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com Clinical Pharmacology

Clinical Pharmacology
Module 1. Autonomic Nervous System
• Chapter 1: Functions of Autonomic Nervous System
• Chapter 2: Adrenergic Drugs
• Chapter 3: Cholinergic Drugs

Module 2. Cardiovascular Drugs


• Chapter 4: Antihypertensive Drugs
• Chapter 5: Antihyperlipidemics
• Chapter 6: Nitrates and Nitroglycerin
• Chapter 7: Cardiac Glycoside Digoxin
• Chapter 8: Anti Arrhythmic Drugs
• Chapter 9: Anticoagulants
• Chapter 10: Antiplatelets Drugs
• Chapter 11: Thrombolytic Drugs

Module 3. Central Nervous System Drugs


• Chapter 12: Antidepressants and Lithium
• Chapter 13: Benzodiazepines and Barbiturates
• Chapter 14: CNS Stimulants
• Chapter 15: Antipsychotics
• Chapter 16: Antiepilepsy Drugs
• Chapter 17: Alzheimer’s and Dementia Drugs
• Chapter 18: Anti-Parkinson’s Drugs
• Chapter 19: Local and general anesthetics

Module 4. Anti-inflammatory Drugs and Autacoids


• Chapter 20: Opioid Analgesics
• Chapter 21: Non-Steroidal Anti-inflammatory Drugs
• Chapter 22: Autocoids Analogs and Antagonists

Module 5. Endocrine Pharmacology


• Chapter 23: Insulin and Anti Diabetics Drugs
• Chapter 24: Thyroids Drugs
• Chapter 25: Gonadal Hormone
• Chapter 26: Adrenal corticosteroids
• Chapter 27: Oral Contraceptives

Module 6. Drugs to treat Musculoskeletal Disorders


• Chapter 28: Osteoarthritis

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• Chapter 29: Disease Modifying Antirheumatic Drugs


• Chapter 30: Gout Arthritis and Hyperuricemia
• Chapter 31: Osteoporosis

Module 7: Drugs to treat other diseases


• Chapter 32: Asthma and COPD
• Chapter 33: Anticancer Drugs and Chemotherapy
• Chapter 34: Gastrointestinal Drugs
• Chapter 35: Drug in Renal Disease
• Chapter 36: Immunomodulators
• Chapter 37: Ophthalmic Medications

Module 8: Antimicrobial Pharmacology


• Chapter 38: Antibacterials
• Chapter 39: Antifungals
• Chapter 40: Anti-Mycobacterial Drugs
• Chapter 41: Anti-Viral Drugs
• Chapter 42: Anti-Malarial Drugs
• Chapter 43: Anti-Helmenths Drugs

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1
Autonomic Nervous System
Nervous System

Central Nervous System (CNS) Peripheral Nervous System (PNS)


Spinal cord and brain

Sensory Somatic Nervous System


Autonomic Nervous System (ANS) 12 pairs of cranial nerves
31 pairs of spinal nerves

Cholinergic Adrenergic

Functions of ANS
• The autonomic nervous system controls involuntary body functions. The ANS is
composed of two divisions.
• Sympathetic (adregenic) system
• Parasympathetic (cholinergic) system

Types of Neurons in ANS


• Efferent neurons (motor neurons): deliver
message from brain to organs
• Afferent neurons. Collects message from
organs to the brain
• Efferent neurons divided into the
Sympathetic (adrenergic) nervous system
• Parasympathetic (cholinergic) nervous
system

ANS is responsible for regulation of


• Internal metabolic activity
• Myocardium
• Smooth muscle of the viscera

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• Glandular activity
• Hormonal activity
• Ensure that the body operates in optimum range

Sympathetic (adrenergic) Parasympathetic (cholinergic)


Originate in the thoracic and lumbar region Originate in sacral and cranial region
Post ganglionic nerve fibre very long Post ganglionic nerve fibre very short
Preganglionic nerve fibre very short Preganglionic nerve fibre very long
Ganglia is near spinal cord Ganglia is near innervated organs
Neurotransmitters Neurotransmitters
• Norepinephrine (NE) • Acetyl choline (ACh)
• Epinephrine (epi)
• Dopamine (D)
• ACh
Symptathetic receptors Parasympathetic Receptors
• Norepinephrine α 1 ,α 2 , β 1 (Not on β 2 ) • ACh; M 1 , M 2 , M 3 , M 4 and M 5 , N 1
• Epinephrine α 1 , α 2 , β 1 , β 2 and N 2
• Dopamine D 1 >β>α
• ACh N 1
Functions Functions
Increase ↑ heart rate ↓ heart rate
Increase ↑ blood pressure ↓ blood pressure
Increase ↑ blood flow to skeletal muscle Constriction of pupil
and heart Constrict lungs
Dilation of ↑ pupil and bronchioles Maintains essential body functions
Adjust in response to stressful situation (Digestive, waste elimination).
(trauma, cold, fear, hypoglycemia, exercise) Oppose or balance the action of
Changes in emergencies (Fight or flight sympathetic.
response). Dominant over sympathetic in rest and
↓ Saliva digest situation
↓ peristalis movements ↑ saliva
↑ peristalis movements
Both the sympathetic and parasympathetic nerves innervate the same structures. Their
actions are opposing but not equal in scope.

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AUTONOMIC SOMATIC
Sympathetic innervation Sympathetic Parasympathetic
of adrenal medulla

Preganglionic
neuron

Ganglionic
transmitter

Acetycholine Acetycholine Acetycholine (no ganglia)

Nicotinic Nicotinic Nicotinic


receptor receptor receptor

Adrenal medulla

Postganglionic
neurons

Neuroeffector Epinephrine (released


transmitter into the blood)
Norepinephrine Acetycholine Acetycholine

Adrenergic
Adrenergic Muscarinic
receptor Nicotinic
receptor receptor
receptor
Effector organs Striated Muscle

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Effector Organ Sympathetic Parasympathetic


Adipose ↑ Lipolysis (β 3 )
Metabolise fatty acids
Arterioles
Skin and mucosa Constriction (α 1 ) Some relaxation (M)
Skeletal muscle Usually relaxation (β 2, M) Some relaxation (M)
Bladder
Detrusor Relaxation (β 2 ) Contraction (M 3 )
Sphincter Contraction (α 1 ) Relaxation (M)
Eye
Radial muscle, iris Mydriasis (α 1 ) -
Sphincter muscle, iris - Miosis (M)
Ciliary muscle Accommodation Contraction for near vision (M)
(Relaxation, β 2 )
Heart
Sinoatrial node ↑Heart rate (β 1 )Chronotropic ↓ Heart rate (M 2 )
Atrioventricular node ↑ Conduction (β 1 )Dromotropic ↓ Conduction (M)
Atria ↑ Contractility (β 1 )Inotropic ↓ Contractility (M)
Ventricles ? ?
Kidney Renin secretion (β 1 ) -
Lacrimal glands - ↑ Tear secretion (M)
Liver Glycogen breakdown (β 2 ) Glycogen synthesis (M)
Lung (bronchial muscle) Relaxation (β 2 ) Contraction (M 2 )
Male sex organs Ejaculation (α 2 ) Erection (M)
Nasopharyngeal glands - Mucus secretion
Pancreas ↓ Insulin secretion (α 2 ) ↑ Fluid secretion (M)
↑ Insulin secretion (β 2 )
Salivary Glands Viscous secretion (α 1 ) Marked water secretion (M)
Stomach & intestine
Motility Decrease (β 2 )  Peristalisis Increase (M)
Sphincters Contraction (α 1 )Spincter Relaxation (M)
Secretion - Stimulation (M)
Sweat glands ↑ Secretion (M) ↑ Secretion (M)
Uterus ↑ Contraction (α 1 ) -
detrusor muscles
Relaxation (β 2 )
Veins (systemic) ↑ Dilation (β 2 ) -
Spleen Contraction (α 1 ) -

Abbreviation and Terminology


ANS Autonomic Nervous System M Cholinergic –Muscarinic
CNS Central Nervous System D Dopamine
EPI Epinephrine ACh Acetylcholine

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2
Adrenergic Drugs
There are four types of adrenergic receptors. These are alpha1 and alpha2 and βeta1
and βeta2. Alpha receptors are located mainly in the blood vessels and pupils. Βeta1
receptors are in the heart and βeta2 receptors are mainly in the lungs, skeletal muscles
and uterus.

Adrenergic Drugs

Adrenergic agonist Adrenergic antagonist

Alpha agonist Beta agonist Mixed agonist

Alpha antagonist Beta antagonist

α1 antagonist α2, antagonist α1,β2, mixed antagonist

Non-selective Cardioselective Partial alpha & Partial agonist &


Beta antagonist Beta antagonist Beta antagonist antagonist

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Adrenergic receptors
ᾳ Receptors ᾳ2 Receptors
Located on vascular smooth muscle of the skin Located in presynaptic nerve terminals,
and splanchnic regions, the gastrointestinal platelets, fat cells and the walls of the GI tract
(GI) and bladder sphincters, and the radial Often produce inhibition (eg. Relaxation or
muscle of the iris. dilation)
Produce excitation (eg. Contraction or Mechanism of action: inhibition of adenylate
constriction). cyclase and decrease in cyclic adenosine
Equally sensitive to norepinephrine and Monophosphate (c AMP).
epinephrine, but only norepinephrine is
Present in concentrations that are high enough
to activate ᾳ receptors.
Mechanism of action: formation of inositol
1,4,5-triphosphate (IP3) and increase in
Intracellular (Ca2+).
ẞ1 Receptors ẞ2 Receptors
Located in the sinoatrial (SA) node, Located on vascular smooth muscle of skeletal
atrioventricular (AV) node, and ventricular muscle, bronchial smooth muscle, and In the
muscle of the heart. walls of the GI tract and bladder.
produce excitation (eg. Increase heart rate, Produce relaxation (eg. Dilation of vascular
increase conduction velocity, increase smooth muscle, dilation of bronchioles,
Contractility). Relaxation of the bladder wall).
Sensitive to both norepinephrine and More sensitive to epinephrine than to
epinephrine and more sensitive than the ᾳ1 norepinephrine.
Receptors. More sensitive to epinephrine than the ᾳ1
Mechanism of action: activation of adenylate receptors. For example, when small amounts
cyclase and production of c AMP. of epinephrine are released from the adrenal
medulla, Vasodilation (ẞ2) occurs; when larger
amounts of epinephrine are released from the
Adrenal medulla, vasoconstriction (ᾳ1) occurs.
Mechanism of actions: same as for ẞ1
receptors.

Important Concept!
• Alpha1. peripheral vascular constrictors (blood vessels)
• Alpha2. inhibitory receptor act on norepinephrine in brain
• Beta1. Increase HR, Conduction, Contraction on heart, ↑Renin secretion
• Beta2. Branchodilators in lung, relaxation of bladder detrussors, vasodilator in skeletol muscles.

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ADRENERGIC AGONIST. Increase heart rate, vascular constriction, branchodilatation


Alpha 1 agonist Phenylephrine, pseudoephedrine, ephedrine
Alpha agonist methoxamine, xylometazoline.
Alpha 2 agonist Methyldopa, clonidine, guanabenz
Beta agonist non-selective Dobutamine, isoproterenol
Beta agonist Beta 2 agonist SABA. Salbutamol, terbutaline,
LABA: Salmeterol, formoterol
Mixed alpha and beta Dopamine, epinephrine, norepinephrine
ADRENERGIC ANTAGONIST. decrease heart rate, vascular dilatation, branchoconstriction
Alpha Alpha 1 antagonist Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin
blockers Alpha 2 antagonist Yohimbine
Alpha 1 and 2 antagonist Phentolamine, phenoxybenzamine

beta blockers Beta antagonist


Nons-selective blockers Propanolol, pindolol, nadolol, timolol, and levobutalol
(beta 1 and beta 2)
Cardioselective b-blockers Esmolol, metoprolol, acebutolol, atenolol, bisoprolol
(beta 1 selective)
Partial alpha and beta Acebutolol, pindolol, oxprenolol
blockers

α1agonists
• Phenylephrine
• Pseudoephedrine
• Ephedrine
• Methoxamine
• Xylometazoline

Pharmacological • Constrict dilated arterioles in the nasal mucosa and reduce


actions airway resistance.
Vasoconstriction
• Bronchodilation
• ↑ Blood pressure
• ↑ Peripheral resistance

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• ↑ Closure sphincter bladder


• Mydriasis
Therapeutic use • Decongestant
Side effects • Tachycardia, palpitation and tremor

α2 agonist, centrally acting antihypertensive

α2 agonists • Methyldopa, Clonidine


Mechanism • Decrease central adrenergic outflow. α2 receptors located on
perineuronal membrane. α2 receptors have inhibitory action
on epinephrine and norepinephrine.
• Increase α2 receptors increase inhibitory action on
epinephrine and norepinephrine.
• ↓ Blood pressure
• ↓ Release of insulin
• ↓ Norepinephrine
• Bradycardia
Therapeutic use • Centrally acting antihypertensive. Hypertension with renal
disease (no decrease blood flow to kidney), and methyldopa is
the drug of choice in pregnancy.
Common side • Rebound hypertension in clonidine
effects
β agonists

β agonists non • Dobutamine (β1>β2) and Isoproterenol (β1 = β2)


selective
Mechanism Tachycardia
• Increase lipolysis
• +ve inotropic effect (increase force of contraction of heart).
• Increase cardiac output
• Increase heart rate
• Bronchodilation
Therapeutic use Dobutamine used in treatment of adults with cardiac
decompensation due to depressed contractility resulting from
organic heart disease or following cardiac surgical procedures in
which parenteral therapy is necessary for inotropic support.
Contraindication Tachycardia and ventricular fibrillation.

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β 2 agonist

β2 agonist Short acting beta2 agonist


• Albuterol (salbutamol)
• Terbutaline

Long acting beta2 agonist


• Salmeterol
• Formeterol (full agonist, short onset)
Mechanism • Bronchodilation, vasodilation
• Slightly decrease peripheral resistance
• Increase muscle and liver glycogenolysis
• Relax uterine muscles
• Increase release of glucagon
Therapeutic use • Treat asthma and COPD.
Short acting • Rapid onset of action and provide relief for 4 to 6 hours.
beta 2 agonist • Indicated in symptomatic treatments, rescue agents, combat acute
bronchoconstriction.
Long acting • Salmeterol has long duration of action, providing bronchodilation for
beta 2 agonist at least 12 hours, and slow onset of action.
• Indicated in maintenance treatment in combination with
corticosteroids especially for nocturnal asthma, and COPD.
• Not indicated in acute asthmatic attacks.
Mixed α and β agonist

Mixed α and β • Dopamine, Epinephrine, Norepinephrine


agonist
Norepinephrine • Alpha receptor effect causes rise in peripheral resistance due
to intense vasoconstriction of vascular beds (including
kidney).
• Baroreceptor stimulates cardiac contractility.
• α1, α2, β1 agonist
Major affects • Vasoconstriction
• ↑ Cardiac contractility
• ↑ Systolic blood pressure (SBP)
• ↑ Diastolic blood pressure (DBP)
• ↑ Peripheral resistance (PR)
• Reflex bradycardia

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• Vasoconstriction  causes peripheral resistance


• Baroreceptor reflex  stimulates cardiac contractility

Epinephrine (adrenaline)

Action α1, α2 at lower doses and at higher doses β1 and β2


Cardiovascular • At high doses beta effects  vasodilation
• At low doses alpha effects  vasoconstriction predominates.
• ↑ oxygen demand
• ↑ the rate of contraction (+ve chronotropic effect, β1 action)
• ↑ the contractility of myocardium (+ve inotropic effect, β1 action).
• ↑ systolic (SBP) and slight decrease diastolic (DBP), reflex
bradycardia.
• Epinephrine strengthens the contractility of the myocardium
(positive inotropic) and increases its rate of contraction (positive
chronotropic), cardiac output therefore increases.
Respiratory • Intense bronchodilator is used for allergic and histamine induced
bronchoconstriction.
Hyperglycemia • Has significant hyperglycemic effect (↑glycogenolysis),
• ↓ Release of insulin and causes lipolysis.
Therapeutic • Acute asthma, anaphylactic shock (type1 hypersensitivity)
use • Glaucoma (2% epinephrine solution).
• In local anesthesia (1:100,000) due to vasoconstrictor.
Side effects • CNS. Anxiety, fear, tension, headache, and tremor.
• Hemorrhage: Elevation of BP may cause hemorrhage.
• Arrhythmias: Can trigger arrhythmias in patient using digitoxin
• Can cause pulmonary edema.

Dopamine

Mechanism. Act on D1, D2, D3, D4, D5, and mixed α1and α2, β1, β2 agonist. Activate
alpha and beta adrenergic receptor. At higher doses it causes vasoconstriction by
activating alpha receptor, whereas at lower dose, it stimulates beta receptor. In
addition, D1 and D2 dopaminergic receptor, occur in the mesenteric and renal vascular
beds where binding of dopamine produces vasodilation.
Major affects
• Has +ve inotropic and +ve chronotropic effects
• Dilates renal arterioles by increasing blood flow to kidney
• Dopamine is drug of choice for shock given by continuous infusion.
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• Metabolizes to homovanillic acid.

Adrenergic Antagonist

Adrenergic antagonist

alpha antagonist Beta antagonist

α1 antagonist α2 antagonist

Non-selective Cardioselective Partial alpha & Partial agonist &


Beta antagonist Beta antagonist Beta antagonist antagonist

α1 antagonists

α1 antagonists • Prazosin, Terazosin, Doxazosin, Tamsulosin (α1A) and Alfuzosin


(α1A).
Mechanism • Prazosin and terazosin decrease peripheral vascular resistance and
lower aterial blood pressure by causing relaxation of both arterial
and venous smooth muscle. In other words ↓total peripheral
resistance.
Therapeutics • Antihypertensive and symptomatic benign prostate hyperplasia by
use blocks post synaptic alpha1 located on prostate capsule, causing
relaxation and decrease resistance to urinary flow.
Side effects • Orthostatic hypotension thus first dose effect (syncope). Fainting,
headache, drowsiness, palpitation, and miosis.
Comments • Starting dose for doxazocin 1 mg once daily and titrate slowly.
• Tamsulosin and alfuzosin are a selective α1A receptor blocker and
has no postural hypotension.

α2antagonist

Yohimbine Yocon and odan


Pharmacological • Blocks presynaptic α2
actions • ↑HR and ↑BP

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Therapeutic use • For impotency treatment


Side effects • Postural hypotension?
Contraindications • Renal and hepatic diseases
• Cardiovascular disease
Mirtazepine • Used as antidepressant
• Act on α2, 5HT, and NE

α1 & α2 antagonists

α1 & α2 antagonist

Phentolamine • Competitive, short acting agent


(Reversible) • α blockade
• ↓BP
• ↓total peripheral resistance , reflex tachycardia.

Therapeutic use • Used occasionally in patients to ↓BP (antihypertensive)


• Pheochromocytoma is catecholamine induced
vasoconstriction
Phenoxybenzamine • Non-competitive long acting blocker
(Irreversible) • NE release is enhanced due to blockade of presynaptic a
receptors causes excessive response.
• Used occasionally in patients to ↓blood pressure.

Beta Blockers
Beta Blockers

Nonselective CardioSelective Beta & Alpha Partial agonist


(β1 & β2) (β 1 only) blockers & antagonist

Nonselective (β 1 & β2) Cardioselective β1, β2 & α1 blockers Partial agonist &
(β 1 only) antagonist
• Propranolol • Esmolol • Labetalol • Acebutolol
• Pindolol • Metoprolol • Carvedilol • Pindolol
• Nadolol • Acebutolol • Oxprenolol
• Timolol • Atenolol
• Levobutolol • Bisoprolol

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Vasoconstriction Vasoconstriction α receptors produce Intrinsic


Reduce intra ocular pressure. without vasodilation sympathomimetic
↓ secretion of aqueous bronchoconstriction activity (ISA)
humor and bradycardia. β blocker cause Minimized
Caution: Peripheral vascular Peripheral disturbances of lipid
diseases. vasoconstriction and carbohydrate
Does not alter serum metabolism.
lipid levels.

Mixed beta1 & beta2 None selective beta blockers:


Antagonist (non-selective) ProPiNaTionaLE
• Propanolol
• Pindolol
• Nadolol
• Timolol
Mechanism
• Ptopanolol. Diminishes cardiac output, having both (-) ve inotropic and chronotropic
effect bradycardia.
• Blocks β2 receptor in lungs causes contraction of bronchiolar smooth muscle.
• Timolol. reduce intraocular pressure: decrease secretion of aqueous humor
• Bradycardia, bronchoconstriction (bronchospasm). Decrease in contractility of heart
and decrease in oxygen consumption.

Beta 1 blockers (Cardioselective)


• Esmolol
Selective "EMAA B"
• Metoprolol
Cardioselective beta
blockers • Acebutolol
• Atenolol
• Bisoprolol
Mixed alpha & beta antagonist
• Labetalol
• Carrveidilol
Mechanism

• Produce vasodilation-decrease in blood pressure.


• Peripheral vasoconstriction.
• Does not alter serum lipid levels
Partial agonist and antagonist
• Acebutolol
• Pindolol
• Oxprenolol
Mechanism
• Intrinsic sympathomimetic activity
• Minimized disturbances of lipid and carbohydrate metabolism
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ISA: Intrinsic Sympathomimetic


Activity
• The partial agonist stimulates the beta receptors to which they are bound;yet inhibit
stimulation by the more potent endogenous catecholamines, epinephrine and
norepinephrine.
• The result of opposing actions is much diminished effect on cardiac rate and cardiac
output.
compared to beta blockers without intrinsic sympathomimetic activity

Side effects
• Bradycardia, heart blockage
• Bronchospasm (avoid non selective in asthma)
• Avoid beta blockers in peripheral vascular disease such as Raynaud’s phenomenon
and intermittent claudication however carveidilol and labetalol can be tried.
• CAUTION in congestive heart failure and left ventricular dysfunction.

Pharmacokinetics
• Propanolol is the best absorbed with food but consistency is the most important
factor.
• Metoprolol is best taken with meals
• These drugs shoukd be taken at about same time everyday.
• Beta blockers that have first pass metabolism propanolol and timolol
• Beta blockers that have no biotransformation atenolol.
• Beta blockers that have alpha blockade effect; labetalol and carveidilol
• Beta blockers that acts as membrane stabilizer is propanolol.
Beta-blockers therapeutic uses.
• Propranolol is used for hypertension, angina, post MI, migraine, essential tremor,
performance anxiety, Hyperthyroidism (acute-thyroid storm).
• Timolol is used for chronic treatment of open angle glaucoma. hypertension, post
MI, and migraine.
• Pindolol used for hypertension
• Cardioselective, metaprolol, atenolol, esmolol and acebutolol used to treat for
hypertension, angina and tachycardias.

Tips
• Drugs that have +ve inotropic and +ve chronotropic effect is dopamine and
epinephrine
• Inotropic is force of contraction (+ve increase in force of contraction)
• Chronotropic isheart rate (+ve increase in heart rate)
• Drugs that have +ve inotropic and –ve chronotropics is digoxin

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• Drugs that have +ve inotropic are ACE Inhibitors.


• Epinephrine (Epipen) is used for anaphylactic reaction or hypersensitive reactions.
• Epinephrine act on alpha1, alpha2, beta1 and beta2 agonist
• Xylometazoline action is on alpha-adrenergic receptors.
• Salbutamol is beta2 agonist
• Beta 2 agonist drugs have no anti-inflammatory effect and act as branchodilators
• SABA always used as prn and tolerance can occur with regular use and also mask the
symptoms of inflammation.
• SABA has additive effect with anticholinergic drugs (Ipratropium)
• LABA always used as daily dose.
• LABA has same effect as SABA but long duration of action.
• LABA has synergistic effect with corticosteroids. (Products available: Fluticosone +
Salmeterol = Advair)
• SABA and LABA are branchodilators.
• Beta-blockers are drug of choice for uncomplicated hypertension in patient age
under 65 years old.
• Beta-blockers are used cautiously in asthma, CHF, diabetes and sever peripheral
vascular diseases.
• Diabetic patient taking beta-blockers monitor? Blood sugar levels
• Digoxin, non-DHP CCB may cause additive Bradycardia with betablockers.
• Beta-blockers do NOT cause orthostatic hypotension.
• What adrenergic blockers are useful in treating Tachycardia? Beta blockers
(Propranolol)
• The longest acting beta-blockers is? Nadolol
• Example of irreversible and noncompetitive alpha1 and alpha2 blocker is 
Phenoxybenzamine
• Examples of drugs that reverse effect of epinephrine associated vasocontriction 
alpha1 blockers.
• Examples of sympathomimetic that should be avoided in Glaucoma 
Phenylephrine, pseudoephedrines.

ABBREVIATION AND TERMINOLOGY


NE Norepinephrine SABA Short Acting Beta Agonist
ProPiNaTionaLE Proparanolol, Pindalol, Nadilol, Timolol, LABA Long Acting Beta Agonist
Esmalol
CO Cardiac output BP Blood Pressure
COMT Cathecol Amine O- Methyl Transferase EMAA Esmolol, Metoprolol, Acebutolol,
Atenolol
ISA Intrinsic Sympathommimetic Activity HR Heart rate
EIA Exercise induce asthma TPR Total Peripheral Resiistance
SBP Systolic Blood Pressure PR Peripheral Resiistance
DBP Diastolic Blood Pressure IOP Intra Ocular Pressure

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Pheochromacytoma: Type of adrenal gland cancer, can cause uncontrolled blood pressure. Can cause
uncontrolled tachycardia, and increase heart rate and palpitation

GENERIC and BRAND


Xylometazoline Otrivin
Fluticasone + Salmeterol Advair

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3
Cholinergic Drugs
The parasympathetic (cholinergic) system slows the heart, constricts the pupil, and
stimulates the GI tract and aids in digestion and elimination. Drugs with a cholinergic
effect will produce similar effects. A cholinergic effect may be direct acting drugs
occupy the cholinergic receptor. Indirect acting drugs inhibit the activity of
cholinesterase, an enzyme that breaks down acetylcholine. By preventing the
breakdown of acetylcholine, there is an accumulation of acetylcholine allowing
increased parasympathetic effects.

Cholinergic

Cholinergic Agonist Muscarinic Antagonist

Direct cholinergic agonist Indirect cholinergic Tertiary amines Quaternary amine


agonist Atropine Ipratropium
Scopolamine Tiotropium
Acetylcholine agonist Benztropine Glycopyrrolate
anticholinesterase
Trihexyphenidyl

Choline ester Pilocarpine


Bethanachol
Carbachol Reversible Reversible Organophosphate
Methanacol Quaternary alcohols Carbamate (Irreversible cholinesterase inh)
Donepezil Physostigmine Echothiophate, Malathion
Neostigmine Parathion
Rivastigmine Sarin
Pyridostigmine

Cholinesterase
Acetylcholine -------------> Acetyl + Choline

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Summary of cholinergic receptors effects


Muscarinic Receptor Effect
Eye –sphincter muscle M3 causes miosis
Heart – SA node M2 Decrease HR (-ve chronotropy), vagal arrest
AV node M2 Decrease conduction velocity (-ve dromotrophy)
Lung- branchioles M3 Branchospasm (contraction)
Glands M3 Increase secretions
GI tract M3 Stomach-increase motility causes cramps
Intestine-increase motility causes diarrhea
M1 Glands – secretion of HCl
Blood vessels M3 Vasodilation but no innervation (to stimulate for action)
Nicotinic N
Adrenal medulla N Increase secretion of epi and norepinephrine
Ganglia
Neuromuscular junction Stimulation causes muscle hyperactivity
Cholinergic receptors (cholinorecetors)

Nicotine receptors Muscarinic receptos


Located in the autonomic ganglia of the Located in the heart, smooth muscle
sympathetic and parasympathetic nervous (except vascular smooth muscle) and
systems, at the neuromuscular junction, glands.
and in the adrenal medulla. The receptors Activated by Ach and muscarine
at these locations are similar, but not Inhibitory in the heart (eg. Decreased
identical. heart rate, decreased conduction velocity
Activated by Ach or nicotine. in AV Node).
Produce excitation. Excitatory in smooth muscle and glands
(eg. Increased GI motility, increased
-Ganglionic blockers (eg.hexamethonium, secretion).
trimethaphan) block the nicotinic Muscarine receptors for Ach are blocked
receptors for by atropine.
Mechanism of action:
1. Heart SA node:inhibition of adenylate
cyclase, which leads to opening of K+
channels,
Slowing of the rate if spontaneous
depolarization and decreased heart rate.
2. Smooth muscle and glands: formation of
IP 3 and increase in intracellular (Ca2).
ACh receptors are also ion channels for
Na+ and K+.

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Side effects of cholinergic drugs Side effects of anticholinergic


Cholinergic! Bradycardia Tachycardia
D = diarrhea Salivation Dry mouth
U= urination Lacrimation Blurred vision and mydriasis
M= myopic Flushing Constipation
B = bradycardia Diarrhea Urinary retention
Hypotension Dizziness and drowsiness
E = Excessive sweat
Tremors Hyper optic accommodation
L = lacrimation Myopic accommodation Increased intraocular pressure
S = Salivation

Direct acting cholinergic drugs

Direct acting • Acetylcholine


Cholinergics • Pilocarpine
• Bethanechol
• Carbachol
• Methacholine
Pharmacological • ↓ Heart rate
actions • ↓ Cardiac output
• ↓ Blood pressure
• ↑ saliva secretion
• Miosis
Bethanecol
Used clinically for its therapeutic effects in postoperative
atony of the bowel, for abdominal distention and urinary
retention. Other drugs in this group are pilocarpine and
carbachol, used in the eye to treat glaucoma.

Pilocarpine
Mechanism. A cholinergic agent most often used to treat
glaucoma since it produces a reduction in intraocular
pressure.
Side effects. Cramps, diarrhea, and increased gastric
acid. May cause bradycardia, flushing and a fall in blood
pressure, bronchoconstriction causing difficulty in
breathing, sweating and salivation.

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Indirect acting cholinergic drugs

Indirect acting cholinergic drugs further categorized as indirect acting reversible or


anticholinesterases and indirect irreversible or organophosphates.

Indirect acting • Physostigmine, Neostigmine, Rivastigmine, Donepezil


reversible
anticholinesterases
Pharmacological • Effects on muscarinic and nicotinic receptors and on NMJ and
action brain.
Therapeutic use • Physostigmine antidote of atropine, can get into brain (3o
amine).
• Neostigmine is used to treat myasthenia gravis. Does NOT get
into brain (quaternary amine salt).
• Edrophonium is not clinically used.
• Donepezil is the drug of choice for the treatment of
Alzheimers, and it is lipid soluble (enter CNS).
Side effects • Diarrhea, cramps, increased salivation, increased bronchial
secretions, miosis, sweating and muscle cramps.
Indirect irreversible • Insecticides, parathion, malathion, and echothiophate.
or
organophosphates

Muscarinic antagonist

Tertiary amines Quarternary amine


Atropine Ipratropium
Scopalamine Tiotropium
Benzotropine Glycopyrrolate
Trihexyphenidyl

Muscarinic antagonists
Anticholinergic • Atropine, ipratropium, tiotropium, scopolamine, benztropine
drugs • tropicamide, glycopyrrolate, and trihexyphenidyl.
Pharmacological • ↓ in salivation cause dry mouth (xerostomia).
actions • ↓ intestinal secretion cause constipation
• Increase HR cause tachycardia
• Mydriasis cause pupil dilatation
• Relaxation of detrussor muscle cause urinary retention.

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Anticholinergic • Dry mouth, blurred vision, tachycardia, constipation and urinary


side effects retention.
Therapeutic use • Atropine is antidote of organophosphates.
• Ipratropium is used as rescue for asthma and COPD
• Tiotropium is in maintenance therapy of COPD
• Scopolamine is used for prevention of motion sickness.
• Benztropine is used to treat Parkinsons disease associated with
antipsychotic drug side effects.
• Tropicamide is used in ophthalmic exams (topical).
• Glycopyrrolate is used as antispasmodic, antisecretory.
• Trihexyphenidyl is used to treat drug induced extrapyramidal
symptoms caused by antipsycotic drugs.

Nicotinic Blockers (Ganglionic blockers)


Nicotine. Depolarizes ganglia, resulting first in stimulation and followed by paralysis of
all ganglia, increase in BP, HR, increased peristalsis, and secretion.
α-Bungarotoxin and botulinum toxin. α Bungarotoxin (α-BgTx) is a postsynaptic
neurotoxin found in the venom of the braided Krait snake (Bungarus multictus). Like
other neurotoxins it blocks neuromuscular transmission.

NMJ blockers

These agents are used for surgical patients to relax the muscles during surgery.
Pharmacological actions. Blocks the cholinergic transmission between motor nerve and
nicotinic receptors. Antagonizes (non depolarizing type) and agonist (polarizing) the
effect of acetycholine.

Classified as two categories of NMJ blockers


Depolarizing NMJ Blockers
Depolarizing Non • Succinylcholine
competitive
Mechanism Blocks the cholinergic transmission between motor nerve and

nicotinic receptors.
• Antagonizes (non depolarizing type) effect of acetylcholine.
Therapeutic use • Clinically used in surgery to produce complete muscle
relaxation.
Side effect • Malignent hyperthermia, hyperkalemia and myalgia
Non-depolarizing NMJ Blockers

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Non Depolarizing • Atracurium


competitive • Tubocurarine
• Doxacurium
• Pancuronium
• Vecuronium
• Mivacurium
Mechanism • Prevents the binding of acetylcholine
• Inhibits muscular contraction. At higher doses, these (non
depolarizing) drugs block the ion channels of end plate and
reduced the ability of antagonists.
Therapeutic uses • Indicated in anesthesia during surgery to relax skeletal
muscles.
Side effects • Decrease BP, paralysis of diaphragm
Antagonist for non • Neostigmine, edrophonium (cholinesterase inhibitors)
depolarizing agents

Myastenia gravis. This disease is a disorder of skeletal (voluntary striated) muscle due to
excessive cholinesterase or lack of acetylcholine (ACh). It is characterized by increasing
fatigue and muscle weakness; some cases are mild, some are severe. Death usually
occurs due to respiratory depression.

Urinary retention is the inability to empty the bladder. It can be due to a number of
conditions such as old age, prolonged surgery, tumours, distended bladder without
voiding for long periods, exposure to cold or anemia.

Glaucoma is disease of the eye characterized by increased intraocular pressure resulting


in damage to the optic nerve and the retina. It can lead to blindness if left untreated.

GENERIC AND BRAND


Pilocarpine Isotocarpine Succinylcholine Anctine, Quelicin, Sucostrin
Atropine Atrezat, AtroPen, Physostigmine Mestinon, Regonol
Ipratropium Atrovent, Atrovent HFA Neostigmine Prostigmine
Scoopolamine IsoptoHyoscine, Pyridostigmine Pyridostigmine
Benztropine Congentin Edrophonium Enlon, Reversol, Tensilon
Tropicamide Mydriacyl Donepezil Aricept, Aricept ODT
Glycopyrrolate Robinul, Robinul forte Tacrine Cognex
Trihexyphenidyl Artane Malathion Ovide
Atracurium Tacrium Echothiophate Phospholine Iodide
Tubocurarium Tubarine, Metubine, Jex Neostigmine Prostigmin
Doxacurium Nuromax Edrophonium Enlon, Reversol, Tensilon
Pancuronium Pavulon Pilocarpine IsotoCarpine
Vecuronium Norcuron Mivacurium Mivacron

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4
Antihypertensive Drugs
This chapter review antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACEi),
Angiotensin receptor blockers (ARBs), beta blockers, alpha1 blockers, calcium channel blockers (CCBs) and
vasodilators mechanism of action, major therapeutic use, side effects, pharmacokinetics, dosage forms
and instructions for counseling.

ACE Inhibitors

Angiotensin II is the body’s most potent circulating vasoconstrictor causing increases


blood pressure. Angiotensin II stimulates aldosterone secretion to increase the kidney
sodium reabsorption and increase in blood volume, which contribute to increase in BP.
The ACE inhibitors are used to treat hypertension and congestive heart failure. The
ACEi also tend to protect the kidneys of diabetics from developing renal failure when
used in the early stages of diabetic nephropathy.
Generic Name Trade Name Generic Name Trade Name
Captopril Capoten Cilazapril Inhibace
Benazepril Lotensin Enalapril Vasotec
Fosinopril Monopril Lisinopril Zestril, Prinivil
Perindopril Coversyl Quinapril Accupril
Ramipril Altace Trandolapril Mavik
Perindopril/Indapamide Coversyl Plus

Angiotensinogen Sympathetic action


(alpha globulin in blood)
Vasodilation
Renin
(kidney)

B P
Angiotensin I Angiotensin II

Bradykinin
ACE I
Na & H2O levels

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Pharmacological actions
ACE inhibitors block the angiotensin converting enzyme that cleaves angiotensin I to
form, angiotensin II. The angiotensin II is potent vasoconstrictor. It also decreases
the secretion of aldosterone resulting in decreased sodium and water retention.
Therapeutic use: 1ST line to treat heart failure, diabetes nephropathy, post MI ,
uncomplicated hypertension, and pre-hypertensive patient, LVH (left ventricular
heart failure) and prior CVA/TIA (cardiovascular attacks/transient ischemic attacks)
& in renal disease

Side effects. Dry cough (5 to 15%), hypotension, hyperkalemia, renal insufficiencies


• Angioedema (rare), reversible neutropenia, proteinuria (presence of protein in
urine) and fatigue.
Contraindications
• Pregnancy (absolute). Can produce hypotension in the fetus leading renal failure and
death, skull hypoplasia and death. Documented angioedema secondary, bilateral renal
artery stenosis.

Pharmacokinetics
• DIs. NSAID’s can reduce the effect of captopril. Diuretics can cause rapid fall of blood
pressure with captopril.
• High fat meals may reduce absorption of quinapril. Food does not affect the other
drugs in this class.
• Captopril should be taken one hour before meals. Dosage captopril is taken bid or
tid due to short half life.

Pregnancy. ACEi are contraindicated in pregnancy.


Angiotensin-Converting Enzyme Inhibitors (ACEi).

Eliminati Food Creatin


on ine
Benazepril renal +
Captopril renal empty + Food has high effect on bioavailability
NOT a prodrug
Cilazapril renal empty +
Enalapril Maleate renal +
Enalaprilat (i.v) renal +
Fosinopril Renal/Fec + No dosage adjustment in renal
al
Lisinopril renal + NOT a prodrug
Perindopril renal Empty + Food has high effect on bioavailability
Quinapril renal +
Ramipril renal +
Trandolapril renal + High potency
• Breast feeding and pregnant mothers should not take ACE inhibitor. If they become pregnant while
on medication, they should contact their physician immediately.
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• Call doctor ASAP if you experience swelling of the face, eyes, lips, tongue, arms, or legs, or if you have
difficulty breathing or swallowing (symptoms of angioedema).
• In case of cause cough symptoms contact doctor to change the medication to ARBs.

ARB Inhibitors (AT1 receptor blockers)

Generic Name Trade Name Generic Name Trade Name


Losartan Cozaar Candesartan Atacand
Valsartan Diovan Irbesartan Avapro
Telmisartan Micardis
Ends with “SARTAN”
These drugs binds to AT 1 receptors and prevent formation of angiotensin II, a naturally
occurring substance that causes blood vessels to narrow (constrict). When these drugs
are administered, blood vessels dilate, thereby lowering blood pressure and decreasing
the workload of the heart. These drugs appear to have the same benefits as ACEi,
without or less producing the common side effect of a dry cough.

Pharmacological actions
• Angiotensin binds to its own receptors are found on vascular muscle and in the
adrenals. Stimulation leads to vasoconstriction and release of aldosterone in the
adrenal gland. It blocks aldosterone secretion
• Losartan has moderate uricosuric effects and may be useful in patients with gout or
hyperuricemia who require antihypertensive therapy.
Side effects. Less dry cough (cough associated with ACEi does appear with these drugs),
bradykinin causes vasodilation of arterioles and venules results ↓TPR, less dry cough.
Dizziness, hypotension(syncope), renal dysfunction (reversible renal failure),
hyperkalemia and angioedema.

Contraindications. Pregnancy (renal fetal toxicity), and bilateral renal artery stenosis
(stenosis, abnormal narrowing of passage or opening, such blood vessels or heart valve).

Pharmacokinetics. Losartan may increase the effects of potassium supplements,


potassium sparing diuretics, and cyclosporine, leading to raise of potassium in the
blood.

Direct Renin inhibitors. Aliskiren 150 mg once daily. Takes 4 weeks to 6 wks realize maximum
antihypertensive effect.

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Side effects. Diarrhea, the incidence of dry cough, and hyperkalemia is low compared with
ACEi.
Avoid use in pregnancy.

β-blockers

Beta-blockers are used to treat hypertension and angina. These drugs act by slowing
the heartbeat, which results in lowered blood pressure since blood pressure is affected
by the heart rate and peripheral resistance. Beta-blockers are categorized into 4 types
based on their action on sympathetic receptors beta1, beta2, alpha1, and alpha2 action.
Beta Blockers

Nonselective CardioSelective Beta & alpha Partial agonist


(β1 & β2) (β 1 only) blockers & antagonist
Nonselective (β 1 & β 2 ) Cardioselective (β 1 β 2 & α 1 Partial agonist &
(β 1 only) blockers antagonist
• Propranolol • Esmolol • Labetalol • Acebutolol
• Pindolol • Metoprolol • Carvedilol • Pindolol
• Nadolol • Acebutolol • Oxprenolol
• Timolol • Atenolol
• Levobutolol • Bisoprolol
Betoxalol

Pharmacological actions
• β 1 decrease heart rate
• β 2 bronchoconstriction
• Peripheral vasoconstriction (Increase TPR)—β 2
• ↓ Na/water retention
• β 2 ↓ glycogenolysis (glycogen  glucose) and gluconeogenesis.
• ↓ glucagon secretions
• Blocks the effect of isoproterenol
Therapeutic use. Beta-blockers are used to treat hypertension and angina. Because of
its action on the lining of arteries, propranolol is also used migraines and it highest lipid
soluble beta blocker.
Abrupt discontinuation may cause rebound hypertension. Labetelol & carvedilol may
cause orthostatic hypotension due to partial alpha blockade.

SEs. Fatigue, bradycardia, decreased exercise capacity, headache, impotence, vivid


dreams. Less common hyperglycemia, depression, CHF, and heart blockade.
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Mechanism of action of beta-blockers


Effect of B receptor Cardiac output
on heart

Renin Angiotensin II Preripheral


BP
resistant
Aldosterones
Blood volume
Na, H2O levels
Cardiac output
Beta blockers
monitored BP HR RFT LFT Blood QTc Mg
glucose
Acebutolol + + + + Only DM
Atenolol + + + + in DM
Bisoprolol + + + + in DM Beta1 antagonist, orthostatic
hypotension
Carvedilol + + + + in DM
Esmolol + + + + in DM Only iv
Labetelol + + + + in DM
Metoprolol + + + + in DM
Nadolol + + + + in DM Long acting
Nabivolol + + + + in DM
Pindolol + + + + in DM
Propranolol + + + + in DM CNS side effects (depression, dizzy, vivid
dreams), and sexual dys.
Sotalol + + + + in DM + + Prevention of recurrence of atrial
fibrillation.
Timolol + + + + in DM Open angle glaucoma
• CHF patients should weigh themselves daily if possible every morning after urinating. If the patient
gains more than one pound a day or 3 to 5 pounds in a week should contact physician. In CHF
patients may cause fluid retention or worsening of heart failure with initiation of therapy or an
increase in dose.
• Report any cases of dizziness, light-headedness, or blurred vision. These may be caused of too low
blood pressure or from bradycardia or heart attack.

Beta blocker effect on blood glucose


Beta blockers – can mask signs and symptoms of hypoglycemia (except sweating); also
some inhibition of glycogenolysis and insulin secretion; cardioselective agents such as
acebutolol MONITAN, SECTRAL, atenolol TENORMIN, bisoprolol MONOCOR, or
metoprolol LOPRESOR,BETALOC may be safer

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α1 blockers

Generic Name Trade Name Generic Name Trade Name


Doxazosin Cardura Alfuzosin Xatral
Prazosin Minipress Tamsulosin Flomax
Terazosin Hytrin
End with "sin"

In addition to being used for hypertension these drugs cause the muscles (sphincter) of
the bladder neck and prostate to relax, thereby making it easier for patients to urinate
thus also used for benign prostatic hyperplasia.

Pharmacological actions. Primary action is due to peripheral vasodilation by inhibiting


post synaptic alpha1 receptors in vascular smooth muscles. Alpha1 also abundant in
smooth muscles of bladder and prostate. Alpha 1a blockade can cause relaxation of
bladder muscle (sphincter) and increase urinary flow.

• ↓ blood pressure by ↓ total peripheral resistance, reflex tachycardia,


Vasodilatations.
• First dose effect (syncope). slow titration of dose can minimize the syncope. and
miosis.
Side effects. Orthostatic hypotension, tachycardia (reflex tachycardia), headache,
vertigo, sexual dysfunction to avoid the first dose effect of hypotension and occasional
syncope, the starting doses should be small and given at bedtime.

α2 agonist – Centrallyacting antihypertensive

Generic Name Trade Name Generic Name Trade Name


Clonidine Catapres Guanabenz
Methyldopa Aldomet

Alpha 2 agonist used to treat hypertension are centrally acting agents, which act directly
in the brain to change the signals send to the heart and blood vessels.

Pharmacological actions
• Decrease central adrenergic outflow.
• α2 receptors have inhibitory action on epinephrine and NE.

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• Increase alpha 2 receptors increase inhibitory action on epi


and norepinephrine.
• ↓ Blood pressure, ↓ insulin secretions, ↓ norepinephrine

• Bradycardia (little)

Therapeutic use. These drugs are not commonly used as it is


difficult to achieve the proper dose with these agents. They are
generally reserved for people who fail to respond to other
therapies. Clonidine is sometimes used to treat withdrawal
symptoms in recovering drug and alcohol abusers.
Clonidine an alpha2 agonist that decrease the neuronal output of norepinephrine, can
be used to blunt the noradrenergic signs/symptoms of withdrawal such as chills and
flushing. Clonidine used adjunctively with opioid can reduce length of hospital stay,
decrease seizures and decrease treatment failure.

Methyldopa is the drug of choice to treat hypertension in pregnancy.

Side effects. Clonidine may cause severe rebound hypertension, decrease lipolysis,
decrease insulin secretions, and sexual dysfunction. Methyldopa has cardiovascular,
bradycardia, orthostatic hypotension, blood related hemolytic anemia,
thrombocytopenia and bone marrow depression. The GI related include dry mouth,
nausea, and diarrhea.
Clonidine. Don’t discontinue abruptly, reduce dose over 2 to 3 days to reduce sever
hypertension.

Pharmacokinetics. Methyldopa is prodrugs. Active product methyldopa is alpha methyl


norepinephrine. Decrease TPR with little change in HR and CO by stimulation of alpha 2
receptors in brain.

Clonidine comes as transdermal patch TT1 (release 0.1 mg/24 h), TT2 (0.2 mg 24/h). TT3
(0.3 mg/24 h). Pruritus and rash at the site of transdermal patch.

α 1 antagonist α 2 agonist
Indication Hypertension, Benign Prostatic Hypertension and Treat withdrawal symptoms in
Hypertrophy (BPH or enlarged recovering drug and alcohol abusers (clonidine)
prostate).

Contraindicati Orthostatic hypotension Orthostatic hypotension and liver disease


on
Side Effects Orthostatic hypotension, Decrease lipolysis
Fainting (syncope) Decrease insulin secretion
Reflex tachycardia Sexual dysfunction
Vertigo Rebound hypertension with clonidine
Sexual dysfunction
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DIURETICS
Diuretics also known as water pills.

Thiazide Loop diuretics K-sparing diuretics Carbonic Osmotic diuretic


diuretics acid inhibitor

Mannitol
"Distal convoluted "Ascending "Collecting duct" Urea
tubule" loop" Spironolactone "proximal"
Triamterene
Chlorothiazide Furosemide Acetazolamide
Amiloride
Hydrochlorothiazide Ethacrynic acid Dorzolamide
Chlothalidone Bemetanide

Serum Electrolyte of Diuretics. In general, the opposite findings of serum electrolytes


are seen in urine
Type of Ca Mg N K Uric Blood Lipids Metabolic Disturbances
diuretic a acid sugar
Thiazide ↑ ↓ ↓ ↓ ↑ ↑ ↑ Hypokalemic metabolic alkalosis (HPERGLUC)
Loop ↓ ↓ ↓ ↓ ↑ ↑ _ Hypokalemic metabolic alkalosis (Loop lose calcium)
K-sparing _ ↑ ↓ ↑ ↑ _ _ Hyperchloremic metabolic acidosis (↑CO 2 ), and
intracellular alkalosis
CAi _ _ _ ↓ ↑ ↑ _ Heperchloremic metabolic acidosis
Osmotic ↓

Thiazide Diuretics

Generic Name Trade Name Generic Name Trade Name


Hydrochlorothiazide Generics Chlorothiazide
Indapamide Metolazone
Pharmacological • It increases Na+ and water excretion causing a decrease in
actions extra cellular volume, resulting in a decrease cardiac output
and renal blood flow.
• ↑ H 2 O, Na+, Cl, K, excretions (↓ levels in body), retain Ca
• May cause alkaline urinary pH by effecting on carbonic
anhydrase.
• Metabolic alkalosis (hypochloremic alkalosis).
Therapeutic uses • Especially useful in elderly ↓ blood pressure.
• Counteract Na/H 2 O retention caused by other
antihypertensive such as hydralazine and β-blockers
and African populations and with chronic renal diseases.
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• Not effective in patient renal clearance less than 50 ml/min


• Not preferable in diabetic and hyperlipidemic patient.
Side effects • Hypokalemia (↑ risk of digoxin toxicity, monitor K levels),
hypomagnesia, hyponatremia, hypercalcemia, hyperuricemia
(thiazides exacerbate gout), hyperglycemia and
hyperlipidemia (did NOT translate into CV events), metabolic
alkalosis. Photosensitivity rashes, acute pancreatitis, libido,
difficulty with erection and ejaculation (long term in 2% in
men).
Thiazide diuretics Na and H2O retention

Thiazide cause HYPERGLUC


Blood Volume Hyperglycemia
Hyperlipidemia
Hyperurecimia
Peripheral resistant Cardiac output
Hypercalcemia

B.P.

Loop Diuretics

Drug Name Trade Name Drug Name Trade Name


Furosemide Lasix Ethacrynic acid
Bumetanide

Mechanism Act at site ascending loop.


Therapeutic uses Edema related diseases such as CHF, pulmonary edema, cirrhosis,
nephrotic syndrome, hypertension and hypercalcemia.
Side effects OH DANG! Ototoxicity, hypokalemia, dehydration, allergy (sulfa),
Nephritis (intestinal), gout. Do not use if patient has renal stones
(loop loose calcium) hypocalcemia.
Pharmacokinetics Can be used in renal diseases (CrCl <50 ml/min). Oral solution,
tablets, and taken by mouth only.
Stability. Exposure to light may cause discoloration.
Dose Store at 15 to 30 ºC in a well closed container. Protect from light.
Protect from freezing. Do not dispense discolored tablets, store in
amber color bottle.

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Potassium sparing

Generic Name Trade Generic Name Trade Name


Name
Spironolactone Aldactone Triamterene
Amiloride
HCTZ/amiloride(50/5) Moduret HCTZ/Triamterine (25/50)
HCTZ/spironolactone (25/25) Aldectazide

Potassium sparing The K+ STAys: Spironolactone, Triamterene, Amiloride

Potassium sparing • Spironolactone, Triamterene, Amiloride


Pharmacological • Act in the early collecting duct to inhibit the electrogenic
actions reabsorption of Na+ by blocking the Na channels and hence
the exchange of sodium for potassium.
• After administration ↑ Na+, Cl- elimination, ↓K+, Ca++
(amiloride).
• Increase Na, H 2 O, HCO 3 excretion (decrease levels in body)
• Decrease K+, H+ excretion.
• Alkaline urinary pH and increase excretion of HCO 3
Aldosterone Spironolactone
antagonist
Pharmacological Competitive inhibits aldosterone at minor aldocorticoid
actions receptors. Decreases potassium excretion.
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Side effects Sulfa drug like allergy.


Endocrine. Gynecomastia, menstrual irregularities.
Electrolytes. Hyperkalemia
CNS. mental confusion.
Metabolic acidosis and intracellular alkalosis
Therapeutics use Drug of choice in ascites
Pharmacokinetics Take drug with food to enhance absorption.
Adverse reactions usually disappear after drug is discontinued.
However, gynecomastia may continue. For children dose crush
tablets and mix in cherry soup as an oral suspension.
Dose Adults. 25 mg to 200 mg PO daily in divided doses
Spironolactone is antiandrogenic and has been used to treat
hirsutisms in doses of 200 mg/day.
Protect drug from light. (store in amber color bottle)

Non aldosterone • Amiloride and triamterene


antagonist
Pharmacological Act directly on late distal tubule and collecting duct. They disrupt
actions sodium exchange with potassium and hydrogen by blocking
sodium channel. Decrease in the driving force for secretion of
potassium and hydrogen.
Therapeutic use Amiloride. Used in nephrogenic diabetic insipidus
Pharmacokinetics Amiloride. 15 to 30 ºC in a well-closed container and take with
meals or milk.
Triamterene. 15 to 30 ºC in a tight, light-resistant container, Take
with meals or milk, Avoid exposure to sun or sunlamp. Turns
urine into blue color.

Osmotic Diuretics

Osmotic • Mannitol and Urea


Pharmacological • Increase excretion of H 2 O, Na+, Cl- and HCO3+ (decrease levels
actions in body).
• Increase alkaline urinary pH, increase excretion of HCO 3
• Increase tubular osmolarity, and increase urine flow.
Therapeutic use Mannitol. Shock, or drug overdose, decrease intracranial or
intraocular pressure.
Side effects Pulmonary edema (absorbs water from extracellular
compartment), and dehydration.
CIs. CHF and anuria (renal failure).

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Carbonic anhydrase Inhibitors

CA Inhibitors • Acetazolamide and Dorzolamide


Pharmacological • Non competitive inhibition of carbonic anhydrase enzyme
actions • Increase excretion of H 2 O, Na, K, and HCO 3 (decrease levels in
body).
• Cause alkaline urinary pH, increase alkaline pH inc. exc HCO 3
Therapeutic use • Glaucoma (not chronically)
• Acute mountain sickness (respiratory alkalosis), high altitude
sickness (mountain sickness). Because of the alkaline diuresis it
produces, acetazolamide has been used for the treatment of
overdoses of acidic drugs.
Side effects • Electrolytes. Hyperchloremic metabolic acidosis (loss of HCO 3 -
), hypokalemia.
• Formation of renal stones (phosphaturia & hypercalciuria).
• CNS. depression, drowsiness, sedation, fatigue, disorientation.
• GI: Nausea, vomiting, and constipation.
• Blood related: Bone marrow depression, thrombocytopenia .
(reduction of number of platelets in blood), hemolytic anemia,
leucopenia (reduction in number of WBC), agranulocytosis
(acute deficiency of neutrophils).
• Hyperchloremic metabolic acidosis and sulfa allergies

Vasodilators
Vasodilators

Direct Vasodilators Indirect Vasodilators


• Hydralazine • ACE inhibitors
• Sodium nitroprusside • Calcium channel blockers
• Minoxidil
• Diazoxide

Important Concepts!
Preload. Volume of blood that fills the ventricle during diastole.
After load. The pressure that must overcome for the heart to pump blood into
the arterial system.
Decrease more diastolic blood pressure than systolic blood pressure

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Vasodilators cause the smooth muscle in blood vessels to relax. Relaxed or dilated
blood vessels allow more blood to flow through, causing a reduction in blood pressure
by decreasing peripheral resistance. As vasodilators work, the blood vessels become
dilated causing a drop in pressure because there is less blood volume to fill the vessel.
The body can compensate for this by retaining enough fluid to fill the blood vessel
sufficiently to raise the blood pressure again.
Hydralazine and minoxidil are direct vasodilators not usually used a sole therapy for high
blood pressure, as their effect is usually short lived when administered alone.
Side effects: flushing and headache
Pharmacological action
• Vasodilators reduce excessive preload and after load.
• Elevated after load causes the heart to work harder to pump blood into arterial
system.
• Dilation of venous blood vessels leads to decrease in cardiac preload by increasing
venous capacitance.
• In arteries dilators reduce systemic arteriole resistance and decrease after load.

Minoxidil

• A prodrugs, which must be conjugated with a sulfate to form the


active drug.
Mechanism • Minoxidil is potent renal vasodilator and stimulator of renin
release.
Therapeutic use • Hypertension and alopecia treatment.
Side effects • Salt and water retention (use a diuretic). Reflex tachycardia.
• pulmonary hypertension and blurred vision.
• Hypertrichosis. Topical solution is now marketed for baldness.
For alopecia • Each mL of clear, colorless to slightly yellow solution contains.
minoxidil 20 mg (2%), in alcohol (63%), propylene glycol (20%)
and water. For external use only. Store at controlled room
temperature (15 to 30°C).
• Hypertrichosis (excessive hair growth) occurs continued
treatment over 4 weeks.

Sodium Nitroprusside
Mechanism • Dilates both resistance and capacitance vessels.
• Nitroprusside when come in contact with red blood cells produces
nitric oxide (NO), which then stimulates guanylate cyclase.
Therapeutic Drug of choice for hypertensive crisis.
use
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Side effects • Short term-excessive vasodilatation and hypotension. Long term-


accumulation of cyanide and thiocyanate (24 hours).
• Concomitant administration of sodium thiosulfate decrease cyanide
accumulation by changing into thiocyanate.
Thiocyanate • Nausea, disorientation and toxic psychoses.
toxicity

Diazoxide

Mechanism • Dilates arterial smooth muscle.


• Used IV for the treatment of hypertensive emergencies.
Therapeutic use
Side effects • Salt and water retention
• Hyperglycemia (↓ release of insulin) and hypertrichosis

Hydralazine

Mechanism Acts directly relaxing arteriolar smooth muscle.


Therapeutic use • Indicated in pregnancy induced hypertension (PIH).
• This drug causes direct vasodilatation, acting primarily on the
arteries and arterioles, resulting in decreased peripheral
resistance which in turn prompts a reflex elevation in heart
and cardiac output.
Side effects • Salt and water retention, which may lead to CHF (use a
diuretic).
• Hematologic-neutropenia, Leucopenia, Agranulocytosis
• Muscle cramps
• Orthostatic hypotension, and tachycardia
• Lupus like syndrome. (long term therapy likely > 6 mo)
Butterfly reaction on face.

Ca2+CHANNEL BLOCKERS
These agents are used to treat hypertension and are effective in treating angina as well.
All muscles, including the smooth muscle of the blood vessels, require calcium in order
to contract. If the CCB block the entrance of the calcium into the muscle, the muscle will
not contract. This will allow the muscle to relax and subsequently reduce the blood
pressure. Other therapeutic uses angina, migraine, and antiarrhythmic.

Nondihydropyridine
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• Diltiazem hydrochloride
• Verapamil hydrochloride
Mechanism
• Verapamil similar to beta blockers in effect
• Verapamil can
cause
bradycardia
• The effect on
heart is graded
from higher to
lower.

Verapamil>Diltiazem>Nifedipine
• Verapamil-avoid using in CHF (cause -ve inotropic effect)
and constipation
Dihydropyridine
• Nifedipine
• Felodipine
• Amlodipine
• Nicardipine
Side effects
• Flushing, headache
• Profound low blood pressure
• Swelling of legs and feet.
• constipation and stomach upset.
• If ankle edema (swelling) of legs and feet occurs, a diuretic
may be added to the regimen.

Nifedipine is similar to nitrate in effect (peripheral, decrease after load, dihydropyridine


can cause tachycardia.
Dihydropyridine relax and dilating arteries. The effect on vascular smooth muscles is
high with dihydropyridine Nifedipine>Diltiazem>Verapamil.
Dihydropyridine (DHP) Non-Dihydropyridines (NDHP)
Phenylalkylamine Benzothiazepines
Nifedipine, Amlodipine, Nicardipine, Verapamil hydrochloride Diltiazem hydrochloride
Felodipine
↓ peripheral vascular resistance ↓ Myocardial oxygen Have both cardiac depress and
vasodilation and hypotension demand and reverse vasodilator.
may lead to reflex tachycardia. coronary vasospasm Decrease arterial pressure without
Often used to treat producing severe degree of reflex cardiac
angina. stimulations caused by dihydropyridines
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Reflex tachycardia bradycardia bradycardia


No heart blockade Peripheral Cause Heart blockade Cause Heart blockade
vasodilatation. Myocardial Myocardial vasodilatation
Peripheral edema (ankle edema vasodilatation Negative (-ve) inotropic effect (worsening
or pitting edema). Negative (-ve) inotropic CHF)
Headache, and flushing effect (worsening CHF)
Constipation
Avoid CYP3A4 Inhibitors/Inducers

Dihydropyridine ( DHP) Non-dihydropyridine (NDHP)


Cause reflex tachycardia Cause bradycardia
No heart blockade Cause heart blockade
Peripheral vasodilation Myocardial vasodilation
Amlodipine long half-life Negative (-ve) inotropic effect (worsening CHF)
Can be used in asthma
Avoid CYP3A4
Inhibitors/Inducers(GFJ)

The most common SEs dizziness, hypotension, headache, peripheral and pulmonary
edema.
Duration of action ranges 4-8 hrs.
Verapamil 4hr (TID to QID)
Diltiazem 6-8hrs (TID to QID)
Nifedipine 4-8hrs (TID to QID)
Nicaradipine 6-8hrs (TID to QID)
Amlodipine 24hr once Daily

Dihydropyridines
Adalat, Adalat XL
Mechanism A calcium blocker which interfere with conduction of signals in
the muscles of the heart and vessels.
Therapeutic use
Given regularly to prevent angina attacks. Reduce high blood
pressure and is often helpful in improving circulation to the limbs
in disorders such as Raynaud’s disease.
Side Effects Blood pressure will fall too low’ and sometimes causes heart
rhythm.
Tachycardia, flushing, headache, dizziness, orthostatic
hypotension, and edema.
Amlodipine
Mechanism A calcium blocker which interfere with the conduction of signals
in the muscles of heart and vessels.

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Therapeutic use Angina and chest pain. Can be safely used by asthmatic and non-
insulin-dependent diabetic.
Side Effects May cause mild to moderate leg and ankle swelling (arterial). and
hypotension.
Non dihydropyridines

DILTIAZEM Cardizem CD once daily, Tiazac XC once daily and IR formulation


TID or QID

Mechanism A calcium blocker that interferes with the conduction of signals


in the muscles of heart and blood vessels.
Therapeutic use Angina. Longer acting formulations are used to treat high blood
pressure.
Side Effects Usually well tolerated, occasional hypotension or orthostatic
hypotension, flushing, arrhythmia, and bradycardia. Use with
caution in patient with CHF.

Tips

• Diuretics that cause metabolic alkalosis: (thiazide, loop diuretics)


• Diuretics that cause intracellular alkalosis: (spironolactone)
• Diuretics that act on distal convoluted tubule: (thiazides)
• Diuretic that cause metabolic acidosis: (CAIs, potassium sparing)
• Diuretics that have greater vasodilatation effect (thiazides)
• What diuretics disturb the electrolyte balance, the most? (loop diuretics)
• Patient taking hydrochlorothiazide should be monitored (BP, glucose and potassium)
• Hypertension + pheochromacytoma which antihypertensive should be avoided beta
blockers.
• Isolated systolic hypertension which drugs should not use beta blockers
• Cardio selective beta-blockers are EMAA.
• The most beta 1 selective blockers that has been studied in lung dysfunction =
bisoprolol.
• What percent of patients diagnosed with high blood pressure have essential
hypertension 90%.
• Name the cation most prevalent in the extracellular fluid of the body --> Na
• Why is bedtime the best time to dose terazosin? orthostatic hypotension (syncope)
• Antihypertensive Lowers blood pressure through reducing the PR or CO.
• Propranolol is best absorbed with food but consistency is the most important factor
• Metoprolol is best taken with meals
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• Beta blockers that have first pass metabolism; propranolol, timolol


• Beta blockers that have no biotransformation; atenolol
• Beta blockers that have α blockade effect: labetalol, carvedilol
• Beta blockers that act as membrane stabilizer; propranolol
• Central α 2 -sympathomimetics cause negative sympathetic outflow and lowering
peripheral resistance.
• The following beta-blockers are used in treatment of angina:
• Beta-blockers with selective intrinsic sympathomimetics activity (ISA): Acebutolol
hydrochloride
• Beta blockers with Non-ISA: Atenolol and metoprolol tartrate can be used.
• Beta blockers with Nonselective, ISA: Pindolol
• Beta blockers with Nonselective, Non-ISA: Nadolol, Propranolol hydrochloride,
Timolol maleate
• The following Calcium Channel Blockers are used in treatment of angina:
• Amlodipine besylate, Diltiazem hydrochloride, Nifedipine, Verapamil hydrochloride

Tips

1 Loop diuretic 6 Triamterene 8 TG


2 Thiazide 7 Amiloride 9 Collecting duct
3 Spironolactone 5 Potassium sparing 10 LDL
4 Acetazolamide
• Diuretics that cause metabolic alkalosis ( 1, 2 )
• Diuretics that cause intracellular alkalosis ( 3 )
• Diuretics that act on distal convoluted tubule ( 2 )
• Diuretic that cause metabolic acidosis (3,4)
• Diuretics that have greater vasodilatation effect (2)
• Potassium sparing diuretic act on (9)
• Thiazide side effects hyperlipidemia NOT generally significant at low doses,
(<25mg/d), at higher doses what type lipid increases: (TG, and LDL)
• Diuretics that cause hypokalemia (1, 2)
• Diuretics that cause hyperkalemia (5)
• A patient taking hydrochlorothiazide should be monitored higher risk patients
lipids, glucose, and uric acid. (hyperGLUC)
• Diuretic that cause intracellular alkalosis (3)
ABBREVIATION AND TERMINOLOGY

TPR Total Peripheral Resistance DHP Dihydropyridine


DBP Diastolic Blood Pressure NDHP Non Dihydropyridine
SBP Systolic Blood Pressure GFJ Grapefruit juice
Hyper HyperGlycemia, Lipidemia, Uricemia, CA Calcium
GLUC Calcemia

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GFR Glomerular filtration rate


CO Cardiac output ARB Angiotensin Receptor Blocker
ADH Antidiuretic hormone NO Nitric oxide
BPH Benign Prostate Hyperplasia RBC Red Blood Cell
ACE Angiotensin converting enzyme PIH Pregnancy Induced Hypertension
HR Heart rate SV Stroke Volume
ISA Intrinsic Sympathomimetics Activity LVH Left Ventricular Heart Failure
EMMA Esmolol, Metoprolol, Acebutolol, Atenolol CVA Cardiovascular attacks
NE Norepinephrine CAIs Carbonic anhydrase inhibitors

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5
Antihyperlipedemic Drugs
Classification of antihyperlipidemic drugs

HMG-CoA reductase inh. Nicotinic acid Bile acid Fibric acid Cholesterol
sequesterants derivatives Absorption
inhibitors
Lovastatin Niacin
Simvastatin Act at liver Cholestyramine Gemfibrozil
Pravastatin Ezetimibe
Cholestipol Clofibrate
Fluvastatin Act at GIT Fenofibrate
Atorvastatin Compete with bile salts
Rosuvastatin prevents reabsorption

Increased intracellular cholestrol results from LDL catabolism inhibits the activity of 3-
hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase, the rate limiting enzyme
for intracellular cholesterol biosynthesis.

Statins
Generic Name Trade Name Generic Name Trade Name Generic Name Trade Name
Atorvastatin LIPITOR Fluvastatin LESCOL Simvastatin ZOCOR
Lovastatin MEVACOR Pravastatin PRAVACHOL Rosuvastatin CRESTOR

Mechanism Liver Cell

Acetyl CoA

HMG CoA
HMG CoA Statins
Reductase
Mevalonic acid

Cholesterol

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LDL is composed of TG 4-8%, free cholesterol 4-8%, cholesterol esters 45-50%,


phospholipids 18-24% and apoproteins 18-22%. The LDL receptors contain apoB-100
and apoE.

Therapeutic use. Lower LDL

Side effects. Mild upper GI disturbance (Constipation, dyspepsia, flatulance, diarrhea,


nausea and vomiting). Myalgia or arthralgia sleep disturbances. Increases liver enzymes
AST and ALT (transaminases). Myopathy and rarely cause rhabdomyolysis (CK-MM). It is
common in renal insufficiency patients. Rhabdomyolysis is disintegration and
dissociation of muscles.
Patient presentation of myalgia is fever, muscle ache, or cramps, unusual tiredness or
weakness.
Rhabdomyolysis is massive muscle necrosis which secondary to acute renal failure.

Drug Interactions. Extreme precaution if combine the medication such as cyclosporine,


itraconazole, erythromycin, clarithromycin, gemfibrozil, niacin, fibrates and grapefruit
juice increase myopathies/myositis and hepatotoxicity, due to inhibition of CYP 3A4
enzyme, which is essential for metabolism of statin niacin.

Pharmacokinetics. Fluvastatin, lovastatin and simvastatin should be taking at nighttime.


Rest other drugs anytime of the day.
• Lovastatin should be always administered with food to increase bioavailability,
otherwise it can decrease 30% bioavailability.
• Atorvastatin can be taken anytime of the day, because has long half-life.
• The best agent for renal disease patient is atorvastatin, because it has minimal renal
elimination, thus do not require dose adjustments.

Statin
Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
Metabolizing CYP3A4 CYP2C9 CYP3A4 not known CYP2C9 CYP3A4
Enzyme (s)
Grapefruit juice Avoid Avoid Avoid
Take Anytime At night At night At night
Food With or With or With or With or With or With or
without after after without without without
Statins (A= atorvastatin, L=lovasatin, F=fluvastatin, S = simvastatin, P = pravastatin); FLS = take at bed time (night); ALS = avoid
grapefruit juice (because grape fruit juice inhibit CYP 3A4); ALS = avoid grapefruit juice (substrate CYP3A4); FLS = take at bedtime; FL
= take with food; A = any time of the day; PF = can taken with grapefruit juice; P = least drug interaction

Pregnacy. All statins are contraindicated to use in pregnancy, breast feeding, and children.
Monitoring. LFT, evaluate liver function and measure serum transaminases and creatin
kinase CK-MM.

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Niacin (Nicotinic acid)


Mechanism • Niacin also known as vitamin B3
• Participation in tissue respiration oxidation, reduction
reactions, which decreases hepatic LDL and VLDL production
• Inhibits tubular secretion of uric acid, causes gout or.
hyperuricemia.
Therapeutic use • TG reduction 20 to 50% (higher dosage). HDL increase 15 to
35% (greatest HDL raising effect).
Side Effects • Intense cutaneous flushing accompanied by uncomfortable
feeling warm and pruritic, dry skin, hyperglycemia,
hyperuricemia, GI distress like reactivation of peptic ulcer, and
hepatotoxicity (if combine with statin can potentiate
hepatotoxicity).
Management • Administration of ASA 325 mg prior to taking niacin decrease
flush. Take with food. Tolerance develops in 1 to 2 weeks.
• Higher dose 2 g/day may produce hepatic damage.
• Niacin IR have high flushing, Niacin SR more frequent
hepatotoxicity.
• No-flush prep contains Inositol + niacin.
Fibrates

Generic Name Trade Name Generic Name Trade Name


Bezafibrate BEZALIP Fenofibrate LIPIDIL
Gemfibrozil LOPID

Therapeutic use. Decrease TG levels, LDL levels and increase HDL levels (moderately).
Very useful in treatment of hypertriglyceridemia in diabetic patients. Prophylaxis for
coronary heart disease and cerebrovascular diseases.
Side effects. Mild GI disturbances. Drug may cause excretion of cholesterol into the bile
leading to cholelithiasis. If tested discontinue the drug. Lithiasis predispose gallstone
formation.
Drug Interactions. Combination with statins may lead to myopathies, or rhabdomyolysis.
Contrainidcations. Sever hepatic and renal dysfunction, potentiates warfarin activity.
Preexisting gall bladder disease.
Monitoring. At 3, 6 and 12 mo, and yearly liver function test. Creatinin kinase complete
blood count, and renal function test.
Pharmacokinetics. Fibrates renally eliminated. Thus no hepatotoxicity. Need dose
adjustment in renal disease.
• Fibrates decrease serum uric levels (uricosuric effect) in normal patients and
hyperuricemic patients.

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Antihyperlipidemics
Elimination Food LFT CK- Uric Tips
MM acid
Atorvastatin Biliary (feces) +
Fluvastatin Biliary (feces) +
Lovastatin Biliary (feces) With +
food
Pravastatin Biliary (feces) +
Rosuvastatin Biliary (feces) +
Simvastatin Biliary (feces) +
Niacin Biliary (feces) + + Avoid in uncontrolled diabetics
Least likely used combination niacin + statin
Fibrates Renal/Biliary LFT/ Good for lowering TG
(feces) RFT Monitor CK, CBC, liver and renal function
Ezetamibe Statin+ezetamibe
Fibrate+ezetamibe
Resins hepatic LFT Monitor LFT and TG
• Pravastatin not extensively metabolized by CYP450. Can be taken with grapefruit juice.
• Should not be used in patients with active liver disease. (statins & niacin)

Resins (Bileacidsequestrant)

Resins • Cholestyramine and colestipol.


Pharmacological • Anion-exchange resins bind with the enzymes in intestine and
action inhibit the synthesis of cholesterol. Bile acids are synthesized
from cholesterol. Decrease LDL 15 to 30% and increase HDL 3 to
10%.
• No change or increase in TG (disadvantage).
Therapeutic use • Drug of choice in pregnancy.
• Cholestyramine also relieves pruritis caused by accumulation of
bile acids in patients with biliary obstruction in cholestasis.
Side Effects • Decrease absorption of ADEK fat soluble vitamins. Some
recommend concurrent supplementation with fat solube
vitamin. High doses of folic acid and ascorbic acid absorption is
reduced. Most common GI problem constipation, flatulance,
stomach fulness,↑ TG and transaminase (reversible).
Drug-Drug • These drug interfere with intestinal absorption of many drugs
interactions (tetracycline, phenobarbital, warfarin, pravastatin, fluvastatin,
aspirin, and thiazide diuretics).
Pharmacokinetics • Urge patient to comply with blood testing, and special diet.
• Urge patient to control weight and stop smoking.
• Recommend high fiber diet to reduce constipation
• Tell patient not to take powder in dry form. Teach patient to

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mix drugs with fluids or pulpy fruits.


Dose • 4 to 24 g/day

Ezetimibe

Mechanism • Selectively inhibit the intestinal absorption of cholesterol and


related phytosterol.
Therapeutic • Used in combination with statins (increasing dose of statins only
use does not decrease LDL levels, hence combination ezetimibe is
recommended).
Side Effects • GI effects. Abdominal cramps, liver problems, sexual dysfunction
and weight loss.
When it used • Muscle pain, chest pains, upper respiratory infections, angioedema,
with statins and skin rash.
Advantage • Does not affects fatsoluble vitamins. Low potential for drug
interactions.
Tips

• FLS: only taken at night (at bedtime), for maximum effect.


• Pravastatin and rosuvastatin have least drug interactions (T/F)
• Statins increase risk of arrhythmias at night (T/F)
• HMG Co A inhibitors are mainly metabolized by CYP 3A4
• HMG Co A inhibitors side effect rhabdomyolysis patient may notice by muscle
pain and CK-MM.
• Which antihyperlipedemic have no effect or increase triglyceride levels  Resins
• Which antihyperlipidemics have equal proportion effect on LDL, HDL and TG -->
niacin
• Resins act what part of GI small intestine
• Lovastatin is given with food because Increase bioavailability
• Drug of choice against cholesterol in DM patients  Fibrates
• Drug that inhibit intestinal absorption cholesterol --> ezetamibe

Find answers from table:


1. < 2.2mmol/L 6. small intestine 11. Simvastatin 16. HMG CoA
2. 0.9 mmol/L 7. large intestine 12. Pravastatin
3. 5mmol/L 8. Hydrochlorothiazides 13. Rosuvastatin
4. Darken urine 9. Lovastatin 14. Resins
5. Niacin 10. Flovastatin 15. Fibrates
• Statins only taken at night (at bedtime), for maximum effect. ( FLS )
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• Statins that have have the least drug interactions ( 12 )


• HMG Co A inhibitors side effect rhabdomyolysis patient may notice by ( 4 )
• Which antihyperlipedemic have no effect or increase triglyceride levels ( 14 )
• Which antihyperlipidemics have equal proportion effect on LDL, HDL and TG(5)
• What part of GI, resins act (small intestine )
• Increase LDL, Decrease HDL and Increase TG (thiazides)
• Lovastatin given with food because (increase bioavailability)
• Cholesterol lowering drug that should not be used diabetes mellitus patients
(niacin, cause hyperglycemia SE ).
• The rate-limiting step in cholesterol biosynthesis is (HMG Co A reductase)
• Lovastatin should be taken with food to (elevate 33% bioavailability)
• HMG Co A inhibitors are mainly metabolized by CYP 3A4 are (ALS)
• A patient taking statins monitor LFT and at CK at 3, 6, 12 months then yearly (true)

ABBREVIATION and TERMINOLOGY

TG Triglycerides DM Diabetes Milletus


CBC Complete Blood Count VLDL Very Low- Density Lipoprotein
HMG 3-hydroxy, 3-methyl glutaric LDL Low- density Lipoprotein
acid
LFT Liver Function Test HDL High-Density Lipoprotein
CK Creatinine Kinase FLS Fluvastatin Lovastatin Simvastatin
ADEK Vitamine A, D, E, K ALS Atorvastatin Lovastatin Simvastatin

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6
Nitrates and Nitroglycerin
Nitrates are antianginal agents. The most common complications associated with
coronary artery disease includes angina pectoris, MI, post MI, ischemic stroke.
Insuficient supply of oxygen to heart can lead to ischemic conditions.

Nitrates

Short duration Intermediate duration Long duration


Sublingual Oral regular or sustained Transdermal
Nitroglycerin release Isosorbide dinitrite Nitroglycerin patch
Isosorbide dinitrite
Inhaled amyl nitrite

Generic Name Brand Name Generic Name Brand Name


Isosorbide dinitrate Cedocard SR (generics) Nitroglycerin SL spray Nitrolingual Spray
Isosorbide mononitrate Imdure Nitroglycerin SL tab,
Nitroglycerin injections, Nitrostat
ointment, patch

Nitrates
Pharmacological action

Nitrate Increase nitrite Increase nitric oxide (NO) Increase cGMP

Vascular smooth muscle relaxation ↑ Dephosphorylation of myosin light chain

Organic nitrates act primarily by vasodilation (especially venodilation), which reduces


myocardial preload and therefore myocardial oxygen demand. Nitrates also promote
redistribution of blood flow to relative ischemic areas. Effects of nitrates and nitrites on
smooth muscle.

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Nitroglycerin
Mechanism • Vascular smooth muscle relaxation.
Action • Two major effects "dilation of the large veins (resulting of
pooling blood in veins this reduces preload and decrease work of
heart.
• Dilates coronary vasculature, providing increased blood supply
to the heart muscles.
Side effects • The most common side effect is headache. Higher doses,
Postural hypotension, facial flushing and tachycardia.

Storage • Amber color, glass and metal capped.


Conditions • Dispense in original container.
• Discard cotton present on tablets in bottle.
• Drug expires after 6 months from the day bottle open.
• Light sensitive, and hygroscopic.
Drug • Additive hypotension effect cause severe hypotension with
interactions sildenafil, tadalafil, and verdanafil.
Dosage forms • Nitroglycerin SL tablets 0.3-0.6 mg for acute.
• Nitroglycerin SL spray 0.4 mg for acute (do not shake but prime).
• Nitroglycerin iv for acute.
Tolerance • Nitroglycerin transdermal patch 0.2-0.8 mg/hr for 12-14 hr for
maintenance.
• Tolerance develops rapidly. This can be overcome by using
“nitrate free period” 10-12 hr and restore sensitivity to drug.
Nitroprusside
Therapeutic • Drug of choice for hypertensive crisis
use
Side effects Cyanide toxicity (releases CN). Sodium thiosulfite is an antidote

(Cyanide Intermediate) + sodium thiosulfite  Sodium
thiocyanate (water soluble).
• Photosensitive
Detoxification of cyanide with thiosulfate and rhodenase

Thiocyanate
Nitroprusside Cyanide (toxic) (nontoxic)

Thiosulfate

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Tips

• Insufficient supply of oxygen to heart can lead to ischemic conditions  angina, MI


• Nitroglycerine spray storage and administration room temperature
• Nitroglycerine SL storage condition require room temperature
• Nitrates should be avoid taking with  sildenafil
• What is active moiety of nitrates  nitric oxide
• Nitroglycerine is chemically classified as nitrates
• Nitroglycerine patch can cause tolerance, to avoid tolerance use nitrate free period.
• At what dose ASA act as antiplatelet  60 to 80 mg
• ASA act as irreversible antiplatelet drug. Antiplatelets dose (ASA 60-81 mg/day)
• The most common form of ischemic heart disease (IHD) is --> angina.
• Aspirin decrease morbidity and mortality.
1 Sildenafil 2 Nitric Oxide 3 Morphine
4 Tadalafil 5 Nitrates 6 Thrombolytics
7 Vardenafil 8 CCB 9 ASA
10 Beta blockers 11 Heparin 12 Nitroglycerin
13 ACEI 14 Digoxin

Write the correct number (s) of the drug(s) that corresponds to the question.
• Nitroglycerin spray storage and administration (room temperature until expiry)
• Nitrates should be avoided taking with (1,4, and 7 )
• What is active moiety of nitrates (2 )
• Nitroglycerin is chemically classified as ( 5 )
• What drugs effective in MI prevention and treatment ( 12 )
• What drugs should be avoided in MI (verapamil and diltiazem)
• It can cause tolerance, to avoid tolerance use nitrate free period. (nitroglycerin
patches)
• Act as irreversible antiplatelet drug in MI prophylaxis ( ASA)
• It is used for only 6 months after opening bottle: Light sensitive  amber glass and
metal cap: Hygroscopic: dispense in same container; discard cotton (nitroglycerin SL)
• Use until expiry, do not shake, prime it. (nitroglycerin SL spray pump)

Select True/False statement


• Nitroglycerine + seldanafil can cause hypotension and this due to vasodilatation
contributed by nitroglycerine and sildanafil (T/F)
• The most common side effect of nitroglycerine is headache; therefore nitroglycerine
should be taken while sitting position (T/F)

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• Nitrates  Increase nitrites Increase nitric oxide (NO)  vascular smooth muscle
relaxation
• Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder,
back and arms.
• Which is usually aggravated by exertion or stress and relieved by nitroglycerine.
• The following Coronary Vasodilators nitrates are used in treatment of angina:
Nitroglycerin, Isosorbide dinitrate, Isosorbide-5-mononitrate.
• ASA = Analgesics, Antipyretics, Antiinflammatory, Antiplatelets

ABBREVIATION AND TERMINOLOGY


LDL Low density lipoprotein STEMI ST-Segment Elevation MI
SL Sublingual NSTEMI NON ST-Segment Elevation MI
CCB Calcium channel blockers ASA Acetyl salicylic acid
MI Myocarddial infarction
ACE Angiotensin converting enzyme

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7
Cardiac Glycosides. Digoxin
Cardiac Glycosides

Cardiac glycosides • Digoxin, and digitoxin


Mechanism • Cardiac glycoside increase myocardial contractility and efficiency
• Improve systemic circulations and improve renal perfusion and
reduce edema.
Positive inotropic • Inhibit the membrane bound Na+/K+ activated ATPase.
effect
• Increase intracellular sodium concentration and reduce calcium
transport form cell thus facilitate calcium entry via voltage gated
membrane channel.
Negative • Increased vagal tone of the sinoatrial (SA) node
chronotropic effect • Reduced CNS sympathetic out flow. Systemic arteriolar and venous
constriction.
Vagomimetic effect  Increased vagal tone of the sinoatrial (SA) node.
Side effects
• Early stages of toxicity GI, anorexia, nausea & vomiting and
diarrhea. CNS headache, visual disturbances (green and yellow
vision) confusion, neuralgia, and delirium.
Generic Brand Generic Brand
Digoxin Lanoxin Digitoxin Crystodigin
Digoxin • Digoxin is the most widely used cardiac glycoside
• Don’t confuse with digoxin with doxepin, Desoxyn, or
digitoxin.

Question Alerts!
Digoxin is?
+ve inotropic (force of contraction)
-ve chronotropic (heart rate)
Vagomimetic

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Pharmacological
action
Therapeutic use CHF, Atrial fibrillation, protects ventricles
Side effects 1st sign: GI effects: Nausea, vomiting, diarrhea, blurry yellow vision, scotoma.
CVS: Arrhythmias, ventricular tachycardia
CNS: visual disturbances (blurred vision)
Bioavailability • 75% bioavailability, 20-40% protein bound
• T1/2 = 40 hr
• Urinary excretion
Monitor • Patient should understand the importance of follow up
laboratory test for this medication.
• Pulse, ECG and Adjust the dose with renal failure patients.

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Digitalis toxicity
Digitalis toxicity Toxicities of digoxin increased by renal failure (decrease excretion)
hypokalemia, or hyperkalemia (potentiates drug effect)
Predisposing factors Hypothyroidism, hypoxia, renal failure and myocarditis also predisposing factors for
digitalis toxicities.
Digitalis toxicity Digitalis toxicity can be managed by discontinue digoxin, monitor blood
Management potassium levels. Sever tachycardia may require the use of Fractionated
antibodies (FAB antibodies). Which bind to inactive digoxin.

Antidote Digifab
Drugs that may cause digitalis toxicity
Drugs that ↑ digoxin levels Drugs that ↓K+ levels
Amiodarone Thiazides
Verapamil Loop diuretics
Erythromycin Corticosteroids
Tetracyclin
Quinidine

Digitalis toxicity symptoms are severe nausea vomiting, anorexia, muscular weakness,
bradycardia, and ventricular premature contractions. Severe toxic symptoms include
blurred vision, disorientation, diarrhea, ventricular tachycardia, AV blockade which
progress to ventricular fibrillation.

Comparison of digoxin and digitoxin


Digoxin Digitoxin
Digoxin has advantage of a relatively short half- Binds strongly to proteins extravascular space,
life, which allows better treatment of toxic resulting in large volume of distribution.
reactions.
Rapid onset of action. Slow onset of action
Digoxin eliminated largely unchanged in urine Extensively metabolized by liver before it excrete in
feces.
Avoid in ventricular arrhythmia. Where as used in
supra ventricular (atrial arrhythmias).

Tips

• Natural source (genus and species) of digoxin Digitalis lanata.


• Digoxin pharmacological action include  positive inotropic, negative chronotropic
and vagomimetic effect
• Comparison of digoxin and digitoxin, which is short acting and why digoxin is more
water soluble, and excrete faster
• Digoxin antidote digifab

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• Symptoms of digoxin toxicity  severe nausea vomiting, anorexia, muscular


weakness, bradycardia, and ventricular premature contractions. Severe toxic
symptoms include: blurred vision, disorientation, diarrhea, ventricular tachycardia,
AV blockade which progress to ventricular fibrillation.
• Drugs that cause digitolis toxicity include --> thiazides, loop diuretics,
corticosteroids, erythromycin, verapamil, and quinidine.
• Digoxin antidote (digifab).
• Pharmacological action of digoxin includes +ve inotropic, -ve chronotropic and
vagomimetics (digoxin).
• Signs of toxicity are nausea and vomiting, palpitation (digitalis toxicity).
• Drugs that can cause digoxin toxicity (hypokalemic drugs, quinidine, verapamil,
tetracyclin).

ABBREVIATION and TERMINOLOGY

CHF Congestive heart failure SA Sinoatrial


ACE Angiotensin converting enzyme ECG Electroencephalograph
CCB Calcium channel blockers CVS Cardiovascular system
CNS Central nervous system

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8
Anti Arrhythmic Drugs
Antiarrhythmic Drugs Classification

Class I Na+ channel Class II Class III Class IV Miscellaneous


blockers β-blockers K+ channel Ca2+ channel Adenosine
Ia- Esmolol blockers blockers Magnesium
Quinidine Propranolol Amiodarone Verapamil
Procainamide Timolol Bretylium Diltiazem
Disopyramide Atenolol Dofetilide Nifedipine
Metoprolol Sotolol
Ib: Lidocaine Nadolol
Mexiletine
Tocainide
Ic: Flecainide
Propafenone

Generic Name Brand Name Generic Name Brand Name


Amiodarone Cordarone (generics) procainamide PronestylSR, (generics)
Disopyramide Rhythmodan (generics) Quinidine Biquin (generics)
lidocaine Xyclocaine propafenone Rythmol (generics)

Arrhythmias: Arrhythmias develop because of abnormal impulse generation,


propagation or both. Cardiac arrhythmias are related to abnormal electrical activity of
the heart resulting in either altered rhythm or impulse conduction.

Antiarrhythmic drugs act on 4 ion channels in cardiac muscles;


Voltage activated Na+ channel
Voltage activated Ca2+ channel
Voltage activated K+ channel (Ikr)
Voltage activated K+ channel (Iks)

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1a Quinidine, Slows phase 0 depolarization


procainamide
disopyramide
1b Lidocaine Shortens phase 3 repolarization (shortens duration of
refractory period)
1c Flecanide, Significantly slow phase 0 depolarization (slow conduction)
propafenone
II Propranolol Decrease phase 4 depolarization (beta 1 blocker action)
III Amiodarone, Prolong phase 3 repolarization (increase refractory period)
dronadarone and
sotalol
IV Verapamil Shortens action potential (increase refractory period AV
node)

Myocardial action potential curve reflects action


potential, which describes electrical activity of five
phases.
This occurs in atrial and ventricular myocytes and
purkinje fibers.

Phase 0: Rapid depolarization Na+ enters the cell.


All class 1a drugs
Phase 1: Early rapid repolarization: K+ leaves the cell
Phase 2: Plateau: Ca+ enters the cell
Phase 3: Final rapid repolarization: K+ pumped out
of the cell
Phase 4: Slow depolarization: K+ inside the cell and Na+ outside the cell

Phase 1 to starting phase 3 is ABSOLUTE


REFRACTORY PERIOD or Effective refractory
Period, the cell cannot respond to any stimuli.

During phase 3 is Ansolute refractory period the


cell ability to respond stimuli increases or cell can
respond to strong stimuli.

Drugs and diseases that can lead to Q-T


prolongation. Phenothiazine and haloperidol-
anyipsychotics. Type III anyiarrhythmic drugs
In patients with renal failure

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Electrocardiograph Wave Forms. The electrical activity occurs during depolarization and
repolarization transmitted through electrode attached to the body and transformed by
an electrocardiograph into series of waveforms.
• P Wave. indicated atrial depolarization
• PR INTERVAL. indicates the spread of impulse from the atria to the purkinje fibers.
• QRS Complex. indicates ventricular depolarization
• ST Segments. indicates phase 2 of the action potential, the absolute refractory
period.
• T Wave. shows phase 3 of the action potential ventricular repolarization.
• Q-T Interval. Mechanical contraction of the ventricles (Torse de pointes)
• U wave. Caused by hypokalemia.

ArrhythmiasTreatment

Class Ia • Quinidine decrease 50% digoxin, SEs Torsades de pointes


• Procainamide (Procaine SR): SE:Torsades de pointes
• Disopyramide (Norpace CR): SE:Torsades de pointes
Pharmacological action
Slow the phase 0 (slow entry of Sodium ion)
Prolong re-polarization
Prolong effective refractory period
Therapeutic use • Indicated to treat SVT, VT
Quinidine. syncope or fainting is cuased by induced changes in the
ventricular rhythm which will decrease cardiac output and cause loss of
consiousness or “syncope”.
Quinidine toxicity. widening of QRS complex more than 25% is a warning
sign that toxic levels are being approached.
Class Ib • Lidocaine
• Tocainamide
• Mexiletine
• Pharmacological action. Minimal effect on phase 0 slow phase –III
repolarization (decrease K pump out).

Therapeutic use • Indicated to treat VT, VA


• iv Lidocaine: used to treat cardioversion related arrhythmias
• Drug of choice in arrhythmias emergencies such as:
• Open heart surgery
• Premature ventricular contractions (PVC’s) following MI
• Digitalis toxicities.
Class Ic • Encainide
• Propafenone: decrease 25-50% digoxin
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• Flecainide
Pharmacological action: Very effective on slowing phase 0 depolarization
Little effect on repolarization
Therapeutic use • Indicated to treat VA
Class II • Propranolol
Beta blockers • Atenolol
• Timolol
Pharmacological action: Competitively block catecholamine induced
stimulation of Beta receptor thereby Suppress phase IV depolarization
Therapeutic use • Indicated to treat AT, SVT, VT, VA
Class III • Amiodarone  blue skin, photosensitivity, photophobia
K+ channel • Bretylium
blockers • Sotalol
Mechanism • Prolong Phase III repolarization (Prolong QT interval)Torose de
pointes
• Indicated to treat VA
Class III agent’s blocks potassium channels and thus diminish the outward
potassium current during repolarization of cardiac cells.

Class IV • Verapamil
Ca2+ channel • Diltiazem
blockers • Nifedipine
Pharmacological action: Shortens action potential
Therapeutic use • Indicated to treat SVA, VA
Digoxin • Pharmacological action: Effects vagotonic response (vegomimetic)
thereby increases AV nodal refractoriness.
• It is contraindicated in ventricular fibrillation.
• Ventricular tachycardia may result from digitalis toxicities
Therapeutic use • Indicated to treat SVA (atrial arrhythmias).
• Contraindicated in ventricular arrhythmias
Quinidine

Mechanism • Binds to sodium activated channels, Inhibits ectopic arrhythmias, VA


• Binds to open and inactivated sodium channels and prevents sodium
influx thus allowing rapid upstroke during phase 0.
Therapeutic use • Atrial, AV junctional, and ventricular tachycardia.
• Maintain sinus rhythm after direct atrial flutter or fibrillation.
Drug-Drug • Antihypertensive, anticoagulant, quinidine may increase the effects of
interaction these drugs.
• Phenobarbital and phenytoin reduce the effect of quinidine
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• Digoxin-Quinidine increases the effects of digoxin (decrease 50%


digoxin dose).
Side Effects • SA and AV block or asystole, nausea, vomiting, diarrhea (cinchonism-
large doses-blurred vision, tinnitus, headache, disorientation and
psychosis. Torsos De pointes (VA).
• Toxic level induce ventricular tachycardia.Increases steady state
concentration of digoxin by displacis plasma protein binding.
Procainamide

Mechanism • Binds to sodium activated channels


Side Effects • Chronic use: lupus like syndrome (25-30%), toxic levels—asystole or
induction of VA.
• GI intolerance is less than quinidine.
• CNS. Depression, hallucinations and psychosis.
Amiodarone

Pharmacological Acts on Na+, K+ and alpha & beta blocker action Amiodarone is
action structurally related to thyroxine, and it contains iodine.

Therapeutic use DOC antiarrhythmic & recommended in more severe LVD & if CI with
beta blockers.
IV Amiodarone effective in terminating VT, more so in preventing
recurrence. Most effective for treatment in electrical storm
Usually used as an empiric therapy.
Side effects SE of amiodarone are due to its long halflife (13 to 103 days)
"4Ps" Respiratory. irreversible Pulmonary damage, including intererstitial
pneumonitis. Respiratory muscle impairment (due to amiodarone
Pulmonary
deposits into lungs).
Peripheral T4-T3
GI. Nausea, anorexia, constipation, hepatitis and cirrhosis.
Pigmentation
Hypothyroidism or hyperthyroidism. Amiodarone inhibit Peripheral
Phototoxicities
conversion of T4 to T3 (due to similarity amiodarone structure with
hepatotoxicity
thyroid hormone structure).
Amiodarone deposits in skin cause bluish tinge skin color
(pigmentation), corneal deposits cause blurred vision, hepatic toxicity,
optic neuritis, erectile dysfunction, and photophobia.

Pharmacokinetics Avoid exposure to sunlight, use sunscreen avoid grapefruit juice.


Monitoring. Serum TSH, chest x-ray, eye exam, and LFT.

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Dronedarone. K+ channel blocker is benzofuran derivative structurally related to


amiodarone but without the iodine component so it does not posses amiodaron's iodine
related organ toxicity (hypothyroidism, pneumonitis, corneal toxicity, pigmentation).

Tips

• What phases of action potential curve have no effect of stimuli phase 1 to 3


• Relative refractory period is  phase 3
• Phase I action potential is 40 (+ve) due to  slow repolraization
• What drug cause QT prolongation (torse des pointes) class III
• Digoxin is contraindicated in what type of arrhthmiasventricular arrhythmias
• Amiodarone side effects are photosensitive reactions, skin pigmentation, blurred
vision. Pulmonary toxicity (pneumonitis) and inhibit peripheral conversion of T4 to
T3.
Tips

Find answers from the table:


1a _procainamie,_quinidine, Slows phase 0 depolarization
1b Lidocaine Shortens phase __3_(Shortens duration of refractory period)
1c Flecanide Significantly slow phase 0__(slow conduction)
II Propranolol Decrease phase _4_(beta 1 blocker action)
III Amiodarone and sotalol Prolong phase 3 repolarization (increase_refractory period__)
IV Verapamil Shortens action potential(increase refractory period AV node)
• What phases of action potential curve have no effect of stimuli  phase 1 to 3
(Absolute refractory period)
• Relative refractory period is  during phase 3
• Phase I action potential is 40 (+ve) due to Na+ enter
• What drug cause QT prolongation (torse des pointes) mainly class III (K+
channel blockers)
• Digoxin is contraindicated in what type of arrhythmiasVentricular arrhythmias
• Amiodarone mechanism  Amiodarone blocks both Na+, K+ channels and has
α and β antagonist action. iv dosage gives effect on K+ channels
• Oral dosage gives effect on  all (Na+, K+, α and β)
• Amiodarone side effects are: (4Ps) Photosensitive reactions (skin pigmentation),
Blurred vision. Pulmonary toxicity (Pneumonitis), Inhibits peripheral conversion
of T4 to T3. can cause hypo or hyper thyroids.

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9
Anticoagulants
Anticoagulants

LMWH
Heparin Vit K antagonist 10:2 Factor 10a Inh Others

Enoxaparin
Catalyzes the Warfarin Fandaparinaux Direct thrombin inh
Dalteparin
inhibition of (indirect) Dabigatran (Pradaxa)
Tinzaparin
thrombin 3 Rivaroxaban
Nadroparin
(direct)
Apixaban
Heparin sodium

Blood clot initiates by two


pathways. Warfarin act on extrinsic

Question Alerts!
1) What is freely available in
blood?

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Heparin (Unfractionated Heparin)


Mechanism • High molecular weight mucopolysaccharide. Heparin directly
deactivates clotting factor II and X. Heparin therapy is monitored by
aPTT assay because aPTT monitors factor II and X as well as other
factors.
• Binds to the antithrombin III (also known as heparin cofactor) to cause
a rapid anticoagulation effect. Heparin catalyzes the factor (thrombin
activation factor) 2a, 9a, 10a, 11a, 12a, and 13a.
Therapeuti • Major antithrombotic drug for DVT and pulmonary embolism. To
c use prevent postoperative venous thrombosis in patient undergoing
surgery. Maximum effect occurs within minutes.
Drug-Drug • Do not take ASA, which may increase the anticoagulant effect of this
interaction drug and the risk of bleeding in the intestines or joints.
Side Effects • Hypersensitivity reaction (chills, fever, urticaria etc), bleeding, heparin
induce thrombocytopenia (HIT).
Contraindic • Alcoholics, bleeding disorders, brain, eye, spinal chord surgeries.
ations
Monitoring • Periodic blood and liver test will be required aPTT (activated partial
thromboplastin time) after 6 hours of initiating heparin.

Advantage • Can be used in pregnancy
Dosage • iv and SC

Heparin Anticoagulation Mechanism

With Heparin Without Heparin


Active clotting factors Active clotting factors
IIa, IXa, Xa, XIa, XIIa, XIIIa IIa, IXa, Xa, XIa, XIIa, XIIIa

Rapid Anti Thrombin III Anti-thrombin III


& Heparin Slow

Inactive factors Inactive


2,9,10,11,12,13

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Low Molecular Weight Heparin


LMWH • Enoxaparin, Dalteparin, Tinzaparin and Nadaroparin
Mechanism Higher effect on factor Xa than heparin. More specific to factor X
and less against factor II (thrombin).
Therapeutic • The prevention of DVT or PE, NSTEMI and unstable angina
Monitoring • Does not change prothrombin levels. Act longer and do not require
close blood monitoring as heparin does. LMWH have predictable
response. Highly predictable dose response relationship.
Side effects • Hypersensitivity reaction (chills, fever, urticaria etc), bleeding.
• Heparin induce thrombocytopenia (HIT) is significantly low LMWH.
• Heparin induced osteoporosis is significant in low in LMWH
Dosage • SC and iv available.
• These administered parenterally as sodium salt. Because poorly
absorbed from GI tract LMWH are not interchangeable with heparin in
their actions and use. Because these highly acidic..

Warfarin
Mechanism • Vitamin K antagonist producing their anticoagulant effect by interfering
with cyclic interconversion of vitamin K and it 2,3-epoxide (vitamin K
epoxide).
• Inhibition of vitamin K-dependent proteins or clotting factors 2, 7, 9
and 10.
Therapeutic • Anticoagulant used to prevent blood clots, mainly in areas where blood
flow is slowest, particularly in the leg and pelvic veins.
Drug-Drug • A wide variety of drugs, such as ASA, barbiturates, oral contraceptives,
interactions cimetidine, diuretics, certain laxatives, certain depressants, and certain
antibiotics interact with warfarin, either by increasing or decreasing the
anti clotting effect.
Side Effects • Bleeding, purple toe syndrome, and skin necrosis
Monitoring • Prothrombin time (PT) ratio and international normalized ratio (INR)
are performed daily upon starting warfarin.
• Oral anticoagulant therapy warfarin INR should be between 2 to 3
Antidote • Vitamin K

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Warfarin

Chronic alcohol
Vitamin K epoxide reductase Barbiturates
Rifampin
Vitamin K VitaminK epoxide Vitamin K
Polypeptides Dark green vegetables
Spinach
O COO- Cheddar cheese
O
HOOC NH2 CO2 HOOC NH2 Cabbage
Ginseng
Precursor of clotting Factors Active Clotting Factors
Sulfonylureas
II, VII, IX, X II, VII, IX, X
Edema
Hypothyroidism
↓INR Cholestyramine
Penicillin (high doses)
Warfarin Nafcillin
Oral contraceptives

Decrease intestinal flora


Acute alcohol
Cotrimoxazole
Metronidazole
Phenylbutazone
Due to decrease synthesis of
clotting factor Cefamindole
Cefaprazone
Warfarin Cefatetan
Cefametazole
INR
Due to additive effects
Heparin
LMWH
Thrombolytic agents

Comparison of heparin, LMWH and warfarin


Heparin LMWH Warfarin
Enoxaparin, Dalteparin,
Tinzaparin, Nadroparin
Source Natural Fractionated heparins Synthetic
Route Parenteral (SC and SC and IV Oral
IV)
Mech Enhances the More specific to factor Xa Inhibits the hepatic
serum protease and less to factor II. synthesis of vit K
antithrombin III dependent factors
results in II, VII, IX, X
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inactivation of
fators IIa, IXa, Xa,
XIa, XIIa, XIIIa.
Antidote Protamin sulfate. Vitamin K,
This works by acid phytanadione
base
neutralization.
Site of In vitro, In vivo In vivo only (liver) or
action Intrinsic and extrinsic pathway
extrinsic only.
Onset of Faster (minutes) Longer half life Slower (half life 6 to
action 8 hours)
Pregnancy Yes LMWH do not cross placenta NO (Terotogenic)
alternate to hep
Renal Can be use in <30 Renally cleared and first Safe in renal
ml/min CrCl order kinestics. Avoid <30
ml/min CrCl.
monitor aPTT No monitoring. predictable INR
dose response relationship.

New oral anticoagulant comparison


Warfarin Dabigatran Apixaban Rivaroxaban
MOA Vitamin K antagonist Direct Thrombin inh. Factor Xa inh. Factor Xa inh.
Dosing Once daily Twice daily Twice daily Once daily
Prodrug No Yes No No
Bioavailability 100% 6% 60% 80-100
15,20 mg taken with food
Time to peak affect 4-5d 1-3 h 1-2h 2-4h
Half life 40 h 11 h 12 h 5-13 h
INR 2-3 Not used NOT used NOT used

Renal clearance None 80% 25% 33

AVOID Safe. No dose CrCl <30 ml/min CrCl <15 ml/min CrCl <30 ml/min
adjustment require
CrCl/dose 110 mg; 30-49, >25 ml/min , check age, (30-49) 15 mg od
>65yo,↑risk factor for weight, SrCr (>50), 20 mg od
bleeding.

AF, DVT, prevention prevention and prevention and prevention and


and reoccurrence of AF reoccurrence of AF reoccurrence of AF reoccurrence of AF
D-D Interaction CYP 2C9, 2C19, 3A4 P-gp CYP3A4, P-gp* CYP3A4, P-gp

D-L interaction PT and INR effective to aPTT, Thrombin Time PT, INR and aPTT are PT, aPTT, Heptest.
assess anticoagulant (TT), Ecarin clotting little affection. Not influenced but none is used
effect. time (ECT). If necessary useful in assessing to assess. PT (not INR) may
test are used to assess anticoagulant effect be used excess
anticoagulant.*** anticoagulant activity.
Antidote Vitamin K NO available NOT available Not available
• * St. John wort strong induce of both CPY3A4, P-gp may lead to reduced drug plasma concentration.

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• Grapefruit juice is only a moderate CYP 3A4 inhibitor, therefore grapefruit juice consumption is not
expected to be clinically relevant.
• ***To assess dabigatran anticoagulant activity PT (INR is NOT useful and should not be used for this
purpose.

Tips

• Prothrombin time (extrinsic pathway)  warfarin


• Partial thromboplastin time (instrinsic pathway)  heparin
• Heparin antidote  protamine sulphate
• Patient taking heparin monitored for aPTT
• Heparin action include factor 2a,9a, 10a,11a, 12a and 13a
• What is the safest anticoagulant in pregnancy heparin
• What are the factors heparin inhibits  factor 2a,9a, 10a,11a, 12a and 13a
• Monitor warfarin through PT, INR
• What do you monitor in low molecular weight heparin (LMWH) none
• Vitamin K supplements and green vegetable effect on INR by  decrease
• Increase in INR can increase risk of --> bleeding
• Heparin + protamine sulfate antidote mechanism of action neutralization
• ASA and NSAIDs interaction with warfarin  increase risk of bleeding
• Warfarin act on what factors vitamin K  2,7, 9, and 10
• Recurrance of heparin induced thrombocytopenia syndrome can be prevented by
using Monitor platelet count every other day for 14 days until heparin therapy is
stopped and use other anticoagulants or antithrombotics
• Warfarin blocks epoxide reductase preventing gamma craboxylation of 2, 7, 9. 10 so
PT, and PTT are prolonged
• Direct acting thrombin inhibitor is --> Dabigatran
• Clotting factor Xa inhibitor --> Fondaperinaux

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10
Antiplatelet Drugs
Antiplatelet drugs

Glycoprotein IIb/IIIa ADP receptor TxA2 Inh COX inhibitor or


receptor antagonists antagonists Dipyridamole irreversible platelet inh.

Clopidogrel ASA
Abciximab
Prasugrel
Eptifibatide
Ticlopidine
Tirofiban

Platelets are the elements of blood cells, tend to clump together. The antiplatelet drugs
interfere with the coagulation by inhibiting platelet aggregation. Heart attacks and
strokes occur when a blood clot that forms in a narrowed portion of an artery blood
flow and cuts off the supply of oxygen and nutrients to the tissue that lies beyond the
site of the clot.

Antiplatelets drugs works by one of the 3 mechanisms


1) Formation of ligands example ASA decrease TxA 2 formation (irreversible platelet
aggregation inhibitor). ASA dose 60 to 80 mg acts as antiplatelets. ASA 81 mg (enteric
coated), and ASA 80 mg (chewable).
The cyclooxigenase (COX) enzyme is present in platelets, which is precursor of
Thromboxane A 2 , and TXA 2 are potent vasoconstrictor and labile platelet aggregation
inducer.

2) Thrombin production releases adenosine diphosphate (ADP). The ADP is potent


inducer of platelet aggregation and stimulates prostaglandin synthesis from
arachidonic acid in platelet membrane.
Blocking interaction of ligands binding with ADP receptor on platelets.
Example Clopidogrel, Prasugrel and ticlopidine

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Clopidogrel and ticlopidine given those who do not tolerate ASA. Interact with
glycoprotein IIb/IIIa (a fibrinogen receptor) resulting in an inhibition of the fibrinogen to
form aggregated plug.

3) Interfere with intracellular signaling (Glycoproteine IIb/IIIa inhibitor). Example


Abciximab, Epifibatide, and Tirofiban.

Acetyl Salicylic Acid (ASA)

The enzyme cyclooxygenase is present in platelets. The cyclooxygenase catalyzes the


production of prostaglandin and then thromboxane A 2 .
• Thromboxane A 2 is potent vasoconstrictor and platelet aggregation inducers.
• The production of thromboxanes is effectively inhibited by ASA, which permanently
inactivates COX through covalent acetylation of COX enzyme.
• ASA antiplatelets action occurs at minimum 60 to 80 mg. Available strengths. ASA 81
mg enteric coated and ASA 80 mg chewable.
ASA 80-325 mg once daily. SEs. GI bleeding (serious GI bleeding less common with
lower doses (80-160 mg daily). Bleeding risk increase if combined with other
antiplatelets or anticoagulants.

Addenosin diphosphate (ADP) receptor blockers


CLOPIDOGREL AND TICLOPIDINE
Thrombin production releases ADP. It is potent inducers of platelet
Pharmacologi aggregation and stimulates prostaglandin synthesis from arachidonic acid
cal action in the platelet membranes.
Therapeutic • Reduce thrombotic risk in patient who cannot use Aspirin.
use
Side effects • Ticlopidine hemorrhagics complications such as bruising or
ecchymosis, epistaxis, this can cause severe neutropenia 2.5%
(agranulocytosis). Rash and diarrhea. Monitor. CBC weekly.
Contraindicati • Presence or history of hematopoietic disorders (such as neutropenia,
ons thrombocytopenia or agranulocytosis).
• Hemorrhagic diathesis or presence of hemostatic disorder
• Conditions associated with active bleeding, such as bleeding peptic
ulcer or intracranial bleeding, severe liver dysfunction.

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Storage • Store at room temperature. Dispense in light-resistant containers.
conditions Blister packs should not be exposed to light.
Dosage • The recommended dose is 250 mg twice daily with food.
Pharmacokine • Ticlopidine should be taken with meals to minimize GI intolerance.
tics Clopidogrel hepatic elimination, renal dose adjustment is not
necessary.

Glycoprotein IIb/IIIa receptor antagonists

Abciximab, Eptifibatide and Tirofiban


The final common pathway in platelet aggregation is the expression of functional
glycoprotein IIb/IIIa (also known as integrin alpha, beta) receptors. These proteins helps
fibrinogen molecules to bind with platelet cell surfaces receptor sites.

Eptifibatide and tirofiban. Indicated for unstable angina, NSTEMI and cutaneous
coronary procedure.

SEs. bleeding (risk of serious bleeding is low). Primarily at puncture sites.


Thrombocytopenia.

Miscellaneous
Epeprostenol is prostacyclin, PGI2, PGX, a bicyclic oxidative prostaglandin metabolites of
arachidonic acid with potent vasodilatory and antiplatelet aggregation properties. .

Tips

• Life of platelets is --> 7 to 10 days


• What dose of ASA act as antiplatelets  80-325 mg
• What is the mechanism of ASA antiplatelets action --> irreversible inhibition of
platelets
• What is the effect of ASA on warfarin  increase risk of bleeding
• Mechanism of action of clopidogrel --> ADP inhibitor
• Abciximab and tirofibatide are examples of --> glycoprotein IIb & IIIa inhibitors

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11
Thrombolytic Drugs
Thrombolytic are used to dissolve already been formed thrombus,
as in conditions such as deep vein thrombosis, acute stroke, acute
pulmonary embolism and acute myocardial infarction. Question Alerts!
Thrombolytics are
used for the treatment
Thrombolytic Drugs of stroke, MI, and DVT,
PE

Streptokinase Anistreptase (Aminase) Urokinase


t-pa
(Strepto protein from Prodrug of streptokinase (Abbokinase)
(tissue type
Group C-B-hemplytic plasminogen activator)
steptococci bacteria
Directly degrade Alteplase (activase)
fibrin and Reteplase (Retevase)
fibrinogen very high affinity to
plasminogen, bound to
thrombus

Generic Name Trade Name Generic Name Trade Name


Alteplase Activase Urokinase Abbokinase
Reteplase Retevase Anistreplase Aminase
Streptokinase Tenecteplase

Thrombolytics also known as fibrinolytics. Tissue plasminogen activator tPA are


alteplase and reteplase.

Pharmacological action. Blood clots are dissolved by the action of the


fibrinolytic system.
• Facilitate conversion of plasminogen to plasmin that subsequently hydrolyzes fibrin
to dissolve clots.
• Recombinant DNA derivatives of tissue plasminogen activator (tPA).
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• They contain 527 and 355 amino acids of natural tPA.
• tPA catalyzes the conversion of plasminogen to plasmin.

VIIa
Blood
IX X
Xa X
Prothrombin (II) Thrombin IIa

Thrombolytics:
Streptokinase XII
Urokinase
Alteplase
Fibrinogen

Catalyzation

Plasminogen Plasmin Fibrin (Soluble)

XIIa

Fibrin degradation product Fibrin (insoluble)


Site of injury

Tissue plasminogen activators (t-PAs)

Alteplase and Reteplase


• These drugs have low affinity for free plasminogen but a very high affinity for
plasminogen bound to fibrin in a thrombus. Both streptokinase and urokinase lack
this specificity and act on free plasminogen inducing generalized thrombolytic state.
• Alteplase has greater specificity to older clots than newer clots.

Streptokinase

Mechanism • An enzyme produce by streptococcus bacteria.


• Dissolve the fibrin of blood clots, especially those in the
arteries of the heart and lungs.
Therapeutic use • Acute coronary syndrome, deep vein thrombosis, pulmonary
embolism and cerebrovascular stroke.
Drug-Drug • There is an increase bleeding when anticoagulants are taken
interactions at the same time as streptokinase.
Side Effects • Can produce allergic reactions (urticaria). Give antihistamine
before starting the treatment.
• Excessive bleeding
• Bronchospasm
• Angioneurotic edema
• Headache

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Monitoring • Don’t give second streptokinase within 6 months of the first
treatment.
Urokinase
Mechanism It is an enzyme with the ability to directly degrade fibrin and
fibrinogen.
Two-chain serine protease obtained from cultured human kidney
cell.
Therapeutic use Coronary artery thrombosis, Pulmonary embolism (PE).
Side effects Allergic reactions may lead to bronchospasm and skin rash

Anistreplase

It is prodrug of streptokinase, It is used to improve streptokinase


pharmacokinetic profile.
APSAC (Anisoylated plasminogen streptokinase activator complex)
Mechanism It is a complex of human lys-plasminogen and streptokinase with anisoyl
group blocking catalyst site.
Therapeutic use Acute MI, coronary artery emboli lysis.

Tips

• t-PAs are  alteplase, and reteplase.


• Thrombolytic therapeutic use is Acute stroke, Acute coronary syndrome (MI or
heart attack) and some cases deep vein thrombosis and pulmonary embolism.
• Streptokinase is produced by? Streptococci (hemolytic bacteria)

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12
Antidepressants
Classification of Antidepressants

Monoamine Oxidase (MAO) Inhibitors Amine reuptake α2 receptor inhibitors + 5HT


Irreversible non selective MAOi inhibitors drugs
Phenelzine Mirtazapine (SARI)
Tranylcypromine
Isocarboxazid
Clorgyline (selective)
Reversible non selective MAOi (RIMA). Non-selective 5HT only
Moclobemide 5HT, NE, D Selective serotonin
reuptake inhibitors
Fluoxetine
Fluvoxamine
5HT, NE Dual action
Paroxetine
Tricyclics (TCA’s) SNRI
Sertraline
Tertiary amine type (5HT & NE) Venlafaxine
Citalopram
Amitriptyline Desvenlafaxine
Escitalopram
Imipramine Duloxetine
Secondary amine type Trazadone
(5HT<NE) sNDRI
Desipramine Bupropion
Nortriptyline

Generic Name Brand Name Generic Name Brand Name


Citalopram Celexa fluvoxamine Luvox (generics)
Fluoxetine Prozac (generics) paroxetine Paxil
sertraline Zoloft (generics)
Abbreviations: 5HT = 5-hydroxy tryptamine (Serotonin), NE = Norepinephrine; SNRI =
Serotonin Norepinephrine Reuptake Inhibitors, NDRI = Norepinephrine Dopamine
Reuptake Inhibitor; RIMAs = reversible inhibitors of monoamine oxidase. TCA = Tricyclic
Antidepressants.

Serotonin has variety of central and peripheral physiological actions such as


vasoconstriction, vasodilatation, regulation of body temperature, mood, sleep and
hormonal regulations.

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Depression occurs due dysregulation in the production, uptake or reuptake


(presynaptic) of 5HT, NE, D, neurotransmitter.

Signs and symptoms of depression. sadness, tearfulness, dejection, self-criticism, loss of


ability to experience pleasure, loss of appetite, inability to sleep and loss of libido.

Selective Serotonin Reuptake Inhibitors (SSRI)


The SSRIs are selective in blocking the reabsorption of serotonin by nerve cells by acting
at the 5HT receptors, and therefore, increasing the amount of serotonin available in the
brain. This class of antidepressants has fewer side effects than MAOi’s or TCA’s. They
are also used for bulimia, obsessive-compulsive disorder and panic attacks.

Mechanism. SSRI selectively block the prejuntional neuronal reuptake pumps in the CNS
that terminate serotonin transmission thus increase activity on serotonin receptors.
SSRIs onset of action is 4 to 6 wks for the treatment of depression symptoms.

Side effects
• GI. Nausea (most common), dry mouth, somnolence and sweating. ↑ risk of GI
bleeding. Constipation
• CNS. Headache, insomnia, nervousness, and fatigue. Sexual dysfunction (orgasmic
delay).

Serotonin syndrome. The serotonin syndrome may occur if the SSRI are combined with
MAOi, SSRI and TCA.

MAO Inhibitors Serotonin symptoms


SSRI • Hyperpyrexia (fever)
TCA • Agitation
• Neuromuscular pains, myoclonus hyper reflexia
• Hypertension or hypotension
• Tremors, shivering
• Seizure
Tramadol • Coma, and death
Meperidine
Amphetamine
Dopamine
Cocaine
Methyldopa
Dextromethorphan
Caffeine
Lithium
SSRI
MAO Inhibitors
TCAs
St. John wort
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Serotonin syndrome is an acute condition due to increase serotonin levels and develops
within minutes to hours (typically within 6 hours) after starting a medication, increasing
the dose of a medication, or overdosing.

Signs and symptoms of Serotonin syndrome


Neurobehavioral confusion, agitation, seizures, coma,
Autonomic Hyperthermia (fever), diaphoresis (sweating), tachycardia,
hypertension, diarrhea
Neuromuscular Myoclonus, rigidity, tremor (shivering), ataxia, shivering,
nystagmus

Serotonin syndrome management. Management of the serotonin syndrome involves


discontinuation of the serotoninergic agent and supportive therapy. Most cases are mild
and resolve spontaneously within 24 to 72 hours. Cardiac arrest, coma, and multiorgan
system failure have been reported as consequences of serotonin syndrome.
Symptoms resolve quickly as soon as offending drug is discontinued. Pharmacist has to
contact the physician and tell the patient to withhold the serotoninergic agent.
Benzodiazepines, propranolol, and cyproheptadine, a serotonin antagonist, have been
used successfully.

Serotonin syndrome occurs with the following agents. All SSRIs, mirtazapine,
venlafaxine and moclobemide. The syndrome is possible when these agents are
combined with each other, MAOi, lithium, meperidine, pentazocine, and
dextromethorphan.

Discontinued syndrome (FINISH)


• Flu like syndrome
• Insomnia
• Nausea
• Imbalance
• Sensory disturbances
• Hyper activity

Wash out period.


Two SSRI’s or SSRI with TCA or MAOi should not combine. If switch from one SSRI to
other (SSRI, TCA or MAOi), waiting period required (washout period). All SSRIs have
washout period for 2 weeks, except fluoxetine (require 5 weeks).

Tricyclic Antidepressants (TCA). Amitriptyline, Clomipramine, Desipramine, Doxepin,


Imipramine, Maprotiline, Nortriptyline, Trimipramine.

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Tricyclic Antidepressants
Generic Brand Name Dose/Dosage form Tips
Name
Amitriptyline generics 10mg, 25mg, 50mg, 75mg,
100mg, 150mg tab, 10mg/ml inj.
clomipramine Anafranil
(generics)
desipramine Norpramin
(generics)
doxepin Sinequan 10mg, 25mg, 50mg, 75mg,
(generics) 100mg, 150mg cap
10mg/ml oral conc
imipramine Tofranil (generics)
maprotiline Generics
nortriptyline Aventyl (generics) 10mg, 25mg, 50mg, 75mg cap
10mg/5ml soln
trazodone Desyrel (generics) 50mg, 100mg, 150 mg, 300 mg
tab
trimipramine Surmontil
(generics)

Tertiary amine type TCAs Secondary amine TCAs


Dibenzocycloheptadiene (e.g. Dibenzocycloheptadiene
Amitriptyline), Dibenzapine (e.g. (e.g.Nortriptyline) dibenzapine (e.g.
Imipramine). Desipramine).
Higher anticholinergic SEs Less anticholinergic SEs than tertiary
NE&5HT NE>5HT

Mechanism. NE and 5HT reuptake inhibitor


Therapeutic use. Antidepressant, neuropathy pain, enuresis in children (bedwetting)
imipramine, anxiety disorder.
Side effects.
• Anticholinergic side effects constipation, blurred vision, urinary retention dry mouth.
confusion, and delirium
• Antihistaminic effect. Sedation, weight gain.
• CVD effects. Orthostatic hypotension, tachycardia (AV blockade)
• Sexual dysfunction
• Bone marrow depression
• Mania with manic depressive illnesses, lower seizure threshold

Overdose symptoms.
• Mydriasis
• Nausea
• Constipation
• Confusion, sedation

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• Sleepiness
• Palpitation (tachycardia)
• Dizziness
• Dry mouth
• Blurred vision
• Fever
• Overdose treatment. Contact physician immediately if any over dose symptoms
appears.
Contraindications. Avoid combining with MAOi and SSRI

MonoaminooxidaseInhibitors

The major route of metabolism of serotonin is oxidative deamination by MAO-A to the


unstable 5-hydroxyindole-3-acetaldehyde.

The monoamine oxidase inhibitors (MAOis) were the first class of compounds used to
treat depression. Patients, taking these drugs, must monitor their diet for tyramine, an
amino acid present in many foods that are fermented, aged or smoked. There are a
number of foods containing tyramine and some drugs must be avoided. Monoamine
oxidase is an enzyme, which inactivates the neurotransmitters, epinephrine,
norepinephrine and dopamine. These drugs inhibit the destruction of these brain
chemicals, which leads to increased concentrations of these neurotransmitters, which
may account for their antidepressant activity.
Generic Name Brand Name
phenelzine Nardil
tranylcypromine Parnate
.
MAO Inhibitors Phenelzine , and tranylcypromine
Mechanism • Irreversibly Monoamine oxidase inhibitors, permitting
neurotransmitter to escape degradation and therefore to
both accumulate within. Inhibit both MAO A and MAO B . Blocks
deamination in brain biogenic amines.
• Clorgyline. MAO A selective
• Selegiline. MAO B selective (used as antiparkinson drug)
Therapeutic use • Antidepressant, anti anxiety and narcolepsy
Side effects CVS. Orthostatic hypotension, tachycardia, arrhythmias, and
stroke.
CNS. Insomnia, CNS stimulations
Weight gain
Sexual dysfunction
Anticholinergic SEs less than TCA

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Drug interactions Avoid concomitant use of meperidine, Amphetamine, SSRI


TCA
Can cause Dopamine
Serotoninergic Cocaine
syndrome Methyldopa
Dextromethorphan, caffeine and lithium
Serotoninergic Serotonin syndrome symptoms includes: Hyperpyrexia
syndrome • Agitation
• Neuromuscular pains
• Hypotension
• Coma, and death
• Use washout period for 2 weeks before administering SSRI.
Hypertensive crisis Inhibitions of MAOi in brain causes catalyze oxidative
deamination of toxic substances such as tyramine. The tyramine
is present in foods such as fermented food cheese, wine etc.
Food to avoid Aged cheese (cheddar, blue and swiss), yogurt, smoked meats,
wine, liquor, yeast, raisins, chocolate, dry salami, pepperoni,
sausage, bananas, figs, tea and coffee.
Drugs sympathomimetics, ephedrine, pseudoephedrine.

Reversible Inhibitors of Monoamine Oxidase (RIMAs)

Moclobemide is short acting, reversible non selective inhibitors of monoamine oxidase,


the enzyme, which inactivates the neurotransmitters, epinephrine, norepinephrine and
dopamine.
Side effects. Headache, abdominal fullness, GI upset, dry mouth. Insomnia and dizziness.

Dual action antidepressants


Dual action • Bupropion
• Venlafaxine, desvenlafaxine, duloxetine
• Mirtazapine
• Trazodone
Bupropion • Serotonin (very little), dopamine and norepinephrine reuptake
inhibitor (sNDRI).
• SEs. Stimulant affect (tachycardia, agitation), aggravation of
psychosis, aggravation of seizure (reduce seizure threshold).
• 1st line treatment for major depression and also used for smoking
cessation (Zyban).
• Least sexual dysfunction and weight gain.
Venlafaxine • At lower dose (75 and 150 mg) it acts on 5HT only, higher dose 5HT
and NE. At higher dose 225 mg/day, it has cardiovascular side effects,
such as dose dependent hypertension. Stimulant affect. Anxiety,

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agitation, headache, and insomnia.


Mirtazapine • Alpha 2 antagonist and potent 5HT 2 receptor antagonist
• Increases release of nor epinephrine and serotonins.
• Side effects. increase appetite (weight gain), sedation
• Increase serum cholesterol levels.

Trazadone SNRI. SEs. Sedation, drowsiness, N&V, headache, dry mouth, priapism
rarely associated with serotonin syndrome. May be combine with SSRIs

Bipolar depression. Hallmark symptoms. Feeling excessive happiness (manic). and


low mood (hypomanic) and almost always includes episodes of clinical depression.

Lithium

• Mood stabilizer drug of choice to treat manic depressions


Therapeutic use • Used prophylactically in treating manic depressive patient and
to treat manic episodes. Bipolar depression (disorder) or mood
swings.
Pharmacokinetics • Steady state reached in 5 days. Low therapeutic window
• Renal excretion.

Therapeutic levels • Acute mania 1 to 1.5 mEq/liter. Maintenance bipolar disorder


0.6 to 1.2 mEq/liter. Increasing dose 300 mg/day raises level 0.2
mEq/liter.
Dose • Start 300 mg PO bid, effective dose 900 to 1800 mg per day
divided bid.
Side effects • Tremor
• Polydipsia
• Hypothermia or hyperthermia
• Weight gain and weight loss
• Nausea or vomiting
• Diarrhea
• Hypothyroidism and hyperthyroidism
Monitoring • Lithium serum levels
• Renal function tests
• Thyroid function tests
Drug interactions • Diuretics, NSAID’s, and ACE Inhibitors

Lithium toxicity

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Lithium is narrow therapeutic index. Drug serum levels >1.5 mEq/L associated with
lithium toxicity. These symptoms includes Cerebral symptoms. Drowsiness, in
coordination, dizziness, blurred vision, confusion. Autonomic symptoms. Tremors,
Change in heart rate or rhythm, fluid retention and CNS like seizures.

Initial Onset SEs Lithium Long term SEs Lithium Toxicity (Serum > 1.5 mEq/L)
N&V, GI upset, Dry mouth, Fine hand tremors Coarse hand tremor
Fine hand tremor, sedation Weight gain Muscle twitching
Muscle weakness Hypothyroidism Vomiting, severe drowsiness, confusion,
Polydypsia acne, psoriasis nystagmus, seizure,
Polyuria rash, alopecia Ataxia, cogwheel rigidity, coma, death
Nocturia Decreased libido
Arrhythmia: Non specific T-
wave changes, Nephrotoxicity
Nephrogenic
Monitor. Li, Na, Serum TSH, CBC, weight, CrCl (No LFT)

Antidepressant Summary
SSRIs • Most anorexic: Fluoxetine
• Most nauseating: Fluvoxamine
• Most weight gain: Mirtazapine
• Citalopram SE: Somnolence
• All SSRIs have common SE: Nausea
• Antidepressants with Less sexual dysfunction are Bupropion, Mirtazapine,
moclobemide
TCAs • Less hypotensive TCA; Nortriptyline
• Most Anticholinergic and sedative TCA; Amitriptyline
• Least sedative of TCA –Nortriptyline
• Less anticholinergic TCA—Nortriptyline
• Take medication daily
• Antidepressants must be taken for two to four weeks for a noticeable effect
• Continue to take medication even if you are feeling better
• Do not stop taking the antidepressant without checking with the physician

Tips

• SSRI onset of action is? → 2 to 4 weeks


• Fluoxetine washout period →5 weeks
• Depression with sexual dysfunction → Bupropion, mirtazapine, moclobemide
• Depression with insomnia →trazodone
• Depression with diabetes → SSRI
• Higher dose of venlafaxine (225 mg/day) have effect on → 5HT and NE
• TCA onset of action is → 2 to 4 weeks
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• A substance found commonly in fermented foods which can be toxic when MAO
inhibitors are used→ Tyramine
• MAO is classified as → Enzyme
• Renal dysfunction and dehydration → Increase lithium toxicity
• Lithium toxicity symptoms --> drowsiness, dizziness, confusion, blurred vision
change in heart rate.

Select TRUE OR FALSE

• Normal blood levels of lithium in adult is <1.5 mEq/L (true/false)


• Lithium concentration varies with Na+ ions (true/false)
• Li+ conc. increases with decrease Na+ (true/false)
• Li+ conc. decreases with Increase in Na+(true/false)
• NSAID decrease Na+ renal perfusion is less (true/false)
• Thiazides deplete Na+ (true/false)
• SSRI inhibit cytochrome CYP2D6 (T/F)
• Mirtazapine may cause higher weight gain (T/F)
• Avoid cheese with Phenelzine, tranylcipramine, isocraboxazide (T/F)
• Milk + MAOI ok take it (T/F)
• St. John's wort have antidepressant effect (T/F)
• Serotoninergic symptoms: fever, hypo or hypertension, agitation, diarrhea
neuromuscular pain, seizure, tremors.
• Drug of choice in bipolar disorders and manic depression --> Lithium
• Normal blood levels of lithium in adult is < 1.5 mEq/L (T/F)
• Lithium concentration varies with Na+ ions (T/F)
• ACEi (decrease Na+)can increase lithium serum concentrations in patients on lithium
therapy. (T/F)
• NSAID decrease Na+ renal perfusion is less (T/F)  Decrease lithium

Concurrent administration of thiazide diuretics (deplete Na+) may result in increase
lithium serum concentration. (T/F)
• Fluoxetine (SSRI) increase Li+ toxicity (T/F)
• Patient on antidepressants and shows with dilated pupil, may be due to TCA
overdose symptoms
• Take SSRI in the preferably morning (T/F)
• Take TCAs in preferably evening or bedtime (T/F)
• Bupropion, trazodone and mirtazapine have least sexual dysfunction (T/F)

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13
Benzodiazepine and Barbiturates
Benzodiazepines

Benzodiazepines (suffix "am") sleeping pill


Generic Name Brand Name Generic Name Brand Name
Alprazolam Xanax (generics) Temazepam Restoril (generics)
Chlordiazepoxide generics Triazolam Halcion (generics)
Diazepam Valium (generics) Clonazepam
Flurazepam Dalmane (generics)
Lorazepam Ativan (generics)
Oxazepam Generics

Benzodiazepine are minor tranquilizers are used to treat insomnia, epilepsy and anxiety.
Short acting Half life (H) Intermediate acting Half life Long acting Half life

Midazolam 1.8 Alprazolam 12 Diazepam 100

Triazolam 2 Lorazepam 15 Flurazepam 100

Oxazepam 8 Clonazepam 34

Temazepam 11 Chlordiazepoxide 100

Nitrazepam
Low hangover effect High hangover effect
Short half life Long half life
Faster withdrawal Slower withdrawal
symptoms symptoms

Benzodaizepines bind to specific, high affinity site in cell membrane, which are separate
from but adjacent to the receptor for GABA. The benzodiazepine receptor found only in
the CNS and their location parallels that of GABA neurons. The binding of
benzodiazepines enhances the affinity of GABA receptor for this neurotransmitter.
resulting in opening of adjacent chloride channel, in turn results in hyperpolarization
and inhibition neuronal firing.

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Benzodiazepine pharmacokinetics

• Long acting benzodiazepines includes diazepam (longest half life), flurazepam,


clonazepam, chlordiazepoxide.

• Intermediate acting. Alprazolam, Lorazepam, Oxazepam, temazepam and


nitrazepam.

• Short acting. Triazolam, midazolam (shortest half life). Short acing benzodiazepine.
have no phase I metabolism, or extra hepatic metabolism.

Other sedatives

• Therapeutic • Reduce anxiety, insomnia, sedative and hypnotic action,


use anticonvulsant action, and muscle relaxant action.
• Dependence • Physical and psychological dependence (at high doses).
Withdrawal symptoms upon abrupt discontinuation.
• Long acting withdrawal symptoms occurs after number of days.
• Short acting benzodiazepine associated with immediate
withdrawal symptoms if it is stopped abruptly.
• Withdrawal • Psychological. Confusion, anxiety, agitation, restlessness,
symptoms insomnia, and tension. Physical. tremors, seizures, tachycardia
and hypertension. Short and intermediate have severe
withdrawal symptoms than long acting. Rapid development of
tolerance and withdrawal symptoms occurs with short acting.

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Zopiclone, Zaleplon, Zolpidem


Mechanism. Acts on subset of benzodiazepine receptors however these drugs are not
benzodiazepine.

Zaleplon
• Short half life 1 hours. Headache. most common
• Reduce sleep latency, used in initial treatment.
• Act on benzodiazepine receptors. No anticonvulsant and muscle relaxant activity.

Zopiclone (Immovane)
• No anticonvulsant and muscle relaxant activity. Short half life 5 hours. Bitter metallic
taste and bad breath.
• Confusion is most common in elderly, do not accumulate, may cause less withdrawal
effects and less rebound insomnia. Less tolerance, minimal additive effect with
alcohol.

Zolpidem (Ambien)
• It is not a benzodiazepine. It is has no anticonvulsant properties, it does not have
muscle relaxing properties.
• Elimination half life is 3 hours
• SEs: NIGHTmares, Dizziness Agitation, GI upset, Headache.

Barbiturates

Barbiturates are used much less commonly than before. They are effective only for a
few weeks since they alter the length of time spent in R.E.M. sleep. They should only be
used for short-term therapy as sedative or hypnotics. Tuinal (a combination of
secobarbital and amobarbital), and secobarbital are reportable controlled drugs.
Phenobarbital is used to control seizure disorders, often in combination with primidone
and/or phenytoin.

Short acting
Amobarbital Long action
Ultra-short action
Secobarbital Phenobarbital
Thiopental
Pentobarbital
• Phenobarbitals: Long acting
• Amobarbital: short acting
• Butabarbital : short acting
• Pentobarbital : short acting
• Secobarbital: short acting
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• Thiopental.shortest acting (acts within second)


• Primidone: active drug is phenobarbital (metabolite)

Mechanism • Barbiturates are thought to interfere with sodium and potassium


transport across cell membranes. This leads to inhibition of the
mesencephalic reticular activating system. Polysynaptic
transmission is inhibited in all areas of CNS.
• Potentiate GABA action on chloride entry in the neuron, although
they do not bind at benzodiazepine receptor.
• Interfere with Na and K transport across membrane.
• Potentiate GABAA action on Cl- entry
• Do not bind to BZ1 and BZ2 receptors
Actions • Sedation (calming effect, reduce excitement), respiratory
depression
Metabolic • Barbiturates induce CYP450 in liver, reduces the effect of several
Enzymes drugs that depends on CYP450.
Therapeutic • Anesthesia, anti seizure, anxiety
use
Withdrawal • Addiction potential.
symptoms • Abrupt withdrawal of barbiturates may cause: Tremors, Anxiety,
Weakness, Restlessness, Nausea, Vomiting, Seizures, Delirium,
Cardiac arrest
• Withdrawal symptoms are more severe than opioids, can cause
death.
Poisoning • Severe depression of respiration
• Cardiovascular depression
• Shock like condition shallow and infrequent breathing
Poisoning • Artificial respiration
management • Purging stomach content
• Hemodialysis
Alkalinization of urine for phenobarbital
Barbiturates • Aminophylline
antagonist

Miscellaneous

Non-barbiturate Chloralhydrate
sedatives Alcohol
Antihistamine

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Buspirone
Chloralhydrate Tri chlorinated derivative of acetaldehyde
Antihistamine Doxylamine and other antihistamine are used as OTC treatment of
sleep disorders
Hydroxyzine
Mechanism H1 antihistamine with antiemetic activity
Therapeutic use Antihistamine, Antiemetic, Anxiety, Sedation prior to dental
procedure, Insomnia
Advantages Low tendency of habituation thus it is useful for anxiety in-patient
who a history of drug abuses.
Buspirone Buspirone acts on 5HT1a receptors and D2 receptors causes minimal
sedation, least addiction liability.
Disadvantage. slow onset of action
Advantage. Less interference with motor functions (helpful in
elderly).
Ethanol Ethanol is metabolized in liver, first to acetaldehyde by alcohol
dehydrogenase and acetate by aldehyde dehydrogenase. Ethanol has
sedative and antianxiety effect.

Ethanol

Alcohol dehydrogenase

Nausea and vomiting


Acetaldehyde headache
Hypotension
Thiamine decrease
bioavailability
Acetaldehyde dehydrogenase

Acetic acid

Tips

• Long acting benzodiazepine include →diazepam, cholordiazepoxide, clonazepam


• Intermediate acting benzodiazepine→oxazepam, temazepam, alprazolam, and
nitrazepam
• Short acting benzodiazepines → triazolam, midazolam
• Least addiction potential sedative drugs are non benzodiazepines
• Least hangover hypnotic benzodiazepine → triazolam, midazolam estazolam

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• Zaleplon and zopiclone act → benzodiazepine receptors


• Ethanol metabolizes to acetaldehyde by enzyme called? alcohol dehydrogenase
• Benzodiazepine that do not have phase I metabolism --> LOT
Find answers from the table:
1 Zopiclone 9. Chlordiazepoxide 17. GABA 24. Midazolam
2 Zaleplon 10. Oxazepam 18. Diazepam 25. Alcohol dehydrogenase
3 Zolpidem 11. Temazepam 19. Clonazepam 26. Aldehyde
dehydrogenase
4 Ginko Biloba 12. Nitrazepam 20. Flurazepam
5 Valerian 13. Alprazolam 21. Triazolam
6 Barbiturates 14. Flumazenil
7 Melatonin 15. Depression 22. Schizophrenia
8 Alcohol 16. Insomnia
A major inhibitory neurotransmitter in CNS( 17 )
• Long acting benzodiazepine include ( 9,18,19, 20)
• Intermediate acting benzodiazepine ( 10, 11,12, 13, )
• Short acting benzodiazepine include ( 21, 24 )
• The lipid soluble BDZ have faster onset such as…( 21, 24 )
• Benzodiazepine have no phase I metabolism or extra hepatic metabolism (LOT)
• Alcohol withdrawal symptom delirium is treated by ( 9.18.19.20 )
• Has high tolerance and addiction potential. ( benzodiazepine and barbiturates )
• Least addiction potential ( 1,2,3 )
• Least hangover hypnotic (1,2,3 )
• Non benzodiazepine drugs acts at Benzodiazepine receptors ( 1,2,3 )
• Used for Insomnia ( short and intermediate acting benzodiazepine )
• Used for memory enhance ( 4 )
• Alcohol oxidizes to acetaldehyde by enzyme called ( 25 )
• Acetaldehyde metabolizes to acetic acid by enzyme called ( 26 )
• Benzodiazepines are used in all of the following conditions except? (depression )
• Benzodiazepine antagonist ( 14 )
• Combination of these two can cause potentiating effect, and this result into
overdose effect of benzodiazepine symptoms such sedation, respiratory
deapression and hypotension. (opioids )
• Benzodiazepine, barbiturates and alcohol bind to GABA-A receptor, therefore 
have cross tolerance

SELECT TRUE OR FALSE


• Drug induced delirium caused by alcohol, benzodiazepines and barbiturates
withdrawal (T/F)
• Alcohol withdrawal symptom delirium is treated by long acting benzodiazepines
• Benzodiazepine has high tolerance, addiction potential and dependency. (T/F)
• Valerian is used for insomnia (T/F)
• Ginko biloba is used for memory enhancer (T/F)
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• Disulfiram inhibit aldehyde dehyrogenase(T/F)


• Overdose of benzodiazepine is treated by flumazenil (T/F)
• Barbiturate antidote is aminophylline (T/F)
• Elderly + BDZ  decrease clearance significantly (true/false)
• Liver disease +BDZ  decrease clearance significantly (true/false)
• Pregnancy + BDZ  neonates may develop withdrawal symptoms (true/false)

Abbreviation and Terminology


GABA Gamma-Aminobutyric Acid TCA Tricyclic Antidepressants
BZ Benzodiazepine PTSD Post-traumatic Stress Disorder
5HT 5-hydroxy tryptamine (Serotonin) OCD Obsessive Compulsive Disorder
OTC Over The Counter GAD Generalized Anxiety Disorder
CBT Cognitive Behavior Therapy SAD Social Anxiety Disorder
SSRI Selective Serotonin Reuptake
Inhibitor

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14
CNS Stimulants
These drugs have a stimulating effect on the CNS. Psychomotor stimulants are used to
treat children hyperactivity and attention deficit disorder. As a side effect, they decrease
appetite and for many years were used as appetite suppressants. Addiction and abuse
were side effects of taking these drugs.

These drugs are also used to treat narcolepsy, a condition where the patient lapses into
momentary sleep while sitting. This may occur as many as 20 times a day and is
dangerous if it were to happen while the patient is driving or operating machinery.

Amphetamines Adderall, Vyvanse, and Dexedrine


Methylphenidate Ritalin

CNS Stimulants

Psychomotor stimulants Psychomimetic stimulants/


Hallucinogenic "higher"

• Methylxanthines
• Cocaine • Phencyclidine (PCP)
• Nicotine • Lysergic acid (LSD)
• Amphetamines • Tetrahydrocannabinol (THC) or
dronabinol (Marijuana) (POT)
• Methylphenidate
• Sativex (pain reliever spray)

Psychomotor Psychological. Increase alertness & attention span, insomnia.


Physical. Decrease appetite, weight loss
Mechanism Excitement, euphoria, decrease feeling of fatigue.
Increase motor activity.
Cocaine Ester type local anesthetic. Blockade of voltage sodium ion
activated channel.
Side effects. Anxiety, depression, seizures, and cardiac
arrhythmias.

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Therapeutic use. Attention deficit hyperactivity disorder (ADHD).


Dexamphetamine Methylphenidate is drug of choice for attention deficit
Methylphenidate hyperactivity disorders.
(Ritalin) Psychological and physical dependency addiction potential
development of tolerance to euphoric and anorectic effects of
chronic use.
Less tolerant to convulsions and toxic CNS effect. All CNS
stimulants including Amphetamine is classified as controlled
drugs.
Methylxanthines Theophylline and tea. Caffeine or coffee, theobromine and cocoa
Psycho mimetic
stimulants
Mechanism Bring changes in thought patterns and mood pattern
Little effect on brainstem and spinal cord.
Hallucinogens Phencyclidine (PCP), Lysergic acid diethylamide (LSD).
Tetrahydrocannabinol (THC) or dronabinol (marijuana).

Amphetamine

Mechanism DA reuptake inhibitors


Amphetamine also stimulates DA release and MAO inhibitor.
Side effects same as cocaine

Methylphenidate

Brand names • Ritalin, Ritalin SR


Mechanism • A short acting, mild CNS stimulant.
Therapeutic use • To treat attention-deficit hyperactivity disorder.
Side Effects • Decrease appetite, insomnia and nervousness, abdominal pain,
headache, fatigue, palpitations and chest pain.
Drug-drug • Anticoagulants, anticonvulsants, and tricyclic antidepressants ↑its
interaction effects with methylphenidate.
• Antihypertensive will reverse its effects with methylphenidate
• Sympathomimetics and MAOis may cause severe hypertension
when used with methylphenidate.
Contraindication • Not recommended to children under 6 yrs.
Monitoring • Physician will assess growth and blood pressure at regular intervals.
Periodic checks of blood.
Call physician • Palpitation and chest pain
NOW
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Tips

1. Theophylline 2 Dextromethorphan 3 Dysphoria


4. LSD 5. Pseudoephedrine 6. MAO Inhibitors
7. Cannabinoids 8. Tylenol 1 9. Marijuana
10 Dimenhydrinate 11 Senna
• It is chemically related to xanthine, which contain purine ring (1 )
• Hallucinogens are  (4,7,9)
• Amphetamines should not be used with (6 )
• Euphoria opposite is OTC drugs that are abused  dimenhydrinate, all CNS
stimulants have addiction potential.
• What are the characteristics of cocaine overdose  dilatation of pupil, euphoria,
tachycardia, peripheral vasoconstriction, and hallucinations.

TRUE OR FALSE

• All CNS stimulants have addiction potential, physical dependency (True/False)


• In ADHD treatment it is important to emphasize non-pharmacological
recommendations such as taking breakfast every day and good sleep in night,
counsel parents and teachers. (True/False)
• Hallucinogens are psychomimetic drugs (True/False)
• CNS stimulants have been used as anorexic agents (True/False)
• Theophylline is chemically related to methylxanthine (True/False)

Abbrevation and Terminology


ADHD Attention Deficit Hyperactivity Disorder THC Tetrahydrocannabinol
PCP Phencyclidine CNS Central Nervous System
LSD Lysergic acid diethylamide

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Pharmacyprep.com Antipsychotic Drugs

15
Anti Psychotic Drugs
The antipsychotic agents are classed as major tranquilizers and are used to help people
with schizophrenia and other psychoses (major mental disorders). Psychotics symptoms
can be categorized as positive and negative symptoms. Positive. hallucination,
delusions, agitation, disorganized behavior. Negative. social withdrawal or isolation.
Cognitive: memory, judgment, and thinking.

The mesolimbic pathway in brain involved in integration of emotions, behaviors and


higher thought process. Increased dopamine neurotransmission in limbic pathway
results in +ve symptoms but not necessarily -ve symptoms, and cognitive symptoms.
Typical antipsychotics inhibits d 2 present in mesolimbic and extrapyramidal pathway.

Mechanism. Inhibition of dopamine action in the mesocortical and mesolimbic


dopaminergic pathways of the CNS or block post junctional dopamine D 2 receptors.
Atypical
(2nd generation)
Clozapine
Antipsychotics Risperidone
D 2 & 5HT 2 inh. Olanzapine
st Quetiapine
Typical (1 generation)
Paliperidone
Aripiprazole
D 2 inhibitors Ziprasidone

Low Potency Intermediate Potency


Chlorpromazine Loxapine High Potency
Methotrimeprazine Perphenazine Haloperidol
Zuclopenthixol Fluphenazine
Trifluoperazine
Flupenthixol
Pimozide
Thiothixene

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Psychotropic (neuroleptic) agents or Antipsychotic drugs or anti-schizophrenia drugs


Generic Name Mechanism of Action Side effects Dose/Dosage form
Chlorpromazine
Fluphenazine generic

Haloperidol Usual: 4–12 mg/day po


generics Divided in 1–3 doses/day
loxapine generics
pimozide Orap
thioridazine generics
thiothixene Navane
Hydroxyzine 10mg, 25mg, 50mg tab
10mg/5ml syrup
25mg/5ml susp
25mg/ml, 50mg/ml inj
Lithium

perphenazine generics
prochlorperazine
Stemetil (generics)
trifluoperazine generics
Second generation antipsychotics
quetiapine Seroquel Usual: 600 mg/day
nd
Olanzapine Usual: 10 mg im. If necessary 2
Zyprexa, Oral tab, Zyprexa im dose of 5–10 mg im may be given
injection, Zyprexa Zydis OD is 2 h after first injection
rapid dissolving tab.
Clozapine Inhibit D 2 , 5HT 2 , D 1-5 , Usual: 300–600 mg/day po
Clozaril, generics Max: 900 mg/day, Divided in 1–3
and H 1 , M, alpha 1-2 doses/day

Risperidone Risperdal Usual: 2–6 mg/day, Max: 8


Risperdal M (rapid dissolving mg/day
oral tab), Risperdal IM slow Frequency: one dose/day,
release injection preferably HS. Injection usual:
25–37.5 mg IM every 2 wk.
Ziprasidone
Paliperidone
Aripiprazole

Typical (haloperidol, loxapine, chlorpromazine, thioridazine) is effective in positive


schizophrenic symptoms. However, a typical or 2nd gen (clozapine, risperidone,
olanzapine, quetiapine) covers +ve & -ve schizophrenic symptoms. Olanzapine, not
effective for the treatment of resistance, and risperidone works for negative and
positive symptoms.

Potency (low, intermediate, high) as determined by dopamine D 2 -receptor binding


affinity.

Low potency (Chlorpromazine, Methotrimeprazine)


• Most commonly associated with sedation. The risk of tardive dyskinesia when
initiating treatment for typical.
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Intermediate potency (Loxapine, Perphenazine, Zuclopenthixol)


• Zuclopenthixol injectable FGA, long T 1/2. Do not use in antipsychotic naive patients.

High potency (Fluphenazine, Trifluoperazine, Flupenthixol, Haloperidol, Pimozide, and


Thiothixene).

Side effects
• CNS. extra pyramidal symptoms such as akathisia, tardive dyskinesia, acute dystonia
and parkinsonism. Alteration of temperature regulating mechanism (poikilothermy).
• CVS. Postural hypotension, and reflex tachycardia.
• Other. Sexual dysfunction and anticholinergic.
• Haloperidol with lorazepam im for acute phase, SEs EPS, QT c prolongation. DOC for
+ve symptoms delirium.
• Pimozide: SEs QT c prolongation with dose 8 mg/day (avoid use with sertraline).
• Haloperidol and phenothiazines have high TD, due to high effect on M-receptors
• Chlorpromazine; SEs QT c prolongation, cholestatic jaundice <1%, ~Seizures <1%

2nd generation antipsychotics (SGAs).Risperidone, olanzapine, quetiapine and clozapine,


paliperidone, ziprasidone, and aripiprazole . The 2nd gen. antipsychotics are strong
inhibitors of serotonin and dopamine. Due to serotonin receptor inhibition these drugs
have less extra pyramidal side effects, and more effective treatment of negative
symptoms.

Side effects
• Significantly reduced risk of EPS (acute dystonia, parkinsonism, akathisia and tardive
dyskinesia) than typical.
• Weight gain (greatest), hyperlipidemia, ↑ glucose abnormalities (diabetes).

Clozapine. Only antipsychotic with proven efficacy in treatment resistant schizophrenia.


MOA. Inhibit D2, 5HT2, D1-5, and H1, M (low affinity), alpha1-2. High affinity to 5HT2 and D2
receptors may produce atypical antipsychotic effect.
• SEs. agranulocytosis (1-2%), need for regular (weekly for first 6 mo) blood
monitoring WBC). Weight gain (greatest), and hyperlipidemia. Hyper salivation.
• Drug of choice for resistance psychosis only
• Improves –ve and +ve symptoms
• Advantage no EPS or TD.

Risperidone
• MOA. Inhibits D 2 and 5HT 2 , also has relatively high affinity at histamine H 1 and
adrenergic alpha 1 and alpha 2
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• Improves –ve symptoms and + ve symptoms


• SEs. Hyperprolactinemia (dose related), EPS, weight gain, dizziness, diabetes
(hyperglycemia) but least likely dyslipidemia.
• NO WBC is monitored.

Olanzapine (Tab and RD tab)


Inhibit D 2 , 5HT 2 , D 1-5 , and H 1 , M, alpha 1-2 . High affinity to 5HT 2 and D 2 receptors may
produce atypical antipsychotic effect.
• SEs. Sedation, restless, Weight gain (greatest), hyperlipidemia, EPS (especially
akathisia), diabetes.
• Use for acute phase. Do not combine with parenteral BDZs (cardiac & respiratory
problems).
• Olanzapine orally disintegrating (Zyprexa zidis). Approved for acute treatment of
mania.

Quetiapine
MOA. Most effectively binds 5HT 2a , H 1 , alpha 1 . alpha 2 in brain and has low affinity
to D 2 receptors.
• Least EPS
SEs. Hyperlipidemia, ↑triglycerides (17%), ↑ cholesterol (11%), hypothyroidism,
akathisia>2%, and diabetes.

Paliperidone. Active metabolites of risperidone. This is not metabolized in liver thus


have low drug interactions. Available as PO daily dose (taken in morning due to
insomnia SE), and prolong released injectable suspension.

Ziprasidone. Agonist of 5HT 1A and moderate inhibition of synaptic reuptake of 5HT and
NE. Thus ziprasidone has potential efficacy in –ve symptoms and depression.

Aripiprazole. partial agonist at 5HT 1a and D 2 receptors. Thus has potential efficacy in –ve
symptoms and depression. Available oral single daily dose. Taken with or without food.
• D 2 inhibitory effect effective produce more pharmacological benefit to treat positive
symptoms.
• 5HT 2A inhibitory effect effective in producing more pharmacological benefit to treat
negative symptoms.

Pharmacological D2 5HT 2 M1 H1 Alpha 1 Alpha 2 5HT 1A QT pro


effects

Clozapine + (low) +++ +/- (low) + + +


Olanzapine + +++ + + + +
Risperidone + +++ + + + +
Quetiapine + (low) +++ Low + + + +
Paliperidone + +++ + + + +
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Ziprasidone + +
Aripiprazole + +
Ziprasidone. moderate 5HT and NE reuptake inh.

• Extra pyramidal symptoms (EPS). "PATD"


• Parkinson’s like symptoms. Tremors, Rigidity, Akinesia, Postural instability.
• Akathisia. motor restlessness (cannot sit still)
• Tardive dyskinesia. Inappropriate postures of neck, trunk and limbs.
• Dystonia. Involuntary contraction of muscles (spasm)
• Neuroleptic malignant syndrome (NMS). This can occur within first few weeks of
therapy. It is characterized by the acute onset of hyperthermia (fever), muscle
rigidity, tremor, tachycardia, mental status changes and diaphoresis.
• NMS can occur frequently in patient receiving FGAs, injectable or depot and patient
are dehydrated, with physical exhaustion.

Antipsychotics
Bp/ BG LFT BMI WBC TG/ Q-T others
pulse TC
Clozapine + ++ + +++ + + Cardio toxicity, Sedation, weight gain,
hypersalivation. (least anticholinergic)
Risperidone + + +++ + + Akathisia, Mild sedation
Olanzapine ++ + +++ + Sedation, weight gain
Quetiapine + + + +++ + Sedation
Ziprasidone ++ Sedation, insomnia, nausea
ECG Weight neutral
Paliperidone Insomnia
Aripiprazole + Insomnia & sedation, dose dependant somnolence,
weight neutral
Haloperidol +

Comparison of anti psychotic drug side effects.


st nd
Typical (1 generation) Atypical (2 generation)
High sedation (except Haloperidol, Fluphenazine) Low sedation (risperidone)
Low weight gain High weight gain (clozapine)
High tardive dyskinesia (↓D 2 ) Low tardive dyskinesia – clozapine
High anticholinergic side effects Low anticholinergic side effects
High sexual dysfunction Low sexual dysfunction (quetiapine)
High EPS (↓↓D 2 ) Low EPS
Neuroleptic malignant syndrome Neuroleptic malignant syndrome

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Tips

• 2nd gen increase risk of lipids? Quetiapine, olanzapine and clozapine


• A patient experiencing social withdrawal --> olanzapine, risperidone
• Clozapine mechanism of action --> act on 5HT, D, M, H 1 , and α
• Clozapine side effects -->Agranulocytosis
• Clozapine monitoring -->CBC or WBC
• Risperidone monitoring include --> BP, cholesterol (No CBC)
• A patient have social withdrawal, what is the drug of choice --> 2nd gen
antipsychotics.
• Treatment of extra pyramidal symptoms --> benztropine, and trihexphenidyl
• 1st generation 4 to 8 weeks no response, change to 2nd generation. For 2 episode,
continue for 2 to 5 yrs

TRUE OR FALSE
• Least extra pyramidal symptoms clozapine, quetiapine (True/False)
• Highest EPS haloperidol, fluphenazine (True/False)
• A patient experiencing hallucination high potency haloperidol, fluphenazine
(True/False)
• 1st generation 4 to 8 weeks no response, change to 2nd generation. (true/false)
• Schizophrenia is characterized by  long standing paranoid delusion. (true/false)
• 2nd generation drugs treatments covers +ve and -ve symptoms (True/False)
• Schizophrenia is characterized by hallucination, social withdrawal etc.
(True/False)
• Metoclopramide and chlorpromazine is low potency 1st generation
antipsychotic (True/False)
• Tardive dyskinesia is caused by antipsychotic drugs side effects (True/False)
• Tardive dyskinesia symptoms involuntary movement trunk, neck, and jaws
(True/False)
• For resistance schizophrenia drug of choice clozapine (True/False)

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• Orthostatic hypotension is SE of antipsychotics cause due to alpha1 receptors


blockade (can cause additive effects with other antihypertensive drugs)
(True/False)

Abbreviation and Terminology


EPS Extra pyramidal symptoms FGA First generation antipsychotics
5HT 5-hydroxytryptamine (serotonin) SGA Second generation antipsychotics
TD Tardive dyskinesia SEs Side effects
DIs Drug Interaction CIs Contraindications

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16
Antiepileptic Drugs
Antiepileptic drugs by mechanism of action

Reduces NMDA Potentiate Reduce Na+ Reduce Ca2+ current


Receptor activation GABA receptors conductance in through T- channels
hyperactive
neurons

Felbamate
Phenobarbital Carbamazepine Ethosuximide
Topiramate
Primidone Phenytoin
Fosphenytoin
Diazepam Lamotrigine
Vigabatrin
Topiramate Valproate
Tiagabine Valproic acid
Gabapentin?

After each depolarization, Na+ channel adopt an inactive state and remain refractory
to reopening for a period of time. While channels are unable to open rapid repetitive
firing is diminished, and spread of electrical seizure to adjacent cells is suppressed.

Generic Name Brand Name Generic Name Brand Name


Carbamazepine Tegretol (generics) clobazam Frisium (generics)
Phenytoin Dilantin clonazepam Rivotril (generics)
Gabapentin Neurontin (generics) diazepam Valium (generics)
vigabatrin Sabril lorazepam Ativan (generics)
phenobarbital Generics primidone Mysoline (generics)
divalproex Epival (generics) lamotrigine Lamictal (generics)
valproic acid Depakene (generics)

Seizure. Abnormal or burst electrical discharge from local areas and spread around the
brain adjacent areas. Condition like hypoxia, uremia, bacterial meningitis, genetic
predisposition and drugs such as cocaine, penicillin G, and anticholinergics can produce
seizure. Withdrawal from chronic use of alcohol, barbiturates, benzodiazepines and
most anti seizure medication can also lead to seizures.

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Epilepsy. Epilepsy is a disorder of the brain characterized by recurrent and spontaneous


seizures, which are self-limiting. Which usually recur unpredictably.
Convulsions. Involuntary contractions (abrupt) of voluntary muscles.
Seizures can be characterized by clinical symptoms and Electroencephalograpy (EEG),
computerized tomography (CT), and magnetic resonance imaging (MRI).

Carbamazepine

Mechanism By blocking Na channels reduces abnormal impulses in brain.


Therapeutic use To treat partial seizures and tonic clonic seizures, trigeminal
neuralgia and bipolar disorder. Avoid in absence seizure (petit-mal),
because it can exacerbate or precipitate.
Side effects • Rash, ↑ liver enzymes, neutropenia, aplastic anemia
• Chronic. drowsiness, vertigo (the sensation of dizziness and a
confused, disoriented state of mind).
• Idiosyncratic. Rash, aplastic anemia, Stevens Johnson syndrome
(skin hypersensitivity reactions).

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• Acute intoxication. Coma, hyperirritability, convulsions and


respiratory depression.
Management • Start low and increase gradually. CR may be better tolerated,
improve compliance. May upset stomach, if so take with food or
milk.

CYP3A4 inhibitors Diltiazem, erythromycin, ↑ clearance of OCPs, Warfarin,


Isoniazid, propoxyphene, and cimetidine Risperidone, TCAs

Carbamazepine clearance is ↓ by CYP3A4 Inh Carbamazepine induce


thus increase plasma levels 1A2, 2C9, 2C19, 3A4

CBZ is principally metabolized by CYP3A4 and also induce CYP3A4 (autoinducer).

Phenytoin

Phenytoin decreases the sodium content of nerve in the brain and thereby decreases
the hyperexcitability of the cells that are involved in initiating seizures.

Mechanism • Stabilizes neuronal membranes to depolarization by


decreasing flux of Na+ ions into neurons in the resting state or
during repolarization.
Therapeutic use • Partial seizures and tonic clonic seizures
• Status epilepticus caused by recurrent tonic clonic seizures
• NOT effective for absence (petit-mal) seizures.
Side effects • Idiosyncratic: Skin rash and Steven Johnsons syndrome
• Gingival hyperplasia (reversible), encephalopathy, blood
dyscrasias, Nystagmus, hirsutism and birth defects like cleft
palate.
Pharmacokinetics • Non linear pharmacokinetics (toxic concentration of are
between (7.5 mcg/ml to 20 mcg/ml). Oral absorption is slow
(extended release phenytoin sodium). Chronic administration
is always oral. The elimination half life for phenytoin in
children increases with age due age dependant decrease rate
of metabolism.
• Metabolized by hydroxylation in liver. At low doses half life is
24 hours. As dose increase hydroxylation becomes saturated,
and can produce large in increase plasma concentration,
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resulting in drug induced toxicity.


• Phenytoin accelerates metabolism of folic acid
Dosages • Chewable tablets (100%), suspension (100%) capsules (92%),
and i.v (92%).
Phenytoin metabolism is inhibited by Sulfonamide, Isoniazid, Chloramphenicol,
Dicumarol.
Phenytoin metabolism is stimulated by Carbamazepine.

Phenobarbital

Primidone Metabolite of phenobarbital


Mechanism
Therapeutic use Epilepsy, insomnia, and anxiety. Sedative drug when combined
with other drugs it is used in anxiety associated with menopausal
symptoms.
Side Effects Unwanted sedation, Skin rash (Phenobarbital), Depression and
libido (Primidone).
Advantage Long t1/2
Disadvantage Metabolism inhibited by valproic acid
Tips Declining use because of side effects

Clobazam

Mechanism Benzodiazepines. Effects gamma aminobutyric acid (GABA) receptors,


high-affinity benzodiazepine receptors and chloride channels.
Therapeutic Useful as “add on” for patients nearly seizure free.
use
Side effects Ataxia
CNS. Insomnia, depression, dizziness, drowsiness, lightheadedness.
Tolerance to therapeutic effects.
Management Advantage. Very safe, rapid onset.
Disadvantage. Tolerance (initially good response then no control for
seizures). Not recommended for use in patients with major depressive
disorder or psychosis in which anxiety is not a prominent feature.
Abrupt withdrawal may lead to symptoms such as anxiety, insomnia,
psychomotor agitation, GI discomfort.
Dose 5 to 15 mg/day.

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Ethosuximide

Mechanism Inhibit Na+ and K+ adenosine triphosphate system (Na+, K+ ATPase).


Therapeutic The drug of choice to treat petit mal (absence seizure)
use
Side effects GI. nausea, anorexia, vomiting, CNS. drowsiness
Management Advantage. Few drug interaction
Disadvantage. For absence seizure only, no protection for generalized
tonic clonic.
Gabapentin

Mechanism Analog of GABA, however, this do not act as GABA mimetic and
does not block Na ion channel. May encourage production of or
discourage degradation of GABA.
Therapeutic use Partial seizures, and trigeminal neuralgia and neuropathic pain.
Side effects When initiating therapy CNS. somnolence, sedation, fatigue,
dizziness vision problems and ataxia.
Advantage Safe, well tolerated, not metabolized, can be used in liver failure,
No interaction with oral contraceptives pills.
Disadvantage Not for generalized seizure. Administration with aluminum,
magnesium antacid may ↓ bioavailability.
Tips Very expensive at high doses, best used as “add on drug”.

Lamotrigine

Mechanism Inhibit glutamate and aspartate release and blocks sodium channels
and prevents repetitive firing.
Therapeutic Anticonvulsant
use
Side effects Dose dependant rash. CNS. Somnolence, dizziness, insomnia
Advantage Broad spectrum, no enzyme induction, some patients more “alert”.
Disadvantage Metabolism inhibited by valproic acid.
Only available in oral form
Comment Very expensive at high doses

Topiramate

Mechanism Enhances GABA activity antagonizes excitatory amino acid


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(glutamate).
Side Effects Cognitive dysfunction, headache, kidney stones and weight loss.
Management Limit use
Advantage Broad spectrum, safe, few drug interaction, weight loss
Disadvantage ↓ efficacy of OCPs, and expensive.

Valproic Acid

Valproic acid and divalproex are related chemicals. Divalproex is a mixture of valproic
acid and sodium valproate. In the body they are metabolized to separate compounds,
and both exert anticonvulsant effects.

Mechanism It may enhance GABA action at inhibitory synapses.


Therapeutic Drug of choice for generalized seizures. Most effective in treatment of
use myoclonic seizures.
Side Effects Most common GI. Nausea, anorexia, indigestion,
tremor, hair loss (alopecia), and edema. Menstrual irregularities and
teratogenicity. Photosensitivity.
Idiosyncratic. skin rash, Steven Johnson’s syndrome, hepatoxicity,
blood dyscrasias.
Pregnancy. Neural tube defects.
Monitoring Liver function test, complete blood count.
Advantages. Low incidence of rash.
No interactions with oral contraceptives
Disadvantage. high drug interaction (but do not reduce OC’s efficacy).
Comment. Drug of choice for patients with mixed generalized seizures,
absence, myoclonus, tonic seizure, and not for partial seizure.
Vigabatrin

Mechanism Inhibits GABA-Aminotransferase,the enzyme responsible or degrading


GABA in the synapse. It does prolongs the sojourn of GABA molecules
and promotes binding in this way.
Side Effects Low incidence of psychosis
Depression
Visual problems
Comment: Limited use because of visual defects
Advantage Well tolerated, few drug interactions, does not cause skin, blood, liver
adverse effect
Disadvantages May worsen absence seizures, myoclonus. Expensive when using high
doses.
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Pregnancy

Patient taking antiepileptic drugs phenytoin, CBZ, and valproic acid should take folic acid
supplements.

Antiepileptic Drugs
Serum Elimination LFT Rash Fever BMI Folic acid
level
Carbamazepine + hepatic + + + ↓absorptio
n
Phenytoin + hepatic + + + ↓absorptio <0.45 mg
n
Valproic acid + hepatic +++ + +
Lamotrigine 90% hepatic +++ Dose related
↑ dose 125 mg % excreted rash
gradually unchanged
Ethosuccimide hepatic
Clobazam hepatic
Gabapentin >90%renal
eliminated
Pregabalin
Topiramate 5-70% renal red eye,
glaucoma (↑IOP),
kidney stones.
Vigabatrin 90% renal
Phenobarbital ↓absorptio
n
• Folic acid ↓absorption can cause deficiency. In pregnancy this can lead to Spina bifida. Vitamin K is
routinely given to all new born at delivery to prevent hemorrhagic disease.
• If skin rashes occurs contact your physician immediately.

Tips

1 Topiramate 2 Vigabatrin 3 Phenytoin


4 Clobazam 5 Valproic 6 Diazepam IV
7 Lamotrgine 8 Gabapentin 9 Phenobarbital
10 Xerostomia 11 Clonazepam 12 Carbamazepine
13 Sialorrhea 14 Chlorhexidine
• Drug that interferes with thyroid function test. (12 )
• Stimulates hepatic microsomal enzymes (HME). (12)
• What drug should be avoided in petit-mal (absence seizures)? ( 2,3, 12)
• Overdose of this drug has zero order (saturated) kinetic. ( 3 )
• Gingival hyperplasia associated with phenytoin is treated by mouth hygiene and…
(14)
• A mouth rinse used for the treatment of gingivitis, stomatitis and mucositis. (14 )
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• These drugs decrease efficacy of oral contraceptives. (3,12,11,1 )


• Drugs with no interaction with oral contraceptives. (8, 5 )
• Drug that cause weight loss, and kidney stones. (1 )
• Antiepileptic drugs that have least drug interactions with OCP. (gabapentin, valproic
acid )
• Available as suspension, iv, chewable tablets and capsule. ( 3)
• Available as chewable tablets and liquid. ( 3 )
• A drug that has a high tolerance. (clonazepam, clobazam, diazepam)
• These drugs have low teratogenic effect (ethosuximide).
• Dryness of mouth. ( xerostomia )
• Excessive saliva outside the mouth. (siallorhhea)
• Vigabatrin + carmazepine+phenytoin? worsen absence seizures ( )
• An antiseptic and disinfectant. (14)

TRUE OR FALSE
• Carbamazepine interferes with thyroid function test (True/False)
• Phenobarbital and phenytoin stimulates CYP 3A4 (True/False)
• Avoid phenytoin and carbamazepine in absences seizure (True/False)
• Phenytoin have gingival hyperplasia and nystagmus side effects (True/False)
• Gingival hyperplasia associated with phenytoin is treated by mouth hygiene and
chlorohexidine oral rinse. (True/False)
• Chlorhexidine is used for treatment of gingival hyperplasia (True/False)
• Carbamazepine, phenytoin, clonazepam are used for partial seizures (True/False)
• Gabapentin, and valproic acid, have no interaction with oral contraceptives
(True/False)
• Topiramate cause weight loss (True/False)
• Gabapentin has least drug interactions, specially with oral contraceptive pills
(True/False)
• Phenytoin available as iv (92%), capsules (92%), suspension (100%) and chewable
(100%) (True/False)
• Carbamazepine available as IR tabs and SR tabs (True/False)
• Clobazam is a benzodiazepine has high tolerance (True/False)
• Gabapentin and lamotrigine GABA analogs (True/False)
• Xerostomia is dry mouth (True/False)
• Sialorrhea excessive saliva (True/False)
• Vigabatrin + carbamazepine and phenytoin are used for partial seizures (True/False)
• Phenytoin blood levels monitored for 10 to 20 mcg/ml (True/False)
• List the monitoring parameters for phenytoin.-->blood levels
• Nystagmus is rapid eye movement (True/False)

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Abbreviation and Terminology


CR Control release LFT Liver Function Test
GABA Gamma-Aminobutyric Acid OCP Oral contraceptive pills
CBC Complete Blood Count

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17
Dementia
Dementia is a declined in mental ability that usually progresses slowly, in which
memory, thinking, judgment, and ability to pay attention and learn is impaired, and
personality may deteriorate.
• Risk factors of Alzheimer’s disease family history, age, and CVD.
• Symptoms of Alzheimer’s disease? Slurred speech, reduced cognitive functions,
reduce sexual function, and decrease in judgment and skills.

Classification of dementia
• Mild. Forgetting daily activities. Example taking medicines, tel. phone number,
finances, paying bills and directions.
• Moderate. Forgetting personal activities bathing, dressing, eating (remember upon
reminders).
• Severe. Forgetting personal activities but cannot recall upon reminders.
• Terminal. Patient must be fed, immobile and mute.

Reversible acetyl cholinesterase inhibitor

Nonselective Selective

Galanthamine Rivastigmine
Donepezil
(relatively selective)

Donepezil
Mechanism • Centrally active reversible, non competitive. It selective and have
greater affinity for AchEi in brain than periphery. Little or no
hepatotoxicity.
• Reduces the hydrolysis of acetylcholine, increasing the amount
available in the synaptic cleft.
Side effects • GI effects. Nausea, vomiting and diarrhea.
• CNS effects. Fatigue, insomnia, headache
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• Other effects. Muscle cramps, anorexia, and difficulty in passing


urine.
Dosage • Daily one dose in the morning or evening
• Initial 5 mg/day, target 10 mg/day adjust dose after 4 wk
Advantage • Toxicity may be ↑ by inhibitors of CYP2D6 or CYP3A4 (e.g.
paroxetine, erythromycin, prednisone, grapefruit juice, nefazodone).
Drug and • Effectiveness may be ↓ by inducers of CYP2D6 or CYP3A4 (e.g.
Drug carbamazepine, phenytoin, rifampin).
Interactions
Monitor • Periodic checks may be performed to see benefit of drug.

Rivastigmine

Mechanism • Inhibits non specific butyrylcholinesterase and reversible


acetylcholinesterase or centrally selective arylcarbamate AchEi,
• It has short half life of 2 hours, but able to inhibit AchEi up to 10
hours. Because of slow dissociation of carbamate enzyme it is
referred as pseudo-irreversible AchEi.
Side effects • Weight loss due to reduced appetite. Nausea, abdominal pain
• Depression, agitation, confusion, drowsiness, dizziness
• Weakness, trembling, sweating, malaise, convulsions (rare).
Therapeutic • Effective in Lewy body dementia.
use • Treatment of Lewy body dementia. Avoid antipsychotics
• Acute pain such as dysmenorrhea (painful periods).
Dosage • For rivastigmine, the initial dose is 1.5 mg PO BID, and can be
doubled to 3 mg PO BID after 30 days, which is the minimum
effective dose.
Galanthamine

Mechanism Selective, competitive, reversible acetylcholinesterase inhibitor and also


enhances the action of acetylcholine on nicotinic receptors.
Therapeutic Effective in Alzheimer’s and vascular dementia.
use
Side effects Nausea, vomiting, abdominal pain, diarrhea, indigestion, decreased
appetite and weight loss, headache, dizziness, tiredness, sleepiness or
sleeplessness, confusion, runny nose, urinary tract infection, falls.
Dosage 16- 32 mg bid.

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Tips

• Alzheimer's dementia occurs due to --> decrease in acetylcholine


• Amnesia  Short time loss of memory
• Donepezil and rivastigmine and galantamine all have anorexia SEs.
• Drug of choice for Alzheimer's is --> donepezil.
• Memantin --> N-methyl D-aspartate (NMDA) receptor antagonist.
• Selective reversible acetylcholinesterase inhibitor (donapezil and rivstigmine)
• Non-selective reversible acetylcholinesterase inhibitor. (Galantamine )
• N-methyl D-apartate (NMDA) blockers (non competitive) ( memantine )

SELECT TRUE OR FALSE


• Donepezil and rivastigmine and galantamine all have anorexia SE. (True/False)
• Delirium is short time agitation, and lack of judgment and memory loss (True/False)
• Amnesia is short time memory loss (True/False)
• Galantamine is classified as non selective acetyl cholinesterase inhibitor (True/False)
Terminology
Delerium is a potentially reversible condition that usually comes so sudden. The person has diminished
ability to pay attention and often confused, disoriented, and unable to think clearly.
Delirium tremens: This condition is induced by chronic alcohol and benzodiazepine withdrawal.

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18
Anti-Parkinson’s Drugs
Parkinson's is a condition, which is characterized by muscle tremors at rest, muscle
weakness, emotionless facial expressions, increased sweating and salivation,
disturbances of motion and increased postural balance difficulty. These patients have a
deficiency of the neurotransmitter, dopamine, allowing acetylcholine to dominate.

DA COMT DA MAOi- B Anticholinergic Anti-viral


precursor inhibitors agonist inhibitor drug

Benztropine
Peripheral dopa Trihexphenidyl
Entacapone Selegiline Amantadine
decarboxylase
Tolcapone Rasagiline
inhibitor

Levodopa Carbidopa D1D2 Non selective


D2 selective
Pramipexole Ergots. Bromocriptine
Ropinirole
Combination
*Sinemet

Generic Name Trade Name Generic Name Trade Name


Levodopa Sinemet Levodopa/carbidopa Sinemet CR
Bromocriptine Parlodel Levodopa/benserazide
Pergolide Permax Selegline Deprenyl
Pramipexole Mirapex Entracapone Comtan
Benztropine Benztropine Tolcapone Tasmar
Domperidone Motilium Amantadine Symmetrel

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Anti-Parkinson’s drugs pharmacology


Brain
GIT Peripheral tissues

3-O-Methyldopa 3-O-Methyldopa

Tolcapone
Entacapone COMT
Tolcapone
Striatal neuron

Levo Levodopa Levodopa


dopa

Carbidopa
Dopamine

Dopamine

D1 and D2 Dopamine
Bromocriptine and
receptors
Pramipexole
Ropinirole
MAO-B
Selegiline
Rasagiline
Dihydroxyphenylacetic
Acid (DOPAC) + H2O2

Levodopa preparations
Mechanism. Levodopa, a dopamine precursor that is converted to dopamine in the
brain by with enzyme dopa decarboxylase, appears to correct akinesia, rigidity and
tremors of Parkinson’s disease by the
formation of dopamine at the nigro
striatial dopaminergic site. Concept!
Side effects. The most common SEs of 1) Wearing off (end dose effect)
levodopa therapy is gastric upset Nausea, 2) On-off motor fluctuation
vomiting, orthostatic hypotension,
dyskinesia, hallucinations, confusion Long
term use of Levodopa/carbidopa therapy can produce mydriasis & precipitation of
glaucoma, melanoma.
Pharmacokinetics. High protein content meals interfere with transport of levodopa into
CNS. Levodopa should be taken on an empty stomach, typically 45 min before a meal
Wearing off. Short duration response or "end dose" effect. The motor complications
include "off periods" of immobility or greater severity of the other parkinsonism

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symptoms and various abnormal movements. This is due to decrease synthesis and
storage of dopamine generated from endogenous or exogenous levodopa.
On-off fluctuations. Most severe form of wearing off effect (abruptly freezes).

Anticholinergic drugs. Benztropine mesylate, Biperidin HCl, Ethonopropazine HCl,


procyclidine HCl, trihexyphenidyl HCl.
SEs. Anticholinergic, avoid in elderly can cause aggravation of glaucoma, memory
impairment.

Benztropine

Therapeutic use Direct acting D2 agonist, antimuscarinic with some DA reuptake


inhibitor.
Side effects Anticholinergic side effects, avoid in elderly, aggravation of
glaucoma, memory impairment. Drowsiness, Dizziness, dyskinesia,
hallucinations and confusion.
Contraindicatio Pregnancy, inhibits the lactation, should not be used in breast-
ns feeding mothers, hypertension.
Counseling Take drug with food, snacks, milk to reduce GI side effects

Antiviral Agent
Antiviral agent with anti-Parkinson properties. Indicated in drug induced PD because
levodopa will reverse the beneficial effect of the drug.
Side effects: anticholinergic side effects, hallucinations, edema of feet & ankles.

Amantadine (Symmetrel)

Mechanism Prevent damage to dopaminergic neurons acting as (NMDA) N-


Methyl-D-Aspartate receptor antagonist.
Therapeutic use Indicated in Parkinson's disease and also for prevention and
treatment of influenza A viral infections.
Drug-Drug Amantadine may add to the effects of anticholinergic drugs.
interaction
Side Effects Anticholinergic side effects, hallucinations, edema of feet &
ankles.

COMT inhibitor (Catecholamine O-Methyl transferase). Entacapone and Tolcapone.


Prolong the action of levodopa by inhibiting the methylation and
subsequent inactivation of dopamine.
SEs. Dyskinesia, nausea, sleep disorders, anorexia, severe diarrhea, hallucinations
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COMT inhibitors are used as an adjunct to L-dopa and carbidopa to reduce response
fluctuation.
The dyskinesia or induction of hallucination can be managed by reducing
the dose of levodopa.

Entacapone

Mechanism Prevent the conversion of levodopa to homovallinic acid in the


peripherally, allowing more levodopa to cross the blood-brain
barrier and resulting in greater production of dopamine in the
brain.
Side Effects Dyskinesia, sleep disorders, hallucinations, nausea, diarrhea, and
anorexia.

Entacapone is preferred over tolcapone which is associated with hepatotoxicity.

Direct acting dopamine agonist. (Bromocriptine, Pergolide, Pramipexole, Ropinirole)


SEs. Nausea, vomiting, orthostatic hypotension, psychosis, pleural fibrosis (chest x ray
before initiating therapy). Ergot alkaloids are bromocriptine and pergolide.

Bromocriptine

Mechanism • Direct acting non-selective D1 and D2 agonist. Inhibiting the secretion


of the hormone prolactin from pituitary gland.
Therapeutic • Relieving symptoms of parkinsonism.
use • Treatment of conditions associated with prolactin production such
as female infertility and male infertility and impotence.
• Treat benign breast condition and some menstrual disorder.
Drug-Drug • Antipsychotics oppose the action of bromocriptine and increase the
interaction risk of parkinsonism.
• Using bromocriptine with ephedrine, Pseudoephedrine, and
phenothiazines, Erythromycin and other macrolide antibiotics may
lead to severe adverse effects.
Contraindica • Pregnancy, hypertension.
tion
Side Effects • Drowsiness, dizziness, dyskinesia, hallucinations and confusion.
• Pleural fibrosis (do chest X-ray before initiating).
• Erythromelalgia (painful red swelling of the legs).
• Used for the treatment of neuroleptic malignant syndrome and is
approved for hyperprolactinemia.
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• Inhibits the lactation, should not be used in breast-feeding mothers.


• Take drug with food, snacks, milk to reduce GI side effects.

Pergolide

Mechanism Direct acting D2 agonist, efficacious and longer effective than


bromocriptine.
Therapeutic use Used with L-dopa when L-dopa not active alone

Pramipexole
Mechanism • Selective D2 receptor agonist.
Therapeuti • Mild to moderate Parkinson’s disease and to manage motor
c use
fluctuation.
Side Effects • Dizziness, insomnia, lightheadedness. Rarely it can cause
hallucinations or dyskinesia. Sudden onset of sleep
Monitoring • Regular monitoring of your Parkinson's symptoms, and report any
changes to the physician.

MAO-B inhibitor. Selegiline, Rasagiline


• Selective inhibitor of MAO type B at low doses. Indicated in early stages of PD and as
an adjunct to levodopa in patients who exhibit deterioration in their response.
• SEs: insomnia, confusion, hallucinations, anorexia, diarrhea, increase dyskinesia.

Summary of anti-Parkinson’s drugs


Drug Role in Parkinson’s disease Common Adverse Effects
Levodopa/Carbidopa or Mainstay of therapy Nausea, hypotension, hallucinations “wearing
Levodopa/benserazide off’, “on-off”, dyskinesia (after 3-5 y).
Dopamine agonists Adjunct to levodopa may be Nausea, headaches, hypotension, sedation
useful as monotherapy to dyskinesias, hallucinations, confusion.
delay initiation of levodopa
Anticholinergic drugs Monotherapy or adjunct to Dry mouth, blurred vision, urinary retention,
levodopa in early stages constipation, confusion, decreased memory,
psychosis, delirium (worsens with age).
Amantadine Monotherapy or adjunct to Dizziness, confusion, nausea, hallucinations,
levodopa in early stages constipation
Selegiline Adjunct to levodopa in mild Nausea, confusion, confusion, depression,
disease insomnia, hypotension
COMT inhibitor
Tolcapone

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The most common side effects of LEVODOPA are nausea, hypotension, and hallucinations. Domperidone
is useful for managing nausea and hypotension.
After 3-5 years of levodopa therapy, patients begin to develop motor fluctuations (“wearing off”, “on-off”)
and dyskinesias. The exact cause of these late side effects is uncertain. Several strategies can be tried in
an attempt to manage motor fluctuations.

Management of Adverse Effects from Drugs Used in Parkinson’s Disease


Adverse Effect Management Strategies
“on-off” (sudden “freezing” Add a dopamine agonist
unrelated to time and dose Switch to Sinemet CR
“Wearing off” Administer levodopa more frequently
Switch to Sinemet CR. Add or increase dose of a dopamine agonist
Switch to a different dopamine agonist.
Dyskinesia Decrease dose of levodopa or dopamine agonist
Switch to a different dopamine agonist
Psychosis, confusion, Decrease dose of levodopa or dopamine agonist. Discontinue
agitation, hallucinations, anticholinergic drugs, amantadine, selegiline
delusions
Orthostatic hypotension Can be caused by anti-Parkinson medications, other medications and by
Parkinson’s disease itself. A lying and standing blood pressure should be
checked at each visit.
Decrease dose of levodopa or dopamine agonist, increase gradually
Add salt to diet.
Add domperidine or fluorocortisone.
Nausea and vomiting Take levodopa with food. Increase dose of levodopa or dopamine agonist
gradually over several weeks.

Tips

• Levodopa side effects --> hypotension, nausea, vomiting, hallucination, dyskinesia


• Entacapone and tolcapone are -->COMT Inhibitors
• Entacapone side effect --> have less hepatotoxicity than tolcapone. Gives orange
color urine.

Find answers from table:


1 Dopamine 2 Selegiline 3 Dyskinesia
4 Levodopa 5 Tolcapone 6 Tardive dyskinesia
7 Carbidopa 8 Pramipexole 9 Akinesia
10 Metoclopramide 11 Ropinirole 12 Bradykinesia

• Parkinson's disease is due to decrease in ( 1 )


• It does penetrate into brain ( 4 )
• Abnormal involuntary movements (3 )
• An antiemetic drug should be avoided in PD patient ( 10 )
• A selective MAO- type B inhibitor ( 2 )
• Decreased voluntary movement ( 9 )
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• Slowness in performing common voluntary movement, including, standing,


walking, eating, writing, and talking. ( 12 )
• What is NOT a Parkinson’s disease symptom ( 6 )
• COMT inhibitor ( 5 )
• Repetitive involuntary choreiform movement of the tongue, limbs and trunk (6 )
• The common side effect of levodopa (90%) (3 )

TRUE OR FALSE

• All antipsychotic required caution in PD (True/False)


• Levodopa/carbidopa is drug of choice in PD (True/False)
• Levodopa does penetrate into brain (True/False)
• Dopamine does not penetrate into brain (True/False)
• Carbidopa does not penetrate into brain (True/False)
• Dyskinesia is repetitive involuntary movement of tongue, limbs, hands, and trunk
(True/False)
• Metochlopramide an antinauseating drug should be avoided in PD patient
(True/False)
• All antipsychotic required caution in PD (True/False)
• Levodopa/carbidopa is drug of choice in PD (True/False)
• Parkinson's is due to decrease in Dopamine (True/False)
• Selegiline is a selective MAOI type b (True/False)
• Akinesia is decreased voluntary movement (True/False)
• Bradykinesia is slow movement (True/False)
• Over treatment of Parkinsonism drugs can result into schizophrenia (True/False)
• Pramipexole and ropinirole are dopamine agonist (True/False)
• Pulmonary fibrosis is side effect of bromocriptine, pergolide (except pramipexole
and ropinirole) (True/False)

Abbreviation and Terminology


COMT Catecholamine O-Methyl transferase PD Parkinson's Disease
DA Dopamine MAO Monoamine Oxidase
TRAP Tartrate Resistent Acid Phosphatase Kinesia motor movements
• Dyskinesias: Involuntary, nonrepetitive, occasionally stereotypical movements affecting distal,
proximal, and axial musculature in varying combinations. Most dyskinesias are due to basal ganglia
disorders.
• Bradykinesia = Slow movement
• Akinesia = No movements
• Extra pyramidal symptoms: Parkinson's like symptoms (TRAP)
• Akthisia = Motor restlessness
• Tardive Dyskinesia = Inappropriate postures of neck, trunk and limbs.
• Chorea is brief, purposeless involuntary movements of the distal extremities and face, which may
merge imperceptibly into purposeful or semipurposeful acts that mask the involuntary motion.
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• Athetosis is writhing movements, often with alternating postures of the proximal limbs that blend
continuously into a flowing stream of movement.

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19
Anesthetics
Local anesthetics

Esters Type Amides Type

Short duration Long duration Medium


Long duration Bupivacaine
Procaine duration
Tetracaine Ropivacaine Lidocaine
Surface active
Medium duration
Benzocaine
Cocaine
Cocaine

• Inhibit sensory nerves that carry stimuli to CNS and block nerve fiber conduction

• Blockade is reversible, must continue administration of the drug for effects to


continue.

• Ester local anesthetics produce para amino benzoic acid (PABA) as metabolic
product.

• Amide local anesthetics metabolized by liver.

• Most local anesthetic solutions contain the vasoconstrictor epinephrine

o Epinephrine used (1:100000) in local anesthetics act as vasoconstrictor.

 Epinephrine in local anesthetic helps to prolong the duration of


action on locally.

 Reduce systemic absorption thereby decrease systemic toxicity.


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General Anesthetics

Inhaled Intravenous

Barbiturate Miscellaneous Dissociative


Gas Volatile liquid Thiopental Propofol Ketamine
Nitrous oxide Halothane
Ether (diethyl Enflurane
ether) Isoflurane Benzodiazepines
Midazolam

Generic Name Trade Name Generic Name Trade Name


Halothane Fluothane Fentanyl Duragesic
Isoflurane Forane Enflurane Ethrane
Sevoflurane Sevorane, Ultane Desflurane Suprane
The minimum alveolar concentration (MAC) is the alveolar anesthetic concentration at
one atmosphere (760 mm Hg) preventing movement in 50% of patients exposed to
noxious stimuli.

Inhaled anesthetics: Inhaled anesthetic are used to provide general surgical anesthesia

Halothane (Fluothane)
• Halothane is used in pediatric anesthesia. It is infrequently used in adults.
• Side effects. Malignant hyperthermia.

Enflurane
Enflurane is used as an inhalation agent for adults, but is not widely used for pediatric
cases.

Isoflurane.
Isoflurane may be the most widely used inhalation agent.

Nitrous Oxide. With a MAC value of 105%, nitrous oxide, by itself is not suitable or safe
as a sole anesthetic agent. Nitrous oxide is an effective analgesic and nitrous oxide in
combination with thiopental for induction, a skeletal muscle relaxant and
hyperventilation to reduce CO 2 .
Use as an adjunct to other inhalation agents allows reduction in their dosage.

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Ketamine
• Short acting non-barbiturate anesthetic induces a dissociated state in which the
patient appears awake but is unconscious and does not feel pain.
• Causes sedation, immobility, amnesia, and nightmares, and uses hypertension and
increases cardiac output-avoid use in stroke and high blood pressure patients.
• Mainly used for short procedures.

Intravenous
• Intravenous are indicated to induce drowsiness and provide relaxation before the
induction of inhalational general anesthetics.

Propofol
• Sedative or hypnotic
• Used in induction and maintenance of anesthesia
• Fast onset (40 seconds of administration).
• Poor analgesic.

Fentanyl
• Narcotic
• Available as transdermal patch, good analgesic property.

Anesthetic Tips

• Sequence of MAC. Nitrous oxide > Ether > Enflurane >Isoflurane > Halothane
• Isoflurane (Forane), enflurane (Ethrane), sevoflurane (Sevorane, Ultane)
and desflurane (Suprane) are frequently used in adults.
1 Epinephrine 2 Local anesthetics 3 Halothane
4 Chlorprocaine 5 Benzocaine 6 NO 2
7 Butamben 8 Procaine 9 PABA
10 Procainamide 11 Cocaine 12 Local anesthetics
13 Thiopental 14 Tetracaine 15 lidocaine
• Ester type of local anesthetic metabolize to … ( 9 )
• A vasoconstrictor ( 1 )
• Its action is to helps prolong duration of action and decrease systemic SE. ( 1 )
• Topical anesthetic used for canker sores and cold sores, dental pains, and
hemorrhoids. ( 5 )
• Ester type local anesthetic include. (5,8,11,14 )
• Antiarrhythmic drug (Na+ channel blocker) shows action similar to quinidine (10)
• Used as an antiarrhythmic drug and it is an amide type local anesthetic (15)
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• Classified as rapid acting barbiturates. (13)


• Malignant hyperthermia associated with what anesthetic. (3)
• Inhaling gas general anesthetic also known as laughing gas (NO 2 )
• General anesthetic safe in children. (3)
• Reason for treating infection prior to use of local anesthetic?  infection and
inflammation lower tissue pH, reducing the diffusion of the agent into the nerve,
thus reduce effectiveness.
• Local anesthetics do not produce loss of consciousness
• Local anesthetics like lidocaine is NOT used for? sunburns
• TRUE OR FALSE
• Ester type of local anesthetic metabolize to para aminobenzoic acid (PABA)
(True/False)
• Epinephrine in local anesthetics act as a vasoconstriction (True/False)
• Epinephrine helps in prolongs duration of anesthesia (True/False)
• Local anesthetic do not produce loss of consciousness (True/False)
• Benzocaine topical anesthetic is used for aphthous ulcers and cold sore (True/False)
• Ester type local anesthetic include benzocaine, tetracaine, and procaine (True/False)
• Amide type anesthetics include bupivacaine, ropivacaine, and Lidocaine (True/False)
• Procainamide class 1a antiarrhythmic drug (True/False)
• Lidocaine is used for class 1b antiarrhythmic drug and local anesthetic (True/False)
• Thiopental is classified as short acting barbiturates (True/False)
• Malignant hyperthermia is side effect of halothane (True/False)
• Halothane is general anesthetic safe in children (True/False)

Abbreviation and Terminology


MAC Minimum Alveolar Concentration PABA Para Amino Benzoic acid
CNS Central Nervous System

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20
Opioid Analgesics

Mixed agonist–antagonist Antagonists


Agonists Pentazocine Naloxone (Full)
Nalbuphine Naltrexone (Partial)
Buprenorphine (partial agonist)

Strong (efficacy &


addiction, abuse) Moderate (efficacy Weak (efficacy &
Morphine & addiction, abuse) addiction, abuse)
Heroin Codeine Propoxyphene
Meperidine Oxycodone
Methadone Hydrocodone
Fentanyl
Levorphanol

Drug Name Trade Name Drug Name Trade Name


Nalbuphine Nubain Pentazocine Talwin, Talwin NX
Naloxone Narcan, Narcan Neonatal Naltrexone Depade, ReVia, Vivitrol
Naltrexone Depade, ReVia, Vivitrol Levorphanol Levo-Dromoran
Meperidine Demerol, Meperitab
Methadone Diskets, Dolophine, Methadose
Fentanyl Duragesic Hydrocodone Hycodan, Hydromet, Hydropane,
Oxycodone Endocodone Propoxyphene Darvon, Darvon-N 100, Darvon-N,

Opioids are derived from opium. These are powerful central nervous system drugs that
are used medically to relieve pain. These drugs are used for moderate to severe pain of
trauma, post-surgical pain, pain associated with myocardial infarction and pain of
terminal illness. Physical and psychological dependence (addiction) can occur when
opioids are administered for some time. When tolerance develops, the patient requires

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increasing amounts of drug to treat pain. All opioids are habit forming, however,
titrated doses to treat pain; the risk of addiction is slight.

Opioid analgesics act primarily on the CNS and the intestines. The perception of and
emotional response to pain are modified when opioid analgesics bind with
stereospecific receptors in the CNS. The most studied subtypes of opioid receptors are
mu (μ), delta (δ) and kappa (κ). Pure opioid agonists such as morphine act primarily at
the mu receptor. Mixed agonist-antagonists such as butorphanol, nalbuphine and
pentazocine are most active at the kappa receptor. Buprenorphine is a partial agonist at
the mu receptor and an antagonist at the kappa receptor.

There are three known peptide neu


rotransmitters that act on mu, delta and kappa receptors.

• Enkephalin mu & delta


• Endorphine mu
• Dynorphine kappa

Mu receptor simulation (supraspinal, spinal) cause


• Analgesia
• Respiratory depression
• Euphoria
• Physical dependency
• Pupil constriction

Kappa receptor simulation cause (spinal analgesia)


• Analgesia
• Miosis
• Sedation (sedation and dysphoria are kappa agonist effect).

• Tolerance. Need to use the high dose of drug to get the same effects.
• Physical dependency
• psychological dependency (craving, euphoria (feeling good).
• Opioid overdose gives three characteristic symptoms such as pinpoint pupil (due to
increase in cholinergic activity), decrease respiration (hypoxia), constipation, coma
and somnolence.

Opioid withdrawal symptoms


• Nausea, vomiting
• Muscle ache
• Lacrimation or rhinorrhea
• Diarrhea
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• Fever and dilated pupil


• Autonomic hyperactivity

Therapeutic use:
• Analgesics (moderate to severe pain)
• Antitussive (dextromethorphan, codeine)
• Antidiarrheal (Loperamide)

Side effects
• Constipation (increase GI tone)
• Sedation, drowsiness
• Miosis
Important!
• Respiratory depression Comparison opioids side effect and
• Urinary retention anticholinergic SEs
• Hypotension

Side effects Withdrawal


• Constipation (increase GI tone) • Diarrhea
• Sedation, drowsiness • Nausea, vomiting, Muscle ache
• • Lacrimation or rhinorrhea
• Miosis • Fever and dilated pupil (mydriasis)
• Respiratory depression • Autonomic hyperactivity
• Urinary retention
• Hypotension

Opioid analgesic therapeutic effects


Drug Therapeutic Effects
Morphine • Act on Mu receptors and for chronic use
Hydrocodone • Cannot be glucuronidase at 6-position. Used in renal failure
• Codeine derivative, used for pain cough suppression
• More addictive than codeine.
Codeine • Used for cough suppression and mild to moderate pain.
• Analgesia does not increase with dose (ceiling effect).
• Additive effect with ASA and acetaminophen
Oxycodone • Codeine derivative, used for pain cough suppression.
• More addictive than codeine.
Methadone • Acts on Mu receptor agonist and NMDA antagonist.
• Oral form, long half-life
• Used for suppressing opioid withdrawal symptoms
• Less emetic effect
• Milder withdrawal symptoms.
Meperidine • Mu receptor agonist
• Used during labor. Anticholinergic effect. No miosis, Tachycardia (IV), Toxic doses may

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cause CNS stimulation.


• The least respiratory depression and less constipation
• Normeperidine (metabolite) - hallucinations and convulsions
• Constipation and urinary retention less than for morphine.
Pentazocine • Weak antagonist at mu receptors (1/30 nalaxone) and agonist at kappa receptors.
• May precipitate (trigger) withdrawal symptoms when given instead of morphine. Oral
and IM dosing.
Butorphanol • strong agonist at kappa. The kappa agonist have lower ceiling analgesic effect than
full mu agonist, thus they are not effective in treating severe pain.
• Same as pentazocine.
• Used for chronic pain only (intranasal, refract headache)
Nalbuphine • agonist at mu receptors and antagonist at kappa
• Same as for pentazocine.
• Low respiratory depression. Little euphoria (excited state of mind). Analgesia during
labor.
Naloxone • Antidote of opioids. Full antagonist at mu receptors
• Full antagonist. IV only because first pass effect is 98%.
• Short half-life.
Naltrexone • Partial antagonist at mu receptors, long half-life. Is given orally.
• Treat alcoholics decrease craving.
Tramadol • The (+)isomer weak mu agonist and (-)isomer neurotransmitter reuptake inhibitor.
Fentanyl • mu agonist. Produce short duration of action 1-2hr. It does not cause histamine
release up on iv injection. Fentanyl patch produce analgesia for 72 hrs.

Tips

• Dyspnea is →
• Avoid opioids in head trauma patients
• Morphine active metabolite →
• Analgesic activity of morphine→
• Codeine is metabolized by →
• Patient taking Tylenol # 3 + hydromorphone →
• Methadone is used for →
• Morphine over dose symptoms →
• Which opioids has highest addiction potential →
• In angina pain what opioids is used →
• Drugs used to treat opioids withdrawal symptoms→
• Opioid antagonist→
• A patient developed seizure after initiating opioids therapy, which opioids would
be responsible→
• Opioids least used in→
• Pinpoint pupil is opioids →
• Avoid opioids with MAOI →

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• Opioid induced constipation treated by →


• Enkephalins are →
• A patient is on opioids, having constipation, started taking psyllium laxatives but
no improvement, you advise him→
• How to apply fentanyl transdermal patch →
• Allergic to morphine can use →
• What is the antidote for an OxyContin overdose? →
• Name the antagonist of choice for an opiod overdose. →
• Least respiratory depression →
• If allergic to morphine →
• Highly fat soluble opioids →
• Preferred opioids in labor →
• Sequence of addiction/abuse liability: Morphine = Meperidine = Methadone =
Fentanyl > codeine > Propoxyphene

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21
Non–Steroidal Anti-
inflammatory Drugs &
Analgesics
• Antipyretic: a drug to reduce fever
• An analgesic: a drug used to relieve pain
• Anti-inflammatory: Drugs that reduce redness and swelling
• Antiplatelet: Prevent platelet aggregation.

Acetyl Salicylic Acid, COX inhibitors, and Acetaminophen

Salicylates Non-selective COX II Acetaminophen


COX inhibitors Inhibitors

ASA

NSAIDs:
*Salicylic acid *Diflunisal *Celecoxib (Celebrex)
*Methylsalicylic *Flurbiprofen *Rofecoxib
*Ibuprofen
*Naproxen
*Indomethacin
*Sulindac
*Piroxicam
*Ketorolac

Generic Name Brand Name Generic Name Brand Name


acetylsalicyclic acid, Aspirin® diclofenac Voltaren® (generics)
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ASA
enteric coated ASA Entrophen®, diflunisal generics
Novasen®
celecoxib Celebrex® floctafenine Idarac® (generics)
flurbiprofen Ansaid® (generics)
ibuprofen Motrin®, Advil® (generics)
indomethacin Indocid® (generics) ketoprofen Orudis® (generics)
ketorolac Toradol® meloxicam Mobicox®
naproxen Anaprox®, Naprosyn® piroxicam Feldene® (generics)
(generics)
sulindac generics tiaprofenic acid Surgam® (generics)
tolmetin Tolectin®

Summary of NSAID’s induced ulcers

Risk factors for • Age >65


Development of upper • Anticoagulants or oral glucocorticoids
GI side effects with • History of peptic ulcer disease
NSAID • History of upper GI conditions
• Comorbid medical conditions
Treatment of NSAID’s Misoprostol
induced ulcers • PGE 1 analog
• Increases bicarbonate secretions
• Increase mucus secretions
• Proton pump inhibitor (omeprazole, lansoprazole)
• Proton pump inhibitors elevate pH 4
• Acts as an antacids
• Prevents and treat NSAID induced ulcers
• Sucralfate
• Mucus protective agent, it is mixture of aluminum
hydroxide and sulphate sucrose (disaccharide).
• Should be avoided with antacids
• Taken empty stomach
Recommendation • Products like misoprostol (Cytotec) act as protectant and are
prescribed with NSAID’s to prevent gastric ulcers.
• Sucralfate (Sulcrate) ranitidine (Zantac) and proton pump
inhibitors, such as omeprazole (Losec), are sometimes often
administered at the same time as NSAIDS to prevent ulcers.
ASA • Reye’s syndrome in children with chickenpox and flu
(primarily ASA)
Salicylate allergies • If allergy with one NSAID’s avoid all other NSAID’s use

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Acetyl Salicylic Acid

Mechanism • In low doses inhibits platelet COX production of thromboxane


A 2 preventing platelet aggregation.
• Cox permanently inhibited for life of the platelet.
Platelet life 7-10 days.
Therapeutic use Analgesic 325 mg Q4 to 6 h
Antipyretic 325 to 650 mg Q4-6h PRN
Anti-inflammatory 650-975 mg Q4-6h
Antiplatelets 81-325 mg daily

• Antiplatelet low dose (60 to 80 mg). Due to permanent action on TxA 2 thus
prevent platelet aggregation
• Analgesia: Moderate dose, may be two tablets (325 mg bid). Due to inhibition of
Cox 1 and Cox 2 (prevent prostaglandin formation).
• Antipyretics. Moderate dose, may be 4 to 8 tablets. Pyrogen increase PGE 2
formation, which is inhibited by ASA
• Anti-inflammatory. Moderate to high dose. Inhibit Cox 2 which is induced during
inflammation.

Tips

• Analgesic action of acetaminophen is due to →


• If allergic to ASA →
• Rye syndrome with →
• Life span of platelet →
• Sulfaslazine metabolism occurs in →
• Acetaminophen least used as →
• Antiplatelet action of ASA at what dose →
• Symptoms of salicylism is treated by→
• Misoprostol is →
• Misoprostol chemically classified as →
• Salicylism generally occurs at what dose→
• Mercapturic acid is produced by →
• Glutathione contains →
• ASA and acetaminophen interchangeable for →
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• All NSAIDs common complication is →


• ASA toxicity →
• In alcoholic patient if acetaminophen given in multigrams, which substance is
decreased→
• Acetaminophen antidote →
• Acetaminophen metabolized by →
• What are pharmacological action of COXII selective →
• Which salicylate cause folic acid deficiency →
• What is mechanism of N-acetylcysteine →
• DOC for ASA induced asthma →
• Which NSAID has most effect on kidney (CrCl) →
• The primary active component of sulphasalazine →
• What if kind of reaction ASA undergoes in stomach→
• Toxicity of ASA in child will be worse than in adults because →
• Rye syndrome →
• Which is the strongest endogenous pain producer→
• Salicylate toxicity excessive respiration is due to →
• Diclofenac eye drops causes →
• Ketorolac is used to treat →
• Celecoxib mechanism of action Cox II inhibitor→
• All cause GI side effects, except →

Abbreviation and Terminology


NSAIDS Nonsteroidal Anti-Inflammatory Drugs COX Cycloxygenase
PGE Prostaglandin MI Myocardial Infarction
ASA Acetyl Saliaylate

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22
Autocoids
Autocoids (local hormones) are chemical mediators that the body releases as a response
to pathogens or noxious substances. Produced in the body and has profound
pharmacological effects. Generally autocoids can characterized as amine type and
endogenous type.

Amines type: Examples: Histamine, and serotonins.


No real clinical application in the treatment of diseases however antihistamines are of
great importance.

Endogenous peptides (ecosanoid): Prostaglandins, prostacyclin, thromboxane,


leukotriene, and bradykinin.
• Site of production for endogenous peptides are GIT, kidneys, lungs, pancreas and
uterus.
• Prostaglandins – pain sensation, development of inflammation, edema
• Thromboxane – aggregation of platelets
• Prostacyclin – inhibition of platelet aggregation
• Leukotrienes – inflammation, chemo tactic properties (pull substances to them),
bronchoconstriction.

Histamines
• Histamines, the autocoids act on three receptors H 1 , H 2 and H 3 .
• Present: Skin, lymph, and GI tract
• Release = mast cells, basophiles
• Stimuli = Drugs such as opioids (except fentanyl), venoms, trauma, and vancomycin
(red man syndrome).

H 1 receptor activation
• H 1 - typical allergic and anaphylactic response to histamines.
• ↑ Bronchoconstriction
• ↑ Vasodilation (via NO): ↓ B.P
• ↑ Increase capillary permeability
• ↑ Spasmodic contractions of gastrointestinal smooth muscle (GI)
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• ↑ Activation of peripheral nocieptive receptors = ↑ pain and pruritus

Histamine H1-receptor blockers


1st generation 3rd generation
• 2nd generation
Diphenhydramine Desloratadine (Aerius)
Dimenhydrinate
Loratadine
Tripelannamine Fexofenadine
Hydroxyzine Cetirizine
Meclizine Terfenadine
Chlorpheniramine
Promethazone

H 1 antagonist pharmacological actions (drugs action)


Blocks histamine effect on:
• Allergic symptoms
• Seasonal rhinitis
• Conjunctivitis
• Rhinoviral infections (common cold)
• Urticaria

H 1 blockers indications:
• Allergic reactions
• Allergic Rhinitis (hay fever), and runny nose
• Motion sickness
• Nausea and vomiting (in pregnancy)
• Preoperative sedation
• Sleep aid
1st generation
• Usually lipid soluble
• Similar in terms of absorption and distribution
• Good absorption after oral administration distribution with peak plasma
concentration of 1 – 2 hours
• Allows some to go to the blood-brain-barrier especially
• Structural resemblance to histamine

H2 -Receptors Activation
• ↑ Gastric acid secretion and ↑ GI ulcer.

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• H 2 -receptors responses to histamine such as: Increased secretion of gastric acid,


Increase pepsin and Intrinsic factor (Castle’s factor).
• H 2 receptor antagonist competitively block H 2 receptors thus blocking the effect of
histamines on gastric secretions.

H2 antagonist: Ranitidine, Cimetidine, Famotidine, and Nizatidine

Serotonin (5-Hydroxy tryptamine – 5HT)

5HT1a 5HT1b/1d 5HT2 5HT3 5HT4

Ergotamine (DHE) Agonist


Agonist Agonist Partial agonist of 5HT1a and Antagonist
Buspirone Ondansetron Cisapride
Triptans 5HT1d
Sumatriptan Antagonist of 5HT2a: Alosetron
Rizatriptan atypical antipsychotic Fabesetron
Zolmitriptan Ramosetron
Olanzapine, clozapine,
Naratriptan and risperidone

Tryptophan (amino acid) → 5-hydroxy tryptophan → Serotonin (Neurotransmitter) → 5-


Hydroxyinolacetic acid.
• Conversion of tryptophan to serotonin takes place in two reaction, first
hydroxylation and decarboxylation catalyzed by tryptophan hydroxylase and L-
amino acid decarboxylase respectively. Serotonin contain indole ring.

Physiological functions of serotonin receptors: Serotonin group has several subtypes of


receptors:
• 5HT 1(A-G)
• 5HT 1 , 5HT 2 , and 5HT 3 →Anxiety, depression, aggression, impulsive and appetite
• 5HT 1D →Auto receptors inhibit presynaptic activity in both serotoninergic and
adrenergic neurons in the CNS.
• 5HT 2 →Vasoconstriction, platelet aggregation
• 5HT 3 →Nausea / vomiting
• 5HT 4 → Release of acetylcholine in the enteric region.

5HT1(A-G)
• Found in the CNS (inhibitory) and smooth muscles (excitatory or inhibitory).
• 5HT1A partial agonist = Buspirone
• Used as anxiolytics (specially general anxiety disorders)
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5HT 1D/1B receptor agonist

TRIPTANS (all are indole derivatives);


• Sumatriptan (Imitrex)
• Rizatriptan (Maxalt)
• Naratriptan (Amerge)
• Zolmitriptan (Zomig)
• Almotriptan
• Frovatriptan
5HT 1D receptor agonist side effects: Feeling of warmth, dizziness, tightness or heaviness
in the chest, rarely patient may experience chest pain.
5HT2: Found in the CNS (excitatory), in periphery stimulation causes vasoconstriction,
GI constriction, branchial and smooth muscle constriction and stimulation of platelet
aggregation.
5HT2A: RESPIRIDONE, OLANZAPINE AND CLOZAPINE = 5HT2A ANTAGONIST
5HT3 : Linked directly to ion channels, activation opens ion channels.
5HT 3 antagonist = setrons (Ondansetron, granisetron)

Serotonin antagonist
5HT 3 receptor antagonist

• Ondansetron (indole derivatives)


• Granisetron (benzimidazole derivative)
Ondansetron side effects: Constipation, headache, dizziness and granisetron; diarrhea
Ergot alkaloids and derivatives with antagonist/partial agonist activity include:
• Ergonovine
• Dihydroergotamine (DHE)
• Methysergide, Bromocriptine

5HT 4 agonist
Found in periphery and GI smooth muscles. Thereby these drugs are used in chronic
constipation.
• Cisapride (a benzamide)
• Ttagaseride (indole derivative).
• Ergotamine-serotonin partial agonist: Ergot alkaloids have agonist and antagonist
properties

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Prostaglandin

Prostaglandin chemical classification


• Prostaglandin has been classified based presence and absence of keto or hydroxyl
groups at 9 and 11. Subscripts relate to the number of double bond present in
aliphatic chains

Physiological functions
Platelet aggregation, Relax bronchial and GI smooth muscles, Relax smooth muscles,
Inhibit gastric acid secretion, Pain, Edema, Inflammation

PGE 1 analogs
• Protection of gastric mucosa
• Vasodilatation
Misoprostol (Cytotec): is used for prevention of NSAID induced GI ulcers.
Chemically it is ecosonides.
Combination products: Naproxen + misoprostol, diclophenac + misoprostol (arthrotec)

Alprostadil
In adults; for the treatment of impotence
Alprostadil (Caverject, Prostin VR pediatrics) is used treating impotence due to erectile
dysfunction.
Alprostadil (prostin VR pediatric) is used for temporary maintenance of a patent ductus
arteriosus when awaiting corrective surgery for congenital heart defects.

PGE 2 analogs: Uterine muscle contraction

Dinoprost, Dinoprostone
• Dinoprostone derovatives  Abortificient
• Dinoprostone (prostin E 2 , prepidil, cervidil) are used for their abortifacient effects
and to induce cervical ripening in pregnancy.
PGF 2α analogs
• Uterine and bronchial muscle contraction
• Decrease intraocular pressure

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PGF 2α analogs are selective prostanoid FP receptor, inhibitors that reduce IOP, and
increase outflow of aqueous humor.
• Latanoprost (Xalatan): (Used topically to lower intra ocular pressure in OAG)
• Travoprost (Travatan) : topical ophthalmic drug
• Bimatoprost (Lumigan) : topical ophthalmic drug
• Unoprostone (Rescula) : topical ophthalmic drug
• Carboprost (Hemabate) :abortificient (withdrawn)
• Precautions: Ophthalmic solutions have been reported to cause changes to
pigmented tissue. The changes include the increased pigmentation and growth of
eyelashes and increased pigmentation of iris and periorbital tissue (eyelid). The
increased pigmentation is permanent.
• Latanoprost (Xalatan): Store unopened bottle under refrigeration. Protect from
light. Once opened store bottle in cool place (refrigerate if possible) for up to 6
weeks.
• Bimatoprost (Lumigan): Store at room temperature, no refrigeration necessary

PGI 2 analogs (Prostacylcin): Platelet stabilizer and vasodilatation


Epoprostenol (Prostcyclin, Flolan):
Used in the treatment of emergency pulmonary hypertension.
Misoprostol Cytotec
Alprostadil Caverject, Prostin VR pediatrics
Dinoprostone Prostin E2, Prepidil, Cervidil
Latanoprost Xalatan
Travoprost Travatan
Bimatoprost Lumigan
Unoprostone Rescula
Carboprost Hemabate
Epoprostenol Prostcyclin, Flolan
Zafirlukast Accolate
Montelukast Singulair

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Prostaglandin

PGE1 PGE2 PGF2α PGI2 TxA2

Protects gastric Pyrogen Bronchoconstricti Decrease Increase Platelets


mucosa elevate PGE2 on contraction of platelets aggregation
contraction of uterus aggregation
uterus
Misoprostol Thromboxane A2
Alprostadil Latanoprost Epoprostenol
Dinoprostone Bronchial & ASA
Blood vessels
Bronchial & smooth muscle Dipyridamol inhibits
dilatation
smooth muscle Bronchial & constriction Platelet aggregation
Inhibit aggregation
dilatation smooth muscle
dilatation

Corticosteroids
Leukotrienes

Lipoxygenase

Membrane phospholoipids Arachinodic acid

NSAID, Aspirin, COX-II


Phospholipase A2
Cyclooxygenase

Prostaglandins G

Hydroperoxidase

PGH2
Dipyridamole

Thromboxane A2
Prostacyclin (PGI2) PGE2 & PGF2

Platelet aggregation Uterine tone Paltelet aggregation


Vascular tone Vascular tone Vascular tone
Bronchial tone Bronchial tone
Uterine tone

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Leukotrienes

Physiological functions
LTC and LTD antagonists
Play important role in numerous physiological functions.
Slow reacting substance of anaphylaxis.
Heart: Negative inotropic, Smooth muscles chemotaxis (Chemotaxis = movement of cell
in response to the chemical gradient)
GI tract: Neutrophil chemotaxis
Pulmonary (major): Bronchoconstriction, increase permeability, and increase mucus
secretion.
Blood: Chemotactic agent for neutrophils, eosinophils, and modify lymphocyte
proliferation and differentiation.
Two important leukotrienes antagonists: LTC 4 and LTD 4
e.g. Zafirlukast (Accolate) and montelukast (Singulair); Peptid mimetic structure.
Indicated in prophylaxis of asthma.

Zafirlukast (Accolate)
• Therapeutic use: For the prophylaxis and chronic treatment of asthma in adults and
children 12 years of age and older. Side effects include: GI upset, liver dysfunction.
• Take empty stomach to enhance it absorption.

Montelukast (Singulair)
• Similar profile to that of zafirlukast.
• Can be used in children over 2-year age
• Montelukast may be taken without regard of food.
• Available as chewable tablet (once daily in the evening). Administer granules directly
into mouth or mix with teaspoon of cold or room temperature applesauce, carrot,
rice or ice cream. Do not take aspirin or NSAIDs while on this medication.
• Drug of choice for aspirin induced asthma
Abbreviation and Terminology
5HT 5-hydroxy tryptamine LTD Leukotriene d
DHE Dihydroergotamine PGI Prostaglandin I
PGF Prostaglandin F OAG Open angle glaucoma
LTC Leukotriene c IOP Intraocular pressure

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23
Insulin and Antidiabetic Drugs
There are two types of diabetes mellitus, type I and type II. For type I diabetes, patients
need insulin injections. Type I diabetes is known as insulin dependent diabetes mellitus
(IDDM). It usually begins in young people under 40 and of normal weight.

• Hyperglycemia. Polyurea, polydipsea, polyphagea, and fatigue.

Hypoglycemia. Sweating, confuse, shaky, tremor, hungry and palpitation.


Autonomic Symptoms. Sweating, shaky, tremor, hungry and palpitation
Neurological symptoms. confuse, disorientation, dizziness

NORMAL BLOOD SUGAR LEVELS (BSL). Question Alerts!


1) Genetic RF? type 2 DM
• Fasting blood sugar levels 5 to 6 mmol/L (100 mg/dL) 2) Autoimmune is? type I
• Random blood sugar levels 11 mmol/L.
• Post prandial 11 mmol/L.
HbA1C normal is 4 to 6%, measures past three months blood sugar levels. Used to
determine antidiabetic drugs compliance of patient.

Insulin Mechanism

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Types of insulin are categorized by their onset of action, and these relative positions
hold true for their effectiveness and their duration of action as well. The delayed onset
action of insulin is due to dimmer and hexamer formation, which takes time to
dissociate.

Diabetes: Insulin

Generic Name Brand Name Generic Name Brand Name


Iletin® Humulin R,N,U Humalog® Humalog Mix25
Novolin® Mixtures of 30/70; NPH (intermediate)
20/80; 50/50; 40/60
Glargine (long acting) Lantus
Types of Insulin

Ultra rapid Regular Intermediate Long acting

Insulin lispro Regular NPH Glargine, Detemir


sc, and iv sc and iv sc only, cloudy sc only
do not mix with insulin
Insulin combinations

Insulin Duration Onset Peak Usual Effective Duration of


(hours) (hours Action (hours)
)
Humalog (H) (lispro) Very short 5-10 30-40 2-3 h
synthetic (fastest iv min min
form)
Regular (R) Rapid (short) ½ -1 h 1-3 h 5-7 (dose-dependent; may
(Suitable for iv dose). SC or iv (in be longer)
Both human and animal emergencies).
source
NPH (N). Intermediate 2-4 h 6-10 h 14-18 h
Amorphous precipitate Semilente not suitable for iv dose
of insulin with zinc ion (30%)
acetate buffer.
Detemir 1.5 h& 6-24h Do not mix with other
Flat insulin
Glargine 1.5h & 24 h Do not mix with other
Flat insulin (acid buffer). No iv
and im
Insulin storage conditions. Should be stored in refrigerator. Can be stored at room temperature 28 days .
Do not shake vigorously. If you notice turbidity or vapors or precipitation, do not use, discard it.

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Oral antidiabetic drugs

Hypoglycemic drugs Antihyperglycemics


Increase insulin secretion

Meglitinides
Sulfonylureas Repaglinide
Neglitinide

st nd
1 Generation 2 Generation 3rd Generation
Chlorpropamide Glyburide Glimepiride
Tolazamide Gliclazide beta and delta extra
Tolbutamide Glipizide pancreatic.

Biguanide Thiazolidinedione DPP-4 inhibitors


Metformin Sitagliptin, Saxigliptine.
Agonist PPAR-γ
Increase insulin sensitivity
Rosiglitazone
Increase glucose uptake in cell 2) Inhibitor of dipeptidyl peptidase enzyme
Pioglitazone
Decrease gluconeogenesis
Same as metformin (DPP-4) that enhances the incretin hormone.
Decrease glycogenolysis 3) DPP-4 inactivates incretin hormone

4) GLP-1 (glucagon like peptide) enhancers. or


α-glucosidase inhibitor Incretin analog.
Acarbose Liraglutide. Incretin hormone analog
Glucosidase breakdown starch 5. Increase glucose excretion in urine Sodium-
and disaccharide into glucose. glucose transport protein 2 (SGLT2) inhibitor
Starch ----> glucose Canagliflozin (Invokana)

Oral Hypoglycemic Agents


Generic Name Brand Name Generic Name Brand Name
acarbose Prandase pioglitazone Actos
metformin Glucophage (generics) rosiglitazone Avandia
repaglinide GlucoNorm chlorpropamide Generics, Diabinase
gliclazide Diamicron, Diamicron MR glimepiride Amaryl
(generics)
glyburide Euglucon, Diaβeta (generics)

Sulfonylureas 1st Generation

Chlorpropamide
Mechanism • Increased insulin release from beta cells of the pancreas
Therapeutic use • To control hyperglycemia in glyburide-responsive DM of
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stable, mild, nonketosis prone, maturity onset or adult type


which cannot be controlled solely by proper dietary
management, exercise and weight reduction or when insulin
therapy is not appropriate.
Contraindications • Patients during stress conditions such as severe infection,
trauma or surgery.
• Patients with liver disease or renal impairment; or frank
jaundice.
• Chlorpropamide not a good choice in elderly (long half life)
Side Effects • Hypoglycemia, GI discomfort, Nausea, weight gain

Sulfonylureas 2ndGeneration

• Gliclazide, and glyburide


Mechanism • Stimulates the production and secretion of insulin from the islet cells
of pancreas.
Therapeutic use • Treat adult (maturity-onset) diabetes mellitus.
Side Effects • Faintness and confusion. Weakness and tremor, sweating,
constipation and diarrhea.
Drug-drug • Corticosteroids, estrogens, diuretics, rifampin, other drugs may
interaction reduce the effect of gliclazide.
Contraindication • Not recommended to pregnant, lactating mothers, and children.
Monitoring • Regular testing of sugar levels in the blood and urine is required.
• Periodic assessment of the eyes, heart, and kidneys may also be
advised.
Meglitinides

Repaglinide • Gluconorm
Mechanism • Stimulate release of endogeneous insulin (rapid-acting),
better post-prandial glucose control.
Therapeutic use • Can be used in sulfa allergies
Contraindications • Hypersensitivity, diabetic ketoacidosis (DKA).
Side Effects • Hypoglycemia (less frequent than with sulfonylureas).

Nateglinide
Mechanism Stimulates the release of insulin
Contraindication Type I and pregnancy
Side effects weight gain, hypoglycemia if meal not taken
Drug-Drug Clearance inhibited by ketoconazole, miconazole, and
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interactions erythromycin. Enhance clearance with barbiturates, rifampin, and


carbamazepine.
Biguanides.Metformin

Important Concept!
SEs. Lactic acidosis! Increased with alcohol renal and hepatic disease.

Mechanism Does not stimulate secretion of insulin like sulfonylureas. Rather


decreases hepatic glucose output by inhibition of gluconeogenesis.
Reduces LDL, VLDL, and cholesterol levels.
Therapeutic To control hyperglycemia. For the treatment of obese diabetic patients.
use
Side Effects The most common side effect is stomach upset or diarrhea.
No weight gain side effect thus preferred in obese patients.
Lactic acidosis (in hepatic or renal failure patient and alcohol intake),
metallic taste, N, V and anorexia.
Contraindica Contraindicated in pregnancy, renal and hepatic impairments.
tion Patient with history of lactic acidosis, irrespective or precipitating
factors.
Drug-Drug Alcohol potentiates effects hypoglycemia. Potentiates other oral
interactions hypoglycemics.

Thiozolidine diones

Mechanism • Increasing insulin sensitivity in type 2 diabetes. It improves


sensitivity to insulin in muscle and adipose tissue and inhibits
hepatic gluconeogenesis.
• PPAR-γ . Peroxisome proliferator-activated receptor activates
nuclear genes involved in glucose & lipid metabolism and
adipocyte differenciation activated. PPAR-γ receptors are located
on cell nucleus.
Therapeutic • As monotherapy, in patients not controlled by diet and exercise
Effects alone.
• To reduce insulin resistance and lower elevated blood glucose in
patients with type II DM.
Pioglitazone
Mechanism • A thiazolidinedione antidiabetic agent that depends on the
presence of insulin for its mechanism of action.
• Decreases insulin resistance in the periphery and liver.
• Improves glycemic control while reducing circulating insulin levels.
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Therapeutic • Increasing insulin sensitivity in type 2 diabetes. It improves


use sensitivity to insulin in muscle and adipose tissue and inhibits
hepatic gluconeogenesis.
Contraindicati • Contraindicated in patients with serious hepatic impairment, acute
ons heart failure.
Side Effects • Weight gain, fluid retention, hemodilution, varying effects on lipids.
Increase HDL, Increase LDL, pioglitazone decrease TG.
Drug-Drug • Increase the risk of pregnancy, recommend adequate
interactions contraception not used.
• Resume ovulation in previously anovulatory (polycystic ovarian
syndrome). TZDs potentiates other hypoglycemic.
• Combination. Rosiglitazone + metformin (Avandamate)
Acarbose
• Prandase, Meglitol
Mechanism • Inhibits alpha glucosidase in intestinal border thus decrease
absorption of starch and disaccharides.
Therapeutic • Type II diabetes mellitus in combination with other antidiabetic
use drugs.
Drug-Drug • May decrease metformin bioavailability
interaction • Potentiates other oral hypoglycemic effects
• Diuretics, corticosteroid, estrogen, oral contraceptives, phenytoin,
and sympathomimetics drugs may increase blood glucose level and
effect diabetic control.
Dose • 50 -100 mg TID with each meal, start low and go slow.
Side Effects • Flatulence, diarrhea, abdominal pain, cramps, and nausea
Monitoring • Regular testing of after meal blood sugar level.
• In combination oral hypoglycemic therapy always use agents from
different class of oral hypoglycemics.
Orlistat(Xenical)

Mechanism Intestinal lipase inhibitor. Blocks the action of stomach and pancreatic
enzymes (lipases) that digest fats, so fats and other fat soluble vitamins
ADEK are not absorb in the body but pass through and excreted in the
feces.
Therapeutic Reduces fats stores and produce weight loss.
use
Drug-Drug Orlistat increases blood levels and toxicity of pravastatin.
interaction
Dose 120 to 360 mg daily

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Side Effects Diarrhea (stethorrhea oily leakage), and abdominal discomfort.

Incretin hormones. DPP-4 enzyme inactivates GLP-1. Gliptins inhibits DPP-4 and thus
enhances endogenous incretin hormone like GLP-1 peptides.

GLP-1 increase glucose dependant insulin release and decrease level of circulating
glucagon and hepatic glucose production.
DPP-4
GLP-1 -------------> Inactive GLP-1

DPP-4 inhibitors. Sitagliptin, and Saxigliptine.


• Inhibitor of dipeptidyl peptidase enzyme (DPP-4) that enhances the incretin
hormone. DPP-4 inactivates incretin hormone.

SEs. N.V, hypoglycemia, weight neutral, upper respiratory tract infections (URI), and
headache.

INCRETIN (GLP-1) ANALOG. LIRAGLUTIDE. EXENATIDE, ARE GLP-1 (glucagon like peptide)
enhancers. INCRETIN HORMONE ANALOG.

Tips

• Examples of hypoglycemic drugs Sulfonylureas, meglitinides


• Examples of antihyperglycemicsBiguanides, Thiazolinediones
• pre-prandial glucose concentrations→ insulin lispro
• Lactic acidosis is rare side effect of --> metformin
• Lactic acidosis risk is increased by --> alcohol intake, CHF, renal and hepatic disease
• Diabetic ketoacidosis risk increases when --> uncontrolled type 2 DM
• What major ketones are observed in DKA --> beta hydroxy butyric acid (80%)
• What antidiabetic medications are not given to type 1 --> sulfonylureas, meglitinides
• Example of glucagon like peptide-1 (GLP-1) agonist--> Liraglutide

Find answers from the table;

1 Orlistat 2 Acarbose 3 Alcohol


4 Rosiglitazone 5 Sulfonylureas 6 Disulfiram like
7 Metformin 8 Meglitinides 9 Insulin
10 Gemfibrozil 11 Glyburide 12 Regular insulin

• Alpha glucosidase inhibitor. ( 2 )


• Intestinal lipase inhibitor. ( 1 )
• Antidiabetic drugs taken before or after meals. (4,5,7,11)
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• Works on cell membrane. ( 9)


• The antidiabetic drug side effect of anorexia. (7 )
• Anticholesterol drug of choice in diabetic patient. ( 10 )
• Which antidiabetic drugs are not used in type I DM. (sulfonylurea, and meglitinide)
• What antidiabetic drug of choice in pregnancy. (9 )
• If patient has admitted in surgical ward and her blood glucose levels high, what is
drug of choice? (9 regular)
• Which of the available forms of insulin should be used to treat diabetic ketoacidosis?
(9 regular )
• What substance that when combined with metformin gives lactic acidosis? ( alcohol)
• Chlorpropamide + alcohol give what reaction. (disulfiram like reaction)
• 2nd generation sulfonylureas. ( glyburide, glimepiride, glicalizide)
• What drug decrease absorption of starch? (2)
• It does not decrease absorption of glucose. ( 2)
• Difference between glyburide and glicalizide These 2 drugs are 2nd gen
sulfonylureas, however glyburide (2 to 3 hr), has shortest half-life and 100%
metabolized in liver and gliclazide has long half-life.

TRUE OR FALSE
• Acarbose mechanism is alpha glucosidase inhibitor (True/False)
• Orlistat mechanism is intestinal lipase inhibitor (True/False)
• Difference between glyburide and glimepiride. glyburide is short acting and
glimepiride is long acting (True/False)
• Antidiabetic drugs taken before or after meals are sulfonylurea, metformin,
glitazones (True/False)
• The most common cause of glaucoma (blindness) is associated with diabetes
mellitus (True/False)
• Insulin works on receptors on cell membrane (True/False)
• The antidiabetic drug that cause side effect of anorexia is metformin (True/False)
• Anticholesterol drug of choice in diabetic patient is fibrates (True/False)
• Metformin monitoring are renal function and liver function tests (True/False)
• Antidiabetic drugs that is not used in type I DM are sulfonylureas and meglitinides
(True/False)
• Glucagon gives hyperglycemia and insulin gives hypoglycemia (True/False)
• Insulin is antidiabetic drug of choice in pregnancy (True/False)
• If patient has admitted in surgical ward and her blood glucose levels high, the drug
of choice is insulin (True/False)
• Metformin monitoring BSL, HbA1C, CrCl, CBC. (T/F )
Abbreviation and Terminology
IDDM Insulin Dependent Diabetes Mellitus HDL High Density Lipoprotein
NIDDM Non Insulin Dependent DM LDL Low Density Lipoprotein

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BSL Blood Sugar Levels TG Triglyarides


DKA Diabetic Ketoacidosis ADEK Fat Soluble Vitamins
HbA1C Percent of hemoglobin bound glucose TZDs Thiazolidine diones
GLP-1 glucagon like peptide-1

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24
Thyroid Drugs
Thyroid Drugs

Hypothyroids
Hyperthyroid

Thyroxine (T4) Triidothyronine (T3)


Synthroid, Eltroxin

131
Thioamides: Lugol's solution (10% KI + 5 %I) I
Methimazole
Propylthiouracil (PTU)

Drug Name Trade Name Drug Name Trade Name


Levothyroxine Eltroxin, Synthroid Methimazole Tapazole
Propylthiouracil Propyl-Thyracil

Levothyroxine

Levothyroxine Eltroxin, Synthroid


Mechanism A major hormone of thyroid gland
Therapeutic Hypothyroidism, goiter, thyroid cancer.
use
Side effects Rare side effects such as anxiety, diarrhea, weight loss, sweating,
insomnia, and muscle cramps.
Drug-drug Antiepileptic, cholestyramine, and sucralfate, iron, Ca and antacids may
interaction reduce the absorption of levothyroxine. Levothyroxine may increase the
effects of warfarin. Take in the morning. Take empty stomach. Glycemic
control may decline with initiation of levothyroxine, potentially necessment of
antihyperglycemic agents.
Over dose Symptoms of hyperthyroidism if over treated possible exacerbation of angina.
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Toxic symptoms are nervousness, palpitation, intolerance to heat and


unexplained weight loss.
Monitoring Periodic tests of thyroid function (normal serum TSH 0.3 mU/L to 6 mU/L).
Monitor TSH levels to adjust initial dosage after 6 to 8 weeks then as required
or annually adrenal insufficiency may adrenal insufficiency may have to be
increased during pregnancy to maintain TSH in desired range. Check TSH each
trimester and 4 to 6 wk after any dosage adjustment.
Food and May decrease absorption of levothyroxine by iron salts, cholestyramine
drug colestipol, and sucralfate.
interactions

Methimazole

Mechanism • Potent inhibitor of thyroid peroxidase enzyme (TPO). This TPO is


responsible for iodination of tyrosine residues to form iodotyronine.
• Inhibit the synthesis of T 3 and T 4 by inhibiting the iodination of
tyrosine in the thyroglobulin.
• Blocks the coupling of the iodo thyroxine.
• Do NOT prevent the uptake of iodine by the gland.
• Obvious effects are very slow since it takes 3 to 4 weeks before the
hormone levels show a decrease.
Pharmacokinetics • Well absorbed, slow excretion and t 1/2 is 6 hours. Both drugs
accumulate in the plasma.
Similarities • Both cross the placental barrier and can accumulate in the thyroid
between gland of the fetus.
Carbimazole and
Methimazole
Side effects Agranulocytosis is rare but the most serious SEs of thioamide therapy.
This can occur suddenly in first 3 mo of therapy. (it sudden so routine
monitoring of CBC is not done). Lupus like syndrome and arthralgia can
occur after 6 mo.
Hepatotoxicity shows up in first 3 mo of therapy.
Propylthiouracil

Mechanism • Manage the overactive thyroid gland. Inhibits the conversion of T 4


to T 3 . Thus thyroid hormone synthesis is decreased.
Therapeutic use • Hyperthyroidism. Drug of choice in pregnancy
Side effects • Reduction in white blood cells leading to the risk of infection
• Nausea and vomiting, joint pain, headache, rash and itching,
• Jaundice, fever.
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Pharmacokinetics • Propylthiouracil rapid absorption after oral administration


• Peak serum levels seen after 1 hour t 1/2 is only 2 hours
• Extensive first pass metabolism. Excreted by the kidneys as
glucuronide (inactive).
• Preferred in pregnancy for it does not cross the placental barrier .
• Strongly protein bound. Secreted in breast milk less than
methimazole.
Disadvantage • More agranulocytosis seen than that of methimazole
Contraindication • Prescribed with caution in pregnant mothers. There is risk of goiter
and hypothyroidism in the newborn infant if too high dose is used.
Reduce dose to infant and children.
Monitoring • Periodic tests of thyroid function, and blood cell counts.
Stop taking drug • Jaundice
and call physician • Sore throat and fever (symptoms of agranulocytosis).
NOW

Iodides

Mechanism • Inhibits the uptake of I 2 by a tyrosine


Therapeutic use • Used in the treatment of thyroid storm
Doses • Therapeutic doses (>6mg/day)
• Results observed within 2-7days

Withdrawal • Causes thyrotoxicosis


Contraindications • Should be avoided in pregnancy as it crosses the placental barrier
thus causing fetal goiter
Side effects • outbreak of acne
• Swollen salivary gland
• Ulceration of the mucous membranes
• Conjunctivitis
• Rhinorrhea
• metallic taste
• Bleeding disorder
• Anaphylactic reaction
Iodide preparations • Lugol's solution (KI + I 2 )
• Oral drops
• May cause stains

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RadioactiveIodine(I131isomerofiodine)

Mechanism • Emission of b-rays, gets incorporated into the storage facility


Therapeutic use • I131 isomer of iodine is used in the treatment of thyrotoxicosis
Pharmacokinetics • Sodium I131 given orally and well absorbed from the GIT
• t 1/2 is 5 days.
Advantage • East admission
• Cheap
• Very effective
• Absence of pain
Disadvantage • Radiation- induced genetic damage
• Leukemia
• Neoplasia
• Cannot be administered to pregnant and nursing mothers cross
placental barrier secreted into the breast milk
Dose • Stop for 5-7 days then give I131
• Take 12 weeks for the glands to be reduced in size
Complications • Hypothyroidism

Tips
• Why is it beneficial to add propranolol to a drug regimen of a patient diagnosed
with hyperthyroidism?→ to decrease heart rate
• What factors changes required dose adjustment in patient using Synthroid?→
age, weight, heart rate and CVD
1 PTU 2 Serum TSH 3 TSH
4 Hyperthyroidism 5 Deiodinase enzyme 6 Calcitonin
7 Hypothyroidism 8 Lugol’s solution 9 Propranolol
• Stimulated by hypercalcemia. ( 6 )
• Secreted from pituitary gland (anterior) (3)
• Monitoring parameter for hypothyroidism. (2 )
• DOC in pregnancy for hyperthyroidism. (1 )
• What condition has the following symptoms; cold intolerance, constipation,
hypertension, bradycardia, and puffy . (7)
• Graves disease, and Plummer disease. (4)
• Myxedema, and Hoshimoto. (7)
• T 4 metabolized to T 3 by what enzyme. (5)
• Its symptom is sweating. (4)
• 10% KI +5% I solution. ( 8)

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• Addition of this drug to a drug regimen is beneficial to patient diagnosed with


hyperthyroidism to decrease tachycardia. (9)
• Direct effect of thyroid hormone on heart  increase heart rate, stroke volume
• In treatment of hypothyroidism with T 4 have effect on  fetus

SELECT TRUE OR FALSE STATEMENTS


• Calcitonin is stimulated by hypercalcemia (True/False)
• TSH is secreted from anterior pituitary gland (True/False)
• In treatment of hypothyroidism with T 4 have effect on fetus? (True/False)
• Hypothyroidism is monitored by serum TSH (True/False)
• Drug of choice in pregnancy for hyperthyroidism is propylthiouracil (True/False)
• Hypothyroidism symptoms are sensitive to cold, bradycardia, weight gain,
constipation, hypertension (True/False)
• Hyperthyroidism is also called Graves' disease and plummer disease (True/False)
• Hypothyroidism is also called Hoshimoto disease and myxidema (True/False)
• Levothyroxine T 4 metabolized to T 3 in liver by deiodinase enzyme (True/False)
• Discontinue antithyroid if patient notice even a single rash (True/False)
• Sweating is symptom of hyperthyroidism (True/False)
• Lugol's solution is KI +I 2 (True/False)
• Lugol's solution can stain. (True/False)
• Diltiazem has been shown to be comparable to propranolol in lowering heart
rate and blood pressure. (True/False)

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25
Gonadal Hormones
And Antagonists
Gonadal Hormones
Ovary
Testes

Testosterone
Estrogen Progesterone
Testosterone
17β-Estradiol Norethindrone Anabolic steroids
Estrone Norgestrol
Norethynodrel
Testosterone Antagonist
Desogestrel
Estrogen antagonist Finasteride
Medroxyprogesterone
Tamoxifen Dutasteride
Clomiphen Cyproterone
Estrogen agonist + Progesterone Nonsteroidal
antagonist (SERM) antagonist Flutamide
Raloxifine Mifepristone Bicalutamide
(RU-486) Nilutamide
Sex hormones
Included in this category are androgens (male sex hormones), estrogens (female sex
hormones) and progestins. These chemicals are needed for the development,
maintenance and function of the sexual organs and are necessary for normal pregnancy
to occur, be maintained and for birth. Clinical Uses for Various Estrogen Preparations

Estrogen
Estrogens are female sex hormones that are used primarily to decrease bone loss and to
treat the symptoms of menopause. Estrogen is used to reduce or prevent osteoporosis
in susceptible women. Estrogens decrease the frequency and severity of hot flashes as
well as the dryness in the vagina that many post-menopausal women experience.

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Estradiol and Estrone (Exist in body in equilibrium)


Estriol
Ethinyl estradiol; 17 alpha estradiol
Mestranol
Quinestrol; used for estrogen replacement therapy (HRT)
Diethylstilbestrol; Non steroidal synthetic estrogen (stilbene
derivatives)
Therapeutic use Estrogen is component of all brands of oral contraceptive pills.
Estrogen is used to reduce or prevent osteoporosis in susceptible
women. (Both senile and post menopausal)
Estrogen is component of Diane 25 & 35 and Alesse oral
contraceptive that are used for the treatment of acne.
HRT (hormone replacement therapy) is used to treat menopause
symptoms such as Vasomotor symptoms, vaginal atropy,
psychological disorders. To treat prostate cancer. To treat primary
hypogonadism.
Side effects GI. Nausea and vomiting are the most common weight gain,
diarrhea
CNS. Headache, breast tenderness.
CVS. Edema, hypertension, stroke, MI, increased risk of
thromboembolic diseases. Prolonged used of unopposed estrogens
(estrogen given without progesterone) in postmenstrual women
increases the risk of endometrial cancer.
Chloasma. skin pigmentation.
Contraindications Deep vein thrombosis or (thromboembolic diseases), coronary
artery diseases, vaginal bleeding, migraine with aura, active liver
disease.
breast cancer and pregnancy.

Estrogen. Increase blood coagulation by decreasing antithrombin effect, thereby


increase risk of edema, hypertension, stroke, MI, and increased risk of thromboembolic
diseases. Estrogen ↑ risk of endometrial cancer and ↑ risk of breast cancer.

Antiestrogens

Tamoxifen, and Clomiphene


Mechanism Inhibit or modify the action of estrogen
These drugs are non-steroidal antiestrogenic compounds equally effective
in oral or injection.
Therapeutic Tamoxifen is used to treat breast cancer
use Clomiphene. Fertility drugs
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Tamoxifen

Mechanism • Tamoxifen competes for binding to the estrogen receptors thereby


inhibits the action of estrogen.
Indication • Tamoxifen is indicated in advanced breast cancer in postmenopausal
women.
Side effects • Hot flashes. Low emitogenic or least nauseating anticancer drugs.
Vaginal bleeding, menstrual irregularities and risk of endometrial
cancer.
Clomiphene (Clomid)

Mechanism • Clomiphene interferes with negative feedback of estrogen on


hypothalamus and pituitary thereby increases the secretion of
gonadotropin releasing hormone (GnRH) and causes stimulation of
ovulation (partial agonist and antagonist).
Therapeuti • Clomiphene is used to treat infertility associated with anovulatory cycles.
c use
Contraindic • Not effective in women whose ovulatory dysfunction is due to pituitary
ation or ovarian failure.
Side effects • Dose related, ovarian enlargement, vasomotor flushes, and visual
disturbances, could give multiple birth.

SelectiveEstrogenReceptorModulator(SERM)

Raloxifene
Reduces bone resorption thereby decrease bone turnover.
• Exhibit estrogen like (agonist) effect on bones and lipid metabolism. Exhibit estrogen
antagonist action on uterine and breast tissues.
• Therapeutic use in prevention of osteoporosis.

Progesterone

Progestins are female sex hormones that may be used with estrogens in oral
contraceptive pills, hormone replacement therapy, and treat menstrual irregularities,
and as cancer treatment.

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Classification of Two types of progesterone


progesterone. • 17-alpha hydroxyprogesterone
• Medroxyprogesterone acetate
• Megestrol acetate
• 17-alpha ethinyl androgens (androgenic progesterone's)
• Norethindrone
Important! • Norethynodrel
1) Androgenic
Commonly used in combined oral contraceptives because
progesterone like
Potent oral activity
norethindrone are
More lipid soluble
potent.
Less first pass metabolism

Mechanism • Progestins in females promote the development of a secretor


endometrium that can accommodate implantation of newly formed
embryo.
• The high level of progestins produced in second half of menstrual
cycle inhibits the production of gonadotropins and thereby further
ovulation.

Therapeutic use • Major clinical use in contraception, generally used with estrogen.
• Not widely used as alone because of its rapid metabolism results in
low bioavailability.
• Progestins are indicated in uterine bleeding, dysmenorrhea,
suppression of postpartum lactone, and endometrium cancer.
• Endometriosis
Side Effects • Weight gain, edema, and depression. Menstrual irregularities
(breakthrough bleeding, amenorrhea).
• Androgen like progestins can increase LDL and HDL ratio cholesterol,
weight gain and edema. Hirsutism, and acne can cause
thrombophlebitis (inflammation of wall of vein).

Antiprogestins-Mifepristone

Mifepristone (RU – 486)


Mechanism Progestin antagonist with partial agonist activity
Mifepristone also has anti glucocorticoid property.
Causes abortion if administered in early pregnancy (85%)due to
interference with progestins and decrease in production of hCG (human
Chorionic Gonadotropin).
Therapeutic Abortificient. Administration of mifepristone used as contraceptive given
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use once a month when progestin levels are high (Prostaglandin E1 and
misoprostol orally after single dose of mifepristone effectively terminates
the gestation.
Side Effects Uterine bleeding, and possibility of incomplete abortion.

Androgens

Testosterone is the androgen that leads to the development of male secondary sexual
characteristics and maintains the male reproductive system.

Androgens are used to treat delayed puberty in males who do not develop normal
testicular function. They are also used illegally by athletes to build muscle mass. They
are very dangerous when used for this as they may lead to aggressive behavior, and may
cause liver and or brain tumors and death.

Androgens Danazol
Nandrolone and oxandrolone
Stanozolol
Fluoxymesterone

Mechanism Testosterone is commonly prescribed in the treatment of female breast


cancer, androgen deficiency, and for stimulation of growth, weight gain,
and red blood cell production. Commonly known as "anabolic steroids"
because they promote muscle growth. They are also commonly used to
help patients recover from a surgery and cancer treatment that resulted in
damage to muscle tissue.

Therapeutic • Used in males with inadequate androgen secretion.


use • Anabolic steroids can be used in sever burns, for speedy recovery from
surgery. Indicated in conjunction with other hormones in pituitary
dwarfism.
• Non-approved uses androgenic steroids in increase of lean body mass,
muscle strength, aggressiveness in body builders and athletes.
• Danazol indicated in endometriosis (ectopic growth of the
endometrium).
• Androgens orally ineffective.
Side effects • In males: priapism (continuous erection), impotency, and
gynecomastia.
• In females; masculinization, acne, hirsutism, deepening of voice,
menstrual irregularities.
• Contra indicated in pregnancy.

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• Increase LDL, decrease HDL levels, increase coronary artery disease,


and fluid retention (edema).

Antiandrogens.Finasteride

• Finasteride, Dutasteride, and Flutamide, Cyproterone acetate


Mechanism • Inhibit the synthesis of androgen. Finasteride inhibits the 5-alpha
reductase. Competitive and specific inhibitor of type II 5-alpha
reductase.
Testosterone ---- ---> Dihydrotestosterone
Therapeutic use • Indicated in BPH and to treat alopecia men who have lost scalp
hair.
Side effects • Decrease libido, sexual dysfunction. Breast tenderness, and
hirsutism.
• Hypersensitive reactions like rashes, pruritic, swelling face and lips
• and testicular pain.
Dose • PROSCAR 5 mg for BPH treatment. PROPESIA 1 mg daily for 3
months for hair growth in men.
Contraindication • Not indicated in woman and children. Woman should not handle or
break tablet when they are pregnant. Finasteride may cause
external genitalia abnormalities in male fetus.
Tips
• Finasteride is type II and dutasteride is type I and II isoenzyme
• The effect of vasopressin on kidney Antidiuretic

Abbreviation and Terminology


HRT Hormone Replacement Therapy LDL Low-density Lipoprotein
ADH Antidiuretic Hormone BPH Benign Prostate Hyperplasia
GnRH Gonadotropin-Releasing Hormone ACTH Adrenocorticotropic Hormone

Generic and brand


Tamoxifen Nolvadex, Soltamox Stanozolol Winstrol
Clomiphene Clomid Fluoxymesterone Halotestin
Mifepristone Mifeprex Dutasteride Avodart
Danazol Danocrine Flutamide Eulexin
Nandrolone Durabolin, Kabolin Cyproterone acetate Diane
Dutasteride Avodant

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26
Adrenal Corticosteroids
Glucocorticoids and mineral corticoids
Generic brand Generic Brand
Cortisone Cortone Triamcilone
Hydrocortisone A-hydroCort, Ala-Cort, Methylprednisolone Depo-Medrol, Medralone
Betamethasone Diprosone, Diprolene Ketoconazole Nizoral Shampoo, Nizoral,
Beclomethasone Beconase, Qvar , Spironolactone Aldactone, Spirono
Prednisolone AK-Pred, Econopred, Mifepristone Mifeprex
Prednisone Deltasone, Predone, Sterapred, Metyrapone Metopirone
Aminoglutethimide Aminoglutethimide
The adrenal hormones, or corticosteroids, are drugs with powerful anti-inflammatory
effects. These are used for replacement therapy in conditions such as, Addison’s
disease, a condition of adrenal insufficiency. In replacement therapy, the adverse effects
are minimal since hormones are being replaced and are not added to those already in
the body. Corticosteroids are used for their anti-inflammatory, antiallergic and
antistress effects. Prednisone is used as replacement therapy and also for its anti
inflammatory effects in many conditions, such as arthritis, allergies and asthma.

Glucocorticoids Mineral corticoids


“cortisones” Aldosterones
Middle layer of cortex Outer layer cortex
Anti-inflammatory, metabolizing Salt/water retention, anti-inflammatory
hormone
Hydrocortisone, prednisone, Fludrocortisone
betamethasone, dexamethasone,
budosenide, and triamcinalone.

Glucocorticoids potency ranking.


Topical glucocorticoids potency ranking Inhaled and intranasal corticosteroids
• Very high potency. Betamethasone (0.05%) • Beclomethasone
dipropionate, Clobetasol (0.05). • Budesonide (highly potent nonhalogenated
• High potency. Amcinonide, Triamcinolone steroid).

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0.5% • Flunisolide
• Medium potency. Betamethasone benzoate • Triamcinolone
(0.025), Triamcinolone 0.025 to 0.1 • Fluticasone
• Low potency. dexamethasone, • Mometasone (quick onset, more local
hydrocortisone absorption and lowest systemic absorption,
consequently fewest systemic SEs).

Glucocorticoids
Short acting (8- • Hydrocortisone
12 hour) • Cortisone

Intermediate • Prednisone
acting (18-36 • Prednisolone
hours) • Methylprednisolone
• Triamcilone
Long acting (1- • Betamethasone
3 days) • Dexamethasone
• Paramethasone
Mechanism • For anti-inflammatory corticoids: Glucocorticoids effects on the
distribution, concentration, and function of leukocytes. These
include decrease in concentration of lymphocytes T and B cells)
and increase in concentration of neutrophils.
• Decrease basophils, eosinophils and monocytes, and inhibition of
the ability of leukocyte and macrophages to responds mitogen and
antigen.
• The above Inhibitory response also results in reduce the amount of
histamine release from basophils to inhibit kinins.
Side Effects • High doses stimulate gastric acid and pepsin production and may
cause peptic ulcers.
• Chronic use causes sever bone loss (Due to decrease in calcium)
and myopathy leads to weakness
• Concentration of topical Glucocorticoids depends on site of use on
the body.
Drug and Food • Take with food.Should not be stopped suddenly, taper off or
interactions gradually decrease dose.
• Diabetic drugs: glyburide, chlorpropamide, glipizide, tolbutamide,
and tolzamide. Can rise blood sugar noticeably. Monitor blood
sugar levels
Therapeutic • To treat severe allergic reaction
use • To treat chronic ulcerative colitis
• To treat nephrotic syndrome and renal diseases
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• Topical agent to treat diaper rash and dermatitis


• Topical agents for ophthalmic disorders
• To treat rheumatic carditis
• To treat severe arthritis
• To treat acute and chronic adrenal deficiencies
• To treat nausea and vomiting associated with cancer
chemotherapy.
Side effects • GI. Peptic ulcer, hemorrhage, acute pancreatitis, ulcerative
esophagitis.
• CNS. headache increased IOP, muscle weakness, euphoria and
dysphoria.
• Hormonal. Weight gain, osteoporosis, hyperglycemia (diabetes),
flushing of face and neck.
• Cushingoid (moon face and buffalo hump) and increase risk of
infections.
• CV. edema and hypertension
• Skin thinning
• Growth suppression (interfere pituitary hypothalamic axis).

Tips

• What is steroid sparing drug → Leukotriene antagonist


• Steroid avoiders → Mast cell stabilizers
• Addison disease → Hypo corticosteroids
• Cushingoid disease → Hyper corticosteroids
• Inhale corticosteroids can cause oral thrush (Candida). How to minimize → rinse
mouth after inhalation.
• How do you minimize oral thrush caused by steroid inhalers  aerochamber and
rinse mouth after inhalation.

Find answers from the table:


1 Adrenal cortex 3 Leukotriene antagonist
2 Addison’s disease 4 Cushing syndrome
• Increase in cortisone cause ( 4 )
• Decrease corticosteroids cause ( 2 )
• What is steroid sparing drug ( 3 )
• Aldosterone is secreted from (1 )
• What is NOT a side effect of systemic corticosteroid therapy (urticaria)
• What are the common side effects of nasal and inhaled steroids? oral thrush (fungal
infections): nasal steroids gives nasal burning, nasal bleeding, throat irritation

26-3
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27
Oral Contraceptives
Oral contraceptives (birth control pills) are combinations of estrogen and progestins or
progestins only.

Mechanism
• The biological activity of OCs can result from the estrogen and/or progestin
component.
• Prevention of ovulation, alteration of cervical mucus and alteration of
endometrial lining.
• Provide (-) ve feedback to the pituitary gland resulting in suppression of FSH and
LH release from pituitary thus prevents the development and maturation of the
follicle egg, resulting in the prevention of ovulation.

Specifically, synthetic estrogen in the pill works to:


• Stop the pituitary gland from producing follicle stimulating hormone (FSH) and
luteinizing hormone (LH) in order to prevent ovulation.
• Support the uterine lining (endometrium) to prevent breakthrough bleeding mid-
cycle.

Meanwhile, synthetic progestin works to:

• Stop the pituitary gland from producing LH in order to prevent egg release.
• Make the uterine lining inhospitable to a fertilized egg.
• Partially limit the sperm's ability to fertilize the egg.
• Thicken the cervical mucus to hinder sperm movement (although this effect may
not be key to preventing pregnancy).

The combination preparations may be monophasic, biphasic or triphasic. They contain


various estrogens and progestins. Some common ones are listed:

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Oral contraceptives

Combination OCP Progestin only

Monophasic Biphasic Triphasic

Three types of combination products


Monophasic. Fixed ratio of estrogen to progestin through the menstrual cycle.

Biphasic. The amount of estrogen is fixed through out the cycle but the amount of
progestin varies (low in the first half and high in the last half).

Triphasic. Low doses of both hormones with minimal effects. The amount of both
estrogen and progestin varies through the cycle in different ratios.

Progestin only
Mechanism of Action. Alteration of cervical mucus, alteration of the endometrium to
inhibit implantation decreased side effects does not suppress the hypothalamus and the
pituitary to the same extent as the combination preparation thus low pregnancy
prevention rate increase in breakthrough bleeding.

Side effects of estrogen. Nausea, bloating, headache, and mastalgia


Side effects of progesterone. Weight gain, hirsutism, acne, tiredness, depression, ↓HDL
and ↑LDL.

Benefit of oral contraceptives:


↓ Dysmenorrhea
↓ Acne (Pimples)
↓ Endometriosis
↓ Osteoporosis
↓ Pelvic inflammatory disease (PVD)
↓ Risk of endometrial and cervical cancers

Component of an oral contraceptive is responsible for the following side effects


Hypertension Estrogen
Hyperglycemia Estrogen

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Hyperlipidemia Estrogen (so more gallbladder infection)


Post pill amenorrhea Progestin
Chloasma Estrogen
Depression Progestin
Ophthalmic disorders Estrogen

Absolute or complete contraindications


• Breast cancer and endometrial cancer
• Cerebrovascular disease (DVT and PE)
• Coronary artery disease myocardial infarction.
• Hepatic tumors and impaired liver functions.
• History of jaundice during pregnancy
• Genital bleeding
• Pregnancy and planning to pregnant
• Women over 35 year with smoker (more than 15 cigarettes/day).
• Uncontrolled hypertension SBP>160 and DBP>100.
• Migraine with aura

Side effects due to excess estrogen Side effects due to estrogen deficiency
Nausea and vomiting, dizziness Nervousness
Fluid retention; edema Dyspareunia (painful intercourse)
Bloatedness Vaginitis
Enlargement and tenderness of the breast Vaginal bleeding
Chloasma (skin pigmentation) Oligomenorrhea
Leg cramps
Alteration in cornea
Visual changes, headaches
Hypertension
Venous thrombosis
Pulmonary embolism
Depression
Side effects due to excess progestin Side effects due to progestin deficiency
Increase appetite Dysmenorrhea
Weight gain Decrease breast size
Oily skin and scalp Heavy menstrual flow with clots
Acne
Depression
Vaginitis
Increase hair growth

When to start oral contraceptive pills?

Miss pills Miss one pill. Take as soon as you remember and take usual pill next day.
This means that you might take two pills in a day.
• Miss two pills in a row.
• First two weeks. Take two pills the day you remember and two pills
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next day. Then take one pill until you finish pack.
• Use back up method of birth control, if you have sex in next seven
days of missing pill.
• Third week. Safely dispose remained pills and start new pack same
day. (If you’re on Sunday start schedule continue one pill until
Sunday). You may not have periods this month. If you miss two
periods in a row call doctor.

Emergency
Levonorgestrel 0.75 mg per dose (Plan B) or minipill or morning after pill.
Contracepti
ves
Progestin only. Very effective within 24 hrs and can be used up to 5 days
unprotected sex.
• Contains 2 pills (use 2nd pill after 12 hours of 1st pill).
• To treat nausea and vomiting associated with this pill can be treated
by dimenhydrinate.
Side effects Nausea (23.1%), vomiting (5%), dizziness, and fatigue and also progestins
side effects.

Tips

• Oral contraceptive that are used for the treatment of ACNE include Dian 35, and
Alesse. Diane 35 approved for acne only. (True/False)
• If missed one contraceptive pill? →Double dose next day
• Plan B is used for emergency contraception→ this should be used immediately
after unprotected intercourse.
• The most common side effect of plan B is nausea & vomiting (True/False)
• Absolute contraindications of OCP are pregnancy, CAD, DVT, breast cancer,
genital bleeding, uncontrolled BP, liver cirrhosis. (True/False)

Find answers from the table"


1 Ovral 2 Plan B 3 Condoms
4 nonoxynol-9 5 pregnancy 6 breast cancer,
7 Deep vein thrombosis 8 bleeding 9 Alesse
10 Dian 25 11 Nausea and vomiting 12 Dimehydrinate
13 Chloasma 14 Breast tenderness 15 Chest pain
16 Headache 17 Eye problems 18 Severe leg pain
19 Tampons 20 Evra patch 21 Nuva ring
22 IUDs 23 Depo provera 24 Abdominal pain

• Emergency contraceptive methods ( 1, 2 )


• Spermicidal: Vaginal contraceptive film (4)
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• contraception method may protect STDs and HIV (3)


• are contraindications of oral contraceptive pills (5, 6, 7, 8)
• Oral contraceptives used for acne (9, 10)
• is the common side effect of plan B (11)
• used as treatment for nausea and vomiting for contraceptives (12 )
• What contraceptive methods can cause toxic shock syndrome (TSS) ( 22)
• Applied for once a week, (20)
• the side effects of oral contraceptive pills (13, 14, 15)
• the danger signals of oral contraceptive pills (18)

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28
Osteoarthritis
Acetaminophen Betamethasone Synovial Fluid Replacement
Nonsteroidal Anti- Cortisone acetate Hylan G-F 20
inflammatory Drug Dexamethasone Hyaluronic acid sodium
Dexamethasone sodium Sodium hyaluronate
Methyl prednisolone acetate
Topical Pain relievers Prednisolone
Capsaicin Triamcinolone
Methyl salicylate Triamcinolone diacetate
Diclofenac

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Osteoarthritis Rheumatoid Arthritis


Stiffness Mainly affects on weight bearing In the morning (last 1 hour) stiffness, fatigue,
joints. myalgias, joint swelling (synovitis), joint pain,
Localized Morning or after inactivity (last weakness, low grade fever, loss of appetite.
Pain 30 min).
Limited affected joints. Not localized. Worsens with prolong
Worsens with activity or after inactivity. (usually improves with activity).
prolong use, (weight bearing Weight bearing and non weight bearing joints
activity). (involvement of small joints in hands and
wrists).
Painfull swollen joints
Affects on soft tissue
Inflammatio Uncommon Common
n
Risk factor >65 years Autoimmune inflammatory condition
Symptoms Degenerative joint disease caused Chronic systemic. Symmetrical synovitis
by breakdown of the cartilage affecting similar joints bilateral.
between bones, degradation of Inflammation.
articular cartilage in synovial
joints.
Treatment Drug of choice is acetaminophen Drug of choice is DMARDs (Disease Modifying
650 mg q4-6 h daily. Max 4 g/day. Anti-Rheumatoid Arthritis) drugs.
Physical Exercise (stretching, low impact, Exercise (aerobic)
activity aerobic, swimming, stationary
cycling, walking)

Acetaminophen
• Dose of acetaminophen for arthritis 650 mg Q4 to 6h maximum 4 g.
• No cross allergy with NSAID, ASA and Cox-II inhibitors.
• SEs. Rash and at high dose hepatotoxicity.
• Antidote is N-acetyl cysteine, should be administered with 8 hours of overdose
(binds to benzoquinoneimine reactive metabolite).
• Overdose. 7 to 10 g daily refer to poison control centre. Overdose 10 to 13 g daily
dose is lethal.
• 3 drinks/day alcohol ↑ increase risk of hepatotoxicity. Warfarin anticoagulant effect
is ↑>2 g is used.
• MO. AST and ALT elevated.

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NSAIDs. Diclofenac(IR,SR),etodolac,sulindac,pyroxicam,meloxicam,tenoxicam,ibuprfe
n,naproxen,ASA,diflunisal
• Avoid NSAIDS and COX II in ASA allergies. However acetaminophen can be used.
• Avoid concomitant use of 2 NSAIDs.
• Past history of GI ulcers, and avoid in CrCl <50 ml/min.
• ASA anticoagulant effect currently using warfarin avoid in age over 65 years due to
increase risk of GI bleeding and renal disease.
• All NSAIDs CI in severe renal disease (CrCl <30 ml/min) since NSAIDs can cause renal
failure.
• All NSAIDS can increase blood pressure and worsen pre-existing BP.
At initiating NSAIDs patient should be assessed for gastrointestinal, cardiovascular (MI,
stroke, fluid retention, hypertension) and renal risk factors and should be monitored for
toxicities.

Elderly patients, history of GI ulcers, cardiovascular disease patient taking long term
NSAID should be combined with PPI or misoprostol. (Diclofenac+misoprostol,
naproxen+esomeprazole)

Avoid NSAIDs including cox2 inh. If history of peptic ulcer disease, cardiovascular risk
factors, renal failure (CrCl <30), heart failure or asthma.

Topical NSAIDs
Diclofenac topical and Methyl salicylates
• For external use only, approved for treatment regiment not more than 3 months
duration (continuous or intermittent).
• SEs. skin dryness or irritation, hypersensitivity, serious GI toxicity has
NOT been reported.
• Note. Patient with GI ulcers history should avoid NSAIDs, Cox-II, anticoagulants, and
corticosteroids.
• Methyl salicylate. May increase warfarin anticoagulant effect. Avoid contact with
eye and mucous membrane.

Cox-2 inhibitors
Celecoxib
• Usual dose do not appear to have antiplatelets action.
• Contraindicated in sulfa allergy.
• Avoid in patient with serious heart diseases like congestive heart failure. Cox2 can
exacerbate hypertension, and promote edema.
The risk of increased cardiovascular events can occur with Celecoxib.
Avoid in pts history of MI, stroke, serious heart diseases, chest pain, CHF.
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Lumiracoxib (Prexig). Withdrawn due to CHF risk and fetal hepatotoxicity can get by
special access program of health Canada.

Topical Pain Relievers


Counter irritant. Capsaicin
• Takes 2 to 3 weeks for pain relief.
• Avoid contact with eyes and open wound.
• Do not apply large area of skin. Transient burning on application (Lidocaine can
decrease burning).

Methyl salicylate (Rub A-535)


• Avoid contact with eyes and mucus membrane warfarin anticoagulant effect is ↑.
• Avoid in ASA allergic patients.

Steroids
Intra articular injections. Methyl prednisone.
• Maximum 3 injections/joint/year. Minimize activity for 3 days after injection benefit
last 4-6 weeks inexpensive, safe and effective therapy for individual joints for esp.
hip, and knee).

Systemic corticosteroids
• Systemic corticosteroids are generally not use for OA. Local (intra articular) may be
used in case of signs of inflammation (minimum in OA) but take to max 3 injections
per year per joint (knee joint).

Viscous supplements. Hyaluron derivatives


• The hyaluron derivatives (also known as viscosupplements) have a longer duration
of action than the local corticosteroid injections. Usually given as a weekly injection
for 5 to 6 weeks, the effect is seen after the last injection (caution in case of allergy
to avian proteins/feathers/egg products). Weight bearing/strenuous activity should
be avoided within 48-72 hours following treatment. (also for corticosteroids 48 to 72
hrs).
• Note. The hyaluron derivatives (hyaluronidase) may also be used in the management
of extravasations caused by antineoplastic drugs/chemotherapeutic agents. (TC
pp1126 for agents causing extravasations).
• Hyaluronans. 1 injection/wk given once or repeated depends on product can give
pseudogout.

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Opioids

Morphine
• Lidocaine potential enhancement of opioids effect
• Oxycodone IR5-10 mg QID for short for acting formulations

Glucosamine sulfate. Short time efficacy in pain control.


Chondritin sulfate 1200 mg/d symptomatic benefit.

Tips

• Risk factors for renal toxicity associated with NSAIDs and COX II inhibitors include
 volume depletion, diabetes, age, and cirrhosis.
• Counseling of Capsaicin  Do not apply on open wounds, cuts, and eyes. Wash
your hand after applies. Do not apply on large areas.
• Osteoarthritis recommended? Weight bearing exercise (walk, run, jog, jump,
light lifting).
• Glucosamine/chondritin? Increase synovial fluid
• Viscous supplement hyluronic acid are? Long acting than steroids.

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29
Disease Modifying Antirheumatic Drugs
DMARD’s Drug Name Trade Drug Name Trade Name
Name
Cytotoxics Methotrexate Azathioprine
Gold preparations Aurothioglucose
Sodium aurothioglucose
Other DMARDs Cyclosporine Neoral Sulfasalazine Salazoprin
Hydroxychloroquine sulfate Penicillamine Cuprimine
Leflunomide Arava Tacrolimus
Minocycline
Biological Adalimumab Humira Etanercept Embrel
response Anakinra Kineret Infliximab Remicade
modifiers

A chronic inflammatory disease with frequent acute attacks. The immune system is
involved in attacking the joints and surrounding structures such as muscle tendons and
most other connective tissue. There is inflammation of the synovial membrane.

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Biological Response Modifiers

Infliximab, Adalimumab, Certolizumab, Golimumab, and Etanercept


Mechanism. Tumor necrosis factor alpha (TNFα), appears to responsible for tissue injury
in the disease. Infliximab. Antibody specific for tumor necrosis factor (TNFα). It does not
bind to TNF-β (lymphotoxin α). Inhibit interleukin-1 (IL-1), a key mediator of
inflammatory necrosis factor synovitis as well as bone and cartilage destruction.
• Improve the sign and symptom of active rheumatoid arthritis. Must be given with
methotrexate to prevent formation of antibodies.
• Infliximab is available as powder for injection in 20 ml single use vials containing 100
mg of the drug. The vials does not contain antibacterial preservative so solution
should be used immediately after reconstitution.
• Storage. Refrigerator (2 to 8°C), do not freeze. Administered by infusion every 8
week by iv.
• Most serious SE is respiratory tract infections (Pneumonitis), and tuberculosis.
Neurological problems include dizziness, visual disturbance and infusion site
reaction. Heart failure if >5 mg/kg/infusion.

Etanercept. Binds to the tumor necrosis factor (TNF alpha and beta).
• Given SC weekly 4 times, it is self injection.
• Side effects. Most common respiratory tract infections.
• Rituximab (Rituxan). B lymphocytes depletor.
• Abatacept (Orencia). T cell co-stimulation inhibitors
• Anakinra (Kinaret). Interleukin-1 (IL-1) receptor inhibitors.
• Toclizumab (Acterma). Interleukin-6 (IL-6) inhibitors.

Methotrexate

Mechanism • Folate analog that inhibits dihydrofolate reductase. This enzyme is


responsible for production of tetrahydrofolate cofactor necessary
for purine and thymidylate biosynthesis.
Therapeutic • Treat rheumatoid arthritis, an anticancer drug and treat
use uncontrolled psoriasis.
Side effects • GI SE nausea, vomiting and diarrhea are common.
• Flu-like aches Oral ulcers (mouth ulcer) treated by folic acid or
folinic supplements.
• Bone marrow and immunosuppressant leucopenia.
• Hepatotoxicity (liver toxicity) abnormal LFT.

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• Renal failure
• Pulmonary toxicities (pneumonitis) in children
• Susceptible to infections (P. carinii)
Dose • Starting 7.5 to 15 mg po Q wk. Increase by 2.5 to 5 mg Q 2-4 wk.
Maximum 25 mg/wk. Maintenance dose 7.5 to 20 mg po, sc or IM
Q wk (single dose if tolerated or divided in 2 or 3 doses Q12h).
• Effectiveness seen after 2 or 6 weeks and administered PO, IM, SC
• If GI upset occurs start 2.5 mg (12 h after) 2.5 mg (12 h after) 2.5
mg
• Methotrexate weekly doses 20 to 25 mg (orally or parenteral) for at
least three months.
• Concurrent use of folic acid reduces oral ulcers side effect. Alcohol
restriction may minimize hepatotoxicity.

Monitoring • Regular monitoring is mandatory. Baseline hepatitis B and C


serology, Chest X-ray, CBC, LFT’s and Creatinine Q 1 to 2
months
Pteridine + PABA

Dihydropteroate synthase Sulfonamide

Dihydropteroic acid

Dihydrofolic acid

Dihydrofolate reductase Trimethoprim, pyrimethamine

Tetrahydrofolic acid (THF)

THF cofactors

Thymine Purines Methionine


Glycine
f-met-tRNA
DNA DNA
RNA Proteins
Azathioprine

Therapeutic • Refractory RA
use • Mechanism cytotoxic agent that suppress T-cell activity
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• Azathioprine is cleaved in vivo to mercaptopurine.


Metabolism
• Drug interaction with allopurinol ( ↑ azathioprine toxicity),
decrease 1/4 dose of azathioprine.
Side effects • Hematologic. Leukopenia and/or thrombocytopenia and rarely as
agranulocytosis.
• GI effects. Nausea and vomiting
• Hepatic. Hepatotoxicity
Contraindicati • Pregnancy and children.
ons • Patients with rheumatoid arthritis previously treated with
alkylating agents (cyclophosphamide, chlorambucil, melphalan or
others) may have a prohibitive risk of neoplasia if treated with
azathioprine.

Hydroxychloroquine

Mechanism Anti-inflammatory and antimalarial


Therapeutic Treat rheumatoid arthritis, and malaria
use
Side Effects
Retinopathy. Irreversible retinal damage (but is rare. In its early form, it
appears reversible upon discontinuation of the drug).
Skin rashes and GI disturbances
Overdose For management of a suspected drug overdose. CPhA recommends that
management you contact your regional Poison Control Centre.

Sulfasalazine

Sulfasalazine: Azulfidine, Salazoprin


Mechanism • A chemical combination of sulfonamide and salicylate (5-ASA)
• Sulfasalazine is a relatively weak inhibitor of the cyclo-
oxygenase enzyme, but a potent inhibitor of 15-prostaglandin
dehydrogenase (PGDH), which is the main metabolic pathway
for the prostaglandins
Therapeutic use • Second line therapy in ulcerative colitis (UC)
Side effects • Blood dyscrasias: aplastic anemia, agranulocytosis, purpura,
thrombocytopenia and hypoprothrombinemia, pancytopenia,
macrocytosis
• Hypersensitivity: erythema multiforme (Stevens-Johnson

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syndrome)
• Skin: facial edema,
• Gastrointestinal: hepatitis, pancreatitis
• Nervous System: smell and taste disorders
Dose • PO or rectally
Pharmacokinetics • About 20% of sulfasalazine is absorbed in the small intestine
after oral administration
Contraindications • In patients with hypersensitivity to component of the product,
sulfonamides, or salicylates. In patients in whom acute
asthmatic attacks, urticaria, rhinitis or other allergic
manifestations are precipitated by ASA or other nonsteroidal
anti-inflammatory agents. Fatal anaphylactic reactions have
occurred in such individuals.
• In patients with intestinal and urinary obstructions.
• In patients with porphyria, as these drugs have been reported
to precipitate an acute attack.
• Infants under 2 year age
Allergies • If allergic to the following drug avoid sulphasalazine
• ASA, Furosemide, Thiazide diuretics, Carbonic anhydrase
inhibitors, Sulfonamides, sulfapyridine and Sulfonylureas
Counseling • Discolors urine and may color skin orange yellow.
• May permanently stain soft lenses
• Take drug after meals to reduce GI distress and to facilitate
passage into intestine.

Leflunomide (Arava)

Mechanism • Isoxazole immunomodulator, inhibits dihydrooratate dehydrogenase.


A rate limiting enzyme in de novo synthesis of pyrimidine.
Reduce lymphocyte proliferation.
Therapeuti • It reduces pain and inflammation and slow progression of structural
c use damage.
Side Effects • Diarrhea and nausea
• Weight loss
• Flu like syndrome
• Skin rash
• Alopecia
• Hypokalemia
Monitoring • Male patient have possible male mediated fetal toxicity. Reliable
contraception during treatment should be guaranteed.
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• Pregnancy must be avoided if either partner receiving leflunomide.


• Leflunomide T 1/2 4 to 28 days. Action in one month. Avoid in
pregnancy for 2 yrs.
• For men having received leflunomide and wishing to have children.
Plasma levels of active metabolite should be less than 0.02 mg/L.
Washout • Using cholestyramine resin.

Cyclosporine(Neoral)

Cyclosporin PO • Neoral or Sandimmune I.V


• 3-10 mg/Kg/day for RA
Therapeutic use • Kidney transplantation
• Organ transplantation rejection
• Psoriasis/Rheumatoid Arthritis/Nephrotic Syndrome
Side effects • Renal; very common: renal dysfunction
• CVS; very common: hypertension (particularly in heart
transplant patients)
• CNS; Very common: tremor, headache
• Metabolic; Very common: hyperlipidemia
Precautions • NSAID therapy should be discontinued or close monitoring of
renal function require.

Drug interactions Drugs that increase cyclosporin serum concentration (CYP3A4


inhibitors) such as Ketoconazole, fluconazole, and itraconazole
Macrolide antibiotics (mainly erythromycin and clarithromycin)
Corticosteroids, and oral contraceptives. Norethisterone or
danazol Calcium channel blockers: Diltiazem, Verapamil,
Nicardipine. Metoclopramide and grapefruit juice should be
avoided.
Drugs that decrease cyclosporin serum concentration (CYP3A4
inducers). As cyclosporin is metabolized by CYP3A4.
Phenytoin or phenobarbital, Rifampin i.v. Sulfadimine i.v. and
trimethoprim i.v. Nafcillin, Carbamazepine, Octreotide,
Barbiturates, Metamizole, Probucol, Orlistat, Hypericum
perforatum (St. John's wort), Troglitazone
Food and drug Grapefruit juice should be avoided
interaction

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Minocycline

Therapeutic use Rheumatoid arthritis


Acne
Chlamydia (lymphogranuloma, Psittacosis)
Rickettsia (Rocky mountain spotted fever)
Mycoplasma pneumonia
Lyme disease
Side Effects Less photo toxicity than tetracycline
CNS; Vestibular problems: dizziness, nausea, vomiting
GI; anorexia, nausea, vomiting, diarrhea, stomatitis, glossitis,
enterocolitis, pancreatitis, pruritus ani, constipation
Skin; maculopapular and erythematous rashes, SJS
Contraindication Pregnancy, children under 13 yrs, breast-feeding.
Newborns, infants and children. The use of tetracycline’s,
including minocycline, during tooth development in last half of
pregnancy.
Teeth and Bone. Dental staining (yellow-gray-brown) in infants of
patient who have last half term of pregnancy.
Drug and food Antacids containing aluminum, calcium or magnesium and oral
interactions iron preparations impair absorption and should not be given to
patients taking oral minocycline.

D-penicillamine

Mechanism Chelating agent


Therapeutic Wilson’s disease (excess copper), chronic lead poisoning
use Active rheumatoid arthritis, for refractory RA, if other drugs fail.
Side Effects Urticaria, Pruritis, Rashes, Bone marrow depression,
Thrombocytopenia, Leucopenia, Tinnitus, Proteinuria and
diarrhea (17%).
Non Wilson 5 to 10 mg of copper can administered as 5-10 drops of Copper
disease sulphate solutions in fruit juice twice daily (do not use in Wilson
patients disease patients). Penicillamine should be given empty stomach.
(increase absorption)

Gold sodiumthiomalate

Therapeutic • Treat Rheumatoid arthritis


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use
Side Effects • Most common
• Skin rashes
• Proteinuria (after IM admin.)
• Nitritoid reaction (low blood pressure and syncope after
injections)
• Pruritis (pruriginous), dermatitis
• Angioedema
• Thrombocytopenia
• Aplastic anemia
• Diarrhea
• Stomatitis
• Proteinuria
Post dose • Arthralgia, flushing, hypotension
reactions

Tips

• Which DMARD cannot be given for life →azathioprine


• Shorter onset of action in DMARDs →penicillamine
• Osteoporosis associated with the use of which of OA drug -->corticosteroids
• Which DMARDs require ophthalmic examination monitoring--> hydroquinolone
• Examples of TNF-alpha inhibitors -->Infliximab, adalimumab, Certolizumab,
etanercept, golimumab
• Pannus means Inflammation of the cornea or conjunctiva particularly in
trachoma
• Symptoms of rheumatoid arthritis is --> morning stiffness, and effects on weight
bearing and non weight bearing joints.
• Drugs that require eye exam? Hydrochloroquine.
• Stomatitis associated with methotrexate is treated by? Folic acid
• Infliximab cardiovascular side effects? Congestive heart failure. The role of TNFa
in reduce inotropic effects; reduce b-receptor mediated response and increases
myocardial cell apoptosis.
• TNF-alpha inhibitors SEs. Common bacterial infections, opportunistic infection
(TB), Malignancy, worsening of CHF.

Find answers from the table:


1 Azathioprine 5 Methotrexate 9 Leflunomide
2 Nutropin 6 Infliximab 10 ASA
3 Gold preparation 7 Folic acid 11 Hydrochloroquine
4 Corticosteroids 8 Penicillamine

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• Drug of choice for RA is DMARDs such as…(5)


• Which DMARD cannot be given for life. (1 )
• Mechanism of this drug is an antibody specific for tumor necrosis factor (TNF )
inhibitor (6)
• Drug used for RA and refractory Crohn’s disease. (6)
• Its storage conditions: refrigerator (2 to 8 oC). ( T/F )
• ASA antipyretic mechanism due to  Decrease in pyrogens.
• Its toxicity increases CO 2 (metabolic acidosis).
• Human growth hormone. ( 2 )
• It is used for rheumatoid arthritis, psoriasis, and as anticancer. ( 5)
• Mucositis (stomatitis) is side effects of which drug(s). (5)
• A patient taking methotrexate, to prevent bucal ulcer, should recommend. (7 )
• Which DMARD drug has shorter onset of action. (8 )
• Osteoporosis associated with the use of which of OA drug. ( 4 )
• Which DMARDs require ophthalmic examination monitoring. (5, 11)

TRUE OR FALSE

• Drug of choice in RA is DMARDs (Methotrexate) (True/False)


• Infliximab mechanism TNF alpha inhibitor (True/False)
• Infliximab storage conditions; refrigerator (True/False)
• ASA antipyretic mechanism due to PGE 2 inhibitor action inhibits pyrogen
(True/False)
• ASA toxicity ;metabolic acidosis, tinnitus (True/False)
• Nutropin is human growth hormone (True/False)
• Methotrexate used for RA, psoriasis, and anticancer (True/False)
• Mucositis (stomatitis) is side effects of methotrexate (True/False)
• Patient taking methotrexate, to prevent buccal ulcer, should recommend folic
acid supplements (True/False)
• Mucositis is side effect of methotrexate (True/False)
• Pannus means inflammation of cornea and conjunctiva (True/False)

Abbreviation and Terminology


DMARD Disease Modifying Antirheumatic Drugs CBC Complete Blood Count
RA Rheumatoid Arthritis UC Ulcerative Colitis
ASA Acetyl Salicylate NSAID Nonsteroidal Anti-Inflammatory Drug
TNF Tumor necrosis factor SJS Steven Johnson Syndrome
LFT Liver Funtion Test OA Osteoarthritis

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30
Gout and Hyperuricemia
Drugs to treat gout and hyperuricemia

Acute gout therapy Hyperuricemia therapy

NSAIDs Antimitotics Corticosteroids


Indomethacin Colchicines Dexamethasone Uricosurics
Phenylbutazone Hydrocortisone Probenecid
Sulindac Methyl prednisolone Sulfinpyrazone
Naproxen Prednisone
Triamcinolone Xanthine Oxidase
Inhibitors
Allopurinol
Fibuxistat

Generic Name Trade Name Generic Name Trade Name


Colchicine Allopurinol Zyloprim
Indomethacin Indocin Sulfinpyrazone Anturane
Probenecid Benemid, Probalan

Gout is a disease in which monosodium urate monohydrate (MSU) crystal deposit in


joints, soft tissues such as cartilage, tendon and bursa or renal tissues such as glomeruli,
interstitium tubules.

Gout arthritis involves 4 stages. Asymptomatic hyperuricemia, acute gouty attacks,


intercritical gout and tophaceous gout

Acute gout attacks are treated by anti-inflammatory drugs like NSAIDS (Indomethacin),
colchicine and corticosteroids. However, chronic hyperurecemia is treated by
antihyperuricemic agents like allopurinol, sulfinpyrazone and probenecid.

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Indomethacin

Mechanism • Anti-inflammatory action


Therapeutic • Use to treat gout arthritis
use
Side effects • Headache (10%). Indomethacin may cause renal damage or bone
marrow depression.
• Hepatotoxicity

Colchicine

Mechanism • Colchicine is as selective inhibitor of microtubule assembly, reduced


leukocyte migration and phagocytosis. The drug may also reduce
production of leukotriene B 4 .
• Because it reacts with tubulin and interferes with microtubule
assembly, this is general mitotic poison. Tubulin is necessary for normal
cell division, motility and much other process, therefore, colchicine has
systemic side effects if used in excess.
Therapeutic • Used only for gout, can be used as IV and low dose for hyperurecemia
use • Anti-inflammatory action and gives analgesic effect in gout attack.
Side effects • Diarrhea, nausea, and abdominal pain (GI distress).
• Chronic use can produce hemorrhagic gastroenteritis, hematuria,
alopecia, agranulocytosis and peripheral neuropathy
Drug-Drug • Taking cyclosporine with colchicine may lead to adverse effects on the
interactions kidneys.

Probenecid

Mechanism • Uric acid is both actively secreted and actively reabsorbed in the
kidney. Probenecid partially inhibits both the active secretion and
the active reabsorption.
• Uricosuric agents are weak acids that compete with uric acid, in
the S2 segment of the proximal renal tubule, for reabsorption by
weak acid mechanism
Therapeutic use • hyperuricemia
Side effects • Before using probenecid check to see that the patient is not a
high excreter of uric acid, otherwise the use of drug may
precipitate uric acid crystals in the kidney

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Counselling • Take plenty of water

Sulfinpyrazone

Mechanism • Uricosuric agent


• Sulfinpyrazone partially inhibits both the active secretion and the
active reabsorption
• Inhibits platelet aggregation
Therapeutic use • Gout arthritis
Side effects Urate crystal formation
Counseling Take plenty of water

Allopurinol(Zyloprim)

Mechanism Allopurinol is a suicide inhibitor of xanthine oxidase (XO)


Inhibits conversion of purine to uric acid.
Metabolism Allopurinol metabolizes to oxypurinol.
Therapeutic hyperuricemia
use
Side effects Hypersensitivity rashes, peripheral neuritis and necrotizing vasculitis
GI intolerance, diarrhea.
In condition with large purine turnover xanthine stone formation may occur.
Alkalinize the urine to increase solubility
Drug-Drug With 6-mercaptopurine like azathioprine (but not thioguanine).
interactions Must decrease by 1/4 if used with allopurinol.
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Xanthine oxidase is main biotransforming enzyme for 6-mercaptopurine.


Counseling Take plenty of water

Febuxostat. Xanthine oxidase inh.


Chemically distinct from allopurinol. (can be used in patient allergy to allopurinol). Can
be used in patients with renal disease.
Avoid. with azathioprine, mercaptopurine, theophylline due to inhibition of XO.
Uricases (Pegloticase and Rasburicase)
It is a uricolytic agent

Fenofibrate and losartan can be used as anithyperuricemic agents.

Tips

• What analgesic is not used in acute gout attack→ acetaminophen


• A uricosuric drug is one that  promotes uric acid excretion in urine.
Find answers from the table
1 Azathioprine 4 Allopurinol
2 Sulfinpyrazone 5 Probenecid
3 Uric acid 6 Colchicine
• Purine structure present in …( 4 )
• Take plenty of fluids (water) with  2, 4, 5.
• Anti-inflammatory and antimitotic, and analgesic effect. ( 6)
• The end product purine metabolism in human. ( 3 )
• Uricosuric agent ( 2, 5 )
• Mainly used for acute gout attacks. ( 6 )
TRUE OR FALSE
• Colchicine relieve pain in 24 hours Purine structure present in allopurinol,
nucleic acid bases (adenine, and guanine) (True/False)
• Take plenty of fluids (water) with allopurinol, sulfinpyrazone and probenecid
(True/False)
• Colchicine act as anti-inflammatory (True/False)
• The end product of purine metabolism is uric acid (True/False)
• Sulfinpyrazone is used as uricosuric agent (True/False)
• A uricosuric drug is one that increase excretion of uric acid (True/False)
• Colchicine is mainly used for gout arthritis (True/False)
• Decrease (1/3) dose of allopurinol if using with azathioprine (False)
• Examples of drugs may be useful as moderate uricosuric effect (losartan and
fenofibrate) (True/False)

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• Purine structure present in allopurinol, nucleic acid bases (adenine, and


guanine) (True/False)
• Take plenty of fluids (water) with allopurinol, sulfinpyrazone and probenecid
(True/False)
• Colchicine act as anti-inflammatory (True/False)
• The end product of purine metabolism is uric acid (True/False)
• Sulfinpyrazone is used as uricosuric agent (True/False)
• A uricosuric drug is one that increase excretion of uric acid (True/False)
• Colchicine is mainly used for gout arthritis (True/False)
• Decrease (1/4) dose of allopurinol if using with azathioprine (True/False)
• Examples of drugs may be useful as moderate uricosuric effect (losartan and
fenofibrate) (True/False)

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31
Osteoporosis

Osteoporosis Treatment

Bisphosphonates Calcium Parathyroid SERMs Zolindronic acid


Supplements hormones

Alendronate Raloxifene
Etidronate Calcium carbonate Teriparatide hydrochloride
Risedronate Calcium gluconate
Pomidronate

Generic Name Trade Name Generic Name Trade Name


Alendronate Fosamax Etidronate Didronel
Alendronate+Vit D Fosavance Risedronate Actonel
Raloxifene Evista
Overall reduction of bone mass is osteopenia, this resulting in thin, fragile bones that is
prone to fracture can be characterized as osteoporosis.
Paget’s disease is bone remodeling disorder, resulting in excessive bone resorption
followed by disorganized.

Screening
• All post menopausal women and men over 50 yr age.
• Bone mineral density testing for >65 yr age and high risk based on major risk factor.
• Height loss >4 cm total or >2 cm in 1 yr
• Steroid use >3 mo

Diagnosis
• Bone mineral density (BMD) scan using Dual Energy X-ray Absorptiometry (DEXA)
machine.
• Portable ultrasound
• X-ray

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• T-Score compares BMD values to healthy reference


• Normal > -1
• Osteopenia > -1 to -2.5
• Osteoporosis > -2.5

Non modifiable Risk factors Modifiable Risk factors


• Age >65 y • Low calcium intake (<1000 mg elemental calcium
• Vertebral compression fractures per day). LOW BMD.
• Postmenopausal woman (not on • Inadequate sun exposure or vitamin D.
estrogen therapy). • Cigarette smoking
• Premature menopause (<45 years) • Excessive alcohol intake
• Gender (female) • Caffeine containing beverages.
• Family history • Sedentary life style
• Thin and small boned • Excessive heparin therapy.
• Low body weight (<60 kg) or major weight • Oral corticosteroid therapy (at least 3 mo).
loss (>10% of weight at age 25).
• Hypogonadism
• Race. Asians, Caucasians.
• Hyperparathyroidism
• Hypocalcemia
• Rheumatoid arthritis

Calcium Supplements. A study shows 61% of adults with osteoporosis did not take
calcium supplements. Inadequate intake of calcium and vitamin increase risk of
osteoporosis.
• Calcium carbonate (40% elemental calcium)
• Calcium phosphate or Tricalcium phosphate or tribasic (39%)
• Calcium chloride (27%)
• Calcium citrate (21%)
• Calcium lactate (13%)
• Calcium gluconate (9.3%)

Calcium carbonate provides most calcium because it has highest elemental calcium,
some products of calcium carbonate are obtained from oyster example O-Calcium.
calcium gluconate has least elemental calcium.

Dose and administration


• Calcium carbonate is more soluble in acidic medium and therefore should be
administered before meals (empty stomach) when stomach acidity is highest.
• The K/DOQI guidelines recommend that the total dose 1,500 mg per day of
elemental calcium and the total daily intake from all sources not exceed 2,000 mg.
• Dose of calcium 4 to 8 year 800 mg/day and 9 to 18 year 1300 mg/day.
Perimenopausal woman not less than 1000 mg/day. Men and women over 50 year
1500 mg/day. Pregnant and lactating woman > 18 year 1000 mg/day.
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Calcium Drug Interactions. Acid suppressing agents such as H2RAs and proton pump
inhibitors may reduce phosphate binding capacity of calcium carbonate by increasing
gastric pH. Calcium acetate is better absorbed in alkaline pH. Calcium interaction
interact with drug such as thyroxin, tetracycline, quinolones, and bisphosphonates.

Vitamin. Active vitamin D is vitamin D3 (cholicalceferal).


Men and woman over 50 year 800 IU (20 mcg) day and under 50 year 400 IU (10 mcg)
day.

Bisphosphonates

Bisphosphonates. Alendronate, Residronate, Etidronate, Pomedronate, and


Zolindronoic acid (Zolindronate).

Bisphosphonates are synthetic analog of pyrophosphate that bind to the hydroxyapatite


that found in bone.
Mechanism • Decrease bone resorption via several mechanisms. Inhibition of the
osteoclastic proton pumps necessary for dissolution of hydroxyapatite.
• Decrease osteoclastic formation or activation.
• Increases osteoclastic apoptosis (cell death) thus decrease resorption.
• Bisphosphonates act as a potent, specific inhibitor of osteoclast
mediated bone death.

Therapeutic • Osteoporosis prevention and treatment. Treatment of post menopause


use bone loss. Treatment of glucocorticoid induced osteoporosis. Paget’s
disease. Excessive activity of osteoclasts. Metastatic bone cancer.
• Bisphosphonates have decreased rate of bone fracture in osteoporosis
and Paget’s disease patients.

Side Effects • Diarrhea, nausea, altered taste, abdominal pain, nighttime leg cramps.
Esophageal ulcers especially if not taken properly. Bisphosphonates
have NO known impact on cardiovascular diseases, or breast or
endometrial cancer.
• Osteomalacia (etidronate only).

Dose
and • Take first thing in the morning empty stomach and take with plenty of
administration water.
• Do not lie down for 30 to 45 min after medications (stay upright).
• Calcium supplements should be at least separated by 2 hours before or
after.
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Alendronate
• Alendronate increase bone mass of all skeleton, and reduces non vertebral fracture
or decrease vertebral fractures or all fracture (including hip).
• Available dosage forms 5 mg, 10 mg, 35 mg, 40 mg, and 70 mg once weekly.
Fosavance 70mg + 2800IU vitamin D QWK, and 70 mg + 5600IU vitamin D QWK.
• Prevention of osteoporosis in postmenopausal women once 5 mg daily.
• Treatment of osteoporosis in women 10 mg once daily or 70 mg tablet once weekly.
• Take empty stomach, 1st in the morning. Do not lie down 30-40 min.

Etidronate
• Increase bone density and secondary prevention of vertebral fractures.
• Etidornate and calcium is used in cyclical therapy to increase bone density
and prevents vertebral fracture . Etidronate 400 mg/day for 14 days than
76 days calcium 500 mg supplements. Calcium supplements are avoided during the 2
weeks of cycle etidronate.
• Calcium is taken between the cycles of etidronate.
• Etidronate has lowest anti resorptive activity.

Risedronate.
• It is almost same as alendronate. Risedronate has highest anti resorptive activity and
than alendronate.
• Risedronate available dosage forms 5 mg/day or 35 mg once weekly, 75 mg two
consecutive weeks for 1 mo. or 150 mg Q month.
• Take at least 30 min before the first food, beverage, or medication. NOT lie down
for 30 min after taking.
• SEs. Esophageal ulceration, night leg cramps, GI symptoms taste changes.

• Zoledronoic acid intravenous 5 mg once yearly.


• Pomidronate 30 to 60 mg iv over 2 to 3 hrs every 3 months.

Raloxifene

Mechanism • Selective estrogen receptor modulator (SERM). Estrogen like action on


bone and lipid metabolism and estrogen antagonist action in breast and
endometrium (has estrogenic and antiestrogenic activity).
Therapeutic • Prevents postmenopausal bone loss, increases bone density
use approximately 3%, decrease vertebral fractures.
Side Effects • Increase risk of deep vein thrombosis, avoid in who are pregnant and

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planning to become pregnant. Aggravate hot flushes.


• Co administration of cholestyramine reduces absorption up to 60%. Do
not take together.
• Lower cholesterol and LDL but no effect on HDL and TG.

Calcitonin salmon
Calcitonin is a hormone secreted from thyroid gland. Hypercalcemia stimulates the
production of calcitonin from thyroid gland. Calcitonin hormone helps bone formation
by transporting Ca from blood to bones.
Mechanism. Directly effect on osteoclast and decrease bone resorption through direct
effect.
Two products are available. Miacalcin 200 IU/day intranasally once daily. Common SEs is
nasal irritation. Calcimar, caltine 50 to 100 IU sc/day or Q 2nd day or 5 days/wk. Not
approved for osteoporosis.

Teriparatide (androgen analog)


A parathyroid hormone (PTH) analogue is an anabolic agent that cause a steady gain in
bone density and 50% reduction in osteoporotic fractures. It may also reduce the pain
associated with vertebral fractures.

RANK ligand inhibitor.Denosumab (Prolia). 60 mg once every 6 mo SC.


Human monoclonal antibody that binds receptor activator of nuclear factor-kappa B
(RANK) ligand.

Drugs used to treat osteoporosis


Generic/Name Pre Tre Tips
v. at
Bisphosphonates increase bone mass reduce risk of fracture (at least 50%).
Alendronate 5 mg daily, 35 mg weekly X X Take on an empty stomach
Fosamax 10 mg daily, 70 mg do NOT lie down for 30 min after taking.
tablet, CrCl <35 ml/min is NOT used. (all
bisphosphonates renally eliminated).
Fosavance 70 mg + Vit.D 2,800 X X Caution on vitamin D supplements
Once week units
70 mg + Vit D, 5,600
units.
Risedronate 5 mg daily, Risedronate/Ca (Actonel Plus Ca) 35 mg
(Actonel) 35 mg weekly, risedronate 1st day of week and next 6 days
75 mg on two calcium.
Risedronate/Ca consecutive days ACTONEL DR 35 mg weekly. 'Take with
(Actonel Plus) once monthly. 150 mg meals.
ACTONEL DR 35 monthly.
mg.

Etidronate Day 1 to 14 Etidronate X X Didrocal packaged with calcium in 3 month


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(Didronel) (day 15 to 3 mo) Cyclic kit.


Taken for 14 days every 3 months followed
by 76 days calcium 500 mg.
While taking etidronate do NOT take
calcium supplement.
Zoledronic acid 5 mg intravenous X also used for moderate to severe
(Reclast) infusion yearly hypercalcemia.
Pomidronate Parenteral injection used for moderate to
severe hypercalcemia.
Raloxifene 60 mg daily X X
(Evista)
Teriparatide 20 mcg subcutaneously X SEs. Leg cramps, hypercalcemia.
(Forteo) daily for up to 2 years
Calcitonin salmon 200 units intranasal X Health Canada Warning. Breast Cancer
(Miacalcin) daily, alternating nares
every other day
Denosumab RANK Ligand inhibitor 60 mg once Q 6 month SC inj.
(Prolia) (human MAB, binds Keep refrigerated
receptor activator
nuclear factor Kappa-B
ligand.

Tips

• Calcium carbonate (40% elemental calcium) provides most calcium. Usually


require an acidic environment for absorption.
• What is NOT risk factor of osteoporosis → obesity or overweight
• Recommended daily allowance of vitamin D is  400 to 800 IU
• Elderly may absorb calcium poorly due to  Decrease gastric acid secretion and
active vitamin D3 (1, 25 dihydroxy vit-D3 concentration).
• Paget’s disease of the bone  is a condition of abnormal bone formation leading
to skeletal malformation & abnormality.
• Risk factors of osteoporosis Post menopause, gender, family history, race,
inadequate Ca and vitamin D, and estrogen deficiency.
• Deficiency of estrogen, may cause? Osteoporosis.
Abbreviation and Terminology

SERM Selective Estrogen Receptor Modulator PTH Parathyroid hormone


SEs Side effects BMD Bone mineral density
DIs Drug Interactions H2RA H2 receptor antagonist
PPI Proton pump inhibitors

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32
Asthma and COPD

Bronchodilators Anti-inflammatory drugs

Leukotriene antagonists
Muscarinic Methyl
β2 agonist xanthene Corticosteroids Mast cell stabilizers
antagonist Leukotriene
Steroid avoiders
receptors antagonist
Theophylline (Steroid sparing)
Cromolyn sodium
Aminophylline
Nedocromil
Ipratropium (short acting) Zafirlukast
Tiotropium (long acting) Montelukast
Inhaled corticosteroids aerosol (ICS)
Fluticasone, beclomethasone, budesonide
oral. prednisone or prednisolone
iv. hydrocortisone, methyl prednisolone
Short acting (Rescue)
Albuterol (salbutamol)
Terbutaline Long acting (Maintenance)
Formoterol (full agonist), quick onset
Salmeterol (partial agonist)
Formoterol fumarate dihydrate (Oxeze)

Drug Name Trade Name Drug Name Trade Name


Salbutamol Ventolin
Salmeterol Advir, Serevent Fluticasone Flonase, Flovent
Metaproterenol Alupent Budesonide Entocort, Pulmicort, Rhinocort,
Terbutaline Brenthin, Bricanyl Beclomethasone Ati-Beclomethasone, Qvar,
Prednisone/ Inflamase, Formoterol + Symbicort
prednisolone Budesonide
Salmeterol + Fluticasone Adviar

Asthma is inflammatory disease that triggers by following factors (factors that increase
Triggers. Early asthmatic response. Symptoms only (i.e. bronchoconstriction).
Cold air, exercise, emotional stress, pets (cats, dogs), environments and non adherence.
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Late asthmatic response;


Worsening asthma
• Allergens (pollens, cockroach, molds, animal dander)
• Respiratory viruses
• Occupational chemicals
• Drugs; ASA, NSAIDs, beta blockers
• Food additives such as sulfites, tartrazine
• Air pollution (including cigarette smoke)
• GERD
• Sinusitis

Bronchodilators

Helps to open airways, decrease bronchospasm, and decrease mucus secretion.


Beta2 Agonist Short acting beta2 agonist (SABA) (onset 1- 3 min).
Salbutamol
Terbutaline

Long acting beta2 agonist (LABA)


Salmeterol
Formoterol (onset 1- 3 min and long duration 12 hours)

Mechanism • B2 receptors agonist relaxes airway smooth muscles through activation


of adenylyl cyclase (AC). This enzyme catalyses the formation of cAMP.
cAMP causes bronchodilatation, vasodilatation and inhibition of
mediator release.
• Slightly decrease peripheral resistance.
• Increase muscle and liver glycogenolysis.
• Relax uterine muscles.
• Increase release of glucagon
Therapeutic use • Treat Asthma
Short acting • Rapid onset of action and provide relief for 4 to 6 hours.
beta 2 agonist: • Indicated in symptomatic treatments, rescue agents, combat acute
Albuterol, bronchoconstriction.
terbutaline, • Albuterol, terbutaline, has little alpha1 and beta1 effects.
• Does not effect by COMT enzymes because these are activated by non
COMT.
• Inhalation route has less toxic side effects than systemic routes.
• Have less tachycardia, hyperglycemia, and hypokalemia effects with
inhalations routes.

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• Short acting are best reserved for treatment of acute exacerbations


and prophylaxis of exercise induce asthma.
Long acting • Salmeterol has long duration of action, providing bronchodilation for
beta 2 agonist: at least 12 hours, and slow onset of action.
Salmeterol • Indicated in maintenance treatment in combination with
corticosteroids especially for nocturnal asthma, EIA, and COPD.
• Not indicated in acute asthmatic attacks.
Side effects • Tremors (shaking) due to effect on beta2 receptors of muscles
• (short acting 1- 3 min. Cardiovascular SE (tachycardia, palpitation) due
to effect on beta1 receptors.

ShortactingBronchodilators (SABA)

Salbutamol Ventolin and others


Mechanism Sympathomimetics bronchodilator that relaxes the muscle surrounding
the bronchioles. Aerosol deposition depends on the particle size 2 to 5
µm, pattern of breathing, and size of the airways.
Therapeutic use Relieve symptoms of asthma, chronic bronchitis and emphysema.
Side effects
Fine tremor of the hands, anxiety, and tension restlessness.
Recommendation Inhalation is considered more effective because drug is delivered
directly to the bronchioles.
Contraindication Caution in diabetes, hyperparathyroidism, and cardiovascular disorders
Onset of Onset is 3-5 min
bronchodilator
Duration of 4-5 hours
bronchodilation

Long actingBronchodilators(LABA)

Salmeterol and Formeterol


Mechanism • It has longest duration of bronchodilation
Therapeutic use • Indicated In COPD And Emphysema
• Prevention Of Nocturnal Asthma
• Prevention Of Exercise Induced Asthma
Side effects • Dry And Irritated Nose, Throat (Inhalations), Tremors,
Nervousness, Cough Wheezing.
Drug-drug • There is an increase risk of low blood potassium levels when high
interaction doses of salmeterol are taken with corticosteroids, theophylline

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and diuretics.

Corticosteroids

Corticosteroids • Prednisone PO, Prednisolone PO, Beclomethasone, Budesonide,


• Fluticasone, Triamcilone
Mechanism • Steroids have no effect on the airway smooth muscles rather
decrease the number and activity of cells involved in airway
inflammation. (Macrophage, eosinophils, and T-lymphocytes).
• Prolonged use for several months reduces the hyper
responsiveness of smooth muscles.
• Anti-inflammatory response reduced by reversal of mucosal edema.

Therapeutic use • Asthma


• Allergic rhinitis
• Inhaled glucocorticosteroid are the drug of choice in moderate to
severe asthma that requires beta2 agonist more than once daily.
• Inhaled corticosteroids are deposited in the airway and mouth
• Severe asthma systemic glucocorticoids (short time use only)
• Glucocorticoids most effective when taken continuous.

Side effects • Oral thrush (candidiasis) and hoarseness. Can be reduced by rinsing
mouth or using spacer or aerochamber.
• Spacers or aerochamber reduces systemic side effects and reduces
thrush.
• Nasal sprays. Systemic absorption is minimal and side effects are
localized nasal irritation, nosebleed, sore throat, hoarseness, rarely
candidiasis.
Recommendation • To reduce corticoids side effects rinse and gargle mouth after
inhalations.
Combination Adviar. Salmeterol (LABA) + Fluticasone
products Symbicort. Formoterol (LABA) + Budesonide

Prednisone/Prednisolone

Mechanism • Prednisolone is the active form of prednisone, is a powerful


corticosteroid.

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Therapeutic use • Skin diseases, rheumatic disorders, and certain blood disorders.
Side effects • Long-term treatment with high doses can cause fluid retention,
indigestion, diabetes, hypertension and acne.
Drug-Drug • It may increase the adverse effects of diuretics.
interaction
Recommendation • Prolonged systemic use can lead to such adverse effects as
diabetes, glaucoma, cataracts, and fragile bones, and may retard
growth in children.
• Dosages are usually tailored to minimize these effects.
Fluticasone

Fluticasone • Flonase, Flovent


Mechanism • It does not produce relief immediately, so it is important to take
it regularly.
Therapeutic use • Prevent asthma attack (by inhaler)
• Prevent allergic rhinitis
Side effects • Fungal infection causing irritation of the mouth and throat
(inhaled form)
• To minimize side effects thorough rinsing the mouth and gargling
with water after inhalation is recommended
Monitoring • Periodic checks of adrenal functions may be required if large
doses are being taken.

Budesonide

Budesonide • Entocort, Pulmicort, Rhinocort, Rhinocort Aqua


Mechanism •
Therapeutic use • Prevent attacks of asthma but not stop an existing attack.
• Enema to treat ulcerative colitis
• Relieve symptoms of Crohn’s disease
Side effects • Fewer and less serious side effects
Drug-Drug • Ketoconazole and other azole antifungal can increase the blood
interaction level of oral budesonide.
Monitoring • When taking in a large dose, periodic checks may be needed to
insure the adrenal glands are working properly
• Children inhalers may have their growth (height) monitored
regularly.

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Beclomethasone

Beclomethasone • Ati-Beclomethasone, Qvar, Rivanase AQ


Mechanism •
Therapeutic use • Relieve the symptoms of allergic rhinitis and to control asthma
• Helps to reduce symptoms such as wheezing and coughing
• Given to people whose asthma is not responding to
bronchodilators alone.
Side effects • Fungal infections causing irritation of the mouth and throat
(inhalers)
Recommendation • Rinse mouth and gargle with water after each inhalation.
Monitoring • When large doses are being used, periodic checks is required to
ensure that the adrenal glands are functioning healthy.

Anticholinergics

Ipratropium Atrovent
Mechanism An anticholinergic bronchodilator that relaxes the muscles. surrounding
the bronchioles. Have longer effect but slower onset.
Therapeutic use Anticholinergics are effective bronchodilators and have low lipid soluble
and poor transport across membrane (does not cross blood brain barrier).
Side effects Anticholinergic

Onset of effect 5 to 15 minutes


Duration of 8 hours
action
Tiotropium • Long acting muscarinic blocker. Available as capsule administered by
(Spiriva) special devise handihaler.
Combivent • Ipratropium bromide + salbutamol (MDI) and nebulizers
All MDI Should shake before use.

Leukotriene inhibitors

Zafirlukast • Accolate
Mechanism • Inhibitors of LTC4 and LTD4 receptors. Steroid sparing properties (Instead
increasing steroid dose LTRA are added.

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Therapeutic Anti-inflammatory and bronchodilator activity. Reduce bronchospasm



use and associated symptoms that are mediated through leukotriene.
• Used for exercise induced asthma and the drug for ASA induced asthma.
Side effects • Sudden withdrawal of corticosteroid patient taking Zafirlukast
precipitated Churg-Strauss syndrome (Severe asthma with increase
eosinophil count in blood).
• Vasculitis angitis: A patchy inflammation of the walls of small blood
vessels.
Drug-Food • Zafirlukast; Food reduces bioavailability take 1 hour before or 2 after
interaction meals. Oral tablets taken an empty stomach
• Used in 12 year or over 12 year old only
Montelukast Chewable tablets and granules.
Mechanism Inhibitors of LTC4 and LTD4 receptors.
Therapeutic Have anti-inflammatory and bronchodilator activity
use Reduce bronchospasm and associated symptoms that are mediated through
leukotriene.
Used in exercise induced asthma and the drug of choice for ASA induced
asthma.
Side effects Headache, nausea and diarrhea, and abdominal pain.
Drug-Food Montelukast may be taken without regard to food.
interaction
Over 2 year old can be used

Theophylline and Aminophylline

Mechanism • (Aminophylline will breaks down to theophylline in the body)


• phosphodiesterase (PDE) inhibitors
• Alter intracellular calcium
• Adenosine antagonisms
• Increase circulating catecholamines
Therapeutic • Anti inflammatory action
use • Chronic asthma mainly decreases symptoms
• Bronchitis and emphysema
• Use as a preventive measure, and is added to standard therapy
Side Effects • GI effects. Nausea, vomiting, abdominal cramps, diarrhea, headache,
• CVS. Palpitation or tachycardia.
• CNS effects. Insomnia, seizures, dizziness, nervousness, restlessness
Recommend • Overdose causes seizures, and arrhythmias.
ation • Dosage should be adjusted based on serum levels
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• Sustain release theophylline allow for a longer dosing interval and


improve compliance. Compliance to oral theophylline also may better
than that inhaled bronchodilators and corticosteroids
• Oral therapy. Sustained released theophylline allows for longer dosing
interval and improve compliance

Monitoring Periodic checks on blood levels are require especially the serum level.
Theophylline are contraindicated in patients with hypersensitivity to
xanthenes compounds. Caution inpatient with peptic ulcers and seizure
diseases.
Factors that Increase theophylline clearance (decrease levels) in age 1 to 9 years, high
alter protein diet, smoking (tobacco, marijuana), fever, drugs such as
theophylline carbamazepine, phenobarbital, phenytoin and rifampin.
clearance
Decrease theophylline clearance (increase levels) in age (elderly, infants,
under 6 months age, premature neonates), CHF, fatty food, high
carbohydrate diet, liver dysfunction and drugs such as oral contraceptives,
non selective beta blockers, CCBs, macrolide antibiotics (erythro and
clarithromycin) , clindamycin, fluroquinolones (ciprofloxacin) , zafirlukast,
and allopurinol.

Cromolyn and Nedocromil

Mechanism • Mast cell stabilizer and has anti-inflammatory action.


Therapeutic use • Effective in prophylactic, has anti-inflammatory effect.
• Not used in acute asthmatic attacks
• Cromolyn administered by inhalation of microfine powder or as
an aerosol solution.
• Cromolyn poor absorption causes more side effects that can be
reduced by powder or aerosol formulations.
• Internasal cromolyn reduces allergic rhinitis symptoms
Side Effects Bitter taste. Irritation of nasal mucosa, pharynx, larynx

Chronic Obstructive Pulmonary Diseases


Chronic obstructive pulmonary diseases (COPD) is due to chronic obstruction in airway
passage. COPD and/or emphysema (high altitude sickness) and chronic bronchitis.
EMPHYSEMA is a disease in which the small air exchange sacs (alveoli) in the lungs
become permanently enlarged and damaged (alveoli walls destroyed) decreasing
oxygen absorption and resulting in shortness of breathe.
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CHRONIC BRONCHITIS is an inflammation of the airways in the lungs that causes lungs to
produce excessive amounts of mucus (phlegm). This reduces the flow of air to the lungs.
Onset age 45 years. The major risk factors are smoking (80-90%), family history,
occupational exposures to certain ducts and fumes, air pollution, second hand smoke
and asthma.

Chronic Obstructive Pulmonary Disease (COPD).

SABD
SAAC Ipratropium
SABA Salbutamol
Terbutaline
LABD
LAAC Glycopyrronium
Tiotropium
Aclidinium
LABA Formoterol
Salmeterol
Indacaterol
Combinations Salbutamol + ipratropium

ICS/LABA budesonide / formoterol


fluticasone/salmeterol fluticasone /
vilanterol
LABA/LAAC indacaterol/glycopyrronium
(LAMA/LABA) umeclidinium/vilanterol
PDE4 Inh roflumilast

Drug used for the treatment of COPD. Beta adrenergic agonists, corticosteroids,
ipratropium, and theophylline.
Patients with COPD, antibiotic or oral corticosteroid therapy in last 3 months use, a class
of antibiotic, which was not previously prescribed. Antibiotic therapy to treat chronic
bronchitis. Azithromycin, doxycycline, amoxicillin and quinolones. Do not use
erythromycin.

Abbreviation and Terminology


ASA Acetyl Salicylate LABA Long Acting Beta2 Agonist
NSAIDS Non-Steroidal Anti-inflammatory Drugs COMT Catechol-O-methyl transferase
SABA Short Acting Beta2 Agonist EIA Exercise Induce Asthma
COPD Chronic Obstructive Pulmonary Diseases CHF Congestive Heart Failure
CCB Calcium Channel Blocker PDE Phosphodiesterases

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Tips
• Theophylline inhibit activity of Phosphodiesterase (PDE) induction (True/False)
• Leukotrienes are chemical derivatives of arachidonic acid(True/False)
• Leukotrienes are produced from arachidonic acid by catalyzed by lipoxigenase
(True/False)
• Long term use of oral corticosteroids may cause osteoporosis, diabetes, Cushing
syndrome, susceptible to infections (True/False)
• Leukotriene antagonist act on LTC4 and LTD4 (True/False)
• Drug of choice for aspirin induced asthma LTRAs(True/False)
• Patient has COPD and pneumonia, what is drug of choice penicillin's doxycycline,
azithromycin(True/False).
• Oral contraceptive effect on theophylline decrease clearance of
theophylline(True/False)
• Dry cough is caused by accumulation of bradykinin(True/False)
• What is differentiating symptoms of asthma from COPD wheezing in asthma
• Smoking is very high risk factor for COPD(True/False)
• What asthma devices do not require shaking powder dose inhalers(True/False)
• Asthma exacerbations are NOT triggered by warm air(True/False)
• Obstruction of airways in lungs is referred as COPD (True/False)
• Permanent enlargement of alveoli is referred as emphysema (True/False)
• Highest clearance of theophylline in which age group 1 to 9 yrs(True/False)
• When can we use leukotriene receptor inhibitors to avoid or minimize use of
steroids (True/False)
• What is important to counsel in patient using steroid inhalers --> rinse mouth after
each use
• Histamines are released from mast cells and basophile(True/False)
• What kinds of changes can you expect to see in aminophylline solutions exposed to
air? --> crystal formation of theophylline

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33
Anticancer Drugs and Chemotherapy
Question Alerts!
Action of DNA
Examples of antimetabolites

Damage DNA or interfere with Inhibit synthesis of DNA, RNA or


replication of DNA functions, protein synthesis
Alkylating agents
Mechlorethamine Antimetabolites
Others 5-fluorouracil
Cyclophosphamide
Actinomycin D Cytarabine
Ifosfamide
Etoposide Mercaptopurine
Chlorambucil
Teniposide (azathioprine)
Melphalan Anticancer antibiotics
Amsacrine Thioguanine
Busulfan (Topoisomerase
Lomustine Methotrexate
Inhibitors)
Carmustine Free radicals
Doxorubicin
Streptozolin Bleomycin
Daunorubicin
Cisplatin Topotecan
Carboplatin Irinotecan
Dacarbazine Interefere with mitotic
Procarbazine spindle formation
Altretamine/Hexamet Vincristine
hylmelamine Vinblastine
Mitomycin Peclitaxel

Drug Name Trade Name Drug Name Trade Name


Fluoroucil Adrucil, Carac, Efudex, Cyclophosphamide Cytoxan, Procytox
Fluoroplex
Methotrexate Rheumatrex, Trexall Irinotecan Camptosar
Cytarabine Cytosar Carmustine BiCNU
Fludarabine Fludara Topotecan Hycamtin
Bleomycin Blenoxane Vincristine Oncovin
Mitomycin C Mitozytrex, Mutamycin Mercaptopurine, 6-MP Purinethol
Vincristine Oncovin, Vincasar Doxorubicin Adriamycin, Rubex

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Vinblastine Velban Dactinomycin Cosmegen


Docetaxel TaxotereT Mechlorethamine Mustargen
Etoposide Etopophos, Toposar Paclitaxel Taxol

Cell Cycle Phases


• All cells must traverse the cell cycle phases before and during cell division.
• Anticancer drugs may act on specific phase. Tumor cells are more responsive to
specific drugs.
• G0 phase – Resting phase
• G1 phase – Synthesis of enzymes needed for DNA synthesis
• S phase – DNA replication (DNA synthesis)
• G2 phase – Synthesis of components needed for mitosis.
• M phase. Mitotic tubule formation. Example vincristine, vinblastine, and peclitaxol.

Cell cycle phase specific drugs. More active against cells that are specific phase of cycle.
• G 1 phase. L-aspraginase and prednisone
• S phase. Methotrexate, 6-thioguanine, cytarabine
• G 2 specific. Bleomycin and etoposide
• M phase. Vincristine vinblastine, and peclitaxol

Cell cycle specific drug (phase-non specific)


• Alkylating agents, antitumor antibiotic and cisplatin.

Cell cycle non-specific agents


• Effective whether cancer cells are in cycle or resting phase radiation, nitrosoureas,
and
mechloretha
nime.

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Alkylating agents. Act by alkylating DNA. The most common site of alkylation
is N-7 position of guanine. The alkylating agent appear to be the most
effective on G 1 or S phase.
Highly reactive agent can alkylate or bind covalently with cellular components of DNA.

Cyclophosphamide

Cyclophosphamide • Cytoxan, Procytox


Mechanism • An alkylating agent use to treat cancer.
Therapeutic use • Lymphomas (lymph gland cancers)
• Leukemia
• Solid tumors (breast and lung)
• Also use for autoimmunediseases
Side Effects • Nausea, vomiting, and hair loss
• Irregular menstruation
• Can affect heart, lungs, and liver (acute hemorrhagic cystitis)
• Bladder damage in susceptible people
Drug-Drug • Phenytoin can increase the breakdown of cyclophosphamide
interaction • Allopurinol and phenothiazines can inhibit breakdown of
cyclophosphamide.
Contraindication • Not advisable for pregnant and lactating mothers.
Monitoring • Periodic checks on blood composition and on all effects of the
drug are usually required.

Antimetabolites.
Antimetabolites prevents the biosynthesis of normal cellular metabolites.
Inhibits essential components of cell synthesis by competing with the natural substrate
for enzyme involved in synthesis of cell components.

Mercaptopurine (6-MP)

Mechanism Inhibits purine synthesis


Analog of hypoxanthine
Structurally similar to allopurinol (purines)
Azathioprine an immunosuppressant exert effect after converting
6-MP.
Causes RNA and DNA dysfunction
Side effects GI; Nausea, vomiting, diarrhea
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Bone marrow depression


Hepatotoxicity
Doxorubicin

Mechanism Effect maximal at S and G2 phase


Anticancer antibiotics

Therapeutic use Widely used anticancer drug (breast, lung etc)


Side effects Irreversible cardio toxicity
Myelosuppression
Stomatitis
Alopecia
Nausea and vomiting
Compounding Should be carried in Vertical laminar air flow hood

Dactinomycin

Mechanism Anticancer antibiotics


Form stable DNA complex and interfere with DNA dependent
RNA polymerase
Side effects Major dose limiting toxicity—bone marrow depression.

Mechlorethamine

Mechanism Alkylating agent

Therapeutic use Primarily used in Hodgkin’s disease (malignant disease of


lymphatic tissue) as part of MOPP regimen (Mechlorethamine,
Oncovin, Prednisone, Procarbazine).

Side effects Severe nausea and vomiting


Sever bone marrow depression
Myelosuppression
Anorexia
Gonadal dysfunction

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Vincristine and vinblastine

Mechanism Mitotic spindle is part of cytoskeleton and essential for internal


movement occurring in the cytoplasm of all eukaryocytic cells.
Mitotic spindle is essential for partitioning two DNA daughter
cells.
Side effects Myelosuppression
Paralytic ileus
Alopecia
Stomatitis

Paclitaxel (Taxol)

Mechanism • Reversible microtubule inhibitor.


Side effects • Serious hypersensitivity reaction,
• Patient should be premedicated with dexamethasone and
diphenhydramine as well as H 2 blockers.
• Myelosuppression
• Peripheral neuropathy
• Alopecia
• Mucositis
• Anaphylaxis
• Dyspnea

Chemotherapy
The treatment of cancer with drugs is called chemotherapy. Antineoplastic drugs, also
referred to as chemotherapeutic agents, are drugs that are used to treat cancer.

Side effects of chemotherapy


Acute. Extravasation, Thrombophlebitis, hypersensitive reaction, Rapid tumor lysis
syndrome and nausea & vomiting.
• Extravasations effects the adjacent tissue. Leakage from iv line into surrounding
tissue resulting in inflammation and necrosis.
• Hand foot syndrome is cool hands and feet during treatment.
• Vesicant drugs damage to tissue/necrosis (burning at site of injection). Example
bleomycin, cisplatin, dactinomycin, donorubicin, vincristine, and vinblastin etc.

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• Thrombophlebitis (inflammation associated with thrombus). Patient with cancer


can develop thrombosis after chemotherapy. Due to activation of fibrinogen. To
manage thrombophlebitis administer offending agent slowly.

Hypersensitive reactions. Examples etopiside, peclitaxol, rituximab (28%),


trastuzumab. Manage by stop infusion.
• Rapid tumor lysis syndrome. Due to large number of tumor cells lysed by
chemotherapy.
• Nausea and vomiting

Chemo side effects Onset


Nausea and vomiting during infusion to days
Alopecia within weeks to months
myocardial ischemia within hrs to days
heart failure within mo to yrs
Anemia weeks to months

Chronic, organ specific.

• Skin.
• Alopecia, dry skin, nail changes, pigmentation (melanoma), and xerostomia.
• Alopecia is the loss of hair. Drug that causes alopecia is doxorubicin, daunorubicin,
cyclophosphamide, vincristine, and paclitaxel.
• Vessicant agents includes dactinomycin, doxorubicin, mechlorethamine, mitomycin,
vincristine, and vinblastine.
• Hair re-growth occurs after 1 to 2 months after stopping chemotherapy.
• Xerostomia. Dry mouth is one of the most common complications associated with
radiation therapy. Reversible after 6 to 12 months of therapy.
• Can be managed by sugar free hard candy, chewing sugar free gum stimulates
salivation. Ice chips, sugarless candies, and commercially available saliva substitute
or cholinergic agonist (Pilocarpine 5 mg tab).

Bone marrow depression (Myelosuppression).


• Complications. Bone marrow depression or suppression is the most dose limiting
side effect of cancer.
• Myelosuppression in general the onset is 7 to 10 days and peak is 10 to 14 days.
Recovery count occurs usually occurs in 2 to 3 weeks.

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• Bone marrow depression can cause neutropenia, and thrombocytopenia. Absolute


neutrophil count and platelet count (usually 10 d after chemotherapy)
and CBC before next dose of chemotherapy.
• Neutropenia treated by colony stimulating factors (G-CSF and GM-CSF) filgrastim or
pegfilgrastim.
• Thrombocytopenia for prevention use oprelvekin (Inerleukin-11).
• Megaloblastic anemia by methotrexate is treated folinic acid (leucovorin, 5-
formyltetrahydrofolic acid).
• Least bone marrow depression anticancer drugs is bleomycin.
• Cancer patient with anemia are treated by erythropoeitins.

Cardiotoxicity
• Risk of congestive heart failure (CHF), commonly seen with (anthracyclines)
doxorubicin, daunorubicin, epirubicin, mitoxantrone and trastuzumab.
• 5-FU, capecitabine can cause coronary spasms, or myocardial ischemia mimicking a
myocardial infarction (avoid in known coronary artery disease patients).
• Cardio toxicity can prevented or lessens by using cardio protective agent
dexrazoxane. Use of dexrazoxane (500 mg/m2) 30 min prior to administration of
doxorubicin protects against cardiomyopathy.

Neurotoxicity
• Common with vinca alkaloids such as vincristine, vinblastine, cytarabines,
methotrexate (very little), 5FU, and interferon alpha.
• Peripheral neuropathies associated with vincristine, peclitaxel can cause peresthesia
(numbness and tingling, pin feeling) can occur with vincristine, which often appears
within few weeks of therapy.
• High dose of cytarabin may produce cerebllar toxicity that manifest initially as loss of
eye hand coordination and progress to coma.
• Fludrabine cause severe neurotoxicity.
• Caramustine and other alkylating agents cause little or no neurotoxicity.

GI toxicity
Mucositis is generalized burning, and pain on the ventral surface of tongue. Floor of
tongue, mouth looks erythromatus.
Stomatitis is generalized inflammation of oral mucosa.
• Mucositis common with doxorubicin, methotrexate, 5-fluorouracil, actinomycin,
bleomycin and capecitabine.
• Recommend mouth hygiene, xylocaine, viscous sucralfate, nystatin, sodium
bicarbonate, for severe cases peliformin (growth factor) can be used. Avoid alcohol,
antihistamine, steroids, and spicy food.
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• Mucositis treatment and prevention. Topical anesthetics for small ulcers apply
benzocaine in orabase. For generalized mucositis topical rinses like viscous
lidocaine, or dyclonine 0.5 or 1%.
• Corticosteroid provides anti-inflammatory action.
• Capsaicin. Produces burning and pain and ultimately desensitizes pain.
• Sucralfate suspension may provide benefit by coating.
• For localized effect use benzocain in orabase.
• Mucositis prevention. Chlorhexidine gluconate 0.12%, may reduce severity
and frequency of mucositis infections.

Nausea and vomiting


• Very high emetics anticancer drugs (High >60%)
• Cisplatin
• Streptozocin
• Cyclophosphamide
• Carmustine
• High emetics anticancer drugs or moderate (30-60%)
• Doxorubicin, daunorubicin
• Methotrexate (250 mg to 1000 mg), 5-flurouracil, etoposide,
• Cytarabine, cisplatin <50 mg/m2
• Lowest emetic anticancer drugs low (<30%)
• Bleomycin
• Methotrexate (under 50 mg)
• Vincristine
• Vinblastine
• Tamoxifen
• Trastuzumab (Hercpetin)
• Rituximab
• Androgen

Management of nausea and vomiting associated with cancer chemotherapy


• The low emitogenic drugs nausea and vomiting is treated by dexamethasone,
metoclopramide, setrons, or chlorpromazine.
• High (moderate and very high emitogenic drugs) associated acute nausea and
vomiting is treated by serotonin 5HT 3 antagonist + dexamethasone + aprepitant
• Drug of choice to treat delayed nausea and vomiting dexamethasone.
• Anticipatory nausea and vomiting benzodiazepine.

Aprepitant is neurokinin (NK-1) receptor antagonist. Fosaprepitant is prodrug and used


iv.
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Acute. Starting within 24 hours of chemotherapy.


Delayed. Starting >24 hours after chemotherapy.
Anticipatory. Starting before chemotherapy as a conditioned response.

Hepatotoxicity

Hepotoxic drugs such as asparaginase, cytarabine, mercaptopurine, and methotrexate.


Hepatotoxicity monitor LFT, jaundice, or hepatitis

Nephropathy
Methotrexate may precipitate in kidney. Monitor elevate BUN and electrolyte
abnormalities: Cisplatin and streptozocin. Amifostine may be used to protect the kidney
from the nephrotoxicity associated with cisplatin.

Sexual dysfunction
Cyclophosphamide, melphalan, and procarbazine associated with significant infertility in
men and women.

Hemorrhagic cystitis
It is a bladder toxicity that is seen most commonly after administration of
cyclophosphamide and ifosfamide.
• These drugs produce a metabolite called acrolein. This cause chemical irritation in
bladder mucosa, resulting in bleeding.
• Hemorrhagic cystitis caused by acrolein can be prevented by excessive hydration
and subsequent frequent urination. The other method is by administering
uroprotecting agent called MESNA, which bind acrolein and prevent from contacting
the bladder mucosa.

Pulmonary toxicity
• Pneumonitis, pulmonary fibrosis commonly seen with bleomycin, carmustine,
cyclophosphamide, mitomycin, methotrexate, and vinca alkaloids.
• Symptoms of pulmonary toxicity includes SOB, non-productive cough, and rarely low
grade fever.
• The most common with bleomycin, mitomycin, and carmustine.

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• Rationale for combination therapy is overcoming or preventing resistance,


Cytotoxicity to resting and dividing cells. Biochemical enhancement of effect.
Beneficial drug interactions rescue host cells.
• Some agents can be administered intrathecally. Methotrexate, cytarabine, and
Thiotepa.
• Warning. Vincristine should be labeled as Intravenous only. Intrathecally vincristine
causes death.

Abbreviation and Terminology


MOPP Mechlorethamine, Oncovin, Prednisone, Procarbazine
PSA Prostate specific antigen
• Neoplasm. New and diseased form of tissue growth
• Benign neoplasms; Non cancer form of tissue growth, which can be removed by surgery. No
metastases.
• Malignant neoplasms; Cancer form of tissue growth. Invasive growth of cancer.
• Malignant neoplasms can be categorized as.
• Bone marrow; Leukemia (cancer of cells in blood)
• Connective tissue; Sarcoma
• Epithelium; Carcinoma
• Lymphoid tissue; Lymphoma (also named as Hodkins disease)
• Myeloid stem cells; Myeloid leukemia
• Endothelium; Kaposis sarcoma
• Skin (melanocytes); Malignant melanoma

Tips

• Melonoma is skin cancer


• dexamethasone are more effective to treat nausea related to chemotherapy
• Methotrexate is used to treat cancer, RA and psoriasis
• Which anticancer drugs cause pulmonary fibrosis→bleomycin
• Hypertropy is increase in cell size
• Hyperplasia is increase in number of cells (leads to tumor)
• Least emetic anticancer drug is bleomycin, tamoxifen, methotrexate
• Cancer patient on cancer chemotherapy, reports shortness of breath, non
productive cough, she may be using drug bleomycin
• Drug of choice for delayed nausea and vomiting → dexamethasone
• Mesna is uroprotective agent
• Doxorubicin preparation should be performed in →vertical laminar airflow hood
• Melatonin induce sleep
• Peclitaxel and docetaxel act on M phase
• Cancer estimated deaths in men: Lung cancer 31% and prostate cancer 11%
• Cancer estimated deaths in women: Lung cancer 25% and breast cancer 15%

33-10
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• Competitive inhibitor of estrogen is --> tamoxifen


• myelosuppression is dose limiting for --> peclitaxel, methotrexate and etoposide.
• What is the screening test is used for prostate cancer --> Prostate specific antigen
(PSA)

Find answers from the table


1 Metoclopramide 8 Filgastrim 15 Mesna
2 Tamoxifene 9 Methotrexate 16 5FU
3 cyclophosphamide 10 Bleomycin 17 Dexrazoxane
4 Carmustine 11 Mitomycin 18 Doxorubicin
5 Dexamethasone 12 Serotonin antagonist 19 Paclitaxel
6 Melatonin 13 Docetaxel 20 Etoposide
7 Erythropoeitins 14 lymphocytes
• Drugs that are considered to be more effective in nausea related to cancer
chemotherapy. (5, 12)
• It is used for RA, cancer and psoriasis. (9)
• Which anticancer drugs cause pulmonary fibrosis? (10)
• Least emetic anticancer drug is .. (10, 2,9 )
• Cancer patient on cancer chemotherapy, reports shortness of breath, non
productive cough, she may be using which drug. (10 )
• Drug of choice for delayed nausea and vomiting. (5)
• Drug of choice for acute chemotherapy induced N & V. ( 5+12)
• Uroprotective agent. (15)
• Example of drug preparation should be performed in vertical laminar airflow
hood. (doxorubicin, donorubicin)
• A neurohormone, it is a sleep-inducing hormone secreted by pineal gland in
response to darkness or low light levels. (melatonin)
• M phase (mitotic tubule inhibitor (19, 13)
• Examples of drugs that are antimetabolites? (5FU, 9, 16)
• Cardio protective agent in chemotherapy. (dexrazoxane)
• The most effected cells with antineoplastic drugs. (14)
• Filgrastim indicated for --> neutropenia
• Erythropoietin's are indicated for -->anemia
• Melonoma is skin cancer or pigmentation
• Hypertrophy is  Increase in cell size
• Hyperplasia is  Increase in number cells

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34
Gastrointestinal Drugs
GI Drugs

Antacids Foaming agents H2 receptor Proton pump


Aluminum hydroxide Alginic acid antagonists inhibitors
Calcium carbonate Sodium alginate Cimetidine Lansoprazole
Magnesium hydroxide Gatroprotective Famotidine Omeprazole
Sodium carbonate agent Nizatidine Pantoprazole
Sucralfate Ranitidine Rabeprazole
Esomeprazole

Generic Name Trade Name Generic Name Trade Name


Omeprazole Losec Cimetidine Tagamet
Lansoprazole Prevacid Famotidine Pepcid
Pantoprazole Pantolac Nizatidine Axid
Rabeprazole Ranitidine Zantac
Esomeprazole Nexium

Antacids

Antacids are used to treat stomach


upset, heartburn and sometimes Question Alert!
ulcers. They are simple chemical 1) Al and Ca gives constipation
compounds that are mildly alkaline, Mg antacids give diarrhea. (Mg = must go)
and some also act as chemical 2) Antacids DIs. Tetracycline, thyroxin,
buffers. They act by neutralizing bisphosphonates, and quinolone, H2RA, PPI
stomach and coating the mucosal and Ketoconazole, digoxin. separate 2 hr
lining of the stomach. Simethicone is
an agent added to antacids that helps relieve gas.

Types of antacids
• Aluminum hydroxide. SEs. Constipation
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• Calcium carbonate. SEs. Constipation


• Mg hydroxide, Mg trisilicate, Mg sulphate (Epson salts), Mg citrate. SEs Diarrhea
(Mg Must go)
• Na carbonate. SEs. hypertension
Magnesium salts are osmotic/saline laxative. onset of action is 30 min-6 hours.

Combined preparations
• Antacids combined with alginates or foaming agents.
• Alginates are intended to float on the content of the stomach to produce a
neutralizing layer to subdue acid that can otherwise rise into esophagus, causing
heartburn.
• Simethicone is antiflatulent agents are intended to relieve flatulence.

Side effects. Aluminum and calcium antacids cause constipation.


• Magnesium antacids cause diarrhea.

Drug interactions with antacids. Tetracycline chelation with bi and trivalent ions,
thereby this can reduce absorption of tetracycline. Antacids decrease absorption of
fluroquinolones, bisphosphonates, and thyroid hormones, by complexation.
Rosuvastatin, gabapentin, levodopa. Antacids increase absorption of levodopa
Ketoconazole and PPIs. The antifungal ketoconazole require acidic medium for
absorption. Concomitant use of antacids can reduce absorption of ketoconazole.

Antacids Drugs interactions Mechanism/ space timing Timing


Fluroquinolones, tetracycline, digoxin, Separate antacids dosing by 2 h
thyroid hormones, bisphosphonates.
Rosuvastatin, gabapentin?, levodopa Levodopa 1 hr, gabapentin and
rosuvastatin 2h
Ketoconazole and PPIs, H 2 RA PPI empty stomach,
ketoconazole?
Al, Mg, Ca, Alginates PRN after meals and
at bedtime as needed

Alginate/Aluminum hydroxide (Gaviscon liquid)--> take after meals


Alginate/Magnesium carbonate (Gaviscon tab) --> take after meals.
Sucralfate is taken?

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Proton Pump Inhibitors


Omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole
dexlansoprazole, are proton pump inhibitors, powerful anti-ulcerogenic drugs that
work by stopping the production of stomach acid completely.
Mechanism Irreversible inhibition of gastric parietal cell proton pump H+/K+
ATPase.
Therapeutic Prevention of reoccurrence of duodenal ulcers and esophagitis
use Pathology hypersecretory states. Multiple endocrine neoplasias
Healing of NSAID induces peptic ulcers. Systemic mastocytosis
A part of the eradication of H. pylori therapy. Drug of choice for
Ellison Zollinger Syndrome.
Duration Short term treatment (4 to 8 weeks).
Side effects Abdominal pain (nausea), diarrhea and headache

Drug Clopidogrel are potent inhibitors of CYP2C19 and PPIs are substrate
interactions of CYP2C19. Thus avoid combination of PPI and clopidogrel.
Pantoprazole has weak interaction, and can be combined.
Taken 30 min before food. May ↓ bioavailability of iron salts,
digoxin, ketoconazole, ↓ theophylline levels.

H2receptor antagonists

H 2 -receptor antagonists inhibit the action of a special type of histamine receptor


present in the stomach. This reduces the amount of gastric acid production, which
helps heal ulcers.

H 2 receptor Cimetidine, ranitidine, famotidine, and nizatidine


antagonists
Therapeutic 90% reduction in acid secretion and useful in promoting healing of
use gastric ulcers. Preventing reoccurrence of ulcers. Management of

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Zollinger-Ellison syndrome.
Side effects Gynecomastia. elevation of prolactin (cimetidine.
Headaches. famotidine and ranitidine, hematologic abnormalities
Decreased hepatic microsomal metabolism of some drugs like
cimetidine, which decreases the metabolism of warfarin, theophylline,
diazepam and phenytoin.
Diarrhea, constipation, fatigue, confusion, cardiac effects
Side effects are more common in elderly and decrease renal function
patients.
Tips Nizatidine is preferable used in elderly and renal disorder patients
Cimetidine and famotidine are now available without prescription in
some countries for the treatment of dyspepsia (2 weeks supply).
Drug Cimetidine: Increases the effects of anticoagulants. Inhibit CYP 3A4
interactions metabolism, thereby inhibit metabolism of warfarin, phenytoin,
theophylline.

Cytoprotective Agents (MucosalProtectiveSulfate)

Sucralfate binds to the ulcer site by forming a viscid sticky gel that coats the ulcer site
and acts as a protecting.

Sucralfate • Aluminum sucrose sulfate is a sulfated disaccharide.


Mechanism • Selectively binds to necrotic ulcer tissues (acts as a barrier to acid,
pepsin and bile). Directly absorb bile thus has chelating property.
Stimulates endogenous prostaglandin synthesis mucus secretion.
Therapeutic • Effective in the healing of duodenal ulcers
use • Reduces the number of H. pylori
Side effects • Causes constipation.
Dose • Dose 1 g qid, take empty stomach
Drug • Requires acid pH to be activated should not be administered with
interactions antacids, H 2 antagonists or proton blockers.

BismuthCompounds

Mechanism • Selectively binds to necrotic ulcer tissues


• Stimulation of mucous production
• Inhibition of pepsin activity
Therapeutic use • Possess antimicrobial activity against H. pylori
• When combined with antibiotics like metronidazole and
tetracycline has 98% healing rate for ulcer
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Contraindications • Should not be given in renal disease and pregnancy

GERD
• Mild GERD, relief of symptoms is with antacids, alginates or non-prescription
strength H 2 RA.
• Severe GERD. PPI are the drug of choice. Use PPI for 2 to 4 weeks.
• The goal is to raise the intragastric pH 4 during periods when reflux is likely to occur.

Peptic ulcers. The common cause of ulcers are due to H. pylori infection or drug induced.
• Gastric ulcers. Due to reflux since has weak pyloric sphincter
• Duodenal ulcers. Excessive secretion HCl from parietal cells
• Acute stress ulcers (Curling’s ulcer) can cause tumors.
• Pathologic acid-hypersecretory states is Zollinger-Ellison syndrome

Treatment of peptic ulcers


• Antacids neutralization of gastric acid.
• H 2 antagonist, proton pump inhibitors reduction of gastric secretion.
• Cytoprotection. Sucralfate
• Eradication of Helicobacter pylori → 2 antibiotics + PPI (triple therapy)

The goal of ulcer therapy is to eradicate H. pylori


• Triple therapy include 2 antibiotics + 1 PPI.
• Losec 1-2-3 A. Clarithromycin 500 mg bid + omeprazole 20 mg daily + Amoxicillin 1 g
bid.
• Losec 1-2-3 M. Clarithromycin 250 mg bid+ omeprazole 20 mg daily + Metronidazole
500 mg bid.
• Quadruple therapy. Tetracycline+ Metronidazole + bismuth subsalicylate +
Omeprazole.

Abbreviation and Terminology


IBD Inflammatory Bowel Disease
IBS Inflammatory Bowel Syndrome
IFN alfa Interferon alfa
GERD Gastro Esophageal Reflux Disease

Tips

• An example of ecosanide is misoprostol


• Misoprostol is PGE 1 analog used for mucosal protection in drug induced ulcers
• Type of pain in GERD is epigastric pain
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• Increase in bilirubin cause cholestatis


• Aluminum salts and calcium can cause SEs constipation
• Magnesium antacids cause SE diarrhea, and cathartic
• H. pylori will cause ulcers
• What type of hepatitis is chronic → hepatitis B and C
• What is treatment of hepatitis →interferon's
• NSAIDs induced ulcers can be treated by PPI
• Independent risk factors for peptic ulcers are H. pylori and NSAIDs (T/F)
• Chronic hepatitis? hepatitis B and C
• Epsom salt is? Magnesium sulfate
• Ulcerative colitis occurs at? colon
• Antiflatulance agent? Simethicone
• What vaccine can be used for traveler’s diarrhea? Dukoral
SELECT TRUE/FALSE STATEMENTS
• Na bicarbonate is contraindicated in-patient with hypertension, CHF, severe
renal disease, and edema. This also contraindicated in ulcers. (T/F)
• CaCO 3 antacids have rebound acidity due to stimulation of acid secretion.
• CaCO 3 antacids avoid in hypercalcemia patients. (T/F)
• Hypophosphetemia and osteomalacia can occur with long-term use of aluminum
containing antacids. (T/F)
• Antacids bind with tetracycline, and fluroquinolones and reduce absorption.
(T/F)
• Antacids may destroy coating of enteric-coated drugs. (T/F)
• Mg antacids can cause cathartic side effects. (T/F)
• Zollinger-Ellison syndrome is gastric hypersecretory states in systemic
mastocytosis which is a rare disorder with increase number of mast cells
systematically and in skin. (T/F)
• H. pylori is gram negative bacteria that cause gastric ulcer (T/F)
• sucralfate is taken --> empty stomach

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35
Drugs in Renal Diseases
Approximate renal dysfunction
Creatinine clearance range 80 to 120 mL/min and renal disease <50% renal elimination.
Rate of excretion = rate of filtration + rate of secretion - rate of reabsorption.

Cockcroft and Gault


Empiric dose adjustment estimate using the weight corrected creatinine clearance
(easier to calculate).

Male. CrCl (mL/s/70kg) = [(140-age) x 1.5]/serum creatinine (µmol/L)


Female. CrCl (mL/s/70kg) = 0.85 x above equation

The normal CrCl for 70 kg male (1.8 to 2 mL/s)

Nephrotoxic Drugs. Potential to worsen renal function if patient renal function is CrCl
(<0.5 mL/s/70kg).

A female 60 yr old, body weight 70 kg, patient SrCr is 100. Doctor wants to
prescribed nitrofurantoin. Doctor wants to know if suitable to prescribe?

CrCl = [(140-60) X 1.5]/100 = 1.2 ml/s/70 kg


female
1.2 x0.85 = 1.02 ml/s/70kg

A 68 yo patient with tonic-clonic seizure, as treatment plan, it has been


agreed that between consultant and you as his supplementary prescriber.
To initiate him levetiraceten on check his lab note. His SrCl 250 (µmol/L) and
weight is 65 kg. Find the CrCl ml per minute

CrCl (ml/min) = [1.23 x (140-age) x weight (kg)]/serum creatinin (µmol/L)


levetiracetam avoid <10 ml/min
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Avoid all of the following drugs.

NSAIDs, aminoglycosides, cyclosporin, bisphosphonates, foscarnet, glyburide, lithium,


cox 2, vancomycin
• Alendronate, clodronate, etidronate (nephrotoxic)
• Amphotericin
• Benzafibrate
• ASA, Celecoxib
• Indomethacin
• Ibuprofen
• Meloxicam
• Mefenemic acid
• Metformin
• Lithium
• Methotrexate

Drugs in renal diseases


Dose of renally eliminated drugs need to be adjusted are;
• All penicillin’s, except nafcillin or dicloxacillin
• Most cephalosporin's (not ceftriaxone)
• H 2 blockers (except. nizatidine).

All Aminoglycosides
The nephrotoxicity is acute tubular necrosis.
• Dose will remain same
• Intervals are increased
• 2 to 5 hours half life.
• Eliminate after 10 to 20 days thereby this give post dose antibiotic effect.
• Serum creatinine concentration is monitored frequently every 2 to 4 days.

If aim is to achieve steady state maximum/peak and minimum/trough concentrations


the interval between aminoglycosides doses should be extended.

Cisplatin and carboplatin nephrotoxicity


Platinum containing anticancer drugs like cisplatin cause renal tubular damage.
Toxicity is prevented by dose reduction and decrease frequency of administration and
avoiding concurrent use other nephrotoxic drugs.

Radiographic contrast media nephrotoxicity


The nephrotoxicity is caused by direct tubular toxicity or renal ischemia. Pre existing
disease particular diabetes is the major risk factor.
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Digoxin (not digitoxin)


• Half life 36 hours
• V d can be reduced in renal failure
• Prolong distribution phase (6 to 12 hours)
• Gastrointestinal metabolism
• Digitalis toxicity. Hypokalemia drugs (thiazide, CA inhibitors, loop diuretics),
quinidine, verapamil, erythromycin, tetracycline, amiodarone, and nifedipine.
• Digitalis toxicity. Cardiac toxicity (arrhythmias).

Hepatically eliminated will need to have dose adjustments


• May produce active metabolically active metabolites that are renally eliminated
• Meperidine; normeperidine
• Verapamil; nor verapamil
• Codeine metabolized to morphine and then gives morphine-6-glucuronide

Drugs needed monitor their therapeutic range. Serum dose concentration monitoring
(SDCM). may help guide dose adjustment.
• Lithium 0.5 to 1.5 mEq/L
• Valproic acid50 to 100 mg/L
• Procainamide4 to 10 mg/L
• Carbamazepine 4 to 12 mg/L
• Quinidine 2 to 6 mg/L
• Vancomycin
• Theophylline
• Aminoglycosides
• Phenytoin
• Cyclosporine

Phenytoin (NON nephrotoxic)


• Hepatically metabolized. Non linear (saturated) clearance.
• Decrease plasma protein binding in-patient with renal failure meaning therapeutic
affect occur at lower serum concentrations.
• Half life 20 to 40 hours.

Theophylline (Non nephrotixic)


• Hepatic metabolism
• Clearance is greater in smokers and children
• Clearance is reduced in patient with heart failure
• Saturation of metabolism may occur at high dose.
• Do not give immediate release products twice a day.
• Dose dumping will select once a day product taken in conjunction with fatty meal.
• Significant drug interactions with erythromycin, clarithromycin and ciprofloxacin.

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• Oral theophylline 100% bioavailability.

Nephrotoxic drugs that are avoided(CrCl <0.5 ml/s).


Antacids like mg, and Al (avoid long term use in renal disease)
Colchicine
Dolasetron
Ethacrinic acid, Hydrochlorothiazide, spironolactone
Foscarnet
Leflunomide
Indapamide
Meperidine,
Nalidixic acid, nitrofurontoin, Probenicid

Tips
• Oliguria: Urine output <400 mL/day
• BUN/Creatinine ratio, normally 10/1.
• Renal azotemia is uremia
• Pylonephritis is? Pelvic inflammation or infections

In renal disease patient what happens to half life of drug and steady state
concentration?
ko
Css = ko = rate of infusion
CL
CL = total body clearance
DL = loading dose
DL = Css x Vd
DM = maintenance dose
Vd = volume of distribution
DM = Css x CL x τ
τ = dosing intervals
ko
Css =
VdK
K el = 0.693/ t 1/2
CL T = V d x (0.693/t 1/2 )

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36
Immunomodulators
Immunomodulators

Immunosuppressants Immunostimulants

Drugs Antibodies

Monoclonal antibodies: Antilymphocyte globulin


Antibiotics (Biological response Lymphocyte immune globulin
Cyclosporin modifiers) Immune globuline
Pimecrolimus Infliximab, Muromonab
Tacrolimus

Glucocorticosteroids
Prednisone Lymphokine Colony stimulating
Aldesleukin Interferons factors (CSF)
Prednisolone
Inteferon-α-2a Filgrastim,
Interferon-β-1b Sargramostim
Anti-TNF α agents Interferon-y-1b
Etanercept
Thalidomide

Cytotoxic agents
Azthioprine
Cyclophosphamide
Methotrexate

Enzyme inhibitors
Mycophenolate mofetil
Leflunomide

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Monoclomal antibodies (biological response modifiers). Infliximab, daclizumab


Indicated in treatment of rhuemathoid arthritis, ulcerative colitis and chrons disease.
• Mechanism. Tumor nechrosis factor (TNFα) inhibitor.

Immunosupressant antibiotics
• Cyclosporin. Indicated for organ transplant rejection, rheumatoid arthritis and as
anticancer drug.

Tacrolimus and Pimecrolimus


These drugs selectively decrease T helper 2 and mast cell activity. Target skin
inflammation without causing immunosuppression.
• Indicated for treatment of eczema, atopic dermatitis and immunosuppressant in
organ transplantation.
• Tacrolimus ointment 0.03% (pediatric >2 yr), and 0.1% (adult).
• Pimecrolimus cream 1%

Cytotoxic drugs
Methotrexate. Indicated for the treatment of cancer, rheumatoid arthritis and psoriasis.
Immunostimulants
• Indicated for the treatment of
• Anemia
• Thrombocytopenia
• Neutropenia
• Bone marrow depression (myelosupression)
• Immunodeficiencies such as HIV.

Filgrastim and Sargramostim


• Indicated for the treatment of neutropenia associated with cancer chemotherapy.

Interferons
Indicated for viral infection like hepatitis B and C and multiple sclerosis.
• The most common SE interferon is flu like symptoms.

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37
Ophthalmic Drugs

Autonamic activity on eye

Cholinergic Drugs Adrenergic Drugs

Agonist Antagonist
Agonist Antagonist Gives mydriosis by
Pilocarpine * Atropine
Gives Miosis
radial muscle
Gives miosis
By spincter muscle
Tropicamides
* contraction
contraction Gives mydriosis
Nonselective Selective
Phenylephrine Timolol Betaxolol
Brimonidine
Psedoephedrine
Xylometazoline
Epinephrine
Propine

Question Alerts!
Mechanism in glaucoma for
Glaucoma
1) Timolol
• Is due to increase intraocular pressure (IOP)
2) Dorzolamide
• Due to closing of schlem canal
3) latanoprost
• Due to increase in aquous humor
4) epinephrine
• Treatment
• Use medications that gives miosis or mydriosis
• Medication that gives mydriosis open schlem canal

Cholinergic drugs

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• Cholinergic agonist (muscarinic receptor activators or parasympathomimetics)


• Directly stimulate muscarinic receptors to contract ciliary muscle and increase
trabecular outflow. Open up schlem canal and ↑ outflow schlem canal.
• Piolocarpine (1%, 2%, 4%, 6% DROPS) is naturally occurring compound, not
hydrolysed by acetylcholinesterase, indicated in the treatment of open angle
glaucoma and xerostomia (dry mouth).

Cholinergic antagonist
• Atropine is plant Belladona atropa product. It is tertiary amine, it enters, where it
acts as an M receptor antagonist.
• Pharmacological effects at higher doses Mydriasis and cyclopegia (paralysed
accommodation ciliary muscles), hyperthermia, tachycardia, sedation, urinary
retention, constipation, behavioral excitation, and hallucinations.
• Tropicamide: Indicated ophthalmology ocular exams (topical).

Beta blockers
• Timolol and betaxalol. They decrease IOP by inhibiting formation of aqueous humor.
• Decrease aquous humor formation by acting on NE at celiary epithelium.
• Timolol is non selective beta blockers and betaxalol is selective beta 1 blocker.

Adrenergic agonists sympathomimetics (NE &


Epi). Concept!
What drugs increase outflow of
• Phenylephrine (α1 ). Decongestant, mydriasis aquous humor
without cyclopegia.
• Tetrahydrozoline Topical decongestant.
• Epinephrine epinephrine cause ↑ outflow.
• Decrease aquous humor formation by acting on NE at celiary epithelium.
• Nor epinephrine shows action by vasoconstriction to celiary body blood vessells.

PGF 2 analog (…Prost). Latanoprost, bimatoprost, travoprost


• Lower IOP by increase outflow of aqueous humor through uvescleral
pathway.
• SEs. Eye brown pigmentation of iris, lengthening of eye lashes
• ↑ outflow of aqueous humor through schlem canal thus decrease IOP.

Topical CA inhibitors (Acetazolamide, Dorzalomide). Decrease IOP by inhibiting CA


enzyme that involved in formation of aqueous humor.

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Drugs to treat ophthalmic disorders

Ophthalmic Lubrication
Ophthalmic lubrication
Carbopol 940
for Artificial eye
Carboxymethylcellulose (CMC)
Tyloxapol
Dextran 70/hydroxypropyl
methylcellulose Enzymatic preparations;
Glycerin Opthalmic antiobiotics Chymotrypsin
Hydroxypropyl cellulose Fusidic acid and polysporin Ophthalmic surgical implant;
Hydroxypropyl methylcellulose Opthalmic antivirals. Idoxuridine Gelatin, absorbable film
(HPMC) Viscoelastic preparations;
Hypromellose Sodium hyaluronate
Polyethylene glycol Prostaglandin PGF2α analog
Polysorbate 80 "prost"
Polyvinyl alcohol
Sodium hyaluronate

Ophthalmic local anesthesia


Proparacaine
Tetracaine

Congunctivitis (red eye or pink eye)


• Allergic is treated by antihistamine
• Bacterial is treated by antibacterial like polymixin, fusidic acid
• Viral eye infection is also known keratoconjuntivitis and is treated by acyclovir,
trifluridine and idoxuridine.

benzalkonium chloride. a preservative known to cause toxic to corneal epthelium. So


avoid in moderate to severe dry eye disease (DED). Alternate oxidative preservatives,
such as polyquaternium-1, sodium chlorite or sodium perborate (also know as vanishing
preservatives) can be used.

Viscosity enhancer. Increase tear retention time and help to protect ocular surface.
examples. CMC, HPMC, polyvinyl alcohol, propylene glycol, and hydroxypropyl-guar.

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Tips

• Glaucoma is two types: Open angle glaucoma (95%), close angle glaucoma (5%)
• Open angle glaucoma: Fluid drains too slowly from anterior chamber. Pressure
gradually rises (increase IOP), almost always in both eyes, causes optic nerve
damage. If not treated, can lead to blindness. DOC  Timolol
• Emergencies of open angle glaucoma  Pilocarpine
• Close angle glaucoma sudden attacks of increased pressure, usually in one eye (T/F)
• Diabetic retinopathy leading cause of blindness, affects the retina. The best way to
prevent is control diabetic condition (T/F)
• Drugs that cause dilation of pupil are  Mydriatic
• Blind spot is also known as  Optic disk
• When light rays come to a focus behind the retina, the eye is characterized as 
Hypermetropic
• The part of the eye that related to focus of eye is  Lens
• Tropicamide indicated in ophthalmology  ocular exams (topical).

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38
Antimicrobials
Antibiotics classifications

Cell Wall synthesis Penicillins


inhibitors Cephalosporin's Question Alert!
Vancomycin Cephalosporin's, quinolones
and sulfa drugs mechanisms
Protein Synthesis Amino glycosides
inhibitors Macrolides
Tetracycline’s
Lincosamide

DNA Synthesis Quinolones/Fluoroquinolones


inhibitors Metronidazole

Folate Inhibitors Sulfonamides


Trimethoprin

Staph. (coagulase +ve)


Strep. (coagulase –ve)

Strep categorized as
Non hemolytic: S. viridans
Hemolytic
Group A (Strep. pyogenes) (GAS)
Group B (Strep. pneumonia)
Group C

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Acid labile (acid sensitive)

• Penicillin G……………….β-lactamase sensitive


• Methicillin…………………β-lactamase resistant
• Nafcillin……………………β-lactamase resistant

Acid stable (acid resistant)


• Penicillin V…………………β-lactamase sensitive
• Oxacillin……………………β-lactamase resistant
• Amoxicillin…………………β-lactamase sensitive
• Ampicillin…………………..β-lactamase sensitive

Tips. PAPA is sensitive to beta lactamases

Beta-Lactamase Inhibitors
• Clavulanate
• Sulbactam
• Tazobactam

Clavulanic acid
• Beta-lactamase inhibitors such as clavulanic acid can be combined with sensitive
Beta-lactams to yield an active combination with resistant organisms.

Penicillins. Types of sensitivity reactions.


1) Immediate reaction occurs within 20 minutes (IgE mediated anaphylactic
reaction.
2) Accelerated reactions, occurs within 30-40 hours. Manifested by rash and
sometimes fever.
3) Delayed reaction, occurs after 3 days usually it consist of skin reactions or other
systemic reactions such as nephritis or serum sickness.

Penicillins • Penicillin G
• Penicillin V
• Methicillin
• Nafcillin
• Oxacillin
• Carbenicillin
• Ticarcillin
• Piperacillin

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Aminopenicillins • Amoxicillin
• Ampicillin

Mechanism • Cell wall synthesis inhibitors


Therapeutic uses • Gram + ve and Gram –ve
Side effects • Hypersensitive reactions, rash, nausea & vomiting,
• Pseudomembranous colitis cause diarrhea
• Intestinal nephritis
• Hemolytic anemia (Coombs test)
• Penicillin's or all beta lactams are NOT effective for
mycoplasma bacteria.
PenicillinsG

Penicillin G
Mechanism • Cell wall synthesis inhibitors
Therapeutic uses • Gram + ve (all of them), Gram –ve for Neisseria
Side effects Hypersensitive reactions, rash,
• Nausea & Vomiting
• Pseudomembranous colitis
• Intestinal nephritis
Side effects Take empty stomach
management
Drug interactions • Interferes and alters test results for urine and serum protein
levels. It does not interfere with test using bromophenol blue.
• Aminoglycoside causes synergistic effect. Most effective
endocarditis infections.
PenicillinV

Penicillin V
Mechanism • Cell wall synthesis inhibitors

Uses • Gram + ve (all of them)


• Gram –ve for Neisseria

Side Effects Hypersensitive reactions, rash,


• GI effects. Nausea & Vomiting, Pseudomembranous colitis

SE management • Give 1 hour before or 2 hour after meals for max absorption.

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Drug interactions • Interferes and alters test results for urine and serum protein
levels. It does not interfere with test using bromophenol blue.

Piperacillinand Carbenicillin

Therapeutic use Gram –ve (E.coli, Enterobacter, Klebsiella, Pseudomonas.

Side Effects
Drug interaction Used combination with β-lactamase inhibitors.
Often mixed with aminoglycoside (not in same IV bag)
Amoxicillin andAmpicillin

Therapeuti • Amoxicillin HELPS enterococci. ("HELPS" = H. influenza, E. coli, Listeria


c use monocytogenes, Pseudomonas, Salmonella. S. pneumonia).
• Synergistic effect with clavulanate, tazobactam and sulbactams.
Side Effects • Hypersensitivity, anaphylaxis
• GI affects nausea & vomiting, and P. colitis (diarrhea).
• Blood related. Thrombocytopenia, leucopenia, agranulocytosis
Drug • Allopurinol. Increases rashes. Hormonal contraceptive—Decreases
interaction contraceptive effect. Methotrexate-effects renal tubular absorption.

1st gen: Gram +Ve


2nd gen. less +ve more -ve
Cephalosporin's 3rd gen: -ve only
4th gen: -ve only
st st
1 generation Cefazolin (iv) Long duration of action in 1 gen. Good penetration into bone.
None of them Cephalothin
enter in CNS. Cephalexin (po) Oral (DOC pharyngitis, cellulites)
Gram +ve cocci, Cephapirin Renal and hepatic elimination. Shortest half life (0.6 to 0.8 h)
staph, skin and
Cephradine (PO & IM)
soft tissue
Cefadroxil (po) Oral
nd
2 generation Cefaclor Oral (associated with serum sickness)
Gram +ve and Cefamandole
Gram -ve Cefoxitin (iv)
Cefuroxime sodium Can cross BBB, can be used in community acquired bronchitis
(iv) or pneumonia in elderly for H. influenza
Cefuroxime axetil Oral, stable for 24 hours when it dissolved in apple juice. It is a
(po) prodrug. Active against beta lactamases producing strain.
Cefotetan (iv)
Cefproxil Oral
Cefonicid
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Loracarbef
rd
3 generation Cefixime (po) Oral once daily
Contain Cefoperazone Hepatic elimination only, does not get in CNS
methylthiotetraz Cefotaxime (iv) Renal and hepatic elimination. Can penetrate in CSF.
ole side chain. Cefpodoxime
Can cause Ceftazidime (iv) Active against Pseudomonas aeruginosa
hypoprothrombo Ceftriaxone (iv) Longest half life (8 hours). Single dose, it has bile excretion.
nemia and Can be used renal diseases. Good penetration in bone.
bleeding
Cefdinir Oral once daily
problems
Ceftibuten Oral
Gram -ve
th
4 generation Cefepime (iv) Activity is same as 3rd generation, but more resistance to β-
lactamases.

Cephalosporin's gives positive coombs test

Cephalosporins 1st Generation

1st Cefazolin, Cephalothin


Generation
Therapeuti Surgical prophylaxis (best for gram +ve)
c use
Side effects Allergic reaction (5-15%), anaphylaxis, skin rash, fever
hemolytic anemia, granulocytopenia. Candida infections (vaginitis). Local
irritation at site of injection.
Seizure in high doses in IV form
Dose IV and PO

Cephalosporins. 2nd Generation

2nd Generation Cefaclor


Cefamandole
Cefoxitin
Cefuroxime

Clinical use Gram -ve coverage.


Parenteral administration except: cefaclor

Side effects Allergic reaction (5-15%) Skin rash, Anaphylaxis


Fever,
Local irritation at site of injection
Blood related  Hemolytic a
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Dose IV and PO

Cephalosporins-3rdGeneration

3rd Generation Cefixime


Methylthiotetrazol Cefoperazone
e ring and Isoxazole Cefotaxime
ring Cefpodoxime
Ceftazidime
Ceftriaxone

Clinical use Gram negative only. Reserved for serious infections (bacterial
meningitis).
These drugs can penetrate Cerebrospinal fluids (CSF) thereby it
indicated for bacterial meningitis infections.
Nosocomial infections (hospital acquired infections).
Unknown origin infections Sepsis in immunocompramized
patients.

Side effects Allergic reaction (5-15%) Skin rash, Anaphylaxis


Fever, Local irritation at site of injection
Blood related  Hemolytic a

Dose IV and PO

Cephalosporins- 4thGeneration

4th Generation Cefepime


Clinical use Best for Gram -ve
Higher potency
Side effects Allergic reaction (5-15%)  Skin rash, Anaph
Fever, Local irritation at site of injection
Blood related. Hemolytic anemia, granulocytopenia
Dose IV and IM

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Vancomycin

Mechanism Cell wall synthesis inhibitor. It is unaffected by beta lactamase, thus used in treatment of
penicillin resistant strains. Bactericidal antibiotic against gram +ve.
Therapeutic A very important drug for treating methicillin-resistant Staphylococcus aureas infections
use (MRSA).
Vancomycin is an alternate drug for treating super infection (superbug) by Clostridium
difficile in patients with P. colitis.
Narrow spectrum of activity against Staphylococcus, Streptococcus and Clostridium sp.
(gram + ve bacteria).
Side effects Chills, fever, ototoxicity, and nephrotoxicity (>75% renal elimination). Monitor, renal
function test or Serum drug concentration.
Precautions Rapid administration (infused <1h) causes red man syndrome
(flushing/rash/hypotension). In renal failure patient drug will accumulate.
Dose adjustment is guided by monitoring serum drug concentration.

Dosage iv and oral (oral is used in only treatment of P. colitis) and half life 6 to 8 h.

Inhibitors Of Protein Synthesis


50 S Antibacterial Agents 30 S Antibacterial Agents

Amino glycosides Tetracycline's


Macrolides Lincosamides Gentamycin Demeclocycline
Erythromycin Clindamycin Streptomycin Doxycycline
Azithromycin Lincomycin Kanamycin Minocycline
Clarithromycin

"TEST CC" T= tetracycline, E = erythromycin S = Sulfadrugs, T = trimethoprin, C = clindamycin C =


Chloramphenicol, are bactereostatic.

Amino glycosides
Gentamicin, Streptomycin, Tobramycin, Kanamycin, and Amikacin

Pharmacokinetics
All amino glycosides renally eliminated.
Half-life 2 to 5 hours. Post dose antibiotic effect (PDAE)
• Only kanamycin and neomycin have oral and topical
• Commonly amino glycosides used as IM or IV
• Streptomycin has only IM.
• Pharmacokinetics is not completely understood.
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• Contain amino sugars structures and have low bioavailability


• Primarily used in infections associated with gram –ve.
• Amino glycoside have little activity against anaerobic.

Gentamicin

Therapeutic Uses Gram –ve


Drug uptake depends of oxygen: active against aerobes
Second line treatment for tuberculosis (mainly streptomycin)
Treatment for plague (streptomycin).
Pseudomonas (streptomycin)
Combined with cephalosporin's (2nd and 3rd) to reduce resistance
Side Effects Respiratory paralysis (decrease Ach at NMJ).
Nephrotoxicity (proximal tubular cell)
Ototoxicity (also occurs in unborn fetus)

Streptomycin

Streptomycin
Uses Gram –ve.
Second line treatment for tuberculosis (mainly streptomycin).
Treatment for plague (streptomycin). Pseudomonas (streptomycin).
Combined with cephalosporin's (2nd and 3rd) to reduce resistance
Side effects Otic nerve toxicity-8th cranial nerve (mainly streptomycin)
Highest ototoxicity and least nephrotoxic.

Ototoxicity. Streptomycin = Kanamycin>amikacin = gentamycin = tobramcycin>


netilmycin

Tobramycin

Uses Gram -ve


Second line treatment for tuberculosis (mainly streptomycin)
Treatment for plague (streptomycin). Pseudomonas
(streptomycin). Combined with cephalosporin's (2nd and 3rd) to
reduce resistance.

Side Effects Respiratory paralysis (decrease Ach at NMJ)


Nephrotoxicity (proximal tubular cell)
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Ototoxicity (also occurs in unborn fetus).


Amikacin

Uses Gram -ve


Second line treatment for tuberculosis (mainly streptomycin)
Treatment for plague (streptomycin).
Pseudomonas (streptomycin)
Combined with cephalosporin's (2nd and 3rd) to reduce resistance

Side Effects Respiratory paralysis (decrease Ach at NMJ)


Nephrotoxicity (proximal tubular cell)
Ototoxicity (also occurs in unborn fetus)

Amino glycoside side effects "AMINO"


• Half-life is 2 to 5 h, however parenteral
• A = Allergy
injections are given every 6 to 12 h.
• M = neuroMascular Blockade
• Highest ototoxicity is with streptomycin
• I = Inactivated when physically
• Highest nephrotoxic is neomycin.
mixed with beta lactam
• Ototoxicity symptoms associated with
• N = Nephrotoxicity
gentamycin and streptomycin are
• O = Ototoxicity, Optic nerve toxicity
vestibular damage this can cause
tinnitus, vertigo, and ataxia.
• Ototoxicity symptoms associated with amikacin and kanamycin are auditory damage
this can cause hearing loss.
• Tobramycin can cause both vestibular and auditory damage.
• To prevent serious side effects associated with amino glycosides monitor blood drug
levels, BUN, serum creatinine levels.
• Blood levels are monitored by peak and trough levels, trough levels of gentamycin
greater than 2 mcg/ml can cause nephrotoxic.

Macrolides
Erythromycin (po, parenteral), Clarithromycin (po), Azithromycin (po), and
Telethromycin (po) (ketolides).
SEs. Erythromycin and clarithromycin have severe GI disturbances.
• Pharmacokinetics. All of macrolides hepatically eliminated, except clarithromycin,
which is renally eliminated.
• All macrolides have oral dosage and erythromycin gluceptate and lactobionate is IV.
• Azithromycin has long half-life 68 hours and used single daily doses.
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• Erythromycin has short half-life 1.2 to 2.6 hours.


• Erythromycin are preferred drug for treatment of Mycoplasma infection.
• Important alternate in patient allergic to penicillin's.
• Erythromycin estolate may cause cholestatic jaundice in-patient used more than 10
to 14 days. (resolved after discontinued treatment).
• Erythromycin and clarithromycin is inhibitor of CYP3A4, thereby potentiates
toxicities of drugs that are metabolized by CYP3A4, e.g. digoxin, corticosteroids,
lovastatin or (ALS), sildenafil, tadalafil, vardenafil and carbamazepine.
• Clarithromycin increase warfarin INR (monitor PT), increases digoxin and
theophylline levels.
• Azithromycin is more active against gram –ve H. influenza than erythromycin.
• Clarithromycin is effective for H. pylori (used along with PPIs in triple therapy).
• Erythro, clarithro & azithro cause QT prolongation. Use cautiously with other drugs
that cause QT prolongation.
Erythromycin
Use Gram + ve (all of them), gram –ve for Neisseria
Side effects Epigastric distress (due to stimulation of motolin receptors)
cholestatic jaundice (in estolate form).
Estolate is salt of lauryl ester.
Ototoxicity (more with erythromycin)
Drug Contraindicated in patient with hepatic dysfunction (it accumulate in
Interactions
liver), theophylline, warfarin, terfenadine, and statins.

Clarithromycin
Use Same as erythromycin. H. influenza, Chlamydia, and Legionella
Side Effects Epigastric distress (nausea, vomiting, burning stomach, diarrhea),
renal (azotemia), Liver. Hepatitis (cholestatic hepatitis)
Contraindication Patient with hepatic dysfunction.
Do not refrigerate the reconstituted suspension.Clarithromycin may
increase levels of benzodiazepine, statins (ALS), CBZ, theophylline,
cyclosporins and tacrolimus.

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Azithromycin
Use Less active for Staph. and Strep than erythromycin. Far more active H.
influenza, Moraxella catarrhalis. Mycobacterium avium, except HIV.
Side Effects Epigastric distress (better tolerated than ery &clary). Oral preps has less
nausea and vomiting.
Contraindic in patient with hepatic dysfunction.
ated
Counseling Suspension do not refrigerate.
may increase warfarin effect (clari>azi).

Tetracycline’s. Tetracycline, doxycycline, and minocycline

Tetracycline

Tetracycline Broad spectrum antibiotics.


Therapeutic Acne treatment (P.acnes), chlamydia (Lymphogranuloma, Psittacosis).
Uses Rickettsia (Rocky mountain spotted fever), Mycoplasma pneumonia
and lyme disease.
Side Effects Tetracycline should not be treated to renally impaired patient.
(accumulated increase azotemia).
Contraindicati Pregnancy, breast feeding, children under 8 old.
on
Counseling Must take empty stomach with glass of water (one hour before or two
hours after meals). Chelates with bi and tri valent ions such as calcium,
magnesium and aluminum ions.
Tetracycline may stain teeth and for topical can stain cloth.
Avoid prolong sun exposure.
Topical. Can continue use of cosmetics. Stinging may occurs and that
may resolve shortly. Tell patient to report continuous nausea,
vomiting, yellowing of eye and skin.

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Doxycycline

Uses Broad spectrum


Prophylaxis in travelers diarrhea
Lyme disease, Chlamydia (lymphogranuloma, psittacosis), Rickettsia
(Rocky mountain spotted fever)
Mycoplasma pneumonia
Side Effects Gastric discomfort (nausea and vomiting). Effect on calcified tissues
(deposition in the bone and primary dentination occurs during growing
children.
Discoloration and hypoplasia of the teeth and temporary stunting of
growth, and fetal hepatotoxicity
Phototoxicity-Severe sunburn.
Super infection (over growth of candida in vagina or resistance to
Staphylococcus in intestine).
Contraindica Pregnancy, children under 8 old, and breast feeding.
tion iron or antacids ↓ doxycycline absorption. However is taken with meals
or after meal. (food decrease GI SEs, take with glass of water to avoid
esophageal ulceration. Avoid concomitant use of milk, antacids or drug
containing Al, Mg, Ca, Fe.
Counseling Take entire medication even if you feel better. Oral take with or after
meal with glass of water. (Food decreases GI side effects avoid milk,
antacids, iron).
Tell patient to check tongue for fungal infection. Stress good oral
hygiene. Avoid prolong sun exposure.

Minocycline

Therapeutic use Acne, and rheumatoid arthritis.


Side Effects Less phototoxicity
Vestibular problems. dizziness, nausea, vomiting
Contraindication Pregnancy, breast-feeding, children under 8 old
Take with or without food

Clindamycin

Clindamycin Lincosamides class of drug.


Uses • Gram + ve and anaerobic bacteria Bacteroid fragilis (abdominal

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infection). Topical clindamycin is used to treat Propionibacterium


acnes.
Side Effects • Diarrhea (C. difficile is resistant to clindamycin). Managed by
discontinue medication. C. difficile diarrhea is treated by
vancomycin or metronidazole (oral).
Contraindica • History of colitis, regional entities, or antibiotic associated colitis.
tion
Counseling • Take with or without food (discourage with food).
• Capsule. Take with full glass (240 ml) of water to prevent dysphagia.
• Do not refrigerate the reconstituted solution since under condition
of low temp, the solution may thicken and difficult to pour.
• Stable at room temp for 14 days.
Precaution • I.M. injection may be painful

Quinolones & Fluoroquinolones


Quinolones & Fluoroquinolones
Quinolo Nalidixic acid (disinfectant)
nes
Fluoroqu 1st
inolones Nalidixic acid
Norfloxacin
nd
2
Ciprofloxacin (t, po, parenteral)
Ofloxacin (t, po, parenteral)

3rd (Respiratory tract antibiotics)


Moxifloxacin (po, parenteral)
Levofloxacin (t, po, parenteral)
4th Travofloxacin

Ciprofloxacin

Mechanism Inhibits topoisomerase II that prevents DNAg (gyrase) which stops


replication of bacteria.

Inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV makes cell


inaccessible and leads to cell death. Different quinolones inhibits different
extent of topoisomerase II and IV. DNA gyrase seems more important in
gram –ve. Topoisomerase IV in gram +ve.

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Therapeutic UTI. E. coli, STD. Gonorrhea, GI infections. E. coli travelers diarrhea.


Uses
Side Effects Most common nausea and vomiting, light-headedness, and
nephrotoxicity.
Cartilage toxicity, avoid in children and pregnancy.
Tendonitis/tendon rupture common in elderly and renal failure patient.
Counseling Ciprofloxacin otic suspension. Store cipro otic suspension at room temp
(15 to 25oC). Do not use otic suspension under 2 year of age.
Auxiliary With or without food. The preferred time is 2 hours after meal or empty
labels stomach (for faster absorption), with full glass of water, (avoid dairy products).
Do not take dairy product alone or within 2 hrs of Calcium intake >800 mg,
avoid excessive caffeine intake.
Avoid taking with antacid, iron, or calcium together, take calcium after two hours.
Photo Photosensitive. Recommend sunscreen (UVA&B). If sunscreens not
toxicity effective, drug should be discontinued at the first of sign of toxicity-sun
burn like rashes.

Ofloxacin

Ofloxacin
Mechanism Inhibits DNA replication of bacterial DNA gyrase
Uses Mainly for E. coli in UTI and STD with exception syphilis.
alternate in gonorrhea
Side effects Hypoglycemia, leukopenia, Neutropenia
Counseling Tell patient to drink fluids liberally.
Separate doses of vitamins, antacids by 2 hours.

Gatifloxacin

Mechanism A quinolone, use to treat several types of bacterial infections.


Therapeutic use Chest infections (pneumonia), Sinus infection, urinary tract infection
Side Effects Q-T prolongation
Drug-drug Oral iron preparation and antacids containing magnesium and
interaction aluminum can interfere the absorption of gatifloxacin
Contraindication Not recommended in children
Monitoring

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Metronidazole

Metronidazole Classified as antiprotozoal drug and has antibiotic actions (anaerobic).


Mechanism • Mode of action is thought to be breakage of cell DNA.
Therapeutic • Indicated in anaerobes such as Bacteroides, C. difficile, C. vaginalis
use • Protozoans (Giardia, Entamoeba, Trichomonas) and H. pylori.
• This drug is also active against trophozoites in the intestinal lumen
and walls.
• Metronidazole has direct anti inflammatory effect (antioxidant action
that contributes to its anti-inflammatory activity).
• Giardiasis and trichomoniasis metronidazole used orally.
Side effects • Metallic taste, furry tongue, and glossitis.
• Must avoid taking alcohol while on this drug can cause disulfiram like
reactions. Disulfiram causes acute psychosis ever if taken within two
weeks.
• Rarely be neurotoxic.
Drug-Drug • Cimetidine prolongs metronidazole half-life and decrease its plasma
interaction concentration. Warfarin potentiates effects resulting in prolongation
of prothrombin time. Phenobarbitone. Increases metronidazole
metabolism.
Precautions • It can cause dark urine
• Do not mix iv metronidazole with any other drug.
Pregnancy and • Caution require in pregnancy and lactation.
lactations
Dosage • Oral capsule and oral tablets.
• Injection. to treat anaerobic infections and protozoal infection
• Vaginal cream and inserts, vaginal gel: for treatment of bacterial
vaginitis
• Topical cream or gel drug of choice for rosacea applied effected twice
daily morning and evening for 9 weeks, then as needed.

FolateantagonistSulfaDrugs

Sulfa drugs Sulfamethoxazole, Sulfadiazine, Sulfisoxazole, Sulfasalazine and


Trimethoprim.
Combination Cotrimoxazole (Sulfamethoxazole+trimethoprim).
drugs
Mechanism Structural analog of PABA that inhibit bacterial dihydropteroate
synthase to block folic acid synthesis and cell growth.
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Therapeutic Drug of choice in UTI and traveler’s diarrhea.


Use Chlamydia trachoma, the most common cause of preventable
blindness.
Topical. burns and wounds.
Side effects Crystalluria. Adequate hydration and alkalinization prevent this
problem
Hypersensitivity. rashes, Stevens-Johnson syndrome, and sulfa
allergies occurs with longer acting agents diuretics, acetazolamide,
thiazide, furosemide, bumetanide, and diazoxide.
Hemolytic anemia G6 PD deficiency.
Kernicterus. In newborns sulfadrugs displace bilirubin from binding.
Counseling Sulfasalazine. Drugs colors urine and may color skin orange yellow.
May permanently stain soft lenses. Take drug after meals to reduce
GI distress and to facilitate passage into intestine.

Pteridine + PABA

Dihydropteroate synthase Sulfonamide

Dihydropteroic acid

Dihydrofolic acid

Dihydrofolate reductase Trimethoprim, pyrimethamine

Tetrahydrofolic acid (THF)

THF cofactors

Thymine Purines Methionine


Glycine
f-met-tRNA
DNA DNA
RNA Proteins

Cotrimoxazole(SMX + TMP)

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Cotrimoxazole
Therapeutic Use Chronic treatment of UTI
Gram –ve: H. influenza, Gonorrhea, E. coli, Klebsiella, Salmonella,
shigella sp. and V. cholera.
Gram +ve: S. pyogenes (GAS), S. viridans, S. aureus
UTI-Acute, recurrent, chronic.
Upper and lower rasp—chronic bronchitis.
Immunocompromised children P. carinii
Not indicated in infections associated with pseudomonas,
mycoplasma.
Side effects Skin reaction (severe in elderly)
GI. N and V
Blood related: Megaloblastic anemia, Thrombocytopenia,
Leukopenia: The above three effects can be reversed by concurrent
administration of folinic acid.
Hemolytic anemia-G6PD deficiency due to SMX
Counseling Drug is not for IM. Shake oral suspension thoroughly before use
Take oral dose with full glass of water.
With or without food. (food decreases GI side effect)
Store in amber glass of bottle.
Store at room temp until expiry and protect from moisture.
Contraindications Last trimester of Pregnancy, lactation.
Children under 2 months. May cause kernicterus.

Steven-Johnson’s Syndrome (SJS). Rash, skin peeling, and sores on the mucus
membrane. In Steven Johnson’s syndrome, a person has blistering of mucus membrane,
typically in mouth, eyes and vagina. Patchy areas of rash. SJS can occur in all age groups.
Due to "SASPAN" Sulfonylurea, Anticonvulsant (phenytoin, carbamazepine, valproic
acid), Sulfonamide, Penicillin, Allopurinol and NSAIDs. Sulfa drugs including topical sulfa
drugs. Treatment of SJS is cortisone.

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39
Antifungal Agents
Mechanisms of Action and Classification of Antifungal Agents

Antifungal Agents

After cell membrane permeability Block nucleic acid synthesis Disrupt microtubule function

Allylamine Pyrimidine
Azoles Polyene Penicillin
Analog
macrolide derivative
* Terbinafine
antibiotics * Flucytosine
* Naftifine * Griseofulvin

* Amphotericin B
Imidazoles Triazoles *Nystatin
* Ketoconazole * Fluconazole
* Miconazole * Itraconazole
* Clotrimazole

Systemic Allylamines Terbinafine. The drug of choice for Onychomycosis


antifungals Antifungal Amphotericin B
Antibiotics Amphotericin B (lipid-based)
Griseofulvin
Echinocandins Caspofungin acetate
Imidazole Ketoconazole
Clotrimazole.
Miconazole
Pyrimidines Flucytosine
Triazoles Fluconazole (oral) The alternate to treat Onychomycosis
Itraconazole (oral). The alternate to treat Onychomycosis
Topical Allylamines Naftifine hydrochloride
Antifungals Terbinafine hydrochloride. Onychomycosis

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Antifungal Nystatin. Candida, oral thrush, vaginitis


Antibiotics
Imidazoles Clotrimazoles. Drug of choice Athletes foot
Econazole nitrate
Ketoconazole
Miconazole nitrate
Oxiconazole nitrate
Tioconazole
Other topical Chlorphenesin
antifungals Ciclopirox olamine
Clioquinol
Selenium sulfide
Tolnaftate powder, spray. Athletes foot
Undecylenic acid

Amphotericin B
• Fungistic, fungicidal.
Therapeutic use • Widest of any agent, systemic fungal infections; candidiasis;
cryptococcos; blastomycosis; histoplasmosis;
coccodiodomycosis; aspergillosis; sprorotichosis; mycosis;
leishmaniasis.
• Availability. 3% cream/lotion/oral suspension. Not absorbed in
the GIT.
Mechanism • Bind to ergosterol from pores resulting in the leakage of cellular
contents.
Side effects • Very toxic. infusion related fever and chills, anorexia, muscle
pain, and headache.
• Non-infusion related nephrotoxic, hyperkalemia,
hypomagnesaemia, tachycardia, anemia, thrombocytopenia,
arrhythmias, VF, HTN, tachypnea, leukoencephalopathy, dry
skin, skin discoloration, SJS, toxic epidermal necrolysis,
agranulocytosis, jaundice, hemorrhage, sore throat
Contraindication • Allergies
Warning • Apply only to patients with progressive, potentially fatal
infections and should not be used to treat non-serious infection
• Monitor lab test sp. Renal function (frequently), liver function,
serum electrolytes particularly magnesium and potassium,
blood count, Hgb conc. Not use for dosage adjustment.
• Does not penetrate CSF therefore administered intrathecally
Drug interaction • Antineoplastics increase renal toxicity, bronchospasm,
hypotension.
• Corticosteroids/ACTH, increase amphotericin B-induced
hypokalemia, renal toxicity.

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• Nephrotoxic agents (Cisplatin, pentamidine, aminoglycoside,


cyclosporine) increase renal toxicity.
• Digitalis glycosides Amphotericin B-induced hypokalemia,
increase digitalis toxicity
• Skeletal muscle relaxantsenhance cureiform
• Others: AZT, chloramphenicol, antithyroid, colchicine,
deferoxamine, streptozocin, plicamycin, lithium, penicillamine.
• Overdose: cardiorespiratory arrest.

Precaution • Storage of dry powder; 2-8 deg, protect from light


• Give slow IV infusion
Counselling • When applying topical on the skin, protect nails and clothes as it
may stain
References • CPS 2004, 854-855,
• Comprehensive Pharmacy Review, 5th Ed. Page 795,

Nystatin
Category • Polyene antibiotic, structurally similar to Amphotericin B, fungicidal,
and fungistatic.
Therapeuti • Active against Candida sp. Primarily use as a topical agent in vaginal
c use and oral candidiasis.
• Not very effective against dermatophytes (Tinea pedis).
Mechanism • Inhibit growth of yeast, binds to sterol in the fungal cell membrane,
increasing permeability and causing leakage of intracellular
components.
Side effects • Irritation e.g. mild digestive upset, nausea & vomiting diarrhea,
cream/vaginal tablet itching, burning, and irritation.
Advantage • Can be use by pregnant women.
Drug
interaction
Precaution • Application of vaginal tablet
Counseling • Nystatin liquid
• Skin ointment or cream.
• Powder. Dust the powder inside shoes and socks.
• Nystatin vaginal tab and cream.
Reference: • CPS 2004 1308-1309

Fluconazol (Triazole) Ketoconazol (Imidazole)


• Triazole type antifungal • Imidazole type antifungal
• Inhibitors of ergo sterol synthesis by • Inhibitor ergo sterol synthesis
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binding to cytochrome. • Not a single dose


• Single doses. • Doesn’t penetrate CNS
• Penetrate CNS (AIDS chemotherapy) • SEs. Hormonal effects such as
• CNS SEs dizziness, headache gynecomastia and menstrual
• No interaction with cimetidine, disturbances.
antacids. • Interaction with cimetidine, antacids
• For systemic infection UTI, peritonitis, • Require acidic conditions for absorption
pneumonia. (avoid antacids concomitantly).
• Potent inhibitor of CYP 2C9 (high) and • Potent inhibitor of CYP 3A4 (high) and
CYP 3A4 CYP 2C9.
• Fluconazole taken with or without • Ketoconazole taken with food or after
food. food. Taken with cola beverage if
achlorhydric or on acid secrete
suppressor

Ketoconazole
Ketoconazole
(Imidazole type)
Therapeutic use • Chronic mucocutaneous candidiasis, systemic and vaginal
candidiasis, Tinea corporis (ringworm), T. cruris (jock itch), T.
pedis (Athlete’s foot), Tinea versicolor (sun fungus),
histoplasmosis, blastomycosis, paracoccidioidomycosis, oral
thrush
• Relative bioavailability: 75 % with meals
• Available as tablet, cream and shampoo
Mechanism • Block the synthesis of ergosterol 14a demethylase in the fungal
CYP 450 complex; hepatic elimination
Side effects • Hormonal effects. Decreased male libido and potency,
gynecomastia, decreased plasma testosterone levels, affects
female menstrual problems, Cardio effects hypertension, fluid
retention.
• GI upset, hepatotoxicity, dizziness, anorexia, Nausea &
vomiting
Contraindication • Hypersensitivity, and teratogenicity.
WARNING • Rebound effect. Apply mild topical corticosteroids in the
morning and ketoconazole at night and gradually decrease
steroid over a period of 2 to 3 weeks. Cross sensitivity.
Precaution • Allergies with imidazoles.
Counselling • Shampoo, 1% or 2%, Cream
References • CPS 2004, 1379-1380

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Fluconazole
Mechanism • Block The Synthesis Of Ergosterol By Inhibit 14A-Demethylase In The
Fungal CYP450 Complex
Therapeutic • Mucocutaneous Candidiasis (Esophageal). Alternative For
use Amphotericin B For Treatment Of Systemic Candidiasis, Cryptococcal
Meningitis, Coccidioidomycosis, Cryptococcosis, HIV Associated
Infections
• Relative Bioavailability 85- 92% With Meals
Side effects • Skin Rash
• GI Effects. Nausea, Vomiting Diarrhea Or commonly Causing GI
Disturbances.
• Liver Effect. Increase liver enzymes, yellowing of the skin, and eyes,
Flu-Like Symptoms,
• CNS. Dizziness, Headache, Exfoliative Skin Reactions, Altered Taste
Buds, Extreme Tiredness, and Seizures.
Drug • Decrease Levels With carbamazepine, H 2 Blockers, INH, Phenytoin.
interaction • Increase Levels Of drugs that substrate of CYP2C9. phenytoin,
warfarin (greatly prolongs PT), and sulfonylureas.
• Less affect CYP3A4 substrates. Anticancer Drugs, Amiodarone,
Benzodiazepine, Cyclosporine, Disopyramide, OCP, Diuretics,
Moxifloxacin, Sotalol, Terfenadine, Quinidine, Valproic Acid,
Thioridazine And Tacrolimus.
Precaution • Decrease elimination of enzyme Inducers Like Rifampin, Allergies To
Fluconazole And Other Antifungals, Irregular Heart Beat, Kidney Or
Heart disease
Reference: • Applied T. Handbook; Chapter. 67, Pp. 67.4 - 67.5
• TC Page 4th Ed Page 1056.

Itraconazole

Therapeutic use • More active treatment against Aspergillus spp., blastomycosis


other mycosis like mucor, fusarium pseudoallescherria boydii;
HIV associated infections; invasive and non-invasive pulmonary
aspergillosis; oral and esophageal candidiasis; chronic
histoplasmosis (acute immunocompromised, an alternative to
amphotericin); cutaneous and lymphatic sporotrichosis,
paracoccioidomycosis and chromomycosis.
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• Dose Aspergillosis: 200 mg IV Q8H X 72 H then 200 mg IV Q12H


• Blastomycosis; 200 mg po BID
• Histoplasmosis: 200 to 400 mg QD po
• Take with meals for adequate absorption
Mechanism • Block the synthesis of ergosterol 14a demethylase in the fungal
CYP450 complex
Side effects • Nausea, epigastric pain rash, headache, edema, hypokalemia,
loss of appetite, shaking, dyspnea, bleeding gums, yellowing of
eyes and skin; hypertriglyceridemia, decrease libido
Contraindication • CHF, left ventricular dysfunction

Warning • Cause CHF; heart attack; irregular heart beat ; lung/ kidney/liver
disease or other serious problems; SOB, coughing up white
phlegm; weakness; excessive tiredness, fast heart beat, swelling
of the feet, ankle or leg; sudden weight gain.

Drug interaction • Cisapride, pimozide, dofetilide, ergot meds, triazolam,


midazolam, quinidine, all may cause irregular heart beat.
• Take antacid one hour before or two hours after itraconazole
• Increased by Itraconazole. antiarrhythmics, anticonvulsants-
CBZ, antimycobacterial-rifabutin, antineoplastics,
antipsychotics, Benzodiazepine, Ca-channel blockers,
gastrointestinal motility agents, HMG-CoA reductase inhibitors
(ALS) Increase risk of developing rhabdomyolysis.
Immunosuppressants, oral hypoglycemics, protease inhibitors,
buspirone, and macrolides.
• Decrease by Itraconazole anticonvulsant, antimycobacterial,
gastric acid suppressants, and NNRTI.
Counselling • Oral solution. Swish 10 ml (2 tsp) in the mouth for a few
seconds and swallow. Repeat is necessary until entire dose is
taken. The solution is usually taken on an empty stomach once
daily or BID for 1-4 weeks.
• Tell Doctor if taking Itraconazole. Do not substitute the capsules
for the liquid because they have different use.

Reference: • CPS 2004, page 1973-1978

Clotrimazole
Therapeutic use • Yeast infection (Vulvovaginal Candidiasis), skin infections, high
concentration needed in bacterial infection, and athletes foot.
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• Availability. Topical cream 1%, and Vaginal cream (1%, 2% and


10%) or vaginal tab 100 mg, 200 mg and 500 mg. lotion or
solution dermatophytes (skin infections), intravaginal
suppositories for vaginal candidiasis, lozenge for oral.
Mechanism • Block the synthesis of ergosterol 14α demethylase in the fungal
CYP 450 complex.
Side effects • Topical. blisters, edema, pruritus, burning, stinging, peeling skin
tissue, increase urinary frequency. Abdominal pain, and
irritation.
• Abnormal liver function test in patient taking lozenge
Contraindication • Not for first trimester of pregnancy.
Management • In case of vaginal infection, refrain from sexual intercourse
cause an ingredient in the cream may weaken certain latex
condoms / diaphragms. If first time of vaginal itching and
discomfort, see a doctor. Do not use products within 72 hours
of this med. Wear cotton underwear and loose fitting pants; no
lozenge for children under 3y/o.
Precaution • Pregnancy
Reference • CPS, 2004, 361-362

Miconazole
Category • Broad spectrum fungistatic
Mechanism • Block synthesis of ergosterol by inhibiting 14a-demethylase in
the fungal cytochrome P450 complex; selective inhibition of RNA
& DNA and mucopolysaccharide precursor.
Therapeutic use • Covers both dermatophytes and candidiasis (Advantage Over
Tolnaftate and Nystatin. Also, effective against Tinea infections
by T. pedis, T. cruris, T. corporis, T. versicolor
Side effects • Itching, skin rash, Nausea &vomiting, burning on the site of
application.
Contraindication • Sensitivity to any of the components of Miconazole, not for
children < 2y/o unless directed by a doctor, do not use for the
infection of the nail.
Drug interaction • Anticoagulants, phenytoin, terbinafine, atypical anti-psychotics,
• Cyclosporins and some statins.
Availability • Topical 2%, aerosol powder, 2 % cream, a kit-2% powder 2y/o
and 2% tincture, 2% vaginal cream and 100 and 200 mg vaginal
suppositories.
Application • Aerosol powder
• Cream Apply sparingly, smoothen well and avoid maceration.

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Massage area gently. Athlete’s foot. dry feet, and wear cotton
socks.
Reference • CPS, 2004, page 1246

Tolnaftate
Category • Fungistic, fungicidal
Mechanism • Damage hyphae and stunt mycelial growth in susceptible fungi
Therapeutic use • Jock itch, athlete's foot, ringworm T. pedis, M. canis, Aspergillus
niger, C. albicans, M. gypseum, M. audounii, M. japonicum, T.
rubrum, T, mentagrophytes, T. schonleinii, A. fumigatus
Side effects • Slight irritation, sting (aerosol solution), burning and itching of
athlete's foot and jock itch should decrease with in 2-3 days
Administration • Do not apply dressings, or mix cosmetics or other skin
medications with tolnaftate treatment.
• Powder. Clean and dry affected area. Sprinkle it between toes
and in socks and shoes treated lightly.
• Spray should be shaken well before use. Apply it from a
distance of at least six inches away. Continue treatment until
symptoms disappear. A total of 4 to 6 weeks necessary. Do not
inhale powder, bring close to a hot object or flame
• Cream. Thoroughly clean the infected area. Allow it to dry and
then rub gently the medication until most of it disappears. Use
sufficient quantity to cover the affected area. Wash hands after
application.
• Solution. If it solidifies, dissolve by warming the closed
container in warm water then follow dosage as directed.
Warning • Aerosols: Flammable.
Contraindication • Allergies to tolnaftate or any preservatives, dyes; pregnancy;
children, 2 yo.

Abbreviation and Terminology


SJS Steven Johnson Syndrome
CSF Cerebrospinal fluid
CPS Compendium of Pharmaceutical Specialties

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Tips

• Nystatin is indicated ? oral thrush, and vaginal candidiasis


• Ketoconazole require acidic conditions for higher bioavailability therefore? avoid
antacids and/or taken with carbonated beverages
• Meningitis fungal infections other CNS infections can be treated by? Amphotericin
• If a child swallowed 5 g of nystatin, and parents are panic, comes to your pharmacy,
what is appropriate action? wait and watch
• Nystatin is ineffective for ? skin infections
• The drug of choice to treat oral thrush? nystatin, miconazole
• The drug of choice to treat vaginal candidiasis? clotrimazole or miconazole, nystatins
• Topical drug of choice to treat Athletes foot ? clotrimazole
• Nystatin suspension counseling? swish, swirl and swallow
• Amphotericin B act by inhibiting the cell membrane function

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40
Anti-Mycobacterial Drugs
Generic Name Trade Name Generic Name Trade Name
Rifampin Rifadin, generics Isoniazid Isoniazid, INH,
Streptomycin generics Rifabutin Mycobutin
Pyrazinamide generics Ethambutol Myambutol

There are two common infections associated


with mycobacteria. These are Mycobacteriam Question Alert!
tuberculosis and Mycobacteriam leprae. 1) Screening and treatment of inactive
tuberculosis?
Mycobacteriam tuberculosis can cause. 2) Where does skin tuberculin test
• Inactive tuberculosis (latent) skin test +ve (Montex) is done? Forearm
(forearm) and chest x-ray +ve. 3) Acid fast bacteria? M. tuberculosis
• The drug of choice for prophylaxis is 4) Tuberculin test is ? Type IV
isoniazid (INH). hypersensitive reaction

• Active tuberculosis. Skin test +ve, & chest


x-ray +ve, sputum test and symptoms weight loss, cough, and fever.
• The drug of choice for treatment INH + rifampin + ethambutol.

Tuberculosis treatment
• Goal of treatment is must eradicate mycobacterium.
• Important issues in tuberculosis treatment are resistance to drugs.
• Drug of choice for the prophylaxis of tuberculosis --> isoniazid
• Drugs that have lowest resistance is --> Isoniazid, rifampin, streptomycin and
combination of these drugs with pyrazinamide, or ethambutol.

Antimycobacterial drugs. Isoniazid, Rifampin, Streptomycin, Pyrazinamide, and


Ethambutol, Capreomycin, and Rifabutin.

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Rifampin Chemical structure of rifampin is a macrocyclin.


This drugs is bactericidal and inhibits RNA synthesis
Mechanism
Therapeutic Use Effective against M. tuberculosis, and M. leprae.
Prophylactic for household members of exposed to meningitis caused
by meningococci or H. influenza type b
Side Effects Serious liver toxicity (hepatotoxicity) thereby LFT should be performed
regularly.
GI: nausea, vomiting, abdominal pain.
CNS: Headache, drowsiness, confusion, fatigue
Rifampin discolors urine, sweat, tears, saliva and feces to orange red.
Body fluids (contact lens staining)
Drug Rifampin is inducer of CYP 1A2, 2D6, 2C9, 2C19, 3A4
interactions Reduce efficacy oral contraceptive.

Isoniazid (INH) Targets enzyme responsible for mycolic acid synthesis


Mechanism
Therapeutic use First line treatment for tuberculosis
Side Effects Most common. Peripheral neuritis or neuropathy (because of pyridoxine
deficiency) vitamin B 6 supplements. Skin rash, jaundice and fever are
common SEs. Supplementing breast fed mothers can provide pyridoxine
25 mg/day deficiency in children.
Most common. Hepatitis (hepatotoxicity symptoms fatigue, flu like,
anorexia and NV. may occurs within weeks to months) is most severe-
fatal, the risk of hepatitis increases with patient age and alcohol abuse.
Monitor LFT .
Hepatotoxicity is age related, more prevalent in elderly. Blood
dyscariasis (agranulocytosis, aplastic anemia, hemolytic anemia and
thrombocytopenia) thereby monitor CBC routinely.
CNS toxicity due to decrease in pyridoxine (vitamin B 6 ) levels.
Administer 15 to 50 mg/day pyridoxine to minimize the peripheral
neuropathy.
Symptoms of CNS or neurotoxicity are insomnia, restlessness,
hyperreflexia, psychosis and convulsions.

Pyrazinamide It is pyrazine analog of nicotinamide


(ZIN)
Mechanism Pyrazinamidase enzyme converts into pyrazinoic acid (active form)
Therapeutic Use Combination with INH and rifampin. Pyrazinamide has activity only
against M .tuberculosis
Side effects Liver dysfunction, Urate retention. And may precipitate gouty attacks
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Abbrevation and Terminology


INH Isoniazid ZIN Pyrazinamide
LFT Liver Function Test
CYP Cytochrome P450
XDR TB Extensive Drug Resistance Tuberculosis.

Tips

• Drug of choice to treat tuberculosis --> INH, rifampin, pyrazinamide or/and


ethambutol
• Peripheral neuritis caused by isoniazid can managed by administering? vitamin B6
• All antitubercular drug should be taken on empty stomach
• What infections gives granulomas? tuberculosis
• Montaoux test for tuberculin indicates? tuberculosis screening
• Tuberculin test is type of hypersensitive reaction? type 4
• Drugs that discolor urine, tears, saliva, feces, sweat --> rifampin and pyrantel
pamoate

Find answers from the table:


1 Isoniazid (INH) 2 Rifampin 5 Cefotaxime
3 Pyrazinamide 4 Isoniazid 6 Cefuroxime
• Drugs that discolor urine, tears, saliva, feces, sweat to orange red. (2)
• Drug of choice for the prophylaxis of tuberculosis. (1)
• Drug of choice to treat tuberculosis. ( 1,2,3 )
• Peripheral neuritis caused by what drug. (1 )
• Drugs that can be used for treatment and prophylaxis of meningitis. (2 )
• What bactericidal antitubercular drug that inhibits cell wall synthesis. ( 5,6 )
• Peripheral neuritis can be managed by administering 15 to 50 mg/day pyridoxine
• All antitubercular drug should be taken empty stomach.
• What infections give granulomas? Mycobacterium tuberculosis
• Monteux test for tuberculin indicates? Mycobacterium tuberculosis infection
• Tuberculin test is type of hypersensitive reaction? Type IV
• XDR TB = Extensive Drug Resistance Tuberculosis.

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41
Antiviral Drugs
Question Alerts!
1) Examples of herpes virus? HSV1, HSV2, VZV, and EBV
2) Cold sore and keratoconjuntivitis is caused by? HSV1
3) Antiviral drugs for HIV such as NRTIs, NNRTIs, NtRTIs, and protease inhibitors side
effects? Pancreatitis, neuralgia, and cardio toxicities.
4) Hepatitis A is acute and transmitted food & H2O
4) Hepatitis B&C are chronic and transmitted by sexual contact, blood transfusion etc.
5) Seasonal flu is caused by Influenza A & B

Common Viruses
• Herpes virus. HSV 1 , HSV 2 , VZV, EBV
• Hepatitis A, B, C, D, E viruses
• Influenza virus A, B (seasonal flu)
• HIV-AIDS
• Measles, Mumps viruses
• Others; Rabies, Rubella (German measles), Variola, Coxsackie virus

Some Antiviral
• Acyclovir; Cover HSV 1 and 2, VZV. Well tolerated.

Genital HSV is treated by? Oral and iv acyclovir or vala.

• Interferon; HBV, HCV. May cause fever like symptoms.


• Lamivudine; HBV, HIV
• Oseltamivir; Influenza A+B. May cause diarrhea
• NRTI, NNRTIs, NtRTI and Protease inhibitors are used to treat HIV
• Zidovudine (AZT); HIV. May cause rash
• Combivir; HIV. May cause N/V and diarrhea.
• Ritonavir; HIV. May cause N/V and diarrhea.

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Examples of Anti-viral Mechanisms


VIRAL LIFE CYCLE ANTIVIRAL THERAPY EXAMPLES
1. Virus attaches to the cell Gamma-globulin (binds to virus) Hepatitis A and B
2. Virus penetrates the cell Gamma-globulin
3. Virus un coats its nucleic acid Amandatine Influenza A
4a. Synthesis of key viral enzymes such Acyclovir, Ribavirin (DNA polymerase Herpes simplex (HSV1,
as polymerases (transcription) inhibitor) HSV2, VZV, Epsteinbar)
Viral nucleic acid replication Valacyclovir
inhibitors Gancyclovir
Idoxuridine (ophthalmic drops)
Trifluorodine (ophthalmic drops)
4b. Viral nucleic acid is synthesized Zidovudine (reverse transcriptase HIV
inhibitor)
5. Late viral structural proteins are Indinavir (protease inhibitor) HIV
synthesized
6. Viral proteins and particles are
assembled
7. Viruses are released from host
cell

Specific inhibitor of herpes virus DNA polymerase. Acyclovir, valacyclovir, gancyclovir.


Acyclovir. Synthetic analog of deoxyguanosine. deoxyacyclovir is a pro-drug form of acyclovir.
Valacyclovir is pro-drug of acyclovir.

Mechanism. Acyclovir is converted by viral thymidine kinase to acyclovir monophosphate,


which is then converted by host cell kinases to acyclovir triphosphate (ACV-TP). ACV-TP, in turn,
competitively inhibits and inactivates HSV-specified DNA preventing further viral DNA synthesis
without affecting the normal cellular processes.
Conversion of active acyclovir monophosphate by phosphorylation reaction. Acyclovir further
converted to di and triphosphate by normal cellular enzyme.
Early use of acyclovir shortens the duration of viral shedding and lesion pain.
Side effects. Potentially serious side effects include renal dysfunction and thrombocytopenia.
The common side effects nausea and diarrhea.

Anti-retroviral therapy
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Delavirdine mesylate Do not combine within the same NNRTIs class
Efavirenz
Nevirapine
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abacavir
sulfate

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Didanosine SEs. Pancreatitis, lactic acidosis, Neuropathy, leukopenia, and pneumonia


(ddI) Increase amylase
o Didanosine. 15 to 30 ºC in a tight container
DR cap/OS/susp/chew. tabs
Stability. Oral solution, keep solution at RT for 4h
Dissolve contents of packet in one-half (4 ounces) glass of water
Oral suspension: keep suspension for 30 days in
Refrigerator up to 30 days. Discard unused portion
Label; Take on an empty stomach
 Refrigerate (suspension)
 Take capsules whole or intact (Capsule)
 Do not swallow tablets whole, chew (tablet
Lamivudine Minimal toxicity/ well tolerated.
(3TC) Lamivudine is an analog of didonsine.
Stavudine Caps/Stability of OS. Reconstituted solution is stable up to 30 days when
(d4T) refrigerated.
SEs. Pancreatitis, reversible peripheral neuropathy, insomnia, depression, nasal signs
and dyslipidemia,
Zalcitabine SEs. Neuropathic pain (35%), oral ulcers/stomatitis, fatigue, hepatic, peripheral
(ddC) neuropathy, skin, blood abnormalities (anemia, leukopenia, eosinophilia,
thrombocytopenia).
Zidovudine Capsule/Tablet/ oral solution protected from light
(AZT) SEs. Myocarditis, photophobia, and myopathy
Protease Inhibitors.
Amprenavir
Indinavir SEs. nephrolithiasis, hyperbilirubinemia.
sulphate Cap. Dispense and store in original container. Do not remove desiccant
Take on an empty stomach or with light meal
Drink plenty of fluids
Nelfinavir
Ritonavir
Ritonavir/lopi
navir
Saquinavir
Combination of antiviral drug therapy is a common approach for treatment of HiV infections.
due to the following benefits.
• Therapeutic antiviral effect
• Decreased toxicity
• Low incidence of drug resistance
• It prolongs the life of AIDS patient

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Tips
1 Zalcitabine 9. Didanosine 17. Tenofavir
2 Erythropeitin 10. Stavudine 18. NRTIs
3 Acyclovir 11. Zidovudine 19. Tenofovir
4 NNRTIs 12. Triflurohexidine 20. Rimantadine
5 Zanamavir 13. Amantadine 21. Oseltamavir
6 Famcyclovir 14. Valacyclovir 22. Hepa A immunization
7 Calamine lotion 15. Flu immunization season 23. Hepa B immunization
8 Antihistamine 16. Oatmeal cream
• Pancreatitis is SEs of what antiviral drugs. (9, 10)
• Peripheral neuropathy is SE of what drugs. (1, 10, 9)
• Didanosine should be avoided with what are the other antiretroviral drugs. (10 )
• October to mid November. (15)
• Treatment of zidovudine induced anemia. (2)
• Drugs of choice to treat HSV 1 and HSV 2 infections. (3)
• Alternate treatment for HSV 1 and HSV 2 . (6, 14)
• Recurrent cold sore treatment. (Abreva )
• Genital herpes can be treated by 5% of what drug. ( 3 )
• Side effects of this drug are bone marrow depression and severe anemia. (11)
• Pancreatitis and neuropathy are side effects of what drug. (9, 10 )
• Peripheral neuropathy is side effect of what drug. (1, 9, 10 )
• What immunization given above for 0, 1 month and 6 month? (23)
• What immunization above given for 1 year old only? ( 22)
• Abacavir (ABC), didanosine (ddl), emtricitabine (FTC), lamivudine (3TC), stavudine (d4T), and
zidovudine (AZT), are examples of what antiviral classification? (NRTI)
• Examples NtRTI (nucleotide Reverse Transcriptase Inhibitor. ( tenofavir (TDF))
• Efavirenz (EFV), Nevirapine (NVP), delavirdine (DLV) and etravirine (TMC-125) are examples
of what drug classification? (NNRTIs)
• Drugs of choice to treat keratoconguntivitis . (trifluridine)
• For influenza A only. (amandatidine)
• Neuroaminidase inhibitors for influenza A and B. (oseltamavir and zanamavir)
• Indicated for influenza A and B. (oseltamavir)
• Herpes simplex virus causes infections of  Genital herpes, keratoconjuctivitis, cold sores
• Who should get flu vaccination  Patients with respiratory, cardio, DM, HIV, elderly over
65, health care workers, and professionals, patient living in long term care facilities, long
term care workers.
• Who is vector (carrier) of flu Health care workers.
• CD 4 count 100 patient require prophylaxis for  Penumocystis carinii Pneumonia
• Flu season in Canada  October to April
• Tenofovir (Viread) a nucleotide reverse transcriptase inhibitor (NtRIs) gives --> renal toxicity,
monitor RFT
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• Influenza A and B virus causes  flu


• TDS = Tinofavir, didanosine and stavudine; Do NOT combine because they cause
pancreatitis
• ZDS = Zalcitabine, didanosine and stavudine; Do NOT combine because they cause
neuropathic pain

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42
Anti-Malarial Drugs
Drug Name Trade Name Drug Name Trade Name
Primaquine Radical cure Chloroquine Aralem
Doxycycline Adoxa Pyrimethamine Daraprim
Mefloquine Lariam Atovaquone-proguanil Malarone

Malaria is infection of red blood cells with the single-celled parasite Plasmodium, which
causes fever, an enlarged spleen, and anemia.

Four species of malaria parasites, Plasmodium falciparum, Plasmodium vivax,


Plasmodium ovale, and Plasmodium malariae can infect people.

Falciparum malaria, caused by Plasmodium falciparum, is the most dangerous form of


malaria and can be fatal.

Chloroquine is the drug of choice for treatment in a person who has malaria caused by
Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae except in a very few
areas where resistance to chloroquine in people with Plasmodium vivax has been
reported.

Primaquine is added to kill persistent parasites in the liver of a person infected with
Plasmodium vivax or Plasmodium ovale. Before primaquine is given, a blood test is done
to look for a relatively common enzyme deficiency (G6PD deficiency). People with G6PD
deficiency who are given primaquine may have a breakdown of their red blood cells.

Malaria Prevention. N, N-Diethyl-m-toluamide (DEET), 5%, 10%, 15% and 30% should be
applied on the skin before outdoor activities during the main hours of malarial
transmission 30% of DEET may be used in children as young as 2 months of age.
• 30% DEET is effective for four to six hrs.
• Citronella is usually effective for less than 1 hr.
• Avoid eye and mucus membrane.

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DEET 5%
DEET 10%
DEET 15%
DEET 30%

Recommended.
10% DEET for 8 yo. repels for 3 hr
15-30% for adults. repels for 6 hr
Avoid in 1 yo (not used <6 mo), take mosquito nets.
Maximum tid
Apply sparingly exposed skin or/and cloth
Refer to travel clinic

Treatment of malaria
Prophylaxis
P. falciparum Chloroquine
P. malariae Chloroquine
P. vivax Chloroquine + primaquine
P. ovale Chloroquine + primaquine
Chloroquine resistant Mefloquine, Primaquine, Quinine + doxycycline, atovaquone-proguanil.
prophylaxis
Treatment Quinine or mefloquine or pyrimethamine/sulfoxine

Side effects of antimalarial drugs


Mefloquine Retinopathy, Nausea, dizziness, and trouble sleeping, may rarely
produce seizures, nightmares. psychiatric problems.
Should also be avoided in people with certain heart
conditions.
Contraindicated in seizures, active depression, anxiety.
Quinine Headache, nausea, vomiting, visual disturbances, and ringing in
the ears a condition known as cinchonism, and retinopathy
Atovaquone- Nausea, vomiting, or abdominal pain and is not used in people
proguanil with poor kidney function, pregnant women, or infants.
Prevention. pyrimethamine-sulfadoxine or atovaquone-proguanil

Abbreviation and Terminology


G6PD Glucose-6-phosphate dehydrogenase
DEET N, N-Diethyl-m-toluamide

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Tips

• The drugs used at Chloroquine malarial resistant area prophylaxis  mefloquine


• Chloroquine resistant area treatment mefloquine
• Plasmodium vivax and ovale infections, treatment must include primaquine
• Cinchonism (ringing in ear, vertigo) is caused by? chloroquine
• Chloroquine side effect include retinopathy
Find answers from the table:
1 Quinine 2 Primaquine
3 Chloroquine 4 Quinidine
5 Mefloquine 6 Quinine

• Quinine + doxycycline or mefloquine is the prophylaxis in area resistant to what


drug? (3)
• Treatment for Chloroquin resistant area. (5)
• Treatment Plasmodium vivax and ovale infections. (2)
• Quinine alkaloids that cause cinchonism. (3)
• Side effect of this drug includes retinopathy. (3)
• Mefloquine prophylaxis, weekly one dose, started 4 wks before travel and during
trip and 2 wks after trip. (True/False)

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43
AnthelminthicDrugs
Question Alerts!
Pinworms treatment and selfcare?

Helminthic Diseases and medication


Species Common infections Mode of Treatment
transmission
Intestinal nematodes
Ascaris Round worm Ingestion Pyrantel pamoate,
lumbricoides mebendazole
Necator Hook worm Percutaneous Pyrantel pamoate,
americanus mebendazole
Trichuris trichuria Whipworm Ingestion Mebendazole
Enterobius Pinworm Ingestion/inhalation Pyrantel pamoate
vermiculars Mebendazole
Strongyloides Threadworm Ingestion Thianendazole
Tissue nematodes
Wuchereria Filariasis Percutaneous Diethylcarbamzine
bancrofti
Onchocerca River Percutaneous Livermectin
volvulus blindness/onchoceriasis
Trichinella spiralis Trichinosis Ingestion Thiabendazole
Cestodes (tapeworms)
Taenia solium Pork Ingestion Niclosamide
Taenia saginata beef ingestion Niclosamide
Diphyllobothrium Fish ingestion Niclosamide
latum
Hymenolepis nana Dwarf Praziquantel,
niclosamide
Trematodes (flukes)
Schistosoma Blood Percutaneous Praziquantel
mansoni

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Schistosoma bilharziasis Praziquantel


haematobium
Clonorchis sinesis Liver ingestion Praziquantel
Fasciolopsis Intestinal Ingestion Praziquantel
Pragonimus Lung Ingestion Praziquantel
• Pinworm infestation can prevented by non-medical recommendation in patients
with pinworm infection include. Bathing every morning, regular cleaning of
undergarments, bedding etc. Handwash, during the following week of treatment all
family members should wear cotton underpants. Frequent washing of toilet seats.

Mebendazole
• Mechanism. Inhibits microtubule synthesis and glucose uptake in nematodes.
• Clinical Use. Pinworm and whipworm infections.
• Contraindicated in pregnancy.

Pyrantel pamoate
• Mechanism. Depolarizing neuromuscular blocker, which causes paralysis of
nematodes.
• Clinical use: Hookworm infections, pinworm infections, Roundworm.
• Caution: Red color urine, feces, stains on vomiting.

Praziquantel:
• Mechanism: Increase membrane permeability to Ca2+ using muscular contraction
and paralysis of the nematode muscles.
• Clinical Use. Drug of choice for Schistosomiasis, clonorchiasis, and pranomiasis.

Niclosamide:
• Clinical Use: Infections from ingestion of beef, pork, and fish.

Tips
1 Mebanedazole 2 Pyrantel pamoate 3 Praziquantel
4 Niclosamide
• Which antihelmenthic drug can cause red color body fluids, such as urine, saliva etc?
Pyrantel pamoate (2)
• Inhibits microtubule synthesis and glucose uptake in nematodes ( 1 )
• use for infections from ingestion of beef, pork, and fish (4)
• depolarizing neuromuscular blocker, which causes paralysis of nematodes (2)
• it causes red color urine, feces, stains on vomiting ( 2 ).
• increase membrane permeability to Ca2+ using muscular contraction and paralysis of
nematode muscles (3).
• DOC for schistosomiasis, clonorchiasis, and pranomiasis ( 3 ).

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