Agam Pharm Compressed

3
2. Rectal:
Certain irritant and unpleasant drugs can be put into rectum as suppositories or
retention enema for systemic effect.
Ex: Diazepam, Indomethacin, Paracetamol, Ergotamine.
ADVANTAGES: DISADVANTAGES:
When the patient is unconscious Inconvenient
and is having recurrent vomiting. Embarrassing
Liver is Bypassed. Absorption is slow
Rectal irritation may occur
3. Sublingual:
• The Tablet or pellet containing the Drug is placed under the tongue or
crushed in the mouth and spread over the buccal mucosa.
• Only lipid soluble and non-irritating drugs can be administered.
Ex: Glyceryl Trinitrate, Buprenorphine, Nifedipine, Desamino-oxytocin
ADVANTAGES: DISADVANTAGES:
Absorption is rapid - within minutes drug Buccal ulceration can occur
reaches the circulation. Lipid insoluble drugs cannot be given.
First pass metabolism is avoided.
After the desired effect is obtained, the
drug can be spat out to avoid unwanted
effects.
General Pharmacology Agam Pharmacology

10
3. Pharmacodynamics:
• The actions of the drug on the body are termed pharmacodynamics.
• Most drugs must bind to a receptor to bring about an effect.
• Pharmacodynamics include physiological and biochemical effects of drugs and
their mechanism of action at organ system, subcellular and macromolecular
levels.
4. Pharmacokinetics:
• The actions of the body on the drug are called pharmacokinetics.
• Pharmacokinetic processes govern the absorption, distribution, binding /
localization / storage, biotransformation and elimination of drugs.
• It has great practical importance in the choice and administration of a
particular drug for a particular patient.
5. Drug:
The WHO in 1966 defined “Drug is any substance or product that is used or is
intended to be used to modify or explore physiological systems or pathological
states for the benefit of the recipient.”
6. Pharmacotherapeutics:
• It is the application of pharmacological information together with knowledge
of the disease for its prevention, mitigation or cure.
• Selection of the most appropriate drug, dosage and duration of treatment
taking into account the specific features of a patient are a part of
pharmacotherapeutics.
7. Clinical pharmacology:
• It is the scientific study of drugs (both old and new) in man.
• It includes pharmacodynamic and pharmacokinetic investigation in healthy
volunteers and in patients; evaluation of efficacy and safety of drugs and
compare with other forms of treatment, surveillance of patterns of drug use,
adverse effects, etc.
• The aim of clinical pharmacology is to generate data for optimum use of drugs
and the practice of ‘evidence based medicine’.

11
8. Toxicology:
It is the study of poisonous effect of drugs and other chemicals (household,
environmental pollutant, industrial, agricultural, homicidal) with emphasis on
detection, prevention and treatment of poisonings. It also includes the study of
adverse effects of drugs, since the same substance can be a drug or a poison,
depending on the dose.
9. Essential drugs:
I. The WHO has defined Essential drugs as “those that satisfy the priority
healthcare needs of the population.”
II. Essential medicines are meant to be available
a. within the context of functioning health systems,
b. at all times,
c. in adequate amounts,
d. in appropriate dosage forms,
e. with assured quality and adequate information,
f. and at a price the individual and the community can afford.
III. Last revised essential drug list was released in 2017 (20th list first being in
1977) which had 433 medicines with dosage forms and strength.
10. Orphan drugs:

a. These are drugs or biological products for diagnosis, treatment, prevention of
a rare disease or condition, for which there is no reasonable expectation that
the cost of development and marketing, will be recovered from the sale of the
drug.
b. Governments in developed countries offer tax benefits and incentives for
developing such drugs.
Ex: Fomepizole, Digoxin antibody, liothyronine, Colchicine, Azacitidine.

23
1. BIOTRANSFORMATION
Biotransformation means the chemical alteration of the drug in the body. It is
needed to render non polar compounds to polar so that they are excreted in the
renal tubules.
Biotransformation of the drug may lead to:

1. Inactivation ex: ibuprofen, paracetamol, lidocaine etc.
2. Active metabolite from an active drug ex: active drug - morphine active
metabolite - morphine-6-glucuronide
3. Activation of an inactive drug ex: levodopa to dopamine
Biotransformation reactions are classified into:

• Phase I (Nonsynthetic) (Functionalization)
• Phase II (Synthetic) (Conjugation)
Phase I
I. Oxidation:
• This reaction involves addition of oxygen or removal of hydrogen. Oxidative
reactions are mostly carried out by a group of monooxygenases in the liver,
which in final step involve cytochrome P-450 hemoprotein, NADPH,
cytochrome P-450.
• The CYP isoenzymes are important for drug metabolism in humans. Ex: CYP2E1
helps in metabolism of paracetamol, alcohol and Halothane. CYP2C19 helps in
metabolism of omeprazole, lansoprazole, phenytoin, diazepam etc
II. Reduction:
• Converse of oxidation and involves working of CYP-450 in opposite direction.
Alcohols aldehydes quinones are reduced. Drugs primarily reduced are
chloramphenicol, halothene, warfarin etc.

24
III. Hydrolysis:
• Cleavage of drug molecule by taking up a molecule of water.
esterase
Example: Ester + water -------› Acid + Alcohol
Drugs that undergo hydrolysis are lidocaine, pethidine, oxytocin etc.
IV. Cyclization:
• Formation of ring structure from a straight chain compound ex: cycloguanil
from proguanil.
V. Decyclization:
• Opening up of ring structures of cyclic drug molecule such as barbiturates and
phenytoin.
Phase II
Glucuronide conjugation:
• It is carried out by a group of UDP glucuronosyl transferases.
• Compounds with hydroxyl or carboxylic acid group are easily conjugated.
ex: Chloramphenicol, aspirin etc.
Acetylation:
• Compounds having amino or hydrazine residues are conjugated with the help
of acetyl coenzyme A, ex: sulfonamides, isoniazid, clonazepam etc.
Methylation:
• Amines and phenols are Methylated by methyl transferases, methionine and
cystin.
• ex: adrenaline, histamine, methyl dopa et.

25
Sulfate conjugation:
• The phenolic compounds and steroids are sulfated by sulfotransferases. ex:
chloramphenicol, methyl dopa, sex steroids etc.
Glycine conjugation:
• Salicylates, nicotinic acid and other drugs having carboxylic acid are conjugated
with Glycine.
Glutathione conjugation:
• This is done by glutathione S transferases forming mercapturate.
• ex: paracetamol
Ribonucleoside/nucleotide synthesis:
• This pathway is important for activation of purines and pyrimidines and are
used in cancer chemotherapy.
➢ The drug metabolising enzymes are divided into microsomal enzymes and non-
microsomal enzymes
Microsomal enzymes:
▪ These are located in Smooth ER of the liver. They catalyse most of the
oxidation, reduction, hydrolysis, and glucronide conjugation.
Non microsomal enzymes:

▪ These are present in the cytoplasm and mitochondria of hepatic cell. Some
oxidation and reduction, many hydrolytic reactions and all conjugation except
Glucuronidation.
▪ These enzymes are deficit in new born especially in premature.

29
3. FIRST PASS METABOLISM
Definition:
First pass metabolism refers to the metabolism of drug during its passage from
the site of absorption into the systemic circulation. It is an important determinant of
oral bioavailability.
Mechanism:
Orally administered drugs
↓
Metabolizes in intestinal wall and liver
↓
A fraction of the drug is lost.
Prevention: By sublingual, transdermal or parenteral routes.
Hepatic extraction ratio (ER Liver):

It is the fraction of drug prevented by the liver from reaching the systemic
circulation.
ER Liver = CL liver
Hepatic blood flow
Systemic bioavailability (F) = Fractional absorption × (I ― ER)
When a drug with high first pass metabolism is given orally with high dose, the
plasma concentration of its metabolites will be higher and if they contribute to the
adverse effects, oral dosing will be less safe.
Attributes of drugs with high first pass metabolism:

• Oral dose is higher than parentral or sublingual dose.
• Individual variation in the oral dose due to differences in the extent of first
pass metabolism.
• Oral bioavailability increases in patients with severe liver disease.
• Oral bioavailability of a drug increases when another drug competes with it in
first pass metabolism. Eg. Chlorpromazine and propanolol.

38
6. New drug delivery system:
To localize and prolong the delivery of the drug to specific target organ.
Eg:
• Liposomes:
>Unilamellar or bilamellar nano vesicles produced by Sonication of
biodegradable phospholipids like lecithin.
Used in:
• Liposomal IV: selectively taken up by reticuloendothelial cells
and malignant cells: therefore, the drug gets delivered
selectively to these cells.
• Liposomal Amphotericin B: in Kala-azar and systemic mycosis.
• Drug releasing implants:

The implants are coated with drug and placed in target organ.
Therefore, to prolong delivery of minute quantities of drug by slow
release.
Eg: i) Progestin (IUCD): gives protection upto 5 yrs.
ii) Antimicrobial drug coated stent: to prevent re-stenosis and in
failure of angioplasty.

71
4. Dose
It is the appropriate amount of drug needed to produce a certain
degree of response in a given patient.
Ex: the dose of aspirin for headache is 0.3-0.6g.
Antiplatelet dose is 60-150mg/day
5. Pharmacogenetics
• It is the study of genetic basis of variability in drug response.
• It deals with the genetic influences on drug action as well as
drug handling by the body.
6. Pharmacogenomics
• It is the use of genetic information to guide the choice of drug
and dose on an individual basis.
• It intends to identify the individual who are either more likely or
likely to respond to a drug, as well as those who require
alternate doses of certain drugs.
• Attempt is made to define the genetic basis of an individual's
profile of drug and to predict the best treatment for him or her.

73
9. Cross Tolerence
It is defined as the development of tolerance to pharmacologically
related drugs.
Eg: Alcoholics are relatively tolerant to barbiturates and genera anaesthetics
Mechanism
• Pharmacokinetic/Drug disposition tolerance: The effective
concentration of the drug at the action site is reduced due to
enhancement of drug elimination on chronic use
Eg: Renal excretion of Amphetamine is increased on chronic use
• Pharmacodynamic/cellular tolerance: Drug action is lessened because
the cells become less responsive. This is due to desensitization or down
regulation of receptors or weakening of response effectuation.
10. TACHPHYLAXIS
• It refers to rapid development of tolerance when doses of a drug
repeated in quick succession result in marked reduction in response.
• Usually seen in indirectly acting drugs (Ephedrine, Tyramine, Nicotine

which act by releasing catecholamines; synthesis of which is unable to
match the rate of release and stores get depleted)
• Other mechanisms –
I. Slow dissociation of drug from its receptor
II. Desensitization/Internalisation/Down regulation of receptor
III. Compensatory homeostatic adaptation

76
1. GENERAL DETOXIFICATION AND SUPPORTIVE MEASURES:
A. Resuscitation and maintenance of vital functions:

• Ensure patent airway, adequate ventilation, give artificial respiration.
• Severe poisoning often makes the patient comatose.
• maintain blood pressure and heart beat by fluid and crystalloid
infusion, pressure agents, cardiac stimulants, pacing, defibrillation.
• Prevent and manage seizures.
• Maintain body temperature.
• Maintain blood sugar level.
B. Termination of exposure(decontamination):
• It is done by removing the patient to fresh air, removing
contaminated clothing and washing the skin and eyes, induction of
emesis with syrup ipecac or gastric lavage.
• Contraindicated in corrosive and CNS stimulant poisoning.
C. Prevention of absorption of ingested poisons:

• Suspension of 20 -40g of activated charcoal, which has large surface
area and can adsorb many chemicals, should be administered in
200ml of water.
• Contraindicated in paralytic ileus or intestinal obstruction.
D. Hastening elimination:
• By inducing dieresis or altering urinary PH.
• Excretion of many poisons, especially those which are eliminated
mainly by hepatic metabolism, is not enhanced by forced dieresis.

77
2. PHARMACOVIGILANCE
• It is related to collection, detection, assessment, monitoring & prevention of

adverse effect of drugs
Started in 2010
(NATIONAL COORDINATING CENTER) INDIAN PHARMACOPEA
COMMISSION IN UP
• AVOID INAPPROPRIATE USE IF DRUGS

• USE APPROPRIATE DOSE, ROUTE AND FREQUENCY OF DRUGS
• HISTORY OF DRUG REACTION
• HISTORY OF ALLERGIC DIAEASE
• SEE POSSIBILITY OF DRUG INTERACTIONS
• LABORATORY MONITORING

80
6. TERATOGENICITY
• It is the capacity of a drug to cause Foetal abnormalities when administered to
the pregnant mother.
• The embryo is the most dynamic biological systems and in contrast to adults,
drug effects are often irreversible.
• Drugs can affect the foetus at 3 stages:
i) Fertilization and implantation-(conception to 17 days) Failure of
pregnancy which often unnoticed.
ii) Organogenesis-(18-55days): Most vulnerable period
iii) Growth and Development (56 days onwards)
• The type of malformation depends on the drug as well as the stage at which
exposure to the teratogen occurred.
• Foetal exposure depends on the blood level and duration of which the drug
remains in the maternal circulation.
EG: Thalinomide – Phocomelia
Alcohol – Foetal alcohol syndrome
ACE inhibitors – Hypoplasia of organs
NSAIDs- premature closure of ductus arteriosus
Valproate – Spina bifida

7
4. Cholinergic crisis
Cholinergic crisis is a clinical condition that develops as a result of
overstimulation of nicotinic and muscarinic receptors at the neuromuscular junctions
and synapses. This is usually secondary to the inactivation or inhibition AChE, the
enzyme responsible for the degradation of ACh. Excessive accumulation of ACh at the
neuromuscular junctions and synapses causes symptoms of both muscarinic and
nicotinic toxicity.
5. Sialogogue
Sialogogue are substances that increases the salivary secretions. These are
useful in treatment of Xerostomia.
Ex: Pilocarpine
6. Edrophonium test
▪ Edrophonium test is used to differentiate myasthenia crisis and cholinergic
crisis.
▪ This test is done by injecting edrophonium (2mg I.V). If there is an
improvement in the weakness then it is myasthenia crisis, if there is no
improvement or worsening occurs then it is due to cholinergic crisis.
7. Chronic Organophosphate poisoning

• Repeated exposure to certain fluorine containing and triaryl
organophosphates results in polyneuritis and demyelination after a latent
period of days to weeks.
• Sensory disturbances occur first followed by muscle weakness, tenderness and
depressed tendon reflexes—lower motor neuron paralysis.
• In second phase, spasticity and upper motor neuron paralysis gradually occurs.
Recovery may take years. It is due to inhibition of ChE; there is no specific
treatment.
ANS Agam Pharmacology

8
1. Anti cholinergic drugs
Pharmacological actions:
(Atropine as prototype)
1. CNS:
• Stimulant action.
• It stimulates medullary centres - Vagal, respiratory, and vasomotor.
• Depresses vestibular excitation and has anti-motion sickness property.
2. CVS:
• Heart- Tachycardia
• BP- No marked effect in BP
• Tachycardia and vasomotor centre stimulation tend to raise BP, while
Histamine release and direct vasodilator action tend to lower BP.

9
3. Eye:
• Topical instillation of atropine causes mydriasis, abolition of light reflex and
cycloplegia lasting 7 to 10 days.
• Causes photophobia and blurring of near vision.
• Intraocular tension tends to rise especially in narrow angle glaucoma.
4. Smooth muscles:
• Smooth muscles receiving parasympathetic motor innervation is relaxed by
atropine.
• Tone is reduced.
• Constipation may occur.
• Causes bronchodilatation, reduces airway resistance in COPD and asthma
patients.
• Relaxant effect on ureter and urinary bladder.
5. Glands:
• Decreases sweat, salivary, tracheobronchial and lacrimal secretion.
• Decreases secretion of acid, pepsin and mucus in stomach.
• Intestinal and pancreatic secretions are not significantly reduced.
• Bile secretion not affected.
6. Body temperature:
• Rise in temperature at higher doses due to both stimulation of sweating as well
as stimulation of temperature regulatory centers.
• Children are susceptible to atropine fever.
7. Local anaesthetic:
• Mild anaesthetic action on cornea
• Sensitivity to atropine varies and can be graded as-
Saliva, sweat, bronchial secretion > eye, bronchial muscle, heart > smooth
muscle of intestine, bladder > gastric glands and smooth muscle

10
Pharmacokinetics:
➢ Rapidly absorbed from g.i.t.
➢ Applied to eyes, freely penetrate to cornea.
➢ Passage through BBB is restricted.
➢ 50% metabolised in liver and rest excreted in urine.
Uses:
❖ Used as pre anaesthetic medications.
❖ Reduced pulmonary secretions, thus employed in pulmonary embolism
❖ As mydriatic and cycloplegic – used in treating iritis, iridocyclitis, choroiditis,
keratitis and corneal ulcer.
❖ Used in counteracting sinus bradycardia and partial heart block in selected
patients where increased vagal tone is responsible.
❖ It is the specific antidote for anti ChE and early mushroom poisoning.
Side effects and Toxicity:

Belladonna poisoning

11
2. ATROPINE SUBSTITUTES
Many semi synthetic derivatives of belladonna alkaloids and a large number of
synthetic compounds have been introduced with the aim of producing more selective
action on certain functions. Most of these differ only marginally from the natural
alkaloids, but some recent ones appear promising.
Quaternary compounds
These have certain common features—
• Incomplete oral absorption.
• Poor penetration in brain and eye; central and ocular effects are not seen after
parenteral/oral administration.
• Elimination is generally slower; majority are longer acting than atropine.
• Have higher nicotinic blocking property. Some Ganglionic blockade may occur at
clinical doses resulting in postural hypotension and impotence as additional side
effects.
• At high doses some degree of neuromuscular blockade may also occur.
Drugs in this category and their uses:
1. Hyoscine butyl bromide: Less potent and longer acting than atropine; used for
oesophageal and gastrointestinal spastic conditions.
2. Atropine methonitrate: for abdominal colics and hyperacidity.
3. Ipratropium bromide: it acts selectively on bronchial muscle without altering
volume or consistency of respiratory secretions.
o Another desirable feature is that in contrast to atropine, it does not depress
muco-ciliary clearance by bronchial epithelium.
o It has a gradual onset and late peak (at 40–60 min) of bronchodilator effect in
comparison to inhaled sympathomimetics.
o Thus, it is more suitable for regular prophylactic use rather than for rapid
symptomatic relief during an attack. Action lasts 4–6 hours.
o It acts on receptors located mainly in the larger central airways contrast
sympathomimetics *whose primary site of action is peripheral bronchioles*.
o The parasympathetic tone is the major reversible factor in chronic obstructive
pulmonary disease (COPD).

12
Therefore, ipratropium is more effective in COPD than in bronchial asthma.

o Transient local side effects like dryness of mouth, scratching sensation in
trachea, cough, bad taste and nervousness are reported in 20–30% patients,
but systemic effects are rare because of poor absorption from the lungs and
g.i.t.
4. Tiotropium bromide: A newer congener of ipratropium bromide which binds very
tightly to bronchial M1/M3 Muscarinic receptors producing long lasting
Bronchodilatation.
Like ipratropium, it is not absorbed from respiratory and G.I. mucosa and has
exhibited high bronchial selectivity of action.
5. Propantheline: it was a popular anticholinergic drug used for peptic ulcer and
gastritis. Use has declined due to availability of H2 blockers and proton pump
inhibitors.
6. Oxyphenonium: similar to Propantheline, recommended for peptic ulcer and
gastrointestinal hypermotility.
7. Clidinium: This antisecretory-antispasmodic has been used in combination with
benzodiazepines for nervous dyspepsia, gastritis, irritable bowel syndrome, colic,
peptic ulcer, etc.
9. Isopropamide: Indicated in hyperacidity, nervous dyspepsia, irritable bowel and
other gastrointestinal problems, especially when associated with emotional/mental
disorders.
10. Glycopyrrolate: Potent and rapidly acting antimuscarinic lacking central effects.
Used as preanaesthetic medication and during anaesthesia.

16
1. SYMPATHOMIMETICS
ACTIONS- mediated through alpha and beta receptors:
Alpha actions Beta actions

17
Blood vessels contraction relaxation

Heart Little action; high ↑rate, force,
doses – arrhythmia conduction and
velocity.
Bronchioles - Dilatation
Eye – aqueous Decreased Increased
secretion
Intestine Relaxation Relaxation
Urinary bladder Trigone – contraction Detrusor- relaxation
Uterus Contraction Relaxation
Splenic capsule Contraction Relaxation
NM transmission ↑Ach release tremors
Insulin &glucagon Inhibited Secreted
Liver - Glycogenolysis
Kidney - Renin release
Male sex organ Ejaculation -
Salivary gland K+ and water Ptylin secretion
secretion
Posterior pituitary - ADH secretion
Nicitating membrane Contraction -
THERAPEUTIC USES:
1. Vascular:
a) Used in shock
➢ Dopamine- increases cardiac contractility without significant
tachycardia, improves renal blood flow, may help to raise blood
pressure.

18
➢ Ephedrine/ mephentermine – causes vasoconstriction and also

counteracts as well as counteract bradycardia..
➢ Adrenaline - drug of choice in Anaphylaxis (0.5mg i.m.)

• It raises blood pressure
• Counteracts Bronchospasm and laryngeal edema that may
accompany.
b) Postural hypotension
c) Adjuvant in local anesthetic – adrenaline is used
d) Control of local bleeding

o Adrenaline can be used
o Phenylephrine – 1% soaked in cotton can control arteriolar and
capillary bleeding
o Noradrenaline – 8mg in 100- 200 ml of saline put in stomach
through a tube can control bleeding from gastric erosions and
stress ulcers.
e) Nasal decongestant
2. Cardiac:
• Cardiac arrest- Adrenaline

• AV block- Isoprenaline
• Congestive heart failure-Dopamine / Dobutamine
• Cardiac stress test- Dobutamine
3. Bronchial asthma and COPD: Adrenergic β2 stimulants.
4. Allergic disorders: Adrenaline- antagonizes histamine
5. Ocular uses:
• Phenylephrine- dilates pupil
• Dipivefrine- adjunctive in open angle glaucoma
• Apraclonidine and brimonidine- 2nd line add on drugs fir glaucoma
6. Central uses:

21
1. ß - BLOCKERS
INTRODUCTION
• ß blockers are group of drugs which inhibit adrenergic response mediated
through ß receptors.
• All ß blockers are competitive antagonists.
• Its prodrug Propranolol blocks ß1 and ß2 receptors but has weak ß3 activity.
It is also an inverse agonist.
PROPRANOLOL
Introduced in 1963, it became the prodrug for ß blockers
PHARMACOLOGICAL ACTIONS
1) Cardiovascular system
a) Heart
• Decreases heart rate , force of contraction , cardiac output and
retarding conduction thus prolonging systole
• CHF may be precipitated

22
• Cardiac work and O2 consumption are reduced as the product of heart

rate and aortic pressure decreases
• Total coronary blood flow is reduced due to blockade of vasodilatory ß
receptors
• In anginal patients there is an improvement of O2 supply and exercise
tolerance
• Abbreviates refractory period of myocardial fibres and thus slows A-V
conduction
• At high doses, a direct depressant and membrane stabilizing action is
exerted which contributes to its anti-arrhythmic action.
b) Blood Vessel
• Blocks vasodilation and fall of BP by isoprenaline and enhances rise of
BP by Adr.
• On prolong administration, BP gradually falls in hypertensive subjects
• Total peripheral resistance(t.p.r) is increased initially but with chronic
use resistance vessels gradually adapt to chronically low C.O so that
t.p.r decreases and both systolic and diastolic BP fall
• Reduced NA releases
• Decreased renin release
• Central action reducing sympathetic outflow
• These factors contribute to its anti-hypertensive action.
2) Respiratory Tract
• Increases Bronchial resistance
• Precipitates severe asthma
3) Central Nervous System
• No overt central effects produced
• Mild behavioural changes, forgetfulness, increased dreaming and
nightmares are observed in some individuals.
4) Local anaesthetic
• Has membrane stabilizing and is a potent local anaesthetic but not used
due to its irritant activity.
• Ocular irritation and corneal anaesthesia occurs and hence ocular use is
terminated.

23
5) Metabolic
• Blocks adrenergically activated lipolysis and consequent increase in
plasma free fatty acids
• Plasma triglyceride levels and LDL/HDL-CH ratio increase
• Glycogenolysis in heart, skeletal muscle and liver that occurs due to
symapathetic stimulation is attenuated.
• Delayed recovery from insulin hypoglycaemia
6) Skeletal muscle
• Inhibits adrenergically provoked tremor
• Reduce exercise capacity by attenuating ß2 mediated increase in blood
flow and limiting glycogenolysis and lipolysis.
7) Eye
• Reduces secretion of aqueous humor.
8) Uterus
• Relaxation of uterus due to isoprenaline and selective ß2 agonists is blocked.
PHARMACOKINETICS
• Well absorbed orally
• Low bioavailability due to high first pass metabolism in liver
• Lipophilic and penetrates the brain easily
• Metabolism dependent on hepatic blood flow. Chronic use of
propranolol itself decreases hepatic blood flow and thus increases
bioavailability and t1/2
• Bioavailability is increased when taken with meals as it reduces first pass
metabolism
• Hydroxylated metabolite is responsible for ß blocking activity.
• Excreted through urine as glucuronides
• 90% of propranolol is plasma protein bound.
INTERACTIONS

24
• Additive depression of sinus node and A-V conduction with digitalis and
verapamil and hence used always with nifedipine – cardiac arrest can
occur.
• Delays recovery from hypoglycaemia due to insulin and oral antidiabetics.
Warning signs of hypoglycaemia are suppressed.
• Phenylephrine, ephedrine and α agonists cause marked rise in BP due to
blockade of sympathetic vasodilatation.
• Indomethacin attenuates anti-hypertensive action.
• Retards lignocaine metabolism by reducing hepatic blood flow.
USES
• Hypertension
• Angina pectoris
• Cardiac arrythmias
• Secondary prophylaxis of MI
• Congestive cardiac failure.
• Thyrotoxicosis(controls sympathetic symptoms , inhibits conversion of T4
to T3)
• Chronic prophylaxis of Migraine
• Anti-Anxiety drug
• Hypertrophic cardiomyopathy.
• Glaucoma
• Dissecting aortic aneurysm.
• Pheochromocytoma.
ADVERSE DRUG REACTIONS

• Accentuate MI insufficiency and precipitates CHF by blocking sympathetic
support to the heart.
• Bradycardia (60 beats/min).
• Worsens COPD and precipitates asthma – CONTRAINDICATED IN ASTHMA.
• Exacerbates vasospastic angina due to unopposed α mediated coronary
constriction.
• Risk of hypoglycaemic episodes and thus avoided in diabetics.
• Plasma lipid profile is altered with triglyceride increase and HDL decrease

25
• Withdrawal after chronic use should be gradual else rebound hypertension,

worsening of angina and even sudden death can occur.
• Contraindicated in partial / complete block
• Tiredness and reduced exercise capacity.
• Cold hand and feet during winter due to blockade of vasodilatory ß2
receptors.
• GI upset, lack of drive, nightmares, forgetfulness.

26
2. GLAUCOMA
Glaucoma is a group of diseases characterized by a progressive form of optic

nerve damage. This is generally but not necessarily, associated with raised
Intraocular tension (>21 mmHg).
Glaucoma is of two types:
A. Open angle (wide angle, chronic simple) glaucoma

B. Angle closure (narrow angle, acute congestive) glaucoma.
Classification:

27
Prostaglandin analogues:
→ Latanoprost
→ Travoprost
→ Bimatoprost
Mechanism of action:
Lower concentration of PGF2α was found to lower I.O.T without inducing
ocular inflammation. It acts by increasing uveoscleral outflow, possibly by increasing
permeability of tissues in ciliary muscle.
Because of good efficacy, once daily application and no systemic complications –they
are used the 1st choice of drugs for open angle glaucoma.
Latanoprost
• Efficacy similar to timolol
• It reduces i.o.t in normal pressure glaucoma also.
• Though ocular pain and irritation are relatively frequent, no systemic side effects
is noted.
• Blurring of vision, increased iris pigmentation, thickening and darkening of
eyelashes have occurred in some cases.
• Macular edema can develop during treatment with any PGF2α analogue.
Travoprost
• Another selective FP-prostanoid receptor agonist, it lowers i.o.t mainly by
increasing uveoscleral outflow and a minor effect on trabecular outflow.
• The effects start within two hours, peaks at 12 hours and last for 24 hours or
more.
• Side effects are comparable to Latanoprost.

28
Bimatoprost
• A synthetic prostamide derivative
• It is found to be equally or more effective than Latanoprost in lowering i.o.t.
• Ocular side effects are similar, but some patients may tolerate it better.
*The current approach of treatment of open angle glaucoma can be summarized as*
❖ Initial monotherapy with Latanoprost or another prostaglandin analogue or a

topical beta blocker.
❖ Brimonidine or dorzolamide are used only when there are contraindications to
PG analogues and/ or beta blockers.
❖ Topical miotics and oral acetazolamide are added only as the last resort.

34
6. Four cardioselective beta blockers :
● Metoprolol
● Atenolol
● Acebutolol
● Esmolol
7. Four first generation beta blockers:
• Propranolol
• Timolol
• Sotalol
• Pindolol
8. Drugs for benign prostatic hypertrophy:
• Alpha adrenergic blockers: prazosin etc

• 5- alpha reductase inhibitor: finasteride / dutasteride
9. Advantages of topical beta blockers over miotics:
• No change in pupil size – no diminution of vision in dim light and in

patients with cataract.
• No induced myopia which is essentially troublesome in younger patients.
• No headache or brow pain due to persistent spasm of iris and ciliary
muscles.
• No fluctuation in i.o.t. as it happens with Pilocarpine drops.
• Convenient twice or once daily application is sufficient.

7
1. MIGRAINE
Drug treatment in migraine is individualized with respect to

 Severity of attacks.
 Frequency of attacks.
 Response of individual patient to drugs used earlier.
Based on the above-mentioned points, migraines are classified into three types, they
are:
Mild
Moderate
Severe
Types Mild Moderate Severe

Frequency < 1 attack per 1 or more attack 2-3 or more attacks
month. per month. per month.
Severity Throbbing but Intense throbbing Severe throbbing
tolerable headache. headache. headache.
time Lasts upto 8 hours. Lasts 6-24 hours. 12-48 hours.
Other features Doesn’t Nausea, vomiting Accompanied by
incapacitate the and other features; vertigo, vomiting
individual. patient is and other
functionally symptoms; patient is
impaired. grossly
incapacitated.
Autacoids Agam Pharmacology

8
 DRUG THERAPY:
i. MILD MIGRAINE:
Simple analgesics / NSAIDs / their combinations ± antiemetic
 Simple analgesics:
 Paracetamol (0.5-1g) /Aspirin (300-600mg) at first indication of
the attack and repeated 4-6th hourly to suppress further attacks.
 NSAIDs:
The drugs are:
 Diclofenac (50 mg 8 hourly)
 Ibuprofen (400 -800 mg 8 hourly)
 Naproxen (500 mg followed by 250 mg 8 hourly)
 Indomethacin (50 mg 6-8 hourly)
 Mephenamic acid (500 mg 8 hourly)
Either alone or combined with analgesic/another sedative/another anti-

histaminic/caffeine is found more satisfactory.

9
 Anti-emetic:
 Metoclopramide (10 mg oral / i.m.)
 Domperidone (10 – 20 mg oral)
 Prochlorperazine (10 – 25 mg oral / i.m.)
They relieve nausea, vomiting and gastric stasis. Diphenhydramine or

promethazine exert sedative as well as antiemetic action.
ii. MODERATE MIGRAINE:

NSAIDs / Triptan / ergot alkaloids + antiemetic
 Simple analgesics not effective.

 Stronger NSAIDs or their combinations (mentioned above) are beneficial.
 Specific anti-migraine drug is also used:
 A triptan: sumatriptan, rizatriptan.
 An ergot preparation.
 Anti-emetics regularly needed.
 Prophylactic therapy advised only when attacks more frequent than 2-3
per month.
iii. SEVERE MIGRAINE:

Triptan / ergot alkaloids + anti-emetic + prophylaxis
 When a triptan is not sufficient, long acting analgesics like naproxen is

combined.
 Prophylactic regimens lasting 6 months or more are recommended.

10
 PROPHYLAXIS OF MIGRAINE:
 β ADRENERGIC BLOCKERS
 Used to reduce frequency as well as severity of attacks upto 70%.
 Starting dose 40 mg BD, which can be increased to 160 mg BD.
 Commonly propranolol is used. Other drugs are timolol, metoprolol,
atenolol, etc.
 TRICYCLIC ANTIDEPRESSANTS
 Amitriptyline (25 – 50 mg at bed time) commonly used.
 CALCIUM CHANNEL BLOCKERS

 Flunarizine (10 – 20 mg OD)
 Used to reduce the attacks
 ANTICONVULSANTS
 Valproic acid (400 – 1200 mg /day)
 Gabapentin (300 – 1200 mg/day)
 Topiramate initially 25 mg OD, gradually can be increased to 50 mg OD
or BD.
 They are indicated in patients who are refractory to other drugs or when
propranolol is contraindicated.
 CGRP ANTAGONIST
 Erenumab – injected s.c. once a month in patients with severe migraine.
 They reduce the number of attacks.
 5 HT ANTAGONISTS
 They are not used now for migraine.

13
3. 5 HT2 ANTAGONISTS
The drugs are:
 Ketanserin
 Ritanserin
 Clozapine
 Risperidone
 KETANSERIN:
 Selective 5HT2 blocker negligible action 5HT1/3/4.
 5HT induced vasoconstriction, platelet aggregation and contraction of airway
smooth muscle are antagonized.
 Weak H1 and dopaminergic blocker.
 Significant α adrenergic blocker and was used as anti-hypertensive but did not
gain popularity.
 RITANSERIN:
 More 5HT2A selective congener of Ketanserin.
 CLOZAPINE:
 5HT2A/2C blocker.
 weak dopaminergic antagonist.
 Atypical anti-psychotic drug.
 Also exert inverse antagonist at cerebral 5HT2A/2C receptor which accounts for
its efficacy in resistant cases of schizophrenia.

14
 RISPERIDONE:
 A combine 5HT2A + dopamine D2 antagonist (similar to clozapine).
 Atypical anti-psychotic drug.
 Ameliorates negative symptoms of schizophrenia but produces extrapyramidal
side effects.
Other drugs that exhibit 5 HT2 Antagonism are olanzapine, quetiapine,

cyproheptadine among others.
4. 5HT3 ANTAGONISTS
 Ondansetron
 Granisetron
 Palonosetron
 Ramosetron
5. FOUR SEMISYNTHETIC ERGOT ALKALOIDS

 Dihydroergotamine (DHE)
 Dihydroergotoxine (Codergocrine)
 Methysergide
 Bromocriptine
6. ADR OF ERGOT ALKALOIDS

 Nausea
 Vomiting
 Abdominal pain
 Muscle cramps
 Weakness
 Paresthesia
 Chest pain

15
1. PROSTAGLANDINS AND THEIR USES
CLASSIFICATION
USES
 Abortion
Medical termination of pregnancy (MTP) upto 7 weeks – administration
of mifepristone (anti-progestin) 600mg orally 2days before a single oral
dose of misoprostol 400 µg.
 Induction or augmentation of labour
Dinoprostone – rarely used now.
 Cervical priming (ripening)
Applied intravaginally or in cervical canal, PGE2 at low doses makes the
cervix soft and compliant, this procedure yield good results in cases with
unfavorable cervix.
 Postpartum hemorrhage
Carboprost injected i.m., it is indicated in patients unresponsive to
ergometrine and oxytocin.
 Glaucoma
Latanoprost, travoprost, bimatoprost are the first-choice drugs in wide
angle glaucoma.

16
 Peptic ulcer
Misoprostol is occasionally used for healing peptic ulcer, especially in
patients who need continued NSAID therapy or whose continue to
smoke.
 To maintain patency of ductus arteriosus
Alprostadil is used.
 To avoid platelet damage
Epoprostenol can be used to prevent platelet aggregation and damage
during hemolysis or cardio-pulmonary bypass. it also improves harvest
of platelets for transfusion.
 Pulmonary hypertension
Primary pulmonary hypertension has been successfully maintained on
Epoprostenol infused continuously in a large vein.
 Peripheral vascular diseases
PGE2 / PGI2 infused i.v. can relieve rest pain and promote healing of
ischemic ulcers in severe cases of intermittent claudication and in
Raynaud’s disease.
 Impotence
Alprostadil injected into penis causes erection lasting 1-2 hours. Not
preferred now.

18
1. NSAIDs
CLASSIFICATION
ASPIRIN
PHARMACOLOGICAL ACTIONS:
Analgesic:
 Weaker analgesic than morphine.
 Effectively relieves inflammatory, tissue injury related, connective tissue
and integumental pain.
 Relatively ineffective in visceral and ischemic pain.

19
NSAIDs inhibit COX-2
inhibition of release of
bradykinin, IL, TNF α
pain sensitizing
mechanism is blocked.
Antipyretic:
aspirin hypothalamic promotes reduces

resets thermostat heat loss fever
*But it does not decrease heat production.

Anti-inflammatory:
 At high doses, signs of inflammation such as pain, tenderness, swelling,
vasodilation and leucocyte infiltration are suppressed.
 Reduce free radical production.
GIT:
 Irritates gastric mucosa, cause epigastric distress, nausea, vomiting.
 Causes gastric ulceration, bleeding
 contraindicated in gastric patients.
Aspirin and gastric ulcer
In acidic pH: aspirin remains unionized

In basic pH:

20
aspirin is ionised in gastric mucosa
promotes back diffusion

becomes indiffusible
of acid
focal recrosis of mucosal

ion trapping occurs
cells & capillaries
gastric toxicity ulcer, congestion, etc.
Blood:
aspirin inhibits
TXA2 synthesis by
platelets
platelet aggregation
is interfered
bleeding time is
prolonged
Metabolic and other effects of high/anti-inflammatory doses:

 Cellular metabolism enhanced; especially in skeletal muscles, decreased
blood glucose, liver glycogen depleted.
 Respiration is stimulated. It results in compensated respiratory alkalosis.
 At higher doses, Hyperventilation followed by respiratory depression.

21
 At higher doses, Respiratory alkalosis  Respiratory acidosis 

Metabolic Acidosis
PHARMACOKINETICS:
 Aspirin is absorbed from the stomach and small intestines.
 Rapidly de-acetylated in gut wall, liver among others.
 Approximately, 80% is plasma bound.
 Entry into brain is flow, crosses placenta freely.
 Conjugated with glycine/ glucuronic acid to form salicyluric acid in liver.
 Excreted by glomerular filtration and tubular secretion.
ADVERSE EFFECTS:
 Nausea
 Vomiting
 Epigastric distress
 Gastric mucosal damage and peptic ulceration.
 Increased blood occult in stools
 Salicylism: dizziness, tinnitus, vertigo, etc.
 Sodium and water retention.
 Acute salicylate poisoning
 More common in children, fatal dose in adults is 15-30 g.
 Manifestations are: vomiting, water and electrolyte imbalance, delirium,
hyperpyrexia among others.
 Treatment: symptomatic and supportive. External cooling, i.v. fluids and
glucose. Continuous monitoring required. Blood transfusion and vitamin
K to be given if bleeding occurs.
CONTRAINDICATIONS:
 Bleeding tendency
 Hypersensitive to aspirin
 Peptic ulcer
 Chicken pox/ influenza
 Chronic liver disease
 Breastfeeding mothers

22
 Diabetics
 G-6PD deficiency
INTERACTIONS:
 Aspirin displaces warfarin, sulfonylureas, phenytoin and methotrexate.
 Aspirin x oral anticoagulants = risk of bleeding.
 Aspirin x probenecid = antagonizes uricosuric action.
 Aspirin blunts diuretic action of furosemide, thiazides and ↓ K + conserving
action of spironolactone.
USES:
 Analgesic: aspirin 0.3-0.6 g 6-8 hourly.
 Antipyretic
 Acute rheumatic fever: 4-5 g or 75-100 mg/kg/day in divided portions provides
symptomatic relief in 1-3 days. Withdrawal should be gradual.
 Rheumatoid arthritis: 3-5 g/day produce symptomatic relief.
 Osteoarthritis
 Past MI and past Stroke patients: aspirin 75-150 mg/day reduces the
incidence of MI.
 Prevention of pre-eclampsia: aspirin 80-100 mg/day administered from 12th
week of gestation to child birth reduce the risk of pre-eclampsia in pregnant
women.

24
 Sinusitis and other ENT disorders
 Dental surgery
 Post-operative pain among others.
3. SELECTIVE COX-2 INHIBITORS

DRUGS:
 Celecoxib
 Etoricoxib
 Parecoxib
Rofecoxib, valdecoxib, lumiracoxib are withdrawn due to serious ADR.
 Celecoxib
 Exerts anti-inflammatory, analgesic and antipyretic effects.
 Tolerability is better
 Pharmacokinetics: absorbed slowly, 97% plasma bound, metabolized
byCYP2C9, half-life 10 hours.
 ADR: abdominal pain, dyspepsia and mild diarrhea.
 Used in osteoarthritis and rheumatoid arthritis
 Dose: 100-200 mg BD.
 Etoricoxib
 Has highest COX-2 selectivity.
 Half-life is 24 hours.

25
 ADR: dyspepsia, abdominal pain, pedal edema, etc.

 Used in osteo/ rheumatoid/ acute gouty arthritis, ankylosing spondylitis,
dysmenorrhea, acute dental surgery pain.
 Dose: 60-120 mg OD.
 Parecoxib
 Prodrug of valdecoxib
 Used in post-operative or similar short-term pain.
 Dose: 40 mg oral/ i.v./ i.m., repeated every 6-12 hours.
ADVANTAGES:
 Does not cause gastric mucosal damage
 They do not affect platelet aggregation.
 COX -2 inhibitors reduce endothelial PGI2 production without affecting platelet
TXA2 synthesis.
DISADVANTAGES:
 They lack the cardioprotective property of aspirin.
 May delay gastric ulcer healing.
 Salt and water retention.
INDICATIONS:
To be used only in patients at high risk of
 Peptic ulcer.
 Perforation or bleeds.
CONTRAINDICATION:
 Ischemic heart disease
 Hypertension
 Cardiac failure
 Cerebrovascular disease

29
1. METHOTREXATE
 1st line anti-rheumatoid drug

 Dihydrofolate reductase inhibitor with prominent immunosuppressant
and anti-inflammatory property.
MECHANISM OF ACTION:
 Methotrexate competitively inhibits dihydrofolate reductase.

 Direct inhibitory effect on proliferation and stimulates apoptosis in
immune inflammatory cells.
PHARMACOKINETICS:
 Well absorbed
 Oral bioavailability is variable
 T1/2=6-9 hours
 Excretion: largely in urine, 30% in bile
ADVERSE EFFECTS:
 Nausea
 Oral ulcers
 Leukopenia
 Anaemia
 GIT ulcer
 alopecia

30
INDICATIONS:
 rheumatoid arthritis
 psoriasis
 polymyositis
 dermatomyositis
 Wegener’s granulomatosis
 Non-Hodgkin lymphoma
 Carcinoma of breast, bladder, head and neck cancers.
CONTRAINDICATIONS:
 Pregnancy
 Breast feeding
 Liver disease
 Active infection
 Leucopenia
 Peptic ulcer
2. TNF-α BLOCKING AGENTS
 Cytokines (particularly TNF-α) play an important role in the process of

inflammation.
 TNF-α binds to membrane bound receptors on T-cells and
macrophages and activate them

36
4. URICOSURIC DRUGS
DRUGS:
 Probenecid
 Sulfinpyrazone
 Lesinurad
 PROBENECID:
 It is second line of drug for treating rheumatoid arthritis since it is less
effective.
probenecid competitvely
blocks
URAT-1 of OATP family
inhibits reabsorption
promotes excretion of uric

acid
PHARMACOKINETICS:
 Completely absorbed orally
 90% plasma bound
 Partly conjugated in liver
 Excreted in kidney
 Plasma half-life: 6-8 hours
INTERACTIONS:
 Probenecid inhibits excretion of penicillin, cephalosporins, sulfonamides,
methotrexate and indomethacin.

37
 It inhibits biliary excretion of rifampicin.

 Pyrazinamide and ethambutol may interfere with uricosuric action of
probenecid.
 Aspirin blocks uricosuric action of probenecid.
CONTRAINDICATION:
 Renal failure
ADVERSE EFFECTS:
 Dyspepsia
 Rashes and hypersensitivity are rare
USES:
 Chronic gout
 Hyperuricemia
 As adjuvant in gonorrhoea
DOSE: 0.5 to 1g O.D
 SULPHINPYRAZONE:
 A pyrazolone derivative is another uricosuric drug.
 Used in chronic gout
 LESINURAD:
 New uricosuric drug
 Mechanism of action similar to probenecid
 Used in hyperuricemia

38
5. ALLOPURINOL
 Hypoxanthine analogue
 It is a uric acid synthesis inhibitor
 1st line agent for the treatment of chronic gout.
 Allopurinol competitively inhibits xanthine oxidase
PHARMACOKINETICS:
 Orally absorbed (80%)
 Not bound to plasma proteins
 T1/2=1-2 hours
 Long duration of action
 Taken once a day
INTERACTIONS:
 Increases effect of Mercaptopurine, azathioprine, warfarin.
 Allopurinol potentiate warfarin and theophylline.
ADVERSE EFFECT: uncommon

 GI intolerance

39
 peripheral neuritis
 vasculitis
 bone marrow suppression
 aplastic anaemia
 hepatic toxicity.
 Stevens-Johnson syndrome
CONTRAINDICATION:
 Hypersensitive patients
 Pregnancy
 Lactation
USES:
 Chronic gout
 Secondary hyperuricaemia
 Chemotherapy & immunosuppressant therapy.
DOSE: 50-100mg per day

1
1. DRUGS FOR BRONCHIAL ASTHMA
INHALATIONAL CORTICO STEROIDS (ICS)

• They are glucocorticoids with high topical and low systemic activity
• They have poor absorption and marked first pass metabolism
• It has been Advocated as step one for all the asthma patients to
prevent bronchial remodeling but currently they are not necessarily
used in mild and episodic asthma patients.
• Peak effect is seen after 4-7 days of administering ICS and the effects
persists for few weeks after discontinuation.
• Dosage: initially 100 - 200µg BD, titrate dose upward for every 3 – 5
days, maximum dose of 400µg QID, beyond which no further benefit
generally occurs.
• They are safe during pregnancy.
Respiratory System Agam Pharmacology

2
FUNCTIONS:
i. Suppress bronchial inflammation.

ii. Increases the peak expiratory flow rate
iii. Reduce need for β2 agonist inhalations
iv. Prevent episodes of acute asthma
ADVERSE DRUG EFFECTS:
▪ Hoarseness of voice
▪ Dysphonia
▪ Sore throat
▪ Symptomatic/ asymptomatic oropharyngeal candidiasis
*prevention: ADR can be minimized by usage of spacers and
gargling of mouth after every dose. Oral candidiasis can be
prevented/ treated by topical nystatin or clotrimazole.*
▪ Dose> 600µg/day causes mood changes, osteoporosis, growth
retardation in children, early cataract, etc.
DRUGS
❖ Beclomethasone dipropionate:
Effective in perennial rhinitis
❖ Budesonide:
Non-halogenated glucocorticoid with high topical: systemic activity
ratio
They are preferred in severe cases
Contraindicated in presence of nasal infection and nasal ulcers.
❖ Fluticasone propionate:
High potency

3
Longer duration
Negligible oral bioavailability
Preferred in patients requiring higher doses
❖ Flunisolide:
Topical steroid used for prophylaxis and treatment of seasonal
and perennial rhinitis.
❖ Ciclesonide:
It is a prodrug that is cleaved by esterases in the bronchial
epithelium to release the active moiety.
Oral bioavailability <1%
ANTI IgE ANTIBODY
Omalizumab:
❖ Humanized monoclonal antibody against IgE.
❖ Administered via subcutaneous route
❖ Mechanism of action: it neutralizes free IgE in circulation without
activating mast cells and other inflammatory cells. On antigen
challenge little IgE is available bound to the mast cell receptors t
trigger mediator release and cause bronchoconstriction.
❖ Uses: reduces exacerbations and steroid requirement in severe
extrinsic asthma. It is reserved for resistant asthma patients with
positive skin tests or raised IgE levels that require frequent
hospitalization.
❖ Very expensive.

7
4. MAST CELL STABILIZERS

▪ Sodium chromoglycate
• Synthetic chromone derivative which inhibits degranulation of mast
cells by trigger stimuli.
• Long term treatment deceases cellular inflammatory response
• Bronchial hyper reactivity is reduced to variable extents.
• Bronchospasm induced by allergens, cold air, exercise may be
attenuated
• Uses:
➢ Bronchial asthma
➢ Allergic rhinitis
➢ Allergic conjunctivitis
• ADR:
➢ Bronchospasm
➢ Throat irritation
➢ Cough
▪ Ketotifen
• Antihistaminic with some chromoglycate like action
• Stimulation of immunogenic and inflammatory cells and mediator
release are reduced.
• ADR:
➢ Sedation
➢ Dry mouth
➢ Dizziness
➢ Nausea
➢ Weight gain.

8
5. TREATMENT OF STATUS ASTHMATICUS
It is a life threatening condition.

Upper respiratory tract infection is the most common precipitant.
TREATMENT:
❖ Hydrocortisone hemisuccinate 100mg ( or equivalent dose of
another glucocorticoid) i.v. stat , followed by 100- 200mg 4-8 hourly
infusion; may take 6 hours to act
❖ Nebulised Salbutamol(2.5 – 5 mg)+ ipratropium bromide 0.5mg
intermittent inhalations driven by oxygen
❖ High flow humidified oxygen inhalation
❖ Salbutamol/ Terbutaline 0.4 mg i.m./ s.c. may be added , since
inhaled drug may not reach smaller bronchi due to severe narrowing/
plugging with secretions
❖ Intubation and mechanical ventilation, if needed
❖ Intensive antibiotic therapy for treating chest infections
❖ Saline+ sodium bicarbonate/ lactate infusion to correct dehydration
and acidosis

7
1. THYROID INHIBITORS
CLASSIFICATION:
THIOAMIDES (ANTITHYROID DRUGS)
thioamides inhibit
thyroid peroxidase
prevent oxidation of
iodine and iodotyrosyl

residues
Hormones Agam Pharmacology

8
Thereby,
 Inhibit iodination of Tyrosine residues in thyroglobulin

 Inhibit coupling of iodotyrosine residues to form T3 and T4
Propylthiouracil Carbimazole
Potency Less potent More potent
Plasma protein bound High Low
Crosses placenta & Less amounts Larger amounts
secreted in milk
Half-life 1-2 hours 6-10 hours
Metabolite None Methimazole
Daily doses Multiple Single
Peripheral conversion of Inhibits Does not inhibit
T4 to T3
PHARMACOKINETICS:
 Quickly absorbed orally
 Crosses the placenta and enters milk
 Metabolized in the liver
 Excreted in urine
ADR:
 Hypothyroidism and goiter can occur due to overtreatment
 GI intolerance
 Skin rashes
 Joint pain
 Liver damage (Propylthiouracil)
 Loss or graying of hair
 Loss of taste
 Fever
 Agranulocytosis

9
USES:
 To control thyrotoxicosis in both graves’ disease and toxic nodular goiter.
 Preoperative surgery before performing subtotal thyroidectomy (Carbimazole
is given)
 Along with radioactive iodine
 In pregnancy, Propylthiouracil is given because it has less placental transfer.

12
4. THYROID STORM
 It is also known as Thyrotoxic crisis

 It is an emergency condition due to decompensated hyperthyroidism.
TREATMENT:
Vigorous treatment is indicated with
 Non-selective beta blockers

Propranolol 1-2 mg slow i.v. may be followed by 40-80 mg orally every 6 hours.
It may be withdrawn gradually when T4 levels normalize.
Affords symptomatic relief
High doses inhibit peripheral conversion of T4 to T3
 Propylthiouracil 200-300mg oral 6 hourly.

Reduces hormone synthesis as well as inhibits peripheral conversion of
T4 to T3
 Iopanoic acid 0.5-1g OD oral one hour after Propylthiouracil or ipodate.

They are potent inhibitors of thyroid hormone release and inhibits
peripheral conversion of T4 to T3
 Corticosteroids: Hydrocortisone 100mg i.v. 8 hourly followed by oral

prednisolone.
Help to tide over crisis, cover any adrenal sufficiency and reduce
peripheral conversion of T4 to T3

13
 Diltiazem: 60-120mg BD oral may be added

If tachycardia is not controlled only by propranolol or when it is
contraindicated.
 Rehydration, anxiolytics, external cooling and appropriate antibiotics.
5. LUGOL’S IODINE SOLUTION
 5% iodine in 10% potassium iodide.

 It is used in the treatment of thyroid storm.
6. ADR OF IODINE
 ACUTE REACTION: occurs in individuals sensitive to iodine.

 swelling of lips, eyelids
 angioedema of larynx
 CHRONIC OVERDOSE – IODISM:

 Inflammation of mucous membrane
 salivation, rhinorrhea, lacrimation
 swelling of eyelids
 burning sensation in mouth

14
1. INSULIN
CLASSIFICATION:
 Insulin acts on specific receptors located on cell membrane of every cell but
their density varies with liver and fat cells being rich.
Insulin receptors have two extracellular alpha subunits which has the binding
site. Two transmembrane beta subunits which have tyrosine protein kinase.
The two subunits are held together by disulphide bonds. The receptor is
oriented as a heterodimer across the cell membrane.

15
insulin binds with α subunit
activates tyrosine kinase on β subunits
resulting in phosphorylation of tyrosine

residues on the receptor
a series of phosphorylation and

dephosphorylation reaction occurs
promotes entry of glucose into the cell
thereby, mediating various actions of insulin
 Tyrosine kinase activity is directed at cytoplasmic proteins like insulin receptor

substrates (IRS) and other proteins.
 IRS binds to the other kinases especially PI3 (Phosphatidylinositol 3) kinase
which results in stimulation of enzymes involved in rapid metabolic action of
insulin.
 It stimulated the translocation of GLUT 4 to plasma membrane for which PIP3
and tyrosine phosphorylated guanine nucleotide exchange proteins play a
major role.
 Alternatively, IRS binds to growth factor receptor binding protein 2 which
translates insulin signal to a guanine nucleotide releasing factor that activates
Mitogen activated protein kinase MAPK system.
USES:
Diabetes mellitus type 1 and 2
Diabetic ketoacidosis (diabetic coma)
Hyperosmolar (non-ketotic hyperglycaemic) coma

16
ADR:
 Insulin Allergy – Immediate type hypersensitivity reaction
 It is a rare condition in which local or systemic urticaria results from
histamine release from mast cells. Anaphylaxis results.
 Immune insulin resistance:

 A low titre of circulating Ig anti-insulin antibodies that neutralise the action
of insulin to a negligible extent develops in most insulin treated patients.
 Rarely it leads to insulin resistance.
 Lipodystrophy at injection sites – atrophy of subcutaneous fatty tissue.

 It is seen occasionally with the older insulin preparations.
 Rare with the newer ones.
 Hypoglycemia
 Common in labile diabetes in whom insulin requirement fluctuates
unpredictably.
 Symptoms: counter regulatory sympathetic stimulation- sweating, anxiety,
palpitation, tremor
 When blood glucose falls (< 40 mg/dl), mental confusion, abnormal
behaviour, seizures and coma occur.
 Treatment: glucose 15-20 g orally reverses the symptoms rapidly in most
cases. If no improvement occurs, repeat after every 15-20 minutes.
In severe cases, 30-50 ml of 50% glucose may be injected i.v. over 10

minutes.
Glucagon 0.5-1 mg i.v. or adrenaline 0.2 mg s.c. may be given if oral and
injectable preparations aren’t available.
 Neuroglycopenic:
 Dizziness, headache, behavioral changes, visual disturbances, hunger, fatigue,
weakness, muscular incoordination, fall in BP.
 Hypoglycemic unawareness tends to develop in patients who experience
frequent episodes of hypoglycemia.

17
MANAGEMENT OF DIABETIC KETO-ACIDOSIS

 Insulin
 Regular insulin is used rapidly to correct the metabolic abnormalities.
 Dose: 0.1 – 0.2U/kg i.v. is followed by 0.1 U/kg/hr infusion.
 The rate is doubled if no significant fall in blood sugar occurs.
 Intravenous fluids
 Dehydration has to be corrected.
 Normal saline is infused i.v. initially at the rate of 1 litre per hour
reducing progressively to 0.5 litre per hour.
 Once stabilised and adequate renal perfusion is assured change over
to 1/2N saline.
 After blood sugar has reached 300mg/dl 5%glucose in 1/2N saline is
the most appropriate fluid.
 KCl
 Hypokalemia can occur when insulin therapy is instituted which is
dangerous. After 2-3 hours it is appropriate to add 10-20 mEq/hr KCl
to the i.v. fluid.
 Sodium bicarbonate
 Acidosis subsides as ketosis is controlled however if arterial blood pH
is greater than 7 acidosis is not corrected spontaneously.
 50 mEq of sodium bicarbonate is added to the i.v. fluid.
 Phosphate
 When serum PO4 is in the low normal range, 3-4 m mol/hr of
potassium phosphate infusion is advocated.
 Faster infusion can precipitate tetany.
 Antibiotics and other supportive measures

18
2. ORAL ANTIDIABETIC DRUG
CLASSIFICATION:
SULFONYLUREAS:
sulfonylureas bind to SUR1 KATP
closes KATP
membrane depolarisation
calcium influx
insulin granules are degranulated
insulin release

19
 They lower the blood glucose levels in normal individuals and in type 2
diabetics, not in type 1 diabetics.
 A minor action reducing glucagon secretion.
 Hepatic degradation of insulin is slowed.
PHARMACOKINETICS:
 They are well absorbed orally.

 Extensively bound to plasma proteins (>90%).
 Metabolized in liver.
 Secreted in milk.
 Excreted in urine.
ADVERSE EFFECTS:
 Hypoglycemia
 Nausea
 Vomiting
 Jaundice
 Allergic reactions
 Disulfiram like reaction

20
DRUG INTERACTIONS:
Enhance SU action Dampens SU action

 Phenylbutazone  Phenobarbitone
 Salicylates  Rifampicin
 Sulfonamides  Phenytoin
 Warfarin  Chronic alcoholism
 Propranolol  Corticosteroids
 Lithium  Contraceptives
 Antihypertensives  Furosemide
 Alcohol  Thiazides

23
4. METFORMIN
It’s a biguanide.
MECHANISM OF ACTION: (not clear)
Metformin acts by activating AMP dependent protein kinase (AMPK).

Resulting in,
 Suppression of hepatic gluconeogenesis
 Increased peripheral utilisation of glucose in skeletal muscle and fat.
 Increased glycogen storage in skeletal muscle.
 Increased fatty acid oxidation.
 Decreased lipogenesis.
 It Causes little or no hypoglycaemia in non-diabetic subjects and even in

diabetics.
 It does not stimulate pancreatic beta cells.

24
 They do not cause insulin release, but presence of insulin is essential for their
action.
PHARMACOKINETICS:
 Well absorbed orally

 not metabolized
 excreted unchanged by kidney.
ADVERSE EFFECTS:
 Lactic acidosis
 Vit B12 deficiency
 Its contraindicated in renal insufficiency because of risk of lactic acidosis.
USES:
 As a first choice of drug for all type 2 DM patients.
ADVANTAGES:
 Antihyperglycemic
 Weight loss promoting.
 Potential to prevent microvascular as well as macrovascular complications.
 No acceleration of beta cell exhaustion or failure in type 2 DM.
 Can be combined with any other oral or injectable antidiabetic.
 Can prevent new onset type 2 DM in obese, middle aged subjects with
impaired glucose tolerance.

26
1. CORTICOSTEROIDS
CLASSIFICATION:
USES:
 Replacement therapy (endocrine diseases)
 Acute adrenal insufficiency:

 It is an emergency.
 Hydrocortisone or dexamethasone are given i.v., first as a bolus

injection and then as infusion, along with isotonic saline with 5%
glucose solution.
 Short-term i.v. infusion of a vasopressor (dopamine) may be needed.
 The cause of adrenal insufficiency should be treated.

27
 Chronic adrenal insufficiency: (Addison’s disease)

 Hydrocortisone given orally is the most commonly used drug along
with adequate salt and water allowance.
 Some patients who continue to excrete excess Na+ need additional

mineralocorticoid: fludrocortisone is added.
 Congenital adrenal hyperplasia: (Adrenogenital syndrome)

 It is a familial disorder due to genetic deficiency of steroidogenic
enzymes, mostly 21-hydroxylase.
 As a result, the synthesis of hydrocortisone and aldosterone suffers.

There is a compensatory increase in ACTH secretion— adrenals
hypertrophy.
 Treatment is to give hydrocortisone 0.6 mg/ kg daily in divided doses

round the clock to maintain feedback suppression of pituitary.
 If salt wasting persists—fludrocortisone 50–200 µg/ day may be

added.
 Pharmacotherapy (nonendocrine diseases)
 Rheumatoid arthritis
 Corticosteroids are indicated only in severe cases as adjuvants to
NSAIDs

28
 Osteoarthritis
 It is treated with analgesics and NSAIDs; systematic use of corticoids
is rare.
 Intraarticular injection of a steroid may be used to control an acute

exacerbation.
 Injections may be repeated 2–3 times a year, but have the potential
to cause joint destruction.
 Rheumatic fever
 Corticoids are used only in severe cases with myocarditis and CHF
with the aim of rapid suppression of symptoms, because they act
faster than aspirin, or in patients not responding to aspirin.
 Gout
 Corticoids (short course) should only be used in acute gouty arthritis
when NSAIDs have failed to afford relief and colchicine is not
tolerated.
 Collagen diseases
 Most cases of systemic lupus erythematosus, polyarteritis nodosa,
dermatomyositis, nephrotic syndrome, glomerulonephritis and
related diseases need corticosteroid therapy.
 They may be life-saving in these diseases.

29
 Severe allergic reactions

 Corticoids may be used for short periods in anaphylaxis,
angioneurotic edema, urticaria and serum sickness.
 However, even i.v. injection of a glucocorticoid takes 1–2 hours to act

and is not a substitute for Adrenaline (which acts immediately) in
anaphylactic shock and angioedema of larynx.
 Topical use is made in allergic conjunctivitis and rhinitis.
 Autoimmune diseases
 Autoimmune hemolytic anemia, idiopathic thrombocytopenic
purpura, active chronic hepatitis responds to corticoids.
 Prednisolone 1–2 mg/kg/day is given till remission, followed by

gradual withdrawal or low-dose maintenance depending on the
response.
 Remission may also be induced in severe cases of myasthenia gravis,

in which their use is adjunctive to neostigmine.
 Patients requiring long term maintenance therapy are better shifted

to other immunosuppressants.
 Bronchial asthma
 Systemic corticosteroids are used only for:
 Status asthmaticus: give i.v. glucocorticoid; withdraw when
emergency is over.
 Acute asthma exacerbation: short-course of high dose oral
corticoid, followed by gradual withdrawal.
 Severe chronic asthma not controlled by inhaled steroids
and bronchodilators: add low dose prednisolone daily or on
alternate days.

30
 Other lung diseases

 Corticosteroids benefit aspiration pneumonia and pulmonary edema
from drowning.
 Given during late pregnancy, corticoids accelerate lung maturation

and surfactant production in the foetal lung and prevent respiratory
distress syndrome at birth.
 Two doses of betamethasone 12 mg i.m. at 24-hour interval may be

administered to the mother if premature delivery is contemplated.
 Infective diseases
 Administered under effective chemotherapeutic cover,
corticosteroids are indicated only in serious infectious diseases to tide
over crisis or to prevent complications.
 They are indicated in conditions like severe forms of tuberculosis

(miliary, meningeal, renal, etc.), severe lepra reaction, certain forms
of bacterial meningitis and Pneumocystis carinii pneumonia with
hypoxia in AIDS patients.
 Eye diseases
 Corticoids are used in a large number of inflammatory ocular
diseases—may prevent blindness.
 Topical instillation as eye drops or ointment is effective in diseases of

the anterior chamber—allergic conjunctivitis, iritis, iridocyclitis,
keratitis, etc.
 Steroids are contraindicated in herpes simplex keratitis and in ocular

injuries.

31
 Skin diseases
 Topical corticosteroids are widely employed and are highly effective
in many eczematous skin diseases.
 Systemic therapy is needed (may be life-saving) in pemphigus

vulgaris, exfoliative dermatitis, Stevens-Johnson syndrome and other
severe afflictions.
 Intestinal diseases
 Ulcerative colitis, Crohn’s disease, coeliac disease are inflammatory
bowel diseases with exacerbations and remissions.
 Corticoids are indicated during acute phases— may be used orally or

as retention enema (for colonic involvement).
 Cerebral edema
 due to tumors, tubercular meningitis, etc., responds to corticoids.
 Dexa or betamethasone are preferred because they don't have Na+

retaining activity.
 Their value in traumatic and poststroke cerebral edema is

questionable.
 Large doses given i.v. soon after spinal injury may reduce the resulting
neurological sequelae.
 A short course (2–4 weeks) of oral prednisolone can hasten recovery

from Bell’s palsy and acute exacerbation of multiple sclerosis.
 In the latter, methylprednisolone 1 g i.v. daily for 2–3 days may be

given in the beginning.

32
 Malignancies
 Corticoids are an essential component of combined chemotherapy of
acute lymphatic leukemia, Hodgkin’s and other lymphomas, because
of their marked lymphocytic action in these conditions.
 Organ transplantation and skin allograft

 High dose corticoids are given along with other immunosuppressants
to prevent rejection reaction.
 Septic shock
 High-dose corticosteroid therapy for septic shock has been
abandoned, because it worsens the outcome.
 However, many such patients have relative adrenal insufficiency.
 Recent studies have documented beneficial effects of low-dose

(hydrocortisone 100 mg 8 hourly i.v. infusion for 5–7 days) therapy in
patients who are adrenal deficient and do not respond adequately to
fluid replacement and vasopressors.
 Thyroid storm
 Many patients in thyroid storm have concomitant adrenal
insufficiency.
 Moreover, corticosteroids reduce peripheral T4 to T3 conversion.
 Hydrocortisone 100 mg i.v. 8 hourly may improve outcome.
 To test pituitary-adrenal axis function

 Dexamethasone suppresses pituitary-adrenal axis at doses which do
not contribute to steroid metabolites in urine.
 Responsiveness of the axis can be tested by measuring daily urinary

steroid metabolite excretion after dosing with dexamethasone.

33
ADVERSE EFFECTS:
 Mineralocorticoid
 Sodium and water retention

 Edema
 hypokalemic alkalosis
 a progressive rise in BP.

34
 Glucocorticoid
 Cushing’s habitus
 Fragile skin, purple striae
 Hyperglycemia
 Muscular weakness
 Susceptibility to infection
 Delayed healing
 Peptic ulceration
 Osteoporosis
 Posterior subcapsular cataract
 Glaucoma
 Growth retardation
 Foetal abnormalities
 Psychiatric disturbances
 Suppression of hypothalamo-pituitary-adrenal axis
CONTRAINDICATIONS:
 Peptic ulcer
 Diabetes mellitus
 Hypertension
 Viral and fungal infections
 Tuberculosis and other infections
 Osteoporosis
 Herpes simplex keratitis
 Psychosis
 Epilepsy
 CHF
 Renal failure

35
2. OUTLINE THE ACTIONS OF GLUCOCORTICOIDS
 Carbohydrate and protein metabolism

 Glucocorticoids promote glycogen deposition in liver (they are
assayed on the basis of this action) by inducing hepatic glycogen
synthase and promoting gluconeogenesis.
 They inhibit glucose utilization by peripheral tissues.
 This along with increased glucose release from liver results in
hyperglycemia, resistance to insulin and a diabetes-like state.
 Lipid metabolism
 The action of glucocorticoids on fat metabolism is primarily
permissive in nature.
 They promote lipolysis due to glucagon, growth hormone, Adrenaline
and thyroxine.
 cAMP induced breakdown of triglycerides is enhanced.
 Fat depots in different areas of the body respond differently—
redistribution of body fat occurs.
 Calcium metabolism
 Glucocorticoids inhibit intestinal absorption and enhance renal
excretion of Ca2+.
 Loss of osteoid (decreased formation and increased resorption)
indirectly results in loss of Ca2+ from bone, producing negative
calcium balance.
 May lead to osteoporosis.
 Spongy bones (vertebrae, ribs, pelvis, etc.) are more sensitive.

36
 Water excretion
 The effect on water excretion is independent of action on Na+
transport; hydrocortisone and other glucocorticoids, but not
aldosterone, maintain normal g.f.r.
 In adrenal insufficiency, the capacity to excrete a water load is
markedly reduced—such patients are prone to water intoxication
from i.v. infusions.
 Glucocorticoids also enhance secretory activity of renal tubules.
 CVS
 Glucocorticoids restrict capillary permeability, maintain tone of
arterioles and myocardial contractility.
 Applied topically, they cause cutaneous vasoconstriction.
 They have a permissive role for the pressor action of Adrenaline and
angiotensin.
 They also play a permissive role in development of hypertension—
should be used cautiously in hypertensives.
 Skeletal muscles
 Optimum level of corticosteroids is needed for normal muscular
activity.
 Weakness occurs in both hypo and hypercorticism, but the causes are
different.
 Hypocorticism: diminished work capacity and weakness are primarily
due to hypodynamic circulation.
 Hypercorticism: excess mineralocorticoid action → hypokalemia →
weakness; Excess glucocorticoid action → muscle wasting and
myopathy → weakness.

37
 CNS
 Mild euphoria is quite common with pharmacological doses of
glucocorticoids.
 This is a direct effect on brain, independent of relief of disease
symptoms, and sometimes progresses to cause increased motor
activity, insomnia, hypomania or depression.
 On the other hand, patients of Addison’s disease suffer from apathy,
depression and occasionally psychosis.
 Stomach
 Secretion of gastric acid and pepsin is increased—may aggravate
peptic ulcer.
 Lymphoid tissue and blood cells

 Glucocorticoids enhance the rate of destruction of lymphoid cells (T
cells are more sensitive than B cells); but in man the effect on normal
lymphoid tissue is modest.
 However, a marked lytic response is shown by malignant lymphatic
cells.
 This is the basis of their use in lymphomas.
 Glucocorticoids increase the number of RBCs, platelets and
neutrophils in circulation.
 They decrease lymphocytes, eosinophils and basophils.

38
 Inflammatory responses
 Irrespective of the type of injury or insult, the attending inflammatory
response is suppressed by glucocorticoids.
 This is the basis of most of their clinical uses.
 The action is nonspecific and covers all components and stages of
inflammation.
 This includes attenuation of—increased capillary permeability, local
exudation, cellular infiltration, phagocytic activity and late responses
like capillary proliferation, collagen deposition, fibroblastic activity
and ultimately scar formation.
 The cardinal signs of inflammation—redness, heat, swelling and pain
are suppressed.
 Immunological and allergic responses

 Glucocorticoids impair immunological competence.
 They suppress all types of hypersensitization and allergic phenomena.
 At high concentrations and in vitro they have been shown to interfere
with practically every step of the immunological response, but at
therapeutic doses in vivo there is no impairment of antibody
production or complement function.
3. LONG ACTING CORTICOSTEROIDS

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2. ANABOLIC STEROIDS
 These are synthetic androgens with higher anabolic and lower androgenic
activity.
 The anabolic effects of these steroids are similar to Testosterone.
 Testosterone has anabolic: androgenic ratio of 1 and hence it is not used.
 These steroids have a higher anabolic selectivity.
 The anabolic effects are mediated through the same receptor as that of
androgenic effects.
DRUGS:
 Methandienone
 Nandrolone phenylpropionate
 Nandrolone decanoate
 Oxymetholone
 Stanozolol
USES:
 During recovery from acute/chronic illness, severe trauma, major surgery or
chronic debilitating diseases.
 To improve appetite and state of well-being in the elderly, under-nourished
and debilitated individuals
 To counteract the catabolic effects of exogenously administered
adrenocortical hormones
 In senile and postmenopausal osteoporosis
 Brief spurts of linear growth can be induced in boys but the final stature is
affected mostly in hypogonadism.
 Increase in RBCs and Hb% in hypoplastic, haemolytic and malignancy
associated anaemia.
 To control itching in chronic biliary obstruction
 To improve the magnitude of improvement in performance in female
athletes but it is illegal.

45
ADVERSE EFFECTS:
 Same side effect profile of Testosterone like
 Acne
 Precocious puberty
 Oligospermia
 Virilization in women
 Gynecomastia
 Salt retention
 Edema
 17-alkyl substituted compounds like Oxymetholone and Stanozolol can
produce
 Jaundice
 Worsen lipid profile
 Premature closure of epiphyses in children leading to
 Impairment of growth
CONTRAINDICATIONS: (Contraindications are same as testosterone)

 Carcinoma of prostate and male breast
 Liver and Kidney diseases
 During pregnancy – can cause masculinization of female foetus
 Men above 65 years and those with CAD or CHF
 Sleep apnoea, migraine and epilepsy
 Listed during the drugs tested for ‘dope test’ in athletes.

54
ADVERSE EFFECTS:
 Leg vein thrombosis
 Pulmonary embolism
 Coronary thrombosis – MI
 Cerebral thrombosis – stroke
 Rise in BP
 Gallstones
 Risk of endometrial and breast cancer
 May precipitate diabetes
2. HORMONAL CONTRACEPTIVES
Hormonal contraceptives are hormonal preparations used for reversible
suppression of fertility.
CLASSIFICATION:

55
Additionally, implants (NORPLANT, PROGESTASERT) and transdermal contraceptives

are available.
Oral
These oral contraceptives are known for their efficacy, convenience, low cost and
overall safety.
Combined pill
 It contains an estrogen and a progestin in a fixed dose for all the days of a
treatment cycle.
 While both estrogens and progestins synergize to inhibit ovulation, the
progestin ensures prompt bleeding at the end of a cycle and blocks the risk of
developing endometrial carcinoma due to the estrogen.
 One tablet is taken daily for 21 days, starting on the 5th day of menstruation.
 The next course is started after a gap of 7 days in which bleeding occurs.
 Thus, a cycle of 28 days is maintained.
 Calendar packs of pills are available.
 This is the most popular and most efficacious method.
Phased pill
 Triphasic regimen have been introduced for reducing the total steroid dose
without compromising efficacy.
 The estrogen dose is kept constant (or varied slightly between 30 40 ug), while
the amount of progestin is low in the first phase and progressively higher in
the second and third phases.
 Phasic pills are particularly recommended for women over 35 years of age and
for those with no withdrawal bleeding or breakthrough bleeding while on
monophasic pill, or when other risk factors are present.

56
Progestin-only pill (Minipill)

 A low-dose progestin-only pill is an alternative for women in whom an
estrogen is contraindicated.
 It is taken daily continuously without any gap.
 The menstrual cycle tends to become irregular and ovulation occurs in 20-
30% of women.
 The efficacy is lower compared to combined pill.
Emergency (postcoital) pill

 These are for use in a woman not taking any contraceptive who had sexual
intercourse risking unwanted pregnancy.
 The most commonly used and standard regimen is
● Levonorgestrel 0.75 mg two doses 12 hours apart, or .5 mg single dose
taken as soon as possible, but before 72 hours of unprotected
intercourse.
● Ulipristal 30 mg single dose as soon as possible, but within 120 hours of
intercourse.
● Mifepristone 600 mg single dose taken within 72 hours of intercourse.
 All emergency regimens have higher failure rate and side effects than regular
low-dose combined pills.
Injectable
 These have been developed to obviate the need for daily ingestion of pills.
 They are given i.m. as oily solution
 Highly effective.
 Their major limitations are
● Animal data indicated carcinogenic potential.
● Menstrual irregularities, excessive bleeding or amenorrhea;
● return of fertility takes 6-30 months after discontinuation
● permanent sterility may occur
● weight gain and headache

57
● decrease in bone mineral density

● menopausal like symptoms.
 Only the long-acting progestin only injections are in use now.
 They are injected once 2-3 months depending on the steroid and its dose.
 Two compounds have been marketed:
 Depot medroxyprogesterone acetate (DMPA) 150 mg I.m. at 3-
month intervals.
 Norethindrone (Norethisterone) enanthate (NEE) 200 mg at 2-
month intervals.
 It is not suitable for adolescent girls and lactating mothers.
 Inhibition of Gn release from pituitary.

Progestin——> reduces LH secretion
Estrogen——> primarily reduces FSH secretion.
 Combined pill- both FSH and LH reduced—> midcycle LH surge

abolished—> follicles fail to develop and fail to rupture—> suppression
of ovulation.
 Low dose Progestin only- pill and injectable regimen- attenuated LH
surge—> irregular ovulation (~1⁄3cycles).
 Postcoital pill- if taken before ovulation, dampen LH surge—> inhibit
ovulation.
 Except in postcoital pill, Progestin—> thick cervical mucus secretion—> hostile to

sperm penetration
 With minipills and postcoital pill, endometrium is out of phase with fertilization
(either hyperproliferative or hypersecretory or atrophic)— not suitable for
nidation.

58
 With minipills and postcoital pill, modified uterine and tubal contractions —>
disfavor fertilization.
 Postcoital pill—> dislodge a just implanted blastocyst or interfere with

fertilization/implantation.
COMPLICATIONS:
 Leg vein thrombosis and pulmonary embolism:
 Coronary and cerebral thrombosis
 Rise in BP
 Genital carcinoma
 Benign hepatomas
 Gallstones

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4. HORMONE REPLACEMENT THERAPY (HRT)
 Due to cessation of ovarian function at menopause women suffer a number of

physical, psychological and emotional consequences.
 HRT is highly efficacious in suppressing the perimenopausal syndrome but

there are various risks and limitations associated with it. So, it is generally
restricted to limited duration of time.
PERIMENOPAUSAL SYNDROME:
 Vasomotor disturbances
Hot flushes, chilly sensation, inappropriate sweating, faintness,
paresthesia, aches and pains.
 Urogenital atrophy
Change in vaginal cytology and pH, vaginal dryness, vulval shrinkage,
dyspareunia, vaginitis, itching, urinary urgency, predisposition to urinary
tract infection.
 Osteoporosis
Loss of osteoid as well as calcium, thinning and weakening of bone,
minimal trauma fractures especially of femur, hip, radius, vertebrae.
 Dermatological changes
Thinning, drying and loss of elasticity of skin, wrinkles, thin and listless
hairs.
 Psychological/Cognitive disturbances
Irritability, depressed mood, loss of libido and self-confidence, anxiety
and dementia.
 Increased risk of cardiovascular diseases

Coronary artery disease, myocardial infarction, stroke.

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DOSE:
 Lesser than that used for contraception.

 Conjugated estrogens - 0.625 mg/day dose (equivalent to Ethinylestradiol
10µg) either cyclically (3 weeks treatment 1week gap) or continuously, but
there is a trend now to use lower doses (0.3–0.45 mg/day).
 A progestin (medroxy progesterone acetate/norethisterone 2.5 mg daily) is
added for the last 10–12 days each month.
Tibolone: 19-norsteroid, converted into 3 metabolites which exert estrogenic,

progestational and weak androgenic actions. Suppress menopausal syndrome and
↓ raised Gn levels.
BENEFITS OF HRT:
Menopausal symptoms are reversed to varying extent
BENEFITS OF HRT HOWEVER THE 1ST LINE DRUG IS

Osteoporosis Bisphosphonates
(vitamin D + calcium + exercise)
Dysmenorrhea PG synthesis inhibitors
Acne topical therapy with antimicrobials,
tretinoin and other drugs
Carcinoma prostate GnRH agonists
RISKS OF HRT:
 Cardiovascular risks
 Gallstones
 Migraine
 Cancer

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5. SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)
 These are drugs which exert estrogenic as well as antiestrogenic actions in a

tissue selective manner.
 Tamoxifen citrate
 Toremifene
 Raloxifene
TAMOXIFENE CITRATE
breast carcinoma inhibits cancer

antiestrogen cells growth
ic action on
tamoxifen citrate
blood vessels hot flushes
uterus
bone ↑ bone mass
estrogenic liver
action on
↓ Gn and
pituitary
prolactin levels
↓ total cholestrol
cholestrol
and LDL
 Tamoxifen is the only drug approved for primary as well as metastatic breast
carcinoma in premenopausal women.
 tamoxifen has also been approved for primary prophylaxis of breast cancer in
high-risk women.

64
 Adjuvant therapy of breast carcinoma with tamoxifen when used in

postmenopausal women is now generally replaced after 2 years by an
aromatase inhibitor, while in premenopausal women, tamoxifen itself is
continued till 5 years postmastectomy.
 PHARMACOKINETICS:
 Effective orally
 Has a biphasic plasma t1/2
 A long duration of action.
 Primary excretion is through bile
 Disadvantages: 2-3-fold increase in the risk of deep vein thrombosis and

endometrial carcinoma
 Side effects: Hot flushes, vomiting, vaginal bleeding, vaginal discharge,

menstrual irregularities
TOREMIFENE: newer congener of tamoxifen with similar actions, uses and ADR.
RALOXIFENE
uterus
antiestrogenic
action on
breast
raloxifene
bone
estrogenic action
on
cvs
 It has high affinity for both ER α and ER β
 Has a distinct DNA target the ‘raloxifene response element’ (RRE)

65
 Uses in osteoporosis
 raloxifene prevents bone loss in postmenopausal women;
 bone mineral density (BMD) may even increase by 0.9–3.4% over
years in different bones, particularly the lumbar vertebrae.
 However, accelerated bone loss occurs when raloxifene is stopped.
 The risk of vertebral fracture is reduced to half, but not that of long
bones. Raloxifene is less efficacious than bisphosphonates in
preventing fractures.
 PHARMACOKINETICS:
 Observed orally but has less bioavailability due to high first pass
metabolism
 T1/2 -28 hours
 Route of excretion-feces
 Side effects: Hot flushes, leg cramps are generally mild; vaginal bleeding is
occasional. The only serious concern is 3-fold increase in risk of deep vein
thrombosis and pulmonary embolism.
 USES: Raloxifene is a second line drug for prevention and treatment of

osteoporosis in postmenopausal women; Ca2+ and vit D supplements enhance
the benefit.

73
There are specific G-protein coupled oxytocin receptors on the
myometrium which mediate response by
 Depolarisation of muscle fibres
 Influx of calcium ions
 Phosphoinositide hydrolysis and IP3 mediated intracellular release
of calcium ions
 Increased PG synthesis and release by the endometrium
Breast
 Oxytocin contracts the myoepithelium of mammary alveoli and forces milk into
the bigger milk sinusoids.
 ‘milk ejection reflex’ is initiated by suckling so that it may be easily sucked by
the infant.
CVS
 Conventional doses used in obstetrics have no effect on BP

 At higher doses cause vasodilatation resulting in brief fall in BP, reflex
tachycardia and flushing.
 The umbilical vessels are markedly constricted.
 Oxytocin may help in their closure at birth.
Kidney
 Oxytocin in high doses exerts ADH-like action - urine output is decreased.

 Pulmonary edema can occur if large amounts of i.v. fluids and oxytocin are
infused together.
 Conventional doses are without any effect.

1
1. NEUROMUSCULAR BLOCKING AGENTS
CLASSIFICATION
*d-TC: δ – tubocurarine
PNS Agam Pharmacology

2
MECHANISM OF ACTION
The site of action (both competitive and depolarizing blockers): the end plate of
skeletal muscle fibres.
➢ Depolarizing Blockers
• Depolarising phase(phase-I):
drug binds with nicotinic receptor
opening of sodium channels
excitation
depolarisation
• Desensitizing phase (phase-II):
continous exposure to SCh
↓ depolarisation of membrane
desensitisation of the receptor
paralysis of the muscle

3
➢ Non-depolarising blockers:
They prevent the depolarisation at the end-plate. They are also known as
competitive blockers.
drugs bind to nicotinic receptor at

NMJ
Prevents binding of ACh to receptor
excitation is inhibited
relaxation of muscle
➢ Skeletal muscles
• Nondepolarizing Blockers
• IV injection rapidly produces muscle weakness—> flaccid
paralysis
• Small fast response muscles (fingers, extraocular) are affected

first; paralysis spreads to hands, feet—arm, leg, neck, face—
trunk—intercostal muscles—finally diaphragm: respiration
stops.
• The rate of attainment of peak effect and the duration for which
it is maintained depends on the drug, its dose, anaesthetic used,

4
haemodynamic, renal and hepatic status of the patient and

several other factors. Recovery occurs in the reverse sequence;
diaphragmatic contractions resume first.
• Depolarising blockers typically produce fasciculations lasting fir few

seconds before inducing flaccid paralysis.
➢ Autonomic ganglia:
• Non-depolarizing neuromuscular blockers produce some degree of
ganglionic blockade as cholinergic receptors in autonomic ganglia are
nicotinic. d-TC has the maximum propensity in this regard, while the
newer drugs (vecuronium, etc.) are practically devoid of it.
• Depolarizing blockers may cause ganglionic stimulation by its agonistic

action on nicotinic receptors.
➢ Histamine release:
• d-TC releases histamine from mast cells
• it also contributes to the hypotension, flushing, bronchospasm
and increased respiratory secretions.
➢ CVS:
• Non-depolarizing Blockers
i. d-TC produces significant fall in BP because of
i. ganglionic blockade
ii. histamine release
iii. reduced venous return.
ii. vagal ganglionic blockade cause tachycardia.
iii. Pancuronium and vecuronium also tend to cause

tachycardia.
iv. All newer nondepolarizing drugs have negligible effects on

BP and HR.

5
• Depolarizing Blockers have variable effects.

i. Generally, bradycardia occurs initially due to activation of
vagal ganglia followed by tachycardia and rise in BP due
to stimulation of sympathetic ganglia.
ii. BP occasionally falls on account of its muscarinic action

causing vasodilatation.
iii. Prolonged administration of SCh has caused cardiac

arrhythmias and even arrest in patients with burns, soft
tissue injury and tetanus.
➢ G.I.T
Competitive Blockers may enhance postoperative paralytic ileus after
abdominal operations.
➢ CNS
▪ They don’t cross blood brain barrier
▪ When δ-TC is administered to brain cortex or injected in the cerebral
ventricles produces strychnine like effects.
USES
• General anaesthesia: neuro muscular blockers are used as adjuvants in general

anaesthesia. They provide adequate muscle relaxation.
• Assisted ventilation: they reduce the chest wall resistance to inflation.
• Convulsions and trauma Prevention from electroconvulsive therapy (ECT).
• Useful in controlling severe cases of tetanus and status epilepticus.

6
2. SUCCINYLCHOLINE (SUXAMETHONIUM)
• A Depolarizing Neuromuscular blocker.
• Succinylcholine is a quaternary ammonium compound. The structure resembles

two molecules of Ach linked together.
• It acts as a partial agonist at NM receptors, hence causes initial fasciculations

and later flaccid paralysis due to prolonged depolarization (phase I block).
• With continued exposure to the drug, the membrane becomes desensitized

which leads to phase II block, which resembles the non-depolarizing block and
is partially reversed by anticholinesterases.
• Succinylcholine is rapidly hydrolysed by pseudocholinesterase, hence has a very

short duration of action (3–8 min).
• It should be avoided in younger children unless absolutely necessary, because

of risk of cardiac arrhythmias and hyperkalaemia is higher.
• APNOEA
Transient apnoea is usually seen at the peak of drug action.

7
SUCCINYLCHOLINE APNOEA
▪ In people with liver disease or atypical pseudocholinesterase due
to genetic defect.
▪ Here, the metabolism of succinylcholine becomes slow which

results in severe neuromuscular blockade leading to respiratory
paralysis with prolonged apnoea.
▪ This is referred to as ‘succinylcholine apnoea’.
▪ There is no antidote available, therefore:

• Fresh frozen plasma should be infused.
• Anaesthesia should be continued until recovery from
neuromuscular blockade.
• Patient should be ventilated artificially until full recovery.
ADVERSE EFFECTS
• Muscle pain is due to initial fasciculations (muscle soreness).
• Increased IOP due to contraction of external ocular muscles and it lasts
for few minutes.
• Aspiration of gastric contents may occur due to increased intragastric
pressure.
• Hyperkalaemia—fasciculations release K+ into the blood.
• Sinus bradycardia is due to vagal stimulation.
• Succinylcholine apnoea (prolonged apnoea).
• Malignant hyperthermia especially when used with halothane in
genetically susceptible individuals. Treatment: IV dantrolene, rapid
cooling, inhalation of 100% oxygen and control of acidosis.

9
ADVERSE EFFECTS
❖ drowsiness
❖ diarrhoea
❖ dizziness
❖ headache
❖ fatigue
❖ hepatotoxicity.
4. CENTRALLY ACTING MUSCLE RELAXANTS

10
• These are drugs which reduce skeletal muscle tone by a selective action in the
cerebrospinal axis, without altering consciousness.
• They selectively depress spinal and supraspinal polysynaptic reflexes involved in

the regulation of muscle tone without significantly affecting monosynaptically
mediated stretch reflex.
• Polysynaptic pathways in the ascending reticular formation which are involved

in the maintenance of wakefulness are also depressed, though to a lesser extent.
• All centrally acting muscle relaxants do have some sedative property. They have
no effect on neuromuscular transmission and on muscle fibres, but reduce
decerebrate rigidity, upper motor neurone spasticity and hyper reflexia.
USES:
❖ Acute muscle spasms

❖ Torticollis, lumbagos, backache and neuralgias
❖ Anxiety and tension
❖ Spastic neurological diseases
❖ Tetanus
❖ Electroconvulsive therapy
❖ Orthopaedic manipulations.

18
2. Comparative features of General and Local Anaesthetics
General Anaesthetics Local Anaesthetics

Site of Action CNS Peripheral nerves
Area of body involved Whole body Restricted area
Consciousness Lost Unaltered
Care of Vital Functions Essential Not needed
Physiological trespass High Low
Poor health patient Risky Safer
Use in non-cooperative Possible Not possible
patient
Major surgery Preferred Cannot be used
Minor surgery Not preferred Preferred
3. LIGNOCAINE
INTRODUCTION
▪ An amide linked LA
▪ introduced in 1948
▪ now widely used LA good for both surface and injections
PHARMACOKINETICS
▪ rapid absorption from mucous membrane but from intact skin is low
▪ Bound to α1 acid GP
▪ Degraded in liver microsomes by dealkylation and hydrolysis
▪ High first pass metabolism in liver

19
MECHANISM OF ACTION
Lignocaine binds with receptor at voltage

sensitive Na+ channels
↓ the entry of Na+ ions
resulting in block nerve conduction
▪ Local:
→ block sensory nerve endings
→ vasodilation
▪ CNS:
→ Depressant - drowsiness, mental clouding, dysphoria, etc.
▪ CVS:
→ Cardiac depressant
→ Antiarrhythmic
→ fall in BP
ADR
▪ CNS-Drowsiness, mental clouding, dysphoria, altered taste, tinnitus
▪ Overdose – Twitching, convulsions, fall in BP, coma, respiratory failure
USES
▪ Surface anaesthesia
▪ conduction block
▪ Spinal anaesthesia
▪ Epidural anaesthesia
▪ Antiarrhythmic drug
▪ TD patch for post therapeutic neuralgia.

7
4. PREANAESTHETIC MEDICATION
They refer to use of drugs before anaesthesia to make it safe and less
unpleasant
The aims are:

 To relief anxiety and apprehension preoperatively and to facilitate smooth
induction
 Amnesia for perioperative events
 Supplement analgesic action of the anaesthetics and potentiate it so less
anaesthetic is needed
 Decrease secretions and vagal stimulations that may be caused by
anaesthetic
 Antiemetic effect extending into post-operative period
 Decrease acidity and volume of gastric juice so that it is less damaging if
aspirated
DRUGS:
Sedative – antianxiety drugs: They allay anxiety and facilitate amnesia.
 Benzodiazepines
 diazepam 5-10 mg oral or lorazepam 2mg oral or 0.05 mg/kg i.m. 1
hour before.
 Promethazine 50 mg i.m.
(it is an antihistamine with sedative, antiemetic and anticholinergic properties.)
 Midazolam i.v. injection can also be used.
H2 blockers/ proton pump inhibitors: to decrease the risk of gastric regurgitation

and aspiration pneumonia. Another advantage is to prevent stress ulcers
 famotidine 20 mg
 ranitidine 150 mg
 omeprazole 20 mg
 pantoprazole 40 mg.
CNS Agam Pharmacology

8
Anticholinergics: to reduce salivary and bronchial secretions.
 Atropine or hyoscine 0.6 mg or 10 – 20 µg/kg i.m. or i.v.

 glycopyrrolate 0.2 - 0.3 mg or 5 -10 µg/kg i.m. or i.v.
Neuroleptics: they allay anxiety, smoothen induction and have antiemetic action.
 chlorpromazine 25 mg
 triflupromazine 10 mg
 haloperidol 2-4 mg i.m.
Antiemetics: to prevent post-operative nausea and vomiting
 Metoclopramide 10-20 mg i.m.

 ondansetron 4-8 mg i.v.
 domperidone can also be used.
Antihistamines: diphenhydramine to prevent allergic reaction.

Opioids: fentanyl and non-opioids like acetaminophen for analgesia.

9
5. KETAMINE
It produces Dissociative anaesthesia – characterized by profound analgesia,

immobility, amnesia with only light sleep.
It acts by blocking N-Methyl-D-Aspartate (NMDA) type of glutamate receptors
 Primary site of action is cortex and subcortical areas

 non- barbiturate anaesthetic - Doesn’t affect reticular activating system
PHARMACOKINETICS:
 lipophilic, rapid acting

 Route- mostly by i.m.; other routes are i.v., oral
 Dose- 0.5-1.5 mg/kg i.v.
3-5 mg/kg i.m.
 Metabolism- In liver it is converted into nor-ketamine which has less CNS
activity
 Excretion- through bile and urine.
 Half-life- 2-4 hours.
Condition makes it suitable for continuous infusion-

 Large Volume of distribution
 Rapid clearance
ACTIONS:
 potent Bronchodilator so it is beneficial in patients with cardio genocide shock,
hypotension, bronchospasm.
 Respiration not depressed
 ↑ muscle tone
 CNS - delirium, hallucination, delusion

10
 CVS - increase in cardiac output, blood pressure, heart rate
ketamine
stimulates
centra sympathetic
outflow
stimulation of heart
↑ BP and cardiac
output
USES:
 For operations of head, neck and face
 For dressing burn wounds
 Can be used in children and asthmatics who are undergoing short procedures
ADR:
 Increases intracranial pressure
 Emergence delirium and hallucinations.
CONTRAINDICATION:
 Hypertension
 Stroke patients
 Ischemic heart disease

14
2. METHANOL POISONING
 A blood level of > 50 mg/dl methanol is associated with severe poisoning.

 Even 15 ml of methanol has caused blindness and 30 ml causes death.
 Fatal dose is 75 – 100 ml.
MANIFESTATIONS: occurs after accumulation of metabolites

 Vomiting
 Headache
 Epigastric pain
 Uneasiness
 Disorientation
 Tachypnoea
 Bradycardia
 Hypotension
 Acidosis causes retinal damage
 Blurring of vision, congestion of optic disc followed by blindness
 If left untreated, death is due to respiratory failure.
TREATMENT:
The patient should be kept in dark, quiet room protect the eyes from light.
Gastric lavage with sodium bicarbonate to be given if the patient is

brought within 2 hours of ingestion of methanol.
Combat acidosis so as to thus prevent retinal damage by i.v. sodium

bicarbonate infusion

15
Potassium chloride infusion to correct hypokalaemia which occurs due to

alkali therapy.
Ethanol is preferentially metabolized by alcohol dehydrogenase over

methanol. At a concentration of 100mg/dl, it retards alcohol
dehydrogenase metabolism and thus methanol metabolism is inhibited.
Ethanol (10% in water) is administered through a nasogastric tube,

loading dose of 0.7 ml/kg, followed by 0.15 ml/kg/hour. Treatment as to
be continued for several days because methanol will be present for long
in the body.
Haemodialysis – clears methanol and its metabolites, hastens recovery.
Fomepizole - a specific inhibitor of alcohol dehydrogenase and drug of

choice in methanol poisoning
A loading dose of 15mg/kg infused i.v. over 30 minutes followed by 10

mg/kg every 12 hours till serum methanol falls below 20 mg/dl.
Folate therapy: Calcium leucovorin 50 mg is injected 6 hourly reduces

formate levels by enhancing its oxidation.

18
LONG ANSWER
1. SEDATIVE – HYPNOTIC
The sedatives and hypnotics are CNS depressants.

Those with quicker onset, shorter duration and steeper dose response
curves are preferred as hypnotics.
slower acting drugs with flatter dose response curves are employed as
sedatives.
CLASSIFICATION:

19
NON-BENZODIAZEPINE HYPNOTICS (non – BZDs)
These lately developed drugs are chemically different from BZDs but act on
the BZD receptors selectively on α1 subunit containing BZD receptors.
They produce hypnotic, weak antianxiety, muscle relaxant and
anticonvulsant activity.
They have lower abuse potential and due to their short duration of action
are preferred for insomnia.
DRUGS:
 Zopiclone
 Eszopiclone
 Zolpidem
 Zaleplon
 Etizolam
ZOPICLONE
 First drug of non-BZDs
 Does not alter REM sleep and tends to prolong stages 3 and 4
 Used to wean off insomniacs taking BZD medication.
 Metabolized by CYP3A4 and hence dose reduction needed in hepatic
impairment and elderly patients and those taking CYP3A4 inhibitors.
 Indicated for short term insomnia
 Side effects - metallic and bitter taste, impaired judgement and
alertness, psychological disturbances, dry mouth.
ESZOPICLONE
 Active (S) enantiomer of zopiclone
 Increases sleep time by prolonging stage 2 with minimal effect on
sleep architecture
 No active metabolite produced, t1/2 is 6 hours.
 Produces little tolerance and dependence and hence used for short
term and chronic insomnia.

20
ZOLPIDEM
 Sleep duration is prolonged in insomniacs but anticonvulsant, muscle
relaxant and antianxiety effects not evident
 Advantages:
 Relative lack of effect on slow wave sleep
 Minimal residual day time sedation
 Minimal fading of hypnotic action on repeated nightly use
 No rebound insomnia on discontinuation
 Low abuse potential
 Completely metabolised in the liver
 Short duration of action (t1/2-2hr)
 Used in sleep onset insomnia and intermittent awakenings
 Currently most commonly used hypnotic.
ZALEPLON
 Shortest acting, rapidly absorbed, oral bioavailability is 30% due to
first pass metabolism.
 Only effective in sleep onset insomnia.
 Can be taken late in night and does not produce morning sedation.
ETIZOLAM
 Produces full range of BZD reaction-anxiolytic, hypnotic,
anticonvulsant, muscle relaxant.
 Absorbed rapidly, metabolised by oxidation
 Chronic intake produces tolerance and dependence
 Indicated for short term management of anxiety, panic and sleep
disorder.
USES
Insomnia, Hypnotic, Anxiolytic
Anticonvulsant (emergency control of status epilepticus and tetanus)
Centrally acting muscle relaxant
Pre-anaesthetic medication
Alcohol withdrawal in dependants
To treat gas or non-specific dyspeptic symptom along with analgesics,
NSAIDs, spasmolytic.

21
2. ACUTE BARBITUATE POISONING

Mostly suicidal or accidental
MANIFESTATIONS:
 patient is flabby and comatose with shallow and failing respiration

 fall in BP
 cardiovascular collapse
 renal shut down
 pulmonary complications
 bullous eruptions
TREATMENT: there is no specific antidote
 Gastric lavage – suspension of activated charcoal

 Supportive measures – patent airway, assisted respiration, maintenance
of blood volume by infusion
 Alkaline diuresis – with sodium bicarbonate 1mEq/kg i.v.
 Haemodialysis and Hemoperfusion.

26
1. ANTIEPILEPTIC DRUGS
CLASSIFICATION:
PHENYTOIN
CNS depressant
Abolishes tonic phase of seizures
Phenytoin prevents repetitive detonation of normal brain cells by
Prolongation of inactivated state of voltage sensitive Na + channel.
Depress presynaptic release of glutamate
Facilitating GABA release
Reduce Ca2+ influx

27
PHARMACOKINETICS:
Absorption: Oral route, slow
Metabolism: CYP2C9 and 2C19 by hydroxylation as well as glucuronide
conjugation (liver)
The kinetics of metabolism is capacity limited i.e. 1st order to zero order
kinetics (over the therapeutic range)
T1/2  12-24 hours
ADVERSE EFFECTS:
Therapeutic plasma concentration
Gum hypertrophy
Hirsutism
Hypersensitivity
Megaloblastic anemia
Osteomalacia
Fetal hydration syndrome
Over dose toxicity due to higher plasma concentrations

Cerebellar and vestibular manifestations  Ataxia, vertigo, diplopia,
nystagmus.
Drowsiness, Hallucination
Nausea, vomiting
i.v.  fall in BP
phenytoin sodium i.v.
local vascular injury
damage and thrombosis

of vein
edema and discoloration

of injected limb

28
INTERACTIONS:
 phenytoin and phenobarbitone – unpredictable overall reaction.
 Phenytoin and carbamazepine induce each other’s metabolism.
 Valproate displaces protein bound phenytoin – plasma level of unbound
phenytoin increases.
 Phenytoin competitively inhibits warfarin metabolism.
USES:
Generalized tonic-clonic seizures
Partial seizures
Trigeminal neuralgia (2nd choice)

31
4. VALPROIC ACID
Valproate is more potent in blocking PTZ seizures.

At anticonvulsant doses, valproate produces little sedation or other central
effects.
Valproate acts by multiple mechanisms:
A phenytoin-like frequency dependent prolongation of Na + channel
inactivation.
Weak attenuation of Ca2+ mediated ‘T’ current.
Enhanced release of inhibitory transmitter GABA due to inhibition of its
degradation as well as increasing the synthesis from glutamic acid.
Blockade of NMDA glutamate receptors.
PHARMACOKINETICS:
Good oral absorption
90% plasma protein bound
Completely metabolized in liver
USES:
Excreted in urine
Absence seizures
1st line of drugs in partial
ADR: seizures and GTCS
Myoclonic seizures
Anorexia
Mania and bipolar illness
Vomiting
Prophylaxis in migraine
Loose motions
Heart burn
Drowsiness
Alopecia
Teratogenic – spina bifida and other neural tube defects

32
5. STATUS EPILEPTICUS
Status epilepticus is a condition in which the seizure activity occur for > 30 min, or
two or more seizures occur without the recovery of consciousness.
Fits have to be controlled as quickly as possible to prevent death and permanent
brain damage.
The first priority is to maintain patient airway. This is followed by 20-50 ml of
50% dextrose injected i.v. to correct hypoglycemia, in case that is responsible
for the seizures.
Other general measures must be taken like fluid and electrolyte balance, BP,
etc.
Lorazepam 4 mg (0.1 mg/kg in children) injected i.v. at the rate of 2 mg/min,
repeated once after 10 min if required.
Diazepam 10 mg (0.2-0.3 mg/kg) injected i.v. at 2 mg/min, repeated once after
10 minutes if required.
Fosphenytoin 100-150 mg/min i.v. infusion to a maximum of 1000 mg (15-20
mg/kg) under continuous monitoring is a slower acting drug which should be
given subsequently irrespective of response to lorazepam. This is useful for
long term seizure treatment.
Phenobarbitone sodium should be used only if Fosphenytoin is not available
because it causes more marked local vascular complications.
Refractory cases who do not respond to lorazepam and Fosphenytoin within
40 mins can be treated with i.v. midazolam/ propofol/ thiopentone
anaesthesia, with or without curarization and full intensive care.

34
1. ANTIPARKINSONIAN DRUGS
CLASSIFICATION:
LEVADOPA:
Specific salutary effect in Parkinson’s disease.

35
CNS
 Symptomatic treatment in Parkinson’s patients.
 Hypokinesia and rigidity resolves first.
 Secondary symptoms like posture, gait, handwriting, speech, facial
expression is gradually normalized.
 The effect of Levodopa on behavior has been described as a general
alerting response.
 It predisposes to emergence of psychiatric symptoms.
CVS
 Tachycardia by acting on Beta adrenergic receptors.
 Postural hypotension is common.
 Impede ganglionic transmission.
CTZ
 Activation of CTZ elicits nausea and vomiting.
 Tolerance develops further.
Endocrine
 Inhibits prolactin release and induces GH release.
 Hypoprolactinemia is common in parkinsonism patients while hyper
GH is not seen.

36
PHARMACOKINETICS
Bioavailability is affected by
 Gastric emptying-slow, then only less concentration center’s blood brain
barrier.
 Amino acid present in food compete for absorption as it is same carrier.
 High first pass metabolism
 1% enters brain
 Pyridoxine is a cofactor for the enzyme dopa-decarboxylase.

37
ADVERSE EFFECTS:
 Nausea and vomiting
 Postural hypotension
 Cardiac arrhythmias
 Exacerbation of angina
 Alteration in taste sensation
On prolonged therapy
 Dyskinesia
 Behavioral effects
 Fluctuations in motor performance
INTERACTIONS:
 Pyridoxine abolishes the therapeutic effect of levodopa
 Phenothiazines, butyrophenones, metoclopramide reverses the therapeutic
effect of levodopa.
 Non-selective MAO inhibitors
 Antihypertensive drugs – postural hypotension may happen.
 Atropine and antiparkinsonian anticholinergic drugs have additive effect

43
2. ATYPICAL ANTIPSYCHOTICS
Second generation antipsychotics.

Has weak D2 blocking but potent 5-HT2 antagonistic activity.
Advantages:
 Extrapyramidal side effects are minimal.
 They tend to improve the impaired cognitive function in
psychotics.
DRUGS:
Clozapine
Risperidone
Olanzapine
Quetiapine
Aripiprazole
Ziprasidone
Amisulpiride
Zotepine
CLOZAPINE:
 First atypical antipsychotic.
 Both positive and negative symptoms of schizophrenia are
improved.
 It is the most effective drug in refractory schizophrenia when
typical neuroleptics are ineffective.
 Quite sedating, moderately potent anticholinergic.
 Metabolised in CYP1A2, CYP2C19 and CYP3A4.
 Higher incidence of agranulocytosis is a limiting factor.
 Other limiting factors are
 Metabolic complications – weight gain, hyperlipidaemia and
precipitation of diabetes.
 Other side effects are – sedation, unstable BP, tachycardia
and urinary incontinence.

44
RISPERIDONE:
 More potent D2 blocker than clozapine.
 Weight gain and incidence of new onset of diabetes are less
compared to clozapine.
 Major side effect is postural hypotension.
 Increased risk of stroke in elderly is noted.
 It is often used as 1st line of drug in schizophrenia.
OLANZAPINE:
 Both positive and negative symptoms of schizophrenia are
improved.
 It is approved for use in mania.
 Metabolized by CYP1A2 and glucuronyl transferase.
 Side effects: dry mouth, constipation, weight gain, ↑ risk of
diabetes and serum triglyceride levels.
QUETIAPINE:
 Short acting
 Used in maintenance therapy in acute mania as well as bipolar
disorder.
 Metabolised in CYP3A4.
 Risk of arrhythmia in high doses.
 ADR: postural hypotension, urinary retention, weight gain, etc.
ARIPIPRAZOLE:
 Risk of arrhythmia in high doses.
 ADR: nausea, dyspepsia, constipation and light-headedness.
 Metabolised by CYP3A4 & CYP2D6.
 Indicated in schizophrenia with positive and negative symptoms.
 It is also used as an augmenting agent in resistant depression and
as maintenance drug in bipolar disorder.

45
ZIPRASIDONE:
 Can cause arrhythmias.
 Nausea and vomiting are common side effects.
 Indicated in mania.
AMISULPIRIDE:
 It is similar to typical psychotics.
 Side effects are hyperprolactinemia, insomnia, anxiety and
agitation.
 Used in schizophrenia.
ZOTEPINE:
 Used in schizophrenia
 Lowers seizure threshold.
 Side effects are weakness, headache

54
2. SSRI
Selective serotonin reuptake inhibitor.
DRUGS:
 Fluoxetine
 Fluvoxamine
 Paroxetine
 Sertraline
 Citalopram
 Escitalopram
 Dapoxetine
ADVANTAGES:
Little or no sedation.
Does not interfere with cognitive and psychomotor function.
No anti-cholinergic side effect.
Devoid of α-blocking, hence no Postural hypotension.
No seizure precipitating propensity.
do not inhibit cardiac conduction.
No weight-gain.
USES:
Prophylaxis of recurrent depression.

OCD – 1st choice of drugs.
Panic disorder
Social phobia
Eating disorders
PMDD
PTSD
Kleptomania

55
Inhibit SERT
block uptake of 5HT into

neuron
↑ 5HT availability in CNS

receptors
enhance serotoninergic
activity
ADVERSE EFFECTS:
Gastrointestinal - nausea, loose motions.

CNS - nervousness, insomnia, headache.
Systemic - epistaxis and ecchymosis
DRUG INTERACTION:
Inhibits the drug metabolizing iso-enzyme CYP2D6, CYP3A4. Hence elevated

level of TCA, haloperidol, clozapine, warfarin, β-blocker, BZD and
carbamazepine.
Serotonin syndrome manifesting as agitation, restlessness, rigidity,
hyperthermia, delirium, sweating, etc when any serotonergic drugs are taken
along with SSRIs.

57
1. OPIOID ANALGESICS:
CLASSIFICATION:
MORPHINE:
Morphine is the principal alkaloid in opium.

Morphine is an agonist which has 3 receptors namely – µ, κ, δ.
All three receptors on stimulation cause analgesia.
 CNS
Analgesia
 It is a strong analgesic.
 Morphine suppress both perception of pain and its emotional
component.
Sedation
 Drowsiness, mental dullness and indifference to the
surroundings is noted.
 High doses progressively induce sleep and then coma.

58
Subjective effects and euphoria

 Prominent calming effect
 Loss of apprehension
 Feeling of detachment
 Mental clouding
 Inability to concentrate.
Respiratory Depression
 Morphine depresses respiratory centre.
 Death in morphine poisoning is due to respiratory failure.
Antitussive Actions
 Suppression of the cough reflex.
Temperature regulation
 Hypothalamic thermostatic centre is depressed.
Nausea and Vomiting

 Nausea and vomiting are caused by activation of the chemoreceptor trigger
zone and are increased by ambulation.
 GIT
Constipation.
↓ G.i. secretion.
↑ tone of duodenum and colon.
 CVS
Vasodilatation
Decreased cardiac work
Intracranial pressure rises due to retention of CO2 leading to cerebral
vasodilatation.
 NEURO-ENDOCRINE ACTIONS
Hypothalamic activation by afferent collaterals is dampened.
Hypothalamic influence on pituitary is reduced.
↓ levels of FSH, LH, ACTH, sex hormones, cortisol.
↑ GH & prolactin

59
 SMOOTH MUSCLE
spasm of sphincter of oddi
↑ intrabiliary pressure
biliary colic
PHARMACOKINETICS:
Oral absorption is unreliable.
High and variable 1st pass metabolism.
30% plasma protein bound.
Wide distribution.
Small fraction crosses BBB.
Freely crosses placenta.
Affects foetus more than the mother.
Excreted by kidney.
ADVERSE EFFECTS:
 Sedation
 Mental clouding, Lethargy
 Vomiting
 Constipation
 Respiratory depression
 Blurring of vision
 Urinary retention
 Allergic reactions
 Apnoea of new born – naloxone 10 µg/kg injected in the umbilicus cord is
treatment of choice.
 Acute morphine poisoning
 Tolerance and dependence

60
USES:
Analgesia
Pre-anaesthetic medication
Balanced and surgical anaesthesia
Relief of anxiety and apprehension
Acute LVF / pulmonary edema
Cough
Diarrhoea

1
1. CAPTOPRIL
INTRODUCTION
 PROTOTYPE of ACE inhibitors.
 Sulfhydryl containing dipeptide surrogate of proline which abolishes the
pressor action of Ang I but not Ang II, because they don’t block AT1 and AT2
receptors.
(Angiotensin converting enzyme is a Non-specific enzyme that splits off

dipeptidyl segment from peptides like bradykinin, substance P, etc in
addition to angiotensin 1.)
ACTIONS
 Increases plasma kinin levels and potentiate the hypotensive action of
exogenously administered bradykinin.
 Kinins contribute for acute vasodepression of captopril but fails on long term
hypotensive effect because
i) minor role in BP regulation
ii) Kininase I is not inhibited by captopril.
 Elevated kinin cause cough and angioedema.

 Captopril interfere with the degradation of Substance P.
 ACE Inhibitors cause rise in stem cell regulator peptides responsible for cardio
 protective effect in CHF.
 Lowers BP and the magnitude is based on
i) Na+ status
ii) Level of RAS activity
 Captopril is given in lower doses initially for CHF patients since renin level is
raised.
 Great fall in BP occurs in Renovascular, accelerated and malignant
hypertension.
 Essential Hypertension: RAS activity is overactive in 20 %, normal in 60% and
hypoactive in rest of the individuals.
 Treatment with ACE inhibitors causes rise in renin results in overproduction of
Ang I.
Blood Agam Pharmacology

2
 Ang I is diverted to produce Ang (1-7) of vasodilator property and contribute to

BP lowering action.
 Captopril induced hypotension is due to decrease in total peripheral
resistance.
 Both systolic and diastolic BP fall.
 Cardiac output: not affected.
 Postural Hypotension: not affected because cardiovascular reflexes are not
interfered.
 Renal blood flow: not compromised.
 Cerebral and coronary blood flow: not compromised.
 It is Safe in ischemic heart patients.
 Reflex changes in plasma aldosterone are abolished.
 Sufficient mineralocorticoid is secreted under the influence of ACTH and
plasma K+.
 Plasma renin and Angiotensin I are increased.
PHARMACOKINETICS
 70% of orally administered captopril is absorbed.

 Presence of food reduce bioavailability.
 Penetrating to brain: poor.
 Partly metabolised and partly excreted unchanged in urine.
 T1/2: 2 hours. Action exists for 6-12 hours.
ADVERSE EFFECTS
 HYPOTENSION: Especially in diuretic patients and some MI patients.
 HYPERKALEMIA: in patients with Impaired renal function and patients who
take K+ sparing diuretics, NSAIDs.
 COUGH: 10-16% of patients. Withdrawal of drug is prescribed. Caused by
inhibition of bradykinin/substance P breakdown in lungs
 RASHES, URTICARIA
 ANGIOEDEMA: rare.
 DYSGEUSIA: Reversible loss or alteration of taste.
 FOETOPATHIC: Foetal growth retardation, hypoplasia of organs.

3
*A 2.7-fold higher malformation rate in foetus on exposure to ACE

INHIBITORS. *
 HEADACHE, DIZZINESS, NAUSEA, BOWEL UPSET.
 GRANULOCYTOPENIA, PROTEINURIA: if renal disease predisposes.
 ACUTE RENAL FAILURE.
INTERACTIONS
 Diuretics synergise with the hypotensive action of captopril by depleting Na+

and raising renin levels.
 Indomethacin attenuate the hypotensive action of captopril by retaining salt
and water. Incidence of renal failure is reported when NSAID was received
along with ACE Inhibitor + diuretics.
 Hyperkalaemia can occur if ACE Inhibitors are given along with K+ sparing
diuretics.
 Antacids reduce bioavailability
 ACE Inhibitors reduce Li+ clearance and leads ro its toxicity.
DRUG DOSE: 25mg BD upto 50 mg TDS.

4
2. LOSARTAN
INTRODUCTION
 An Angiotensin Receptor Blocker.
 It is an AT1 receptor antagonist. AT1 Receptors are present in vascular &
myocardial tissue, brain, kidney & adrenal glomerular cells.
 Affinity of Losartan is 10000 times for AT1 receptors than AT2 receptor.
 It does not interfere with degradation of bradykinin and other ACE substrates.
ACTIONS
 Blocks all actions of Angiotensin II like
 vasoconstriction, central and peripheral sympathetic stimulation,

 Stops release of aldosterone from adrenals.
 Promote salt & water excretion
 Reduce plasma volume
 central actions like thirst, vasopressin release and growth-promoting
actions on heart and blood vessels
 Losartan causes fall in BP in hypertensive patients which lasts for 24 hours

 HR remains unchanged and cardiovascular reflexes are not interfered.
 No significant effect on plasma lipid profile, carbohydrate tolerance, insulin
sensitivity.
 A mild probenecid like uricosuric action is produced.
PHARMACOKINETICS
 Absorption: oral, not affected by food.

 Distribution: 98% plasma bound
 Metabolism: In liver it is partially carboxylated to an active metabolite (E3174),
Doesn’t enter brain.
 E3174 is 10 –30 times more potent noncompetitive AT1 receptor antagonist.
 Half-life: 2 hours.
 Excreted: kidney

5
 No dose adjustment is required in renal insufficiency, but dose should be

reduced in presence of hepatic dysfunction.
ADVERSE EFFECTS
 Losartan is well tolerated; placebo—like side effects

 hypotension and hyperkalemia, but first dose hypotension is uncommon.
 Considered to be free of cough and dysgeusia (An altered or impaired sense of
taste) inducing potential.
 Angioedema (very rare), Headache, dizziness, weakness and upper GI side
effects are mild and occasional.
 Losartan is not administered during pregnancy.
USES
 HYPERTENSION – preferred has 1st line of drugs.
 CONGESTIVE CARDIAC FAILURE – they provide symptomatic relief as well as
survival benefits.
 MYOCARDIAL INFARCTION
 DIABETIC NEPHROPATHY – they are renoprotective in type 2 DM

14
1. CONGESTIVE CARDIAC FAILURE
 CLASSIFICATION:

15
DIGOXIN
 MECHANISM OF ACTION
(With reference to the above diagram)

16
Digoxin selectively binds to Na+ - K+ ATPase
Inhibition of the enzyme
accumulation of Na+ intracelularly
↓ transmembrane gradient of Na+
diminished calcium extrusion
intracellular calcium accumulation
↑ force of cardiac contraction
 K+ decreases binding of glycoside to Na+ - K+ ATPase, hence its toxicity is

partially reversed by infusing K+.
 Excessive Ca2+ loading of SR results in spontaneous cycles of Ca 2+ release and
uptake producing oscillatory delayed after-depolarizations and after-
contractions.
 PHARMACOLOGICAL ACTIONS
● Heart
 Force of contraction
 positive inotropic action (dose dependent increase in force of
contraction).
 The digitalized failing heart regains some of its capacity to contract
more forcefully when subjected to increased resistance to ejection,
 causing cardiac output to increase and end diastolic volume to
reduce.

17
 Heart rate
 decreased by vagal (increase in vagal tone) and extra vagal (direct
depression of SA and AV nodes) actions.
 Electrophysiological properties-
a. Action potential (AP):
 The RMP is decreased progressively with dose; the rate of phase 0
depolarization decreases; phase 4 slope increases;
 potential duration is reduced and amplitude of AP is diminished.

18
b. Effective refractory period:

 Decreased in atrium
 increased in AV node and bundle of His and abbreviated by direct
action.
c. Conduction:
 at therapeutic dose, A-V conduction slowed
 at high dose, conduction in PFs also slowed
d. ECG:
 decreased amplitude or inversion of T wave
 increased P-R interval
 shortening of Q-T interval
 depression of S-T segment.
● Blood vessels
 Has direct vasoconstriction, but in CHF indirectly reflex sympathetic activity
is withdrawn.
 Digoxin has no significant effect on BP or coronary circulation;
hypertension and coronary insufficiency is no contraindication.
● Kidney
 Causes diuresis in CHF patients by improving circulation
 no diuresis occurs in normal individuals and individuals with edema due
to other causes.
● CNS
 Therapeutic dose - no apparent effect
 Higher dose - CTZ activation: nausea and vomiting
 Still higher dose - produce hypercapnia, central sympathetic stimulation,
mental confusion, disorientation and visual disturbances.
● G.I.T.
 effects are only of toxicological nature.
 PHARMACOKINETICS

19
 Digoxin is a cumulative drug

 food in stomach delays absorption
 volume of distribution is large; concentrated in the heart, skeletal muscle liver
and kidney
 rate of excretion is altered parallel to creatinine clearance.
 CONTRAINDICATIONS
● Hypokalemia: enhances digitalis toxicity

● Elderly, renal or severe hepatic disease: more susceptible to digoxin toxicity
● Thyrotoxicosis: more prone to digoxin arrhythmias, in hypothyroid patient’s
digoxin elimination is slowed
● Ventricular tachycardia: may precipitate ventricular fibrillation
● Partial A-V block: maybe converted to complete A-V block
● Wolff-Parkinson-White syndrome: It decreases the ERP of bypass tract causing
ventricular fibrillation.
 INTERACTIONS
 Diuretics cause hypokalemia, increasing risk of toxicity. Potassium

supplements should be given prophylactically
 Calcium synergizes with digitalis—> precipitates toxicity.

20
 Drugs that increase plasma concentration of digoxin to variable extents:

 Quinidine
 Verapamil
 diltiazem
 captopril
 propafenone
 amiodarone
 Adrenergic drugs induce arrhythmias in digitalized patients.
 Drugs that additively depress A-V conduction and oppose positive inotropic
action:
 Propranolol
 Verapamil
 Diltiazem
 Disopyramide
 Drugs that decreases digoxin absorption:

 Metoclopramide
 Sucralfate
 Antacids
 Neomycin
 Sulfasalazine
 atropinic drugs including Tricyclic antidepressants increases its absorption.
 USES
 Heart failure
 Digoxin is used for relief of congestive symptoms and restoration of
cardiac performance by increasing the force of cardiac contraction.
 The drug therapy for cardiac failure aims at:
 Relief of congestive symptoms, restoration of cardiac
performance and treatment of acute decompensation

21
 Inotropic drugs
 Diuretics
 RAS inhibitors
 Vasodilators
 Synthetic BNP
 ß blocker.
 Arrest/ reversal of disease progression
 ACE inhibitors/ ARBs
 ß blocker
 Aldosterone antagonist
 Neprilysin inhibitor
 Atrial fibrillation (AF) and atrial flutter (AFl)

 Digoxin can be used for controlling ventricular rate in AF and AFI,
because it decreases the number of impulses passing down the A-V node
and bundle of His (increases ERP of A-V node by direct vagomimetic and
antiadrenergic action).
 But it cannot cure the arrhythmia.
 AFL may be converted into AF because digoxin abbreviates atrial ERP.
 Digoxin is not the preferred drug for rapid control of heart rate.
 However, it is preferred when AF /AFl is attended by heart failure.
 The maintenance dose can be titrating with heart rate (should not
decrease to ≤60 per min at rest).
 Digoxin can also be combined with ß blocker/ CCB.
 Paroxysmal supraventricular tachycardia (PSVT)

 Digoxin may be injected i.v. as it increases vagal tone and depresses
conduction of A-V node, or the ectopic focus and terminate the
arrhythmias.

27
amrinone inhibits
PDE3
↓ intracellular
degradation of cAMP
↑ myocardial cAMP
↑ transmembrane
influx of Ca2+
 Pharmacokinetics:
 In CHF patients i.v. amrinone acts rapidly
 its action lasts for 2-3 hours
 elimination t1/2 is 2-4 hours
 Adverse drug effects:

 Thrombocytopenia
 Nausea
 Diarrhea
 abdominal pain
 liver damage
 fever
 arrhythmias
 Indication
 only for short term i.v. use in severe and refractory CHF
 it is used as an additional therapy with digoxin, diuretics and
vasodilators.

36
2. AMIODARONE
o Belongs to class III antiarrhythmic drugs.
o An unusual iodine containing highly lipophilic drug.
 Prolongs Action potential duration (APD) and Q-T interval attributable to block
of myocardial delayed rectifier K+ channels.
 Preferentially blocks inactivated Na+ channels with relatively rapid rate of

channel recovery, more effective in depressing conduction in cells that are
partially depolarized or have longer APD.
 Partially inhibits myocardial Ca2+ channels
 has non-competitive β adrenergic blocking property and alters thyroid

function.
 Conduction is slowed
 Ectopic automaticity is markedly depressed, but that of SA node is only slightly

affected.
 Effect of oral doses on cardiac contractibility and BP are minimal, but i.v.
injection frequently causes myocardial depression and hypotension.

37
ADVANTAGES:
Despite prolongation of APD, the arrhythmia (torsades de pointes)

provoking potential of amiodarone is low, probably because it does not
exhibit ‘reverse use-dependence’ of APD prolongation or because of its
multiple antiarrhythmic mechanisms.
Unlike other drugs in class III, amiodarone does not depend on the rate of
activation.
PHARMACOKINETICS:
 Oral bioavailability:35-65%
 Oral-action develops over several days to weeks
 i.v.-action develops rapidly.
 Large vol of distribution, accumulates in muscles and fat and is released slowly
 Long acting
 Metabolized by CYP3A4
 T1/2: 3-8 weeks
 Excreted in bile
ADVERSE EFFECTS:
Mnemonic: the periphery of my lung and cornea is photosensitive
The Thyroid dysfunction

Periphery Peripheral neuropathy
Of Ophthalmoplegia
My Myocardial depression
Lung Lung fibrosis
And Alveolitis (pulmonary)
Cornea Corneal microdeposits
Is
Photosensitive photosensitivity

38
INTERACTIONS:
 Amiodarone Increases digoxin and warfarin levels by reducing their renal

clearance.
 Additive a-v block can occur in patients on β blockers or calcium channel
blockers
 Inhibits CYP3A4, CYP2C9
 Inducers or inhibitors of CYP3A4 respectively decrease or increase amiodarone
levels.
USES:
 Amiodarone is effective in a wide range of conditions

 Ventricular arrhythmias
 Supraventricular arrhythmias
 PSVT
 Nodal and ventricular tachycardias
 Atrial flutter
 Atrial fibrillation
 The most important indications are resistant ventricular tachycardias and
recurrent ventricular fibrillation.
 It is used to maintain sinus rhythm in atrial fibrillation if other drugs have
failed.
 WPW tachyarrhythmia is terminated by suppression of both normal and
aberrant pathways.
 Long duration of action is suitable for chronic prophylactic therapy
3. VERAPAMIL
 Belongs to class IV
 It blocks L type Ca2+ channels and delays their recovery.
 The basic action of verapamil is to depress Ca2+ mediated depolarization.
 This suppresses automaticity and re-entry dependent on slow channel
response.
 Phase-4 depolarization in SA node is reduced resulting in bradycardia.
 Reflex sympathetic stimulation due to vasodilatation partly counteracts the
direct bradycardia producing action.
 Delayed after-depolarizations (DAD) in Purkinje fibres are dampened.

39
USES:
 PSVT—Verapamil can terminate attacks of PSVT; 5 mg i.v. over 2–3 min is

effective approximately in 80% cases.
For preventing recurrences of PSVT, verapamil 60 to 120 mg TDS
may be given orally.
 To control ventricular rate in Atrial flutter (AFl) and in atrial fibrillation (AF).
Verapamil causes a dose dependent reduction in ventricular rate in
AF and AFl, and is a first line drug for this purpose (digoxin added if
not responsive).
PRECAUTIONS AND CONTRAINDICATIONS:
 Contraindicated in broad QRS complex WPW tachycardia in which it may

abbreviate the ERP of bypass tract.
 i.v. verapamil carries the risk of marked bradycardia, A-V block, cardiac arrest
and hypotension.
 Verapamil has poor efficacy in ventricular arrhythmias.
 In some patients of VT, i.v. injection of verapamil has precipitated VF:
therefore contraindicated.
 It is also not recommended for digitalis toxicity, because additive A-V block
may occur. It is contraindicated in partial heart block and sick sinus.
 It should not be used if PSVT is accompanied with hypotension or CHF.

43
1. ANTI ANGINAL DRUGS
 CLASSIFICATION:
 NITRATES
o Glyceryl trinitrate as prototype
o All organic nitrates share the same action, differ only in time course.
o They are pro drugs - release nitric oxide, mainly causes vasodilation and
also arteriolar dilation, hence reducing both afterload and preload.

44
MECHANISM OF ACTION: reference to the image
nitrates are de-nitrated enzymatically
releases nitric oxide
stimulates cytosolic soluble guanyl

cyclase
increases cGMP
Dephosphorylation of MLCK
↓ Ca2+ conc in cytosol
vascular smooth muscle fibres

relaxation

45
PHARMACOKINETICS:
 Lipid soluble-well absorbed from buccal mucosa, skin and intestine.
 All undergo extensive first pass metabolism (except isosorbide mono nitrate)
 Transdermal route is used for prolonged effect.
 Metabolites are mainly excreted in urine as glucuronide derivatives.
ADVERSE EFFECTS:
 Headache
 Postural hypotension
 Tachycardia
 Palpitation
 Flushing and rarely syncope
INTERACTIONS:
 Sildenafil and PDE-5 inhibitors cause dangerous potentiation of nitrates:
hypotension, MI and death.
USES:
 Angina pectoris
 Acute coronary syndrome
 Myocardial infarction
 CHF and LVF
 Cyanide poisoning
 Esophageal spasm

46
2. NIFEDIPINE
INTRODUCTION
o Calcium channel blocker belongs to class dihydropyridines (DHP).
o It is a prototype of DHP.
o This class of drug has much greater affinity for vascular calcium channels
beneficial in treating hypertension.
o Shows little interactions with other cardiovascular drugs.
PHARMACOKINETICS:
o Oral - Dose- 5-20 mg BD-TDS orally
o Plasma T1/2- 3-8 hrs.
o rapid and short action.
binds to L-type
calcium channels
blocks inward
movement
dilation of
arterioles
o Doesn’t cause vasodilation in veins

47
USES:
o Angina pectoris
o Hypertension (safe during pregnancy)
o Cardiac arrhythmias
o Hypertrophic cardiomyopathy
o Alterative drug for premature labor
o Reduces severity of Raynaud’s episodes.
(In Hypertensive patients who also have asthma, diabetes, peripheral vascular
diseases, angina).
ADVERSE EFFECTS:
o Gingival hyperplasia
o Dizziness
o Headache
o Fatigue
o Constipation

48
3. NICORANDIL
o It’s a dual mechanism antianginal drug.
PHARMACOKINETICS:
o absorbed rapidly sub- lingually or orally
o Plasma T1/2- 1 hr
o Dose- 20mg BD
o Completely metabolized in liver
o Excreted in urine
o Elimination- biphasic elimination
 initial rapid phase T1/2 is 1 hr
 later slow phaseT1/2 is 12 hr
Activates ATP sensitive K+

channels
hyperpolarisation of
smooth muscle membrane
relaxation of smooth
muscle
ALSO, IT ACTS AS NO DONOR BY

49
↑ cGMP
relaxes blood vessels
reduces both preload

and afterload
USES:
o as antianginal drug
Exert cardioprotective action by stimulating ischemic preconditioning- short
period of ischemia preceding and reperfusion to reduce myocardial injury,
prolong survival.
ADVERSE EFFECTS:
o flushing
o palpitation
o weakness
o headache
o dizziness
o nausea
o vomiting.

50
4. DRUG THERAPY FOR MYOCARDIAL INFARCTION

Myocardial infarction is ischemic necrosis of a portion of the myocardium.
TREATMENT:
Myocardial infarction (MI) is ischemic of a portion of the myocardium due to
occlusion of a branch of coronary artery.
o Pain, anxiety and apprehension
After pain is not relieved by 3 doses of GTN give 5 min apart, an opioid
analgesic (morphine) a diazepam is administered parenterally.
o Oxygenation
By oxygen inhalation and assisted respiration, if needed
o Maintenance of blood volume, tissue perfusion and microcirculation
Slow iv infusion of saline/dextrose.
o Correction of acidosis
i.v. sodium bicarbonate infusion
o Prevention and treatment of arrhythmia
Prophylactic administration (i.v. or oral) of a beta blocker (metoprolol, etc.) as
soon as the MI patient is seen and its continuation orally for a few days has
been shown to reduce the incidence of arrhythmias mortality.
Tachyarrhythmias may be treated with lidocaine, procainamide or
amiodarone.
Bradycardia and heart block may be managed with atropine and electrical
pacing.
o Pump failure
 Furosemide: indicated if pulmonary wedge pressure is>20 mm hg.
 Vasodilators: GTN slow i.v. infusion. Supplemented by iv esmolol or
labetolol.
 Inotropic agents: dopamine or dobutamine iv infusion.

52
1. ANTIHYPERTENSIVES
 CLASSIFICATION:

53
 ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)
o These groups of drugs were developed as alternatives for ACE inhibitors.
MECHANISM OF ACTION
ARBs
competitively inhibit
Angiotensin receptors
(AT1 &AT2)
DRUGS:
o Losartan
o Candesartan
o Valsartan
o Olmesartan
o Irbesartan
o Telmisartan
Losartan:
o Competitive antagonist and inverse agonist
o 10,000 times more selective for AT1 than AT2 receptor
o it does not block any other receptor or ion channel, except thromboxane A2
receptor.
o It causes fall in BP in hypertensive patients which lasts for 24 hrs while heart
rate remains unchanged.

54
Candesartan:
o It has the highest affinity for the AT1 receptor
o produces largely unsurmountable antagonism, due to slow dissociation from
the receptor desensitization.
Valsartan:
o AT1 receptor affinity is similar to that of Losartan.
Olmesartan:
o It is potent ARB with high affinity for AT1 receptor.
o It is available as an ester prodrug which is completely hydrolyzed during
absorption from the gut.
Irbesartan:
o Oral bioavailability of this drug is relatively high.
Telmisartan:
o AT1 receptor blocking action is similar to Losartan
o does not produce any active metabolite.
Uses:
o Hypertension: ARBs are now the first line of drugs, compared in efficacy and
desired features to ACE inhibitors.
o CHF: It provides symptomatic relief as well us survival benefit in CHF.
o myocardial infarction
o Diabetic nephropathy: ARBs are renoprotective in type 2 DM, independent of
BP lowering.

55
 MANAGEMENT AND TREATMENT OF HYPERTENSIVE EMERGENCIES

AND URGENCIES
Hypertensive emergencies
 systolic BP >220
 diastolic bp >120 mmHg
 evidence of target organ damage (TOD)
Hypertensive urgencies
 while the same elevation of BP with symptoms, but no sign of acute

TOD.
Controller reduction of BP over minutes in emergencies or hours in urgencies to

counter threat to organ functioning and life in the following situations:
● Cerebrovascular accidents
● Hypertension encephalopathy
● Hypertension acute LVF and pulmonary embolism
● Acute coronary syndrome
● Dissecting aortic aneurysm
● Acute renal failure with raised BP
● Eclampsia
Drugs for hypertensive emergencies
parenteral drugs
oral drugs

56
PARENTERAL DRUGS
 Nicardipine
 rapid action
 DHPs lowers BP in severe hypertension.
 Dose: initially 5mg/hour i.v. infusion, increase rate of infusion as needed
upto 15 mg/hour.
 Sodium nitroprusside
 Instantaneous, potent and combined arteriovenous dilatory action.
 To be avoided in ischemic and hemorrhagic stroke
 Glyceryl trinitrate
 Dose: i.v. infusion (5 – 20 µg/min) GTN acts within 2 -5 min.
 to be avoided in severe hypertension associated with ischemic and
hemorrhagic stroke.
 Labetalol
 Dose: 20 – 40 mg i.v. every 10 min till response or 20 mg/hour i.v.
infusion, increased up to 120 mg/hour.
 Both α+β adrenergic blockers
 Efficacious hypotensive
 Carries low risk of causing excessive hypotension.
 Can be used in severe hypertension complicating with aortic dissection,
MI, ischemic stroke, intracranial hemorrhage and pre-eclampsia
 Its use is precluded due to heart failure and asthma
 Esmolol
 Short acting
 Dose: 0.5 mg/kg bolus i.v. injection followed by 50 – 200 µg/kg/min i.v.
infusion acts in 1 – 2 min.
 The action lasts till 10 – 20 mins after infusion is terminated.
 Hydralazine
 Injected i.m. or i.v. slowly
 Acts in 20 – 30 min
 Keeps BP low for 4 – 6 hours
 Furosemide
 Dose: 20 – 80 mg slow i.v.

57
ORAL DRUGS
 Labetalol
 Dose: 100 – 200 mg BD
 Amlodipine
 Dose: 10 mg oral repeated after 12 hours and the once daily
 Captopril
 Dose: 25 mg repeated as required
 Clonidine
 Dose: 100 µg every 1 – 2 hours

60
4. MINOXIDIL IN ALOPECIA
 When minoxidil is applied topically (2% twice daily), it promotes hair
growth in
 male pattern baldness
 alopecia areata.
 The response is slow, it takes 2 – 6 months and is incomplete.
 The mechanism of action is not clearly known, it may be due to

 Opening of K channels and enhanced micro circulation around hair
follicles
 Direct stimulation of resting hair follicles
 Alteration of androgen effect on genetically programmed hair
follicles.
 Side effects include

 Local irritation
 Itching
 Burning sensation
5. FOUR ANTIHYPERTENSIVE COMBINATIONS TO BE AVOIDED

 An α or β adrenergic blocker with clonidine – apparent action of clonidine
action.
 Hydralazine with DHP or prazosin – similar pattern of hemodynamic action.
 Verapamil or diltiazem with β blockers – marked bradycardia, A – V block
can occur.
 β blocker with diuretic – increased risk of developing diabetes.
6. FOUR CALCIUM CHANNEL BLOCKERS (CCB)

 Verapamil
 Diltiazem
 Nifedipine
 Amlodipine

1
1. DIURETICS
THIAZIDE DIURETICS
PHARMACOLOGICAL ACTION
➢ Inhibitors of Na+- Cl- symport at the luminal membrane.
➢ They are medium efficacy diuretics.
➢ They act on distal tubular cell.
➢ They do not cause significant alteration in acid – base balance of the body.
➢ Decrease renal calcium excretion
➢ Increase magnesium excretion
Kidney Agam Pharmacology

2
MECHANISM OF ACTION
USES
1. Edema: They act best in cardiac edema and they are less effective in hepatic and
renal edema.
2. Hypertension: chlorthalidone and indapamide are the first line of drugs.
3. Diabetes Insipidus: decreases positive free water clearance.
4. Hypercalciuria: reducing calcium excretion.
COMPLICATIONS
❖ Hypokalemia
❖ Acute saline depletion: overuse of diuretics may cause dehydration and marked
fall in BP, hemoconcentration and increased risk of PVT.
❖ Dilutional hyponatremia: patients feel very thirsty due to decreased salt in the
body
❖ GIT and CNS disturbances: Nausea, vomiting, diarrhea, headache, giddiness etc
may be seen
❖ Hearing loss

3
❖ Allergic manifestations
❖ Hyperuricemia
❖ Hyperglycemia and dyslipidemia
❖ Hypocalcaemia
❖ Magnesium depletion
❖ Toxemia of pregnancy leading to increased risk of miscarriage, fetal death
INTERACTIONS
1. Thiazide and high ceiling diuretics potentiate all other hypertensives.
2. Hypokalemia induced by diuretics enhances digoxin toxicity, increases risk of
polymorphic ventricular tachycardia
3. High ceiling diuretics and aminoglycoside antibiotics are both ototoxic and
nephrotoxic
4. Indomethacin and other NSAIDS diminish the action of High ceiling diuretics.
5. Probenecid competitively inhibits tubular secretion of furosemide and thiazides.
6. Serum lithium level rises

4
2. FUROSEMIDE
➢ Furosemide is classified under the high ceiling loop diuretics

➢ Inhibits the Na+-K+-Cl- co-transporter.
➢ First prototype of this class, rapidly acting, highly efficacious.
➢ It is secreted in the proximal tubule by the organic anion transport and
reaches thick ascending loop where it acts on the luminal surface of the
membrane.
➢ K+ secretion is increased mainly due to high Na+ load reaching distal tubule.
Other actions of furosemide:

• Intravenous furosemide causes prompt increase in systemic venous
capacitance and decreases left ventricular filling pressure, even before the
diuretic response is apparent. This action also appears to be PG mediated
and is responsible for the quick relief it affords in LVF and pulmonary
edema.
• Furosemide has weak CAse inhibitory action; increases HCO3 ¯ excretion as

well; urinary pH may rise but the predominant urinary anion is Cl¯.
Therefore, acidosis does not develop.
• Causes acute changes in renal and systemic hemodynamics. Renal- after

5mins of i.v injection, renal blood flow is increased and there is
redistribution of blood flow from outer to mid-cortical zone.
• G.F.T is not increased due to compensatory mechanism. Systemic-pressure

relationship between vascular, tubular and interstitial compartments is
altered the net result is decreased PT reabsorption.
• Increases Ca+ excretion as well Mg2+ excretion
• Increases blood uric acid level by competing with its proximal tubular
secretion and also PT reabsorption as a result of reduced g.f.r

5
Binds with the Cl binding site of the 12 membrane spanning domain of

Na -K+-2Cl¯ co-transporter.
+
Pharmacokinetics:
• Bioavailability: 60%
• Lipid solubility: low
• Binding to plasma membrane: high
• Plasma t1/2: 1-2 hrs, prolonged in pulmonary edema, renal and hepatic
insufficiency.
• Excretion: partly conjugated with glucoronic acid and mainly secreted
unchanged in the urine
• Similar drugs:
▪ BUMETANIDE ( 40 times more potent, Hyperuricemia, k+ loss,
glucose intolerance and ototoxicity less marked)
▪ TORSEMIDE (2-3 times more potent)

8
4. SPIRONOLACTONE
▪ Steroid chemically related to aldosterone

▪ Classified under potassium sparing diuretics.
Aldosterone combines with intracellular mineral corticoid receptor (MR) and

induces the formation of aldosterone induced proteins (AIP’s). Spironolactone
acts from the interstitial side of the tubular cell, combines with MR and inhibits
the formation of AIPs in a competitive manner.
→ K+ sparing action starts develops over 3-4 weeks.

→ Has mild Diuretic action because majority of Na+ is reabsorbed proximal to its
site of action.
Pharmacokinetics
• Oral bioavailability: 75%
• Metabolism in liver: highly bound to plasma proteins and completely
metabolized to form active metabolites.
• Active metabolite: canrenone
• T1/2 of Spironolactone: 1-2 hrs
• T1/2 of canrenone : ~8 hrs

9
Adverse effects:
• Drowsiness
• Ataxia
• mental confusion
• epigastric pain
• loose motions
• Most serious action is hyperkalaemia (especially in renal failure)
• Acidosis(especially if cirrhotic)
• Peptic ulcer is aggravated
• Spironolactone reacts with progestin and androgen receptors causing

estrogen clearance leading to
• Gynaectomasia
• Erectile dysfunction
• Loss of libido in men
• Breast tenderness or menstrual irregularities in women.
Interactions:
• Spironolactone and K+ supplements may produce dangerous
hyperkalaemia.
• More pronounced hyperkalaemia in patients receiving ACE/ARD inhibitors.
• Increases digoxin concentration.
• Aspirin blocks tubular excretion of canrenone.
Uses:
• To counteract k+ loss due to thiazide and loop diuretics
• Edema
• Hypertension
• Heart failure
• Primary hyperaldosteronism

7
1. ANTICOAGULANTS
 CLASSIFICATION
 HEPARIN:
 Strongest organic acid in human body.
 Highly electronegative at physiological pH, hence can’t be given orally (given
parenteral)
 Is an anticoagulant both In-vitro and In-vivo.
 Sources: richest – lung, liver, intestinal mucosa.

8
 Anticoagulant:
 MECHANISM OF ACTION:
At low conc: At high conc:
heparin binds with heparin binds with AT

Antithrombin-3 3
complex is formed complex is formed
Increases its function by complex binds to

1000 fold. factor
Binds and inhibits factor Xa, IIa, IX a, XIa,

Xa and thrombin XIIa,XIIIa
inhibition of conversion
of fibrinogen to fibrin inactivates them
 Anti-platelet:
 At higher dose inhibit platelet aggregation and prolongs bleeding time.

9
 Lipemia clearing:
low dose of heparin
↑lipoprotein lipase
hydrolysis of triglyceride
and LDL to FFA
clears turbid post

prandial lipaemic plasma
PHARMACOKINETICS:
 ABSORPTION:
 ionized hence not absorbed orally.
 Injected IV  instant action.

Injected SC  after 60mins.
 DISTRIBUTION:
 Doesn’t cross BBB/Placenta.

Therefore, drug of choice in pregnancy.
 METABOLISM: Liver
 EXCRETION: Urine (Kidney).
USES:
 Anticoagulants
 Antiplatelet

10
ADVERSE EFFECTS:
 Bleeding due to overdose - Risk increased in renal failure.
 Heparin induced thrombocytopenia (HIT)
 Alopecia
 Hyperkalemia
 Osteoporosis – at long term and high doses.
 Rarely hypersensitivity.
CONTRAINDICATIONS:
 Bleeding disorders
 History of HIT
 Severe hypertension
 threatened abortion
 haemorrhoids.
 Ocular and neurosurgery
 lumbar puncture
 Liver (chronic alcoholics) and renal failure.
 Aspirin and other anti-platelet drugs should be given cautiously.

11
2. VITAMIN K ANTAGONIST
 Warfarin and its congeners.

 Acts only In-vivo.
MECHANISM OF ACTION
 They act as competitive antagonist
Inhibit Vitamin K
epoxide reductase
↓ active vitamin K
regneration
↓ synthesis of factors
2, 7, 9, 10.
prevents coagulation
sequence to proceed

12
PHARMACOKINETICS:
 ABSORPTION:
Orally Rapidly and completely absorbed from intestine.
 DISTRIBUTION:
99% plasma protein bound.
 METABOLISM:
By cytochrome P enzyme.
 EXCRETION:
Undergo entero-hepatic circulation and finally excreted in urine.
ADVERSE EFFECTS:
 Bleeding
 Skin necrosis
 Purple toe syndrome
 Teratogenicity
CONTRAINDICATIONS:
 Bleeding disorder
 Severe hypertension, threatened abortion, piles
 Ocular and neuro surgery, lumbar puncture
 Liver (chronic and alcoholics) and renal failure
 Aspirin and other anti-platelet drugs should be used cautiously
 Coumarin oral anticoagulants should not be used in pregnancy.
 Warfarin in pregnancy – if given early causes fetal warfarin syndrome. If
given late, it causes CNS defects, fetal hemorrhage, fetal death and
accentuates neonatal hypoprothrombinemia.

13
DRUG INTERACTIONS
i. Enhanced anticoagulant action

 Broad spectrum antibiotics
 Cephalosporins – ceftriaxone, cefoperazone
 Aspirin
 Long acting sulfonamides, indomethacin, phenytoin and
probenecid
 Chloramphenicol, erythromycin, celecoxib, etc.
 Tolbutamide and phenytoin
 Liquid paraffin
ii. Reduced anticoagulant action

 Barbiturates, rifampin, griseofulvin.
 Oral contraceptives
3. FOUR COAGULANTS
 Vitamin k1 (phytonadione)
 Vitamin k3 (menadione, acetomenaphthone)
 Fibrinogen (Human)
 Anti-hemophilic factor
 Desmopressin
4. FOUR LOCAL HEMOSTATICS (STYPTICS)
 Fibrin
 Gelatin foam
 Oxidized cellulose
 Thrombin

14
5. TWO SCLEROSING AGENTS AND THEIR USES

 Sclerosing agents are used for treatment of hemorrhoids, varicose vein
mass
 Ex: sodium tetradecyl sulfate, polidocanol
6. TWO FIBRINOLYTICS AND THEIR USES

 Alteplase, reteplase, tenecteplase.
 Uses: Acute MI, deep vein thrombosis, pulmonary embolism and stroke.
7. FOUR ANTIPLATELET DRUGS

 Aspirin
 Ticlopidine
 Dipyridamole
 Abciximab
8. HEPARIN ANTAGONIST AND ITS USES

 Protamine sulphate.
 Uses: treatment of heparin induced bleeding
To terminate heparin action rapidly (Ex. After injuries).
9. HEPARIN VS WARFARIN
Heparin Warfarin
Natural anticoagulant Synthetic anticoagulant
Act by breakdown of factor 2a and Acts by inhibiting the synthesis of
10a. factors 2, 7, 9, 10.
Administered parenterally Administered orally
Acts both In-vitro and In-vivo. Acts only In-vivo.

16
1. HYPOLIPIDAEMIC DRUGS
 CLASSIFICATION:
 STATINS:
 Lovastatin
 Simvastatin
 Pravastatin
 Atorvastatin
 Rosuvastatin
 Pitavastatin
 MECHANISM OF ACTION:
𝐻𝑀𝐺 − 𝐶𝑜𝐴 −→ 𝑀𝑒𝑣𝑎𝑙𝑜𝑛𝑎𝑡𝑒 −→ 𝐶ℎ𝑜𝑙𝑒𝑠𝑡𝑟𝑜𝑙

↑
𝐻𝑀𝐺 − 𝐶𝑜𝐴 𝑟𝑒𝑑𝑢𝑐𝑡𝑎𝑠𝑒 ← 𝑠𝑡𝑎𝑡𝑖𝑛𝑠
*Red colour: inhibition

17
 DRUGS:
Drugs Route of 1st pass Half life Excretion LDL – CH

administration metabolism reduction
Lovastatin Oral Extensive 2 – 4 hrs Bile Low to
moderate
Simvastatin Oral Extensive 2 – 3 hrs Bile ↑ HDL – CH
level, if low
Pravastatin Oral Extensive 1 – 3 hrs Bile Low to
moderate
Atorvastatin Oral Extensive 14 – 18 hrs Bile Moderate
(55 – 60%)
Rosuvastatin Oral Extensive 18 – 24 hrs Bile high
Pitavastatin Oral Extensive 12 hrs Bile 40%
 ADVERSE EFFECTS: Mnemonic: HMG

 Hepatotoxicity (INFREQUENT)
 Headache and sleep disturbances
 Myopathy: muscle pain and weakness
 Gastrointestinal: anorexia, nausea, vomiting and diarrhoea
 USES:
 Primary hyperlipidaemias with raised LDL – CH levels and total CH levels
 Secondary hypercholesterolaemia
 Secondary prophylaxis in MI – cardioprotective effects
 Atherosclerotic plaque stability
 Anti-oxidant property
 Anti-inflammatory actions
 ↓ platelet aggregation
 ↑ endothelium nitric oxide production
 Reduction in venous thrombo-embolism
 Dyslipidaemia in diabetics – 1st choice of drugs

21
3. ADR OF FIBRATES
 Epigastric distress
 Loose motions
 Skin rashes
 Eosinophilia
 Impotence
 Body ache
 Blurred vision.
4. BILE ACID SEQUESTRANTS

 Cholestyramine
 Colestipol
 Colesevelam

1
1. Peptic Ulcer Classification, Proton Pump Inhibitors

Classification
Proton pump inhibitors (PPIs):

• These are potent acid suppressing drugs.
➢ Omeprazole: prototype drug, which inhibits the final step in gastric acid secretion.
Mechanism of Action:
o Omeprazole is inactive at neutral pH.
o At pH less than 5 it rearranges into two charged cationic forms.
o They react covalently with SH group of H+K+ATPase enzyme and
inactivates it irreversible.
Pharmacokinetics:
o All PPI are enteric coated tablets that are protected from gastric juice.
o PPI is reduced by intake of food and its oral bioavailability is 50 percent.
o It is metabolized in the liver by CYP2C19 and CYP3A4.
GIT Agam Pharmacology

2
Adverse Effects:
o Nausea, Vomiting, Loose stools, Headache, Abdominal pain.
o No harmful effects in pregnancy.
o Accelerated osteoporosis among elderly patients has been seen with long term
use of this drug.
➢ Esmoprazole: have higher bioavailability and produces better control of

intragastric pH than omeprazole.
➢ Lansoprazole: more potent than Omeprazole but somewhat reversible in it's

mechanism of action. Higher oral bioavailability is present.
➢ Pantoprazole: similar in potency and clinical efficacy to omeprazole but more acid
stable and has higher oral bioavailability.
➢ Rabeprazole: It causes faster acid suppression due to high pKa.
➢ Ilaprazole: this drug was developed in Korea and it has similar properties to that
of omeprazole.
Uses of PPIs
● Peptic Ulcer treatment
● Bleeding peptic ulcer
● Stress ulcer
● GERD
● Zollinger Ellison syndrome
● Aspiration pneumonia

5
● Prokinetic drugs: Metoclopramide, mosapride and other Prokinetic drugs may

relieve regurgitation and heartburn by increasing LES tone, improving
oesophageal clearance and facilitating gastric emptying.
4. Ranitidine, Uses of H2 Blockers

Ranitidine is non imidazole H2 blocker, it has several desirable features compared
to Cimetidine.
● About 5 times more potent than Cimetidine. T1/2 and pharmacokinetics is
similar to Cimetidine.
● No anti-androgenic action, it does not increase prolactin secretion or spare
estradiol from hepatic metabolism - no effect on male sexual function and
gynecomastia.
● Less permeability into brain.
● Less marked inhibition of hepatic metabolism of other drugs.
● Side-effects is lower: headache, diarrhoea/constipation
Uses of H2 blockers:
A. Peptic Ulcer
B. Non ulcer dyspepsia
C. Bleeding from stress ulcer and erosive gastritis
D. GERD
E. Urticaria

6
5. Ulcer protectives
• Sucralfate
• Colloidal bismuth subcitrate
Sucralfate
→ Basic aluminum salt of sulfated sucrose.

→ No acid neutralizing action
→ Delays gastric emptying
Sucralfate polymerizes at pH < 4 by cross linking molecules thus
forming a sticky gel-like consistency.
It adheres to ulcer base. The surface proteins at the ulcer base are
precipitated, together they act as physical barrier between acid, bile, pepsin
and ulcer.
Pharmacokinetics:
Should be taken 1 hour before meal. Minimal absorption through oral
route administration. Action is entirely local.
Not used has first line of drugs because of effective PPI\ H2 blockers.
ADR:
Side effects are minimal
• Constipation ( In 2% cases)
• Hypophosphatemia

7
Uses:
• Promote healing of ulcers
• Used in bile reflux, gastritis and prophylaxis of stomach.
Interaction:
➢ Interferes with absorption of tetracyclines, fluoroquinolone,
cimetidine, digoxin and phenytoin.
➢ Antacids decrease efficacy of Sucralfate
CBS
→ Colloidal bismuth compound

→ Water soluble but precipitates at pH < 5
→ To be taken ½ an hour before meal in empty stomach
→ Milk and antacids should not be taken concomitantly.
→ Excreted in faeces.
→ Used in gastritis and non-ulcer dyspepsia associated with H.pylori.
It’s not clear, probably it maybe
➢ Increase mucosal PGE2, mucus and bicarbonate production.
➢ Precipitate mucus glycoprotein and coat ulcer base.
➢ Inhibit H.pylori directly.
ADR:
Diarrhea, headache and dizziness.

8
6. ADR of Cimetidine
• Side effects like headache, dizziness, bowel upset and dry mouth are generally
mild.
• Rapid or high dose i.v. injection can cause confusion states, hallucinations,
convulsions, bradycardia, cardiac arrhythmias or cardiac arrest.
Cimetidine has anti-androgenic action which in high doses causes gynecomastia, loss
of libido, impotence, and short lasting decrease in sperm count.
7. Drug interactions of Omeprazole

• Omeprazole inhibits oxidation of certain drugs: diazepam, phenytoin and
warfarin levels may be increased.
• It interferes with activation of clopidogrel by inhibiting CYP2C19.
• Reduced gastric acidity decreases absorption of ketoconazole and iron salts.
• Clarithromycin inhibits omeprazole metabolism and increases its plasma
concentration.
8. Antacid combinations
● Fast (Magnesium hydroxide) and slow (Aluminium hydroxide) acting
components yield prompt well sustained effect.
● Magnesium salts are laxative and aluminium salts are constipating:
combination may annul each other action and bowel movement remains
unaltered.
● Gastric emptying is least affected while alum. salts tend to delay it and mag.
salts tend to hasten it
9. Sodium Alginate
• It increases the viscosity of gastric contents, forms a thick frothy layer which
floats on them like a raft and may prevent contact of acid with oesophageal
mucosal.
• It has no effect on LES tone. Combination of Alginate and antacids can be
used instead of antacids alone.

9
1. Antiemitics, Prokinetic Drugs
ANTIEMETICS
ANTICHOLINERGICS H1 NEUROLEPTICS PROKINETIC 5-HT3 NK1 RECEPTOR ADJUVANT

ANTIHISTAMINICS (D2 BLOCKERS) DRUGS ANTAGONISTS ANTAGONISTS ANTIEMETICS
HYOSCINE PROMETHAZINE CHLORPROMAZINE METOCLOPRAMIDE ONDANSETRON APREPITANT DEXAMETHASONE

DICYCLOMINE DIPHENHYDRAMINE TRIFLUPROMAZINE DOMPERIDONE GRANISETRON FOSAPREPITANT BENZODIAZEPINES
DIMENHYDRINATE PROCHLORPERAZINE CISAPRIDE PALONOSETRON DRONABINOL

(OTHERS)
DOXYLAMINE MOSAPRIDE RAMOSETRON
MECLOZINE ITOPRIDE
(MECLIZINE)
LEVOSULPIRIDE
CINITAPRIDE
Prokinetic Drugs
Drugs which promote gastrointestinal transit and speed gastric emptying by
enhancing coordinated propulsive motility.
I. Metoclopramide
Mechanism of Action:
I. D2 antagonism: Blocks D2 receptors - hastens gastric emptying and enhances
LES tone by augmenting Ach release.
Central action is on CTZ and it is majorly responsible for its antiemetic actions
II. 5-HT4 agonism: 5-HT4 receptor activation on PAN -> activate excitatory
interneurones -> enhance Ach release from myenteric motor neurons ->
Gastric hurrying and LES tonic effects.
Synergised by bethanechol and attenuated by atropine

10
III. 5-HT3 antagonism: High concentrations, block 5-HT3 receptors on inhibitory

myenteric interneurones and in the NTS/CTZ -> auguments ACh release. It is a
minor mechanism.
Large doses – Central action -> control CINV.
Effects:
➢ Increase in tone of LES
➢ Increase in tone and amplitude of antral contractions
➢ Relaxation of pyloric sphincter
➢ Increase in peristalsis of small intestine
➢
Pharmacokinetics:
• Rapidly absorbed orally
• Enters brain, crosses placenta and is secreted in milk
• Partly conjugated in liver; excreted in urine within 24 hours
• t ½ is 3-6 hours
• Action: Oral: in ½ to 1 hour; i.m: in 10 minutes; i.v: 2 minutes
• Action lasts for 4-6 hours
Uses:
i) Anti-emetic: Vomiting – postoperative, drug induced, disease associated
(especially migraine), radiation sickness. Prophylaxis and treatment for
vomiting induced by emetogenic anticancer drugs like cisplatin.
ii) Gastrokinetic: Accelerate gastric emptying – emergency general
anaesthesia and to relieve postvagotomy and diabetic gastroparesis
associated with gastric stasis.
iii) Symptomatic relief for dyspepsia and other functional GI disorders.
iv) To treat persistent hiccups.
v) Mild cases of GERD can be treated.
ADR:
• Sedation, dizziness, loose stools, muscle dystonia (especially in
children).
• Long-term use can cause parkinsonism, galactorrhoea and
gynaecomastia

11
• Suckling infants can develop loose stools, dystonia, myoclonus –

secreted through mother’s milk.
II. Domperidone
MOA:
o D2 receptor antagonist
o Low celling/efficacious antiemetic and prokinetic actions
o Antiemetic action through CTZ
o Prokinetic action through upper GI D2 receptor blockade
Pharmacokinetics:
• Absorbed orally
• Bioavailability – 15% due to first pass metabolism
• Completely biotransformed and metabolites are excreted in urine
• Plasma t ½ is 7.5 hours
Uses:
Mild-to-moderate cases of postoperative, drug and disease induced nausea
and vomiting
ADR:
▪ Dry mouth, loose stools, headache, rashes, galactorrhoea – mild.
▪ Cardiac arrhythmias may develop on rapid IV injection

12

13
III. Cisapride
MOA:
❖ Mainly through 5-HT4 agonism and 5-HT3 antagonism
❖ Promotes cAMP-dependent Cl- secretion in the colon -> increases
water content of stools
ADR:
➢ Ventricular arrhythmias and death, mainly among patients who
concurrently took CYP3A4 inhibitors.
➢ At high concentrations, blocks delayed rectifying K+ channels in heart
-> prolongs Q-Tc interval -> predisposes torsades de
pointes/ventricular fibrillation.
➢ Banned for its cardiotoxicity
IV. Mosapride
▪ Congener of Cisapride and similar actions
▪ Though preclinical studies ruled out cardiotoxicity, it was reported
among patients.
Uses:
❖ Nonulcer dyspepsia
❖ Diabetic gastroparesis
❖ GERD (as adjuvant to PPIs)
❖ Chronic constipation
V. Itopride
• D2 antidopaminergic and anti-ChE activity

• Low affinity for 5-HT4 receptor -> unlikely to cause cardiac effects
• Metabolized by flavin monooxygenases and not by CYP450
isoenzymes -> no interaction with CYP3A4 inhibitors.
VI. Levolsulpiride
o Central as well as peripheral D2 receptors

o Atypical antipsychotics, prokinetic and antiemetic properties

14
Uses:
▪ Symptomatic relief for dyspepsia, nausea, bloating, GERD, irritable
bowel syndrome and several other functional GI disorders.
VII. Cinitapride
➢ Inhibits 5-HT2 and D2 receptors; stimulates 5-HT4 receptors in

myenteric plexus
Uses:
❖ Functional GI disorders like non-ulcer dyspepsia, delayed gastric
emptying and GERD
❖ Partial to complete symptomatic relief for epigastric pain, belching,
reflux, early satiety, dysphagia, nausea and vomiting in dyspepsia.
ADR:
▪ Drowsiness, diarrhea, muscle dystonias of head, neck and tongue,
mental confusion, allergy.
▪ Driving is not advised after taking Cinitapride.

15
2. Ondansetron
5 HT3 Antagonists
MOA:
• Blocks depolarisation of 5HT through 5T3 receptors on vagal
afferents.
• Blocks emetogenic impulse in GIT.
Pharmacokinetics:
• Oral bioavailability 60-70%
• Hydroxylated by CYP enzyme by glucuronide & sulfate conjugation.
Uses:
• Control cancer chemotherapy / radiatiotherapy included vomiting
• Post-operative Nausea and Vomiting
Side Effects:
• Headache & Dizziness
• Hypotension, Bradycardia, Chest pain – I.V. Injection

23
3. ROLE OF ANTIMICROBIALS IN DIARRHOEA

One or more antimicrobial agent is almost routinely prescribed to most patients
of acute diarrhoea. However, it's use in all cases is not justified because:
● Bacterial pathogen is responsible only for few cases
● Even in bacterial diarrhoea, antimicrobials alter the course of illness in selected
cases
● It may prolong the carrier state
Antimicrobial drugs used: Norfloxacin, Ciprofloxacin, ofloxacin, rifaximin,
cotrimoxazole, tetracycline, erythromycin, metronidazole
Types of acute diarrhoea:
(a) Non-invasive diarrhoea- abundant watery diarrhoea lacking mucus or blood,
usually dehydrating with frequent vomiting, periumblical crumps, but little or no
fever.
o source is small intestine
o caused by adhesive but non-invasive enterotoxigenic bacteria
such as cholera, Enterotoxigenic E.coli(ETEC), Salmonella
enteritidis, Staph.aureus, Bacillus cereus or by rota virus and
other viruses
- ORS and not antimicrobials are main therapy.
(b) Invasive diarrhoea- slightly loose, smaller volume stools, frequently with
mucus and/or blood, abdominal cramps, urgency, mild dehydration, usually with
fever but not vomiting
-colonic involvement and mucosal invasion
- caused by enteroinvasive organisms like Shigella, enteropathogenic E.coli
(EPEC), Campy.jejuni, Salmonella typhimurium, Yersinia enterocolitica, E.histolytica,
Clostr.difficile
- antimicrobials are needed
Role of Antimicrobials
A. Antimicrobials are of no value: In diarrhoea due to infective causes, such as:
● Irritable bowel syndrome
● Coeliac disease
● Pancreatic enzyme deficiency

24
● Tropical sprue (except when there is secondary infection)

● Thyrotoxicosis
Rotavirus, along with other diarrhoea causing viruses, is not amenable to
chemotherapy
B. Antimicrobials are useful in severe disease:
1. Salmonella food poisoning- generally a self-limiting disease.
- However, antibiotics if used should be restricted to severe illness or that
in infants/elderly or immunocompromised patients
- Drugs used: Ciprofloxacin or Azithromycin or i.v. ceftriaxone
2. Travellers’ diarrhoea- mostly due to ETEC, campylobacter or virus
- Ciprofloxacin, Norfloxacin, doxycycline or cotrimoxazole reduce duration
of diarrhoea and total fluid needed only in severe cases
- Rifaximin: oral rifamycin active against E.coli and many other gut
pathogens
Uses are,
● Travellers’ diarrhoea (400mgTDS for 3 days); superior to placebo and as
effective as Ciprofloxacin
● Diarrhoeal phase of IBS as well as prophylaxis before and after gut surgery
● 550mg tablet for reducing risk of hepatic encephalopathy recurrence
-Tolerability similar to placebo
-Side effects: flatulence, abdominal pain, defecation urgency and headache.
No systemic toxicity due to poor absorption.
3. Invasive diarrhoea-
● Drugs used: Ciprofloxacin, ofloxacin, Norfloxacin, cotrimoxazole or
doxycycline
● Symptomatic relief as well as eradicate the pathogen
C. Antimicrobials are useful in all cases:
● Cholera: Tetracycline (to reduce stool volume nearly to half); cotrimoxazole as
alternative in children; for MDR cholera, Norfloxacin/ Ciprofloxacin given.
Ampicillin and erythromycin are also effective
● Campylobacter jejuni: Norfloxacin and other fluoroquinolones eradicate
organism. Erythromycin is preferred in children

1
1. DRUG RESISTANCE
RESISTANCE:
Unresponsiveness of an organism to the antimicrobial agent
TYPES:
 Natural
 Acquired
NATURAL RESISTANCE:
Some microbes show resistance inherently. This is because they lack the metabolic
process or target site which is affected by the particular drug.
E.g.: Penicillin G – gram negative bacilli
ACQUIRED RESISTANCE:
This refers to development of resistance by an organism due to use of an AMA over a
period of time.
Resistance may be developed by
 Mutation
 Gene transfer
Mutation Gene transfer

Definition Stable and heritable Resistance causing gene
genetic change that is passed from one
occurs spontaneously and organism to other.
randomly among
microorganisms.
Transfer of resistance Vertical Horizontal
Time Slow process Rapid process
Degree of resistance Low High
Resistance acquired by Single step Conjugation
Multi step Transduction
Transformation
Conjugation
Antimicrobials Agam Pharmacology

2
The R-factor is transferred from cell-to-cell by direct contact through a sex pilus
or bridge and the process is known as conjugation.
Transduction
Plasmid DNA is transferred through the bacteriophage, i.e. virus which infects
bacteria.
Transformation
Resistant bacteria may release genetic material into the medium which is taken
up by other bacteria.
Resistant organisms can broadly be of following three types:
 Drug tolerant – the microorganism loses affinity for a particular AMA

 Drug destroying – the resistance microbe elaborates an enzyme which
inactivates the drug
 Drug impermeable – loss of porins
CROSS RESISTANCE:
 Resistance seen among chemically related drugs
 Development of resistance to one drug is also resistant to other chemically
related drugs.
 E.g.: Tetracyclines
PREVENTION OF DRUG RESISTANCE

 No inadequate or unduly use of AMAs.
 Use narrow spectrum AMAs whenever possible
 Use combination

5
1. FLUOROQUINOLONES (FQs)
CLASSIFICATION:
CIPROFLOXACIN:
 All fluoroquinolones have same mechanism of action.
In gram negative bacteria,

Bacterial DNA gyrase has two subunits: A and B
Subunit A Subunit B
• does nicking • introduces
and resealing negative
of DNA supercoils

6
FQs bind to bacterial DNA

gyrase
prevents its strand cutting

and
interferes with the resealing

function
In gram positive bacteria
FQ bind to topoisomerase IV
damages DNA
by interferring with nicking of DNA
and seperating of daughter DNA

strands
results in DNA damage
signalling of exonuclease
production
digestion of DNA

7
RESISTANCE:
 Mutation in the target enzyme resulting in decreased affinity for the drug
 Decreased permeability of the organism to the drug
 Increased efflux of drugs
SPECTRUM:
 Gram-negative organism like
Gonococci, Meningococci, H. influenza, E. coli, Salmonella, Shigella,

Enterobacterium
 Gram-positive organism like
Staphylococci
PHARMACOKINETICS:
 Rapidly absorbed
 First pass metabolism occurs
 20% metabolised
 Excreted in urine
 Half-life: 3-5 hours
ADVERSE REACTIONS:
 GI: nausea, vomiting
 CNS: dizziness, headache
 Skin: hypersensitivity, rashes
 Tendonitis

8
USES:
 Urinary tract infection
 Chancroid
 Typhoid
 Respiratory tract infection
 Tuberculosis
 Anthrax
 Diarrhea

10
3. COTRIMOXAZOLE
 The combination of trimethoprim and sulfamethoxazole is cotrimoxazole.

 Both the drugs approximately have same half-life.
SPECTRUM:
 Gram-positive and gram-negative organisms like Staph. aureus,
Streptococci, Meningococci, C. diphtheriae, E. coli.
 Sulfonamides inhibit the conversion between PABA to di hydro folic acid.

 Trimethoprim inhibits the conversion between Di hydro folic acid and tetra
hydro folic acid.
RESISTANCE:
DHFRase enzyme coding plasmid

11
PHARMACOKINETICS:
Trimethoprim sulfamethoxazole
Absorption Oral - rapid Oral - slow
Distribution Large volume Less volume
Crosses BBB and placenta Yes Poor entry
Protein plasma bound 40% 65%
Metabolized Partly High fraction acetylated
Excretion Urine Urine
Half-life 10 hours 10 hours
ADVERSE EFFECTS:
 Nausea
 Vomiting
 Headache
 Stomatitis
 Rashes
 Megaloblastic anemia
 Renal failure
 Teratogenicity
USES:
 Urinary tract infections
 Respiratory tract infections
 Pneumocystis jirovecii pneumonia
 Chancroid

12
1. PENICILLIN
CLASSIFICATION:
PENICILLIN G:
ANTIBACTERIAL SPECTRUM:
 Narrow spectrum – limited primarily to Gram-positive bacteria (GPB), few

gram-negative bacteria (GNB) and anaerobes.
 Cocci – streptococcus, pneumococcus (GPB), Neisseria gonorrhea, N.
meningitidis (GNB)
 Bacilli – B. anthracis, C. diphtheriae, Clostridia, listeria, spirochetes
PHARMACOKINETICS:
 Destroyed by gastric acid

 1/3 of oral dose absorbed
 Sod. PnG i.m. – absorption rapid
 Peak plasma level in 30min, t1/2 – 30min
 Distributed extracellularly
 Rapid renal excretion. Tubular secretion of PnG blocked by probenecid.

13
ADR:
 Local irritancy
 Pain at i.m. site
 thrombophlebitis on i.v.
 nausea on oral ingestion
 Brain toxicity
 Confusion
 Muscle twitching
 Convulsions
 Coma
 Hypersensitivity
 Rash
 Itching
 Urticaria
 Fever
 Wheezing
 Angioneurotic edema
 Serum sickness
 Anaphylaxis
USES:
 Streptococcal infections – pharyngitis, otitis media, scarlet fever, rheumatic

fever (strep. Pyogenes), Subacute bacterial endocarditis (Strep. Viridians or
faecalis)
 Pneumococcal infection- lobar pneumonia, meningitis
 Meningococcal infection – meningitis
 Syphilis – PnG is DOC. Early & latent syphilis treated by procaine penicillin, late
syphilis by benzathine penicillin
 Leptospirosis
 Diphtheria- procaine penicillin to prevent carrier state
 Tetanus and gas gangrene
 Prophylaxis of rheumatic fever and bacterial Endocarditis

14
2. CEPHALOSPORINS
 They are bactericidal
CLASSIFICATION:
 A rigid cell wall protects the bacterial cell wall from lysis.
 Bacterial Cell Wall has peptidoglycan.
 Peptidoglycan is the chief compound which is responsible for the
synthesis of cell wall.
 Peptidoglycan = peptide chain + glycan chain and they are both cross-
linked;
 glycan chain is composed of alternating amino sugars, NAM (N-
acetyl-muramic acid) and NAG (N-acetyl-glucosamine).
 This cross linking gives the cell Wall its strength:
 pentapeptide (five amino acids), linked to NAM, has a
pentaglycine, attached to it.

15
 This pentaglycine is cross linked with a pentapeptide of adjacent

strand.
 The synthesis of peptidoglycan cell wall requires an enzyme
Transpeptidase, which is responsible for linking the peptide & glycan
chains.
 Transpeptidase (penicillin binding protein) causes cross linking between
the pentaglycine residue of one strand and fourth amino acid (d-alanine)
of adjacent pentapeptide, by cleavage of the terminal d-alanine (fifth
amino acid residue)
 The cross linking makes the cell wall rigid and stable.
cephalosporins inhibit
transpeptidase enzyme
leading to inhibiton of
peptidoglycan
cell wall deficient forms are formed
interior of bacterium become

hyperosmotic
bacterial lysis occur
USES:
 As alternatives to penicillins for ENT, upper respiratory and cutaneous

infection
 Respiratory, urinary and soft tissue infection caused by gram-negative
organisms
 Penicillinase producing staphylococcal infections and infection due to MRSA
 Septicemias produced by gram-negative bacteria

16
 Surgical prophylaxis
 Meningitis
 Gonorrhea by penicillinase producing enzymes
 Typhoid
 Mixed aerobic-anaerobic infection in cancer patients, etc.
 Hospital acquired infection
 Prophylaxis and treatment of infection in neutropenic patients
ADR:
 Hypersensitivity reactions like skin rashes, fever, serum sickness and rarely
anaphylaxis are seen.
 Nephrotoxicity
 Diarrhoea
 Bleeding is due to hypoprothrombinemia
 Low WBC count (rarely)
 Pain at the injection site.

23
1. TETRACYCLINE
 They are bacteriostatic antibiotics.
 Has broad spectrum of activity.
Tetracycline binds
30S ribosme of susceptible

organisms
blocks attachment of aminoacyl

tRNA
to acceptor(A) site
peptide chain doesnt grow
SPECTRUM:
 More active against gram-positive than gram-negative bacteria.
 Cocci: Active against Streptococcus pyogenes, streptococcus

pneumoniae, etc.
 Most gram-positive bacilli: like clostridia
 Anaerobes: listeria, cornybacteria, etc.
 Gram-negative bacilli: H. ducreyi, V. cholerae, etc.
 Spirochetes, rickettsiae, protozoa.

24
RESISTANCE:
Mechanism:
 Resistant bacteria acquire capacity to pump tetracyclines out
 Plasmid mediated synthesis of protection protein which protect the ribosomal
binding site from tetracyclines.
 Elaboration of tetracycline inactivating enzyme.
Partial cross resistance between tetracyclines and chloramphenicol is noted.
PHARMACOKINETICS:
 Poor oral absorption.
 i.m. injection should not be given.
 Widely distributed
 Plasma T1/2 - 6-12 hours.
 Peak plasma concentration- 2-4 hrs.
 Tetracycline crosses placenta and enters fetal circulation and amniotic fluid.
 Excreted in urine
USES:
 Empirical therapy – mixed infection

 As 1st choice of drugs in
 Venereal disease – chlamydial non-specific urethritis, endocervicitis
 Atypical pneumonia
 Cholera
 Brucellosis
 nd
As 2 choice of drugs in
 Tetanus
 Anthrax
 Gonorrhea
 Urinary tract infections
 Community-acquired pneumonia
 Amoebiasis

25
ADVERSE EFFECTS:
 Epigastric pain
 Nausea
 Vomiting
 Diarrhea
 Phototoxicity
 Hepatic toxicity
 Renal toxicity
 Brown discoloration of the teeth.
CONTRAINDICATIONS:
 Pregnancy
 Lactating mothers
 In children

26
2. DOXYCYCLINE
 It is the semisynthetic member of tetracyclines and is similar to Minocycline.
Similar to tetracycline
Doxycycline binds
30S ribosme of susceptible

organisms
blocks attachment of aminoacyl

tRNA
to acceptor(A) site
peptide chain doesnt grow
RESISTANCE:
 Doxycycline is not effectively effluxed.

 Some organisms not responding to other tetracyclines may be inhibited by
therapeutic concentration of doxycycline.
PHARMACOKINETICS:
 It has high potency than any other tetracyclines but less than Minocycline.
 95-100% absorbed in intestines.
 No interference by food
 High plasma protein binding

27
 Excreted in faeces as conjugates.

 Plasma half-life: 18-24 hour.
ADVERSE EFFECTS:
 It has least effects on intestinal flora.
 Low incidence of diarrhoea
 High photo toxic effect
 Low renal toxicity.
USES:
 Chlamydial non-specific urethritis /endocervicitis.

 Along with quinine it is used to treat Falciparum malaria and vivax malaria.
 Leptospirosis
 Brucellosis

39
2. CLARITHROMYCIN
 Semisynthetic macrolide
SPECTRUM:
 similar to erythromycin (G+ and few G- bacteria) + MAC (Mycobacterium
avium complex), M. leprae, other atypical mycobacteria.
PHARMACOKINETICS:
 Oral bioavailability- 50% due to 1st pass metabolism
 T1/2 - 4-6 hrs (lower doses), 16-9 hrs (higher doses)
USES:
 Respiratory tract infections
 Sinusitis
 Otitis media
 Whooping cough
 Atypical pneumonia
 Skin infections- Streptococcus pyogenes & Staph. aureus
 Anti H. pylori regimen
 MAC infections in AIDS patients
 M. avium complex- second line drug
ADVERSE EFFECTS:
 GI disturbances
 Reversible hearing impairment
 Hypersensitivity
 Pseudomembranous enterocolitis
 Hepatic dysfunction
 Rhabdomyolysis (rare)
DRUG INTERACTIONS
 Inhibits CYP3A4

44
1. ANTI TUBERCULAR DRUGS
CLASSIFICATION:

45
ISONIAZID
INTRODUCTION:
 Isoniazid is an excellent antitubercular drug
 It is primarily tuberculocidal.
 Fast multiplying organisms are rapidly killed, but quiescent ones are only
inhibited.
 It acts on extracellular as well as on intracellular TB (bacilli present within
macrophages), and is equally active in acidic or alkaline medium.
 Isoniazid (INH) enters sensitive bacteria.
catalase
Isoniazid --------------> active metabolite ----------> adducts with NAD and NADP
peroxidase
NAD adduct NADP adduct
inhibits 'InhA' and inhibits mycobacterial

'KasA' gene DHFRase
mycolic acid DNA synthesis is

synthesis is interrupted
interfered

46
RESISTANCE:
The most common mutation is
 KatG gene which produces catalase peroxidase
Other mutations are
 InhA gene and KasA gene
PHARMACOKINETICS:
 INH is completely absorbed orally
 Penetrates all body tissues, tubercular cavities, placenta and BBB.
 It is extensively metabolized in liver - most important pathway being N-
acetylation by NAT2.
 The acetylated metabolite is excreted in urine
INTERACTIONS:
 Aluminium hydroxide inhibits INH absorption.
 INH retards phenytoin, carbamazepine, diazepam, theophylline and
warfarin metabolism by inhibiting CYP2C19 and CYP3A4, and may raise
their blood levels.
ADVERSE EFFECTS:
 Peripheral neuritis
 Neurological manifestations.
INH neurotoxicity is treated by pyridoxine 100 mg/day.
 Hepatitis
Other side effects:

 Lethargy
 Rashes
 Fever
 Acne
 Arthralgia

47
2. RIFAMPIN (RIFAMPICIN, R)
 Semisynthetic derivative of rifamycin

 First line antituberculous drug
 It kills both intracellular and extracellular bacilli
 It also has resistance preventing actions
rifampin binds to β subunit

of
mycobacterial DNA
dependent RNA polymerase
interrupts DNA synthesis
PHARMACOKINETICS:
 Orally well absorbed from GIT
 Presence of food reduces its absorption
 Distributed widely across body
 Metabolized in liver
 Active deacylated form undergoes enterohepatic circulation
 Excreted in urine and bile
INTERACTION:
 Microsomal enzyme inducer – CYP450, CYP3A4, etc.

48
USES:
 Tuberculosis
 Leprosy
 Prophylaxis of meningococcal and H. influenzae meningitis
 2nd or 3rd choice of drug for MRSA, diphtheroids and legionella infections.
 In combination with doxycycline used in brucellosis as first line therapy
ADVERSE EFFECTS:
 Hepatitis
 Flushing
 Rashes
 Headache
 Malaise
 Nausea
 Vomiting
 Diarrhoea
 Orange-red urine

51
4. DRUG REGIMEN IN DRUG SENSITIVE TB
TYPE OF INTENSIVE PHASE CONTINOUS TOTAL

PATIENT PHASE DURATION
NEW HRZE – 2months HRE – 4 months 6 months
PREVIOUSLY HRZES – 2 months HRE – 5 months 8 months
TREATED + HRZE – 1 month
H – isoniazid
R – rifampin
Z – pyrazinamide
E – ethambutol
S – streptomycin
5. FOUR 2ND LINE ANTITUBERCULAR DRUGS
 Kanamycin
 Capreomycin
 Ethionamide
 Fluoroquinolones
6. DRUG REGIMEN IN MAC INFECTION

52
1. ANTILEPROTIC DRUGS
CLASSIFICATION:
DAPSONE
 Mechanism of action similar to sulfonamides.
 Dapsone act by the inhibition of PABA incorporation into folic acid by folate
synthase, cause the antibacterial action of dapsone is antagonized by PABA.
 It is leprostatic at very low concentrations, while the growth of many other
bacteria sensitive to sulphonamides is arrested at higher concentrations.
RESISTANCE:
 Primary – when dapsone resistance is encountered in an untreated patient
and it indicates that the infection was contacted from a patient harbouring
resistant bacilli.
 Secondary – resistance which develops during monotherapy with dapsone.
 Persisters – the drug sensitive bacilli which become dormant, hide in some
tissues and are not affected by any drug and relapse occurs when the drug is
withdrawn.

53
PHARMACOKINETICS:
 Completely absorbed after oral administration
 Widely distributed in the body
 Penetration in CSF is poor.
 70% plasma protein bound
 Concentrated in the skin, muscle, liver and kidney.
 Acetylated as well as glucuronide and sulphate conjugated in liver.
 Metabolites are excreted in bile and reabsorbed from intestine.
 Ultimate excretion occurs mostly in urine.
 Elimination take 1-2 weeks or long.
ADVERSE EFFECTS:
 Mild haemolytic anaemia is common.
 GIT intolerance
 Nausea
 Anorexia
 Other side effects

 Methemoglobinemia
 Headache
 Paraesthesia
 Mental symptoms
 Drug fever
 Cutaneous side effects

 Itching
 Allergic reactions
 Hypermelanosis
 Phototoxicity

54
 Sulfone syndrome
 develops 4-6 weeks after starting dapsone treatment, generally seen
in malnourished patients.
 Manifestations are
 Fever
 Malaise
 Lymph node enlargement
 Desquamation of skin
 Jaundice
 Anaemia
 Treatment includes withdrawal of dapsone and instituting
corticosteroid therapy along with supportive measures.
CONTRAINDICATIONS:
 Severe anemia
 In those showing hypersensitivity reactions.
USES:
 Leprosy
 Dapsone + pyrimethamine is used in chloroquine resistant malaria,
toxoplasmosis and P. jirovecii infection.

57
3. MULTI DRUG THERAPY (MDT) OF LEPROSY
 Introduced in 1981 by WHO and implemented by NLEP
OBJECTIVES:
 To deal with Dapsone resistant strains
 Shorten the duration of treatment
 To eliminate microbial persisters
ADVANTAGES:
 Effective in cases of primary dapsone resistance
 Prevents emergence of Dapsone resistance
 Affords quick symptom relief, stops progression, prevents further
complications and renders MBL cases noncontagious within few days
 Reduces total duration of therapy and chances of relapse < 1%
 Efficacy, safety, acceptability of MDT for both PBL and MBL is excellent
 No resistance to rifampicin has developed after use of MDT
 Relapse cases have been successfully treated with the same MDT
CLASSIFICATION:
PAUCIBACILLARY LEPROSY (PBL) MULTIBACILLARY LEPROSY (MBL)

1-5 skin lesions 6 or more skin lesions
No or one nerve involvement, ± 1-5 skin >1 nerve involved irrespective of number
lesions. of skin lesions.
Skin smear negative at all sites Skin smear positive at any one site.
DRUGS:
 Rifampicin
 Dapsone
 Clofazimine

58
OLD REGIMEN:
 PBL – Dapsone + Rifampicin for 6 months
 MBL – Dapsone + Rifampicin + Clofazimine for 2 years
NEW REGIMEN:
DRUGS MBL PBL
RIFAMPIN 600 mg once a month 600 mg once a month
supervised supervised
DAPSONE 100 mg daily self- 100 mg daily self-
administered administered
CLOFAZIMINE 300 mg once a month -
supervised + 50 mg daily
self-administered
DURATION 12 months 6 months
CHILD DOSE
RIFAMPIN 10 mg/kg once monthly
CLOFAZIMINE 1 mg/kg daily + 6 mg/kg once monthly
DAPSONE 2 mg/kg daily
 Relapse of Leprosy  Same MDT

 Leprosy and TB coinfection  MDT is continued but rifampicin is given daily
for TB
 Leprosy in HIV patients  MDT can be given safely

60
1. ANTI FUNGAL DRUGS
 Drugs that are used for deep and superficial fungal infections.
CLASSIFICATION:

61
AMPHOTERICIN B (AMB)
Amphotericin B is a polyene antibiotic molecule
AMB has ↑ affinity for ergosterol
AMB combines with it andget inserted into the membrane
several polyene molecules orient themselves to form

micropore
the hydrophilic side forms interior of the pore
through which water soluble substances move out
sterols fill up the outer surface and stabilise the outer

membrane (lipophilic)
cell permeability is markedly ↑
AMB enhance immunity thus help in immunocompromised individuals of fungal

infections.

62
SPECTRUM: broad spectrum

 Active against wide range of yeasts and fungi: Candida albicans, Histoplasma
capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides
immitis, Torulopsis, Aspergillus, Rhodotorula, Spirothrix, etc.
 Dermatophytes are inhibited in vitro.
 Fungicidal at high concentration and static at low concentration.
 Resistance is rare (Among Candida)
 Also active on various species of Leishmania.
PHARMACOKINETICS:
 Not absorbed orally but can be given for intestinal candidiasis without
systemic toxicity.
 Administered i.v. as a suspension made with the help of DOC (Deoxy cholate).
 Penetration in CSF is poor.
 Binds to sterol in tissues and to Lipoproteins in plasma and stays in body for
long periods.
 T½: 15 days.
 Metabolised in liver (60%).
 Excreted slowly in urine and bile.

63
ADVERSE EFFECTS: High toxicity

ACUTE REACTION:
 Chills
 Fever
 Body ache
 Pain
 Nausea
 Vomiting
 Dyspnoea for 2-5 hours
 thrombophlebitis
Probably due to loss of cytokines (IL, TNF-alpha). Dose to be increased based on

intensity of the reaction, intensity decreases on continued medication.
Hydrocortisone injection 0.6 mg/kg along with AMB infusion decreases
reaction.
LONG TERM TOXICITY:
 Nephrotoxicity: dose related, reduced on discontinuing therapy.
Manifestations:
 Azotemia
 Reduced GFR acidosis
 Hypokalaemia
 Inability to concentrate urine
 Anemia: Progressive. Due to bone marrow depression, reversible.
 CNS toxicity: (Only on intrathecal injection)
 Headache
 Vomiting
 Nerve palsies

64
USES:
Applied topically for oral, vaginal, cutaneous candidiasis, fungal corneal ulcer and
Otomycosis. GOLD STANDARD FOR ANTIFUNGAL THERAPY.
 It is the most effective for systemic mycosis.
1st choice in
 Candidiasis
 Cryptococcosis
 Histoplasmosis
 Coccidioidomycosis
 Blastomycosis
 Disseminated sporotrichosis
 Aspergillosis
 Mucormycosis
2nd choice of drugs in

 Paracoccidiodomycosis
 In initial induction of therapy in immunocompromised patients.

 Febrile neutropenia
 Leishmaniasis
INTERACTIONS:
 Flucytosine has supra additive with AMB
 Aminoglycosides, vancomycin, cyclosporine increase renal impairment along
with AMB.

67
3. GRISEOFULVIN
 Insoluble fungistatic drug

 Derived from penicillium griseofulvum
 Used in systemic dermatophytosis but not against fungi causing deep mycosis.
Griseofulvin
interacts with polymerised

microtubules
distrupts the mitotic spindles
daughter nuclei fails to move or move

short distance
inhibits mitosis - fungistatic action
PHARMACOKINETICS:
 Absorption - incomplete oral absorption
 Absorption can be improved along with fatty foods
 Metabolism - methylation in liver
 Excretion - kidneys
 Plasma t½ - 24 hrs

68
USES:
 Dermatophytosis (dose-125-250 mg QID)
 For scalp - 4 weeks
 Palms, soles - 6 to 8 weeks
 Finger nails - 6 to 8 months
 Toe nails - 10 to 12 months
 Effective in athletes’ foot

 Onychomycosis
 Tinea capitis
ADVERSE EFFECTS:
 Headache
 g.i.t disturbances
 CNS symptoms
 Peripheral neuritis
INTERACTIONS:
 Hastens warfarin metabolism
 Efficacy of oral contraceptives maybe lost

69
4. KETOCONAZOLE (KTZ)
 First oral azole to be produced.

 Broad spectrum antifungal drug.
Azoles inhibit
fungal CYP450 enzyme -

lanosterol 14-methylase
impairs ergosterol synthesis
leads to cascade of
membrane abnormalities
increases the susceptibility of

fungus
PHARMACOKINETICS:
 Well absorbed from the gut
 Food and low pH enhance absorption
 Extensive hepatic metabolism
 Metabolites are excreted in urine and faeces
 Half-life: 4-8 hours
USES:
 Mucocutaneous candidiasis and dermatophysis
 Cushing’s syndrome
 Cutaneous leishmaniasis
 Monilial vaginitis

70
ADVERSE REACTION:
 Nausea
 Vomiting
 Headache
 Loss of appetite
 Gynaecomastia
 Infertility
 Decreased Libido
 Azoospermia
 Hypertension
INTERACTIONS:
 Rifampicin induce the metabolism
 Inhibition of CYP450 enzymes and increases the plasma level of several drugs
like sulfonylureas
 Proton pump inhibitors ↓ oral absorption of KTZ

79
1. ANTI RETROVIRAL DRUGS
CLASSIFICATION:
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

Zidovudine is the prototype drug
zidovudine is
phosphorylated
to zidovudine
triphosphate
selectively inhibits
viral reverse
transcriptase
terminates proviral DNA

80
NRTIs ADR USES

ZIDOVUDINE (AZT) Anaemia, neutropenia, A component of
nausea, anorexia, alternative regimen.
abdominal pain, etc.
DIDANOSINE (ddl) Peripheral neuropathy, Infrequently used due to
diarrhoea, nausea, etc. high toxicity
STAVUDINE (d4T) Metabolic complications No longer used
like lactic acidosis,
peripheral neuropathy,
etc.
LAMIVUDINE (3TC) Headache, fatigue, Triple line drug in WHO
nausea, anorexia, etc. and NACO regimen.
Chronic hepatitis B
ABACAVIR (ABC) Hypersensitivity 1st line WHO regimen for
reactions. Flu-like children
respiratory and
constitutional symptoms
EMTRICITABINE (FTC) Fatigue, headache, 1st line anti-HIV drugs.
nausea, diarrhoea, etc. Pre-exposure prophylaxis
of HIV in high risk adults.
TENOFOVIR (TDF) Renal toxicity 1st line WHO regimen for
adults and adolescents.

81
2. PRINCIPLES AND GUIDELINES IN TREATMENT OF HIV
The treatment of HIV infection and its complications is complex, prolonged, needs
expertise, strong motivation and commitment of the patient, resources and is
expensive.
INITIATING ANTIRETROVIRAL THERAPY:
The WHO (2016) guideline has recommended that ART should be started in all adults
including
 Pregnant and breast-feeding women
 Adolescents as well as children
as soon as possible after diagnosis of HIV infection is confirmed irrespective of
 CD4 cell count
 the HIV-RNA load
 the clinical stage of the disease.
THERAPEUTIC REGIMENS:
NACO selects first line regimens for untreated patients on the following principles:
 All regimens should have 2 NRTI+1NNRTI.
 Include lamivudine in all regimens.
 The other NRTI can be zidovudine or stavudine.
 Choose one NNRTI from nevirapine or efavirenz.
 Choose efavirenz in patients with hepatic dysfunction and in those
concurrently receiving rifampin.
 Do not use efavirenz in pregnant women or in those likely to get pregnant.

82
CHANGING OF FAILING REGIMEN:
An ART regimen is considered to have failed when:

 Plasma HIV-RNA count is not rendered undetectable (<50 copies/μl) within 6
months therapy.
 Repeated detection of virus in plasma after initial suppression to undetectable
levels despite continuation of the drug regimen.
 Clinical deterioration, fall in CD4 cell count, serious opportunistic infection
while continuing drug therapy.

83
PROPHYLAXIS OF HIV INFECTION:
 Pre-exposure prophylaxis (PrEP)

 Post-exposure prophylaxis (PEP)
 Prophylaxis after sexual exposure
 Perinatal HIV prophylaxis
3. PROPHYLAXIS OF HIV INFECTION
PRE-EXPOSURE PROPHYLAXIS
 This serves to protect people at high risk of contracting HIV infection
POST-EXPOSURE PROPHYLAXIS
 Health care workers and others who get accidentally exposed to the risk of HIV
infection by needlestick or other sharp injury or contact with blood/ biological
fluid of HIV patients or blood transfusion should be considered for PEP.
 The aim of PEP is to suppress local viral replication prior to dissemination, so
that the infection is aborted.

84
PROPHYLAXIS AFTER SEXUAL EXPOSURE:
 Though there is no data to evaluate the value of prophylaxis after sexual

exposure, the same regimen as for needle stick may be used.
PERINATAL HIV PROPHYLAXIS:
 HIV may be transmitted from the mother to the child either through the
placenta, or during delivery, or by breastfeeding.

85
 The highest risk (>2/3rd) if transmission is during the birth process. As per
current recommendation, all HIV positive women, who are not on ART, should
be put on the standard 3 drug ART.
 This should be continued through delivery and into the postnatal period and
has been shown to prevent vertical transmission of HIV to the neonate, as well
as benefit the mother’s own health.
 The first line NACO regimen for pregnant women is:
Tenofovir 300mg + Lamivudine 300mg + Efavirenz 600mg
 In addition, the neonate should be given syrup nevirapine for 6 weeks

88
1. ANTIMALARIAL DRUGS
CLASSIFICATION:
CHLOROQUINE (CQ):
 Rapidly acting erythrocytic schizontocide against all species of plasmodia
 Controls most clinical attacks in 1-2 days with disappearance of parasites in
peripheral blood
 Does not prevent relapse of vivax and ovale malaria.
 No gametocidal activity
 It’s a basic drug

89
MECHANISM OF ACTION: Not exactly known
CQ (a weak base) is taken up by
acidic vacuoles of parasite
where it is concentrated
it prevents formation of
hemozoin
by forming a drug-haeme
complex
damages plasmodial membrane
PHARMACOKINETICS:
 Oral
 50% binds to plasma
 Increased affinity for melanin and nuclear chromatin
 Selective accumulation in retina  ocular toxicity
 T1/2: 3- days, since tightly bound, persist for 1-2 months.
ADR:
 Nausea LONG TERM USE
 Vomiting
 Loss of hearing
 Anorexia
 Rashes
 Uncontrollable itching
 Photoallergy
 Epigastric pain
 Myopathy
 Headache
 Graying of hair

90
USES:
 D.O.C. for P. vivax, ovale, malaria
 Extraintestinal amoebiasis
 Rheumatoid arthritis
 Lepra reaction
 Discoid lupus erythematous (very effective)
 Photogenic reaction
 Infectious mononucleosis – symptomatic relief

91
2. TREATMENT OF CHLOROQUINE RESISTANT MALARIA

94
4. PRIMAQUINE
 It is a synthetic 8- aminoquinoline
 More active against pre-erythrocytic stage of P. falciparum
 Highly active against gametocytes and hypnozoites
 Poor erythrocytic schizontocide
 Primaquine differs from all other available anti-malarial in having marked
effect in primary as well as secondary hepatic phase of malarial parasite
Not known but reactive metabolites of primaquine  generate intraparasitic toxic
oxidative species  disrupt electron transport in plasmodial mitochondrion
PHARMACOKINETICS:
 Oral ingestion
 Plasma t1/2 6-8 hours
 Oxidised in liver
 Excreted in urine within 2-4 hours
ADR:
 Abdominal pain
 GI upset
 Weakness
 Uneasiness in chest
 Leucopenia  large doses
Important toxic potential is dose related: due to oxidant property
 Hemolysis
 Methemoglobinemia
USES:
 Tachypnoea
 Cyanosis  Vivax malaria
 Falciparum malaria

97
6. MANAGEMENT OF CEREBRAL MALARIA
7. FOUR ERYTHROCYTIC SCHIZONTICIDAL AGENTS

 Mefloquine
 Atovaquone
 Chloroquine
 Halofantrine
8. FOUR ARTEMISININ DERVIATIVES OF MALARIA

 Dihydroartemisnin
 Artesunate
 Artemether
 α/β arteether

98
1. ANTIAMOEBIC DRUGS
CLASSIFICATION:
METRONIDAZOLE - MECHANISM OF ACTION:

99
PHARMACOKINETICS:
 Metronidazole is available for oral, i.v. and topical administration.
 Well absorbed after oral administration
 Poorly bound to plasma proteins.
 Diffuses well into the tissues including brain
 Therapeutic levels are achieved in various body fluids—saliva, semen, vaginal
secretion, bile, breast milk and CSF.
 Metronidazole is metabolized in liver {by Oxidation & glucuronide
conjugation}
 The metabolites are excreted mainly in urine.
 Half-life: 8hours
ADR:
 Gastrointestinal: Anorexia, nausea, metallic taste, dry mouth, epigastric
distress, abdominal cramps and occasionally vomiting.
 Allergic reactions: These include skin rashes, Urticaria, itching and flushing.
 CNS: Dizziness, vertigo, confusion, irritability, headache, rarely convulsions and
ataxia may occur. Polyneuropathy may occur on prolonged therapy.
 Thrombophlebitis
INTERACTIONS:
 Disulfiram-like reaction (nausea, vomiting, abdominal cramps, headache,
flushing, etc.) may occur if taken with alcohol; hence patient should be
warned to avoid alcohol during treatment with metronidazole.
 Cimetidine ↓ metronidazole metabolism.
 Metronidazole enhances warfarin action.
CONTRAINDICATIONS:
 Neurological disease
 Blood dyscrasias
 Should be avoided in pregnant women in 1st trimester
 Cautious use needed in chronic alcoholics.

100
USES:
 Amoebiasis:
 Dose: (400–800 mg TDS for 7–10 days)
 first-line agent for the treatment of both intestinal and extraintestinal
amoebiasis except in asymptomatic carriers.
 Trichomonas vaginitis:
 Metronidazole (400 mg TDS orally for 7 days) is the drug of choice.
 Both sexual partners should be treated simultaneously.
 Giardiasis:
 Metronidazole is very effective and is given orally (200 mg TDS for 7
days).
 Anaerobic infections:
 Metronidazole is highly effective in most of the anaerobic infection.
 15 mg/kg infused over 1 hour followed by 7.5 mg/kg every 6 hours till
oral therapy can be instituted with 400-800 mg TDS.
 H. pylori infections:
 Treatment done with a combination of Metronidazole (400 mg TDS) /
tinidazole (500 mg BD) with amoxicillin / clarithromycin and a proton
pump inhibitor (omeprazole)
 Pseudomembranous colitis
 250- 500mg TDS or 7-14 days.

108
When used for schistosomes and visceral flukes, symptoms like

 Itching
 Urticaria
 Rashes
 Fever
 Body ache
 Destruction of cysticerci in brain cause neurological complications.
5. IVERMECTIN
 It is an extremely potent semisynthetic derivative of the antinematodal

principle
 Obtained from Streptomyces avermitilis.
 Nematodes develop tonic paralysis when exposed to ivermectin.
 It acts through special glutamate gated Cl channel found only in invertebrates.
 Potentiation of GABAergic transmission in the worm has also been observed.
PHARMACOKINETICS:
 Well absorbed orally
 Widely distributed in body but does not enter CNS, liver and fat.
 Has long terminal t½ of 48-60 hrs.
 Metabolized by CYP3A4 in liver.
 No drug interactions.

109
USES:
 Drug of choice for single dose treatment of onchocerciasis and
strongyloidiosis
 It is comparable to DEC for bancroftian and brugian filaria.
 It is microfilaricidal but not macrofilaricidal
 Ivermectin (0.2 mg/kg single dose) is also highly effective in cutaneous larva
migrans and ascariasis, while efficacy against Enterobius and Trichuris is
moderate.
 Add-on drug to albendazole/Mebendazole in heavy Trichuriasis.
ADVERSE EFFECTS:
 Mild pruritis
 Giddiness
 Nausea
 Abdominal pain
 Constipation
 Lethargy
 Transient ECG changes
Reactions due to degeneration products of the Microfilariae are

 Fever
 Urticaria
 Myalgia
 Edema
 Tender lymph nodes

110
6. 1ST CHOICE OF DRUGS FOR HOOKWORM INFESTATION.

 Mebendazole
 Albendazole
 Pyrantel pamoate
7. FOUR USES OF ALBENDAZOLE

 Round worm
 Pin worm
 Neurocysticercosis
 Hydatid disease
8. RATIONALE OF ALBENDAZOLE IN NEUROCYSTICERCOSIS

 Course of treatment is shorter
 Cure rates are higher
 Corticosteroids enhance the absorption of albendazole
 Cheaper

3
5. General toxicity of cytotoxic drugs

 Bone marrow: granulocytopenia, agranulocytosis
 Lymphoreticular tissue: Lymphocytopenia, inhibition of lymphocyte function –
suppression of cell mediated and humoral immunity.
 Skin: alopecia, dermatitis
 Foetus: abortion, foetal death
6. Anticancer antibiotics
 Actinomycin D
 Daunorubicin
 Epirubicin
 Mitoxantrone
7. Vinca alkaloid drugs and its uses

 Vincristine: induce remission of childhood acute lymphoblastic leukaemia
 Vinblastine: employed in Hodgkin’s disease, Kaposi sarcoma, breast and
testicular carcinoma
8. Rationale of L-asparaginase in malignancy

 Leukaemia cells were found to be deficient in L-asparagine synthase enzyme. L-
asparaginase degrades L-asparagine to L-aspartic acid depriving the leukemic
cells of essential metabolite and causes cell death.
Anticancer Agam Pharmacology

1
1. Immunosuppressant Classification, Cyclosporin
 Immunosuppressants are drugs which inhibit cellular/humoral/both

type of immune response and used in organ transplantation and
autoimmune disease.
 CLASSIFICATION
CYCLOSPORINE
I. Mechanism of action
 Inhibits T-lymphocyte proliferation, IL-2 and other cytokine production.

 Inhibits the response of T-cells to IL-1 without affecting the suppressors.
 Lymphocytes are averted in G0 and G1 phase.
Miscellaneous Drugs Agam Pharmacology

2
The CD-4 molecules associated with T-cell receptor on helper T-cells anchors
MHC-2 and activates T-cell receptor.
Activated T-cell
Phosphorlyates
PLL
Hydrolysis
PIP2  DAG + IP3
PKc  MAP Kinase release Ca2+

binds
Calmodulin
activates
Serine/Threonine phosphate
(Calcineurin)
Acts and
dephosphorylates
NFAT
NFAT permits intracellular migration and transcription of cytokine gene.
Leading to production of IL-2, interleukins, GM-CSF, TNFα.
IL-2 responsible for T-cell multiplication and diffentiation.
 Cyclosporine enters the target cells and binds to cyclophilin (immunophilin

class of protein), binds and inactivates calcineurin.  response of helper T-
cells to antigen stimulation fails.
 Cyclosporine enhances the expression of transforming growth factor β(TGF-
β) and inhibits IL-1  attenuates IL-2  stimulates T-cell proliferation 
production of killer lymphocytes.
II. Uses:
 Suppress cell mediated cell mediated immunity.
 Prevents graft rejection.
 Leaves the patient with enough immunity to combat bacterial infection.
 Unlike cytotoxic immunosuppressants it is free of toxic effect on bone
marrow and RE system.
 Humoral immunity is intact.
 2nd line of drug in autoimmune diseases.

3
III. ADR:
 It is nephrotoxic
 Impairs liver function
 Sustained rise in BP, precipitation of drugs, anemia, lethargy, hyperkalemia,
hyperuricemia, infections, hirsutism, gum hyperplasia, tumors and seizures.
IV. Drug interactions:

 Cyclosporine interacts with large number of drugs
 Nephrotic drugs like aminoglycosides, vancomycin, amphotericin B and
NSAIDs enhancing their toxicity, decreasing renal function.
 Phenytoin, phenobarbitone, rifampin and other enzyme inducers lower its
blood level that transplant rejection may result.
 CYP3A4 inhibits erythromycin, ketoconazole, and related drug inhibit
metabolism to increase bioavailability and cause toxicity.
 Potassium supplements and K+ sparing diuretics can produce marked
hyperkalemia.

2
2. Vitamin D
ACTIONS
a. Vitamin D helps in absorption of Calcium:
Calcitriol helps in absorption of Calcium and phosphorous from
intestine; in brush border surface of intestine it is absorbed by Na-Ca
exchange mechanism.
b. Effect of Vitamin D in bone:
 Mineralization of bone is increased by activity of osteoblast.
 Calcitriol co-ordinates the remodelling action of osteoblast and
osteoclast cells.
c. Effect of Vitamin D in renal tubules:
 Calcitriol increases the reabsorption of calcium and phosphorous
by renal tubules.
 Both minerals are conserved.
USES:
 Prophylaxis for vit D deficiency – 400 IU/day
 treatment of nutritional vitamin D deficiency – 3000 – 4000 IU/day
 Metabolic rickets
o Vitamin D resistant rickets – phosphate + calcitriol/ alfacalcidol (high
dose)
o Vitamin D dependent rickets - calcitriol/ alfacalcidol (normal dose)
o Renal rickets - calcitriol/ alfacalcidol/ dihydroachysterol
 Senile or post-menopausal osteoporosis – calcitriol therapy
 Hypoparathyroidism - calcitriol/ alfacalcidol/ dihydroachysterol
 Fanconi syndrome
 Plaque type psoriasis - calcipotriol

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General Pharmacology Agam Pharmacology

General Pharmacology Agam Pharmacology

10. Orphan drugs:

General Pharmacology Agam Pharmacology

Biotransformation of the drug may lead to:

Biotransformation reactions are classified into:

General Pharmacology Agam Pharmacology

Drugs that undergo hydrolysis are lidocaine, pethidine, oxytocin etc.

General Pharmacology Agam Pharmacology

Non microsomal enzymes:

▪ These enzymes are deficit in new born especially in premature.

General Pharmacology Agam Pharmacology

3. FIRST PASS METABOLISM

Prevention: By sublingual, transdermal or parenteral routes.

Hepatic extraction ratio (ER Liver):

Systemic bioavailability (F) = Fractional absorption × (I ― ER)

Attributes of drugs with high first pass metabolism:

General Pharmacology Agam Pharmacology

6. New drug delivery system:

• Drug releasing implants:

General Pharmacology Agam Pharmacology

General Pharmacology Agam Pharmacology

• Usually seen in indirectly acting drugs (Ephedrine, Tyramine, Nicotine

General Pharmacology Agam Pharmacology

1. GENERAL DETOXIFICATION AND SUPPORTIVE MEASURES:

A. Resuscitation and maintenance of vital functions:

C. Prevention of absorption of ingested poisons:

General Pharmacology Agam Pharmacology

• It is related to collection, detection, assessment, monitoring & prevention of

• AVOID INAPPROPRIATE USE IF DRUGS

General Pharmacology Agam Pharmacology

General Pharmacology Agam Pharmacology

7. Chronic Organophosphate poisoning

ANS Agam Pharmacology

1. Anti cholinergic drugs

ANS Agam Pharmacology

ANS Agam Pharmacology

Side effects and Toxicity:

ANS Agam Pharmacology

ANS Agam Pharmacology

Therefore, ipratropium is more effective in COPD than in bronchial asthma.

ANS Agam Pharmacology

ACTIONS- mediated through alpha and beta receptors:

Alpha actions Beta actions

ANS Agam Pharmacology

Blood vessels contraction relaxation

ANS Agam Pharmacology

➢ Ephedrine/ mephentermine – causes vasoconstriction and also

➢ Adrenaline - drug of choice in Anaphylaxis (0.5mg i.m.)

c) Adjuvant in local anesthetic – adrenaline is used

d) Control of local bleeding

• Cardiac arrest- Adrenaline

3. Bronchial asthma and COPD: Adrenergic β2 stimulants.

4. Allergic disorders: Adrenaline- antagonizes histamine

ANS Agam Pharmacology

ANS Agam Pharmacology

• Cardiac work and O2 consumption are reduced as the product of heart

ANS Agam Pharmacology