the treatment of type 1 diabetes. It has
also been suggested that sulphonylureas preparations also inhibit the process of
gluconeogenesis in the liver and to some extent increase the number of insulin receptors
on target cells. Similarly to insulin sulphonylureas can cause hypoglycaemia and weight
gain due to increased appetite. Other unwanted effects are mild and rare and include
various gastrointestinal disturbances.

• Non-sulphonylurea secretagogues such as repaglinide [NovoNorm] are novel short-

acting drugs with similar mode of action to sulphonylureas. They are less likely to
produce hypoglycaemia, but like sulphonylureas can produce mild gastrointestinal
disturbances.

• Thiazolidinediones (TZDs or glitazones) such as pioglitazone [Actos] and rosiglitazone

[Avandia] are the latest oral hypoglycaemic drugs that lower blood glucose by improving
target cell response to insulin. They have a unique mechanism of action that is dependent
on the presence of insulin for activity. Their mechanism of action is poorly understood
but is thought to involve binding to nuclear receptors that regulate the transcription of a
number of insulin responsive genes critical for the control of glucose and lipid
metabolism. Unwanted effects are largely related to fluid retention and fat redistribution
and include weight gain, oedema, mild anaemia, and worsening of congestive heart
failure. These drugs are therefore not recommended for use in patients with moderate-to-
severe congestive heart failure or those with severe anaemia. A combination of
rosiglitazone and metformin is available as Avandamet.

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95
• α-glucosidase inhibitors such as acarbose [Glucobay] are competitive inhibitors of α-
glucosidases, brush-border enzymes in the proximal small intestine that serve to break
down complex carbohydrates into monosaccharides. These agents delay the absorption of
carbohydrates such as starch, sucrose, and maltose but do not affect the absorption of
glucose and other monosaccharides. To be effective, acarbose must be taken at the
beginning of each carbohydrate-containing meal, usually three to four times per day.
Acarbose is minimally absorbed systemically. Unwanted effects are mild gastrointestinal
disturbances.

Other hypoglycaemic drugs

• Exenatide [Byetta] is the first of a new class of medications called incretin mimetics.
Incretins are a type of gastrointestinal hormone that cause an increase in the amount of
insulin released from the beta cells of the islets of Langerhans after eating, even before
blood glucose levels become elevated. The main ones are glucagon-like peptide 1 (GLP-
1) and gastric inhibitory polypeptide (GIP). Exetide is a synthetic 39 amino acids peptide
that mimics the effect of GLP-1. It is given by subcutaneous injection twice a day,
usually combined with either sulfonylureas, metformin and thiazolinediones.

• Dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin [Januvia] reduce activity of

enzyme DPP-4 that inactivates incretins in blood. DPP-4 inhibitors elevate the blood
levels of incretins and enhance their activity. Sitaglipin is usually used in combination
with metformin, sulphonylureas or thiazolidinediones. Unwanted effects are very mild
(nausea); it has significantly less effect on lowering blood glucose level than
sulphonylureas.

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 DRUGS USED IN THYROID DISORDERS

The thyroid is essential for many physiological processes. It secretes three main hormones:
thyroxine (T4), triiodothyronine (T3) and calcitonin. T4 and T3 are critically important for
normal growth and development and for energy metabolism, whereas calcitonin is involved
in the control of plasma calcium.

Thyroid hormones are synthesised by iodination of tyrosine residues on a large glycoprotein

thyroglobulin within the thick colloid in the lumen of the thyroid follicle. This process is
carried out by an enzyme thyroperoxidase, which catalyses the oxidation of iodide and its
attachment to thyroglobulin forming mono-iodotyrosine (MIT) and di-iodotyrosine (DIT).
MIT and DIT then join to form T3 (MIT + DIT) and T4 (DIT + DIT). The stored
thyroglobulin is endocytosed, broken down, and thyroxine (T4) and triiodothyronine (T3) are
secreted into the plasma.

Synthesis and secretion of T3 and T4 are regulated by glycoprotein thyrotrophin (thyroid

stimulating hormone, TSH) produced by anterior pituitary under the influence of the
hypothalamic tripeptide thyrotrophin releasing hormone (TRH). Thyrotrophin acts on
receptors on the membrane of thyroid follicle cells and its main second messenger is cAMP.
It controls all aspects of thyroid hormone synthesis. The other main factor influencing thyroid
function is the plasma iodide concentration. A reduced iodine intake with reduced plasma
iodide concentration will result in a decrease of hormone production and an increase in TSH
secretion.

T3 and T4 actions are:

• to stimulate metabolism generally, causing increased O2 consumption and increased
metabolic rate
• to influence growth and development

The hormones act by a mechanism rather similar to that of the steroids. After they enter the
cell, T4 is converted to T3, which binds with high affinity to a specific receptor protein
associated with DNA in the nucleus. The binding induces a conformational change in the
receptor protein and this leads to the synthesis of specific messenger RNA and protein, the
effects produced depending on the cell type. The affinity of the receptor for T4 is less by a
factor of 4-10, and only small amounts of T4 are bound. Thus T4 can be regarded mainly as a
prohormone.

Abnormalities of thyroid function include:

• hyperthyroidism (thyrotoxicosis), caused by Graves’ disease, multinodular goitre or toxic
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97
 adenoma
• hypothyroidism; in infants it is congenital and leads to cretinism (impairment of growth
and mental retardation); in adults it is mainly caused by autoimmune destruction of the
thyroid gland or as a result of treatment of hyperthyroidism with surgery of radioactive
iodine
• simple non-toxic goitre, due to dietary iodine deficiency

Drugs used in treatment of hyperthyroidism

• Thioureas such as carbimazole [Neo-Mercazole] and propylthiouracil [Propylthiouracil]

are the most important oral antithyroid agents. They decrease the synthesis of thyroid
hormones through inhibition of enzyme thyroperoxidase thus reducing iodination of
thyroglobulin. However, they have a delayed effect (usually two weeks), because
thyroglobulin stores must first be used up before the effect is seen. When thioureas are
given for Graves’ disease at least 1 year of treatment is necessary, and even then
recurrence occurs eventually in over half the patients usually within 2 years of stopping
treatment. Such exacerbation can be managed by a repeated course of treatment. The
most important unwanted effect of thioureas is granulocytopenia (low leukocyte count)
commonly presenting with frequent bacterial respiratory tract infections especially of the
throat, which, fortunately, is relatively rare. Rashes are more common.

• Radioiodine (131I) given orally in one dose, is selectively taken up by the thyroid and
damages cells by emitting short range β-radiation. Radioiodine is used in selected cases
as first-line treatment for hyperthyroidism or for treatment of relapse of hyperthyroidism
after thiourea therapy or surgery. The main disadvantage of treatment with radioiodine is
that many patients eventually develop hypothyroidism and long-term follow up is
necessary. Radioiodine-induced hypothyroidism is treated with supplements of thyroxine.

• Iodine, given orally in high doses in form of potassium iodide solution (“Lugol’s
iodine”), transiently reduces thyroid hormone secretion and decreases vascularity of the
gland. The mechanism of action is not entirely clear, but it may inhibit proteolysis of
thyroglobulin after endocytosis, thus preventing release of thyroid hormones. Allergic
reactions can occur in form of rashes, fever, lacrimation (watery eyes), conjunctivitis,
pain in the salivary glands and a common cold-like syndrome. Iodine is not suitable for
long-term treatment of hyperthyroidism and it is usually given to patients who have been
scheduled for surgical resection of the thyroid gland since iodine significantly reduces

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98
 blood flow through the thyroid (less bleeding during surgery).

• Non-selective β adrenoceptor antagonists such as propranolol do not affect the thyroid

gland but instead alleviate somatic symptoms of hyperthyroidism (mainly tremor,
restlessness and tachycardia), and they are given only for short-term treatment (e.g.,
patients waiting for admission when a full assessment will be done or while waiting
administered thioureas to start working).

Drugs used in treatment of hypothyroidism

• Thyroxine [Oroxine, Eutroxsig ] has all the actions of endogenous T4. Given orally in
sufficient dose thyroxine relieves symptoms of hypothyroidism. The dose is fine tuned by
measuring the level of TSH. Normal level of TSH (in primary hypothyroidism it is
elevated) suggests that thyroxine is exhibiting negative inhibitory effect on TSH release
and therefore thyroxine level in blood is good. Too large dose of thyroxine will produce
signs/symptoms of hyperthyroidism.

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 Diagram showing the main modes of action of drugs used in
thyroid diseases

HYPOTHALAMUS

TRH

1
∅ Thyroperoxidase
I- I- + H2O2

⊕ Io
PITUITARY
TSH R
⊕ DIT
GLAND T
Protein T T MIT T3
synthesis T TG T T TG T4
⊕ T T T T4
T T4
4
T4 2
TG
∅ TG
T4
5 3
T3 T3
Ly FOLLICLE LUMEN
FOLLICLE CELL

6
∅ Tissue
effects

LEGEND:
TG thyroglobulin
T4 thyroxine Drugs used in thyroid diseases:
T3 triiodothyronine 1. Thyoureas
T tyrosine 2. Iodine excess
DIT diiodotyrosine 3. Radioiodine
MIT monoiodotyrosine 4. Thyroxine
Ly lysosome 5. Liothyronine
TSH thyroid stimulating hormone (thyrotrophin) 6. β adrenoceptor antagonists
TRH thyrotrophin-releasing hormone
R TSH receptor

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 DRUGS USED IN HYPERLIPIDAEMIA

Lipids are transported in the plasma as lipoproteins, of which there are four classes:

• chylomicrons which transport triglycerides and cholesterol from the gastrointestinal tract
to the tissues where they are split by lipoprotein lipase and the free fatty acids are taken up
for energy use or storage; chylomicron remnants are taken up in the liver and processed

• very low density lipoproteins (VLDL) which transport cholesterol and repacked/newly
synthesised triglycerides from the liver to the tissues, where triglycerides are removed as
before, leaving LDL (VLDL is the main source of plasma LDL); cholesterol can also be
synthesised in the liver from acetyl coenzyme A under the control of enzyme HMG-CoA
(hydroxy methylglutaryl coenzyme A) reductase

• low density lipoproteins (LDL) with a large component of cholesterol, some of which is
taken up by the liver and some by other tissues (LDL is the main source of cholesterol for
peripheral tissues), by endocytosis via specific LDL receptors (the hepatic receptor
mediated removal of LDL is the main mechanism for controlling plasma LDL levels)

• high density lipoproteins (HDL) which collect excess cholesterol derived from cell
breakdown in tissues (including arteries) and transfer it to VLDL and LDL.

Hyperlipoproteinaemia may be primary (genetically determined, classified in five types

according to Frederickson) or secondary to other conditions such as diabetes mellitus,
alcoholism, hypothyroidism, dietary excess of cholesterol and saturated fats and
administration of drugs such as β blockers, thiazide diuretics, corticosteroids, oral
contraception (most patients with hyperlipoproteinaemia have these secondary forms). On the
other hand primary hyperlipoproteinaemias are more dangerous, especially type II familial
hypercholesterolaemia and familial combined hyperlipidaemia (autosomal dominant
disorders). There is a strong positive correlation between the plasma concentration of LDL
cholesterol and the development of atherosclerosis in medium and large arteries, and
consequently risk for coronary artery disease and stroke.

Therapy that lowers LDL and raises HDL has been shown to reduce the incidence and
progression of coronary atherosclerosis. To achieve this dietary management for at least six
months is essential and frequently sufficient, especially in secondary forms (ingestion of
saturated fats and cholesterol suppresses hepatic LDL receptor activity, thus retarding the
clearance and raising the levels of plasma LDL). Drugs are added when correction of
cholesterol level with diet fails, which is usually found in primary hyperlipoproteinaemia.
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There are several mechanisms how drugs can affect levels of lipids in the blood:

• Binding bile acids in the intestine, which will both reduce the absorption of exogenous
lipids/cholesterol and especially increase the metabolism of endogenous cholesterol into
new bile acids. Commonly given drugs in this group are cholestyramine [Questran] and
colestipol [Colestid] and since these drugs are not absorbed, systemic toxicity is low, but
gastrointestinal symptoms of nausea, abdominal bloating, constipation or diarrhoea are
common and dose related. Bile acid sequestrants are mainly used when high blood
cholesterol is due to raised LDL concentration.

• Inhibiting synthesis of cholesterol in the liver, when the resulting decrease in hepatic
cholesterol synthesis leads to increased synthesis of LDL receptors and thus increased
clearance of LDL. Drugs can reduce cholesterol synthesis by blocking HMG-CoA
reductase, and they are popularly called ‘statins’ (simvastatin [Lipex, Zocor, Zimstat,
Simvar, Simvabell, Ransim, Zimstat], fluvastatin [Lescol], pravastatin [Pravachol,

Cholstat, Lipostat, Liprachol], atorvastatin [Lipitor]) and rosuvastatin [Crestor]. They

are claimed to be able to lower blood cholesterol by up to 40%. These drugs are well
tolerated and are now usually the drugs of first choice to reduce cholesterol levels.
Unwanted effects are mild and infrequent and include gastrointestinal disturbance,
insomnia and rash. In few patients myalgia and myopathy and drug-induced hepatitis have
been reported.

• Reducing cholesterol absorption in small intestine with ezetimibe [Ezetrol]. Although

the exact molecular action of ezetimibe is not fully understood, ezetimibe localises at the
brush border of the small intestine and inhibits the absorption of cholesterol, leading to a
decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of
hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.
Ezetimibe does not increase bile acid excretion (like bile acid sequestrants) and does not
inhibit cholesterol synthesis in the liver (like statins). Ezetimibe can be given together
with statins (ezetimibe is combined with simvastatin in Vytorin). It is generally well
tolerated with minimal unwanted effects.

• Increasing the activity of lipoprotein lipase and enhancing the clearance of LDL by the
liver with fibrates such as gemfibrosil [Jezil, Lopid, Ausgem, Gemhexal, Lipazil],
clofibrate [Atromid-S] and fenofibrate [Lipidil]. These drugs produce a modest decrease
in LDL (about 10%) but they cause a marked fall of plasma triglyceride levels (about
30%). The main indication is therefore hypertriglyceridaemia. These drugs can cause a
variety of mild gastrointestinal symptoms, but are usually well tolerated.

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 Diagram showing lipid metabolism and the main sites of action of
lipid-lowering drugs

LIVER INTESTINE
Portal vein

1 Bile acids and Bile

ACoA acids
∅ cholesterol
HMG-CoA
∅
Bile duct
reductase 3

Cholesterol
Fat in diet
TG
R
⊕
2 Chylomicrones Fatty acids
VLDL TG>Ch Cholesterol
TG>Ch

Ch Chylomicron
remnants
HDL Ch>TG
Ch LDL
Ch

2 2
⊕ ⊕
LL LL
PERIPHERAL TISSUES
Cholesterol Fatty acids Fatty acids

LEGEND:
TG triglyceride
Ch cholesterol Drugs used in hyperlipidaemia:
HMG-CoA hydroxy methylglutaryl coenzyme A 1. HMG-CoA reductase inhibitors
ACoA acetyl coenzyme A 2. Fibrates
LL lipoprotein lipase 3. Cholestyramine, colestipol
R liver receptor for LDL

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103
 PHARMACOLOGY OF THE REPRODUCTIVE SYSTEM

The ovaries, in addition to producing ova, also secrete sex hormones, oestrogens and
progesterone. The endogenous oestrogens are oestradiol (the most potent), oestrone and
oestriol; there are numerous exogenous oestrogens (equine or synthetic compounds), e.g.,
ethinyloestradiol, mestranol, which are more effective following oral administration. The
endogenous progestogen is progesterone. Examples of exogenous progestogens are
medroxyprogesterone, norethisterone, levonorgestrel, desogestrel, gestodene and
drospirenone.

DRUGS USED FOR CONTRACEPTION

There are two main types of contraceptive drugs:

• combination of an oestrogen with a progestogen (the combined pill)
• progestogen alone (the progestogen-only preparations).

The combined pill

The oestrogen in most combined preparations is ethinyloestradiol and only one preparation
contains mestranol instead. The progestogen may be norethisterone, levonorgestrel, or the
newer compounds desogestrel, gestodene and drospirenone which are more potent because
they are not degraded in the liver as readily as natural progesterone and have less incidence of
unwanted effects.

Combined oral contraceptives simulate the hormonal profile of early pregnancy and thus
provide negative feedback to the hypothalamus, inhibiting gonadotrophin-releasing hormone,
so that the pituitary does not secrete gonadotrophins (FSH and LH) to stimulate follicle
development and ovulation. Furthermore, the endometrium of the uterus becomes unsuitable
for implantation and the cervical mucus becomes thick and impermeable to sperm. The
combined pill is very reliable and if no tablets are omitted the pregnancy rate is <0.2% after 1
year. To stop ovulation from occurring a woman needs to take seven consecutive active pills.
In addition, if more than seven days are missed a woman risks ovulation and, if unprotected
intercourse occurs, pregnancy. To be sure, it is advised that some alternative method of

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contraception is practiced until the pill has been taken for consecutive 14 days.

The pill comes in 21 day or 28 day packs. Both packs have 21 hormone pills. With the 21 day
pack there is a break of seven days between each pack. The 28 day pack has seven pills that
have no hormones (dummy sugar pills). It is usual to start the combined pill on first day of
the period. After 28 days a withdrawal bleeding that looks like menstruation occurs. Advice
given to women in relation to missed pills:

• If you are less than 24 hours late taking a pill, take it as soon as you remember, and
then take the next one at the usual time. You will still be protected against getting
pregnant.
• If you are more than 24 hours late, or have missed more than one pill, take a pill
when you remember, and the next pill at the usual time. Then keep on taking the pills
as usual, but use other contraception (eg condoms) as well, for the next seven days.
• The lengthening of the pill free interval is one of the most common causes of pill
failure and is often associated with a woman starting her new pill packet late.

Available preparations at the time of writing are:

Composition Brand names

ethinyloestradiol + cyproterone*
ethinyloestradiol +
norethisterone
Brenda-35 ED, Diane-35 ED, Estelle-35 ED,
Juliet-35 ED
Brevinor, Brevinor-1, Synphasic, Norimin,
Norimin-1, Improvil 28 Day

ethinyloestradiol + gestodene Femoden ED, Minulet

ethinyloestradiol +
levonorgestrel
ethinyloestradiol + desogestrel
mestranol + norethisterone
Levlen ED, Loette, Logynon ED, Microgynon 20
ED, Microgynon 30, Microgynon 30 ED,
Microgynon 50 ED, Microlevlen ED, Monofeme,
Nordette, Trifeme, Triphasil, Triquilar ED
Marvelon 28
Norinyl-1

ethinyloestradiol + drospirenone Yasmin

ED = every day
* Cyproterone is a progestogen with anti-androgen activity. Combinations of
ethinyloestradiol + cyproterone are used in treatment of signs of androgenisation in
women such as severe acne (involving risk of scarring) where prolonged oral
antibiotics or local treatment alone has not been successful, or idiopathic hirsutism of
mild to moderate degree. Such combination will also provide effective oral
contraception in this patient group.

Mild adverse effects of combined pill are common and can be divided into:

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105
 • mainly oestrogen-caused, such as nausea, headache, breast tenderness and
enlargement, bloating, fluid retention and weight gain, non-infective vaginal
discharge, slight reversible hypertension because oestrogen increases production of
angiotensin
• mainly progestogen-caused, such as increased appetite and weight gain, acne,
greasy hair, nervousness or depression, reduced libido

Serious unwanted effects are rare. There is evidence for slightly increased risk of breast
cancer and thromboembolic disease (due to increased synthesis of blood clotting factors in
the liver) but this risk diminishes after discontinuation. During lactation the combined
preparations reduce the amount of milk produced and the concentration of protein and lipids
in the milk. Therefore, combination oral contraceptives are not advised for breastfeeding
mothers; progestogen only formulations should be used. Progestogens may lead to increased
resistance to insulin in peripheral tissues and oral contraceptives should be, if possible,
avoided in diabetes, especially in the presence of vascular diabetic complications. Also,
current recommendations are that women older than 35 years who smoke should not be given
combination contraceptives.

In a few women ovulation remains inhibited for a few months after they stop taking the pill
(‘post pill amenorrhoea’), but the pill does not cause permanent sterility or affect the outcome
of pregnancies conceived after it has been discontinued.

Several beneficial effects have also been identified:

• a decrease of the incidence of irregular periods, abnormal dysfunctional uterine bleeding,
dysmenorrhoea, premenstrual tension, iron deficiency anaemia, benign breast disease,
uterine fibroids and dysfunctional cysts of the ovaries
• decreased risk for endometrial and ovarian cancers by about 50%; it seems that this
reduced risk persists for at least 10-15 years after discontinuation

The progestogen-only preparations

Progestogen-only preparations may be administered in three different ways:

• The progestogen-only pill (POP or ‘the minipill’) uses levonorgestrel [Microval,

Microlut, Mirena] or norethisterone [Locilan 28 day, Micronor, Noriday 28] and is

taken continuously. It differs from the combined pill in that the contraceptive effect is
less reliable (97%) and is mainly due to the alteration of cervical mucus; inhibition of

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106
 ovulation is variable and inconsistent. Disturbances of menstruation are common; in
particular irregular bleeding is likely to occur. Transient amenorrhoea in duration of few
months has been observed, but many women maintain almost normal menstrual cycle.
Because of these unwanted effects and questionable reliability progestogen-only pill is
recommended only when oestrogens are contraindicated, as during breast feeding
(oestrogens interfere with lactation). However progestogen only contraceptives lack other
important unwanted effects of the combined contraceptives.

• Subcutaneous implant in the upper arm containing etonorgestrel [Implanon] slowly

releases its content and is very effective for 3 years. At the end of this period the inserted
rod (4cm x 2 mm) capsule needs to be removed and replaced because it is not
biodegradable. Also if the women decides to have a child while the capsule is in place it
has to be surgically removed when ovarian activity and return of fertility is almost
immediate. Disturbances of menstruation are also common, together with weight gain,
acne, headache and breast tenderness. Effectiveness of Implanon compares very well with
combined pill.

• Intramuscular injection of medroxyprogesterone [Depo-Provera, Depo-Ralovera] is

sufficient for three months. It is extremely effective; the pregnancy rate at 1 year is only
0.1%. Commonly reported adverse effects are abnormalities of the menstrual cycle,
weight gain, nervousness and headache. Because of lag time in clearing
medroxyprogesterone from the body, resumption of ovulation is delayed for a variable
period, up to 1 year after the last injection. This has to be told to the woman who is
planing pregnancy after the effect wears off. Effectiveness of such injection is reported to
be similar to combined pill.

Emergency contraception

Emergency contraception, sometimes called the “morning after pill”, treatment consists of 2
tablets of levonorgestrel [Postinor-2, Levonelle-2], one of which has to be taken as soon as
possible after unprotected sexual intercourse (but within 72 hours), followed 12 hours later
by a further 1 tablet. This should be reserved for emergencies only and never used as a
routine means of contraception. The mechanism of action is probably prevention of
implantation of a fertilized ovum in the lining of the uterus if conception has occurred
(abortive effect). Efficacy appears to decline with time after intercourse: 95% within 24
hours, 85% 24 to 48 hours, 58% if used between 48 and 72 hours. Efficacy after 72 hours is

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107
unknown. Nausea and vomiting, breast tenderness and irregular bleeding are commonly
reported unwanted effects. Emergency contraception is available in Australia over-the-
counter in pharmacies (S3 drug).

POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY (HRT)

HRT stands for use of oestrogen hormones alone or in combination with a progestogen in
postmenopausal women aiming to achieve certain health benefits. This is arguably one of the
most controversial areas of medicine as there are conflicting opinions and findings about
benefits and risks associated with the use of HRT. Several comprehensive studies have been
done examining the proposed benefits of HRT and comparing oestrogen-only preparations
with combined oestrogen-progestogen ones. The main findings are:

• HRT slightly increases risk breast cancer, oestrogen only preparation to lesser extent
compared to combined oestrogen-progestogen.

• HRT slightly increases risk for venous thrombosis/pulmonary embolism and stroke,
oestrogen only preparation to lesser extent compared to combined oestrogen-
progestogen.

• There is no protective effect on the heart in regards to prevention of coronary heart

disease with HRT. Combined HRT actually increases risk for coronary heart disease.
This means that combined HRT should not be initiated and continued for primary
prevention of coronary heart disease.

• HRT decreases risk for osteoporosis related fractures such as wrist, vertebrae and hip.
Oestrogens given in HRT increase calcium absorption, decrease bone resorption by
antagonising effects of parathyroid hormone and prevent bone loss (however, they do not
significantly add bone mass).

It is generally agreed that HRT substantially reduces the menopausal symptoms associated
with the decline in oestrogen production, namely the hot flushes, excessive sweating,
paraesthesiae (tingling sensation), palpitations, atrophic vaginitis (dryness of the vagina with
painful intercourse), insomnia, mood changes etc. The severity of these symptoms varies
greatly between women and when they are too troublesome HRT may be given over a
relatively short period of time (12-18 months) during which these problems largely disappear
spontaneously. Such treatment is probably reasonably safe even in the light of new evidence.

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108
HRT is definitely not a substitute for healthy life style that includes nutritious and balanced
diet with adequate intake of calcium, regular physical activity and avoidance of smoking. All
of these measures can slow down bone loss and reduce risk of bone fractures, especially if
started long before the menopause. Long-term HRT is very likely to carry more risks than
benefits.

HRT preparations can be given orally as tablets, transdermally as skin patch/gel or by

subcutaneous implant.

Oestrogen-only preparations at the time of writing are:

Composition Brand names (formulation)

Aerodiol (nasal spray)
Climara, Dermestril, Estraderm, Estraderm
MX, Estradot, Femtran, Monorest (all
oestradiol transdermal patches)
Estrofem, Progynova, Zumenon (tablets)
Oestradiol Implants (implants)
Sandrena (transdermal gel)

oestrone Genoral, Ogen (tablets)

oestriol Ovestin (tablets)

oestrogens mixture Premarin (tablets)

Oestrogen-progestogen preparations at the time of writing are:

Composition Brand names (formulation)

oestradiol + drospirenone Angeliq 1/2 (tablets)

oestradiol + cyproterone Climen (tablets)

Estalis Continuous, Estalis Sequi, Estracombi

oestradiol + norethisterone (all transdermal patches)
Kliogest, Kliovance, Trisequens (tablets)

oestradiol + dydrogesterone Femoston (tablets)

oestrogens mixture +
Premia (tablets)
medroxyprogesterone
tibolone (unique compound that
splits inside body into
Livial (tablets)
substances with both oestrogen
and progestogen activity)

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109
 PHARMACOLOGY OF PAIN AND INFLAMMATION

The control of pain is one of the most important indications for drug administration. Pain
receptors or nociceptors (mostly non-myelinated nerve endings), when stimulated by noxious
stimuli, send impulses into the dorsal horn of the spinal cord. Synaptic transmission here is
mainly mediated by glutamic acid (glutamate) acting on various types of glutamate receptors
(e.g., AMPA and NMDA). The relay neurons (second order sensory neurons) transmit pain
information to the thalamus through the lateral spinothalamic tract and then to the sensory
cortex (postcentral gyrus). It appears that the cortex is not necessary for pain perception but it
is essential for the mapping of pain (close association of pain sensation with a certain body
part).

This mechanism by which noxious peripheral stimuli are transmitted to the central nervous
system is called nociception. It is not always associated with pain (certain people can be
trained to tolerate pain, while others may even enjoy it). Pain is therefore a subjective
experience, severity of which can vary in different individuals for the same noxious stimulus.
Chemical stimuli acting on nociceptors to cause pain include bradykinin and serotonin (5-
HT). Nociceptors are sensitised by prostaglandins, which explains the analgesic effect of
aspirin-like drugs (see later), particularly in the presence of inflammation.

Transmission in the dorsal horn is subject to various modulatory influences, forming the
“gate control” mechanism. Descending pathways from the midbrain and brainstem exert a
strong inhibitory effect on dorsal horn transmission, thus limiting the amount of pain reaching
the cortex. It is also known that other mechanical stimuli (e.g., touch and pressure in
massage, or physical activity through proprioceptors) can reduce the pain by activating the
inhibitory interneurons in the dorsal horn. The inhibitory interneurons suppress the pain
transmission through the second order sensory neuron by inhibitory neurotransmitters such as
GABA (γ-amino butyric acid) and glycine, and producing their hyperpolarisation. Also
opioid peptides appear to reduce release of excitatory neurotransmitters such as glutamate
between the first and second order sensory neurons and thus reduce transmission of impulses
(presynaptic inhibition). Since intensity of pain as perceived in the brain is related to
frequency of pain impulses coming into the brain, reduction of excitatory neurotransmitter
release and hyperpolarisation of the second order sensory neuron substantially decreases the
number of pain impulses that are getting through the “gate” (second order sensory neuron).
Opioids cause analgesia partly by activating the descending pathways, and partly by directly
suppressing transmission in the dorsal horn.

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110
 Pain transmission pathways and proposed ‘gate control’
mechanism for control of pain

GIN
Opioids

OR -
GABA
GA
-
Pons
Midbrain
FOSN

SOSN
- GA GR + Thalamus
OR -
Opioids
ON GA
GABA Sensory
Pain receptor cortex

Damaging NA DIP
stimuli Other sensation + MR
(eg, pressure, heat) 5-HT
IIN

LEGEND:

FOSN first order sensory neuron GR glutamic acid receptor MR monoamine receptor
SOSN second order sensory neuron OR opioid receptor NA noradrenaline
GA glutamic acid ON opioid neuropeptides 5-HT serotonin
IIN inhibitory interneurons GABA gamma amino butyric acid
GA GABA receptor
GIN GABA i hibi DIP d di i hibi h

Analgesic drugs fall into the following main categories:

• morphine-like drugs (opioids)
• drugs for neuropathic pain
• non-steroidal anti-inflammatory drugs (aspirin and related substances)

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111
 OPIOID ANALGESIC DRUGS

Opium is an extract of the juice of the poppy Papaver somniferum, which has been used for
social and medicinal purposes for thousands of years, as an agent to produce euphoria,
analgesia and sleep, and to prevent diarrhoea. Besides morphine opium contains many
alkaloids related to morphine and papaverine which is a smooth muscle relaxant.

Opioid neuropeptides (17-31 amino acids) are naturally occurring endogenous substances,
which are involved in pain modulation, and morphine and related drugs mimic their action.
The most important opioid neuropeptides are endorphins, enkephalins and dynorphin.

The main groups of opioid analgesics are:

• Morphine analogues are closely related in structure to morphine, and often synthesised
from it. The main agents in this group are morphine [Morphine, MS Contin, MS Mono,
M.O.S., Ordine, RA-Morph, Anamorph, Kapanol, Sevredol], heroin (diacetylmorphine,

diamorphine, twice as potent as morphine, not used in medical practice), codeine

(methylmorphine) [Codeine phosphate], hydromorphone (morphine ketone) [Dilaudid]
and oxycodone (derived from the opium alkaloid thebaine) [Endone, OxyContin,
OxyNorm, Proladone]. Codeine is often mixed with paracetamol, aspirin and ibuprofen

and found in various combined simple analgesics (see later).

• Synthetic derivatives have structures unrelated to morphine. Examples are pethidine

[Pethidine], fentanyl [Actiq, Durogesic patches, Sublimaze injection], alfentanyl
[Rapifen injection], methadone [Physeptone, Biodone Forte], dextropropoxyphene
[Doloxene; with paracetamol Di-Gesic, Capadex, Paradex], buprenorphine [Subutex,
Temgesic, Norspan Transdermal Patch] and tramadol [Tramal, Tramedo, Tramahexal,

Zydol].

All opioids act on specific opioid receptors (different types of receptors exist). μ receptors
are thought to be responsible for most analgesic effects of opioids, and all analgesic opioids
are μ receptor agonists (opioid neuropeptides also activate these receptors). Most μ receptors
are presynaptic and therefore are found on first order sensory neuron terminals. Their
stimulation, via G-protein and second messengers, reduces influx of calcium needed for
release of glutamate neurotransmitter .That leads to decrease of glutamate release and
reduction of postsynaptic excitatory potential triggered by released glutamate. Small number
of μ receptors is postsynaptic and found on second order sensory neuron. These receptors

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112
appear to work by opening potassium channels which reduces neuronal excitability by
producing hyperpolarisation. More postsynaptic inhibition is contributed by GABA. Overall,
the end result is that significant temporal summation of incoming pain impulses is needed to
depolarise the second order sensory neuron (e.g. 5 impulses from the periphery needed to
produce one at the level of the second order sensory neuron which is then passed into the
CNS). Less impulses reaching the brain means less pain felt.

Opioids can also cause activation of certain neurons probably indirectly by inhibiting GABA
inhibitory neurons that posses receptors for opioid. Release of inhibitory neurotransmitter
GABA is reduced which leads to ‘inhibition of inhibition’ (activation). Opioids act both in
the spinal cord and higher centres in the brain to reduce transmission of pain impulses as well
as psychological interpretation of pain that presumably occurs in the limbic system.

• analgesia with reduction of the affective component of pain

(many patients given morphine are still very much aware of
pain but it does not bother them)
• euphoria (sense of contentment and well being) and sedation
• respiratory depression and suppression of cough, but no
suppression of the cardiovascular centres (heart rate and blood
pressure remain normal)
MAIN EFFECTS
OF MORPHINE • nausea and vomiting (through the stimulation of the
chemoreceptor trigger zone)
• pupillary constriction (important diagnostic feature in opioid
overdose)
• reduced gastrointestinal motility, leading to constipation
• histamine release, causing urticaria (hives) and itching at the
site of the injection, sometimes bronchoconstriction and
vasodilation (hypotension)

Morphine may be given by injection (intravenous or intramuscular), or orally, often as slow-

release tablets. The most troublesome unwanted effects are nausea, constipation and
respiratory depression (in acute overdose coma and respiratory failure). Today strong opioids
are usually given for severe pain (e.g., trauma, burns, postoperative pain, cancer pain, pain in
myocardial infarction, acute pancreatitis or urinary colic associated with kidney stones).
Codeine is also used for suppression of cough and for treatment of serious diarrhoea with
significant dehydration.
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113
Tolerance (increase in the dose required to produce a given pharmacological effect) to
morphine analogues develops rapidly but the mechanism of this is poorly understood. This is
especially evident with sedation, euphoria and respiratory depression. Interestingly miosis,
constipation and analgesia show little tolerance development. Dependence develops also,
including psychological as well as physical factors, but rarely occurs in patients being given
opioids as analgesics. Considering that strong opioids are frequently given to terminally ill
patients, dependence is not an issue in that clinical context. If it develops, abrupt withdrawal
results in a craving to take the drug, together with a withdrawal syndrome characterised by
yawning, sweating, fever, tremor, irritability, anorexia, nausea, vomiting, diarrhoea,
abdominal pain and pain in joints and muscles. The symptoms are maximal in about 2 days
and largely disappear in two weeks. Certain opioid analgesics, such as codeine,
buprenorphine and tramadol are much less likely to cause physical or psychological
dependence and may be a better option for prolonged use.

Opioid antagonists (short-acting naloxone [Narcan, Naloxone] and long-acting naltrexone

[Revia]) rapidly reverse all opioid effect especially respiratory depression, and are used
mainly to treat opioid overdose (e.g., with heroin).

Opioid withdrawal can be eased with methadone substitution because of its long half-life and
less profound sedation and withdrawal syndrome. Naltrexone detoxication does not relieve
any of withdrawal symptoms but blocks the effects of opioids if taken while the patient is on
naltrexone.

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114
 Diagram showing the ‘gate control’ of pain transmission and the
main sites of action of analgesic drugs

SENSORY
CORTEX

Periaqueductal Third order

grey area ⊕ sensory neuron

⊕ THALAMUS

∅ 1
∅
∅ ⊕
⊕

Lateral spino-
Nucleus reticularis thalamic tract
paragigantocellularis
SPINAL
Descending CORD
inhibitory
pathways
Second order
sensory neuron
Transmitters:
• noradrenaline
1
• opioid neuropeptides ∅
• serotonin ∅
∅ ⊕
⊕
CNS ⊕

First order
sensory neuron

Inflammation Receptors for touch/ pressure/

vibrations/temperature
Tissue damage
Direct action
Sensitising ∅ 2
Noxious Direct Pain receptor
Stimulus damage

LEGEND:

1. Opioids Inhibitory interneuron

2. NSAIDs

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115
 DRUGS FOR NEUROPATHIC PAIN

Neuropathic pain refers to pain produced by pathologic neural activity in different locations
in the nervous system such as periphery, central nervous system and sympathetic nervous
system due to injury of disease. Examples are diabetic neuropathy pain, neuropathy induced
by alcohol and some drugs (e.g. some anticancer drugs, some HIV medications, anti-TB
drugs isoniazide), neuralgia (postherpetic, trigeminal), phantom limb syndrome and
compression syndromes such as sciatica or carpal tunnel syndrome. Typical features of
neuropathic pain include shooting/lancinating pain, burning pain, tingling, numbness and
allodynia (pain produced by a normally non-painful stimulus). Mechanisms of neuropathic
pain are only partially understood but may include:

• Existence of ectopic foci as a result of nerve compression, or abnormal sensitivity to

mechanical stimulation occurring at the nerve stump, in areas of myelin damage, or
in the dorsal root ganglion soma

• Ephaptic transmission (cross-excitation) is due to damage to myelin; as a result of

the lack of insulation between neurons, excitation of one neuron may induce activity
in another neuron

• Other maladaptive changes in spinal cord, thalamus or cerebral cortex

Management of neuropathic pain is difficult as conventional analgesics are or ineffective or

only modestly effective. Some relief can be obtained by using selective antiepileptic drugs
such as gabapentin [Neurontin, Nupentin, Gantin, Pendine] and pregabalin [Lyrica]. The
mechanism of action of gabapentin is unknown. Pregabalin is an analogue of inhibitory
neurotransmitter GABA. Another antiepileptic carbamazepine [Tegretol, Teril] is of value in
trigeminal neuralgia. It works by blocking voltage dependent sodium channels and thus
reducing cell membrane excitability.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Prostaglandins are ubiquitous fatty-acid derivatives that are important mediators involved in
many different physiological processes in addition to their well recognised role in
inflammation, pain generation and immune response modulation. Prostaglandins are involved

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116
in as diverse normal processes as renal function, vasomotor tone, platelet aggregation and
blood clotting, differentiation of immune cells, wound healing, nerve growth, bone
metabolism, ovulation, and initiation of labour. In pathologic conditions tissue damage
activates phospholipase A2 which causes arachidonic acid to be split off the cell membrane
phospholipids where it is found in esterified form. Arachidonic acid is often referred to as ω-
6 20-carbon fatty acid where ω-6 signifies that the first double bond exists as the sixth
carbon-carbon bond from the terminal CH3 end (ω) of the carbon chain.

Most arachidonic acid in the human body is derived from dietary linoleic acid (18-carbon ω-
6), which comes both from vegetable oils and animal fats. The fate of the released
arachidonic acid depends on which of several possible pathways it takes. There are two main
pathways; the lipoxygenase pathway leads to the formation of leukotrienes whereas the cyclo-
oxygenase pathway leads to formation of prostaglandins and thromboxanes like TXA2.
Important prostaglandins generated through COX pathway:
• PGD2
• PGE2
• PGI2 (also called prostacyclin)
• PGF2α
All have 20 carbons but also 5 carbon ring and have various
functions in different tissues (number 2 refers to number of double bonds, so called series-2
PGs). Individual prostaglandins require additional enzymes for their synthesis like PGE
synthase,

Two types of cyclo-oxygenase have been identified:

1. COX-1: Constitutive (“good”) cyclo-oxygenase, found in a variety of tissues and

stimulates the formation of prostaglandins involved in physiological, ‘housekeeping’
processes. In the stomach, COX-1 stimulates the synthesis of PGE2 that has
cytoprotective actions and plays an important role in maintaining the integrity of the
gastric mucosa. PGE2 in the kidney maintains normal blood flow through its vasodilatory
effect.

2. COX-2: Inducible (“bad”) cyclo-oxygenase is found mainly in inflammatory and

immune cells (neutrophils, macrophages, mast cells, etc). At the site of inflammation
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117
 synthesis of more COX-2 is induced and this COX-2 is responsible for the generation of
the hyperalgesic and pro-inflammatory prostaglandins. However while COX-1 does not
appear to be involved in mediation of inflammation and pain, COX-2 does operate in
some physiologic processes as well, such as ovulation and implantation (see later).

Primary action of the conventional 1st generation NSAIDs is the inhibition of cyclo-
oxygenase with little or no selectivity between the two COX types. Anti-inflammatory and
analgesic effects are clearly achieved through blocking of COX-2 and several important
unwanted effects are a consequence of COX-1 inhibition.

Some important examples of 1st generation NSAIDs are:

o aspirin [Alka-Seltzer, Aspirin, Ecotrin, Disprin, Aspro, Cartia, Cardiprin]

o ibuprofen [Brufen, Bugesic, Butalgin, Advil, Nurofen, Panafen, Pro-Ven, Rafen,
Tri-Profen]

o ketoprofen [Orudis, Oruvail SR]

o naproxen [Naprosyn, Naprogesic, Nurolasts, Proxen, Inza, Anaprox, Aleve,
Crysanal]

o indomethacin [Indocid, Arthrexin]

o piroxicam [Feldene, Mobilis, Pirohexal-D]
o diclofenac [Voltaren, Diclohexal, Clonac, Dinac, Fenac, Imflac]
o meloxicam [Mobic, Movalis]
o mefenamic acid [Ponstan, Mefic]
o tiaprofenic acid [Surgam]
o paracetamol [Panadol, Febridol, Duatrol SR, Dymadon, Panamax, Paralgin,
Parahexal, Parmol, Perfalgan].

Combination simple analgesics contain one of NSAIDs and codeine:

o aspirin + codeine [Apalgin, Codiphen, Codis, Codral Forte, Disprin Forte, Veganin]
o codeine + paracetamol [Codalgin and Codalgin Forte, Codalgin Plus, Codapane and
Codapane Forte, Dolaforte, Dymadon Co., Dymadon Forte, Fiorinal, Mersyndol,

Mersyndol Forte, Panadeine, Panadeine Forte, Panalgesic, Panamax Co., Prodeine

Forte]

o codeine + ibuprofen [Nurofen Plus, Panafen Plus]

It should be mentioned that aspirin (acetylsalicylic acid) causes irreversible inactivation of

cyclo-oxygenase (causing its acetylation) while all other NSAIDs are reversible inhibitors of

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118
COX, and in addition to its anti-inflammatory actions, aspirin inhibits platelet aggregation
and is important in the prevention and therapy of myocardial infarction. Paracetamol (called
acetaminophen in USA) has analgesic and antipyretic but not any significant anti-
inflammatory actions. Its mechanism of action is inhibition of COX-1 variant in the brain
(sometimes called COX-3) without inhibition of prostaglandin formation in the periphery.
Because of these properties paracetamol is usually used as a pain killer and antipyretic rather
then an anti-inflammatory agent.

Most of these drugs have three major types of effect:

• Anti-inflammatory action: the decrease in synthesis of vasodilator prostaglandins (PGI2)

means less vasodilation and vascular permeability, and less oedema formation. However
inhibition of prostaglandin synthesis by NSAIDs reduces rather than abolishes
inflammation because they do not inhibit formation and action of other numerous
mediators of inflammation.

• Analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptic

nerve endings to the inflammatory mediators bradykinin and serotonin. Relief of headache
is probably due to decreased prostaglandin-mediated vasodilation. NSIADs are generally
not effective in management of visceral pain (e.g., in myocardial infarction, renal colic,
peptic ulcer) and opioid analgesics must be used instead.

• Antipyretic effect: this is partly due to a decrease in the mediator prostaglandin (which is
generated in response to the inflammatory pyrogen interleukin 1 released from leukocytes)
that is responsible for elevating the hypothalamic set-point for temperature control in
fever. NSAIDs do not reduce the normal body temperature.

Unwanted effects of NSAIDs are common, particularly in the elderly. Important ones are:

• Dyspepsia (indigestion), nausea and vomiting, acute gastritis with bleeding and peptic
ulcer with chronic use due to neutralisation of the protective effect of PGE2 on gastric
mucosa and the fact that most NSAIDs are acidic drugs that can directly irritate the gastric
mucosa. Selective COX-2 inhibitors appear to be much less likely to cause these unwanted
effects although long-term studies will be necessary.

• Skin allergy-like such as rashes and urticaria (hives) have been reported as well as
bronchospasm in asthmatics; bronchospasm is probably caused by shift of arachidonic
acid metabolism towards leukotrienes which have strong bronchoconstricting effect .

• Therapeutic doses of NSAIDs in healthy individuals pose little threat to kidney function,
but in susceptible patients (or with existing renal impairment) they cause reduced
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 glomerular filtration, fluid and sodium retention and even hypertension due to decreased
PGE2-mediated vasodilation in the kidneys and reduced renal blood flow.

• Analgesic-associated nephropathy presenting as chronic renal failure can occur following

long-continued high doses of NSAIDs (more particularly paracetamol), when it is caused
by prolonged mild ischaemia in the kidneys.

• Less commonly liver damage and bone marrow depression may develop in long-term
treatment (blood count and liver function tests should be monitored).

The 2nd generation NSAIDs represent a new class of drugs (selective COX-2 inhibitors) and
are considered a major advance in the management of pain and inflammatory diseases. They
have been developed to address the unwanted effects of conventional NSAIDs that prevent
many patients from taking large enough doses to combat pain and inflammation in certain
conditions such as rheumatoid arthritis. Currently approved drugs in Australia in this
category are celecoxib [Celebrex] for oral use and parecoxib [Dynastat] for parenteral use in
postoperative pain. Rofecoxib [Vioxx] and lumiracoxib [Prexige] have been withdrawn from
the market due to evidence that it can increase risk for thrombosis and in that way risk for
myocardial infarction and stroke. This risk appears to be shared by all COX-2 inhibitors.

Recent reports have suggested that COX-2 inhibitors may produce temporary reversible
infertility in women by preventing ovulation or delaying it until the egg is no longer viable.
Also they could have a negative effect on implantation after conception has occurred, and
even lead to spontaneous miscarriage. Menstrual cycle is generally unaffected in these
women. Non-selective COX inhibitors appear to be less likely to produce these unwanted
effect, but it would be better if women who plan to conceive do not take any NSAID.

Clinical uses of the NSAIDs:

• For analgesia in painful conditions (e.g., headache, dysmenorrhoea, backache,

postoperative pain, osteoarthritis); NSAIDs are generally not effective in management of
visceral pain (in myocardial infarction, renal colic, peptic ulcer, pancreatitis etc)

• For anti-inflammatory effects in chronic inflammatory conditions (e.g., rheumatoid

arthritis and related connective tissue disorders); with many NSAIDs the dosage required
for chronic inflammatory disorders is considerably greater than for simple analgesia and
treatment may need to be continued for long periods; thus unwanted effects and toxic
effects are likely to be seen. NSAIDs do not alter the course of these conditions.

• To lower temperature - paracetamol and ibuprofen are preferred because they lack
gastrointestinal unwanted effects.
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Both COX-1 and COX-2 also metabolise two other essential fatty acids – dihomo-gamma-
linolenic acid (DGLA; ω-6) and eicosapentaenoic acid (EPA; ω-3) to give the series-1 and
series-3 prostaglandins, some of them are less inflammatory than series-2, some of them have
no pro-inflammatory activity. ω-3 signifies that the first double bond exists as the third
carbon-carbon bond from the terminal CH3 end (ω) of the carbon chain. DGLA and EPA
compete with arachidonic acid for the COX pathways which accounts for antiinflammatory
properties of dietary sources of DGLA (vegetable/plant oils such as flaxseed/linseed, evening
primrose) and EPA (fish oil like salmon sardine mackerel).

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 Diagram showing the main sites of action of NSAIDs and
glucocorticoids

Membrane phospholipids Glucocorticoids

(via annexin)
∅
Phospholipase A2
∅
NSAIDs
Arachidonic acid ∅
Lipoxygenase Cyclo-oxygenase

Leukotriene A4 (LTA4) Prostaglandin H2 (PGH2)

Leukotriene B4 (LTB4)
chemotaxis
Prostacyclin (PGI2)
vasoconstriction,
inhibition of platelet
Leukotriene C4 (LTC4)
aggregation
vasoconstriction,
bronchospasm,
increased permeability
Thromboxane A2 (TXA2)
vasoconstriction, platelet
Leukotriene D4 (LTD4) aggregation
vasoconstriction,
bronchospasm,
increased permeability
Prostaglandin D2 (PGD2)
vasodilation, oedema

Leukotriene E4 (LTE4)
vasoconstriction,
bronchospasm, Prostaglandin E2 (PGE2)
increased permeability vasodilation, oedema,
gastric cytoprotection

Prostaglandin F2α (PGH2α)

vasodilation, oedema,
uterine constriction

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 Arachidonic
acid

COX-1 COX-2

Constitutive Induced (IL-1, TNF)

Inhibition Inhibition
undesirable desirable

Homoeostatic functions Inflammation

• Gastrointestinal tract Pain
• Renal tract
• Platelet function
• Macrophage
differentiation

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 GLUCOCORTICOSTEROIDS

The principal adrenal steroids are those with mineralocorticoid and glucocorticoid activity,
but some sex steroids, mainly androgens, are also secreted. The mineralocorticoids affect
water and electrolyte balance and the main endogenous hormone is aldosterone. The
glucocorticoids affect carbohydrate and protein metabolism (increased gluconeogenesis) and
the main endogenous hormones are cortisol (hydrocortisone), cortisone and corticosterone.

In addition to their metabolic effects, glucocorticoids also have anti-inflammatory and

immunosuppressive activity, and it is for these actions that are most commonly used
therapeutically. When they are used as anti-inflammatory and immuno-suppressive agents, all
of their other actions are unwanted unwanted effects. Synthetic steroids have been developed
in which it has been possible to separate the glucocorticoid from the mineralocorticoid
actions, but it has not been possible to separate the anti-inflammatory actions from the other
actions of glucocorticoids. Synthetic glucocorticoids are preferred today for most clinical
purposes because they have higher efficacy, are less rapidly inactivated (longer duration of
action), and have little or no salt-retaining properties.

The main stimulus for synthesis and release of the glucocorticoids is corticotrophin (ACTH)
secreted from the anterior pituitary. Corticotrophin-releasing factor (CRF) from the
hypothalamus regulates ACTH release and is in turn regulated by neural factors and negative
feedback of plasma glucocorticoids. Mineralocorticoid release from the adrenal cortex is
controlled by the renin-angiotensin system.

Glucocorticoids are available in different formulations for different indications.

• Glucocorticoids for oral use:

o hydrocortisone [Hysone]
o cortisone [Cortate]
o prednisone [Sone]
o prednisolone [Solone, PredMix Oral Liquid, Redipred Oral Liquid]
o prednisone + prednisolone [Predsone, Predsolone, Panafcort, Panafcortelone]
o budesonide [Entocort]
• Glucocorticoids for parenteral use:
o hydrocortisone [Solu-Cortef]
o methylprednisolone [Solu-Medrol, Depo-medrol, Depo-Nisolone]
o triamcinolone [Kenacort-A]
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 o dexamethasone [Dexmethasone]
o betamethasone [Celestone Chronodose]
• Glucocorticoids for topical use on skin:
o methylprednisolone [Advantan]
o hydrocortisone [Cortaid, Cortef, Egocort, Sigmacort]
o triamcinolone [Aristocort, Tricortone]
o betamethasone [Antroquoril, Betnovate,Eleuphrat, Diprosone]
o mometasone [Elocon, Novasone]
o clobetasone [Becoderm-C]
• Glucocorticoids for inhalation (asthma):
o fluticasone [Flixotide]; also fluticasone + salmeterol [Seretide]
o budesonide [Pulmicort]; also budesonide + eformoterol [Symbicort Turbuhaler]
o beclomethasone [Qvar]
o ciclesonide [Alvesco]
• Glucocorticoids for intranasal application (allergic rhinitis):
o triamcinolone [Telnase]
o budesonide [Rhinocort, Budamax]
o mometasone [Nasonex]
o fluticasone [Beconase Allergy & Hayfever 24 hour]
o beclomethasone [Beconase Allergy & Hayfever 12 hour]

Glucocorticoids interact with intracellular receptors, and the resulting steroid-receptor

complex then interacts with DNA to modify gene transcription, including synthesis of some
proteins and inhibiting synthesis of others. Through such process steroids stimulate synthesis
of a protein called annexin that inhibits enzyme phospholipase A2, which is normally
responsible for the formation of arachidonic acid, the precursor of inflammatory mediators
prostaglandins and leukotrienes (together called eicosanoids). Glucocorticoids also inhibit the
formation of inducible cyclo-oxygenase (COX-2), which then decreases synthesis of
prostaglandins. They also suppress transcription and synthesis of various pro-inflammatory
cytokines and consequently their release by inflammatory cells. These mechanisms appear to,
at least partially, underlie the anti-inflammatory effect of glucocorticoids.

The main anti-inflammatory and immunosuppressive actions are:

• Reduced vasodilation, decreased fluid exudation, reduced oedema formation

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• Decreased proliferation of new blood vessels (angiogenesis), reduced synthesis of
collagen, less fibrosis and less scarring

• Decreased number and activity of leukocytes (in acute inflammation) and lymphocytes
and macrophages (in chronic inflammation); reduced synthesis of various cytokines

• Decreased production of new T and B lymphocytes, reduced immune response,

especially of cell mediated type (CMI)

Unwanted effects are seen mainly with prolonged systemic use as anti-inflammatory or
immunosuppressive agents (in which case all the metabolic actions are unwanted), but not
usually with replacement therapy. The most important are:

• decrease in the protective aspects of the inflammatory response and decreased healing
ability (e.g., slow wound healing), increased susceptibility to infections and reduced
clearance of infections

• suppression of endogenous glucocorticoid synthesis, leading to adrenal atrophy. It may

take 6-12 months for normal adrenal function to fully recover once the therapy is stopped;
this is the reason why steroid therapy must be withdrawn gradually to avoid adrenal
insufficiency

• metabolic actions (increased gluconeogenesis and tendency to hyperglycaemia, increased

breakdown and reduced synthesis of proteins)

• increase in bone breakdown and osteoporosis through inhibition of the activity of

osteoblasts and stimulation of the activity of osteoclasts

• increased peripheral vascular resistance and blood pressure (glucocorticoids enhance

effects of noradrenaline and adrenaline on smooth muscle in peripheral arterioles by
increasing expression of α1 adrenergic receptors)

• after long term therapy iatrogenic Cushing’s syndrome can be observed in various grades
of severity (buffalo hump on the lower neck, moon face with red cheeks, thinning of skin,
easy bruising, increased abdominal fat, thin arms and legs, muscle wasting, increased
appetite, hypertension, euphoria and emotional lability, sometimes psychotic symptoms)

Clinical use of glucocorticoids:

• Replacement therapy for patients with adrenal failure (e.g., Addison’s disease). All the
actions of the glucocorticoids are required, and a mineralocorticoid (usually
fludrocortisone [Florinef]) will have to be given along with a glucocorticoid.

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126
• Anti-inflammatory/immunosuppressive therapy:
o in asthma (by inhalation or, in severe cases systemically)
o topically in various inflammatory conditions of skin, eye, ear or nose (e.g., atopic
eczema or allergic contact eczema, allergic conjunctivitis or rhinitis)
o in hypersensitivity states (e.g., severe allergic reactions to food, drugs or insect bites)
o in many autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus
erythematosus, inflammatory bowel disease)
o to prevent graft rejection following organ or bone marrow transplantation

• In neoplastic disease:
o in combination with cytotoxic drugs in treatment of specific malignancies (e.g., acute
lymphoblastic leukaemia, lymphoma)
o to reduce cerebral oedema in patients with metastatic or primary brain tumours and
after brain trauma
o as a component of anti-emetic treatment in conjunction with chemotherapy

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 Diagram showing the mechanism of action of glucocorticoids

HYPOTHALAMUS ∅
Protein Effects
synthesis
CRH

mRNA
PITUITARY
GLAND
∅
DNA
S R

ACTH S R
1

S
S + R
ADRENAL
GLAND

LEGEND:

CRH corticotrophin releasing hormone

ACTH adrenocorticotrophic hormone Drugs:
(corticotrophin) 1. Corticosteroid drugs (mimic
S glucocorticoid hormones effects of endogenous hormones)
R cytoplasmatic glucocorticoid receptor

ANTIRHEUMATIC DRUGS

Rheumatoid arthritis (RA) is the commonest form of chronic inflammatory joint disease:
symmetrical, destructive and deforming polyarthritis affecting small and large peripheral
joints with associated systemic disturbances and a variety of extra-articular features, It is a

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complex autoimmune process in which primary inflammatory cytokines, IL-1 and TNF-α,
have a major role in pathogenesis.
Management of RA includes:
• NSAIDs
• glucocorticoids
• disease-modifying antirheumatic drugs (DMARDs

DMARDs generally improve symptoms and can reduce disease activity in rheumatoid
arthritis but whether they actually halt the long-term progress of the disease is hotly debated.
It is today accepted that DMARD therapy should be initiated as soon as a definite diagnosis
of RA has been reached. Their clinical effects are usually slow (weeks - months) in onset, and
it is usual to provide NSAID and glucocorticoid 'cover' during this induction phase. If therapy
is successful (and the success rate is not always high), concomitant NSAID or glucocorticoid
therapy can generally be dramatically reduced. The following are commonly used DMARDs
in RA.

Methotrexate [Methotrexate, Methoblastin]

• folic acid antagonist which suppresses DNA synthesis and thus cell proliferation
• has cytotoxic (anti-cancer) and immunosuppressant activity and potent anti-
rheumatic action
• commonly a first-choice DMARD and has a more rapid onset of action than other
DMARDs
• it is used orally once a week (better tolerated than with daily administration), and
usually folic acid is used (daily) as well (reduces unwanted effects but does not affect
immunosuppressive action !)
• common unwanted effects (dose-related): anorexia, nausea, diarrhoea, bone marrow
suppression and potential liver toxicity

Leflunomide [Arava, Arabloc]

• has a relatively specific inhibitory effect on activated T cells by reducing their
proliferation probably by inhibiting synthesis of nucleotides
• only currently approved for RA and psoriatic arthritis
• used orally, often together with methotrexate (liver functions need to be closely
monitored)
• relatively well tolerated by most patients and may produce beneficial effects fairly
soon (1 month) after beginning treatment

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129
 • common unwanted effects: skin rashes, nausea, reversible hair loss, raised liver
enzymes with potential liver toxicity

Hydroxychloroquine [Plaquenil] and chloroquine [Chlorquin]

• originally used in treatment of malaria; it is unclear what effect is responsible for
anti-rheumatic activity
• given orally, usually used in patients who cannot tolerate other DMARDs, or in
combination with another DMARD (eg. methotrexate) for more comprehensive
treatment
• considered relatively safe drugs but take often months to produce improvement
• the major concern is that high doses can produce irreversible retinal damage which is
rare in doses used in practice (eye checks needed)
• nausea, diarrhoeas and skin rashes can occur

Sulfasalazine [Salazopyrin, Pyrin]

• more often used in treatment of chronic inflammatory bowel disease, but it also has
anti-rheumatic activity
• its mode of action in RA is unknown but its anti-inflammatory effect (possible
interaction of metabolism of arachidonic acid) and antibacterial effects in the gut
have been suggested (significance in RA?)
• used orally, usually in combination with other DMARDs
• unwanted effects: anorexia, nausea, vomiting, skin allergy, risk for bone marrow
suppression and liver toxicity (dose-related) – full blood count and liver function
tests should be monitored

Penicillamine [D-Penamine]
• more commonly used as a chelating agent in the treatment of Wilson’s disease (over
accumulation of copper) and heavy metals poisoning (will enhance the urinary
excretion of copper, lead, mercury and others)
• produced by hydrolysis of penicillin and appears in the urine after treatment with
that drug
• the basis for the antiarthritic effects is unknown although immunosuppressant effect
has been observed
• considered to be fairly toxic when compared with other DMARDs; unwanted effects
include fever, joint pain, skin rashes and itching, and swelling of lymph glands; more
dangerous is potential kidney and liver toxicity
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Gold compounds auranofin [Ridaura] and aurothiomalate [Myocrisin]
• the first DMARD introduced, can be very effective is some patients but not all - they
work slowly often taking months
• man be used orally (Ridaura) and by weekly intramuscular injection (Myocrisin)
• the mode of action unclear – potential accumulation in macrophage lysosomes with
consequent reduction in release of lysosomal enzymes into the synovium
• unwanted effects are common and include anorexia, nausea, vomiting, skin rashes,
bone marrow suppression and kidney toxicity with proteinuria (less marked with oral
formulation)

Biological DMARDs
• proinflammatory cytokines, most notably tumour necrosis factor-α (TNF-α ) and
interleukin-1 (IL-1) play a central role in the pathophysiology of RA
• this insight led to the development and clinical use of biological agents directed
against TNF-α and IL-1
• they are all parenteral drugs (no oral use is possible)
• due to their high cost they are approved for patients who meet certain criteria in
relation to severity of RA and failure to improve with more conventional DMARDs
• they are usually used with methotrexate; the most common unwanted effect is
increased susceptibility to infections especially of the respiratory tract
• etenercept [Enbrel] is a “fake TNF-α receptor” given subcutaneously once or twice a
week
• infliximab [Remicade] is a mouse/human chimeric monoclonal antibody against
TNF-α that is given intravenously every 4–8 weeks
• adalimumab [Humira] is a recombinant human monoclonal antibody against TNF-α
that is administered subcutaneously every other week
• rituximab [Mabthera] is a mouse/human chimeric monoclonal antibody directed
against the CD20 molecule found on the surface of B cells (leads to their depletion)
that is given iv in form of two infusions 2 weeks apart
• anakinra [Kineret] is IL-1 antagonist given daily by sc inj
• several new biological DMARDs that interfere with other aspects of chronic
inflammatory process are under development with encouraging results

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 HISTAMINE ANTAGONISTS

Histamine is a mediator released from mast cells and basophils in various physiologic and
pathologic conditions and acts by binding two types of histamine receptors H1 and H2.

• H1 receptors are responsible for increased vasodilation, vascular permeability, oedema

formation and itching in allergic reactions, decreased blood pressure and reflex
tachycardia, bronchoconstriction and stimulation of gastrointestinal smooth muscle
leading to increased motility and diarrhoea.

• H2 receptors are mainly found on gastric parietal cells where they stimulate gastric-acid
secretion.
Consequently there are two classes of histamine antagonists: H1 and H2 receptor antagonists.
The term “antihistamine” refers to the H1 receptor antagonists, which can be used:

• For allergic reactions including allergic rhinitis (hay fever) and allergic conjuctivitis, skin
rashes, insect bites, drug hypersensitivities where they reduce inflammation, redness,
swelling and itching. Drugs that lack sedative or muscarinic receptor antagonist actions
(e.g., cetrizine [Zyrtec], azatadine [Zadine], loratadine [Lorastyne, Allereze, Claratyne,
Clarinase], desloratadine [Claramax] and fexofenadine [Telfast, Xergic]) are preferred.

Antihistamines that can produce sedation are feniramine [Avil], dexchlorpheniramine

[Polaramine], cyproheptadine [Periactin], promethazine [Phenergan] and trimeprazine
[Vallergan]. Topically applied antihistamines are levocabastine [Livostin] - application to
the nasal mucosa in cases of allergic rhinitis, and to the eyes in allergic conjunctivitis;
olopatadine [Patanol] - used as drops in allergic conjunctivitis and azelastine [Azep] –
nasal spray for allergic rhinitis.

• As anti-emetics for the prevention of motion sickness or other causes of nausea

(dimenhydrinate [Dramamine])

• For sedation: some drugs (e.g., promethazine [Phenergan]) and trimeprazine [Vallergan])
are fairly strong sedatives and may be used for this action.

Unwanted effects:

• What is defined as unwanted will depend to a certain extent on what the drugs are used
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 for. When used for purely antihistamine action, all the CNS effects are unwanted. When
used for their sedative and anti-emetic actions, some of the CNS effects such as dizziness
and fatigue are unwanted.

• Some antihistamines produce peripheral antimuscarinic actions. The commonest of these

is dryness of the mouth, but blurred vision, constipation and urine retention can occur.

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 PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM

ANXIOLYTIC AND HYPNOTIC DRUGS

Anxiolytic drugs, also known as minor tranquillisers, are used to treat the symptoms of
anxiety and hypnotic drugs are used to treat insomnia (sleeplessness). Although the clinical
objectives are different, the same drugs are often used for both purposes, which is a reflection
of the fact that drugs that relieve anxiety generally cause a degree of sedation and drowsiness.
At the same time this is one of the main drawbacks in the clinical use of anxiolytic drugs for
relief of anxiety where sedation is generally unwanted. Anxiolytics are one of the most
prescribed drugs worldwide.

The chief manifestations of anxiety are:

• Verbal complaint. The patient says that they are excessively tense, anxious, worried, in
anticipation of misfortune to self and others.
• Somatic and autonomic effect. The patient is restless and agitated, has tachycardia,
muscle tremor, increased sweating with cold and clammy hands, often gastrointestinal
disorders (indigestion, nausea, diarrhoea), frequent urination and lump in the throat.
• Interference with normal productive activities (easy distractibility, difficulties
concentrating on work and communicating with others). This is usually an indication that
some form of treatment is necessary.

Since anxiety may be a reaction to a stressful life situation or too much work and pressure, it
is important to try to identify those causes and deal with them in appropriate way. Skilful
professional counselling and various stress management techniques frequently offer more
long-term benefit than anxiolytic drugs. The ordinary anxiety and tension associated with the
stress of everyday life usually does not require treatment with an anxiolytic agent.
Occasionally anxiety is so stressful and mentally painful that drug therapy can be considered.

Main classes of anxiolytic and hypnotic drugs are:

1. Benzodiazepines: the most important class, used for treating anxiety states and insomnia
2. Novel anxiolytics and sedatives
3. Selected antidepressants
4. Antihistamines: some antihistamines produce enough drowsiness to enable their use as
hypnotics

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 Benzodiazepines

They act by enhancing the inhibitory effect of GABA (γ-amino butyric acid, a product of
decarboxylation of glutamic acid) which is the main inhibitory neurotransmitter in the CNS
(glutamate is the main central excitatory transmitter). It has been estimated that about a third
of all synapses in the brain are GABA inhibitory ones. It appears that biochemical and
pathophysiologic basis of anxiety may be too much stimulation or insufficient GABA-
mediated inhibition. GABA receptor is directly coupled to a chloride channel, so its
activation opens the chloride channel allowing influx of Cl- ions along their concentration
gradient, and hyperpolarisation of the cell (postsynaptic neuron), rendering the cell more
resistant to activation (the cell is inhibited). This action is known as postsynaptic modulation
and controls postsynaptic neuronal excitability. Benzodiazepines bind to a modulatory site on
the GABA receptor distinct from the GABA-binding site; they increase the affinity of GABA
receptors for GABA, and therefore duration of chloride channel opening. In experimental
settings in the absence of GABA, benzodiazepines do not affect Cl- conductance and have no
clinical effect.

There are at least two different benzodiazepine receptors with different physiologic effects:

o BZ1 – associated with anxiolytic and sedative effects

o BZ2 – associated with muscle relaxation, memory and learning

The main pharmacological effects of benzodiazepines are:

• reduction of anxiety and agitation (the most important outcome); benzodiazepines
generally do not have antidepressant properties
• sedation, leading to improvement of insomnia (benzodiazepines shorten the time
taken to get to sleep and increase the total duration of sleep)
• muscle relaxation by a central action independent of the sedative effect which is
an important action because increased muscle tone is a common feature of anxiety
• suppression of convulsions (antiepileptic effect)

Benzodiazepines are usually given orally and are relatively fast-acting medications producing
their effect within hours, some in even less time. Various benzodiazepines differ mainly in
respect to their duration of action. Benzodiazepines are relatively safe in overdose (in contrast
to barbiturates), producing only prolonged sleep with minimal and clinically insignificant
respiratory depression but no cardiovascular depression.

The main unwanted effects are drowsiness, confusion and impaired motor coordination,
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135
which can interfere with certain precise activities such as driving or operating machinery, as
well as logical thinking. Irregular menstrual periods and altered sexual desire can also occur.
Other disadvantages are long-lasting hangover effects (1-2 days) and the development of
dependence. Dependence will usually develop in 6-7 weeks of regular treatment (in one
patient it has taken only 2 weeks!), with withdrawal symptoms of anxiety, insomnia, tremor,
dizziness, nausea and diarrhoea if the treatment is suddenly discontinued. Tolerance is also
well documented when patients need increased doses to obtain the same therapeutic effect. To
avoid the withdrawal syndrome after benzodiazepines have been taken for an extended
period, the dosage is gradually tapered off before being completely stopped. Benzodiazepines
have additive or synergistic effects with other central depressants such as alcohol,
barbiturates and sedating (‘drowsy’) antihistamines, and shouldn’t be taken in combination
with any of them.

Main examples of anxiolytic benzodiazepines:

o lorazepam [Ativan]
o diazepam [Valium, Ducene, Antenex, Valpam]
o oxazepam [Alepam, Serepax, Murelax]
o alprazolam [Alprax, Xanax, Kalma, Alepam, Zamhexal]
o clobazam [Frisium]
o bromazepam [Lexotan]

Main examples of hypnotic benzodiazepines:

o nitrazepam [Mogadon, Alodorm]
o triazolam [Halcion]
o flunitrazepam [Hypnodorm]
o midazolam [Hypnovel, Midazolam] – parenteral application
o temazepam [Normison, Temaze, Temtabs]

Main examples of antocovulsant benzodiazepines:

o clonazepam [Rivotril, Paxam]

Clinical uses of benzodiazepines:

• As hypnotics for troublesome insomnia, e.g., for jet lag or bereavement (short term use)
• As anxiolytics for severe anxiety (short term use)
• For preoperative sedation as a part of anaesthetic premedication to calm the patient (one
dose only the night before the surgery)
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136
• For symptomatic relief of acute alcohol withdrawal symptoms
• As anticonvulsants in epilepsy, especially in epileptic status (usually parenteral diazepam
and lorazepam)
• As muscle relaxants in chronic muscle spasm and spasticity (e.g., after stroke or spinal
injury)

Many benzodiazepines have long half-life which contributes to their tendency to accumulate
in the body and cause long hangovers. Flumazenil [Anexate] is a competitive antagonist of
benzodiazepines that can reverse their effects, which is usually rarely needed.

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 Diagram showing the main modes of action of anxiolytic and
hypnotic drugs

Inhibitory neuron
Resting membrane
-70 mV potential
GABA-M
-55 mV Threshold
GABA GABA-T

GABA

Anxiolytic
given
GABA
Benzodiazepine
Cl-

BeS GaR
⊕
Postsynaptic Hyperpolarisation
Cl- inhibitory potential (neuron inhibition)

LEGEND:

GABA γ-amino butyric acid

GABA-T GABA transaminase
GABA-M GABA metabolites
GaR GABA receptor
BeS benzodiazepines binding site

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138
 Novel anxiolytics and sedatives/hypnotics

Buspirone [Buspar] is a novel anxiolytic with unclear mechanism of action (does not
interfere with GABA receptors). There is some evidence that it can activate serotonin 5-HT1A
and dopamine D2 receptors but probably indirectly affects other neurotransmitters. Buspirone
causes little or no drowsiness, no significant impairment of cognitive or motor performance
and does not seem to cause dependence or withdrawal symptoms when ceased. Interestingly
the relief of anxiety increases progressively over several weeks and it is not as fast as with
benzodiazepines which is considered to be the main shortcoming of buspirone. Also
buspirone has no muscle relaxant and anticonvulsant properties. Unwanted effects are mild
and include nausea, headache, dizziness, light headedness, and rarely allergic reactions.

Zolpidem [Stilnox, Dormizol, Stildem, Zolpibell] is a hypnotic structurally unrelated to

benzodiazepines but has a similar mechanism of action through binding to BZ1 receptor on
postsynaptic GABAA receptor. The most common unwanted effect is drowsiness/dizziness,
but less effect on motor coordination and memory/learning.

Zopiclone [Imovane, Imrest] belongs to a novel chemical class which is structurally

unrelated to existing hypnotics. The pharmacological profile of zopiclone is similar to that of
the benzodiazepines. Unwanted effects are also similar.

Selected antidepressants

Several antidepressants have been shown to have anxiolytic effects and can be used for
patients who have combined anxiety and depression or patients who do not tolerate other
anxiolytics due to unwanted effects. Antidepressants used in anxiety are mainly SSRIs
paroxetine [Paroxetine, Aropax, Extine, Paxtine] and escitalopram [Esipram, Lexapro]. If
required they can be combined with other anxiolytics.

Antihistamine sedatives

Doxylamine [Dozile, Restavit] is one of antihistamines which is used for the temporary relief
of sleeplessness because of its sedative effect. The drug is also used in combination with
antitussives and decongestants for the temporary relief of cold and cough symptoms. A
similar drug is diphenhydramine [Unisom, Snuzaid]. In children antihistamines promethazine
[Phenergan] and trimeprazine [Vallergan] in form of syrups are often used for sedation.

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 NEUROLEPTIC DRUGS

Neuroleptic drugs are also known as antischizophrenic drugs, antipsychotic drugs or major
tranquillisers, and are used in treatment of psychosis. The most important types of psychosis
are:
• schizophrenia
• affective disorders (e.g., mania)
• organic psychoses (mental disturbances caused by head injury, alcoholism, brain tumour
or other kinds of organic disease)

Psychotic illness is characterised by:

• delusions (beliefs held despite the evidence to the contrary), often

paranoid or grandiose in nature
• auditory hallucinations (e.g., voices discussing the patient in the third
person, commenting on his action or thoughts, expressing accusations
etc.)
• visual illusions in form of distorted unreal images
• thought disorder-depersonalisation (the patient may feel that his
POSITIVE
thoughts “have been inserted and controlled by someone else”, the
SYMPTOMS
patient feels that he is actually someone else, conclusions are therefore
irrational)
• thought broadcasting (patient’s feeling that everyone can hear their
thoughts)
• thinking that lacks logical flow, speech jumps from one subject to
another and appears incoherent to observer (“wild trains of thought”)

• social withdrawal; the patient loses interest in himself and other people
NEGATIVE
SYMPTOMS • emotional apathy, blunted emotions
• poverty of speech, reflecting the poverty of thinking

Schizophrenia usually begins in young adult life and may follow exacerbations-remissions
course or be chronic and progressive. Acute episodes (mainly positive symptoms) frequently
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recur and develop into chronic schizophrenia, with predominantly negative symptoms and
dementia.

Schizophrenia affects about 0.5-1% of population, with a strong, but not invariable,
hereditary component. Genetics factors are the main risk factors in 70-80% of patients;
environmental factors (traumatic upbringing, social stresses, prenatal brain injury) underlie
the rest. Few hypotheses try to explain the pathogenesis of schizophrenia (developmental
abnormality involving temporal lobes and the limbic system, slow virus infection, possibly
associated with an autoimmune process). Pharmacological evidence is generally consistent
with dopamine overactivity in the CNS hypothesis because all effective neuroleptics are
antagonists at dopamine receptors (so far 4 identified: D1, D2, D3 and D4). Some
neuroleptics, especially atypical ones, block certain serotonin (5-HT) receptors, particularly
5-HT2. New observation suggests reduced function of glutamate on NMDA type of glutamate
receptors in schizophrenia. The significance of this finding is not fully clear.

By releasing dopamine in the brain amphetamines can produce a behavioural symptoms that
closely resembles acute schizophrenic episode. However, direct proof for dopamine
overactivity is still missing. Researchers couldn’t manage to demonstrate higher
concentrations of dopamine in the brain of schizophrenic patients, nor any significant
derangement of dopamine metabolism. The amount of HVA (homovanillic acid – the main
metabolite of dopamine) in the cerebrospinal fluid of schizophrenic patients is normal or even
low, rather than high. Because there are many interactions between dopaminergic,
serotoninergic and noradrenergic neurons in the brain, the underlying abnormality may be
much more complex.

There main dopamine-rich locations in the CNS:

• limbic system: increased dopamine transmission here seems to be the primary

neurochemical change associated with schizophrenia (important for action of
antipsychotic drugs) – this change lead to changes in function of other neurotransmitters
in other CNS areas

• nigrostriatal pathway: connects midbrain substantia nigra to forebrain corpus striatum

(basal ganglia) – it belongs to so-called extra-pyramidal motor system that controls
voluntary movements by dampening them and adjusting muscle tone; automatic
movements also originate here

• tubero-infundibular pathway: connects the hypothalamus and pituitary gland where

dopamin acts to inhibit prolactin release (it acts as a prolactin inhibitory factor);
interestingly this pathway is not overactive as expected according to the hypothesis

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 (prolactin production is normal, not low)

Neuroleptic drugs produce their therapeutic effect probably in the mesolimbic pathway and
other areas of the limbic system (including prefrontal cortex), and their adverse effects are the
consequence of blocking dopamine in other pathways. The main wanted effects are sedation,
reduced initiative and emotions, inhibition of hyperactivity behaviour and aggressive
tendencies. However the patient can be aroused easily and responds to questions accurately
without any confusion or loss of intellectual ability. Not surprisingly, these effects are
unlikely to efficiently counteract the negative symptoms in schizophrenia.

The main classification of neuroleptic drugs is into:

• Typical neuroleptics such as chlorpromazine [Largactil], fluphenazine [Modecate,
Anatensol], thioridazine [Aldazine], trifluoperazine [Stelezine], haloperidol [Serenace,

Haldol], droperidol [Droleptan], flupenthixol [Fluanxol], zuclopenthixol [Clopixol] and

pericyazine [Neulactil]
• Atypical neuroleptics such as clozapine [Clozaril, Clopine, CloSyn], olanzapine
[Zyprexa], quetiapine [Seroquel], risperidone [Risperdal], ziprasidone [Zeldox] and
aripiprazole [Abilify]

The most dramatic difference between the typical and atypical drugs is the ability of the
atypical neuroleptics to address the negative symptoms of schizophrenia. Also atypical
neuroleptics tend to be associated with a lower incidence of unwanted movement disorders
but the reason for this is not known. It has been suggested that they may have more selective
affinity for brain regions involved in schizophrenia symptoms and reduced affinity for areas
associated with unwanted effects (reduced affinity for D receptors in the limbic system and
pituitary gland).

It is not known how neuroleptic drugs reduce the severity of the symptoms in schizophrenia.
Since all neuroleptic drugs are antagonists at dopamine D2 receptors and their neuroleptic
potency generally runs in parallel to activity on these receptors, it is assumed that
schizophrenia is associated with overactivity in the mesolimbic pathway. However,
neuroleptics induce their antipsychotic effects slowly taking days or weeks to work despite
the fact that their blocking effect is achieved immediately, which suggests that factors other
than simple blocking of D2 receptors might be involved. This delay in onset of clinical
improvement correlates well with time taken for upregulation of dopamine receptors
(increased number and/or sensitivity) to occur although it is not clear how could this explain
the therapeutic effect of neuroleptics. On the other hand sedative effect of neuroleptics is seen

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right after the administration.

Apart from blocking dopamine receptors, these drugs can also block other types of receptors
such as adrenergic, muscarinic, histaminergic, thus producing various unpleasant unwanted
effects. Neuroleptic drugs vary in binding affinity to these receptors and in unwanted effects
occurrence.

Main unwanted effects of neuroleptic drugs:

• Acute dyskinesias and dystonias (involuntary movements such as muscle spasms,

protruding tongue, sustained postures such as torticollis – wry neck) and Parkinson-like
syndrome which resembles Parkinson’s disease and consists of tremor, rigidity and
reduced mobility; these are probably the direct consequence of block of nigrostriatal
dopamine receptors (particularly common with depot injections). Dyskinesias/dystonias
often subside in time and both and Parkinson-like syndrome are reversible on stopping
the treatment.

• Akathisia (agitation, restlessness) manifests as an inner compulsion to move continually

(fidgeting, taping the feet, pacing the room).

• Tardive dyskinesia is one of the most serious problems with neuroleptic drug treatment. It
comprises mainly involuntary movements of face and tongue, but also trunk and limbs,
appearing after years of neuroleptic treatment (hence the term “tardive”- delayed) in 20-
40% of neuroleptic-treated patients, depending on dosage and the age of the patient
(usually in patients over 50 years). Commonly observed phenomena are lip smacking or
sucking, rolling the jaw, tongue sticking out, grimacing and tics. The syndrome can be
severely disabling, often irreversible, and the treatment is generally unfortunately
unsuccessful. It is not known what causes tardive dyskinesia, but because it can
sometimes be made worse by removing the drug, it has been suggested that the striatal
dopamine receptors become supersensitive. Tardive dyskinesia closely resembles the
dyskinesia that may develop after prolonged treatment of patients with parkinsonism with
levodopa (discussed later).

• Typical neuroleptics may cause increased prolactin release leading to gynaecomastia and
reduced libido in men, lactation (galactorrhoea), painful breasts, menstrual irregularities
such as amenorrhoea in women; these are secondary to dopamine-receptor block in the
pituitary gland.

• Sedation and weight gain are also common, partly due to an action on histamine H1
receptors in the CNS. Other unwanted effects (dry mouth, constipation, blurred vision

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 and hypotension) are due to block of muscarinic and α1 adrenoceptors. Skin allergic
reactions are common in the first few weeks of treatment, but are not serious and usually
subside in time.

• Atypical neuroleptics produce few or no motor and prolactin-related adverse effects but
may cause sedation, dry mouth, constipation, weight gain, hypotension and reflex
tachycardia.

Neuroleptic drugs are effective in controlling symptoms of acute schizophrenia, mania and
violent impulsive behaviour, when large doses may be needed. Long-term neuroleptic
treatment is often effective in preventing recurrence of schizophrenic attacks, and is a major
factor in allowing schizophrenic patients to lead normal lives. Neuroleptics are generally not
addictive.

Typical neuroleptic drugs are not generally effective in improving negative schizophrenic
symptoms in contrast to atypical ones which do offer some benefit. Overall about 30% of
schizophrenic patients show only limited improvement, and 7% can’t be controlled at all by
neuroleptic therapy (neuroleptic-resistant cases).

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 DRUGS USED IN AFFECTIVE DISORDERS

Affective disorders are characterised primarily by changes of mood (depression or mania)

rather than thought disturbances. Depression is the most common manifestation, and it may
range from a very mild condition, bordering on normality (e.g., after some disappointment or
failure), to severe clinical depression, sometimes called psychotic depression when patients
lose touch with reality.

Three types of depressive states have been described in literature:

• reactive depression (the most common type, 75% of all cases) is linked to distressing life
situations; post-natal depression is a variant of reactive depression
• endogenous depression occurs with no known provoking factor and shows a familial
pattern
• bipolar (manic depression) with oscillation between depression and mania; every episode
lasts 3-6 months and episodes may be separated by the period of normal mood; there is
strong hereditary link which is consistent with some undiscovered underlying
biochemical abnormality in the brain

Mood disorders are the most common psychiatric disorders and estimates for prevalence of
reactive/endogenous depression are 6-8% for women and 3-5% for men while bipolar
depression is less common, having a prevalence of 1%. Interestingly there is no difference in
prevalence of bipolar disorder between the sexes.

• loss of pleasure in life (anhedonia)

• a general feeling of misery, apathy, pessimism and hopelessness
• low self-esteem, feelings of guilt, inadequacy and ugliness
• indecisiveness, loss of motivation, poor concentration, retardation
SYMPTOMS
OF CLINICAL of thought and action
DEPRESSION • sleep disturbance usually in form of insomnia, loss of appetite,
indigestion, constipation, reduced libido
• fatigue, headache, other pains such as chest or abdominal pain
• in more severe form suicidal thoughts, plans, threats or even
attempts

Mania is in most respects exactly the opposite, with excessive energy level, enthusiasm and
self-confidence, and excessive physical activity, these signs often being combined with

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irritability, impatience and anger if others do not share the same mood. Patients switch
quickly from one topic to another, as if they cannot get their thoughts out fast enough; their
attention span is often short, and he can easily be distracted. As with depression, the mood is
generally inappropriate to circumstances.

The monoamine theory (proposed in 1965) suggests that depression results from
functionally deficient monoaminergic (noradrenaline and/or serotonin) transmission in the
CNS. This theory is based on the ability of known antidepressant drugs to facilitate and
enhance monoaminergic transmission. However, expected defects in central noradrenergic
and serotoninergic systems haven’t been discovered in the brain of patients suffering from
these disorders. Moreover, all types of antidepressant drugs take about 2 weeks to produce
any beneficial effects, even though their pharmacological effects are produced immediately,
suggesting that secondary adaptive changes such as decreased number of receptors and/or
sensitivity to transmitters (so called ‘down regulation’) are important. This has suggested
alternative theory: Alternative depression may be caused by increased sensitivity of
monoamine receptors and clinical improvement may occur as a result of decreased sensitivity
induced by enhanced monoaminergic transmission.

Interestingly unwanted effects of antidepressants start developing almost immediately rather

that after 2 weeks period. Also cocaine which blocks monoamine uptake and amphetamine
which displaces noradrenaline from its vesicles have no antidepressant properties even
though they technically potentiate the noradrenergic transmission, which is not consistent
with the theory.

Main types of antidepressant drugs are:

• selective serotonin reuptake inhibitors (SSRIs)
• tricyclic/tetracyclic antidepressants
• monoamine oxidase inhibitors (MAOIs)
• atypical neuroleptics

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin (5-hydroxytryptamine) is a neurotransmitter widely distributed in the CNS. Several

distinct types of 5-HT receptors with different functions have been described:

• Stimulation of 5-HT1 receptors is associated with antidepressant and anxiolytic effects.

• Stimulation of 5-HT2 receptors produces nervousness, anxiety, insomnia and sexual
dysfunction.
• Stimulation of 5-HT3 receptors is associated with nausea, headache, drowsiness and
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 dizziness and blockade reverses the nausea (discussed earlier).
By preventing the reuptake of 5-HT presynaptically SSRIs ultimately lead to more efficient
central 5-HT function, but unfortunately they are not specific in their action on different 5-
HT receptors. Thus, while 5-HT1 stimulation results in antidepressant and anxiolytic effects,
5-HT2 and 5-HT3 stimulation results in common SSRI adverse effects are nausea, anxiety,
insomnia, headache, drowsiness, dizziness, restlessness and sexual dysfunction (diminished
sex drive and anorgasmia in both sexes, and erectile difficulties in 20-40% of patients).

Examples include fluoxetine [Prozac, Lovan, Fluohexal, Fluoxebell, Zactin], paroxetine

[Aropax, Exitine, Paxtine], reboxetine [Edronax], sertraline [Zoloft, Setrona, Eleva,
Xydep], fluvoxamine [Luvox, Faverin, Movox, Voxam], citalopram [Cipramil, Ciazil,

Celapram, Talam, Talohexal] and escitalopram [Esipram, Lexapro]. The SSRIs are safe in

overdose (important in patients with recognised or suspected suicidal tendencies), have a

wide therapeutic margin and are now generally accepted as first-line drugs, especially in
patients with cardiovascular disease.

Depolarisation

Ca2+
5-HT

Ca2+

SSRIs
5-HT

5-HT1 5-HT2 5-HT3

antidepressant/ nervousness, nausea, headache,

anxiolytic effects restlessness, drowsiness and
anxiety, insomnia dizziness
and sexual
dysfunction

UNWANTED EFFECTS

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 Tricyclic/tetracyclic antidepressants

These drugs owe their name to their characteristic multi-ring basic chemical structure. They
mainly act by inhibiting uptake of noradrenaline and to some extent of serotonin by
monoaminergic nerve terminals (mixed reuptake inhibitors), thus increasing noradrenergic
and serotoninergic transmission. Prolonged administration down-regulates β1 adrenergic
receptors on the postsynaptic membrane of the neurons and probably also serotonin receptors,
which is a possible final common pathway for their antidepressant activity.

Important examples are imipramine [Tofranil, Tolerade], trimipramine [Surmontil],

amitriptyline [Endep], nortriptyline [Allegron], clomipramine [Anafranil, Placil], dothiepin
[Dothep, Prothiaden] and doxepin [Sinequan, Deptran].

In most situations tricyclic antidepressants are probably as effective as SSRIs and more
effective in severe depression that responds poorly to SSRIs. However, tricyclic
antidepressants can be dangerous in acute overdose, causing confusion, agitation, mania,
cardiac arrhythmias, coma, convulsions and respiratory depression. Also they cause a strong
potentiation of the effects of alcohol for reasons not well understood, and respiratory
depression may follow a bout of drinking. Tricyclic antidepressants, probably indirectly,
produce few unwanted effects that are consistent with blockade of other types of
neurotransmitter receptors such as sedation and weight gain (block of histamine H1

receptors), postural hypotension (α1 block), dry mouth, blurred vision, constipation
(muscarinic block). Disturbances of libido and potency are not uncommon and are similar to
SSRIa.

Because of postural hypotension and stimulation of the cardiovascular system in overdose

most tricyclic antidepressants are unsuitable for patients with ischaemic heart disease or
cerebral atherosclerosis (risk for myocardial or brain infarction).

Mianserin [Lumin, Tolvon] and mirtazapine [Avanza, Axit, Mirtazon, Remeron] belong to a
group of tetracyclic antidepressants with different molecular structure and activity from
tricyclic preparations. Their mode of action is complex but appears to be related to blockade
of monoamine presynaptic receptors as well blockade of postsynaptic 5-HT2 and 5-HT3
receptors. Consequently they increase both noradrenergic and serotoninergic transmission.
Their advantage over tricyclic antidepressants is lower unwanted effect profil. Due to their
different chemical structure they virtually have no anticholinergic activity.

Venlafaxine [Efexor] is a novel antidepressant chemically unrelated to other antidepressant

agents. It has a similar mode of action as tricyclic antidepressants but its adverse effect profile

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is more benign corresponding to that of SSRIs. However, it appears more effective than
SSRIs in severe or refractory depression.

Depolarisation

Ca2+ NA
5-HT

Ca2+

⊕
U
Tricyclic
antidepressants
NA 5-HT

β1 5-HT1,2,3

antidepressant effect (CNS) wanted and unwanted

but also heart stimulation effects similar to SSRIs

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase (MAO) is an enzyme located intracellularly within serotonin, dopamine

and noradrenaline nerve terminals and has the effect of regulating the free intraneuronal
concentration of these biogenic amines and hence their releasable stores. MAOIs, by
irreversibly inhibiting MAO, increase stores of noradrenaline, dopamine and serotonin in
nerve terminals, allowing more of these neurotransmitters to be released during the synaptic
transmission.

Main examples are phenelzine [Nardil], tranylcypromine [Parnate] and moclobemide

[Aurorix, Amira, Arima, Clobemix, Maosig, Mohexal].

MAOIs can cause hypertensive crisis, palpitations (tachycardia) and throbbing headache in
response to tyramine containing foods such as matured cheese (e.g., Cheddar), Vegemite,
bananas, broad beans, raisins, beer, red wine, chocolate, sour cream, soy sauce, caviar, liver,
processed meat products, beer due to the block of MAO in the gut wall and liver that
normally intercepts and destroys ingested noxious amines. Tyramine is known to be able to

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displace noradrenaline from adrenergic neurons. This reaction is known as “cheese reaction”
and is the main reason why MAOIs are today mostly underused and are usually given for
refractory depression that does not respond well to SSRIs. Similar type of reaction may be
observed when indirectly acting sympathomimetic amines that release the stored
noradrenaline (e.g., pseudoephedrine as found in many ‘cold and flu’ combinations) are given
with MAOIs because MAOIs cause noradrenaline to accumulate within the adrenergic
neurons. Moclobemide is a selective MAO inhibitor but it, unlike other MAOIs, produces
reversible inhibition of MAO. This is thought to be responsible for substantially reduced risk
of food interactions. Unfortunately due to this nature of MAO blockade moclobemide is
inferior to as other MAOIs in regard to antidepressant activity. Other unwanted effects of
MAOIs are postural hypotension (mechanism not known), dry mouth, blurred vision,
constipation, increased appetite and weight gain, CNS stimulation causing restlessness,
insomnia and sex life difficulties as with other antidepressants.

Depolarisation

Ca2+ Monoamine
transmitters
Metabolites
2+
Ca
MAO MAO inhibitors
⊕
U

Monoamine
transmitters

Monoamine
receptors

antidepressant effect
unwanted effects

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 Atypical neuroleptics

Atypical neuroleptics such as olanzapine and clozapine are increasingly used in

management of difficult to treat major unipolar depression. Particular indication for their use
is psychotic depression. Their advantage over other established antidepressants is
comparatively low incidence of unwanted effects. Atypical neuroleptics can be used alone or,
more often, in conjunction with other antidepressants

Antimanic drugs
Lithium

This inorganic ion is taken orally as lithium carbonate (Li2CO3) [Lithicarb, Quilonum] for

prophylaxis; it prevents the manic phase in bipolar disorder, as well as having antidepressant
activity. Because of delayed onset of action (around 10 days) it is not efficient in acute
episodes of mania, when neuroleptics are preferred. Mechanism of action in not fully
understood, but it is known that Li is a monovalent cation, which resembles sodium in
excitable tissues and can be accumulated inside the cells. Accumulated Li interferes with the
production of second messengers such as cAMP and InsP3, which might be responsible for
observed inhibition of noradrenaline release from nerve terminals and enhanced action of the
amine uptake pump. Two thirds of patients with bipolar disorder respond to lithium.
Unfortunately it has a narrow therapeutic index (acute overdose causes severe headache,
vomiting, confusion, convulsions and cardiac arrhythmias) and lithium blood levels must be
strictly monitored and the dose fine-tuned.

The main reported unwanted effects are nausea, diarrhoea, thirst and polyuria (inhibition of
action of ADH – nephrogenic diabetes insipidus), goitre and hypothyroidism (inhibition of
action of TSH), fine tremor, weakness, mental confusion, exacerbations of acne and potential
to cause birth defects (teratogenesis).

Antiepileptics

Carbamazepine [Tegretol, Teril] and valproate [Epilim, Valpro] also have mood-stabilising
properties and can be used in patients who do not respond to, or can not take lithium because
of adverse drug effects.

Antipsychotics

Also olanzapine [Zyprexa] and other atypical neuroleptics, may be used for management of
acute mania in bipolar disorder, as well as long term prevention of manic episodes.

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 ANTIEPILEPTIC DRUGS

Epilepsy is a very common disorder, affecting approximately 0.5% of the population. Usually
there is no recognisable cause, although it may develop as a consequence of various forms of
brain damage, such as trauma, infection or tumour growth. Epilepsy (especially generalised)
tends to run in families (hereditary component involved).

The characteristic event is the seizure, which is often associated with convulsions (fits), but
may occur in many other forms. The seizure is caused by an abnormal high frequency
electrical discharge from a group of neurons, starting locally and spreading to a varying
extent to affect other parts of the brain.

Seizures may be partial or generalised depending on the location and spread of the abnormal
neuronal discharge. Partial seizures are often associated with damage to the brain, whereas
generalised seizures occur without any obvious cause. The attack may involve mainly motor
(jerking), sensory (tingling sensations, visual such as colours and simple shapes or olfactory
such as smell) or behavioural phenomena (changes in mood such as fear, anxiety, apparent
‘drunkenness’ state, sexual arousal or bizarre stereotyped behaviour). The produced
phenomena are obviously various, depending on the affected region of the CNS.
Unconsciousness occurs when the brainstem reticular activating system (RAS) is involved
since RAS is normally responsible for maintenance of the conscious state.

Partial seizures

In partial seizures, electrical discharge starts as localised phenomenon and usually remains so.
• Simple partial seizures consist of motor, sensory or behavioural phenomena without loss
of consciousness. In Jacksonian epilepsy focal motor symptoms begin in one hand and
then “march” up the extremity. Other focal attacks can first affect the face area, then
spread down the body to involve an arm and sometimes a leg. Sensory partial seizures
present with visual or olfactory hallucinations or with localised tingling and numbness
reflecting the affected area of the brain.

• In complex partial seizures the patient loses contact with the surroundings for 1-2
minutes and presents with automatic purposeless movements such as rubbing or patting,
produces unintelligible sounds or expresses more complex behaviour such as hair-
combing or dressing. After the attack the patient recovers not remembering the event.

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 Generalised seizures

Generalised seizures involve the whole brain, including the reticular system, and are
characteristically accompanied by the loss of consciousness. Two common forms of
generalised epilepsy are tonic-clonic seizure (grand mal) and absence seizure (petit mal).

• A tonic-clonic seizure consists of tonic phase lasting for about 1 minute (rigid contraction
of all skeletal muscles accompanied by characteristic cry as the air is suddenly expelled
from the lungs, cease of respiration, defecation, micturition and salivation) followed by a
series of violent synchronous jerks (clonic phase) lasting for 2-3 minutes. After few
minutes, the patients regain consciousness, feeling ill (headache, muscle aches, tiredness)
and confused.

• Absence seizures occur in children, usually many of them each day, and a patient stops
what he was doing (in the middle of the sentence or freezing in the middle of the
movement), with no significant motor disturbances apart from occasional lip smacking
and eyelid fluttering. The patient is unaware of the surroundings and recovers quickly in
just 10-30 seconds with no after-effects. Absence seizures may be misinterpreted by
parents and especially teachers as unexplained and frequent day-dreaming, and may
substantially interfere with learning.

The neurochemical basis of the abnormal discharge is not well understood. It may be
associated with enhanced excitatory amino acid transmission (e.g., glutamate), impaired
inhibitory transmission, or abnormal electrical properties of the affected cells with resulting
self-excitation. Prolonged epileptic discharge (status epilepticus) in which fits follow each
other without consciousness being regained, can cause neuronal death (excitotoxicity).

Current anticonvulsant drugs are thought to act by three main mechanisms:

• reducing electrical excitability of cell membranes (probably by blocking use-dependant
sodium channels, e.g., those in very excitable and active areas, but not in others)
• enhancing GABA-mediated inhibition (facilitation of postsynaptic action of GABA,
inhibition of GABA transaminase which inactivates GABA, blocking uptake of GABA)
• inhibiting the release of excitatory neurotransmitter glutamate

It is possible that certain drugs may inhibit so-called spike-generating calcium current in
thalamic neurons, thought to be responsible for absences.

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 Major anticonvulsant drugs

Drug therapy completely eliminates seizures in 1/3 of patients and greatly reduces the
frequency of seizures in another 1/3. No single drug controls all types of seizures and
different drugs may be required for different patients. Once seizures are well controlled the
drug should be continued without interruption until at least 1 year is seizure free. At that time
discontinuing the drug should be considered which must be done very slowly as sudden stop
may precipitate seizure. Overall about 2/3 of patients with well controlled seizures eventually
discontinue drugs without relapse and therefore can be regarded as cured.

It should be noted that most antiepileptic drugs can cause birth defects if given during
pregnancy. Carbamazepine appears to be the least teratogenic and valproate may be the most
teratogenic. Commonly reported birth defects are cleft lip and palate, cardiac defects, growth
retardation, abnormal face, abnormalities of fingers, spina bifida. Since in many female
patients drug therapy can not be stoped in pregnancy, pregnancy is better postponed until the
remission is achieved. However, the risk of a mother treated for epilepsy giving birth to a
baby with serious birth defect is estimated at 4-6%, which is only 2-3 times that of the
general population.

All antiepileptics tend to produce many unwanted effects including gastrointestinal

disturbances (nausea, vomiting, altered appetite), weight gain, ataxia (poor motor
coordination, unsteadiness), headache, confusion, drowsiness, sedation, learning difficulties,
allergic skin rash, suppression of bone marrow activity (anaemia, leukopenia) and possible
liver damage (liver function tests should be monitored). Also many antiepileptics cause
induction of the hepatic drug-metabolising enzymes and thus can accelerate metabolism and
removal of other drugs metabolised by the same system.

Tonic-clonic seizures are treated with phenytoin [Dilantin], carbamazepine [Tegretol,

Teril], oxcarbazepine [Trileptal] and valproate [Epilim, Valpro]; single drug use is preferred

if possible. Phenytoin, carbamazepine and oxcarbazepine are thought to act by reducing

electrical excitability of cell membranes, probably be blocking voltage dependent sodium
channels and stimulating removal of sodium from neurons across cell membranes (phenytoin
is also used as an antiarrhythmic drug). Mechanism of action of valproate is not clear, but is
attributed to the blockade of voltage dependent sodium channels and increased brain levels of
GABA. Newer drugs such as vigabatrine [Sabril], lamotrigine [Lamictal, Lamitrin,
Lamogine, Elmendos, Seaze], tiagabine [Gabitril], gabapentin [Neurontin, Nupentin,

Gantin, Pendine] and topiramate [Topamax] are reserved for patients in which epilepsy is not

satisfactorily controlled by phenytoin, carbamazepine and valproate. Vigabatrine acts by

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irreversibly inhibiting GABA transaminase, increasing the GABA stores and thus facilitating
GABA-mediated inhibition. Lamotrigine and topiramate are thought to act by inhibiting the
release of glutamate, an excitatory neurotransmitter, as well as blocking voltage gated sodium
channels. Tiagabine inhibits uptake of GABA resulting in an increase in GABA-mediated
inhibition in the brain. It is not known what underlies antiepileptic effect of gabapentin.

Partial seizures are also initially treated with carbamazepine, valproate and phenytoin.
Resistant cases are treated with vigabatrine, lamotrigine, tiagabine, gabapentin, levetiracetam
[Keppra] or pregabalin [Lyrica]. The precise mechanism of action by which levetiracetam
induces seizure protection is unknown, but appears unrelated to the mechanisms of current
antiepileptic drugs. Pregabalin is a GABA analogue, and has anticonvulsant and analgesic
activity (in neuropathic pain).

Absence seizures are mainly managed with ethosuximide [Zarontin]. Its mechanism of
action is unknown but it probably works by blocking calcium current. Difficult to manage
cases can be given some of the newer antiepiletics mentioned earlier.

Status epilepticus must be treated as an emergency, with benzodiazepines diazepam [Valium]

or lorazepam [Ativan] intravenously and the main treatment regimen should be reassessed.
All benzodiazepines enhance GABA-mediated inhibition, as described earlier.

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 Diagram showing the main modes of action of antiepileptic drugs

Inhibitory neuron Seizure

spread
4
⊗
GABA-T
GABA-M Action
⊕
potential
GABA
Glu
⊕
GABA 6
∅ Stimulatory neuron

1 GABA Na+ Na+ ∅

Cl- 2 5
⊕ ∅
BeS GaR GlR

⊕ ⊕
∅ Na+ Na+
-
Cl Depolarisation
(neuron activation)
Hyperpolarisation
(neuron inhibition) “Low treshold spikes” Ca2+ 3
∅
Ca2+

LEGEND:

GABA γ-amino butyric acid Drugs used for epilepsy :

Glu glutamate (glutamic acid) 1. Benzodiazepines
GlR glutamate receptor 2. Na+ channel blockers
GaR GABA receptor - phenytoin
BeS benzodiazepines binding site - carbamazepine
GABA-M GABA metabolites - valproate
GABA-T GABA transaminase - lamotrigine
- topiramate
3. Ca2+ channel blockers
- ethosuximide
- valproate
4. GABA transaminase inhibitors
- vigabatrine
- valproate
5. Inhibition of glutamate release
- lamotrigine
- topiramate
6. Inhibition of GABA uptake
- tiagabine

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 DRUGS USED IN PARKINSON’S DISEASE

Parkinson’s disease is a progressive degenerative disease of the basal ganglia in the CNS
causing movements disorders that occur most commonly in the elderly (most common
between ages 50-75, however 10% of cases are younger than 40). There are currently 30.000
sufferers in Australia. Main signs and symptoms are:

• tremor at rest, usually starting in the hands and diminishing during voluntary
activity
• muscle rigidity, which is detectable as an increased resistance to passive limb
movement (continuous ‘lead pipe’ type, superimposed tremor may add some ‘cog
wheel’ effect; rigidity of the facial muscles gives the face a mask-like appearance
with mouth open and diminished blinking
• voluntary movements (e.g., cutting food, buttoning a shirt, writing) are difficult to initiate
and consequently very infrequent and slow; the terms used to describe these phenomena
are bradykinesia and hypokinesia
• characteristic shuffling gait with short paces and diminished arm swinging, which takes
some effort for them to begin, and once in progress they cannot quickly stop or change
direction
• normal sensory perception and reflexes
• dementia in one third of patients

Parkinson’s disease often occurs with no obvious underlying cause, but it may be the result of
viral encephalitis or other types of brain damage. Reversible Parkinson like syndrome can be
drug induced (neuroleptic drugs). It appears that unlike schizophrenia, Parkinson’s disease
has no significant hereditary component, and it seems that environmental factors (toxins,
chemicals?) are more important in its development. It is unclear which exogenous or
endogenous toxin is important or alternatively there may be a defect in cells that could lead to
premature cell death (known as apoptosis). There is a great deal of interest in oxidative stress
in dopaminergic neurons as a possible causative factor.

Neurochemical basis in Parkinsonism is marked degeneration of the dopaminergic

nigrostriatal tract. The cell bodies of this tract are located in the substantia nigra (so called
because it contains melanin-pigmented neurones) in the midbrain and their axons extend to
the corpus striatum (basal ganglia). It seems that overt symptoms of Parkinsonism appear
only when more than 80% of dopaminergic neurons have been lost, which means that the

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condition develops for at least 4 years before becoming symptomatic. The corpus striatum is
also very rich in acetylcholine which has excitatory function whereas dopamine acts as an
inhibitor, so it appears than symptoms result from the imbalance between these two.

Dopamine Acetylcholine

In healthy individuals normal balance is maintained

Dopamine

Acetylcholine

In Parkinson’s disease there is an imbalance due to lack of dopamine

Drugs used in treatment of parkinsonism act by counteracting deficiency of dopamine in

basal ganglia or by blocking ACh on muscarinic receptors. Replacement therapy with
dopamine itself is not possible because it does not pass the blood-brain barrier and
consequently does not penetrate into the brain.

Levodopa

The most effective drug is levodopa (dihydroxyphenylalanine), a dopamine precursor that

easily passes the blood-brain barrier, where it is decarboxylated to dopamine. However,
orally administered levodopa is largely metabolised outside the brain and it must be given
together with a selective extracerebral dopa-decarboxylase inhibitor, which will prevent
metabolic degradation of dopa, before it reaches the brain. Levodopa is effective in most
patients initially, and bradykinesia/hypokinesia and rigidity are helped most, although tremor
is often substantially reduced.

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Main unwanted effects of levodopa are:
• dyskinesias or involuntary movements of the face and limbs (tics, jerks, grimaces, head
rocking, flailing of the limbs etc), which occur in some degree in most patients within 2
years (they tend to respond to simple dose reduction)
• fluctuations in effect (on-off phenomenin)
• nausea and vomiting (stimulation of the chemoreceptor trigger zone by dopamine)
• depression that may even require antidepressant treatment (depression is also a feature of
parkinsonism)
• postural hypotension with dizziness or fainting (peripheral dopamine effects)
• occasionally psychiatric symptoms in large doses (vivid dreams, hallucinations, psychotic
states and confusion due to stimulation of the mesolimbic dopamine receptors)
• increased sexual activity (unwanted effect?)
• urine may have pink to red tint and turn black on standing (dopamine metabolites); this is
not harmful but the patients should be informed

As mentioned earlier efficacy of levodopa may be improved by combination with peripheral

decarboxylase inhibitors carbidopa [these combinations are Sinemet, Kinson] or benseraside
[this combination is Madopar].

Acetylcholine antagonists

These drugs were the main form of treatment of Parkinson’s disease before levodopa was
introduced. Muscarinic receptors exert an excitatory effect on the striatal neurons and also are
involved in presynaptic inhibition of dopaminergic neurons (inhibition of dopamine release).
Therefore, blocking of these receptors can partially compensate for the lack of dopamine
action. The main drugs in this group are benztropine [Cogentin, Benztrop], benzhexol
[Artane] and biperiden [Akineton].

Acetylcholine antagonists are used alone in the early stages of treatment and later to
supplement levodopa. Unfortunately they have many troublesome unwanted effects such as
dry mouth, constipation, urine retention, blurred vision and tachycardia. These drugs are also
of great value for Parkinson-like syndrome when it develops during treatment with
neuroleptic drugs that work by blocking dopamine receptors and where levodopa can not be
used.

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 Alternative drugs

1. Bromocriptine [Parlodel, Kripton], pergolide [Permax] and cabergoline [Cabaser] are

drugs that directly activate dopamine receptors in the basal ganglia (dopamine agonists).
Their effectiveness and unwanted effects are similar to levodopa, but the unwanted
effects are more common and more serious. They may be combined with levodopa with
both given is smaller doses.

2. Selegiline [Eldepryl, Selgene] is a monoamine oxidase type B (MAOB) inhibitor that

reduces metabolism of dopamine in the brain and potentiates the actions of levodopa (it is
usually added to levodopa therapy when levodopa is no longer sufficient to control
symptoms). MAOB seems to be concentrated within dopamine-containing areas of the
CNS such as substantia nigra, and selegiline lacks unwanted peripheral unwanted effects
of non-selective MAOIs. For example it doesn’t provoke “cheese reaction” (discussed
earlier) by interfering with neutralisation of tyramine from food. Selegiline is virtually
free of unwanted effects with only dry mouth being reported by some patients. On the
other hand it can potentiate the unwanted effects of levodopa.

3. Entacapone [Comtan] is a catechol-O-methyltranferase (COMT) inhibitor that decreases

the metabolic degradation of levodopa by the enzyme COMT in peripheral tissues,
mainly in the liver. The amount of levodopa available to the brain is increased (by up to
50%) and more dopamine is formed in the central nervous system. Entacapone thus
prolongs the clinical response to levodopa and, like selegiline, it may be introduced when
levodopa has started to loose its efficacy. Not surprisingly unwanted effects are largely
those of levodopa. A combination of carbidopa + entacapone + levodopa is available as
Stalevo. It has been found that adding COMT inhibitor to levodopa can reduce

occurrence of “on-off” phenomenon.

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 Diagram showing the main modes of action of drugs used in
Parkinson’s disease

Nigrostriatal
neuron
Metabolites
1
⊕
3 l-dopa
∅ MAOB
DD
ACh DA
DA DA

ACh DA
2 4
∅ ⊕
MR DR

Excitation Inhibition

LEGEND:

ACh acetylcholine
DA dopamine Drugs used in Parkinson’s disease:
MR muscarinic receptor 1. Levodopa
DR dopamine D2 receptor 2. Acetylcholine antagonists
MAOB monoamine oxidase B 3. MAOB inhibitors
DD dopa decarboxylase 4. Dopamine agonists

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 DRUGS USED IN ALZHEIMER’S DISEASE

Alzheimer’s disease is a progressive dementia characterised by confusion, memory

impairment, disorientation, loss of logical thinking and judgement, personality changes,
speech disturbances, increased dependency to the point of being bed bound. Alzheimer’s
disease excludes other types of dementia such as those caused by brain injury, stroke or
chronic alcoholism. The condition is responsible for about half of all cases of dementia and it
is on the increase in most countries in the world. Its prevalence rises sharply from the age of
about 60 years, and reaches 90% or more by the age of 95.

The main pathological features of Alzheimer’s disease are formation of amyloid plaques
(extracellular deposits of so-called β–amyloid protein), neurofibrillary tangles (filaments of a
protein normally associated with intraneuronal microtubules) and a loss of neurons,
especially cholinergic neurons of the basal forebrain. While the actual mechanism of
neurodegeneration is still unclear, loss of cholinergic neurons is believed to be responsible for
at least memory and learning deficit seen in Alzheimer’s disease sufferers.

Current pharmacotherapy can not prevent or cure Alzheimer’s disease. Mechanisms of action
of currently available drugs:

• Prolonging the effect of acetylcholine on central cholinergic synapses acting as

reversible acetylcholinesterase inhibitors. Enhanced cholinergic transmission can to
some extent improve cognitive functioning. Examples of such drugs are donepezil
[Aricept], rivastigmine [Exelon] and galantamine [Reminyl]. By potentiating the
effect of acetylcholine in autonomic and somatic efferent systems these drugs can
produce unwanted effects such as muscle cramping, nausea, vomiting, diarrhoea,
fatigue, headache and insomnia.

• There is increasing evidence that malfunctioning of glutamatergic

neurotransmission, in particular at NMDA (N-methyl-D-aspartate) receptors,
contributes to both expression of symptoms and disease progression in
neurodegenerative dementia. Memantine [Ebixa] is an uncompetitive NMDA
receptor antagonist that has been shown to improve cognitive functions. However it
does not slow or reverse the neurodegenerative processes of Alzheimer’s disease.

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 DRUGS USED IN MULTIPLE SCLEROSIS (MS)

MS is slowly progressive, chronic, inflammatory, demyelinating condition of the CNS that

leads to development of characteristic plaques in white matter. MS destroys oligodendrocytes
processes which are responsible for creating and maintaining the myelin sheath around axons;
however demyelination is, at least initially, reversible. Symptomatology of MS depends on
areas involved by the process but involves various sensory and motor symptoms. The
condition appears to result from involvement of the immune system although details of its
pathogenesis are unknown.
High doses of intravenous corticosteroids is the routine therapy for acute relapses. They
provide short-term clinical benefit by reducing the severity and shortening the duration of
episodes. Unwanted effects of short-term glucocorticoid therapy include sodium and fluid
retention, potassium loss (hypokalaemia), weight gain, gastric disturbances, skin acne and
emotional lability. However it is widely believed that corticosteroids do not significantly alter
the course of the condition.
Consequently other treatment called disease-modifying therapies is preferred:
• Immunomodulatory therapy with recombinant interferon-β 1b [Betaferon;
subcutaneously every second day] and recombinant interferon-β 1a [Avonex – im
once a week; Rebif – im every second day] can induce the remission and help
decrease the progression of the disease and development of disability. They are more
effective in relapsing-remitting form of MS than in progressive form. Their
mechanism of action in MS is unclear. Unwanted effects are very common: irritation
at the injection site with development of lipoatrophy, flu-like symptoms, depression
and potential liver toxicity.
• Immunomodulator glatiramer [Copaxone] given subcutaneously daily. It is a
polymer of 4 amino acids found in myelin which appears to inhibit immune reaction
to myelin but the mechanism is not fully understood. Unwanted effects are relatively
mild (injection site reaction, aches, fever, chills) and the drug is better tolerated than
interferons. Some studies have showed that it is effective as interferons in dealing
with MS relapses, while others did not; its clinical evaluation is ongoing.
• Natalizumab [Tysabri] is a monoclonal antibody to integrin molecules expressed on
surface of lymphocytes that help them adhere to and cross through the endothelial
lining of the blood-brain barrier. The precise mechanism of action in MS in still
unclear. It is administered by intravenous infusion every 28 days. It is arguably the
most effective drug in management of MS, both in terms of inducing remission and

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 reducing progression. The main problem: increased risk for serious opportunistic
viral infection progressive multifocal leukoencephalopathy which can cause death or
serious disability.

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 PHARMACOLOGY OF INFECTIOUS DISEASES

BASIC PRINCIPLES OF CHEMOTHERAPY

The term chemotherapy was coined at the beginning of the century to describe the use of
synthetic chemicals to destroy infective agents. In recent years the definition of the term has
been broadened to include antibiotics - substances produced by some microorganisms that
kill or inhibit the growth of other microorganisms. The term chemotherapy is now also
applied to the use of chemicals (either natural or synthetic) which inhibit the growth of
malignant or cancerous cells within the body.

To be effective, chemotherapeutic drugs should be toxic for invading organisms and harmless
for the host; such selective toxicity depends on the presence of exploitable
biochemical/structural differences between the parasite (e.g., bacterium) and the host. When
microbial metabolism is analysed several classes of biochemical reactions which are potential
targets for chemotherapy can be identified:

Class I reactions are low level reactions mainly comprising the utilisation of glucose for the
generation of energy and of simple carbon compounds (such as intermediates of the citric
acid cycle) which are used as precursors in the next class of reactions. These are poor targets
since energy production processes are virtually identical in microorganisms and human cells.

Class II reactions are the utilisation of the energy and precursors to make all the necessary
small molecules: amino acids, nucleotides, phospholipids, amino sugars, carbohydrates.

• Folate (folic acid) synthesis in bacteria is inhibited by sulphonamides. Folate utilisation

is inhibited by folate antagonists e.g., trimethoprim in bacteria and methotrexate in
human cells (an anticancer and immunosuppressive drug). The selective toxicity of the
sulphonamides depends on the fact that human cells take up folate supplied in the diet,
but susceptible bacteria lack this ability and must synthesise folate. Trimethoprim is
selective to bacteria because its affinity for the bacterial enzyme dyhydrofolate reductase
is 50,000 greater than its affinity for the equivalent human enzymes. Unfortunately
methotrexate is not specific but affects all rapidly proliferating cells such as cancer and
immune cells, but also to some extent bone marrow cells and cells in the gastrointestinal
lining.

Class III reactions encompass assembly of the small molecules into macromolecules:
proteins, RNA, DNA, polysaccharides and peptidoglycan.

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• Peptidoglycan synthesis necessary for construction of bacterial cell walls can be
selectively inhibited by β-lactam antibiotics such as penicillin. Human cells don’t contain
peptidoglycan and antibiotics that block its synthesis are usually very safe with minimal
unwanted effects.

• Protein synthesis can be selectively inhibited in bacteria by antibiotics that prevent

binding of tRNA to mRNA (e.g., tetracyclines), cause misreading of mRNA (e.g.,
aminoglycosides), inhibit transpeptidation (e.g., chloramphenicol), inhibit translocation
of ribosomes (e.g., erythromycin). Selectivity of these antibiotics to bacteria relies on
slightly different ribosomal structure between bacterial and human cells.

• Nucleic acid synthesis can be inhibited by altering base-pairing of DNA template (e.g.,
zidovudine), inhibiting DNA polymerase (e.g., acyclovir, ganciclovir) or inhibiting DNA
gyrase (e.g., ciprofloxacin). Drugs in this category have variable selectivity to micro-
organisms. Many anti-viral drugs, especially anti-retrovirals, can be toxic to host cells
and therefore can cause many unwanted effects. Ciprofloxacin and related antibiotics are
generally safe because human cells have no DNA gyrase.

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 Diagram showing three classes of biochemical reactions that are
potential targets for chemotherapeutic agents

Peptidoglycan
Amines
Precursor Proteins
Amino
I molecules II acids III
& ATP RNA
Nucleotides
DNA

Diagram showing the main structural features of bacterial cells

Ribosomes DNA (chromosome)

Gram-positive

Outer layer

Cell membrane Cell wall

Gram-negative

Resistance to antimicrobial drugs

Resistance to antimicrobial drugs is rapidly becoming a very important problem. It can be

acquired or innate. In the latter case, an entire bacterial species may be resistant to a drug
before its introduction. For example, Pseudomonas aeruginosa has always been resistant to
penicillin. More important clinically is acquired resistance, where bacteria that were once

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sensitive to a drug become resistant. Resistance is a natural phenomenon which is facilitated
by rapid multiplication of bacteria and chance mutation. For example the doubling time of
bacteria can be as short as 20 minutes.

Resistance is partly related to improper use of antimicrobials (over-prescribing and non-

compliance in relation to completing the full course) and excessive use of antibiotics in stock
food that is responsible for presence of antibiotics in the meat we eat.

Mechanisms responsible for resistance to antimicrobial drugs include:

• Production of enzymes that inactivate the drug: e.g., β-lactamases, which inactivate
penicillin; acetyltransferases, which inactivate chloramphenicol; kinases and other
enzymes, which inactivate aminoglycosides.

• Alteration of the drug-binding sites: this occurs with aminoglycosides and erythromycin.

• Reduction of drug uptake by the bacterium: e.g., tetracyclines.

• Alteration of enzymes: e.g., dihydropteroate synthetase becomes insensitive to

sulphonamides.

• Some strains of staphylococci have multiple resistance to virtually all current antibiotics
involving the above mechanisms, resistance being transferred to next generations.

In time resistant microorganisms proliferate as sensitive ones are eliminated. Bacterial genes
responsible for the resistance can be transferred from one organism to another, effectively
increasing the number of resistant forms. The antibiotic resistance genes may be carried in
plasmids, which are small autonomously replicating extrachromosomal pieces of DNA within
the bacteria. The plasmids are usually transferred from one organism to another by
conjugation (the formation of a tube between the organisms). A good example of such
exchange is between vancomycin-resistant enterococci (VRE) and multiresistant
Staphylococcus aureus (MRSA), which do not respond to almost all antibiotics except
vancomycin. VRE are gut flora that only rarely produce infections (they tend to be serious
such as sepsis as a complication in hospitalised patients) but have developed resistance to
vancomycin and can pass the ‘recipe’ to MRSA. Some MRSA have been found with
resistance to vancomycin which causes great concern.

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 ANTIBACTERIAL AGENTS

Certain principles should be borne in mind when choosing an antibiotic to treat a bacterial
infection. In general, two important requirements are to identify the infecting organism (if
practicable) and to determine its susceptibility to antibacterial agents by carrying out
antibiotic susceptibility test. In addition, certain host factors should be taken into account,
such as previous exposure to antibiotics (allergies?), age, renal and hepatic function, site of
infection (some antibiotics do not diffuse readily into bones or brain), concurrent
administration of other drugs that might interact with the antibiotic, and whether the patient is
pregnant or has a compromised immune system.

Bacteria are classified by their shape (cocci are spherical, bacilli are rod-shaped, spirochaetes
are spiral) and by the result of the Gram’s method of staining. In this method (named after
Hans Christian Joachim Gram, a Danish doctor) two dyes are used: crystal violet and safranin
(pink-red). Bacteria that retain the blue-violet stain are known as Gram-positive; those that do
not and accept the pink-red stain are known as Gram-negative. This reflects important
structural differences in the bacterial cell envelope. Gram-negative bacteria also have the
outer membrane outside the cell wall consisting of a lipid bilayer similar in some respect to
the plasma membrane. Difficulty in penetrating this complex outer membrane is probably the
most important factor responsible for relatively modest sensitivity of Gram-negative bacteria
to antibiotics.

Certain antibiotics are bacteriostatic (e.g., sulphonamides, tetracyclines), meaning that they
can inhibit growth of the bacteria, not to kill them. This effect can only be useful if infection
is not very advanced and the host immune system is still capable enough to combat the
bacteria. Penicillins and cephalosporins are bactericidal, and they cause lysis of bacteria. It
is, however, important to mention that this action (bacteriostatic or bactericidal) is often dose
related, which means that in lower doses penicillin antibiotics are likely to be only
bacteriostatic.

The number of species of microorganisms that are sensitive to the action of the antimicrobial
agent represent its spectrum of activity, which can be narrow and broad. This spectrum
should not be confused with potency/efficacy, which means that narrow is not the same as
weak, and broad is not the same as strong. Broad spectrum antibiotics are especially suitable
fro mixed infections (e.g., of the respiratory tract) or when the bacterium responsible for the
infection is unknown.

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 Antibacterial drugs interfering with nucleic acid synthesis

1. Sulphonamides are bacteriostatic drugs that are structural analogues of para-

aminobenzoic acid (pABA) and compete with pABA for folic acid (folate) synthesis and
thus with nucleotide synthesis. They were discovered in 1930’s when an aniline-based
dye was found to have antibiotic properties. Indications for sulphonamides are very few
because most bacteria are today resistant. The only registered sulphonamide is currently
sulphadiazine [Sulfadiazine] is used topically for infected burns. Unwanted effects
include crystalluria (precipitations in the urine leading to lumbar pain, haematuria and
dysuria), hypersensitivities (rashes, fever, anaphylactic reactions) and gastrointestinal
disturbances.

2. Trimethoprim [Triprim, Alprim] is bacteriostatic and it acts by folate antagonism,

preventing the metabolism and utilisation of folic acid. It may be given for certain urinary
tract and respiratory infections.

3. Co-trimoxazole [Bactrim, Septrin, Resprim] is a mixture of trimethoprim and

sulphamethoxazole, which affects bacterial nucleotide synthesis at two points. It is an
option for certain urinary tract and respiratory infections, especially for infection with
Pneumocystis carinii, which causes pneumonia in patients with AIDS (so called PCP).

4. Metronidazole [Flagyl, Metrogyl, Metronide, Rozex] after diffusion into the

microorganism undergoes chemical modification during which chemically reactive
metabolites inhibit DNA synthesis and/or damage DNA. Metronidazole is the drug of
choice in certain protozoal infections (e.g., Giardia, Trichomonas) and it is active against
Helicobacter pylori and several anaerobic bacteria.

5. Quinolones (ciprofloxacin [Ciproxin, Profloxin, Proquin, C-Flox, Ciprol], norfloxacin

[Noroxin, Insensye, Norflohexal, Norfloxacin, Nufloxib, Roxin] and moxifloxacin
[Avelox]) inhibit DNA gyrase (topoisomerase II) enzyme that has an important role in
DNA synthesis and division of genetic material during bacterial replication. Human cells
do not contain this enzyme. Important properties of quinolones are their good
penetration into tissues and cells (e.g., bone and brain), their effectiveness when given
orally, and their relatively low toxicity. The main uses are urinary infections (mainly
norfloxacin because it is concentrated in the urine and has no significant systemic
activity), osteomyelitis, meningitis/encephalitis, gonorrhoea, prostatitis, infections caused

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 by Pseudomonas aeruginosa etc. Quinolones are also applied topically in complicated eye
infections. Unwanted effects include GI tract upsets (nausea, vomiting, dyspepsia and
abdominal pain), hypersensitivity reactions (usually rash), headache and dizziness
(danger if driving or operating machinery). There are several reports indicating the
possible link between convulsions and quinolones, and this is the reason why quinolones
should be avoided in patients with history of convulsions (e.g., epilepsy). Through
unclear mechanism they may cause tendon pain and inflammation (tendinopathy).
Quinolones are contraindicated in pregnancy and children because of their ability to
produce damage of developing joints.

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 Diagram showing the mechanism of action of drugs that interfere
with the synthesis of folic acid

pABA

Sulphonamides
Dihydropteroate ∅
synthetase

Folate

Trimethoprim
Dihydrofolate ∅
reductase

Tetrahydrofolate

Synthesis of
nucleotides

DNA

H2N N N

N O O
N CH2 O C

N C N C H
H
H CH2
CH2

C
O O

Folic acid

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 Antibacterial drugs affecting bacterial peptidoglycan synthesis

The most important antibiotics in this category are penicillins and cephalosporins. The
structure of penicillins and cephalosporins share the common feature of a β–lactam ring,
which is essential for antimicrobial activity. Various side chains have been attached to this
basic structure resulting in many semisynthetic antibiotics with slightly different
pharmacodynamic and pharmacokinetic properties. Penicillins were discovered by Fleming in
1928 but only in 1942 it was demonstrated that they have antibacterial properties in humans
and that they are safe to use.

These antibiotics have bactericidal action through interference with peptidoglycan synthesis
in bacterial cell wall, by irreversibly inhibiting the transpeptidation enzyme that cross-links
the peptide chains forming peptidoglycan. Bacteria possess a cell wall to protect them from
changes in osmotic pressure in their environment. When the bacteria divide new cell walls
must be produced around progeny cells. Antibiotics that block this process essentially make
the newly produced bacteria very vulnerable to outside influences, which leads to their
destruction (lysis)

1. Penicillins are available in different forms:

• The first penicillin introduced in clinical practice was benzyl penicillin [BenPen] which is
still available today but very rarely used because of its very short half life. Procaine
penicillin [Cilicaine Syringe] and benzathine penicillin [Bicillin] are derivatives of benzyl
penicillin that have longer duration of action and are generally favoured drugs. Both of
them (including benzyl penicillin) are largely destroyed by gastric acid if taken orally and
have to be given by intramuscular injection (usually once a day). Benzyl penicillin can
also be given intravenously for serious infections. Phenoxymethylpenicillin [Abbocillin,
Cilicaine V and VK, LPV, Cilopen VK, Penhexal VK] has similar efficacy, but is active

orally. Spectrum: Gram-positive and Gram-negative cocci and some Gram-negative

bacteria. Many bacteria (including most staphylococci) are now resistant because they
produce enzymes (β-lactamases known as penicillinases) that open the β–lactam ring
rendering penicillins inactive.

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 β–lactam ring

β–lactamase opens

• β-lactamase-resistant penicillins, e.g., flucloxacillin [Floxapen, Floxsig, Flubiclox,

Flopen, Staphylex, Aspen Flucil] and dicloxacillin [Diclocil, Distaph, Dicloxsig] have

similar actions to benzylpenicillin, but they are active against β-lactamase-producing

bacteria. Unfortunately many staphylococci are now resistant (they are called
‘multiresistant Staph. aureus’ – MRSA) and they have to be tackled by intravenous
vancomycin.

• Broad spectrum penicillins, e.g., amoxycillin [Amoxil, Amohexal, Bgramin, Cilamox,

Ibiamox, Maxamox, Moxacin, Alphamox, Aspen Fisamox], ampicillin [Aspen Ampicyn,

Alphacin, Austrapen, Ibimicyn], are given orally and, apart from Gram-positive bacteria,

are active against some Gram-negative bacteria (e.g., E. Coli, Haemophilus influenzae
and Salmonella) because they manage to pass through the bacterial outer
lipopolysaccharide membrane more easily than benzylpenicillin. β-lactamase-producing
bacteria are resistant to amoxycillin and ampicillin. A combination of clavulanic acid (β-
lactamase inhibitor) plus amoxycillin [Augmentin, Clavulin, Clamoxyl, Clamohexal,
Curam] is effective against many β-lactamase-producing organisms but not MRSA.

Penicillins have very low toxicity. Unwanted effects are mainly hypersensitivities (skin
rashes, acute anaphylactic shock is very dangerous but fortunately very rare) and rarely
gastrointestinal disturbances (nausea, vomiting, diarrhoea).

2. Cephalosporins have similar chemical structure and the same mechanism of action and
pharmacology as penicillins but generally are not affected by penicillinase enzymes.
However certain types of bacteria produce another type of β-lactamases known as
cephalosporinase that can inactivate cephalosporins. Cephalosporins have a broader anti-
bacterial spectrum than the penicillins. Oral drugs, e.g., cephalexin [Keflex, Ibilex, Ialex,
Cilex, Sporahexal], cefaclor [Ceclor, Aclor, Keflor, Karlor, Vercef] and cefuroxime

[Zinnat] are used in urinary and respiratory infections. Parenteral drugs, e.g., cefpirome
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[Cefrom], cefotaxime [Cefotaxime], cephazolin [Cefazolin, Kefzol], cephalothin [Keflin],
ceftazidime [Fortum], ceftriaxone [Ceftriaxone, Rocephin], cefepime [Maxipime], cefoxitin
[Mefoxin] and cephamandole [Mandol] are active against Staph. aureus (but not MRSA
strains), H. influenzae, E. coli and Proteus; ceftazidime [Fortum] has anti-pseudomonas
activity. Unwanted effects are more common than with penicillins and include nausea,
vomiting, diarrhoea with oral agents, potential renal toxicity and hypersensitivities (allergies)
with all. Due to structural similarities a person allergic to penicillin has around 10% chance to
develop an allergic reaction to cephalosporins.

3. Vancomycin [Vancocin, Vancomycin] is a glycopeptide bactericidal antibiotic that is not

absorbed orally and must be given by injection. Precise mechanism of action is inhibition of
the release of peptidoglycan building blocks from a lipid carrier outside the bacterial cells.
The main unwanted effects appear to be dose-related ototoxicity and nephrotoxicity.
Intravenous vancomycin is a remaining option for serious infection caused by MRSA,
although certain strains of Staph. aureus have emerged that are resistant to vancomycin as
well. Currently, antibiotic alternatives for those infections are very limited.

4. Other antibacterial drugs in treatment of MRSA infections caused by so-called

vancomycin intermediate-resistant Staphylococcus aureus (VISA) are glycopeptide antibiotic
teicoplanin [Targocid] given by injection only; linezolid [Zyvox]; clindamycin [Cleocin,
Dalacin]; rifampicin [Rifadin, Rimycin]+ fusidic acid [Fucidin]; rifampicin + a quinolone and
tetracycline.

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 Diagram showing the mechanism of action of antibiotics that
interfere with the peptidoglycan synthesis

Synthesis of
building blocks

INSIDE
BB

LC BB LC

CELL
LC BB LC MEMBRANE

∅
BB
2 OUTSIDE
Growing
1
peptidoglycan layer
∅

LEGEND:

BB peptidoglycan building block

(N-acetylmuramic acid + Drugs:
N-acetylglucosamine + 1. Penicillins, cephalosporins
short peptide chain) 2. Vancomycin
LC transmembrane lipid carrier

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176
 Antibacterial drugs affecting bacterial protein synthesis

1. Tetracyclines are orally given broad-spectrum bacteriostatic antibiotics effective against

many Gram-positive and Gram-negative bacteria, Mycoplasma (atypical pneumonia),
Rickettsia (Q-fever, scrub typhus) and Chlamydia (non-specific urethritis, pelvic
inflammatory disease). Organisms sensitive to tetracyclines accumulate the drug partly by
passive diffusion and partly by active transport. However, many strains of organisms have
become resistant to these agents (resistant organisms do not accumulate the antibiotic),
decreasing their usefulness. Absorption from the gut is variable and is reduced by calcium
(e.g., from milk) and magnesium (e.g., from antacids).

Important examples are tetracycline [Tetrex], doxycycline [Doryx, Doxylin, Doxsig, Doxy,
Doryhexal, DBL Doxycycline, Frakas, Vibramycin], minocycline [Minomycin, Akamin] and

tigecycline [Tygacil].

Clinical uses are:

• they are drugs of first choice for infections with intracellular organisms such as rickettsia,
mycoplasma and chlamydia, as well as cholera and plague (tetracyclines readily enter
both the human host-cells and the bacterial cells)
• they are useful in mixed infections of the respiratory tract and skin acne where they are
given to combat Propionibacterium acnes which appears to be important in pathogenesis
of acne

Unwanted effects: gastrointestinal disturbances (diarrhoea and nausea), deposition in growing

bones (impairment of growth) and teeth (staining). They are contraindicated in children and
pregnant or lactating women.

2. Chloramphenicol is a bacteriostatic, broad-spectrum antibiotic that can be administered

by injection [Chloromycetin] or topically in form of eye drops and ointments
[Chloromycetin, Chlorsig].

Clinical use of chloramphenicol should be reserved for serious infections in which the benefit
of the drug is greater than the risk of toxicity, such as:
• meningitis caused by H. influenzae resistant to other drugs
• typhoid (enteric) fever (Salmonella infection) but ciprofloxacin, amoxycillin or co-
trimoxazole are similarly effective and less toxic
• bacterial conjunctivitis where unwanted effects are virtually non-existent due to topical
application

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177
Unwanted effects: dose related anaemia due to some inhibition of protein synthesis in red
blood cells in the bone marrow, dose independent (idiosyncratic) and rare depression of the
bone marrow resulting in pancytopenia (a markedly decreased count of all blood cell
elements) which is very serious (can be fatal), sometimes hypersensitivity reactions and
gastrointestinal disturbances.

3. Aminoglycosides are not absorbed orally and must be given by injection. They are
bactericidal antibiotics but have a low therapeutic index and are potentially toxic.
Main examples: gentamycin [Gentamycin, Septopal], neomycin [Neosulf], amikacin
[Amikin, Amikacin] and tobramycin [Tobramycin, Nebcin]

Aminoglycosides are most widely used against Gram-negative enteric organisms (e.g.,
Pseudomonas aeruginosa), commonly combined with one penicillin/cephalosporin or
vancomycin. Streptomycin is active against Mycobacterium tuberculosis, but today has been
largely replaced by more efficient and safer anti-tuberculosis drugs.

The main unwanted effects are dose-related nephrotoxicity (kidney damage) and ototoxicity
(impairment of hearing).

4. Macrolides have a similar antimicrobial spectrum to benzylpenicillin (narrow spectrum,

mainly against Gram-positive organisms), and can be used as an alternative drug in
penicillin-sensitive patients. However, they are also effective against Mycoplasma,
Chlamydia and Legionella (legionnaires’ disease).

Important compounds are erythromycin [Eryc, E-Mycin, EES, Eryhtrocin, DBL

Erythromycin], clarithromycin [Klacid, Clarac, Clarihexal, Kalixocin], azitromycin

[Zithromax] and roxitromycin [Biaxsig, Roxar, Roximycin, Rulide]

Clarithromycin is active against H. pylori and may be included in anti-helicobacter

combinations in treatment of peptic ulcer. The macrolides are very safe drugs. Unwanted
effects are nausea and vomiting (in high doses) and rarely mild hypersensitivity reactions.

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178
 Diagram showing the mechanism of action of antibiotics that
interfere with the bacterial protein synthesis

Amino acid

Polypeptide
chain tRNA
RIBOSOME
Anticodon

Codons Competition with tRNA for the codon:

• tetracyclines
mRNA

Transpeptidation

Abnormal codon:anticodon recognition

→ misreading of the genetic message:
• aminoglycosides

Release
Inhibition of transpeptidation:
• chloramphenicol

Translocation of
the ribosome

Inhibition of translocation:
• macrolides

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179
 ANTIVIRAL DRUGS

Viruses, the smallest infective agents, consist essentially of nucleic acids (RNA or DNA)
enclosed in a protein coat.

Lipoprotein envelope (does not

exist in some RNA viruses)

Protein spikes (used for

docking to host cells)

Nucleic acid core

Nucleocapsid
Coat (capsid)

Viruses are not cells and, having no metabolic machinery of their own, are obligate
intracellular parasites, e.g., they have to use the metabolic processes of the host cell which
they enter and infect. Since their replication cycle is so intimately connected with the host
cell metabolism, it has proved extremely difficult to develop drugs that are selectively toxic
to viruses.

1. DNA viruses normally enter the host cell nucleus and direct the generation of new
viruses. Main examples are varicella-zoster, herpes simplex, Epstein Barr (glandular
fever), polio, echo, coxsackie and hepatitis B.
2. RNA viruses direct the generation of new viruses normally without involving the host
cell nucleus. Main examples are influenza virus, measles, mumps, german measles,
rabies, other hepatitis viruses (e.g., A and C).
3. RNA retroviruses (e.g., HIV) are a subgroup of RNA viruses that contain an enzyme,
reverse transcriptase, which makes a DNA copy of the viral RNA. This DNA copy is
integrated into the host cell genome and directs the generation of new virus particles.

Viral replication generally goes through the following phases:

1. Docking of viruses to susceptible cells
2. Viral penetration through the cell membrane
3. Synthesis of non-structural proteins (enzymes)
4. RNA or DNA synthesis
5. Synthesis of structural proteins

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180
 6. Assembly of viral particles
7. Release of viruses through the cell membrane

Most antiviral drugs interfere with synthesis of viral nucleic acids, although other
mechanisms can also be used.

Envelope Capsid attachment

by forming holes Nucleic acid

(naked viruses)

penetration
by budding
(enveloped viruses)
release

uncoating
assembly
capsids form around
nucleic cid
capsid shed

replication
synthesis of viral mRNA,
synthesis of viral proteins,
synthesis of viral nucleic acids

HIV has a unique life cycle as seen of the following diagram. Te first step in HIV entry
into susceptible cells which occurs through binding of viral glycoprotein GP41 and
cellular CD4 receptors mainly found on a subtype of lymphocytes known as CD4+
(helper) lymphocytes. Replication of HIV within infected cells includes one unique step –
synthesis of viral DNA from viral RNA which is controlled by viral enzyme reverse
transcriptase. After that viral DNA is incorporated into genetic material of infected cells,
which is controlled by viral enzyme integrase. From here viruses direct synthesis of viral
components and formation of viral particles - controlled by viral enzyme protease.

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 Mechanism of action of antiviral drugs

1. Inhibition of virus spreading:

• Neuraminidase is a glycoprotein found on the surface of the influenza viruses that

allows them to break through cell walls and thus gain access into the cell. After
replication viruses use neuraminidase to leave infected cells in order to infect other
cells. Neuraminidase inhibitors block neuraminidase on intracellular viruses
effectively preventing their entry but even more so escape from host cells and
spreading. They are indicated for the treatment of infections due to influenza A and B
viruses and the treatment should commence as soon as possible but no later than 48
hours after the onset of the initial symptoms of infection. Zanamivir [Relenza] is
administered by oral inhalation, using the provided inhalation device (Diskhaler),
while oseltamivir [Tamiflu] is taken orally. Both of them are tolerated well and the
treatment lasts five days.

2. Inhibition of nucleic acid synthesis:

• Acyclovir (alternative spelling aciclovir) [Zovirax, Acyclo-V, Zyclir, Acihexal,

Lovir], a guanosine (guanine-based nucleoside; nucleoside is composed of a

nitrogenous base and pentose sugar) derivative, selectively inhibits viral DNA

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182
 polymerase, and it is effective against herpes viruses. Acyclovir has minimal
unwanted effects because it is inactive until phosphorylated by viral enzymes, which
makes it selectively antiviral. It is effective topically, orally and perenterally and is
widely used in the treatment of HSV genital infections and severe shingles (herpes
zoster infection). Related drug is valacyclovir [Valtrex] which is converted into
acyclovir in the body and therefore has the same mechanism of action and same
indications.

• Famciclovir [Famvir] also interferes with DNA synthesis of herpes simplex virus type
1 and 2 infections, varicella zoster and to some extent cytomegalovirus. It appears that
it has longer-lasting antiviral activity than acyclovir. It is given orally in management
of acute herpes simplex and shingles, as well as genital herpes.

• Ganciclovir [Cymevene], a guanosine derivative, is also phosphorylated and then

incorporated into viral DNA, suppressing its replication; used in cytomegalovirus
(CMV) infection, especially CMV retinitis in AIDS patients (CMV is resistant to
acyclovir). Ganciclovir must be administered intravenously. Other antiviral used for
CMV infections are valganciclovir [Valcyte], cidofovir [Vistide] and foscarnet
[Foscavir].

• There are several anti-viral drugs used in treatment of HIV/AIDS (so called anti-
retrovirals).

¾ Reverse transcriptase inhibitors interferes with activity of the reverse

transcriptase enzyme:

o Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside

(nitrogenous base + ribose) analogues perform competitive inhibition of
the enzyme; examples are zidovudine [Retrovir], lamivudine [3TC,
Zeffix], stavudine [Zerit], zalcitabine [Hivid], didanosine [Videx],

emtricitabine [Emtriva], abacavir [Ziagen] and tenofovir [Viread].

ƒ combinations: zidovudine + lamivudine = [Combivir]; abacavir +
lamivudine = [Kivexa]; abacavir + lamivudine + zidovudine =
[Trizivir]; emtricitabine + tenofovir = [Truvada]

o Non-nucleoside reverse transcriptase inhibitors (NNRTI) are not

substrate analogues but directly inhibit the enzyme (non-competitive
inhibition of the enzyme); examples are delavirdine [Rescriptor],
nevirapine [Viramune] and efavirenz [Stocrin].

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183
 ¾ Protease inhibitors block final assembly of viral particles; examples: saquinavir
[Invirase, Fortovase], indinavir [Crixivan], ritonavir [Norvir], nelfinavir
[Viracept], amprenavir [Agenerase], atazanavir [Reyataz], fosamprenavir
[Telzir].
o combinations: lopinavir + ritonavir = [Kaletra]

¾ Unfortunately, resistance to anti-retrovirals develops quickly so such treatment

must include more that one drug. It is usual to combine two NRTIs with either one
NNRTI or one protease inhibitor (this is called Highly Active Antiretroviral
Therapy – HAART); in case of failure fusion inhibitors can be used.

¾ Unwanted effects of anti-retrovirals are common and include headache, nausea,

diarrhoea, vomiting, stomach pain, difficulty sleeping, anxiety, depression, muscle
aches, joint pains, rashes, peripheral neuropathies, lipodystrophy (loss of
subcutaneous adipose tissue especially visible on the face)

¾ Fusion inhibitors prevent fusion of HIV to host cells by binding of HIV surface
glycoprotein GP41 to the CD4 receptors on the patient’s cells, preventing viral
entry; example is enfuvirtide [Fuzeon] – it is given by subcutaneous injection
twice daily (the main disadvantage). The main advantage is minimal unwanted
effects and it is usually considered in patients who can not tolerate unwanted
effects of other anti-retrovirals.

• Ribavirin is a synthetic guanosine analogue that has broad-spectrum antiviral activity

against various DNA and RNA viruses. It may be given in form of aerosols to
hospitalised infants with serious pneumonia caused by respiratory syncytial virus
(RSV) [Virazide]. Oral ribavirin can also be given in combination with interferon
alpha for treatment of chronic hepatitis B and C (see later). The mechanism of action
of ribavirin in not completely understood. Ribavirin can temporarily lower red blood
cell count and platelet count – this may cause tiredness, shortness of breath and
decreased energy. Ribavirin has been shown to cause birth defects so combination
therapy is contraindicated in pregnancy and breastfeeding.

• Adefovir [Hepsera] is a nucleotide analogue of adenosine monophosphate with

activity against human hepatitis B virus (HBV). It is used orally for chronic hepatitis
B in adults with evidence of HBV replication and abnormal liver function tests (active
disease).

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3. Immunomodulators:

• Interferon alpha-2a [Roferon-A] and interferon alpha-2b [Intron-A] are natural

glycoprotein products of virus-infected cells that stimulate formation of an enzyme
within virus-free cells which destroys the genetic material of invading viral particles
before they can be multiplied sufficiently to produce cell destruction. Today
interferons are produced by recombinant DNA technology. They must be given by
subcutaneous injection, usually in chronic progressive hepatitis B and C. Unwanted
effects of interferons vary for each person and may become less severe as treatment
continues. Common ones are initial fever, chills, muscle aches and headaches; some
people experience tiredness, loss of appetite, insomnia, nausea, vomiting, skin
dryness/itching, hair thinning and weight loss.
• For chronic hepatitis C standard treatment involves the use of pegylated interferon
(alpha-2b) and ribavirin as combination therapy [Pegatron Combination Therapy].
The pegylated interferon used in the treatment of hepatitis C is a synthetic compound
that is slightly different to a natural one in order to have longer duration of action.
Pegylated interferon treatment is self-administered by a subcutaneous injection once
a week while ribavirin is given orally. The combination of ribavirin with interferon
results in a better treatment response than with either drug used on its own – duration
of treatment is 24 or 48 weeks depending on viral genotype. Effectiveness of
combination therapy largely depends on viral genotype - about 80% in genotype 2
and 3, approximately 50% in genotypes 1 and 4

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185
 ADVERSE DRUG REACTIONS

The majority of adverse drug reactions can be divided into those that are dose related and
those that are non-dose related; the latter, which occur infrequently, often have an
immunological basis.

DOSE RELATED ADVERSE DRUG REACTIONS

Dose related adverse drug reactions are predictable and caused by an excess of the drug’s
wanted pharmacological effect (e.g., hypoglycaemia with insulin, bleeding with
anticoagulants) or sometimes a drug’s parallel unwanted actions (e.g., constipation with
morphine, drowsiness produced by antihistamines, dry mouth and blurred vision with anti-
spasmodic drugs). Dose related harmful effects occur most often with drugs that have a small
difference between therapeutic and toxic doses (low therapeutic index).

Generally it is calculated as Lethal dose of a drug for 50% of the population (LD50) divided
by Effective dose for 50% of the population (ED50) (note: impossible on humans)
Higher therapeutic index means a drug is safer and less likely to cause toxic effects when
taken in accidental or deliberate overdose. Some examples are: digitalis 3, pethidine 8,
paracetamol 27, penicillin >>100.
Commonly used drugs with a low therapeutic index include anticoagulants, hypoglycaemic
drugs including insulin, cardiac glycosides, anti-arrhythmics, aminoglycoside antibiotics,
tricyclic antidepressants, cytotoxic and immunosuppressant drugs.

Dose related adverse drug reactions are usually due to incorrect dosage (too high) or altered
pharmacokinetics, usually impaired drug elimination (e.g., renal failure) or drug interactions.
Drug interactions, when the administration of one drug can alter the action of another, may
be in form of:

1. Pharmacodynamic interactions occur when one drug alters the sensitivity or

responsiveness of tissues to another drug. Examples are:

• benzodiazepines and alcohol have additive depressant effects on the CNS

• in asthmatic patients non-selective β–blockers will oppose β–agonists and may
precipitate asthma episodes

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186
 • hyperglycaemic effect of thiazide diuretics may counteract the blood glucose lowering
action of insulin or oral antidiabetic drugs
• potassium-depleting diuretics by causing hypokalaemia increase the effects of digoxin

2. Pharmacokinetic interactions occur when one drug alters absorption, distribution,

metabolism or excretion of another drug. Examples are:

• metal-containing products (iron salts, antacids, dairy products) slow absorption of

tetracyclines and quinolone antibiotics
• diuretic drugs reduce renal clearance of lithium and increase its activity
• hepatic enzyme inducers such as phenytoin, phenobarbitone and carbamazepine can
decrease the efficacy of drugs metabolised by the same enzymes such as warfarin or
oral contraceptives
• hepatic enzyme inhibitors such as cimetidine and erythromycin potentiate effects of
other drugs such as anticoagulant warfarin

NON-DOSE RELATED ADVERSE REACTIONS

Non-dose related (idiosyncratic) adverse drug reactions are relatively rare, but are
unpredictable, and in contrast to many dose related adverse drug reactions can be very
serious. For example, chloramphenicol causes severe bone marrow depression (aplastic
anaemia) in approximately 1:50,000 patients, penicillin antibiotics very rarely can cause
anaphylactic shock, roughly in 1:2,000,000 administrations. Mechanisms responsible for
idiosyncratic reactions are often poorly understood, but in certain proportion of cases
hypersensitivity reactions or abnormal biochemistry in affected individuals seem to underlie
them.

Large molecules, e.g., antisera, insulin, can themselves be immunogenic but most drugs are
small molecules and are not immunogenic on their own. In some patients they, or their
metabolites, can combine with various tissue proteins, forming antigenic complexes which
trigger an immunological reaction. Although drug allergy is unpredictable, it is more likely to
occur in patients with a history of atopic disease (hay fever, asthma, eczema).

Drug-induced allergic reactions may be antibody-mediated (type I, II, III) or cell-mediated

(type IV). Important clinical manifestations include:

• Anaphylactic reactions (type I): The severity of this allergic reaction may range from only
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187
 minor skin rash with itching to life-threatening anaphylactic shock. Many drugs can cause
the condition such as penicillin antibiotics or NSAIDs.

• Antibody-dependent cytotoxicity (type II): These are responsible for many harmful
haematological reactions such as:
o haemolytic anaemia (sulphonamides and methyldopa)
o leukopenia or even agranulocytosis (effective absence of leukocytes in blood), which
can be irreversible (sulphonamides, chloramphenicol and carbimazole)
o thrombocytopenia (thiazide diuretics, heparin)

• Immune complex reactions (type III): Immune complexes composed of the drugs (e.g.,
penicillins, sulphonamides, gold salts used in treatment of rheumatoid arthritis) and
antibodies can be deposited in kidneys, joints and blood vessel walls initiating a cascade
of inflammatory reactions responsible for fever, arthralgia and glomerulonephritis

• Delayed type reactions (type IV): These occur with many topically applied drugs such as
antibiotics, antihistamines and even skin care products, and are in form of usually mild
allergic contact dermatitis

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188
 DRUGS IN PREGNANCY

One in twenty five (1:25) babies born in this country has a birth defect. A small proportion of
these birth defects are caused by medications taken by the mother during pregnancy.
Teratogenesis is the occurrence of foetal developmental abnormalities caused by drugs taken
during the first trimester of pregnancy (organogenesis). Most drugs cross the placental barrier
to some extent and, if possible, drugs should be avoided during pregnancy. The mechanisms
of action of teratogens are not clearly understood, though DNA damage is a factor in many
cases.

In relation to risk of causing foetal damage drugs can be classified into several categories:

• Category A – drugs taken by a large number of pregnant women without any evidence of
foetal malformations or any other direct or indirect harmful effect on the human foetus
• Category B – similar to category A but taken by limited number of pregnant women
(insufficient data to draw a final conclusion). These drugs are further classified according
to the result of animal studies into:
o B1: animal studies have not shown evidence of increased occurrence of foetal
damage
o B2: animal studies are inadequate, and may be lacking but available data show no
evidence of an increased occurrence of foetal damage
o B3: studies in animals have shown evidence of increased incidence of foetal
damage, the significance of which is considered uncertain in humans
• Category C – drugs that owing to their mechanism of action have caused or may be
suspected of causing reversible harmful effects on the human foetus but without
producing malformations
• Category D – drugs that are known for causing harmful irreversible damage or
malformations of the human foetus and should be avoided in pregnancy
• Category X – drugs that have very high risk of causing permanent damage to the foetus
and are contraindicated in pregnancy

For compherensive information please check TGA booklet “Prescribing medicinces in

pregnancy” found at http://www.tga.gov.au/docs/html/medpreg.htm

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 DRUG INDEX

Generic names are in this font; brand names are in this font!

Alphapril · 54 Aspen Ampicyn · 174

Alprax · 136 Aspen Fisamox · 174
A alprazolam · 136 Aspen Flucil · 174
Alprim · 170 aspirin · 69, 118
abacavir · 183 alteplase · 70 Aspirin · 118
Abbocillin · 173 Alvercol · 88 Aspro · 118
abciximab · 69 Alvesco · 76, 125 Astrix 100 · 69
Abilify · 142 Amaryl · 95 Atacand · 54
acarbose · 96
Amfamox · 81 Atacand Plus · 63
Accolate · 77 amikacin · 178 atazanavir · 184
Accupril · 54 Amikacin · 178 Atehexal · 41
Accuretic · 63 Amikin · 178 atenolol · 41
acetylcysteine · 79
Aminophylline · 75 Ativan · 136, 155
Acihexal · 182
Amira · 149 atorvastatin · 102
Acimax · 82 amitriptyline · 148 Atromid-S · 102
Aclor · 174 Amizide · 63 Atropine Sulphate · 36
Acquin · 54 amlodipine · 50, 53, 58 Atropt · 36
Actacode · 79 Amohexal · 174 Atrovent · 36, 75
Actifed Dry · 79 Amoxil · 174 Attenta · 42
Actilax · 88 amoxycillin · 174 Augmentin · 174
Actiq · 112 ampicillin · 174
Aurorix · 149
Actos · 95 Amprace · 54
Ausfam · 81
Actrapid · 93 amprenavir · 184
Anafranil · 148 Ausgem · 102
Actuss · 79 Auspril · 54
Acyclo-V · 182 Anamorph · 112
Anaprox · 118 Ausran · 81
Acyclovir · 182
Anatensol · 142 Austrapen · 174
Adalat · 50, 53, 58
Anexate · 137 Avandamet · 95
Addos · 50, 53, 58
Angeliq · 109 Avandia · 95
Adefovir · 184
Anginine · 49 Avanza · 148
Advantan · 125
Anpec · 50 Avapro · 54
Advil · 118
Anselol · 41 Avapro HCT · 63
Aerodiol · 109
Antenex · 136 Avelox · 170
Aeron · 75
Antroquoril · 125 Avil · 87, 132
Agenerase · 184
Anzemet · 87 Avomine · 87
Aggrastat · 69
Apalgin · 118 Avonex · 163
Airomir · 74
Apidra · 93 Axit · 148
Akamin · 177
Apoven · 36, 75 Aylide · 95
Akineton · 159
azatadine · 132
Albalon · 40 Arabloc · 129
Azep · 132
Aldactone · 63 Arava · 129
azitromycin · 178
Aldazine · 142 Aricept · 162
Aldomet · 42 Arima · 149
Alepam · 136 aripiprazole · 142 B
Aleve · 118 Aristocort · 125
alfentanyl · 112 Aropax · 139, 147 Bactrim · 170
Alka-Seltzer · 118 Artane · 159 beclomethasone · 76
Allegron · 148 Arthrexin · 118 Becoderm-C · 125
Allereze · 132 Arthrotec · 83 Beconase Allergy &
Alodorm · 136 Asasantin SR · 69 Hayfever 12 hour · 125
Alphacin · 174 Asig · 54 Beconase Allergy &
Alphamox · 174 Asmol · 74 Hayfever 24 hour · 125
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190
Bekunis · 89 Capadex · 112 Claratyne · 132
belladonna extract · 36 Carafate · 83 Clarihexal · 178
Benadryl Dry · 79 carbamazepine · 116, 154 Clarinase · 132
Benatuss · 39 carbidopa · 159 clarithromycin · 178
BenPen · 173 carbimazole · 98 Clavulin · 174
benseraside · 159 Cardiprin · 69, 118 Cleocin · 175
benzathine penicillin · 173 Cardizem · 50 Clexane · 68
benzhexol · 159 Cardol · 41 Climara · 109
Benztrop · 159 Cartia · 69, 118 Climen · 109
benztropine · 159 carvedilol · 41, 58 clobazam · 136
benzyl penicillin · 173 Catapres · 40 Clobemix · 149
Betaferon · 163 Ceclor · 174 clofibrate · 102
Betagan · 41 cefaclor · 174 clomipramine · 148
Betaloc · 41 Cefazolin · 175 Clonac · 118
betanechol · 35 cefepime · 175 clonazepam · 136
Betaxolol · 41 cefotaxime · 175 clonidine · 40
Betnovate · 125 Cefotaxime · 175 clopidogrel · 69
Betoptic · 41 cefpirome · 174 Clopine · 142
Betoquin · 41 Cefrom · 175 Clopixol · 142
Bgramin · 174 ceftazidime · 175 CloSyn · 142
Biaxsig · 178 ceftriaxone · 175 clozapine · 142, 151
Bicillin · 173 Ceftriaxone · 175 Clozaril · 142
cefuroxime · 174 Codalgin · 118
Bicor · 41
Celapram · 147 Codalgin Forte · 118
Biodone Forte · 112
Celebrex · 120 Codalgin Plus · 118
biperiden · 159
celecoxib · 120
bisacodyl · 89 Codapane · 118
Bisalax · 89 Celestone Chronodose · 125
Codapane Forte · 118
Bisolvon · 79 Cellulone · 88
codeine · 79, 112, 118
cephalexin · 174
Bisolvon Dry · 79 Codiphen · 118
cephalothin · 175
bisoprolol · 41 cephamandole · 175 Codis · 118
Brenda-35 ED · 105 cephazolin · 175 Codral Forte · 118
Breviblock · 41 cetrizine · 132 Cogentin · 159
Brevinor · 105 C-Flox · 170 Colese · 36, 90
Brevinor-1 · 105 Chloramphenicol · 177 Colestid · 102
Bricanyl · 40, 74 Chloromycetin · 177 colestipol · 102
bromazepam · 136 chlorpromazine · 142 Colofac · 36, 90
bromhexine · 79 Chlorquin · 130 Coloxyl · 88
Bromocriptine · 160 Chlorsig · 177 Coloxyl with Senna · 88
Brondecon · 75 cholestyramine · 102
Combivent · 75
Brufen · 118 Cholstat · 102
Combivir · 183
budesonide · 76 Ciazil · 147
Bugesic · 118 Comtan · 160
ciclesonide · 76
bumetanide · 62 cidofovir · 183 Concerta · 42
buprenorphine · 112 Cilamox · 174 Copaxone · 163
Burinex · 62 Cilex · 174 Coras · 50
Buscopan · 36, 90 Cilicaine · 173 Corbeton · 41
Buspar · 139 Cilicaine Syringe · 173 Cordilox · 50
Buspirone · 139 Cilopen · 173 Cortaid · 125
Butalgin · 118 cimetidine · 81 Cortate · 124
Butamol · 74 Cipramil · 147 Cortef · 125
Byetta · 96 ciprofloxacin · 170 Co-trimoxazole · 170
Ciprol · 170 Coumadin · 67
Ciproxin · 170 Coversyl · 54
C citalopram · 147 Cozaar · 54
Clamohexal · 174 Crestor · 102
Cabaser · 160 Clamoxyl · 174 Crixivan · 184
cabergoline · 160 Clarac · 178 Cromese · 76
Calcihep · 68 Claramax · 132 cromoglycate · 76
candesartan · 54
_________________________________________________________________________________
191
Crysanal · 118 Dilaudid · 112 Dymadon · 118
Curam · 174 Diltahexal · 50 Dymadon Co. · 118
Cyklokapron · 70 diltiazem · 50 Dymadon Forte · 118
Cymevene · 183 Dilzem · 50 Dynastat · 120
cyproheptadine · 132 dimenhydrinate · 87, 132
cyproterone · 105, 109 Dimetapp · 39
Cytotec · 83 Dimetapp Nasal · 40 E
Dimirel · 95
Dinac · 118 Ebixa · 162
D Dindevan · 67 Ecotrin · 118
diphenhydramine · 139 Edronax · 147
Dalacin · 175 diphenoxylate · 89 EES · 178
dalteparin · 68 Diprosone · 125
danaparoid · 68 efavirenz · 183
dipyridamole · 69 Efexor · 148
Daonil · 95 Disprin · 118 eformoterol · 40, 74
DBL Doxycycline · 177 Disprin Forte · 118 Egocort · 125
DBL Erythromycin · 178 Distaph · 174 Eldepryl · 160
delavirdine · 183
Dithiazide · 63 Eleuphrat · 125
Delta-Cortef · 76
Ditropan · 36, 90 Eleva · 147
Demazin · 39 dobutamine · 40
Depo-medrol · 124 Elmendos · 154
Dobutamine · 40 Elocon · 125
Depo-Nisolone · 124 Dobutrex · 40 emtricitabine · 183
Depo-Provera · 107 docusate sodium · 88 Emtriva · 183
Depo-Ralovera · 107 Dolaforte · 118 E-Mycin · 178
Deptran · 148 Dolapril · 54 Enahexal · 54
Deralin · 41 Doloxene · 112 Enalabell · 54
Dermestril · 109 donepezil · 162 enalapril · 54
desloratadine · 132 Donnalix · 36, 90 Enbrel · 131
desogestrel · 105 Donnatab · 36, 90
dexamethasone · 87 Endep · 148
Dormizol · 139 Endone · 112
Dexamethasone · 87
Doryhexal · 177 enfuvirtide · 184
dexamphetamine · 42
Doryx · 177 enoxaparin · 68
Dexamphetamine · 42
dexchlorpheniramine · 132 Dothep · 148 Entacapone · 160
Dexi-Tuss · 79 dothiepin · 148 Entocort · 124
Dexmethasone · 125
doxepin · 148 Epaq · 74
Doxsig · 177 ephedrine · 42, 52
dextrometorphan · 79
dextropropoxyphene · 112 Doxy · 177 Epilim · 151, 154
DHC · 79 doxycycline · 177 eprosartan · 54
Doxylamine · 139 Ergotamine · 52
Diabex · 94
Doxylin · 177 Eryc · 178
Diacare · 89
Dozile · 139 Eryhtrocin · 178
Diaformin · 94
D-Penamine · 130 erythromycin · 178
Diamicron · 95 escitalopram · 147
Dramamine · 87, 132
Diane-35 ED · 105 Esipram · 139, 147
Drixine · 39
Diapride · 95 esmolol · 41
Drixine Nasal · 40
diazepam · 136, 155 esomeprazole · 82
Droleptan · 142
Diclocil · 174 Estalis · 109
droperidol · 142
diclofenac · 118
drospirenone · 105, 109 Estelle-35 ED · 105
Diclohexal · 118 Estracombi · 109
Duatrol SR · 118
dicloxacillin · 174 Estraderm · 109
Ducene · 136
Dicloxsig · 174 Estraderm MX · 109
didanosine · 183 Duphalac · 88
Duride · 49 Estradot · 109
Di-Gesic · 112
Durogesic · 112 Estrofem · 109
digoxin · 47
ethinyloestradiol · 105
Dihydergot · 53 Durolax · 89
ethosuximide · 155
dihydrocodeine · 79 Durolax SP Drops · 89 etonorgestrel · 107
Dihydroergotamine · 53 Duro-Tuss · 79 Eutroxsig · 99
Dilantin · 154 dydrogesterone · 109 Exelon · 162
Dilatrend · 41, 58
_________________________________________________________________________________
192
Exitine · 147 Frakas · 177 Hydralyte · 89
Extine · 139 Frisium · 136 Hydrene · 63
ezetimibe · 102 frusemide · 62 hydrochlorothiazide · 63
Ezetrol · 102 Fruside · 62 Hydrocortisone · 76
Fucidin · 175 Hyforil · 63
Fuzeon · 184 hyoscine · 36, 87, 90
F Hypnodorm · 136
Hypnovel · 136
Famciclovir · 183 G Hypurin Isophane · 93
Famohexal · 81 Hypurin Neutral · 93
famotidine · 81 gabapentin · 116, 154 Hysone · 76, 124
Famvir · 183 Gabitril · 154 Hytrin · 40
Faverin · 147 galantamine · 162
Febridol · 118 Ganciclovir · 183
Feldene · 118 Gantin · 116, 154 I
felodipine · 50, 53, 58 Gastrolyte · 89
Felodur · 50, 53, 58 Gastro-Stop · 89 Ialex · 174
Femoden ED · 105 Gatrogel-Ranitidine · 81 Ibiamox · 174
Femoston · 109 Gavilast 12 hour · 81 Ibilex · 174
Femtran · 109 gemfibrosil · 102
Ibimicyn · 174
Fenac · 118 Gemhexal · 102
ibuprofen · 118
feniramine · 132 Genlac · 88 Imdur · 49
fenofibrate · 102 Genoral · 109 Imflac · 118
fentanyl · 112 gentamycin · 178
Imigran · 53
fexofenadine · 132 gestodene · 105
imipramine · 148
Fibogel · 88 glibenclamide · 95
gliclazide · 95 Imodium · 89
Fibsol · 54
Glimel · 95 Imovane · 139
Filpril · 54
glimepiride · 95 Implanon · 107
Fiorinal · 118
glipizide · 95 Improvil 28 Day · 105
Flagyl · 170 Glucobay · 96 Imrest · 139
Flixotide · 76, 125 Glucohexal · 94 Imtrate · 49
Flomax · 40 Glucomet · 94 Inderal · 41
Flopen · 174 Glucophage · 94 indinavir · 184
Florinef · 126 Glucovance · 95 Indocid · 118
Floxapen · 174 Glyade · 95 indomethacin · 118
Floxsig · 174 glyceryl trinitrate · 49, 53 Insensye · 170
Fluanxol · 142 Gopten · 54 Inspra · 63
Flubiclox · 174 granisetron · 87 insulin · 92
flucloxacillin · 174 guaiphenesin · 79 Insulin detemir · 93
fludrocortisone · 126 Insulin lispro · 93
Flumazenil · 137 Intal · 76
flunitrazepam · 136 H Interferon alpha-2a · 185
Fluohexal · 147 interferon alpha-2b · 185
Fluoxebell · 147 Halcion · 136 Intron-A · 185
fluoxetine · 147 Haldol · 142 Invirase · 184
flupenthixol · 142 Inza · 118
haloperidol · 142
fluphenazine · 142
Harmonise · 89 Ipratrin · 36, 75
fluticasone · 76
fluvastatin · 102 heparin · 68 ipratropium · 36, 75
fluvoxamine · 147 Heparin · 68 Ipravent · 75
Foradile · 40, 74 Hepsera · 184 irbesartan · 54
Fortovase · 184 Hivid · 183 Iscover · 69
Fortum · 175 Humalog · 93, 94 Isomonit · 49
fosamprenavir · 184 Humira · 131 isoprenaline · 40
Isoprenaline · 40
foscarnet · 183 Humulin · 94
Foscavir · 183 Isoptin · 50
Humulin NPH · 93
fosinopril · 54 Isopto Carpine · 35
Humulin R · 93
Fosipril · 54 Isordil · 49
Hydopa · 42
Fragmin · 68 Isosorbide · 49

_________________________________________________________________________________
193
ispaghula · 88 lercanidipine · 53, 58 Mandol · 175
Isuprel · 40 Lescol · 102 Maosig · 149
Levemir · 93 Marevan · 67
levetiracetam · 155 Marvelon 28 · 105
J Levlen ED · 105 Maxamox · 174
levobunolol · 41
Maxipime · 175
Januvia · 96 Levocabastine · 132
levodopa · 158 Maxolon · 87
Jezil · 102 mebeverine · 36, 90
Juliet-35 ED · 105 Levonelle-2 · 107
levonorgestrel · 105, 106, 107 Medrol · 76, 87
Lexapro · 139, 147 medroxyprogesterone · 107,
109
K Lexotan · 136
mefenamic acid · 118
Linctus Tussinol · 79 Mefic · 118
Kaletra · 184 Lipazil · 102 Mefoxin · 175
Kalixocin · 178 Lipex · 102 Melizide · 95
Kalma · 136 Lipidil · 102 meloxicam · 118
Kapanol · 112 Lipitor · 102 Memantine · 162
Karlor · 174 Lipostat · 102 Meprazol · 82
Karvea · 54 Liprace · 54 Mersyndol · 118
Karvezide · 63 Liprachol · 102 Mersyndol Forte · 118
Keflex · 174 Lisinobell · 54 mestranol · 105
lisinopril · 54 Metamucil · 88
Keflin · 175
Lisodur · 54 Metformin · 94
Keflor · 174 methadone · 112
Lithicarb · 151
Kefzol · 175 Methoblastin · 129
lithium · 151
Kenacort-A · 124 Methotrexate · 129
Livial · 109
Keppra · 155 methylcellulose · 88
Livostin · 132
ketoprofen · 118 Methyldopa · 42
Locilan 28 day · 106
Kineret · 131 methylphenidate · 42
Loette · 105
Kinson · 159 methylprednisolone · 76, 87
Lofenoxal · 89 metoclopramide · 87
Kivexa · 183
Logicin Cough Suppressant Metohexal · 41
Klacid · 178
· 79 metoprolol · 41
Klacid Hp 7 · 84
Logynon ED · 105 Metrogyl · 170
Kliogest · 109
Lomotil · 89 Metrol · 41
Kliovance · 109 loperamide · 89 Metronidazole · 170
Kredex · 41, 58 Lopid · 102 Metronide · 170
Kripton · 160 Lopressor · 41 Mianserin · 148
Kwells · 36, 87 Lorastyne · 132 Micardis · 54
Kytril · 87 loratadine · 132 Micardis Plus · 63
lorazepam · 136, 155 Microgynon 20 ED · 105
losartan · 54 Microgynon 30 · 105
L Losec · 82 Microgynon 30 ED · 105
Lovan · 147 Microgynon 50 ED · 105
labetalol · 41 Lovir · 182 Microlevlen ED · 105
Lac-Dol · 88 Lumin · 148 Microlut · 106
Lactocur · 88 lumiracoxib · 120
lactulose · 88 Micronor · 106
Luvox · 147
Lamictal · 154 Microval · 106
Lycinate · 49
Lamitrin · 154 midazolam · 136
Lyrica · 116, 155 Midazolam · 136
lamivudine · 183
Lamogine · 154 Minax · 41
lamotrigine · 154 Minidiab · 95
M
Lanoxin · 47 Minipress · 40
lansprazole · 82
M.O.S. · 112 Minitran · 49
Lantus · 93 minocycline · 177
Mabthera · 131
Largactil · 142 Minomycin · 177
macrogol · 88
Lasix · 62 Madopar · 159 Minulet · 105
Lax-Tab · 89 Magicul · 81 Mirena · 106

_________________________________________________________________________________
194
mirtazapine · 148 Neulactil · 142 olanzapine · 142, 151
Mirtazon · 148 Neurontin · 116, 154 Olmetec · 54
Misoprostol · 83 nevirapine · 183 Olmetec Plus · 63
Mixtard · 93, 94 Nexium · 82 Omalizumab · 77
Mobic · 118 Nexium Hp 7 · 84 Omepral · 82
Mobilis · 118 Nidem · 95 omeprazole · 82
moclobemide · 149 nifedipine · 50, 53, 58 ondansetron · 87
Modecate · 142 Nifehexal · 50, 53, 58 Ondaz · 87
Moduretic · 63 nimodipine · 50, 53, 58 Ordine · 112
Mogadon · 136 Nimotop · 50, 53, 58 Orgaran · 68
Mohexal · 149 nitrazepam · 136 Oroxine · 99
Monace · 54 Nitro-Dur · 49 Orudis · 118
Monodur · 49 nitroglycerin · 49 Oruvail · 118
Monofeme · 105 Nitrolingual Pumpspray · 49 oseltamivir · 182
Monoplus · 63 Nitrostat · 49 Otrivin · 40
Monopril · 54 Nizac · 81 Ovestin · 109
nizatidine · 81 oxazepam · 136
Monorest · 109
Nordette · 105 oxcarbazepine · 154
montelukast · 77
Nordicort · 76 Oxis · 40, 74
morphine · 112
norethisterone · 105, 106, 109 oxprenolol · 41
Movalis · 118
Norflohexal · 170 oxybutynin · 36, 90
Movicol · 88 oxycodone · 112
norfloxacin · 170
Movox · 147 OxyContin · 112
Norfloxacin · 170
Moxacin · 174 oxymetazoline · 39, 52
Noriday 28 · 106
moxifloxacin · 170 OxyNorm · 112
MS Contin · 112 Norimin · 105
MS Mono · 112 Norimin-1 · 105
Mucilax · 88 Norinyl-1 · 105 P
Mucomyst · 79 Normison · 136
Murelax · 136 Noroxin · 170 Pamacid · 81
Murine Clear Eyes · 40 Norspan · 112 Panadeine · 118
nortriptyline · 148 Panadeine Forte · 118
Mylanta Ranitidine 12 hour
Norvasc · 50, 53, 58
· 81 Panadol · 118
Myocrisin · 131 Norvir · 184
Panafcort · 124
Noten · 41
Panafcortelone · 76, 124
Novasone · 125
Panafen · 118
N NovoMix · 94
Panafen Plus · 118
NovoNorm · 95
Panalgesic · 118
naloxone · 114 NovoRapid · 93
Panamax · 118
Naloxone · 114 Nuelin · 75
Panamax Co. · 118
naltrexone · 114 Nufloxib · 170
Naphazoline · 40 pantoprazole · 82
Nupentin · 116, 154 paracetamol · 112, 118
Naphcon · 40
Nurofen · 118 Paradex · 112
Naprogesic · 118
Nurofen Plus · 118 Parahexal · 118
Naprosyn · 118
Nurolasts · 118 Paralgin · 118
naproxen · 118
Nyal · 39 Parcodin · 79
Naramig · 53
naratriptan · 53 Nyal Cough Medicine · 79 parecoxib · 120
Narcan · 114 Nyefax · 50, 53, 58 Pariet · 82
Nardil · 149 Nyogel · 41 Parlodel · 160
Nasonex · 125 Parmol · 118
Navoban · 87 Parnate · 149
Nebcin · 178
O paroxetine · 147
Paroxetine · 139
nedocromil · 76
Negastro · 89 Odrik · 54 Paxam · 136
nelfinavir · 184 oestradiol · 109 Paxtine · 139, 147
oestriol · 109 Pegatron Combination
Neo-Mercazole · 98
oestrone · 109
neomycin · 178 Therapy · 185
Ogen · 109
Neosulf · 178 Pendine · 116, 154
_________________________________________________________________________________
195
Penhexal · 173 Probitor · 82 Repalyte · 89
pentoxyverine · 79 Procaine penicillin · 173 Rescriptor · 183
Pepcidine · 81 prochlorperazine · 87 Respolin · 40
Pepzan · 81 Prodeine Forte · 118 Resprim · 170
Perfalgan · 118 Profloxin · 170 Restavit · 139
pergolide · 160 Progynova · 109 reteplase · 70
Periactin · 132 Proladone · 112 Retrovir · 183
pericyazine · 142 promethazine · 87, 132, 139 Revia · 114
Perindo · 54 propantheline · 36, 90
Reyataz · 184
perindopril · 54 propranolol · 41
propylthiouracil · 98 Rhinocort, Budamax · 125
Permax · 160
Proquin · 170 Ribavirin · 184
Persantin · 69 Ridaura · 131
pethidine · 112 protamine · 68
Protamine Sulphate · 68 Rifadin · 175
Pethidine · 112 Rikodeine · 79
phenelzine · 149 Protaphane · 93
Rimycin · 175
Phenergan · 87, 132, 139 Prothiaden · 148
Risperdal · 142
phenindione · 67 Pro-Ven · 118
risperidone · 142
pheniramine · 87 Proxen · 118 ritonavir · 184
Phenoxymethylpenicillin · 173 Prozac · 147 rivastigmine · 162
phenylephrine · 39, 52 pseudoephedrine · 42, 52 Rivotril · 136
phenytoin · 154 psyllium · 88
pholcodine · 79 Robitussin DM · 79
Pulmicort · 76, 125 Rocephin · 175
Physeptone · 112
Pyrin · 130 Roferon-A · 185
Picolax · 89
Pico-Prep · 89 rosiglitazone · 95
picosulphate sodium · 89 Roxar · 178
pilocarpine · 35
Q Roximycin · 178
Pilocarpine · 35 Roxin · 170
Questran · 102 roxitromycin · 178
pindolol · 41
quetiapine · 142
pioglitazone · 95 Rozex · 170
Pirohexal-D · 118 Quilonum · 151
Rulide · 178
piroxicam · 118 quinapril · 54
Placil · 148 Qvar · 76, 125
Plaquenil · 130 S
Plavix · 69
R
Plendil · 50, 53, 58 Sabril · 154
Polaramine · 132 rabeprazole · 82 Salazopyrin · 130
Ponstan · 118 Rafen · 118 salbutamol · 40, 74, 75
Postinor-2 · 107 salmeterol · 40, 74
Ramace · 54
Pramin · 87 Sandrena · 109
ramipril · 54
saquinavir · 184
Pravachol · 102 RA-Morph · 112
Seaze · 154
pravastatin · 102 Rani 2 · 81
prazosin · 40, 54 Selegiline · 160
ranitidine · 81
PredMix Oral Liquid · 124 Selgene · 160
Ranoxyl · 81
Prednefrin · 39 Sennesoft · 88
Ransim · 102
prednisolone · 76 Sennetabs · 89
Rapifen · 112
Predsolone · 124 Senokot · 89
reboxetine · 147
Predsone · 124 Septopal · 178
Redipred · 76
Prefrin · 39 Septrin · 170
Redipred Oral Liquid · 124
pregabalin · 116, 155 Serenace · 142
Relenza · 182
Premarin · 109 Serepax · 136
Remeron · 148
Premia · 109 Seretide · 76, 125
Remicade · 131
Presolol · 41, 58 Serevent · 40, 74
Reminyl · 162
Pressin · 40 Seroquel · 142
Renihexal · 81
Prexige · 120 sertraline · 147
Renitec · 54
Prilace · 54 Setacol · 36, 90
Renitec Plus · 63
Prinivil · 54 Setrona · 147
ReoPro · 69
Pro-Banthine · 36, 90 Sevredol · 112
repaglinide · 95
Sigmacort · 125
_________________________________________________________________________________
196
Sigmaxin · 47 Talohexal · 147 Tricortone · 125
Simvabell · 102 Tamiflu · 182 Trifeme · 105
Simvar · 102 Tamsulosin · 40 trifluoperazine · 142
simvastatin · 102 Targocid · 175 Trileptal · 154
Sinemet · 159 Tazac · 81 trimeprazine · 132, 139
Sinequan · 148 Tegretol · 116, 151, 154 Trimethoprim · 170
trimipramine · 148
Sinex · 39 Telfast · 132
Triphasil · 105
Singulair · 77 telmisartan · 54
Telnase · 125 Triprim · 170
Snuzaid · 139
Telzir · 184 Tri-Profen · 118
Soflax · 88
Temaze · 136 Triquilar ED · 105
Sofradex · 87
temazepam · 136 Trisequens · 109
Solavert · 41
Temgesic · 112 Tritace · 54
Solone · 124
Temtabs · 136 Trizivir · 183
Solu-Cortef · 124
tenofovir · 183 tropisetron · 87
Solu-medrol · 87 Truvada · 183
Tenopt · 41
Solu-Medrol · 124 Tryazan · 54
Tenormin · 41
Somac · 82 Tryptanol · 148
Tensig · 41
Sone · 124 Tysabri · 163
terazosin · 40, 54
Sorbidin · 49 terbutaline · 40, 74
Sorbilax · 88 Teril · 116, 151, 154
sorbitol · 88 tetracycline · 177 U
Sotacor · 41 Tetrex · 177
sotalol · 41 Teveten · 54 Ultac · 81
Spiriva · 36, 75 Teveten Plus · 63 Unisom · 139
spironolactone · 63 theophylline · 75 Uremide · 62
Sporahexal · 174 thioridazine · 142 Urocarb · 35
Stalevo · 160 Thyroxine · 99
Staphylex · 174 tiagabine · 154
stavudine · 183 tiaprofenic acid · 118
tibolone · 109 V
Stelezine · 142
Stemetil · 87 Ticlid · 69
ticlopidine · 69 valacyclovir · 183
Stemzine · 87 valganciclovir · 183
tigecycline · 177
sterculia · 88 Valium · 136, 155
Tilade · 76
Stildem · 139 Vallergan · 132, 139
Tilodene · 69
Stilnox · 139 Valpam · 136
Timolol · 41
Stocrin · 183 Valpro · 151, 154
Timoptol · 41
Streptase · 69 tiotropium · 36, 75 valproate · 151, 154
streptokinase · 69 tirofiban · 69 Valtrex · 183
Sublimaze · 112 tobramycin · 178 Vancocin · 175
Subutex · 112 Tobramycin · 178 Vancomycin · 175
Sucralfate · 83 Tofranil · 148 Vasocardol · 50
Sulfadiazine · 170 Tolerade · 148 Veganin · 118
sulphadiazine · 170 Tolvon · 148 Venlafaxine · 148
sumatriptan · 53
Topamax · 154 Ventolin · 40, 74
Surgam · 118 verapamil · 50
topiramate · 154
Surmontil · 148 tramadol · 112 Vercef · 174
Suvalan · 53 Tramahexal · 112 Vibramycin · 177
Symbicort · 76 Tramal · 112 Vick’s Cough Syrup · 79
Symbicort Turbuhaler · Tramedo · 112 Videx · 183
125 Trandate · 41, 58 vigabatrine · 154
Synphasic · 105 trandolapril · 54 Viracept · 184
tranexemic acid · 70 Viramune · 183
Transiderm-Nitro · 49 Virazide · 184
T tranylcypromine · 149 Viread · 183
Travacalm · 36, 87 Visken · 41
Tagamet · 81 Travacalm HO · 36 Vistide · 183
Talam · 147 triazolam · 136
Voltaren · 118
_________________________________________________________________________________
197
Voxam · 147 Z Zocor · 102
Vytorin · 102 Zofran · 87
zolmitriptan · 53
Zactin · 147
Zoloft · 147
Zadine · 132
W zafirlukast · 77 Zolpibell · 139
zalcitabine · 183 Zolpidem · 139
Warfarin · 67
Zamhexal · 136 Zomig · 53
Zanamivir · 182 Zopiclone · 139
Zanidip · 50, 53, 58 Zoton · 82
X Zantac · 81 Zovirax · 182
zuclopenthixol · 142
Zarontin · 155
Xanax · 136 Zumenon · 109
Zeffix · 183
Xergic · 132 Zyclir · 182
Zeldox · 142
Xolair · 77 Zydol · 112
Zerit · 183
Xydep · 147 Zyprexa · 142, 151
xylometazoline · 40, 52 Zestril · 54
Zyrtec · 132
Ziagen · 183
Zyvox · 175
zidovudine · 183
Y Zimstat · 102
Zinnat · 174
Yasmin · 105 Zithromax · 178

_________________________________________________________________________________
198