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 Concept Based Learning
Video Companion on Each Chapter

Next Generation

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Comprehensive Review Series

“PHARMACOLOGY”
Active Recall Based
Integrated Edition
Published by Delhi Academy of Medical Sciences (P) Ltd.

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ISBN : 978-93-89309-28-7

First Published 1999, Delhi Academy of Medical Sciences

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 Contents
Chapter 1 General Pharmacology 1-35
Chapter 2 Autonomic Nervous System 36-74
Chapter 3 Respiratory System 75-86
Chapter 4 Autacoids 87-110
Chapter 5 Cardiovascular System 111-132
Chapter 6 Blood 133-147
Chapter 7 Diuretic & Anti 148-154
Chapter 8 Central Nervous System 155-197
Chapter 9 Endocrine System 198-225
Chapter 10 GastroAfraTafreeh.com
Intestinal System 226-241
Chapter 11 Antimicrobials 242-307
Chapter 12 Anticancer Drugs 308-338
Chapter 13 Immunomodulators 339-347
Chapter 14 Special Topics Drugs Useful for Obesity 348-351
AfraTafreeh.com
 1 General Pharmacology

CONCEPTS
 Concept 1.1 General Introduction

 Concept 1.2 Pharmacokinetics

(drug absorption, distribution,
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metabolism and excretion)

 Concept 1.3 Pharmacodynamics

 Concept 1.4 Drug development

 Concept 1.5 Adverse drug reactions

2 | Pharmacology
Concept 1.1 : Introduction
Learning objectives: To know the scientists name who contributed invention related


pharmacology
To study the components of prescription
To know the different nomenclature of drug name

Time Needed
1st reading 15 mins
2 reading
nd
5 mins

Contributions of Scientists:
1 Oswald Schmiedeberg Father of Pharmacology.
Propounded some of the fundamental concepts of pharmacology.

2 Colonel Ram Nath Father of Indian Pharmacology.

Chopra Established the first center for study and research in pharmacology in India, at
the Calcutta School of Tropical Medicine.

3 Sir James Black Father of Modern Pharmacology

4 Langley Observed the mutual antagonism of atropine and pilocarpine in 1878, and
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proposed that both acted on the same ‘receptive substance’ or ‘receptor’ on
the cell.

5 Clarke Propounded receptor occupation theory in 1937.

6 Rudolph Buchheim Founded the first institute for research in pharmacology in Germany in 1847.

7 Otto Loewi transmission across nerve junctions to be mediated by neurotransmitters

8 Ahlquist Classified adrenergic receptors into α and β types.

Components of a Prescription:
Part of prescription Refers to

Superscription Rx. It means ‘take thou’. It is a tribute to Lord Jupiter

Inscription Main body of the prescription

Subscription Specific instructions to the pharmacist

Signatura / Transcription Specific instructions to the patient

 General Pharmacology | 3

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Fig.1.1

Different Names for Drugs:

Name of drug Refers to

1 Chemical name Structure of the drug

2 Generic name Non-proprietary name of the drug

3 Brand / Trade name Proprietary name

For example:
• Chemical name- Acetyl salicylic acid
• Generic name- Aspirin
• Brand name- Ecosprin
4 | Pharmacology
Definitions:
1. Drug – 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
(WHO, 1966).
ORPHAN DRUGS:-used for diagnosis/treatment/prevention of a rare disease or
condition(Fomepizole, digibind, liothironine)
Essential drugs- Drugs that meet health needs of the majority of population,
it should be affordable by all people and it should be available in all time,
most of the essential drugs prepared as single compound.
2. Pharmacology – The science of drugs that deals with the interaction of exogenously
administered chemical molecules with living systems.
3. Pharmacy – The art and science of compounding and dispensing drugs or preparing
suitable dosage forms for administration of drugs to man or animals. It includes
collection, identification, purification, isolation, synthesis, standardization and quality
control of medicinal substances.
4. Pharmaceutics – The large scale manufacture of drugs.
5. Pharmacotherapeutics – The application of pharmacological information together
with the knowledge of the disease for its prevention, mitigation or cure.
6. Clinical pharmacology – The scientific study of drugs (both old and new) in man.
7. Toxicology – The study of poisonous effect of drugs and other chemicals (household,
environmental pollutant, industrial, agricultural, homicidal) with emphasis on
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detection, prevention and treatment of poisonings.
8. Pharmacovigilance (PV or PhV), also known as drug safety, is the
pharmacological science relating to the collection, detection, assessment,
monitoring, and prevention of adverse effects with pharmaceutical products.

One-liners:
Greek word: Pharmacon – Drug
French word: Drogue – Dry herb
The first ‘Model List of Essential Drugs’ was brought out by the WHO in – 1977
Current Model List of Essential Drugs – 17th (2011)
National Essential Drugs List released by India in – 1996
Current national list of essential medicines in India contains – 348 drugs
 General Pharmacology | 5
Concept 1.2 : Pharmacokinetics:
Learning objectives: To know the components of pharmacokinetics
To know the factors modifying absorption of drug
To know the different methods of drug transport
To know the various factors that modify drug distribution
To know the clinical importance protein bind of drugs
To know the different types drug metabolism
To know th clinical importance of microsomal enzyme
To know orders of kinetic of excretion
To know the importance of half life of the drug

Time Needed
1 reading
st
40 mins
2 reading
nd
20 mins

Definition: The quantitative study of drug movement, in, through and out of the body.
• Includes – (Mnemonic: ADME)
• Absorption
• Distribution
• Metabolism
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• Excretion
Note: Some scientists prefer to include dissolution of drugs also in pharmacokinetics
(DADME)

(A) Absorption:
The two major factors that are responsible for drug absorption include lipid solubility
and Non-Ionisation.
Non ionisation of drug is depends upon pH of the environment ( acidic drug become non
ionised in acidic medium, basic drugs become non ionised in basic medium).
strongest acidic drugs and strongest basic drugs always seen in ionised form.
Site of absorption for orally administered drugs:
Weakly acidic drugs like aspirin, barbiturates arenonionised in acidic media, so they are
well absorbed from stomach.
• Weakly basic drugs---morphine, diazepam --- non ionised in alkaline pH------absorbed
from duodenum.
• Most common site of drug absorption: Upper duodenum (because intestine has
large surface area and thin mucosa than stomah).
6 | Pharmacology

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Fig. 1.2

• Conversely, Alkalinisation of urine is done for excretion of acidic drugs.

• Acidification of urine can be done for excretion of basic drugs, but not practically
advised due to increased risk of renal stone formation.

E.g. of acidic drugs E.g. of basic drugs

Sulfonamides Morphine
Barbiturates Atropine
NSAIDs Amphetamines
Penicillin V Ephedrine
Chloroquine
Polymyxin B
Vancomycin
 General Pharmacology | 7
Drug Transport:
1. Simple passive diffusion(no need of energy or carrier)
2. Facilitated passive diffusion(carrier dependent, no need of energy)
3. Active transport (energy and carrier dependent)
4. Pinocytosis (cell drinking process)
ƒ Most common method of drug absorption: Simple diffusion
ƒ Simple diffusion is quantified using: Fick’s law
Fick’s law: R = (ΔC x A x P) / T, where
• R = Rate of simple diffusion across a membrane
• ΔC = Concentration gradient across the membrane
• A = Surface area available for diffusion
• P = Permeability coefficient of the drug (indicates its lipophilicity)
• T = Thickness of the membrane

Drugs which are absorbed by active Transport:

• Levodopa
• α-Methyldopa

One-liners: AfraTafreeh.com
• pH independent transport is seen for – Ethanol and Diethyl ether
• Alcohol absorption is from – Small intestine > Stomach

Bioavailability(F):
• Percentage of administered drug that enters the systemic circulation in unchanged
form.
• Expressed as percentage (It has no units).
• Denotes – Rate and extent of drug absorption.
• Depends upon
ƒ Route of administration (Most important).
ƒ Local binding to proteins or other structures.
ƒ First pass metabolism.
• Route with maximum bioavailability – Intravenous (100% or 1 as entire drug is
administered directly into systemic circulation).
• Formula: Froute = AUCroute / AUCIV
8 | Pharmacology

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Fig. 1.3: Plasma concentration versus time curve of a drug after a single dose

C max- Maximum plasma concentration obtained.

T MAX- is the time to reach C max (rate of absorption).
AUC- bioavailability(extend of absorption).

Fig. 1.4
 General Pharmacology | 9
Same drug, same dose, same dosage forms-on comparison not having more
than 20%- difference in bio availability means it is called as Bioequivalent.
Factors decreasing oral bioavailability of drugs:
1. Decreased oral absorption
2. High first pass metabolism
1. Decreased oral absorption. This could be due to –
ƒ Polar nature of drugs (E.g: Amino­glycosides).
ƒ Cleavage in stomach by acid (e.g: Penicillin G, Erythromycin, PPI).
ƒ Metabolism by enzymes in GIT (e.g: Insulin, Vasopressin).
ƒ Presence of other drugs (e.g: Calcium decreases absorption of tetracyclines;
antacids decrease absorption of digoxin).
ƒPresence of food ( exception- lithium, Halofantrine, griseofulvin,fibrates and
some more drugs(look at the table)- these drugs will be more absorbed in
the presence of food).

Food decreases absorption of Food increases absorption of

• Ampicillin • Carbamazepine
• Captopril • Griseofulvin (fatty food)
• Digoxin • Lithium
• Isoniazid • Lumefantrine
• Levodopa
AfraTafreeh.com• Nitrofurantoin
• Rifampicin • Riboflavin
• Tetracycline • Fibrates
• Erlotinib

2. High first pass metabolism:

Extent of first pass metabolism:

Low Intermediate High

Not given orally Given orally in high doses

Phenobarbitone Aspirin Hydrocortisone Propranolol

Phenylbutazone Quinidine Isoprenaline Alprenolol
Pindolol Desipramine Lignocaine Salbutamol
Tolbutamide Metoprolol Testosterone Verapamil
Theophylline Nortriptyline Nitroglycerine
Isosorbidemononitrate Chlorpromazine Morphine
Pentazocine Pethidine
Methyltestosterone
Propoxyfene
10 | Pharmacology

One-liners:
• Route with highest first pass metabolism – Oral
• Most common site of first pass metabolism on oral administration – Liver
• First pass metabolism in small intestine occurs with – Levodopa
• Rectally given drug absorbed through External hemorrhoidal vein mean - no first metabolism
HENDERSON HESSELBACH EQUATION-pKa = pH +log( ionized A-)/( un ionized HA)
pKA = pH means what is the inference?- 50% of drug is in the ionized form & 50% non ionized form

(B) Distribution:

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Fig. 1.5

Low volume of distribution Large volume of distribution

Fig. 1.6 Fig. 1.7

Drugs having large volume of distribution for rapid action needs loading dose (loading
dose is depend upon Vd)
There is no role for hemodialysis for drugs having large Vd
 General Pharmacology | 11
Volume of distribution (Vd):
• Formula – Dose administered / Immediate plasma concentration
• Expressed in litres or litres/kg body weight
• Indicates – Extent of tissue penetration of drug
• Greater the volume of distribution, more is the tissue penetration

Scenario Volume of distribution Examples

Drug is highly bound to Vd = Plasma volume Warfarin LowVd

plasma proteins (3L or 0.15L/kg) Diclofenac

Drug is restricted to Vd = Blood volume (5L) Heparin Low Vd

intravascular compartment Streptokinase Removed by hemodialysis

Drug is distributed in the Vd = ECF volume Aminoglycosides

extracellular fluid (15L or 0.25L/kg)

Drug penetrates into the Vd> ECF volume Digoxin (6L/kg) High Vd
tissues (>15L or >0.25L/kg) Propranolol (4L/kg) No role for dialysis
Morphine (3.5L/kg)

Factors governing volume of distribution of drugs:

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• Lipid:water partition coefficient of the drug (Lipophilicity)
• pKa value of the drug
• Degree of plasma protein binding
• Affinity for different tissues
• Fat:lean body mass ratio (varies with age, sex, obesity)
• Systemic diseases (CHF, uremia, cirrhosis of liver)

Plasma protein binding of drugs:

Acidic drugs binds with albumin.
Basic drugs binds with alpha1 acid glycoprotein.
Each molecule of albumin has two binding site (can able to accomadate two acidic drug)
In hypo albunemia (nephrotic syndrome, liver failiure), free level of acidic drug will be
high.
• Usually prolongs the half-life due to delayed metabolism and excretion.
• Free form is responsible for therapeutic effect and toxicity.
• Bound form acts as a reservoir.
12 | Pharmacology
Drugs highly bound to plasma proteins:
To albumin To α1-acid glycoprotein

Barbiturates β-blockers
Benzodiazepines Bupivacaine
NSAIDs Disopyramide
Penicillins Imipramine
Phenytoin Lignocaine
Sulfonamides Methadone
Tetracyclines Prazosin
Tolbutamide Quinidine
Valproate Verapamil
Warfarin

Distibution / Accumulation of drugs in various tissues:

Organ Drugs getting concentrated

Skeletal muscle, heart • Digoxin

• Emetine

Liver
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• Chloroquine
• Digoxin
• Emetine
• Tetracyclines

Kidney • Chloroquine
• Digoxin
• Emetine

Thyroid • Iodine

Brain • Acetazolamide
• Chlorpromazine
• Isoniazid

Retina • Chloroquine (bound to nuceloproteins)

Iris • Atropine (bound to melanin)

• Ephedrine

Bones and teeth • Bisphosphonates (bound to hydroxyapatite)

• Heavy metals (bound to mucopolysaccharides of connective tissue)
• Tetracyclines
 General Pharmacology | 13

Adipose tissue • DDT

• Ether
• Minocycline
• Phenoxybenzamine
• Thiopentone

Bone • Tetracycline
• Lead
• Arsenic
• Radium

Redistribution:
• Seen with highly lipid soluble drugs.
• Get distributed immediately to organs of high blood flow followed by redistribution to
organs of lower blood flow.
• Rapid onset and rapid termination of action of drug.
• E.g: thiopentone sodium.
• Drugs that can be eliminated by hemodialysis.

• Carbamazepine • Ethylene glycol

• Lithium AfraTafreeh.com
• Methyl alcohol (Methanol)
• Phenobarbitone • Salicylates
• Theophylline
• Valproate

Drug that cannot be removed by dialysis:

A- amphetamine
V- Verapamil
O- Opioids, OPC
I- impramine (TCA)
D- digoxin
Dialysis-
Diazepam(BZD)
Blood Brain Barrier absent -- Pituitary, Pineal, Area Prostrema CTZ,
Median Eminence(example for drugs which never cross BBB-Streptomycin,
neostigmine, glycopyrolate, dopamine)

(C) Metabolism:
Conversion of lipophilic moiety into hydrophilic one, so that excretion is
possible.
14 | Pharmacology
Fate of drug during metabolism:
1. Active drug converted to inactive metabolite (Most common)

2. Active drug converted to active metabolite

Active drug Active metabolite

Allopurinol Alloxanthine (Oxypurinol)

Amitryptyline Nortriptyline

Cefotaxime Desacetylcefotaxime

Chloral hydrate Trichloroethanol

Codeine Morphine

Diazepam Desmethyl diazepam, Oxazepam

Digitoxin Digoxin

Imipramine Desipramine

Losartan E3174

Morphine Morphine-6-glucuronide

Primidone
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Phenobarbitone, Phenylethylmalonamide

Procainamide N-acetylprocainamide

Spironolactone Canrenone

3. Inactive drug (Prodrug) converted to active metabolite

Prodrug Active metabolite

Acyclovir, Valacyclovir Acyclovir triphosphate

Famcilovir Penicyclovir

Bacampicillin Ampicillin

Cyclophosphamide Aldophosphamide, Phosphoramide mustard, Acrolein

Dipivefrine Epinephrine (Adrenaline)

Enalapril Enalaprilat

5-Fluorouracil Fluorouridine monophosphate

Levodopa Dopamine

6-Mercaptopurine Methylmercaptopurineribonucleotide

α-methyldopa α-methylnorepinephrine
 General Pharmacology | 15

Prednisone Prednisolone

Proguanil Cycloguanil

Sulfasalazine 5-aminosalicylic acid

Sulindac Sulindac sulphide metabolite

Metabolism of xenobiotics:
Phase 1 reactions Phase 2 reactions

Non-synthetic in nature Synthetic in nature

Metabolites of drugs are formed Conjugates of drug metabolites are formed (hence,
also called as conjugation reactions)

Products are usually lipophilic or hydrophilic Products are usually hydrophilic

Occur in microsomes Occur in cytoplasm (except glucuronidation)

E.g: E.g.:
• Oxidation ( most common Phase I reaction) • Acetylation
• Reduction • Methylation
• Cyclization AfraTafreeh.com • Sulfation
• Decyclization • Glucuronidation (most common Phase II reaction)
• Hydrolysis • Glutathione conjugation
• Glycine conjugation

One-liners:
Endogenous metabolite undergoing xenobiotic metabolism – Bilirubin

Examples of drugs undergoing acetylation (These drugs also cause lupus-like

reaction as a side effect) – (Mnemonic: SHIPP-C or CHIPPS)

• Sulfonamides + Dapsone
• Hydralazine
• Isoniazid
• Procainamide
• Para-amino salicylic acid (PAS)
• Clonazepam
• Hoffman’s elimination- Non enzymatic self degradation without the help of liver or kidney
• Example- ATRACURIUM ( safe in renal and hepatic failure)
16 | Pharmacology
Nomenclature of micosomal enzymes:

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Fig 1.8: Nomenclature of microsomal enzymes

The enzymes are named based on –

• Cytochrome – meaning coloured components of the cell (proteins are coloured
due to the presence of heme).
• P450 – Peak light absorption at 450 nm wavelength.
• Family number.
• Sub-family number.
• Individual enzyme number.
CYP450 enzymes primarily involved in drug metabolism and drugs metabolized
by them:
Enzyme Drugs metabolized by the enzyme
CYP3A4 Most of the drugs
CYP2D6 • Neuroleptics
• Tricyclic antidepressants (TCAs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Antiarrhythmics
• β-blockers
• Codeine converted into morphine by CYP2D6
• Tamoxifen activated by CYP2D6 (Fluoxetine inhibits CYP2D6 ), fluoxetine inter-
fere with tamoxifen activation
 General Pharmacology | 17

CYP2C8/9 • Phenytoin
• Warfarin
• Carbamazepine
• Ibuprofen
• Tolbutamide
• Repaglinide
• Celecoxib
• Losartan
CYP2C19 • Omeprazole
• Clopidogrel(pro drug) activated with the help of CYP2C19(omeprazole interfere the
activation of clopidogrel, Pantaprazole, Rabeprazoledonot hasno drug interaction with
clopidogrel)
• Voriconazole
• Phenytoin
• Diazepam
• Propranolol
CYP1A1/2 • Procarcinogens to carcinogens
• Theophylline
CYP2E1 • Paracetamol to NABQI (N-acetyl-p-benzoquinonimine- hepatoto toxic metabolite)
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• Alcohol will induce CYP2E1, so chronic alcoholic are more prone for hepatotoxicity
with paraeetamol

Examples of CYP enzyme inducers and inhibitors –

CYP inducers CYP inhibitors
• Rifampicin • Ketoconazole
• Griseofulvin • Itraconazole
• Phenytoin • Erythromycin
• Phenobarbitone • Clarithromycin
• Carbamazepine • Ciprofloxacin
• Cigarette smoke (CYP1A1/2) Verapamil
• Chronic alcoholism • Diltiazem
• St john’s wort(natural antidepressant) • Cimetidine
• Ranitidine
• Valproate
• HIV protease inhibitors (most potent is RITONAVIR)
• Grapefruit juice
• Isonaizid (for all CYP enzymes except CYP2E1)

One-liners:
• PPI prevent activation of – clopidogrel (as both are metabolized by CYP2C19
• Drugs precipitating paracetamol toxicity – Isoniazid , zidovudineand Alcohol
18 | Pharmacology
(D) Excretion:
Most important organ for drug excretion – Kidney
First-order kinetics Zero-order kinetics = Saturation kinetics
A constant fraction of the drug is excreted in unit A constant amount of the drug is excreted in unit
time time
Rate of excretion is directly proportional to the Rate of excretion is constant and independent of
plasma concentration; also varies in the same plasma concentration
direction with changes in drug dose
T½ is constant T½ increases with increase in dose of the drug
Clearance is constant Clearance decreases with increase in dose of the
drug
Fall in plasma concentration is exponential Fall in plasma concentration is linear

Examples of drugs following zero-order kinetics:

• Alcohol , Aspirin • Phenytoin
• Theophylline • Tolbutamide
• Warfarin

One-liners:
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• Alcohol is the only drug that follows zero-order kinetics in all doses.
• Other drugs only follow at high doses – hence, also called as ‘pseudo-zero order’ kinetics.

Clearance of a Drug:
•Volume of plasma that is completely cleared of the drug in unit time.
•Expressed in – volume per unit time (conventionally mL/min).
•Denotes the – ability of the human body to excrete the drug.
•Formula for renal clearance –
CL = UV/P
U = Urinary concentration of drug
P = Plasma concentration of drug
V = urine flow rate
Drugs Excreted Partly via Saliva and Sweat:
• Lithium • Potassium iodide
• Rifampicin • Heavy metals

HALF-LIFE / T½ (also known as elimination half-life):

• Time taken for the plasma concentration of the drug to decrease to half.
• Measured in units of – time (minutes, hours, days, etc).
• Denotes the – rate of drug elimination.
 General Pharmacology | 19
• Also denotes the duration of action of the drug.
• In first order kinetic 97% drug is eliminated after 5 half life.
• Regarding absorption, after 5 half lives – the drug reaches steady state plasma level
97%.
• Formula –
ƒ T½ = (0.693 x Vd) / CL.
Hit and run drugs – have short half-lives but long durations of action.
E.g.:

• MAO inhibitors
• PPIs(half life 2-4hrs, but acting for 24 hrs, due to irreversible inhibiton of protonpump)
• Guanethidine
• Reserpine
• Anti-platelet effect of aspirin

Percentage of drug eliminated in successive half-lives:

Half-life Percent of drug eliminated
1 50
2 75
3
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87.5
4 93.75
5 96.875

One-liners:
Almost complete elimination of drug occurs in – 5 T½ OR 4-5 T½

Steady-state Concentration of Drug (Cpss):

• Concentration at which fluctuation of drug levels in plasma is considered negligible.
• Also known as Target Cpss as clinicians aim to attain this drug concentration in plasma.
• Attained after – 5 T½ OR 4-5 T½.
Formulae:
• Loading dose formula = (Cpss x Vd).
• Maintenance dose formula = (Cpss x CL).

One-liners:
• Loading dose depends up on – Volume of distribution
• Maintenance dose depends up on – Clearance
20 | Pharmacology

Concept 1.3 : Pharmacodynamics

Learning objectives: To study the effect of drug in the body
To know the clinical importance of log dose response curve
To study the different types of receptor
To know the importance of therapeutic index

Time Needed
1 reading
st
25 mins
2 reading
nd
10 mins

Definition – The study of drug effects on the human body.

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Fig 1.9: Dose response curve and log dose response curve

Dose Response Curve (DRC):

• Magnitude of effect produced by the drug (Y-axis) is plotted against the dose of the
drug (X-axis).
• Shape – Parabolic.
Log Dose Response Curve (Log DRC):
• Magnitude of effect produced by the drug (Y-axis) is plotted against the logarithm of
the dose of the drug (X-axis).
• Shape – Sigmoid.
Advantages of Log DRC Over DRC:
1. Central portion of the graph is a straight line; therefore, the response increases
linearly with the logarithm of the dose.
2. A wider range of drug doses can be plotted.
3. Comparison between agonists and antagonists becomes simple.
 General Pharmacology | 21
Pharmacodynamic Parameters Defined From Log DRC:
• Potency– The dose of the drug at which the response starts appearing.
Whichever drug produces response at a lower dose is said to be more potent.
2. Efficacy–The maximum response produced by a drug.
Whichever drug produces a greater maximum response is said to be more efficacious.

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Fig 1.10: Potency and efficacy of drugs

In the above Figure, Drug A is more potent while Drug B is more efficacious.
Quantal dose response curve – The percentage of population showing a response is
plotted against the logarithm of the dose of the drug.
Pharmacodynamic Parameters Defined From Quantal DRC:
1. Effective dose 50 (ED50) – Dose which produces therapeutic response in half (50%)
of the population.
Indicates – Potency of the drug.
2. Lethal dose 50 (LD50) – Dose which produces toxicity (toxic effect) in half (50%) of
the population.
Indicates – Safety of the drug.
Maximum response (height of the curve) - efficacy.
22 | Pharmacology

Fig 1.11:Quantal dose response curves for therapeutic and toxic effects of a drug

In the above figure, point A represents ED50 while point B represents LD50.

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Fig. 1.12

Therapeutic Index (TI):

• Formula: LD50/ED50.
• Best indicator of safety of drug.
 General Pharmacology | 23
E.g. of drugs with narrow therapeutic index: (Mnemonic: DAT-LAAT).

• Digoxin
• Antiarrhythmics
• Theophylline
• Lithium
• Aminoglycosides
• Anti-epileptics
• Tricyclic antidepressants

Action of Drugs in Receptors:

Drug Effect Intrinsic activity

Agonist Induces active conformation 1

Partial agonist Induces partially active conformation 0 to 1

Antagonist No effect on receptor 0

Inverse agonist Induces inactive conformation Negative (0 to -1)

Classification of receptors on the basis of location:

Intranuclear AfraTafreeh.com
Intracytoplasmic Located on the cell surface
(located in nucleus) (located in cytoplasm)

• Vitamin A • All steroid hormones except • Rest all

• Vitamin D estrogen
• Thyroxine
• Estrogen
• PPAR

One-liners:
• Testosterone and progesterone receptors were originally thought to be cytoplasmic in
location; now proposed to be nuclear in location (not convincingly proven).
• Steroid hormone receptors are called nuclear receptors as – They act at the level of
nucleus to modulate transcription.
• All amine hormones act on cell membrane except thyroid hormone (acts on nucleous).

Classification of cell surface receptors on the basis of second messenger/s:

1. G-protein coupled receptors (GPCRs) (serpentine in shape).
2. Ion channels.
3. Tyrosine kinase coupled receptors.
4. JAK-STAT coupled receptors.
24 | Pharmacology
Examples of receptors that act as ion channels:

• Nicotinic cholinergic (NM and NN)

• GABAA
• Glycine
• Excitatory glutamate (Kainate, NMDA, AMPA)
• 5-HT3

Example for GPCR (G protein coupled receptor).

Muscarinic receptors ( M2, M4- Gi pathway, M1, M3, M5 – Gq pathway).
Beta receptors (Gs pathway).
Alpha 2 receptor ( Gi pathway).
Alpha 1 receptor (Gq pathway).
Enzyme linked receptor (Tyrosine Kinase).
Insulin.
Examples of molecules that act through JAK/STAT receptors:

• Growth hormone
• Prolactin
• Interferons
• Many cytokines AfraTafreeh.com
Examples of chemical antagonism:

• Chelating agents complex toxic heavy metals.

• KMnO4 oxidizes alkaloids during gastric lavage in case of alkaloid poisoning.
• Tannins form insoluble alkaloid altannates with alkaloids in case of alkaloid poisoning.
• Methemoglobin reacts with cyanide to form cyanmethemoglobin.

Example of physiological antagonism.

Adrenaline antagonism on histamine action in anaphylactic shock.
Drugs that may react when mixed in the same syringe or infusion bottle:

• Thiopentone sodium + Succinylcholine chloride

• Penicillin G sodium + Succinylcholine chloride
• Heparin + Penicillin / Tetracyclines / Streptomycin / Hydrocortisone

Therapeutic drug monitoring (TDM): Monitoring for the plasma levels of the drug at
regular intervals.
Indications:
1. Drugs with narrow therapeutic index.
2. Drugs with a high inter-individual variation in plasma concentrations.
 General Pharmacology | 25
3. Drugs whose therapeutic effect cannot be determined clinically.
4. Nephrotoxic drugs are to be administered in patients with renal failure.
5. Monitoring of patient compliance (best method).
6. Diagnosis of toxicity.
TDM is not required in case of :
1. Drugs whose therapeutic effect can be determined clinically (e.g.: Warfarin – PT-INR
can determine its therapeutic effect).
2. Pro-drugs.
3. Drugs with irreversible action.
4. Drugs with hit-and-run effect.
E.g. of drugs requiring TDM: (Mnemonic: DAT-LAAT-MC)
• Digoxin
• Antiarrhythmics
• Theophylline
• Lithium
• Aminoglycosides

• Anti-epileptics
• Tricyclic antidepressants
• Methotrexate
• Calcineurin inhibitors
AfraTafreeh.com
26 | Pharmacology
Concept 1.4 : Drug development
Learning objectives: To study the various phases of clinical trial

Time Needed
1st reading 20 mins
2 reading
nd
10 mins

Clinical Trials:
Mandatory / Compulsory phases of clinical trials :
Phase Also known as Approximate number of
participants

1 Human pharmacology and safety 20 – 80

2 Therapeutic exploration and dose ranging 100 – 500

3 Therapeutic confirmation / comparison 500 – 3000

4 Post-marketing surveillance General population

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Mandatory / Compulsory phases of clinical trials :
Phase Conducted on To determine

1 Small group of healthy individuals Safety

Pharmacokinetics
Pharmacodynamics

2 Small group of patients Efficacy

Safety

3 Large group of patients Efficacy

Safety

4 Post-marketing surveillance Rare adverse effects

Chronic adverse effects
Effect of the drug on special populations

One-liners:
• Best phase for determining drug efficacy – Phase 3 (due to large sample size).
• Best phase for determining drug safety – Phase 3 (due to large sample size).
• Minimum mandatory duration of Phase 4 studies – 2 years.
 General Pharmacology | 27
Optional Phases of Clinical Trials:
Phase Conducted on To determine
Pre-clinical Laboratory animals Effect of the drug on animals
0 Small group of healthy volunteers Pharmacokinetics – specifically
(Microdosing – a sub-therapeutic dose is bioavailability
administered)
5 Effectiveness research Active reporting of effectiveness of drug in
different populations

One-liners:
• Investigational new drug (IND) – Application to conduct a human study for a new
drug.
• IND is submitted between – Pre-clinical studies and Phase 1.
• New drug application (NDA) – Application for marketing a new drug.
• NDA is submitted between – Phase 3 and Phase 4.

Regulation of Clinical Trials:

Good clinical practices Set of guidelines to be followed while Not applicable for –
(GCP) conducting a clinical trial Pre-clinical studies
Good laboratory practices AfraTafreeh.comNot applicable for –
Set of guidelines to be followed while
(GLP) working in a laboratory Phase 4
CPCSEA (Committee for the Purpose of Control and Supervision on Experiments
in Animals) GUIDELINES FOR PRECLINCAL STUDIES-
28 | Pharmacology
Concept 1.5 : Adverse drug reactions
Learning objectives: To study the classification of adverse drug reaction
To know about pharmacogenomic reaction
To study about teratogenicity

Time Needed
1 reading
st
20 mins
2nd reading 10 mins

Classification of ADR:
TYPE A- augmented )reactions:Eg.Hypoglycemia with insulin.
Constipation with morphine.
TYPE B (bizarre) reactions:Eg.anaphylaxis- penicillin allergy.
TYPE C(chronic) reactions: Eg.tardive dyskinesia with Neuroleptics.
Analgesic nephropathy.
TYPE D (delayed) reactions: Eg.teratogenesis, carcinogenesis:
Diethylstilbestrol, thalidomide
TYP E (end of use) reactions: Eg.adrenocortical insufficiency due to sudden withdrawal
of corticosteroids.
TYPE F (failure of drug action)
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Fig. 1.13

One-liners:
• In India, pharmacovigilance programme is conducted by – Central Drugs Standards
Control Organization (CDSCO).
• International collaboration centre for reporting of ADRs – Uppsala Monitoring Centre
in Sweden.
• Central Drugs Laboratory in India situated in – Kolkata.
 General Pharmacology | 29
Phototoxicity and Photoallergy:
Phototoxicity Photoallergy
Drug or its metabolite accumulates in the skin Drug or its metabolite induces a T-cell mediated
↓ immune response
Absorbs light and undergoes a photochemical ↓
reaction Exposure to light
↓ ↓
Damage to surrounding skin Papular or eczematous contact dermatitis-like
lesions
Occurs on exposure to UV-B (290 – 320 nm) Occurs on exposure to UV-A (320 – 400 nm)
More common Less common
Short duration after exposure Long duration after exposure
E.g : E.g :
• Amiodarone • Chloroquine
• Dapsone • Chlorpromazine
• Sulfonamides • Carbamazepine
• Fluoroquinolones • Griseofulvin
• Nalidixic acid • Sulfonamides
• Phenothiazines • Sulfonulyureas
• Thiazides
AfraTafreeh.com
• Tetracyclines
• Tar products

Examples of Pharmacogenetic Considerations:

1. Atypical pseudocholinesterase or pseudocholinesterase deficiency can cause prolonged apnea due to
succinylcholine.
2. G6PD deficiency can cause hemolysis due to certain drugs.
3. Low activity of CYP2C9 leads to reduced warfarin metabolism and increased risk of bleeding.
4. Thiopurinemethyltransferase (TPMT) deficiency increases risk of severe bone marrow toxicity due to
6-mercaptopurine and azathioprine.
5. UGT1A1*28 allele of UDP-glucuronosyl transferase increases the risk of diarrhea due to irinotecan.
6. Severe 5-fluorouracil toxicity occurs in patients with dihydropyrimidine dehydrogenase (DPD)
deficiency.
7. Over-expression of p-glycoprotein results in tumour resistance to many cancer chemotherapeutic agents.
8. Polymorphism of N-acetyltransferase-2 (NAT-2) results in rapid and slow acetylator status of isoniazid.
9. Acute intermittent porphyria is precipitated by barbiturates due to genetic defects in repression of
porphyrin synthesis.
10. CYP2D6 abnormality causes poor metoprolol / debrisoquin metabolizer status.
11. Malignant hyperthermia after halothane is due to abnormal calcium release channel (ryanodine receptor)
in the sarcoplasmic reticulum of skeletal muscles.
12. Genetic inability to hydroxylate phenytoin can lead to toxicity at usual doses.
30 | Pharmacology

13. Resistance to coumarin anticoagulants is due to an abnormal VKOR1 that is less sensitive to the
coumarins.
14. Attack of angle closure glaucoma is precipitated by mydriatics in individuals with narrow iridocorneal
angle.
15. HLAB5701 in this alle patient - abacavir causing SJS.

Drugs Causing Hemolysis in G6PD Deficiency:

Group Definite risk Possible risk Doubtful risk

Antimalarials Primaquine, Chloroquine Quinine

Dapsone /
Chlorprogaunil

Sulfonamides Sulfomethoxazole, Sulfasalazine, Sulfisoxazole,

Other sulphonamides, Sulfadimidine Sulfadiazine
Dapsone

Antibacterials Cotrimoxazole, Ciprofloxacin, Chloramphenicol,

Nalidixic acid, Norfloxacin p-amino salicylic acid
Nitrofurantoin, (PAS)
Niridazole
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Analgesics / Acetanilide, Acetylsalicylic acid Acetylsalicylic acid
Antipyretics Phenazopyridine (Aspirin) >3g/d (Aspirin) <3g/d,
Acetaminophen
(Paracetamol),
Phenacetin

Others Naphthalene, Vitamin K analogues, Doxorubicin,

Methylene blue, Ascorbic acid >1 g Probenecid
Rasburicase

US FDA Risk category of drugs during pregnancy:

Category Animal studies Human studies Examples

A (No risk to Not teratogenic OR Not teratogenic • Magnesium sulfate

humans) Not available • Thyroxine

B (No evidence Not teratogenic Not available • Penicillin V

of risk to • Amoxicillin
humans) Teratogenic Not teratogenic
• Cefaclor
• Erythromycin
• Paracetamol
• Lidocaine
 General Pharmacology | 31

C (Risk cannot Not available Not available • Morphine

be ruled out) • Codeine
Teratogenic Not available
• Atropine
• Corticosteroids
• Adrenaline
• Thiopentone
• Bupivacaine

D (Benefit Teratogenic Teratogenic; but use of • Aspirin

may outweigh the drug is acceptable • Phenytoin
potential risk) despite the potential risk • Carbamazepine
• Valproate
• Lorazepam
• Methotrexate

X (Risk may Teratogenic Teratogenic; use of the • Estrogens

outweigh drug is not acceptable • Isotretinoin
potential due to potential risk • Ergometrine
benefit)
• Thalidomide

Human Teratogenic Drugs:

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Thalidomide phocomelia, multiple defects of internal organs.

Anticancer drugs cleft palate, hydrocephalus, multiple defects, foetal death

(methotrexate).

Androgens: virilization; limb, esophageal, cardiac defects

Progestins: virilization of female foetus.

Stilboestrol: vaginal carcinoma in teenage female offspring.

Tetracyclines: discoloured and deformed teeth, retarded bone growth.

Warfarin: depressed nose; eye and hand defects, growth retardation

Phenytoin hypoplastic phalanges, cleft lip/palate, microcephaly.

Phenobarbitone: various malformations

Carbamazepine: neural tube defects, assorted abnormalities.

Valproate sod: spina bifida and other neural tube defects, heart and limb

Abnormalities.

Alcohol: low IQ baby, growth retardation, foetal alcohol syndrome.

ACE inhibitors: hypoplasia of organs, growth retardation, foetal loss.

32 | Pharmacology
Lithium: Epstein anomaly, foetal goiter, cardiac and other abnormalities.

Antithyroid drugs: foetal goiter and hypothyroidism.

Indomethacin / aspirin: premature closure of ductus arteriosus.

Isotretinoin: craniofacial, heart and CNS defects, hydrocephalus.

Miscellaneous
Examples of Enantiomers and their Importance:
Enantiomer Advantage claimed

S-atenolol Half dose, better tolerated

S-metoprolol Half dose

S-amlodipine Half dose, less peripheral edema

S-omeprazole (Esmoprazole) Better oral bioavailability

S-pantoprazole More potent

R-salbutamol More active, S- may antagonize R-

S-citalopram (Escitalopram)
AfraTafreeh.com
Lower dose, less side effects

S-naproxen Less burden on kidney (but inversion occurs in vivo)

Cisatracurium 4x more potent, less histamine release

Levofloxacin More active, slower elimination

Levocetrizine Half dose, only R-form active

Desloratidine Half dose

Drugs Available as Transdermal Patch:

In India Outside India

• Nitroglycerine • Isosorbidedinitrate
• Fentanyl • Hyoscine
• Nicotine • Clonidine
• Estradiol
 General Pharmacology | 33
Drugs Available as Liposomal Preparations:

• Amphotericin B
• Cytarabine
• Doxorubicin
• Daunorubicin
• Morphine
• Vincristine
• Verteporfin (Age-related ARMD)

• Verteprofin is approved for – Age-related macular degeneration (ARMD)

• Size of liposomes – 60 – 80 nM.

Young’s formula: for dosing in children:

Child dose = (Age / Age + 12) x adult dose

Dilling’s formula: for dosing in children:

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Child dose = (Age / 20) x adult dose
34 | Pharmacology

Worksheet
• MCQ OF “GENERAL PHARMACOLOGY” FROM DQB

Active recall-
Two important property needed for a drug to get
better absorptions are

Low volume of distribution means the drugs are seen

mainly in which compartment

Mention the areas in brain were blood brain barrier

is absent

AfraTafreeh.com
Thiopentone sodium has very short half life because
of

What is the active metabolite of spirnolactone

Most common phase II biotransformation reaction is

Example for drug undergoing Hoffmann degradation

is
 General Pharmacology | 35

Examples for drug undergoing zero order kinetic of

excretion are

Examples for ligand gated receptors

Location of thyroid receptor

Therapeutic index indicates

AfraTafreeh.com
In the presence of competitive antagonism what will
happen to log dose response cure

Phase IV clinical trail indicates

Malignant hyperthermia due to succinyl choline is

example for what type of adverse effect

Moebius syndrome is the teratogenicity caused by

 2 Autonomic Nervous System

CONCEPTS
 Concept 2.1 Cholinergic neurotransmission

 Concept 2.2 Muscarinic Receptor Agonists and

Antagonists

 Concept 2.3 Nicotinic receptors agonist and

antagonist
AfraTafreeh.com
 Concept 2.4 Anticholinesterase Agents

 Concept 2.5 Anti cholinergic agents

 Concept 2.6 Adrenergic neurotransmission &

classification of adrenergic

 Concept 2.7 Adrenergic receptors

 Concept 2.8 Alpha receptor agonist and

antagonist

 Concept 2.9 Beta receptor agonist and antagonist

 Autonomic Nervous System | 37
Concept 1.1: Cholinergic neurotransmission
Learning Objectives:
• Know the mechanisms o synthesis, storage, release, and destruction of Ach
• Know the sites of release of Ach as neurotransmitter

Time Needed
1 reading
st
10 mins
2nd reading 5 mins

Synthesis, Storage, Release & Metabolism Of Acetylcholine(Ach):

AfraTafreeh.com

Fig. 2.1

Steps Modified by
Choline uptake (rate limiting step) Blocked by hemicholimium
Vesicular uptake of Ach Blocked by vesamicol
Release of Ach Blocked by botulimnum toxin,
Release Increase by spider venoum

Lambert eaten syndrome Defect in the presynaptic calcium Treated by 3, 4 di aminopyridine

channel result in poor release of Ach (dalfampridine). this drug is also
useful in multiple sclerosis to improve
walking ability
38 | Pharmacology
Common drug metabolized by pseudocholinesterase
Drug Half Life Property
Ach Few seconds Not used clinically
Sch 3- 5 minutes Fastest & shortest acting SMR
Preferred in treacheal intubation
Mivacurium 15- 20 minutes Day care SMR
Remifantanyl 3- 5 minutes Day care analgesic
Esmolol ∼9 Min Ultra short acting beta blocker

AfraTafreeh.com

Fig. 2.2

Sites of release of Ach

Fibre Transmitter
All the preganglionic fibres of sympathetic and parasympathetic fibres at the Ach
ganglia
A nerve fibre supplying adrenal medulla Ach
At neuromuscular junction Ach
(NMJ).
Post ganglionic parasympathetic fibre Ach
Post ganglionic sympathetic fibres supplying sweat gland Ach
 Autonomic Nervous System | 39
Concept 2.2 : Muscarinic Receptor Agonists and Antagonists
Learning objectives:
• Know the location, functions and drugs acting on various muscarinic receptors
• Know the uses and toxicities o muscarinic receptor agonists and antagonists.

Time Needed
1 reading
st
20 mins
2nd reading 10 mins

Muscarinic receptors
Subtypes M1, M2, M3, M4 and M5 (clinically important are M1, M2 and M3), all are G
protein coupled receptors.

M1 M2 M3 M4 M5

Gq Gi Gq Gi Gq

Receptor Location Function

Muscarinic Receptors Agonist

AfraTafreeh.com
M1 Central nervous system Anterograde transmission of Oxotremorine
(post-synaptic neurons) the cholinergic impulse

Gastric glands Increased gastric acid

secretion

M2 Heart Decreased heart rate Methacholine

(-ve chronotropic effect)
Decreased
conduction
(-ve dromotropic effect)

Smooth muscles Contraction

Pre-synaptic neurons Inhibition of acetylcholine

release

M3 Exocrine glands Increased glandular secretions Pilocarpine, CEVIMELINE

Smooth muscles Contraction Bethanechol

Eye Miosis Pilocarpine

40 | Pharmacology
M1

Fig. 2.3

M2

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Fig. 2.4

M3

Fig. 2.5
 Autonomic Nervous System | 41
SMOOTH MUSCLE

AfraTafreeh.com
Fig. 2.6

EYE

Fig. 2.7
42 | Pharmacology

AfraTafreeh.com
Fig. 2.8

EFFECT OF TEST DRUG ON RABBIT EYE

Fig. 2.9
 Autonomic Nervous System | 43
EFFECT OF TEST DRUG ON RABBIT EYE

Fig. 2.10
AfraTafreeh.com
EFFECT OF TEST DRUG ON RABBIT EYE

Fig. 2.11
44 | Pharmacology
Smooth muscles in which M3 receptors cause contraction:
Smooth muscle Effect due to contraction
1 Sphincter pupillae Miosis
2 Bronchial smooth muscle Bronchoconstriction
3 GI smooth muscle Increased motility and peristalsis
4 Detrusor (urinary bladder) Voiding of urine

GLANDS

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Fig. 2.12

Relatively Selective Agonists and Antagonists:

Receptor Relatively selective agonist Relatively selective antagonist
M1 MCN-343A Pirenzepine
Oxotremorine Telenzepine
M2 Methacholine Methoctramine
Tripitramine
M3 Bethanechol Darifenacin
Solefenacin
 Autonomic Nervous System | 45

Worksheet
Location Selective agonist Selective antagonist

M1

M2

M3 GI & Bladder smooth muscle

AfraTafreeh.com

M3 EYE

M3 Exocrine glands
46 | Pharmacology
Concept 2.3 : Nicotinic receptor agonist and antagonist
Learning objectives:
• Know the location, functions and drugs acting on various nicotinic receptors

Time Needed
1st reading 10 mins
2 reading
nd
5 mins

Nicotinic receptors (Nm & Nn)

Nm receptor-
Receptor Nm

Type Ligand gated

Location Neuro muscular junction (NMJ)

Function Contraction of skeletal muscle

Agonist Phenyl trimethyl ammonium (PTMA)

Nicotine

Antagonist
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Tubocurarine
α-Bungarotoxin

Nn receptor
Receptor Nn

Type Ligand gated

Location & function Autonomic ganglia-Anterograde transmission of impulse

Adrenal medulla
Secretion of catecholamines
Central nervous system
Excitation or inhibition

Agonist Dimethyl phenyl piperazinium (DMPP)

Nicotine

Antagonist Hexamethonium
Trimethaphan
Mecamylamine
 Autonomic Nervous System | 47

AfraTafreeh.com

Fig. 2.13
48 | Pharmacology

Worksheet
To do
No depolarizing skeletal muscle relaxant acts by
blocking which receptor

Name the ganglionic blocker useful to control

smoking habbit

AfraTafreeh.com
Name the ganglionic blocker useful to produce
controlled hypotension
 Autonomic Nervous System | 49
Concept 2.4 : Anticholinesterase agents
Learning objectives:
• Know the classification of cholinergic agents
• Know the uses and toxicities o drugs and agents that inhibit AChE.

Time Needed
1 reading
st
10 mins
2nd reading 5 mins

Classification of Cholinomimetics:
Direct cholinomimetics : Directly activate the cholinergic receptors.
Indirect cholinomimetics : Increase acetylcholine levels in the synapse by decreasing
acetylcholinesterase activity
• Examples of direct cholinomimetics:
Choline esters – Alkaloids – (suffix INE)
• Acetylcholine • Muscarine
• Methacholine • Pilocarpine
• Carbachol • Arecoline
• Bethanechol • Lobeline
• Cevemeline
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Examples of indirect cholinomimetics:
REVERSIBLE – IRREVERSIBLE –
Carbamates – Organophosphates –
• Physostigmine (Eserine) • Dyflos (Di-isopropyl fluoro phosphate or DFP)
• Neostigmine • Echothiophate
• Pyridostigmine • Malathion
• Edrophonium • Diazinon
• Rivastigmine • Tabun
• Donepezil • Sarin
• Galantamine • Soman
• Acridine – • Carbamates –
• Tacrine • Carbaryl
• Propuxur

Examples of organophosphate nerve gases:

• Tabun
• Sarin
• Soman

Insecticides:
• Malathion
• Diazinon
• Parathion
50 | Pharmacology
OPC Poisoning:
• OPC inhibits cholinesterase enzyme by binding with esteritic site only.
• First line drug of choice for OPC- Atropine (dose depends upon signs and symptoms
of atropinisation).
• Oxime are cholinesterase reactivators (oxime binds with anionic site of cholinesterase
enzyme).
• Pralidoxme given 1=2gm slow IV infusion for about15-30minutes.
• Obidoxime is the most potent oxime.
• Diacetyl mono oxime is highly lipid soluble.
Oxime will not be useful for treating carbomate poisoning (because carbomate binds
both anionic aswell as esteritic site of cholinesterase enzyme
Chronic OPC poisoning may cause neurological damage due to inhibition of neuropathy
target esterase enzyme

Properties of Direct Cholinomimetics:

Drug Hydrolysis by Actions
AChE BuChE Muscarinic Nicotinic
Acetylcholine ++ + + +
Methacholine + - + ±
Carbachol - - + ++
Bethanechol -
AfraTafreeh.com
- + -

Uses of anticholinesterase
Condition Anti cholinesterase
Alzheimer’s disease – • Tacrine (causes hepatotoxicity)
• Rivastigmine
• Donepezil
• Galantamin
Atropine and Dhatura poisonings Physostigmine (lipid soluble crosses BBB)
Post-operative atony Neostigmine
• Pyridostigmine
Myasthenia gravis • Neostigmine Cobra bite
• Neostigmine
Reversal of prolonged post-operative neuro- Neostigmine
muscular blockade
Cobra bite Neostigmine + atropine
 Autonomic Nervous System | 51

Worksheet
To do
Condition Drug

Preferred anticholinesterase for myasthenia gravis

Anticholinesterase useful for diagnosis of myasthenia

gravis

AfraTafreeh.com
Drug of choice for atropine poisoning

Examples for nerve gases

52 | Pharmacology
Concept 2.5 : Anticholinergic agents
Learning objective: To know the anticholinergic drugs and their uses

Time Needed
1st reading 20 mins
2 reading
nd
10 mins

Classification of Anticholinergics:
• Direct anticholinergics – Directly antagonize the cholinergic receptors.
• Indirect anticholinergics – Decrease acetylcholine levels in the synapse.
Examples of Direct Anticholinergics:
Natural Alkaloids –
• Atropine (Hyoscyamine)
• Scopolamine (Hyoscine)
Semi-Synthetic Derivatives –
• Homatropine
• Atropine methonitrate
• Hyoscine butyl bromide
• Ipratropium bromide
• Tiotropium bromide AfraTafreeh.com
Synthetic Compounds – Mydriatics:
• Cyclopentolate
• Tropicamide(fastest and shortest acting)
Antisecretory-antispasmodics:
• Quarternary ammonium compounds – Propantheline, Oxyphenonium, Clidinium, Pipenzolate methyl
bromide, Isopropamide, Glycopyrrolate
• Tertiary amines – Dicyclomine, Valethamate, Pirenzepine
Vescioselective:
• Oxybutynin
• Flavoxate
• Tolterodine
Antiparkinsonian:
• Trihexyphenidyl (Benzhexol)
• Procyclidine
• Biperidin
 Autonomic Nervous System | 53
Comparison between atropine and hyoscine:
Property Atropine Hyoscine

1 Source Atropa belladonna, Datura Hyoscyamys niger

stramoneum

2 Alkaloidal ester of tropic acid Tropine (base) Scopine (base)

with

3 CNS effects Low dose – Mild excitation Low dose – Depression

High dose – Strong excitation High dose – Excitation

4 Anticholinergic property More potent on heart, bronchial More potent on eye and
muscle and intestine secretory glands

5 Duration of action Longer Shorter

6 Anti-motion sickness activity ++ +++

Comparison between Atropine and Glycopyrrolate:

Action Atropine Glycopyrrolate
Antisecretory ++ +++
Tachycardia +++ ++
CNS effects
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+ -
Bronchodilation ++ ++

One-liners:
• Atropine is a – Racemic mixture. But only L-atropine is biologically active.
• Scopolamine is – L-Hyoscine.
• Enzyme atropinase is present in – Rabbits
• Glycopyrrolate is devoid of CNS effects because – It is a quarternary ammounium
compound; hence does not cross blood brain barrier. Thus why it is preferred pre anaesthetic
agent
• Anticholinergic used to hasten dilation of cervix during labour – Valethamate

Examples of indirect anticholinergics:

Drug Mechanism of action
1 Hemicholinium Inhibits choline uptake by pre-synaptic nerve terminals (rate-limiting step
in ACh biosynthesis).
2 Vesamicol Inhibits active uptake of ACh into synaptic vesicles.
3 Botulinum toxin Inhibits release of ACh from pre-synaptic nerve terminals.
4 Black widow spider toxin Causes massive release of ACh from pre-synaptic nerve terminals and
hence, depletion of ACh.
54 | Pharmacology
Indications and Side Effects of Anticholinergics:
Receptor Effect Indication Side effect
M1 Decreased Drug induced Parkinson’s disease Excitement
transmission of • Trihexyphenidyl (Benzhexol) (DOC) Psychotic
cholinergic impulse • Benztropine behaviour
• Biperidin Ataxia
• H1 antihistaminics Delirium
Motion sickness Dreadful visual
• Hyoscine hallucinations
Cholinomimetic poisoning
(Organophosphorus poisoning, Carbamate
poisoning, Early type of mushroom poisoning)
• Atropine
Decreased acid Peptic ulcer disease -
secretion • Pirenzepine
• Telenzepine
M2 +ve chronotropic - Tachycardia
effect
+ve dromotropic AV block -
effect AfraTafreeh.com
Atropine
M3 Decreased exocrine Pre-anesthetic medication to reduce secretions Dry mouth
secretions • Glycopyrrolate Drying of
secretions
Difficulty in
swallowing and
talking
Dry, flushed and
hot skin
Dilation of sphincter Any ophthalmic procedure requiring papillary Photophobia
pupillae (Mydriasis) dilation Blurring of near
• Atropine (longest acting) vision
• Homatropine
• Cyclopentolate
• Tropicamide
Anterior uveitis
• Atropine
Bronchodilation Bronchial asthma and COPD -
• Ipratropium bromide
• Tiotropium bromide
• Oxytropium bromide
 Autonomic Nervous System | 55

Relaxation of GI As antispasmodics Constipation

musculature
• Dicyclomine
• Hyoscine butyl bromide
Decreased urinary Overactive bladder (Unstable bladder or Urinary retention
voiding Detrusor instability
• Oxybutynin (DOC)
• Tolterodine
• Trospium
• Darifenacin
• Solefenacin
• Flavoxate
• Imipramine
NM Relaxation of Adjuvants to general anesthesia to facilitate Respiratory
skeletal muscle intubation paralysis
• d-Tubocurarine
• Doxacurium
• Pancuronium
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• Vecuronium
• Rocuronium
• Rapacuronium
• Atracurium
• Cisatracurium
• Mivacurium
NN Decreased Hypertension (Ganglion blockers not used Bradycardia
ganglionic nowadays) Hypotension
transmission

Antidotes for Mushroom Poisoning:

Type of mushroom poisoning Antidote
Early mushroom (Muscarine) type Atropine
INOCYBE toxin
Late mushroom (Phalloidin) type Thioctic acid
A phalloieds,
Hallucinogenic type No specific antidote
ISOXAZOLE
56 | Pharmacology
Indications of Botulinum Toxin (BoTox):
• Cosmetic – Masking of facial wrinkles
• Achalasia cardia
• Spasmodic dysphonia
• UMN lesions
• Long-standing back/neck pain
• Blepharospasm
• Strabismus

Valathamate - anti cholinergic- useful for cervical ripening (facilitating child birth)

• Ona botulinum toxin - useful in prophylaxis of chronic migraine, overactive bladder.

• Saxitoxin,Tetradoxin - origin from Dinoflagellates, blocks sodium channel- causing skeletal muscle
paralysis.
• Alpha bungarotoxin = Component of venom of banded krait, Antagonist at NM receptor, causing skeletal
muscle paralysis, reversed by neostigmine.

Other Drugs Having Anticholinergic Properties

AfraTafreeh.com

Fig. 2.14

Condition Treatment
Motion sickness Hyosine
Sea sickness Meclizine (I gen antihistamine)
Mountain sickness Acetazolamide
Morning sickness Doxylamine + Vit B6
 Autonomic Nervous System | 57

Worksheet
To do
DRUG USES

Pirenzepine, telenzepine

Darifenacin

Tolterodine

Trospium
AfraTafreeh.com

Trihexyphenidyl

Glycopyrrolate

Valathamate
58 | Pharmacology
Concept 2.6 : Adrenergic neurotransmission
Learning objective: To know the synthesis, storage, release & metabolism of NE

Time Needed
1st reading 15 mins
2 reading
nd
5 mins

Synthesis, Storage, Release and Metabolim of Noradrenaline

AfraTafreeh.com

Fig. 2.15

Enzyme involved in synthesis of NE Enzyme involved in metabolism of NE

Tyrosine hydroxylase ( Rate limiting enzyme) Mono amino oxidase
-Dopa decarboxylase Catechol o methyl transferase
-Beta hydroxylase

Co-factors for various enzymes involved in catecholamine synthesis:

Enzyme Co-factor
Tyrosine hydroxylase Tetrahydrobiopterin
Aromatic amino acid decarboxylase Pyridoxal phosphate
Dopamine-β-hydroxylase Ascorbate
Phenylethanolamine-N-methyltransferase S-adenosylmethionine
 Autonomic Nervous System | 59
Molecules released in the nerve endings along with catecholamines:
• ATP
• Dopamine-β-hydroxylase
• Chromogranin
• Enkephalin / Neuropeptide Y

One-liners:
• Rate limiting enzyme (tyrosine hydroxylase) blocked by- METYROSINE
• DOPA DECARBOXYLASE blocked by- carbidopa, ebnzaraside
• In the synaptic vesicles: NA is stored along with ATP in the ratio 4:1, adsorbed on the
protein chromogranin.
• Reserpine inhibits – Vesicular monoamine transporter 2 (VMAT2).
• Valbenazine – VMAT2 BLOCKER – useful in treatment of Tardive dyskinesia.
• Droxidopa – Prodrug of NA/Adr; approved for neurogenic orthostatic hypotension,
dialysis-induced hypotension and hypotension associated with fibromyalgia and chronic
fatigue syndrome.
• Reuptake of NE is blocked by – TCA, SNRI, NDRI, cocaine.

AfraTafreeh.com
60 | Pharmacology

Worksheet
To do
STEP BLOCKE BY

Tyrosine hydroxylase

Dopa decarboxylase

Vesicular uptake of dopamine

AfraTafreeh.com
Beta hydroxylase

Release of norepinephrine

Reuptake of norepinephrine
 Autonomic Nervous System | 61
Concept 2.7 : Adrenergic receptors
Learning objective:
• To know the location & functions of adrenergic receptor
• To know the endogenous and exogenous catacholamines

Time Needed
1 reading
st
20 mins
2nd reading 10 mins

Receptors in the Sympathetic Nervous System:

Receptor Location Function Selective agonist
α1 Smooth muscle Contraction Nasal decongestant-
E.g: Naphazoline
• Dilator pupillae – Mydriasis Oxymetazoline
• Urinary sphincter – Urinary Xylometazoline
retention Mydriatic -Phenylephrine
• Vascular smooth muscle – To treat
Vasoconstriction and rise in BP postural hypotension-
Methoxamine
AfraTafreeh.com Mephentaeramine
Midodrine
Central nervous Multiple unknown functions
system

α2 Central nervous Hypotension Anti hypertensive-

system Analgesia Clonidine.
Drying of secretions Methyl dopa.
Sedation Guanafacine
Anxiolysis (Mnemonic: HADSA) Guanabenz
Moxonidine
Rilmonidine
Anti glaucoma-
Apraclonidine
Brimonidine
Skeletal muscle relaxant=
Tizanidine

Preanaesthetic medication
Dexmedetomidine
62 | Pharmacology

β1 Heart Increased heart rate (+ve Dobutamine

chronotropic effect)
Increased conduction (+ve
dromotropic effect)
Increased force of contraction (+ve
inotropic effect)
Increased excitability (+ve
bathmotropic effect)
Increased relaxation (+ve lusitropic
effect)
Juxta-glomerular Increased rennin release
(JG) cells of kidney
β2 Smooth muscle Relaxation Bronchodilators
E.g: Salbutamol
Bronchial smooth muscle – Terbutaline
Bronchodilation Salmetrol
Uterus – Tocolysis Formetrol
Vascular smooth muscle – Indacaterol
Vasodilation and fall in BP Uterine relaxant
Ritordine
AfraTafreeh.com Isoxuprine
Skeletal muscles Tremors
Liver Glycogenolysis
β3 Adipocytes Lipolysis Anti obesity
SIBUTRAMINE(withdrawn
because of cardiotoxicity)
MIRABEGRON-
beta 3 agonist
Relax detrusor-
overactive bladder
 Autonomic Nervous System | 63

Classification of adrenergic
Examples of Endogenous Catecholamines:
Catecholamine Action on receptors

Adrenaline (Epinephrine) All α and β

Noradrenaline (Norepinephrine) All α and β except β2

Dopamine D1, beta 1, alpha 1

D 1 – D4

Indications of Adrenaline:
• Anaphylactic shock (DOC) – 0.5 mL of 1:1000 dilution IM.
• Cardio-pulmonary resuscitation.
• As an adjuvant to local anaesthetics.

Exogenous (Synthetic) catacholamines

Exogenous Catecholamine Action on receptors

Isoprenaline β1, β2, β3

AfraTafreeh.com
Dopexamine ­D1, β2

Dobutamine ­1
β
t1/2 = 2 minutes

Fenoldopam D1 (IV infusion, HT emergency with renal

impairement)

Effects of intravenous catecholamines on cardiovascular parameters:

Catecholamine Heart rate Systolic blood Diastolic blood
pressure pressure

Adrenaline ↑ ↑ Low dose:↓

High dose:↑

Noradrenaline ↓(Reflex vagal) ↑ ↑

Isoproterenol (Isoprenaline) ↑ ↑ ↓

Dale’s vasomotor reversal:

Adrenaline + α-blocker → Fall in BP (due to β2 mediated vasodilation).
Re-reversal of Dale’s vasomotor reversal:
Adrenaline + β -blocker → Rise in BP (due to α1 mediated vasoconstriction).
64 | Pharmacology
Examples of indirect sympathomi­metics (increase release of NA from adrenergic
nerve endings):

• Tyramine (develops tachyphylaxis)

• Amphetamines

Examples of mixed action sympathomimetics (act both directly and indirectly):

• Ephedrine
• Dopamine
• Mephentermine

AfraTafreeh.com
 Autonomic Nervous System | 65

Worksheet
To do
Site Receptor

Radial muscle of iris

Myocardium

Bronchial smooth muscle

AfraTafreeh.com

Adipose tissue

Internal urethral sphinter

66 | Pharmacology
Concept 2.8 : Alpha receptor agonist and antagonist
Learning objective:
• To know the alpha receptor agonist and antagonist
• To know the uses & adverse effects of alpha receptor agonist and antagonist

Time Needed
1 reading
st
20 mins
2nd reading 10 mins

Drug Characteristics

1 Phenylephrine • Used as a mydriatic

• Devoid of cycloplegia
• Hence, preferred in elderly

2 Phenylpropanolamine • Vasoconstrictor
• Approved for shock
• Not used nowadays due to side effect of – Hemorrhagic stroke

3 Ephedrine • Vasoconstrictor of choice in pregnancy

• High incidence of tachyphylaxis as side effect
AfraTafreeh.com
4 Xylometazoline • Vasoconstrictors
• Decrease blood flow to nasal mucosa and relieve congestion
5. Oxymetazoline
• Hence, called nasal decongestatnts
6 Nafazoline • Used for common cold and allergies
• Long-term side effect – Rhinitis medicamentosa

7 Methylphenidate • CNS stimulant

• Amphetamine derivative but devoid of amphetanergic effects
• Used for attention deficit hyperactivity disorder (ADHD)

8 Fenfluramine • Suppress appetite in CNS

• Hence, called ‘anorectics’
9 Dexfenfluramine
• Cause weight loss
10 Sibutramine • Approved for obesity
• Only phentermine used now; others have been withdrawn
11 Phentermine

12 Dexmedetomidine • Central selective α2 agonist

• Approved for sedating critically ill patients in ICU

13 Clonidine • Central selective α2 agonist

• Acts as a central sympatholytic
• Used for – Hypertension, Opioid withdrawl and Autonomic
diarrhea
 Autonomic Nervous System | 67

14 Moxonidine • Central selective α2 agonist

Rilmonidine • Acts as a central sympatholytic
• Used for – Hypertension, Opioid

15 Guanafacine • Central selective α2 agonist

Guanabenz • Acts as a central sympatholytic
• Used for- ADHD, TICS

16 Apraclonidine • Used for GLAUCOMA

Brimonidine

17 Tizanidine • Centrally acting skeletal muscle relaxant

18 LOFEXIDINE • Useful to control opioid withdrawal symptoms

Classification of α-blockers:
Non-selective Selective
Non-equilibrium type Equilibrium type α1 selective α2 selective
• Phenoxy-benzamine • Phentolamine • Prazosin • Yohimbine
• Tolazoline • Terazosin • Rauwolscine
AfraTafreeh.com • Doxazosin • Idazoxan
• Tamsulosin
• Alfuzosin
• Silodosin
• Bunazosin
• Indoramine
• Urapidil

Alpha-receptor Antagonists:
Drug Characteristics
1 Phenoxybenzamine • Irreversible blocker of α receptors
• Long-acting
• Gets accumulated in fat
• Preferred for BP control in pheochromocytoma
2 Phentolamine • Short-acting
• DOC in cheese reaction
• DOC in clonidine withdrawl
• To control hypertension during phochromocytoma surgery
• To treat oxime induced hypertension
68 | Pharmacology

3 Tolazoline • Vasodilator
• Used in spasms of peripheral blood vessels
• Antidote for vasoconstriction due to 5-HT2A agonists
4 Prazosin • Vasodilator
• Approved for hypertension
• Preferred in hypertension due to scorpion sting
• Also preferred in hypertension + BPH
• s/e – Postural (Orthstatic) hypotension
• Significant after first dose; hence called ‘first-dose effect’
• Prevented by starting drug in low dose at bedtime
• Starting dose – 0.5 mg OD HS
• Gradually increased to full therapeutic dose – 1-4 mg BD/TDS
5 Tamsulosin • Selective α1A antagonist
• Preferred for BPH
• Symptomatic improvement by increasing urinary voiding
6 Yohimbine • No approved indication
• Used as aphrodisiac for recreational purposes

One-liners:
AfraTafreeh.com
• α-blocker with additional phosphodiesterase inhibitory action – Prazosin.
• Retrograde ejaculation is a side effect of – Tamsulosin.
• Problem of floppy iris during cataract surgery is encountered with – Tamsulosin.
• Alpha blockers causing apoptosis of prostate – Doxososin, Terazosin.
 Autonomic Nervous System | 69

Worksheet
To do
Drug Receptor activity Uses

Phenylephrine Alpha 1 agonist

xylometazoline

Methyldopa

Tizanidine

AfraTafreeh.com

Lofexidine

Tamsulosin

Phenoxybenzamine
70 | Pharmacology
Concept 2.9 : Beta Receptor Agonist and Antagonist
Learning objective:
• To know the beta receptor agonist and antagonist
• To know the uses and adverse effects of beta agonists and blockers

Time Needed
1 reading
st
20 mins
2nd reading 10 mins

β1 Heart Increased heart rate (+ve Dobutamine

chronotropic effect)
Increased conduction (+ve
dromotropic effect)
Increased force of contraction (+ve
inotropic effect)
Increased excitability (+ve
bathmotropic effect)
Increased relaxation (+ve lusitropic
effect)
Juxta-glomerular Increased rennin release
(JG) cells of kidney
AfraTafreeh.com
β2 Smooth muscle Relaxation Bronchodilators
E.g: Salbutamol
Bronchial smooth muscle – Terbutaline
Bronchodilation Salmetrol
Uterus – Tocolysis Formetrol
Vascular smooth muscle – Indacaterol
Vasodilation and fall in BP Uterine relaxant
Ritordine
Isoxuprine
Skeletal muscles Tremors
Liver Glycogenolysis
β3 Adipocytes Lipolysis Anti obesity
SIBUTRAMINE (withdrawn
because of cardiotoxicity)
MIRABEGRON-
beta 3 agonist
Relax detrusor-
overactive bladder
 Autonomic Nervous System | 71
Beta blockers
1st generation 2nd generation 3rd generation
non selective beta blocker cardioselective beta blockers beta blockers with additional properties

Cardio selective beta blockers

Drug Extra property
Nebivolol (Most cardio selective) releases NO
Betaxolol useful in Glaucoma, safe in asthmatic.
Bisoprolol useful in CCF
Atenolol lipid insoluble
Esmolol Ultra short acting(~9Min) due to rapid
metabolism by pseudocholinesterase,given
IV, only for Emergency purpose
Acebutolol Partial agonistic action, membrane
stabilizing action
Metoprolol- useful in HT. Angina, MI, CCF
Celiprolol Nitric oxide releasing property, weak beta 2
agonistic action
AfraTafreeh.com
3rd generation beta blockers (beta blockers with additional properties)
Drug Properties
Labetalol b & α blocker, NERI
USE- HT emergency in pregnancy
ADR-Postural hypotension, hepatotoxic
Carvedilol β & α Blocker
Anti oxidant
anti-inflammatory
CCB
USE- CCF, HT
Bucindolol β & α Blocker
Bevantolol
Nipradilol
Nebivolol Release of NO
Nipradilol, Bopindolol
Celiprolol, Carteolol
Tilisolol Opening Of K+ Channel
Sotalol K+ Channel Blocker
Carvedilol Calcium channel blocker
Betaxolol
72 | Pharmacology

Property Drugs
Highest membrane stabilizing propranolol
Highest lipid soluble- propranolol
Lipid insoluble beta blockers nadalol, atenolol, sotalol, celiproolol, bisoprolol,
aceutaolol-lipid insoluble beta blockers undergoes
renal route of excretion- unsafe in renal failure
Highest intrinsic sympathamimetic pindalol
Favourable effect on lipid profile pindalol
Antidote for beta blocker poisoning Glucagon

Condition Recommended drugs

Beta blockers useful in CCF Metoprolol, bisoprolol, carvedilol, nebivolol
Beta blockers useful in glaucoma Timolol, betaxalol, levobunolol, cartiolol,
metipronolol
Pheochromocytoma Phenoxybenzamine + beta blocker
Beta blocker useful to control tachycardia, beta
blockers are not first line choice
thyrotoxicosis Propranolol
AfraTafreeh.com
Controls symptoms, inhibits peripheral conversion
of T4 to T3
Hypertrophic obstructive cardiomyopathy Beta blockers

One-liners:
• β-blockers with Additional 2 Receptor Agonism-Celiprolol.Bopindolol.Carteolol
β

• β-blockers with Additional Calcium Channel Blocking Property Carvedilol, Betaxolol,

Bevantolol.
• Shortest acting -blocker – Esmolol, T½: 8-10 min. Duration of action: 15-20 min
β

• Longest acting beta blocker- nadolol (>40hrs

• BETA BLOCKERS USEFUL IN LVF- carvedilol, bisoprolol, metoprolol
• Beta blockers useful in glaucoma – Timolol,Betaxolol (safe in asthmatic)
Carteolol, Levobunolol, Metipranolol

β-blockers that have Membrane Stabilizing (Local Anesthetic) Property:

Profound Mild
• Propranolol. • Pindolol.
• Acebutolol. • Metoprolol.
• Carvedilol. • Betaxolol.
• Labetalol.
 Autonomic Nervous System | 73
Drug interactions with β-blockers:
Interaction Drug/s

Additive depression of SA node and AV conduction. Digitalis.

Verapamil.

Delayed recovery from hypoglycaemia Insulin.

Oral hypoglycaemic agents.

Marked rise in BP. Phenylephrine.

Ephedrine.
Other α agonists.

Decreased antihypertensive action seen with NSAIDs.

Propranolol metabolism inhibited by Cimetidine.

Propranolol inhibits metabolism of. Lignocaine.

Propranolol increases bioavailability of (by decreasing first pass Chlorpromazine

metabolism)

AfraTafreeh.com
74 | Pharmacology

Worksheet
To do
Selective beta 1 agonist

Very long acting beta 2 agonist

B3 agonist useful for overactive bladder

Cardio selective beta blocker having nirtic oxide

releasing property AfraTafreeh.com

Safer beta blocker for glaucoma in bronchial

asthmatic patient

Beta blocker useful for hypertensive emergency

Antidote for beta blockers overdose

3 Respiratory System

CONCEPTS
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 Concept 3.1 Drugs useful in Bronchial Asthma

 Concept 3.2 Drugs useful for cough

76 | Pharmacology
Concept 3.1 : Drugs useful in Bronchial Asthma
Learning objectives:
• To know the classification of drugs useful for cough
• To know the actions uses adverse effects of beta 2 agonists in asthma
• To know the actions uses adverse effects of anticholinergic drugs in asthma
• To know the actions uses and adverse effects of methylxanthine
• To study the role steroids in asthma
• To know the importance of leukotriene antagonist & mast cell stabilizers in asthma
• To know the newer drugs useful in asthma

Time Needed
1 reading
st
30 mins
2 reading
nd
15 mins

Classification of Anti-Asthmatic
Drugs:
Direct bronchodilators Anti-inflammatory
β2 agonists Corticosteroids
AfraTafreeh.com
Anti-cholinergics Selective PDE-4 inhibitors 5-LOX inhibitors
LT receptor antagonists Mast cell stabilizers
Monoclonal antibodies
Methylxanthines (both bronchodilator and anti-
inflammatory)

Treatment of acute severe asthma (status asthmaticus):

• Salbutamol / Terbutaline (Inhaled).

• Ipratropium (Inhaled).
• Hydrocortisone hemisuccinate (Intravenous).

Maintenance of Bronchial Asthma:

Gradation Treatment
Mild intermittent No daily medication needed
(Inhaled β-agonist SOS)
Mild persistent Low dose inhaled corticosteroid (ICS)
Moderate persistent Low dose inhaled corticosteroid
(ICS) + Inhaled β-agonist
Severe persistent High dose inhaled corticosteroid
(ICS) + Inhaled β-agonist
 Respiratory System | 77

• Very long acting (acting for >24hrs)

• Indacaterol
• Vilanterol
• abedeterol

(A) β-receptor agonists:

Classification:
Short-acting (T½: 2-4 hours) Long-acting (T½: 12-14 hours)
• Salbutamol (Albuterol) • Salmeterol
• Terbutaline • Formoterol
• Bambuterol
Inhalational route of administration is preferred over oral route because of:

• Faster onset of action.

• Greater bioavailability (due to significant reduction in first pass metabolism).

One-liners:
• Bambuterol is a pro-drug of – Terbutaline.
• AfraTafreeh.com
Indacaterol – ultra long acting β-agonist for COPD.
• β-agonist available as subcutaneous injection – Terbutaline.
• DOC for acute severe asthma (status asthmaticus) – Salbutamol.
• LABA(long acting beta agonist) effective in acute asthma – Formoterol (due to rapid onset
of action).
• Most common adverse reaction to β-agonists – Muscle tremors.

(B) Anticholinergics (Also Known As Inhaled Anticholinergics):

Examples:
• Ipratropium bromide
• Tiotropium bromide
• Oxytropium bromide

Advantages of tiotropium bromide over ipratropium bromide:

Property Tiotropium bromide Ipratropium bromide
1 Duration of action Longer (24 h) Shorter (4-6 h)
2 Frequency of administration Once a day Four times a day
3 Efficacy More Less
4 Antigonism of pre-synaptic M2 Less More
autoreceptor
78 | Pharmacology

One-liners:
• % of inhaled dose that is swallowed – 80-90% (only 10-20% reaches the airways).
• DOC for COPD – Tiotropium.
• Aclidinium – long acting anticholinergic for COPD.
• Adverse effects due to inhaled anticholinergics are seen in – 20-30%.

(C) Methylxanthines:
Alkaloid Structure
Theophylline 1, 3-Dimethylxanthine
Theobromine 3, 7-Dimethylxanthine
Caffeine 1, 3, 7-Trimethylxanthine

Theophylline v/s Caffeine:

Theophylline Caffeine
CNS stimulation at low dose ++ +++
CNS toxicity +++ ++
Heart – stimulation +++ ++
Blood vessel relaxation
AfraTafreeh.com++ +
Bronchodilation +++ +
Divuresis ++ +
Increased skeletal muscle contractility ++ +++
Gastric mucosal irritation ++ +
Phosphodiesterase inhibition +++ ++
Adenosine antagonism +++ ++

Mechanisms of Action of Theophylline:

• Phosphodiesterase (PDE) 3, 4 and 5 inhibition (mainly PDE4)
• Adenosine receptor antagonism
• Increased interleukin-10 release
• Histone deacetylase activation
• Inhibition of NF-κB
• Induction of apoptosis
• Increase release of calcium
 Respiratory System | 79
Drug interactions of theophylline:
Metabolism increased by Metabolism inhibited by
• Barbiturates • Allopurinol
• Barbecued / charcoal broiled meat • Cimetidine
• Rifampicin • Ciprofloxacin
• Phenytoin • Erythromycin
• Smoking • Oral contraceptives
• Marijuana • Fluvoxamine
• Alcohol • Zileuton
• High-protein, low- carbohydate diet • Zafirlukast
• Children (1-16 years of age) • Congestive heart failure Liver failure Pneumonia
• Viral infection
• Vaccination
• High carbohydrate diet
• Old age

Increased Dose of Theophylline with:

Phenytoin 1.5 times
Rifampicin 1.5 times
Cigarette smoking AfraTafreeh.com
1.6 times

Decreased dose of theophylline with:

Condition Decrease in dose of theophylline
Allopurinol Cimetidine Ciprofloxacin Erythromycin 0.67 times (2/3rds of original dose)
Oral contraceptives
Age >60 years 0.6 times
Congestive heart failure 0.6 times
Pneumonia 0.4 times
Liver failure 0.2 – 0.4 times

One-liners:
• Sustained release (SR) formulation of theophylline is preferred due to – uniform absorption.
• Theophylline is insoluble in water; cannot be given parenterally. Hence, parenteral salts
are prepared –
• Aminophylline (Theophylline ethylenedia- mine; 85% theophylline).
• Etophylline (Hydroxyethyl theophylline; 80% theophylline).
• Vd of theophylline = 0.5L/kg.
• Plasma protein binding of theophylline – 50%.
• Normal plasma levels of theophylline – 5-15 mg/L.
• Theophylline is mainly metabolised mainly by – CYP1A2.
80 | Pharmacology

Concomitant administration of Increase in dose of theophylline

Phenobarbitone 1.2 times
Charcoal boiled meat meal 1.3 times

Inhaled corticosteroids: Examples:

• Beclomethasone dipropionate
• Fluticasone propionate
• Triamcinolone acetonide
• Budenoside
• Ciclesonide
• Flunisolide

Measures to decrease the local tissue deposition of drugs:

• Use of spacer – directs the drug directly into the airways.
• Frequent mouth rinsing.
• Use of soft steroids – prodrugs that are activated by esterases in the lung alveoli (e.g.: beclomethasone
dipropionate, ciclesonide).

One-liners: AfraTafreeh.com
• DOC for maintenance of BA – In-haled steroids.
• Tipredane – Inhalational corticoste- roid, that was proved ineffective in clinical trials.
• Oral steroids are less preferred than inhalational steroids for maintenance of BA due to –
Increased adverse effects and increased requirement for tapering.

(D) 5-Lipoxygenase inhibitors

E.g.:
• Zileuton
• Inhibits leukotriene synthesis.
• Purely anti-inflammatory action.
• Given orally.
• Only used for maintenance of BA.
• MC adverse effect – Sinusitis.
• Also hepatotoxic.

(E) Leukotriene receptor antagonists

E.g.:
• Montelukast.
• Zafirlukast.
• Pranlukast.
 Respiratory System | 81
• Inhibit action of leukotrienes on cysteinyl-LT receptors.
• Purely anti-inflammatory action.
• Given orally.
• Only used for maintenance of BA.
• Rare adverse effect – Increased risk of Churg Strauss syndrome (headache,
eosinophilia, vascculitis).
• MEPOLIZUMAB-IL-5 Antagonist – useful for treating churgstraus syndrome.

One-liners:
• DOC for exercise induced asthma – Inhaled short acting β-agonist(- SABA).
• DOC for aspirin-induced asthma – Leukotriene receptor antagonist.
• T½ of Montelukast – 2-6 h.
• T½ of Zafirlukast – 10 h.

Mast cell stabilizers:

E.g.:
• Sodium cromoglycate (Cromolyn sodium).
• Nedocromil sodium.
• Ketotifen.
AfraTafreeh.com
One-liners:
• Apart from mast cell stabilizer, ketoti- fen is also a–H1 antagonist and LT receptor
blocker.
• Antihistamine having mast cell stabilizing property - OLAPATA- DINE

Examples of Selective PDE-4 Inhibitors:

Drug Approved for
Roflumilast
Cilomilast Bronchial asthma
Tofimilast
Drotaverine Anti-spasmodic
Apremilast Psoriatic arthritis

Examples of Monoclonal Antibodies Approved for Bronchial Asthma:

Drug Target antigen
Omalizumab IgE
Lebrikizumab IL-13
Gomiliximab CD23
Resilzumab IL- 5
82 | Pharmacology

One-liners:
• Omalizumab is administered by – s.c. route.

Newer Drugs for Bronchial Asthma:

Benralizumab Anti IL-5 receptor (CD125). Targets the α chain of the receptor.
Fevipiprant Oral selective Prostaglandin D2 receptor-2 antagonists.
Setipiprant
Seratrodast Thromboxane A2 antagonist.
Pitrakinra IL3 and IL4 antagonist.

One-liners:
• COPD patients are considered eligible for α1-antitrypsin replacement therapy if the serum
α1-antitrypsin level is below – 50 mg/dL (11µM).
• The only pharmacological therapy that has demonstrated an unequivocal decrease in
mortality rates in COPD patients is – Supplemental oxygen.

AfraTafreeh.com
 Respiratory System | 83
Concept 3.2 : Drugs useful in cough
Learning objectives:
• To know the classification of drugs useful in cough
• To know the drugs useful for different types of cough

Time Needed
1 reading
st
15 mins
2nd reading 8 mins

Pharyngeal demulcents Lozenges, cough drops and linctuses containing –

Syrup
Glycerine
Liquorice
Expectorants (Mucokinetics)
Bronchial secretion enhancers Sodium citrate
Potassium citrate
Potassium iodide
Guaiphenesin (Glycerylguaiacolate)
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Balsam of Tolu
Vasaka
Ammonium chloride
Mucolytics Bromhexine
Ambroxol
N-acetylcysteine
Carbocisteine
Antitussives
Opioids Codeine
Ethylmorphine
Pholcodeine
Non-opioids Noscapine
Dextromethorphan
Chlophedianol
Antihistamines Chlorpheniramine
Diphenhydramine Promethazine
Peripherally acting Prenoxdiazine
Adjuvant antitussives Salbutamol
Terbutaline
84 | Pharmacology
Indications of N-acetylcysteine:
• As a mucolytic.
• Antidote in paracetamol poisoning.
• Prevention of radiocontrast-induced nephropathy.
• Prevention and treatment of hemorrhagic cystitis.
Treatment of interstitial lung disease

One-liners:
• Bromhexine is a derivative of – alkaloid Vasicine obtained from Adhatodavasica
(Vasaka).
• Prenoxdiazine was developed in – Hungary.

Treatment of Specific Types of Cough

Etiology Treatment approach
Upper / Lower respiratory tract infection Appropriate antibiotics
Smoking Cessation of smoking
Chronic bronchitis Avoidance of pollutants
Bronchiectasis Steam inhalation
Postural drainage
Pulmonary tuberculosis
AfraTafreeh.com
Antitubercular drugs
Asthmatic cough Inhaled β2 agonists
Ipratropium
Inhaled corticosteroids
Cough in pulmonary eosinophilia Diethyl carbazine citrate (DEC)
Inhaled corticosteroids
Postnasal drip due to sinusitis Antibiotics
Nasal decongestants
H1 antihistamines
Postnasal drip due to allergic / perennial rhinitis Avoidance of precipitating factors
Corticosteroid nasal spray
H1 antihistamines
Gastroesophageal reflux Bed head elevation
Light dinner
Diet modification
H2 antagonists
PPIs
Mosapride
ACE inhibitor-associated cough Substitute ACE inhibitors with losartan
NSAIDs may reduce cough
Post-viral cough No specific treatment, subsides by itself
 Respiratory System | 85
Recent FDA Approved Drugs:
Drug Mechanism Indication
1 Grastek Timothy grass pollen allergen extract Grass-pollen induced allergic rhinitis
2 Oralair Sweet Vernal, Orchard, Perennial Grass-pollen induced allergic rhinitis
Rye, Timothy and Kentucky Blue with or without conjunctivitis
grass mixed pollens allergen extract
3 Ragwitek Short ragweed pollen allergen extract Short ragweed pollen-induced allergic
rhinitis
4 Reslizumab Monoclonal antibody targeting IL-5 Maintenance of asthma
5 Olodaterol Long acting β-receptor agonist Maintenance of COPD
6 Umeclidinium Anticholinergic – Blocks M3 and M2 COPD
bromide receptors in bronchial smooth muscles
7 Lumacaftor Prevents misfolding of the abnormal Cystic fibrosis with ΔF508 mutation
CFTR protein
8 Ivacaftor Potentiates the defective CFTR Cystic fibrosis with G551D mutation
channel function
9 Nintedanib Inhibits VEGFR, FGFR and PDGFR Idiopathic pulmonary fibrosis
tyrosine kinases
10 Pirfenidone Reduces fibrosis through
anti- Idiopathic pulmonary fibrosis
AfraTafreeh.com
inflammatory action
86 | Pharmacology

Worksheet
To do
Most common side effect of salbutamol

Adverse effects of theophylline due to blockade of

adenosine receptor

Mast cell stabilizer having antihistamine activity

Mucolytic useful in treating paracetamol poisoning

AfraTafreeh.com

Monoclonal antibodies useful in bronchial asthma

PDE inhibitors useful in COPD

Side effect of Chronic use of leukotriene antagonists

 4 Autacoids

CONCEPTS
 Concept 4.1 Anti histamines

 Concept 4.2 Serotonin (5HT) modulators

 Concept 4.3 Prostaglandin analogues

AfraTafreeh.com
 Concept 4.4 NSAIDs

 Concept 4.5 Drugs useful for rheumatoid and

gouty arthritis

 Concept 4.6 Drugs useful in erectile dysfunction

 Concept 4.7 Drugs useful pulmonary hypertension

88 | Pharmacology
Concept 4.1 : Antihistamines
Learning objectives:
• To know the classification of antihistamines
• To know the action uses of antihistamines
• To know the drugs useful in vertigo

Time Needed
1 reading
st
25 mins
2 reading
nd
15 mins

H1 Antihistaminics:
Histamine Receptors:
H1 H2 H3
Receptor type Gq-protein coupled Gs-protein coupled Auto receptor
Gi-protein coupled
Effector pathway ↑ IP3/DAG and release Adenylyl cyclase Restricting Ca2+ influx;
of Ca2+ from intracellular activation → ↑cAMP K+ channel activation;
stores; ↓cAMP
Protein kinase C
AfraTafreeh.com
activation; NO release →
↑cGMP
Selective agonists 2-methylhistamine (8:1); Dimaprit (1:2000); (R) α-methyl histamine
2-pyridylethylamine Impromidine (1:10,000) (1:3000);
(30:1) ; Imetit
2-thiazolyl ethylamine
(90:1)
Selective Mepyramine (6000:1); Cimetidine (1:500); Thioperamide
antagonists Chlorpheniramine Ranitidine (1:>500) (1:23,000); Impromidine;
(15,000:1) Clobenprofit Ciproxifan
Proxyfan Tiprolisant (or)
pitolisant

Location and Actions of Histamine Receptors:

Receptor Location Function
H1 Smooth muscle Contraction (e.g.: intestine, airways, uterus)
Smooth muscles of larger vessels Vasoconstriction
Endothelium Release of NO and PGI2 leading to vasodilation
Afferent nerve endings Stimulation
Ganglionic cells Stimualtion
Adrenal medulla Release of catecholamines
Brain Neurotransmitter
 Autacoids | 89

H2 Gastric glands Increased acid secretion

Smooth muscles of blood vessels Vasodilation
Heart Atria: +ve chronotropic effect;
Ventricles: +ve inotropic effect
Uterus (rat) Relaxation
Brain Neurotransmitter
H3 Brain (presynaptic) Inhibition of histamine release, leading to sedation
Lung, spleen, skin, gastric mucosa Decreased histamine release
Ileum Inhibition of Ach release from myenteric plexus neurons
Certain blood vessels Inhibit NA release, leading to vasodilation

One-liners:
H4 receptor was identified in – 2001 on – eosinophils, mast cells and basophils.

Classification of 1St Generation H antihistaminics

Highly sedative Diphenhydramine
AfraTafreeh.com
Dimenhydrinate
Promethazine
Hydroxyzine

Moderately sedative Pheniramine

Cyproheptadine
Meclizine
Buclizine
Cinnarizine

Mildly sedative Chlorpheniramine

Dexchlorpheniramine
Triprolidine
Clemastine
Cyclizine
90 | Pharmacology

One-liners:
• Meclizine useful in motion sickness.
• Cyproheptadine- has anti histaminic. Anti cholinergic and anti serotonin property- useful
as an appetite stimulant, prophylaxis of chronic migraine and also for serotonin syndrome.
• Hydroxyzine has anti anxiety activity, produces active metabolite called cetirizine.
• Doxepin – a tricyclic antidepressant has high antihistamine property – useful in atopic
dermatitis, lichen simplex to control pururitis.
• Cinnerazine- has anti histaminergic anti cholinergic and anti serotonin activity- useful
for vertigo.

Anticholinergic Actions of H1 antihistaminics:

High Low Minimal / Absent
• Promethazine • Chlorpheniramine • Fexofenadine
• Diphenhydramine • Hydroxyzine • Astemizole
• Dimenhydrinate • Triprolidine • Loratadine
• Pheniramine • Cyproheptadine • Cetrizine
• Mizolastine

Examples of Second Generation H1 antihistaminics

• Terfenadine AfraTafreeh.com
• Olopatadine
• Fexofenadine • Azelastine
• Cetrizine • Mizolastine
• Levocetrizine • Ebastine
• Loratadine • Acrivastine
• Desloratadine • Astemizole
• Rupatadine

One-liners:
• Fexofenadine is an active metabolite of – Terfenadine.
• Cetirizine is the metabolite of hydroxyzine.
• H1 antihistaminic with additional PAF antagonistic properties – Rupatadine.
• A mast cell stabilizer has high antihistamine activity- ketotifen.
• Terfenadine and Astemizole have been withdrawn due to – QTc prolongation.
• Pitolisant / Tiprolisant – Inverse agonist at H3 receptor; useful for narcolepsy(FDA
approved), under trial for Schizophrenia and Parkinson’s disease.

Topical anti histamines

Azelastine - Nasal spray
Olopatadine - Nasal spray. Ophthalmic drop, oral
- Mast cell stabilizing action
Alcaftadine - Ophthalmic drop
 Autacoids | 91
Examples of Substances that Release Histamine from Mast Cells /
Basophils
• Tissue damage due to trauma.
• Stings and venoms.
• Proteolytic enzymes.
• Phospholipase A.
• Antigen-antibody reaction involving
• IgE antibodies.
• Polymers – Dextran, Polyvinyl pyrrolidone (PVP).
• Basic drugs – d-Tubocurarine, Morphine, Atropine, Pentamidine, Polymyxin-B, Vancomycin,
dexferioxamine.
• Some antihistaminics.
Surface acting agents – Tween 80, Compound 48/80.

Labyrtinthine suppressants – Inhibit end-organ receptors or central cholinergic pathways in

vestibular nuclei
1. Antihistaminics with anticholinergic action • Cinnarizine
• Dimenhydrinate
• Diphenhydramine
AfraTafreeh.com • Promethazine
2. Anticholinergics • Atropine
• Hyoscine
3. Antiemetic phenothiazines • Prochlorperazine
• Thiethylperazine
Vasodilators – Improve blood flow to labyrinth and brainstem • Betahistine
• Codergocrine
• Nicotinic acid
Diuretics – Decrease labyrinthine fluid pressure • Acetazolamide
• Thiazides
• Furosemide
Anxiolytics and antidepressants – Modify the sensation of vertigo • Diazepam
• Amitriptyline
Corticosteroids – Suppress labyrinthine edema

One-liners:
• Most effective drug for violent vertigo and vomiting – Parenteral prochlorperazine.
• DOC for refractory pruritus – Chlorpromazine.
• DOC for refractory hiccups – Chlorpromazine.
92 | Pharmacology

Worksheet
To do
Anti histamine with highest anticholinergic action is

Anti histamine useful in morning sickness

Cetirizine is the metabolite of

Anti histamine causing QT prolongation are

AfraTafreeh.com

Mast cell stabilizer having antihistamine activity

Antihistamine having platelet activating factor (PAF)

inhibitory action is
 Autacoids | 93
Concept 4.2 : Serotonin (5HT) Modulators
Learning objectives:
• To know the drugs modifying actions of various serotonin receptors
• To the drugs useful in migraine

Time Needed
1 reading
st
20 mins
2 reading
nd
10 mins

Drugs Acting on Serotonin Receptors:

Serotonin (5-HT) Receptors:
Receptor Location Function

5-HT1A Raphe nuclei and hippocampus Inhibits serotonergic activity

GIT Slow depolarization of enteric plexus neurons

5-HT1B/1D Cranial blood vessels Vasoconstriction

5-HT2A Vascular smooth muscles Vasoconstriction

AfraTafreeh.com
Visceral smooth muscles Contraction

Platelets Aggregation

Neurons (post-junctional) Activation

5-HT3 GIT Fast depolarization of enteric plexus neurons, Release of

5-HT from enterochromaffin cells, Emesis, ↑ peristalsis

Heart Bradycardia, transient hypotension

Neurons Apnea, pain, itch

5-HT4 GIT ↑ peristalsis, ↑ intestinal secretion

Lower esophageal sphincter Contraction

Enteric plexus Increased ACh release

One-liners:
• All 5-HT receptors are G-protein coupled except – 5-HT3 (ion channel).
94 | Pharmacology
Drugs acting on 5-HT receptors:
Receptor Agonist Antagonist

5-HT1A (Partial agonists)

• Buspirone
• Gepirone
• Ipsapirone

5-HT1B/1D • Triptans
• Ergot alkaloids

5-HT2A/2C • Methysergide
• Ketanserin
• Lidanserin
• Cyproheptadine
• Atypical antipsychotics

5-HT3 • Ondansetron
• Granisetron
• Tropisetron
• Palonosetron
AfraTafreeh.com • Alosetron

5-HT4 • Cisapride
• Mosapride
• Renzapride
• Tegaserod
• Prucalopride

One-liners:
• Methysergide is not used because of – Retroperitoneal fibrosis.
• DOC for chemotherapy-induced vomiting – Ondansetron.
• DOC for radiotherapy-induced vomiting – Ondansetron.
• 5-HT3 antagonist with maximum receptor affinity – Palonosteron.
• Longest acting 5-HT3 antagonist – Palonosetron.
• Alosteron is approved for – Diarrhea-predominant IBS.
• Cisapride has been withdrawn due to – QTc prolongation.
• Tegaserod has been withdrawn due to – Increased risk of cardiovascular events.
• Prucalopride has been approved for – Constipation-predominant IBS.
 Autacoids | 95
Pharmacokinetics of Triptans:
Characteristic Suma Frova Riza Nara Zolmi
Oral bioavailability (%) 15 25 45 70 40
Tmax (h) 1.5-2 2-4 1-1.5 2-3 1.5-2
Plasma T½ (h) ~2 26 2-3 6 2-3
Initial oral dose (mg) 50-100 2.5 5-10 2.5 2.5
Maximum oral dose in 24 h (mg) 200 5-7.5 20 5 10

One-liners:
• DOC for acute migraine – Sumatriptan.
• Triptan with highest oral bioavailability – Naratriptan (70%).
• Longest acting triptan – Frovatriptan (duration of action: 26 h).
• Sumatriptan and ergot alkaloids should not be administered within – 24 hours of each
other.

Classification of Ergot Alkaloids:

NATURAL ERGOT ALKALOIDS AfraTafreeh.com
Amine alkaloids Ergometrine (Ergonovine)
Amino acid alkaloids Ergotamine
Ergotoxine
SEMISYNTHETIC ERGOT ALKALOIDS
Dihydroergotamine
Dihydroergotoxine (Codergocrine)
Bromocriptine
Methysergide

Drugs for Migraine:

Acute attack Prophylaxis
• Triptans • Propranolol and other non-selective β-blockers
• Ergot alkaloids (except Methysergide) • Amitriptyline / Other TCAs
• NSAIDs • Flunarizine,verapamil- CCB
• Valproate
• Topiramate
• Gabapentin / Pregabalin
• Methysergide
• Cyproheptadine
96 | Pharmacology
Treatment of migraine:
Mild Simple analgesics / NSAIDs or their combinations ± Antiemetics

Moderate NSAID combinations / A triptan / An ergot alkaloid + Antiemetics

Severe A triptan / An ergot alkaloid + Antiemetic + Prophylaxis

One-liners:
• Most commonly used drug for migraine prophylaxis – Propranolol
• Calcitonin gene-related peptide (CGRP)- Olcegepant, Telcagepant—both are
hepatotoxic.
• Lasmiditan- 5HT1F agonist under clinical trial for mirgraine.

MABs useful in migraine

• Erenumab, fremanezumab, galcanizumab

AfraTafreeh.com
 Autacoids | 97

Worksheet
To do
Example for 5HT1A agonists

Sumatriptan acts on which receptor

Lorcoserin was withdrawn because of

AfraTafreeh.com
Name one female sexual stimulant useful for female
with hypoactive sexual desire disorder

Metoclopramide acts on which receptors

98 | Pharmacology
Concept 4.3 : Prostaglandins
Learning objectives:
• To know the actions of various prostaglandins
• To know the actions uses and adverse effects of prostaglandin analogues

Time Needed
1 reading
st
15 mins
2 reading
nd
10 mins

PGE2 PGF2α PGI2 TXA2

Blood vessels Vasodilation, ↓ BP Vasodilation mostly Vasodilation Vaso-
(larger veins (marked and constriction, ↑
constrict), little effect widespread), ↓↓ BP BP
on BP
Heart Weak inotropic, reflex Weak inotropic - -
cardiac stimulation
Platelets Variable effect - Anti-aggregatory Aggregation and
release reaction
Uterus
relaxes non-gravid
AfraTafreeh.com
Contraction (in vivo),Contraction (in
vivo and in vitro),
- -

human uterus in vitro, softening of cervix

softening of cervix
Bronchi Dilation, Inhibits Constriction Dilation (mild), Constriction
histamine release Inhibits histamine
release
Stomach ↓ acid secretion, ↑ - ↓ acid secretion -
mucus production (weak), mucosal
vasodilation
Intestine Contracts longitudinal Spasmogenic, ↑ Weak spasmogenic, Weak
and relaxes circular fluid and electrolyte inhibits toxin- spasmogenic
muscles, ↑ peristalsis, secretion (weak) induced fluid
↑ chloride and water secretion
secretion
Kidney Natriuresis, ↓ - Natriuresis, Vaso-constriction
chloride reabsorption, vasodilation, renin
Inhibits ADH action, release
vasodilation, renin
release
CNS Pyrogenic - - -
Release of NA ↑ or ↓ ↑ or ↓ - -
 Autacoids | 99

Afferent Sensitize to noxious - Sensitize to -

nerves stimuli → Tenderness noxious stimuli →
Tenderness
Endocrine Release of anterior Release of - -
system pituitary hormones, gonadotropins and
steroids, insulin. TSH- prolactin, luteolysis
like action (in animals)
Metabolism Anti-lipolytic, - - -
insulin-like action,
mobilization of bone
calcium

Prostaglandin Analogues:
Prostaglandin Synthetic preparation / s Indications

PGE1 Misoprostol NSAID-induced ulcers

1st trimester medical termination of pregnancy

Alprostadil Erectile dysfunction

To maintain the patency of ductusarteriosis

PGE2 Dinoprostone
AfraTafreeh.com
Cervical ripening

PGF2α Dinoprost Induction of labour

Carboprost tromethamine Post-partum haemorrhage

Latanoprost Glaucoma
Isopropyl unoprostone
Travoprost
Bimatoprost
Tafluprost

PGI2 Epoprostenol Pulmonary arterial hypertension

Treprostinil
Iloprost

One-liners:
• DOC for NSAID-induced ulcer – PPIs.
• Specific drug for NSAID-induced ulcer – Misoprostol.
• Misoprostal - teratogen - causing moebius syndrome.
100 | Pharmacology
Concept 4.4 : NSAIDs
Learning objectives:
• To know the classification of NSAIDs
• To know the clinical signs and symptoms of aspirin and paracetamol poisoning

Time Needed
1 reading
st
40 mins
2 reading
nd
20 mins

A: Non-Selective Cox Inhibitors

Salicylates • Aspirin
Propionic acid derivatives • Ibuprofen
• Ketoprofen
• Flurbiprofen
• Naproxen
Fenamate (Anthranilic acid derivatives) • Mefenamic acid
Enolic acid derivatives • Piroxicam
• Tenoxicam
Acetic acid derivatives AfraTafreeh.com
• Ketorolac
• Indomethacin
• Nabumetone
Pyrazolone derivatives • Phenylbutazone
• Oxyphenbutazone
B: Preferential Cox-2 Inhibitors
• Nimesulide
• Meloxicam
• Diclofenac
• Aceclofenac
• Etodolac
C: Selective Cox-2 Inhibitors
• Celecoxib
• Etoricoxib
• Parecoxib
• Lumiracoxib
D: Analgesic-Antipyretic with Poor Anti-Inflammatory Action
• Paracetamol
• Metamizol
• Propiphenazone
• Nefopam
 Autacoids | 101

Selective COX2 inhibitors causing side effects of thrombosis, myocardial infarction, heart failure and
hypertension

Effects of Aspirin on Uric Acid

Dose Effect
< 2g/d Urate retention and antagonism of all other uricosuric agents
2-5 g/d Variable effects, often no change
> 5g/d Increased urate excretion

Acute Salicylate Poisoning:

• More common in children
• Fatal dose: 15-30 g for adults, lower for children
• Serious toxicity seen at plasma levels > 50 mg/dL

Signs and Symptoms:

• Vomiting • Delirium
• Dehydration • Hallucinations
• Electrolyte imbalances
AfraTafreeh.com • Hyperpyrexia
• Acidotic breathing • Convulsions
• Hyper / hypo glycemia • Coma
• Petechial hemorrhages • Death due to respiratory failure
• Restlessness • + Cardiovascular collapse

Treatment
• Supportive and symptomatic.
• External cooling.
• IV fluid and electrolyte replacement.
• Glucose.
• Gastric lavage to remove the unabsorbed drug.
• Alkaline diuresis or hemodialysis to remove the absorbed drug.
• Blood transfusion and Vit. K if bleeding occurs.

Acute paracetamol poisoning:

• More common in small children.
• Toxicity seen at doses >150 mg/kg or > 10g in adults.
• Fatality seen at doses >250 mg/kg.
• Toxic metabolite is N acetyl benzoquinoimuno amine (hepato toxic).
102 | Pharmacology
Signs and Symptoms:
Early manifestations • Nausea
• Vomiting
• Abdominal pain
• Liver tenderness
• No impairment of consciousness
After 12-18 hours • Centrilobular hepatic necrosis
• Renal tubular necrosis
• Hypoglycemia
• May progress to coma
After 2 days • Jaundice

Fulminant hepatic failure and death due to paracetamol are more likely if plasma levels are above the line
joining – 200 µg/mL at 4 h and 30 µg/mL at 15 h.

Treatment
• Induction of vomiting.
• Gastric lavage.
• Activated charcoal.
• Antidote: N-acetylcysteine: 150 mg/kg IV infusion over 15 min f/b same dose over next 20 h OR 75 mg/
AfraTafreeh.com
kg oral every 4-6 h for 2-3 days .
• Alternative to N acetylcysteine I is methionine

One-liners:
• Reye’s syndrome is most commonly associated with – Aspirin.
• Safest conventional NSAID / Conventional NSAID with least side effects – Ibuprofen.
• Most selective COX-2 inhibitor – Lumiracoxib.
• NSAID that inhibits COX-3 – Paracetamol(Acetaminophen).
• The enzyme COX-3 has been so far identified and localized in – Dog brain.
• According to a recent FDA recommendation, the dosage of paracetamol in a single tablet should not
exceed – 325 mg.
• NSAID undergoing enterohepatic circulation – Piroxicam.
• NSAID with longest half-life – Piroxicam (~ 75 h).
• Single dose NSAID / NSAID that can be administered as OD dosing – Piroxicam.
• Phenylbutazone has been withdrawn due to – Agranulocytosis.
• Rofecoxib has been withdrawn due to increased risk of – myocardial infarction.
• Phenacetin has been withdrawn due to – Analgesic nephropathy.
• Nimesulide is contraindicated below – 12 years of age.
• NSAIDs decrease the therapeutic effect of antihypertensives.
• Dual COX/LOX inhibitors – Licofelone, Tepoxalin.
• Idrocilamide – Skeletal muscle relaxant and anti-inflammatory medication used as a topical cream to
treat lumbago and other kinds of muscular pain.
 Autacoids | 103
Concept 4.5 : Drugs useful for Gout and Rheumatoid Arthritis
Learning objective:
• To know the drugs useful in treating acute and chronic gout
• To know the drugs useful for rhenumatoid arthritis

Time Needed
1 reading
st
20 mins
2 reading
nd
10 mins

Treatment of Gout:
Drugs for gout:
ACUTE GOUT • NSAIDs .
• Colchicine (disturbs microtubules, safe in
renal failure, ADR- DIARRHOEA).
• Steroids.

MAINTENANCE OF GOUT

Xanthine oxidase inhibitors (Inhibit the synthesis of • Allopurinol –(ADR- allergry, SJS)
uric acid)
AfraTafreeh.com • Febuxostat

Uricosuric drugs (increase urinary excretion of uric • Probenecid

acid) • Sulfinpyrazone
• Benzbroorine
• Lesinurod

Increase metabolism of uric acid to allantoin • Rasburicase (Recombinant uric acid oxidase)
For rapid control of uric acid in case of tumor lysis • Pegloticase (pegylated form of uric acid oxidase)
syndrome

IL 1 blockers • Anakinra, canakinumab, rilonacept

One-liners:
• DOC for acute gout – NSAIDs.
• NSAID not used in acute gout – Aspirin (due to its uric acid retention effects).
• Colchicine is derived from – Colchicum autumnale.
• DOC for Familial Meditteranean fever – Colchicine.
• Allopurinol is an analogue of – Hypoxanthine.
• Non-purine inhibitor of xanthine oxidase – Febuxostat.
• Most common side effect of probenecid is – Dyspepsia (25%).
104 | Pharmacology
Drug Interactions of Probenecid:
Decrease urinary excretion of Decreases the biliary excretion of
• Penicillins • Rifampicin
• Cephalosporins
• Sulfonamides
• Methotrexate
• Indomethacin
• Nitrofurantoin

Standard Preventive Approach for Tumourlysis Syndrome

• Vigorous hydration.
• Urinary alkalinization.
• Oral / IV allopurinol
• Rasburicase (DOC).

Drugs Causing Hyperuricemia as a Side Effect

• Thiazides.
• Loop diuretics.
• Pyrazinamide.
AfraTafreeh.com
• Ethambutol.
• Levodopa.

Drugs useful for treating rheumatoid arthritis

conventional synthetic (cs) biologic (b)
csDMARDs bDMARDs

Methotrexate TNF-α–blocking agent

Azathioprine, IL-1blockers (anakinra, rilonacept, canakinumab)
Chloroquine IL-6 blockers (Tocilizumab)
Hydroxychloroquine B-cell cytotoxic agent (Rituximab)
Cyclophosphamide T-cell–modulating biologic (Abatacept)
Cyclosporine
Leflunomide (inhibits dihydro orotate
dehydrogenase)
Mycophenolate mofetil
Sulfasalazine
Tofacitinib (janus kinase 1, 3 blocker)
 Autacoids | 105
TNF-α blockers
• Infliximab
• Adalimumab
• Eternacept
• Golimumab
• certolizumab

TNF-α blockers side effects-

• Anti drug antibody formation, allergic reaction
• Activation of latent infection,hepatotoxicity, heart failure, secondary cancer

Contraindications to anti-TNF-α agents:

• Hepatitis B.
• HIV and other immunocompromised states.
• Active tuberculosis.
• Multiple sclerosis.
• Systemic lupus erythematosus.
• Pregnancy. AfraTafreeh.com
• Lactation.
106 | Pharmacology

Worksheet
To do
NSAIDs useful in acute gout

Mechanism of action of colchicine

Examples for uric acid metabolism enhanzers

Target of rituximab
AfraTafreeh.com

Mechanism of action of leflunomide

IL 6 blocker useful in RA
 Autacoids | 107
Concept 4.6 : Drugs useful in Erectile Dysfunction
Learning objectives: To know the drugs useful in erectile dysfuntion

Time Needed
1st reading 10 mins
2 reading
nd
5 mins

PDE V blockers Local ( intracavernous ) Other drug useful in erectile

injection into penis dysfunction
• Sildenafil • Alprostadil • Apomorphine
• Vardenafil • Phentolamine • Trazadone
• Tadalafil (longest acting) • Papaverine • Avaptadil- VIP
• Avanafil • Ketanserin
• Naltrexone
• Gingeng, Kava
• Gingko

Sexual problem and treatment

Premature ejaculation Delayed orgasm Sexual stimulants
• SSRI
AfraTafreeh.com
• Amantidine • Yohimbine
• PDEV inhibitors • Buspirone • Zinc
• Cyproheptadine • Ginkgo biloba
• ginseng
108 | Pharmacology

Worksheet
To do
Most common group of drug useful for erectile
dysfunction

Sildenafil should not be given with nitrate because

of risk of

Depoxetine is the SSRI approved for

AfraTafreeh.com

Alpha 2 agonist used as a sexual stimulant is

Prostaglandin E1 analogue useful in erectile

dysfunction is
 Autacoids | 109
Concet 4.7 : Drugs useful in Primary Pulmonary Hypertension
Learning objectives: To know the various classes of drugs useful in pulmonary
hypertension

Time Needed
1 reading
st
15 mins
2 reading
nd
7 mins

CCB Nitric oxide PDE V Endotheline PGI 2 Rho kinase Direct guanyl Newer drugs
inhibitors receptor analogues enzyme cyclase
blockers inhibitor activators
Nifedipine Ihalation Sildenafil Bosentan Epoprostenol- Fasudil Riociguat, Trebenanib
nitric oxide Tadalafil Ambresentan (IV- infusion) Cinociguat Anigiopoietin 1
Macitentan ADR- inhibitor
hypotension, Extra cellular
headache, elastase
myalgia, jaw inhibitors-
pain
sivelestat, elafin
Treprostinil
(IV/SC-
infusion,
inhalation, oral)
Beroprost- oral
AfraTafreeh.com(first PGI2
analogue), not
approved
Ilioprost-
inhalation (first
PGI2 analogue)
110 | Pharmacology

Worksheet
To do
Examples of direct guanyl cyclase activator useful in
pulmonary hypertension

What is fasudil

Examples for endothelin receptor blockers useful in

pulmonary hypertension

AfraTafreeh.com
Acute side effects of sildenafil

What is Treprostinil

Example for extra cellular elastase inhibitor

 5 Cardiovascular System

CONCEPTS
 Concept 5.1 Anti anginal agents
AfraTafreeh.com
 Concept 5.2 Anti arrhythmic agents

 Concept 5.3 Drugs useful for heart failure

 Concept 5.4 Anti hypertensive agents

112 | Pharmacology
Concept 5.1 : Anti Anginal Agents
Learning objectives:
• To know the classification of anti anginal agents
• To know the mechanism , uses and adverse effects of nitrates
• To know the role of beta blocker in angina and in myocardial infarction
• To know the uses and adverse effects of CCB
• To know the newer drugs useful in angina

Time Needed
1 reading
st
45 mins
2nd reading 20 mins

Classification
Vaso dilators Cardia depressants Vasodilatation Pathway of fatty Newer drug
& cardiac acid oxidation
suppression (pFOX)inhibitors
(antioxidants)

Nitrates Beta blockers Calcium channel Trimetazidine Ivabradine

Nicorandil blocker (diltiazem) Ranolazine
(potassium channel
AfraTafreeh.com Molsidomine
opener)

Nitrates
Drugs MOA Uses ADR Drug interaction

Short acting- Releases nitric Cardiac- Headache With sildenafil –

Glyceryl trinitrate oxide- activate Angina, MI, CCF Hypotension with produces severe
(Nitroglycerine) guanyl cyclase- reflex tachycardia hypotension
Amyl nitrite accumulates cGMP-
Non cardiac Development of
causing smooth
Intermediate acting- tolerance (Monday Beta blockers when
muscle relaxation Achalasia cardia
Isosorbide dinitrate morning headache) added with nitrate
Biliary colic pain controls the reflex
Long acting- Methemoglobinemia
Isosorbide Cyanide poisoning tachycardia
Skin rashes
mononitrate
Longest acting-
Pentaerythritol
tetranitrate
 Cardiovascular System | 113

One-liners:
• All nitrates are long-acting except – Nitroglycerine.
• Shortest-acting nitrate – Nitroglycerine amylnitrite.
• Longest-acting nitrate – Pentaerythritol tetranitrate.
• All nitrates undergo extensive first-pass metabolism except – Isosorbide mononitrate.
• DOC for angina pectoris – Nitrates.
• Nitrate preferred in acute angina - NTG, ISDM.
• Sublingual for rapid action should be in lipid soluble and in non ionized form.
• Skin rashes are maximum with penta ertyhritol tetra nitrte.
• Nitrates should not be combined with – Sildenafil.
• Most common side effect of nitrate – headache.
• Nitrate causes hypotension with reflex tachycardia.
• Methemoglobinemia produced by nitrate useful in treating cyanide poisoning.
• Non cardiac use of nitrate - biliary colic pain, achalasia cardia.

Role of beta blockers

In angina In MI
Reduces heart rate & force of contraction- Reduces work load- reduces oxygen demand
Reducing work load- Has anti arrhythmic action- so controls arrhythmia in
Reduces oxygen demand AfraTafreeh.com MI, thereby prevents mortality

Classification of Calcium Channels:

L-type T-type (Transient N-type (Neuronal)
(Long-lasting current) current)
Conductance 25 pS 8 pS 12-20 pS
Activation threshold High Low Medium
Inactivation rate Slow Fast Medium
Location and function Cardiac and smooth SA node – Pacemaker Neurons in CNS,
muscles – Excitation- activity; sympathetic and
contraction coupling; Thalamic and other myenteric plexuses –
SA node and AV node – neurons – T currents and Transmitter release
Conductivity; repetitive spikes;
Endocrine cells – Endocrine cells –
Hormone release; Hormone release;
Neuro – transmitter Certain arteries –
release Constriction
Antagonists Verapamil Diltiazem Mibefradil Flunarizine ω-conotoxin
Dihydropyridines Ethosuximide
Valproate Topiramate
Gabapentin
Pregabalin
114 | Pharmacology

One-liners:
• CCB with –ve chronotropic action: Verapamil > Diltiazem.
• CCB with –ve dromotropic action: Verapamil > Diltiazem.
• CCB with –ve inotropic action: Verapamil > Diltiazem.

Pharmacokinetics of CCBs:
Drug Oral bio- Vd (L/kg) CL (L/h/kg) Active Elimination
availability metabolite T½ (h)
(%)

Verapamil 15-30 5.0 0.9 Yes 4-6

Diltiazem 40-60 3.0 0.7 Yes 5-6

Nifedipine 30-60 0.8 0.42 Minor 2-5

Felodipine 15-25 10.0 1.0 None 12-18

Amlodipine 60-65 21.0 0.42 None 35-45

AfraTafreeh.com
One-liners:
• Most popular DHP – Amlodipine.
• DHP supposed to be useful in CHF – Amlodipine.
• CCB used to treat cerebral vasospasm following sub arachnoid hemorrhage(SAH) –
Nimodipine (due to excellent blood brain barrier penetration).
• FASUDIL(Rho kinase inhibitor is also useful in SAH.
• Long-acting DHPs – Benidipine and Lercanidipine (due to slow dissociation from the
channels).
• CCB causing paradoxical angina – Nifedipine.
• CCBs should never be combined with – Clarithromycin.
• Clarithromycin inhibits CYP enzymes, leading to elevated CCB levels, leading to an
increased risk of hospitalization due to acute kidney injury.
• CCB useful in hypertensive emergency- Intravenous clevidipine, nicardipine.
• CCB useful for prophylaxis of chronic migraine- Flunarizine (additionally has sodium
channel blocking action and anti oxidant action), verapamil.
• Verapamil is P-glycoprotein inhibitor.
• Class IV anti arrhythmic - verapamil, diltiazem.
 Cardiovascular System | 115
Potassium channel openers
Drug Uses ADR

Nicorandil (K channel opener + Angina Hypotension, headache, aphthous

releases nitric oxide) ulcer

Hydralazine (K channel opener + Hypertension (preferred in Hypotension, fluid retention, SLE

releases nitric oxide) preganancy)

Minoxidil Hypertension, alopecia Hypotension, fluid retention,

hirsutism

Diazoxide Insulinoma, hypertension Hyperglycemia, hyperuricemia

Adenosine Supra ventricular arrhythmia Bronchospasm

Anti oxidant
Drug name ADR

Ranolazine ) anti oxidant + sodium channel block) QT prolongation

Trimetazidine GI upset
Thrombocytopenia
AfraTafreeh.com Liver dysfunction
Risk of movement disorders

One-liners:
• Anti-anginal with cardioprotective effects – Ranolazine.
• Anti-anginal causing HbA1c reduction – Ranolazine

Newer drugs
Drug MOA Action Uses ADR

Ivabradine Funny current Causing Angina , CCF Bradycardia

sodium channel bradycardia Luminous
blocker phenomina-
PHOSPHENES
(visual disturbance

Molsidomine Releases Vasodilatation Prophylaxis of Headache

nitricoxide angina
116 | Pharmacology
For stable angina
First line drugs Second line drugs
Beta blockers pFOX inhibitors
CCB- Diltiazem Trimetazidine , Ranolazine
Nitrates If Na channel blocker
Ivabadine
K channel opener-
Nicorandil

Drugs for Myocardial Infarction

Pre-admission:
• Anti-platelet agent: ASPIRIN to arrest the progression of clot (First drug to be given).
• Opioid analgesic: MORPHINE for pain relief (Pethidine, Pentazocin Should be used as They Cause
Tachycardia).
• 100% oxygen inhalation.
Prophlyactic β-blocker to prevent arrhythmias

On admission:
• Thrombolysis (PTCA or Pharmacological)
• Nitrates
AfraTafreeh.com
• ACEi / ARB
• β-blocker
Anticoagulant Heparin / LMWH followed by Warfarin

On discharge:
• Antiplatelet agents
• Statins
β-blocker / ACEi / ARB to prevent remodeling

Drugs useful in peripheral vascular disease

Drug MOA ADR
Pentoxifylline non selective PDE inhibitor Severe nausea & vomiting
rheologic modifier (Flexibility of RBC)

Cilastazole Selective PDE III inhibitor Headache, arrhythmia,

 Cardiovascular System | 117

Worksheet
To do
Nitrates acting by

Nitrates should not used along with

CCB safe in CCF

CCB useful in SAH

CCB useful for prophylaxis of chronic migraine

AfraTafreeh.com
CCB having anti arrhythmic action

Potassium channel opener useful in angina

Mechanism of action of ivabradine

pFOX inhibitor useful in angina

Mechanism of action of cilastazole

118 | Pharmacology
Concept 5.2 : Anti-Arrhythmic Agents
Learning objectives:
• To know the classification of anti-arrhythmic agents
• To know the uses adverse effects of various classes of anti-arrhythmic agents
• To know the appropriate antiarrhythmic agents for appropriate arrhythmias

Time Needed
1 reading
st
45 mins
2 reading
nd
25 mins

Classification of anti-arrhythmic agents

Class I (Na+ channel blockers)

Class IA • Quinidine
• Procainamide
• Disopyramide

Class IB • Lignocaine
• Phenytoin
• Mexilitene
AfraTafreeh.com
• Tocainide

Class IC • Flecainide
• Encainide
• Propafenone

Class II (β-blockers) • Propranolol

• Esmolol

Class III • Amiodarone

• Dronedarone
• Bretylium
• Sotalol
• Ibutilide
• Dofetilide
• Vernakalant

Class IV (Calcium channel blockers) • Verapamil

• Diltiazem

Miscellaneous • Digoxin
• Adenosine
• Magensium
• Atropine
 Cardiovascular System | 119
Class Ia drugs
• Quinidine may cause thrombocytopenia due to hypersensitivity reaction on bone marrow.
• The most common adverse reaction due to quinidine is – Diarrhoea (30-50%).
• Procainamide undergoes acetylation may cause SLE.
• Dispyramide has highest antivagal action

Class Ib drugs
• All class Ib drugs useful only for ventricular arrythmia.
• Lignocaine causes convulsion(first sign of convulsion: nystagmus, first symptom of convulsion: circum
oral paraesthesia).
• Mexilitine off lable use- diabetic neuropathy.
• Phenytoin useful for treating digitalis induced VT (drug of choice is lignocaine).
• Tocainide causes AGRANULOCYTOSIS.

Class Ic drugs
• Class Ic drugs are pro arrhythmic, but useful for WPW syndrome
• Propafenone has additionally beta blocking property
AfraTafreeh.com
Class II { beta blockers)- useful for both ventricular and atrial arrhythmias
Class III (potassium channel blockers)
AMIODARONE:
1. Whorl like pattern cornea (cornea verticilata)
2. Pulmonary fibrosis
3. Pseudo alcoholic liver injury
4. Hypo or hyper thyroidism

BRETYLIUM:
Chemical defirilator

Drugs converting AF into NSR (given IV)

1. Amiodarone
2. Ibutilide
3. Vernakalant
• Dronedarone do not contain IODINE (no thyroid problem.
• Bretylium – chemical defibrillator.
• Sotalol- beta blocker with potassium channel blocking action.
• Ibutilide useful for converting atrial fibrillation into normal sinus rhythm.
120 | Pharmacology

• Percentage of iodine in amiodarone – 33-37%.

• Photosensitization and skin pigmentation seen with amiodarone.
• Pulmonary alveolitis and fibrosis is rare if daily dose of amiodarone is less than – 200 mg.
• pseudo alcoholic liver injury, hypo or hyper thyroidism can be the adverse effect of amiodarone.

Class IV
Drugs Uses
Verapamil & diltiazem Mainly useful for atrial and supra ventricular
arrhythmia

Miscellaneous drugs
• ADENOSINE- drug of choice for SVT, Suseful to produce Controlledhypotension, is also called
Endogenousantiepileptic, its action antagonized by Methyl xanthane- theophylline, action
potentiated by Dipyridamole.
• IV. Magnesium sulphate (MgSO4)- drug of choice for long QT syndrome, Eclampsia.
• Most common adverse effect of Mgso4 is – Diminishing deep tendon reflex, most serious
isRespiratory failure, antidote for MgSo4 is - caclium gluconate.
• Atropine- anticholinergic drugs, causing tachycardia, useful for symptomatic bradycardia, first degree
heart block, Mobitz type I second degree heart block
AfraTafreeh.com
• Digoxin- has vagomimetic property, acts on AV node, reducing conduction velocity, useful for atrial
fibrillation and atrial flutter

One-liners:
• Classification of antiarrhythmics is given by – Vaughan Williams and Singh.
• DOC for congenital QT syndrome – β-blocker.
• DOC for acquired QT syndrome – MgSO4.

Drugs that can Prolong QTC Interval

Anti-arrhythmics • Class IA agents
• Class IC agents
• Class III agents
Antimalarials • Quinine
• Mefloquine
• Artemisinin
• Halofantrine
Antibacterials • Sparfloxacin
• Moxifloxacin
• Gatifloxacin
 Cardiovascular System | 121

Antihistaminics • Terfenadine
• Astemizole
• Ebastine
Antidepressants • TCAs
Antipsychotics • Thioridazine
• Pimozide
• Aripiprazole
• Ziprasidone

Clinical Classification of Antiarrhythmics:

Supraventricular arrhythmias Ventricular arrhythmias only Supraventricular + Ventricular
only arrhythmias
Adenosine Verapamil Diltiazem Class IB agents Amiodarone
Dronedarone Digoxin β-blockers Class IA agents Class
IC agents

One-liners:
• DOC for supraventricular arrhythmias – Verapamil.
• DOC for PSVT – Adenosine. AfraTafreeh.com
• DOC for ventricular arrythmias – Lignocaine.
• Management of choice for ventricular arrhythmias – DC cardioversion / Defibrillation.
122 | Pharmacology

Worksheet
To do
Class I drug with highest ant ivagal action

Anti arrhythmic useful only for ventricular

arrhythmia

Antiarrhythmic causing pulmonary fibrosis

Antiarrhythmic drug causing hypothyroidism

CCB having antiarrhythmic property

AfraTafreeh.com

Anti arrhythmic drug useful for treating first degree

heart block

Antidote for MGSO4

Antidote for digoxin

\
 Cardiovascular System | 123
Concept 5.3 : Drug Useful For Heart Failure
Learning objectives:
• To know the classification of drugs useful in acute and chronic heart failure
• To know the action uses and adverse effects of drugs interfering RAAS system
• To know the natriuretic peptides and their analogues
• To know the role of inotropic agents in heart failure
• To know the newer drugs for heart failure

Time Needed
1 reading
st
30 mins
2nd reading 20 mins

Drugs useful for acute heart failure (only for Drugs useful for controlling progression of heart
symptom relief) failure (disease modifying drugs)- RAAS pathway
inhibitors

Diuretics(furosemide) and natriuretics β blockers, ACEI,ARB & Mineralo corticoid

Vasodilators receptor antagonist
Inotropes (digoxin, dopamine, dobutamine,
PDEIII inhibitors) AfraTafreeh.com
Drugs Acting on Renin-angiotensin System:
Group Mechanism Examples

Renin release inhibitors Inhibiting the release of renin Beta blockers

from Gella of kidney Clonidine, methyldopa

Direct renin inhibitors Inhibit conversion of • Aliskiren

angiotensinogen to AT-I • Remikiren
• Enakiren

Angiotensin converting enzyme Inhibit conversion of AT-I to AT-II • Captopril

(ACE) inhibitors • Enalapril
• Lisinopirl
• Perindopril
• Fosinopril
• Ramipril
• Quinapril
• Trandolapril
• Imidapril
• Benzaepril
124 | Pharmacology

Angiotensin receptor blockers Prevent action of AT-II on the • Losartan

(ARBs) receptors • Candesartan
• Irbesartan
• Valsartan
• Olmesartan
• Telmisartan

One-liners:
• Angiotensinogen is an – α2 globulin secreted by Liver.
• Angiotensin-I contains – 10 amino acids.
• Angiotensin-II contains – 8 amino acids.
• Angiotensin-III contains – 7 amino acids.
• Angiotensin-IV contains – 6 amino acids.
• Aliskiren has been approved for – Hypertension.

Structure and Pharmacokinetics of Ace Inhibitors:

Drug Chemical Time to peak Elimination Duration of Dose (mg/d)
nature action (h) half-life (h) action (h)

Captopril Sulfhydryl AfraTafreeh.com

1 2 6-12 25-150

Enalapril Carboxyl 4-6 11 24 2.5-40

Lisinopril Carboxyl 6-8 12 ≥ 24 5-40

Fosinopril Phosphinate 3-5 12 24 10-40

Perindopril Carboxyl 6 25-30 > 24 2-8

Ramipril Carboxyl 3-6 8-48 > 24 1.25-10

One-liners:
• All ACE inhibitors are prodrugs except – Captopril and Lisinopril.
• DOC for diabetic nephropathy – ACE inhibitors.
• DOC for scleroderma renal crisis – ACE inhibitors.
• All ACEI undergoes mainly renal route of excretion except- fosinopril (mainly bile,
minimally through kidney.
• Bradykinin is the cause for dry cough and angioedema due to ACE INHIBITOR.
• BRADYKININ ANTAGONIST - Icatibant.
• ARB with maximum affinity for receptor – Candesartan.
• ARB with anti-platelet action and uricosuric action – Losartan.
• ARB with insulin sensitizing action – Telmisartan (due to PPAR-γ agonism).
 Cardiovascular System | 125
Natriuretics:
Example Mechanism Current status
Nesiritide Recombinant BNP analogue Approved for acute decompensated
heart failure Given IV, short
acting(20minutes)
Rapid metabolism by vasopeptidase
Carperitide Recombinant ANP analogue Not used much nowadays
Omapatrilat sampatrilat Dual neutral endopeptidase (NEP) and Withdrawn due to high incidence of
ACE inhibitor angioedema
Sacubitril Ecadotril Neutral endopeptidase ( N E P ) Recently approved for CHF
inhibitor

One-liners:
• Nesiritide is administered as an – IV infusion (due to short T½)

BETA BLOCKERS USEFUL IN LVF- carvedilol, bisoprolol, metoprolol

Mineralocarticodi antagonist useful in LVF- spironolactone, eplerenone

Inotropes: AfraTafreeh.com
One-liners:
Digoxin is derived from – Digitalis lanata. Digitoxin is derived from – Digitalis purpurea. Ouabain
is derived from – Strophanthus gratus. Cardiac glycosides were first used for dropsy by –
William Withering.
Cardiac glycoside found in toad skin – Bufotoxin.

Digoxin
MOA Uses Non Cardiac Cardiac Adr Treatement for Antidote for
Adr Digxoin Induced Digoxin
Arrhythmia
Inhibits CCF Nausea, Vomiting Atrial arrhythmia Correction Digibind
Na+K+ATPase (most common) of electrolyte (anti-digoxin Fab
pump, thereby DNS depression imbalance fragments)
atrial fibrillation AV block
increases (K, Mg)
and atrial flutter.
intracellular
Yellow
Calcium, Ventricular
vision defect Propranolol for
increase the force arrhythmia
(Xanthopsia) atrial arrhythmia
of contration

Gynecomastia Atropine for AV

Vagomimetic
block
property- reduces
AV conduction-
controls heart Lignocaine
rate for ventricular
arrhythmia
126 | Pharmacology
Digoxin
Effects of digoxin on cardiac Effects of digoxin on ECG Factor aggravating digoxin
action potential toxicity

• Resting membrane potential is • Decreased amplitude or • Hypokalemia

progressively decreased . inversion of the T wave . • Hypercalcemia
• Hypomagnesemia
• Rate of phase 0 depolarization • Increased PR interval. • Severe renal disease
is reduced resulting in slowing • Severe hepatic disease
of conduction. • Shortening of QT interval. • Myocardial ischemia
• Thyrotoxicosis
• Slope of phase 4 depolarization • Depression of ST segment. • Myxedema
is increased in the Purkinje • Ventricular tachycardia
fibres. Ectopic automaticity • Inverted tick mark sign. • Partial AV block
is enhanced and latent • Acute myocarditis
pacemakers become overt • Wolff-Parkinson White
at high doses producing (WPW) syndrome
extrasystoles.

• Action potential duration is

reduced and amplitude of the
action potential is diminished
AfraTafreeh.com
Pharmacokinetic Properties of Digoxin
Oral bioavailability ~ 75%

Plasma protein binding 20 – 30%

Therapeutic serum levels 0.5 – 2 ng/mL

T½ ~ 36 h

One-liners:
• Digoxin undergoes renal route of excretion(glomerular filtration), digitoxin
undergoes hepatic route of excretion
• Most characteristic feature of digitalis-induced arrhythmias – Atrial tachycardia with
AV block.
• Most common arrhythmia produced by digoxin- ventricular bigemini.
• DC cardioversion is contraindicated in –Patients with elevated digitalis levels (It
may precipitate ventricular fibrillation).
• No role for hemodialysis in digoxin poisoning (due large volume of distribution).
 Cardiovascular System | 127
Effects of Dopamine at Various Doses
Dose (µg/kg/ min) Receptor Primary action

Low (< 2) D1 Renal and sphlancnic vasodilation

Intermediate (2-10) β1 Inotropic effect

High (> 10) α1 Vasoconstriction

Examples of Calcium Sensitizers

• Levosimendan (also has PDE iii blocking property).Pimobendan.

Examples of PDE3 Inhibitors

• Inamirinone – most common side effect is Thrombocytopenia.
• Milrinone – most common side effectis arrhythmia.
• Vesnarinone.
• Enoximone

Newer drugs: AfraTafreeh.com

ISTAROXIME- inhibits Na + K +ATPase pump- inotropic action.
Omecamitiv mecarbil (Direct myosin activator)-positive inotropic action.

Reduce Mortality in CCF:

Beta Blockers (carvedilol, bisoprolol, metoprolol).
A.C.E. Inhibitors.
Angiotensin Receptor Blockers. Spironolactone.
ISDN + HYDRALAZINE.
Sacubitril + valsartan
128 | Pharmacology

Worksheet
To do
Diuretic of choice for rapid symptom relief in CCF

Disease modifying diuretic in CCF

All ACEIs are prodrug except

ARB having PPAR gamma agonistic action is

BNP analogue useful for CCF

AfraTafreeh.com

Selective neprilysin inhibitors

Calcium sensitizer examples

Uses of ivabradine
 Cardiovascular System | 129
Concept 5.4 : Anti-Hypertensive Drugs
Learning objectives:
• To know the classification of antihypertensive drugs
• To know selection of appropriate antihypertensive drug for appropriate person

Time Needed
1 reading
st
25 mins
2 reading
nd
15 mins

Drugs for Hypertension:

1 Diuretics

2 Drugs inhibiting RAS • ACE inhibitors

• ARBs
• Aliskiren (Direct renin inhibitor / DRI)

3 Peripheral sympatholytics • α-blockers

• β-blockers

4 Central sympatholytics • Clonidine

• α-methyldopa
AfraTafreeh.com
• Rilmenidine
• Moxonidine

5 Calcium channel blockers

6 Potassium channel openers hydralazine, minoxidil, diazoxide

7 Nitrates

8 Other vasodilators • Sodium nitroprusside

• Hydralazine
• Fenoldopam
• Fasudil

One-liners:
• Coombs’ test is positive upon administration of – α-methyldopa.
• Cyanide poisoning can occur due to overdose of – Sodium nitroprusside- unsafe in
pregnancy.
• ACE inhibitor used in hypertensive emergencies – Enalaprilat (IV route).
• Fenoldopam acts as a – D1 receptor partial agonist.
• Fasudil acts as a – Rho kinase inhibitor- useful for primary pulmonary hypertension,
subarachnoid hemorrhage, angina pectoris.
130 | Pharmacology
Selection of 1st Line Antihypertensive Agents:
Compelling indications Suitable for To be avoided in

Diuretics

• Heart failure • Older patients • Gout or family history of gout

• High CAD risk • Isolated systolic hypertension • Abnormal lipid profile
• Recurrent stroke prevention • Obese with volume overload • Pregnancy induced
• Diabetes mellitus • Low cost therapy hypertension

ACE inhibitors / ARBs

• Heart failure • Relatively young patients • Bilateral renal artery stenosis

• Post-MI • Patients with left ventricular • Pregnancy
• High CAD risk hypertrophy • Hyperkalemia
• Diabetes mellitus • Gout • Pre-existing dry cough (ARBs
• Chronic kidney disease • Peripheral vascular disease can be given)
• Recurrent stroke prevention • Dyslipidemic patients

β-blockers

• Stable heart failure • Co-existing anxiety or • Asthma

• Post-MI
AfraTafreeh.com
tachycardia • COPD
• High CAD risk • Relatively young patient • Bradycardia
• Migraine patients • Conduction disease
• Low cost therapy • Decompensated heart failure
• Peripheral vascular disease
• Abnormal lipid profile

Calcium channel blockers

• Recurrent stroke prevention • Older patients with poor • Verapamil and Diltiazem –
arterial wall compliance • Myocardial inadequacy
• Isolated systolic hypertension • CHF
• Asthma • Conduction defects
• COPD • Sick sinus syndrome
• Peripheral vascular disease • Receiving β-blockers
• Pregnant hypertensive • DHPs –
• Diabetes mellitus • Ischemic heart disease
• Post-MI
• Males with prostate
enlargement
• Gastroesophageal reflux
 Cardiovascular System | 131

Condition Preferred drug Better avoid

HT with DM ACEIs, ARBs or CCBs Beta blockers, thiazide diuretics

HT with dyslipidaemia ACEIs, ARBs, alpha blockers, Beta blockers, thiazide diuretics
CCB

HT with CAHD Beta blockers, CCB (diltiazem) Arteriolar dilators

HT with CCF ACEIs, ARBs, diuretics Beta blockers, CCB (diltiazem,

verapamil)

HT with chronic renal failure Diuretics, CCB

HT with Bronchial asthma CCB, diuretic, ACEi, ARB Non selective beta blokcers

HT due to pheochromocytoma Non selective alpha blockers Don’t use beta blocker as a first
line choice

Hypertensive emergency Hydralazine

Esmolol
Labetalol
Enelaprilat
AfraTafreeh.com
Nitroprusside
Nicardipine, clevidipine
Fenoldopam

HT with pregnancy Alpha methyl dopa ACEIs, ARBs

Labetalol, hydralazine
132 | Pharmacology

Worksheet
To do
Anti hypertensive causing side effect of SLE

DOC hypertensive emergency in pregnancy

First line drugs for treating hypertension are

Hypertension with BPH preferred anti hypertensive

drug is

AfraTafreeh.com
Adverse effects of sodium nitroprusside

CCB useful for hypertensive emergency

D1 agonist useful for hypertensive emergency is

Preferred antihypertensive medication of young

patient with chronic migraine problem is
 6 Blood

CONCEPTS
 Concept 6.1 Thrombolytic agents
AfraTafreeh.com
 Concept 6.2 Anti coagulants

 Concept 6.3 Anti platelets

 Concept 6.4 Hypolipidemic agents

134 | Pharmacology
Concept 6.1 : Thrombolytic Agents
Learning objectives:
• To know the examples for thrombolytic agents
• To know the uses , contra indications of thrombolytic agents

Time Needed
1 reading
st
10 mins
2 reading
nd
5 mins

Examples of Fibrinolytics:
Drug Source T½
Streptokinase Obtained from β-hemolytic Group C streptococci 60 – 80 min
Urokinase Commercially prepared from cultured human kidney cells 10 – 15 min
Alteplase (rt-pA) Recombinant tissue plasminogen activator (tPA) 4 – 8 min
Reteplase Modified longer acting form of rt-PA 13 – 15 min
Tenecteplase Genetically engineered substitution mutant of native t-PA 13 – 15 min

Newer Drugs
AfraTafreeh.com
• ALFIMEPRASE- obtained from copperhead snake (venom).
• DESMOTEPLASE- obtained from Vampire bat (saliva).

One-liners:
• Thrombolytic drugs acts by activation of plasminogen.
• First fibrinolytic to be clinically used – Streptokinase.
• Fibrinolytic resistant to inhibition by tissue plasminogen activator inhibitor-1 – Tenecteplase.
• Fibrinolytic that can be administered as a single IV bolus dose over 10 seconds – Tenecteplase.
• Thrombolytic agents are very useful for ST elevation MI, and for acute pulmonary embolism

Contraindications to Pharmacological Thrombolysis:

• h/o intracranial hemorrhage
• h/o ischemic stroke in the past 3 months
• h/o head injury in the past 3 months
• Intracranial tumour / vascular abnormality / aneurysms
• Active bleeding / bleeding disorders
• Peptic ulcer
• Esophageal varices
• Any wound or recent fracture or tooth extraction
• h/o major surgery within 3 weeks
• Uncontrolled hypertension
• Pregnancy
 Blood | 135
Anti fibrinolytics (antidote for thrombolytic agents)
• Epsilon-aminocaproic acid (EACA)
• Tranexemic acid
• Aprotinin

One-liners:
• Tranexamic acid is – 7 times more potent than EACA

AfraTafreeh.com
136 | Pharmacology
Concept 6.2 : Anticoagulants
Learning objectives:
• To know the classification of anticoagulants
• To know the various types of injectable anticoagulants and their uses
• To know the various types of oral anticoagulants and their uses

Time Needed
1 reading
st
30 mins
2 reading
nd
20 mins

Injectable Anticoagulants:
Unfractionated Heparin (UFH) v/s Low Molecular Weight Heparins:
UFH LMWH
Inhibits Xa = IIa Xa > IIa
Route of administration IV, s.c. Only s.c.
Subcutaneous bioavailability Poor Good
Plasma and tissue protein binding Extensive Negligible
Anticoagulant effect AfraTafreeh.com
Less consistent or less More consistent or more
predictable predictable
Regular monitoring Required with aPTT Not required
May be needed in severe obese
patients and in renal failure
patients(monitor anti factor Xa)
Metabolism Metabolized by heparinase Mainly excreted unchanged by
enzyme in plasma kidney
Safe in renal failure Yes No
Adverse effects More likely Less likely
Heparin-induced thrombocytopenia Yes No
Antidote Protamine sulphate Not available

Examples of Low Molecular Weight Heparin (LMWH) Preparations:

• Enoxaparin • Nadroparin
• Dalteparin • Reviparin
• Tinzaparin • Pamparin
• Ardeparin • Certoparin
• Bemiparin • Semuloparin
 Blood | 137
Examples of synthetic pentasaccharides (acting via antithrombin III – inhibists
mainly Xa).

• Fondaparinux
• Idraparinux
• Idrabiotaparinux

One-liners:
• T½ of Fondaparinux – 17 h
• T½ of Idraparinux – 80 h.
• Idraparinux is administered as – weekly subcutaneous injections

Examples of Parenteral Direct Coagulation Factor Inhibitors:

Factor Inhibitors
IIa (Thrombin) Lepirudin
Desirudin
Bivalirudin
Pegmusirudin
Argatroban
AfraTafreeh.com Flovagatran
Va ART123
VIIa Tifacogin
Xa Otamixaban
XIa Clavatadine
Dual IIa/Xa Tanogitran

One-liners:
• Drug used in heparin-induced thrombocytopenia – Lepirudin
• Injectable DTI safe in renal failure- argatroban

Oral anticoagulants
Examples of Coumarin Derivatives:

• Bishydroxycoumarin
• Warfarin
• Acenocoumarol
• Ethylbiscoumacetate
• Phenindione
138 | Pharmacology
Factors Affecting Warfarin Action:
Enhance warfarin action Reduce warfarin action
• Debility • Pregnancy
• Malnutrition • Nephrotic syndrome
• Malabsorption • Genetic warfarin resistance
• Liver disease • Drugs that induce warfarin metabolism –
• Chronic alcoholism Barbiturates, Carbamazepine, Rifampicin,
• Hyperthyroidism Griseofulvin
• Newborns • Oral contraceptives
• Broad spectrum antibiotics
• Drugs causing hypoprothrombinemia –
Ceftriaxone, Cefoperazone
• Aspirin
• Drugs that displace warfarin from protein
binding sites – Long-acting sulfonamides,
Indomethacin, Phenytoin, Probenecid
• Drugs that inhibit metabolism –
Chloramphenicol, Erythromycin, Celecoxib,
Cimetidine, Allopurinol, Amiodarone,
Metronidazole, Tolbutamide, Phenytoin
• Liquid paraffin AfraTafreeh.com

One-liners:
• Name ‘warfarin’ is derived from ‘Wisconsin Alumni Research Foundation coumarin
derivative’.
• Dose of warfarin – 2-10 mg/d.
• Warfarin sensitivity – < 1.5 mg/d of warfarin is needed.
• Warfarin resistance – > 20 mg/d of warfarin is needed.
• Regular monitoring for warfarin is done with – PT-INR.
• PT-INR for warfarin is done – once a week.

Recommended INR for Various Indications of Warfarin:

• 2.0 – 2.5 • Prophylaxis of deep vein thrombosis
• 2.0 – 3.0 • Treatment of deep vein thrombosis
• Pulmonary embolism
• Transient ischemic attacks
• Prior to hip surgery
• 3.0 – 3.5 • Recurrent thromboembolism
• Arterial disease (MI)
• Prosthetic heart valves
 Blood | 139
Clinical Features of Fetal Warfarin Syndrome (CONTRADI SYNDROME):
• Hypoplasia of nose, eye sockets and hand bones
• Growth retardation
• CNS defects
• Fetal hemorrhages

Anticoagulation During Pregnancy:

• 1-12 weeks • Unfractionated heparin

• 12-36 weeks • Warfarin

• 36 weeks – Delivery • Unfractionated heparin

• Post-partum • Warfarin

Oral Direct Thrombin(IIa) Inhibitors (DTIs):

• Ximelagatran (withdrawn due to hepatotoxicity)
• Dabigatran
AfraTafreeh.com
Oral Factor Xa Inhibitors:
• Rivaroxaban
• Apixaban
• Edoxaban
• Batrixaban

Adverse effects of heparin and warfarin (ABOUT is the pneumonic)

Heparin Warfarin

A- alopecia A- alopecia
B-bleeding B- bleeding
O-osteoporosis O- oral( Gi intolerance)
U-utricaria( Hypersensitivity) U- dermatitis
T- thrombocytopenia T- teratogenicity
Hyperkalemia
Warfarin may also causes hypercoagulation, dermal
necrosis, purple toe syndrome due to inhibition of
protein C
140 | Pharmacology
Antidotes for Various Anticoagulants:
Anticoagulant Antidote
Heparin Protamine sulphate
Warfarin Vitamin K1(Phytonadione)

Idrabiotaparinux Avidin
Oral direct thrombin inhibitor( dabigatran) Idarucizumab
Oral direct Xa inhibitors Andexanet alfa-
Common antidote for both oral IIa and Xa inhibitor is CIRAPARANTAG

One-liners:
• Protamine sulphate is obtained from – sperm
• of certain fish.
• 1 mg of protamine sulphate neutralizes – 100 U of heparin
• Protamine antagonizing heparin is example for- chemical antagonism

AfraTafreeh.com
 Blood | 141
Concept 6.3 : Antiplatelet Drugs
Learning objective: T
 o know the various types of antiplatelet drugs and their
mechanism of action

Time Needed
1 reading
st
20 mins
2 reading
nd
10 mins

TXA2 Antagonist P2Y12(ADP) Antagonist GP2B3A ANT Agonist PAR-1 Antagonist

Txa synthesis inhibitors Ticlopidine Clopidogrel Abciximab Eptifibatide Vorapaxar Atopaxar

Low dose aspirin Prasugrel Ticagrelor Tirofiban
(inhibits irreversibly Cangrelor
COX 1 enzyme)
Dezoxiben- inhibits
thromboxane synthase
enzyme

TXA2 receptor blockers

Ifetroban AfraTafreeh.com
Sultroban Daltroban
Losartan Vapiprost

Avoid omeprazole with

clopidogrel

Safer PPI that donot

have drug interaction
with clopidogrel are
pantoprazole and
rabeprazole

Monitoring:
• Anti platelet drugs- prolongs bleeding time
• Heparin ( intrinsic pathway)- prolong aPTT
• Warfarin ( extrinsic pathway)- prolongs PT
• LMWH- monitor anti factor Xa ( renalfailure, obese)
142 | Pharmacology
Drugs Employed in Drug Eluting Stents:

• Paclitaxel
• Sirolimus (Rapamycin)
• Temsirolimus
• Everolimus
• Zotarolimus

Drugs to be Stopped before Surgery:

• ACEi • On day of surgery

• ARBs • On day of surgery

• Lithium • 2 days

• Sulfonylureas • 2-4 days

• Metformin • 2-4 days

• Oral anticoagulants • 4 days

• Estrogen containing OCPs • 2-4 weeks

AfraTafreeh.com
 Blood | 143

Worksheet
To do
Example for oral direct thrombin inhibitor

Antidote for oral direct Xa inhibitor

Antidote for thrombolytic agents

Clot specific thrombolytic are

AfraTafreeh.com

Antiplatelet drug having PAR antagonistic action are

DOC for treating patient with heparin induced

thrombocytopenia

Clopidogrel and omeprazole drug interaction is due

to which microsomal enzyme
144 | Pharmacology
Concept 6.4 : Hypolipidemic Agents
Learning objectives:
• To know the different goup of cholesterol lower agents
• To know the action, uses and adverse effects of statins
• To know the mechanism of action adverse effects of fibrates
• To know the actions of niacin, bile acid binding resins
• To know the newer cholesterol lowering agents

Time Needed
1 reading
st
40 mins
2nd reading 20 mins

Statins
Drugs Mechanism of action a Adverse effects

Lovastatin Inhibits HMG CoA reductase Myopathy

Simvastatin Upregulate LDL receptors Myalgia
Pravastatin Rhabdomyolysis
Fluvastatin Hepato toxic
Atorvastatin C/I- pregnancy
Cerivastatin
AfraTafreeh.com
Rosuvastatin
Pitavastatin

Prodrug Lovastatin , Simvastatin

Long acting Atorvastatin, Rosuvastatin

Least myopathy Pravastatin

Rosuvastatin

Statin Metabolism
CYP3A4, 3A5 CYP2C9 No hepatic metabolism

Atorvastatin Fluvastatin Pravastatin

Lovasatatin Least drug interaction
Simvastatin Least myopathy
Less entry to CNS
↓ Sr. fibrogen

Preferred in Renal Dysfunction Preferred in Liver Dysfunction

Atorvastatin Pravastatin, Rosuvastatin

 Blood | 145

11yr & older children 8yr & older children

Atorvastatin Pravastatin
Lovastatin
Simvastatin

One-liners:
• Statin may increase risk of developing diabetes
• When statin dose are doubled there will be addition reduction 6% LDL-C from the base
line value (rule of six)
• Cholesterol lowering effect of statin achieved within 7-10days of therapy
• Statin not giving benefit in patients with Homozygous Familial Hypercholesterolemia
• PLEOTROPIC EFFECT- Anti inflammatory action, Reduces endothelial dysfunction
• Anti oxidant action

Fibrates
Drug Mechanism of action ADR

Clofibrate PPAR alpha stimulation- Myopathy, hepatotoxic

Fenofibrate
AfraTafreeh.com
activating lipoprotein lipase –
Bezofibrate reducing triglycerides
Gemfibrozil

Niacin (vit B3)

Mechanism of action Actions Adverse effects

Inhibits lipolysis in adipose Reduces LDL, LPa Cutaneous Flushing

tissue Increases HDL Dyspepsia
Hyperurecimia
Diabetes
Hepatotoxicity
Myopathy

Drugs Inhibiting Dietary Cholesterol Absorption

Drug Mechanism of action Adverse effecgt

Ezetimibe Inhibits NPC1L1 (Niemann Pick steatorrhea

C1 Like1
146 | Pharmacology
Bile Acid Sequestrants
Drugs Mechanism of action Adverse effects

Cholestyramine Binds with bile salt loss more bile Increases the activity of hepatic
Colestipol acid synthesis taking place from HMG coA reductase- poor long
Colesevelam- cholesterol- leads to depletion term efficacy
cholesterol
Compensatory increase in
LDL receptor in liver –leads to
reduction in LDL

Newer Drugs
PCSK9 inhibitor- Cholesterol ester Microsomal Inhibits conversion Inhibits ApoB100
transport protein triglyceride Cholesterol to Reduces VLDL
inhibitor transport cholesterol ester
protein inhibitor ACAT- 1 inhibitor

Alirocumab Torcetrapib Lomitapide Avasimibe Mipomersen

Evolocumab Dalcetrapib
Evacetrapib
AnacetrapibAfraTafreeh.com
 Blood | 147

Worksheet
To do
Statin preferred in renal disease

Cholesterol lowering agent safe in pregnancy

PPAR alpha agonists are

AfraTafreeh.com
Adverse effects of niacin

Examples for MAB useful for lowering cholesterol

CETP inhibitors useful for lowering cholesterol

 7 Diuretic & Anti

CONCEPTS
 Concept 7.1 Diuretic & Anti Diuretics
AfraTafreeh.com
 Diuretic & Anti | 149
Concept 7.1 : Diuretic & Anti Diuretics
Learning objectives:
• To know the site of action and mechanism of actions of various diuretics
• To know the uses and adverse effects of various class of diuretics
• To know the uses and adverse effects of antidiuretic

Time Needed
1 reading
st
40 mins
2 reading
nd
20 mins

Sites and Mechanisms of Actions of Diuretics:

Diuretic Site of Action Mechanism of Action

Carbonic anhydrase inhibitors Proximal convoluted tubule Inhibit Na+ and HCO3- absorption
due to carbonic anhydrase enzyme

Osmotic diuretics PCT, Mainly in the loop of Henle Draw water by osmosis

Loop diuretics Thick ascending limb of loop of Inhibit Na+-K+-2Cl- symport

Henle

Thiazides Early distal convoluted tubule Inhibit Na -Cl symport

+ -

AfraTafreeh.com
Aldosterone antagonists Late distal convoluted tubule Inhibit Na+ and H2O absorption by
aldosterone

Amiloride Late distal convoluted tubule Inhibits epithelial sodium channel

(ENaC)

Triamterene Late distal convoluted tubule Inhibits epithelial sodium channel

(ENaC)

Effect of Diuretics on Urine Electrolytes:

Drug Urine electrolyte excretion Max % of Efficacy
filtered load
Na+ K+ Cl- HCO3- excreted

Furosemide ↑↑↑ ↑ ↑↑ ↑,- 25 High

Thiazide ↑↑ ↑ ↑ ↑ 8 Intermediate

Acetazolamide ↑ ↑↑ ↑,- ↑↑ 5 Mild

Spironolactone ↑ ↓ ↑ -,↑ 3 Low

Amiloride ↑ ↓ ↑ -,↑ 3 Low

Mannitol ↑↑ ↑ ↑ ↑ 20 High
150 | Pharmacology

One-liners:
• All diuretics acting proximal to late DCT cause – Potassium loss and hypokalemia.
• All diuretics acting at or distal to late DCT cause – Potassium retention and hyperkalemia.
• Maximum hypokalemia caused by – Carbonic anhydrase inhibitors (due to most
proximal action).
• All diuretics require access to tubular lumen except – Aldosterone antagonists.

Carbonic anhydrase enzyme inhibitors

Drugs Uses Adverse effects Contraindications
• Acetazolamide • Acetazolamide- • Metabolic acidosis • Hepatic failure
• Dorzolamide • Mountain sickness • Hypokalemia • Metabolic acidosis
• Brinzolamide • Periodic paralysis • Hypersensitivity
• Absence seizure and reaction (bone marrow
catamenial seizure suppression)
• To control intra cranial
tension
• For making urine
alkalinization
• AfraTafreeh.com
For glaucoma
• Oral – acetazolamide
• Topical – dorzolamide,
brinzolamide

Examples of Loop Diuretics:

• Furosemide. • Axosemide.
• Bumetanide. • Piretanide.
• Torsemide. • Tripamide.
• Ethacrynic acid.

One-liners:
• Synergistic diuretic activity seen with the combination of – Loop diuretic + Thiazide
diuretic.
• Loop diuretics are – High ceiling diuretics.
• All loop diuretics are well absorbed orally except – Axosemide.
• All loop diuretics are mainly eliminated by kidney except – Torsemide.
• Most potent loop diuretic – Bumetanide.
• Bumetanide is – 40 times more potent than furosemide.
• Torsemide (longest acting) is – 3 times more potent than furosemide.
 Diuretic & Anti | 151
Drugs that Increase the Risk of Ototoxicity with Loop Diuretics:
• Aminoglycosides. • Paclitaxel.
• Carboplatin. • Vancomycin .

• Highly ototoxic loop diuretics is Ethacrynicid.

• Loop diuretic aggrevates the adverse effects of digoxin by causing hypokalemia and
hypomagnesemia.

• Diuretic of choice in the presence of Renal failure is loop diuretics, thiazides are ineffective except
metolazone.
• Loop diuretic relieve only the symptoms of LVF not modify the disease.

Examples for thiazide diuretics

• Hydrochlorthiazide. • Metolazone.
• Hydroflumethiazide. • Quinethazone.
• Benzthiazide . • Xipamide.
• Bendroflumethiazide. • Indapamide.
• Chlorthalidone. • Clopamide

Thiazides:
AfraTafreeh.com
Drug Daily dose (mg) Duration of action (h) Carbonic anhydrase
inhibition

Hydrochlorthiazide 12.5-100 6-12 +

Chlorthalidone 50-100 48 ++

Metolazone 5-20 12-24 +

Xipamide 20-40 12 +

Indapamide 2.5-5 12-24 -

Clopamide 10-60 12-18 ±

One-liners:
• Thiazides are not effective in renal failureexcept – Metolazone.
• Thiazide and loop having opposite action on calcium (loop looses calcium in
urine, thiazide retains calcium from urine).
• Thiazide have anti diuretic action (DOC- nephrogenic DI).
• Thiazide are first line therapy for hypertension.
• JNC VIII (first line therapy for HT) are- Thiazides, ACEI, ARBs and CCB.
• Thiazides because of inhibiting calcium excretion useful in Idopathic
hypercalciuria (William’s syndrome), Treatment for Calcium Nephrolithiasis
152 | Pharmacology

Comparing to loop diuretic thiazide diuretic causes maximum metabolic side effects like- hyperuricemia,
hyperglycemia and hyperlipidemia
Thiazide diuretic may cause erectile dysfunction which may aggravated when given with beta blokcers

Potassium Sparing Diuretics:

Aldosterone antagonist Epithelial sodium channel (ENac) blockers
Spironolactone Amiloride
Canrenone (active metabolite of spirinolatone) Triamterene
Eplerenon (no problem of gyenecomastia) Anti microbial having ENaC blocking property-
Drospirenone (progesterone) Pentamidine Trimethoprim

Potassium sparing diuretics:

Drug Action Uses Adverse effects
Spironolactone Acting from interstitum • Primary Hyper- Hyperkalemia
against aldosterone aldosteronism (conn’s Metabolic acidosis
receptor syndrome). Impotence
• Edema of Liver Cirrhosis. Gynecomastia
• Heart Failure (disease
modifying drug)
AfraTafreeh.com
Amiloride Acting from lumen • Lithium-induced diabetes Hyperkalemia
against ENac insipidus (DI). Metabolic acidosis
• Cystic fibrosis.
• Treatment for Liddle’s
Syndrome (↑ENaC).

One-liners:
• DOC for Lithium-induced DI – Amiloride.
• DOC for nephrogenic DI- thiazides
• DOC for cranial DI- DESMOPRESSIN
• DOC for cirrhotic edema – Spironolactone.

Osmotic Diuretics
Drug Site of action Uses Adverse effects Contra indication
Mannitol LOH Glaucoma ADR- C/I-
Isosarbide PCT Cerebral edema Hyponatremia Pul edema- LVF
Urea Cisplatin toxicity Headache Cerebral Hge
Glycerol Dialysis
disequilibrium
syndrome
 Diuretic & Anti | 153
Natriuretics:
Example Mechanism Current status
Nesiritide Recombinant BNP analogue Approved for acute decompensated
heart failure Given IV, short acting
(20minutes)
Rapid metabolism by vasopeptidase
Carperitide Recombinant ANP analogue Not used much nowadays
Omapatrilat sampatrilat Dual neutral endopeptidase (NEP) and Withdrawn due to high incidence of
ACE inhibitor angioedema
Sacubitril Ecadotril Neutral endopeptidase (NEP) inhibitor Recently approved for CHF

One-liners:
• Nesiritide is administered as an – IV infusion (due to short T½)

Anti-diuretics (Vasopressin)
Name Uses
Selective v2 analogue Desmopressin Cranial di
AfraTafreeh.comNocturnal enuresis
Hemophilia
Bleeding due to- Def vwf
Selective v2 antagonist Lixivaptan, Mozavaptan, (drug of choice for SIADH
Tolavaptan.
Selective v1 analogues terlipressin, felypressin, esophageal varices, but drug of
lypressin choice is octreotide
Selective v1 antagonist Relcovaptan Hypertension
Non selective V1 and V2 blocker Conivaptan, maximally blocks in SIADH, given IV
V2 than V1

One-liners:
Drugs causing SIADH- Chlorpropamide. MAO inhibitor, Carbamazepine,
Phenothiazine, Oxytocin high dose SSRI, TCA, Vasopressin, Vincristine,
Nicotine
154 | Pharmacology

Worksheet
To do
Diuretic of choice for rapid relief of symptom of
LVF

Diuretic causing metabolic acidosis

Diuretic contra indicated in liver failure

Diuretic useful in nephrogenic DI

AfraTafreeh.com
Diuretic cause adverse effect of gynecomastia

Drug of choice for nocturnal enuresis

Example for selective V1 antagonist

Antimicrobial having ENac blocking property

8 Central Nervous System

CONCEPTS
 Concept 8.1 Sedative & Hypnotics

 Concept 8.2 Ethyl & Methyl Alcohol

 Concept 8.3 Anti Epileptics

 Concept 8.4 Anti Parkinosinian Drugs

AfraTafreeh.com
 Concept 8.5 Anti Psychotics

 Concept 8.6 Anti Manic Drugs

 Concept 8.7 Anti Depressants

 Concept 8.8 Anti Anxiety Agents

 Concept 8.9 Opioids

 Concept 8.10 Newer Drugs In Cns

156 | Pharmacology
Concept 8.1 : Sedative & Hypnotics
Learning objectives:
• To know synthesis, storage release and metabolism of neurotransmitter GABA
• To know drugs acting via GABA receptors
• To the various uses of BZD
• To know the drugs useful for treating BZD poisoning
• To know the general properties of barbiturates
• To know “Z” compounds
• To know the GABA analogues
• To know melatonin analogues

Time Needed
1st reading 30 mins
2 reading
nd
20 mins

Synthesis, storage, release and metabolism of GABA

AfraTafreeh.com

Fig. 8.1
 Central Nervous System | 157
GABA
Enzyme involved in synthesis Glutamic acid decarboxylase
Drugs activating glutamic acid decarboxylase Sodium valproate,
Enzyme involed in metabolism of GABA GABA transaminase
Drugs inhibiting GABA transaminase Vigabatrine, sodium valproate
GABA undergoes reuptake by GABA transporter (GAT)
GABA reuptake blocked by Tiagabine

Drugs acting on GABAA receptor:

Site Agonist Antagonist
1 • GABA • GABA • Bicuculline
• Muscimol
2 • Alpha,gamma unit of GABA • Benzodiazepines • Flumazenil
A receptor • DMCM / β-carboline
(Inverse agonist)
3 • Other miscellaneous sites • Mucimol, Alphaxolone • Antagonist-
• Alcohol, Propofol • Bicuculline
• Picrotoxin- Cl channel
4 • Barbiturates
AfraTafreeh.com
• Ivermectin • No specific antidote
• Alpha,beta units of GABA A
receptor

Uses of BZD
Benzodiazepines used as anti- Benzodiazepines used as Benzodiazepines used as Pre-
anxiety drugs Anticonvulsants Anaesthetic Medications
Chlordiazepoxide. Diazepam. Diazepam.
Diazepam. Lorazepam. Lorazepam
Oxazepam. Clonazepam. Midazolam.
Lorazepam. Clobazam. Remimazolam
Alprazolam.

Benzodiazepine Uses
Diazepam DOC-Acute febrile seizure Status epilepsy
delirium tremors
Lorazepam DOC- Status epilepsy
Alprazolam Insomnia, Anxiety Disorder
chlordiazepoxid DOC- alcohol withdrawal
(delirium tremors)
158 | Pharmacology

One-liners:
• Specific antidote for benzodiazepine poisoning / overdose – Flumazenil.
• Flumazenil is administered as – IV infusion.
• T½ of flumazenil – ~ 1 hr.
• Duration of action of flumazenil – 30 to 60 min.
• The maximum dose of flumazenil to be administered in a case of suspected benzodiazepine
overdose is – 5 mg.
• Competitive antagonist of BZD – FLUMAZENIL.
• Non competitive antagonist of BZD – BICUCULINE.
• Competitive antagonist of GABA – BICUCULINE.
• Direct chloride channel blocker – PICROTOXIN.
• Inverse agonist of benzodiazepine – DMCM (β-carboline).
• BZD-Safe in Liver Failure:
□ Temazepam, Lorazepam, Oxazepam:
□ Date Raping Drug - Flunitrazepam (Anterograde amnesia)
□ Ketamine (general anaesthetic agent also used as date raping agent)

Barbiturates:
• Thipentone sodium- intravenous induction GA, ultra short acting (due to rapid redistribution)
•
AfraTafreeh.com
Methohexitone- useful in electro convulsive therapy
• Phenobarbitone is the active metabolite of primidone
• Classical synptoms of barbiturate poisoning Flabby, Comatose, shallow and failing Respiration, bullous
eruptions.
• Barbiturate are microsomal enzyme inducer- C/I in acute intermittent porphyria

Non-benzodiazepine Sedative Hypnotics (Z compunds):

• “Z” compounds (useful in sleep onset insonmnia)
• Zolpidem (most commonly used drug)
• Zaleplone (shortest acting)
• Zopiclone
• Eszopicolne
 Central Nervous System | 159
GABA Analogues:
Drug Mechanism of action Remarks
1 Tiagabine • GABA reuptake inhibitor
2 Valproate • GABA Transaminase Inhibitor • DOC - infabtile spasm with tuberous
sclerosi
• ADR - bilateral visual field defect,
psychosis
3 Ganaxalone • Neurosteroid • Useful in catamanial seizure
• Direct chloride channel opener • Abasence seizure
4 Levatiracetam • Ligand for SV2A protein (which • Anti epileptic
modify release of GABA &
Glutamate)
5 Valproate • Inhibits GABA transaminase • Broade spectrum anti epileptic
• Stimulate glutamic acid • Also useful in prophylaxis of chronic
decarboxylase migraine, Bipolar disorder
6 Gabapentin • Promotes synthesis and release of • DM neuropathy, post herptic
Pregabalin GABA neuralgia
• Binds to alpha 2 delta subunit of
voltage gated sodium channel,
inhibits voltage gated calcium current
AfraTafreeh.com
and decreases synaptic transmission

GABA B (GPCR)
Agonist:
Baclofen(central acting skeletal Muscle relaxant, useful in Hiccough, controls Craving of
alcohol).
Antagonist: Saclofen

Melatonin analogues-
• Ramelteon – synthetic melatonin analogue.
• Mechanism of ramelteon – Agonist at MLT-1 and MLT-2 receptors.
• Oral bioavailability of ramelteon – < 2 h.
• T½ of ramelteon – ~ 2 h.
• Plasma protein binding of ramelteon – ~ 80%.
• Tasimelteon – Congener of ramelteon. Melatonin MLT-1 and MLT-2 agonist for treatment of non-24-
hour sleep–wake disorder in totally blind people.
• AGOMELATINE- Agonist on MT1/ MT2, Antagonist on 5-HT2C – useful as an anti depressant.

Newer drug for insomnia

SUVOREXANT (FDA approved)- Non- selective OREXIN receptor antagonist useful
in treating Insomnia.
160 | Pharmacology

Worksheet
To do
GABA transaminase inhibitors

GABA reuptake inhibitor

DOC of status epilepticus

Antidote for BZD

BZD safe in liver failure

AfraTafreeh.com

Melatonin analogue useful in insomnia

Orexin receptor antagonist useful in insomnia

Examples for Z compounds

 Central Nervous System | 161
Concept 8.2 : Ethyl & Methyl Alcohol
Learning objectives:
• To know the Percentages of Alcohol in Various Alcoholic Beverages
• To know drugs useful for deaddiction and preventing craving for alcohol
• To know the drugs useful for treating alcohol withdrawal symptoms
• To know the drugs useful for treating methyl alcohol poisoning

Time Needed
1st reading 20 mins
2 reading
nd
10 mins

Percentages of Alcohol in Various Alcoholic Beverages:

Alcoholic beverage % of alcohol

Malted liquors (Stout, Beer) 3–6

Strong beer Up to 10

Light wines (Claret, Cidar) 9 – 12 (does not exceed 15)

Fortified wines (Port, Sherry) 16 – 22

Effervescent wines (Champagne) AfraTafreeh.com

12 – 16

Spirits (Rum, Gin, Whiskey, Brandy, Vodka) 40 – 55

Rectified spirit 90

Absolute alcohol 99

One-liners:
• Denatured / Methylated spirit: 5 parts of methyl alcohol(wood naphtha) + 95 parts
of rectified spirit.

Drugs useful for deaddiction & prevention of craving against alcohol:

Deaddiction Anti-craving agents

• Disulfiram (aldehyde dehydrogenase enzyme • Naltrexone (opioid antagonist)

inhibitor) • Acamprosate (NMDA blocker with GABA
agonist action)
• Topiramate (anti epileptic)
• Baclofen (GABA B agonist)
• Ondansetron
• Fluoxetine
162 | Pharmacology
Drugs causing disulfiram like reaction:
Deaddiction Drugs causing disulfiram like reactions
• Disulfiram • Chlorpropamide, Cefoperazone
• Metronidazole
• Procarbazine
• Griseofulvin
• Tinidazole
• Nitrofurantoin

Drugs useful for treating alcohol withdrawal symptoms

• DOC for uncomplicated alcohol withdrawl (delirium and Tremor) – Chlordiazepoxide.
• DOC for complicated alcohol withdrawl –
• Diazepam.

One-liners:
• Disulfiram inhibits – Aldehyde dehydrogenase enzyme.
• Chronic alcoholism causes thiamine deficiency.
• Chronic alcoholism will induce CTP2E1 enzyme.
• AfraTafreeh.com
Alcohol undergoes zero order kinetic of excretion.

Methanol Poisoning:
• Etiology: Consumption of illicit / adulterated liquor.
• Toxic level: 60-100 mL.
• Primary toxic metabolite: Formic acid.
• Formic acid mainly accumulates in: Retina and optic nerve.
• Clinical features: Obscured, snowy vision that ultimately progresses to complete
blindness.
• Antidotes: Ethanol and Fomepizole.
• Ethanol: Saturates alcohol dehydrogenase enzyme.
• Fomepizole: competitively inhibits alcohol dehydrogenase enzyme.
• Calcium leucovorin and hemodialysis are also effective.
 Central Nervous System | 163

Worksheet
To do
Drug inhibiting alcohol dehydrogenase

Drug inhibiting aldehyde dehydrogenase

Mechanism of action of acamprosate

AfraTafreeh.com
Wernicke encephalopathy is due to deficiency of

Microsomal enzyme induced by chronic alcoholism

is

Antifungal drug causing disulfiram like reaction is

164 | Pharmacology
Concept 8.3 : Anti Epileptic Drugs
Learning objectives:
• To know the classification of antiepileptic drugs
• To know the uses and adverse effects of anti epileptics
• To know newer antiepileptic drugs

Time Needed
1 reading
st
40 mins
2 reading
nd
25 mins

Classification of antiepileptic drugs:

Predom- inant Mechanism of Examples
Action

Sodium channel blockers • Phenytoin and Fosphenyt- oin(prodrug, water solu- ble)
• Carbamazepine, Oxcarba- zepine and Eslicarbazepine
• Valproate and Divalproex
• Lamotrigine
• Topiramate
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• Rufinamide (approved for
• lennox gestaut syndrome)
• Lacosamide

GABA • Progabide (prodrug, gets converted to GABA)

enhancers • Vigabatrin (Inhibits GABA transaminase en- zyme)
• Tiagabine (Inhibits GABA transporter-1 mediated re- uptake of
GABA)
Direct:
• Barbiturates (Increase duration of chloride chan- nel opening)
• Benzodiazepines (In- crease frequency of chlo- ride channel
opening)

T-type calcium channel blockers • Ethosuximide, Valproate

• Zonisamide
• Gabapentin
• Pregabalin
 Central Nervous System | 165

Fig. 8.2

Other NMDA blockers:

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Fig. 8.3
Anti epileptic drugs uses and adverse effects
166
Generic Name Trade Name Principal Uses Typical Dose: Half-Life Therapeutic Adverse Effects Drug
Dose Interval Range Neurologic Systemic Interactionsa
Brivaraostam Bnviact FocaFonset 100-200 mg/d: 7-10 h Mot established Fatigue Gastrointestinal May increase
bid Dizziness irritation carbamazepine-
Weakness epoxide causing
Ataxia decreased
Mood changes tolerability
May increase
phenytoin
| Pharmacology

Carbamazepine Tegretolc Tonic-c Ionic 600-1800 mg/d 10-17 h 4-12 µg/mL Ataxia Aplastic anemia Level decreased
Focal-onset (15-35 mg/ (variable due to Dizziness Leukopenia by enzyme-
kg, child 1: autoinduction: Diplopia Gastrointestinal inducing
bid (capsules complete Vertigo irritation drugsb Level
or tablets), 3-5 wk after Hepatotoxicity increased by
tid-qid (oral initiation) Hyponatremia erythromycin,
suspension) propoxyphene,
isoniazid,
cinrietidine,
fluoxetine
Clobazam Onfi Lennox 40-50 mg/d 36-42 h Net established Fatigue Constipation Level increased
Gastaut (5-20 mg/d for (71-82 h for Sedation Anorexia Skin rash by CYP2C19
syndrome patients <30 kg less active Ataxia inhibitors
body weight); metabolite) .Aggression
bid Insomnia
Clonazepam Klonopin Absence 1-12 mg/d: 24-48 h 10-70 ηg/mL Ataxia Anorexia Level decreased
Atypical qd-tid Sedation by enzyme-

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absence Lethargy inducing drugsb
Myoclonic
Ethos uximide Zarontin Absence 750-1250 mg/d 60 h, adult 40-100 µg/mL Ataxia Gastrointestinal Level decreased
(20-40 me/kg): 30 h, child Lethargy imtabon Skin rash by enzyme-
qd-bid Headache Bone martow inducing drugsb
suppression Level increased
by valproic acid
Felbamate Felbatoi Focal-onset 2400-3600 16-22 h 30-60 µg/mL Insomnia Aplastic anemia Increases
Lennox- mg/d, tid-qid Dizziness Hepatic failure phenytoin,
Gastaut Sedation Weight loss valproic
syndrome Headache Gastrointestinal acid, active
Tonic-clonic irritation carbamazepine
metabolite
Generic Name Trade Name Principal Uses Typical Dose: Half-Life Therapeutic Adverse Effects Drug
Dose Interval Range Neurologic Systemic Interactionsa
Gabapentm Neurontin Focal-onset 900-2400 mg/d; 6-9 h 2-20 µg/mL Sedation Gastrointestinal No known
bd-qid Dizziness irritation Weight significant
Ataxra Fatigue gain Edema interactions
LaCoSamide Vntipat FocaMwset 200-400 mg/d: 13 h Not established Dizziness Gastrointestinal Level decreased
bid Ataxra Diplopia imitation by enzyme-
Vertigo inducing drugsb.
Cardiac
conduction
(PR interval
prolongation)
Lamotrigine Lamictalc FocaFonset 150-500 mg/d: 25 h 2.5-20 µg/mL Dizziness Skin rash Stevens- Level decreased
Tonic-clonic bid (immediate 14 h {with Diplopia John son syndrome by enzyme-
release), daily enzyme- inducing
Atyptcaf Sedation
(extended inducers). 59 h drugsb and oral
absence release) (lower Ataxia contraceptives
(with valproic
Myoclonic daily dose acid) Headache Level increased
Lennox- for refimnens by valproic acid
Gastaut with valproic
acid: higher
syndrome
daily dose for
regimens with
an enzyme
inducer)

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Levetiracetarn Kepprac FocaFonset 1000-3000 6-8 h 5-45 µg/mL Sedation Anemia No known
mg/d: bid Fatigue Leukopenia significant
(immediate Incoordination interactions
release), daily Mood changes
(extended
release)
Oxcartiazepine: Trileptal Focal-onset 900-2400 mg/d 10-17 h 10-35 µg/mL Fatigue See Level decreased
Tonic-clonic (30-45 mg/kg. (for active Ataxia carbamazepine by enzyme-
child): bid metabolite) inducing drugsb
Central Nervous System

Dizziness
May increase
Diplopia
|

phenytoin
Vertigo
Headache
167
Generic Name Trade Name Principal Uses Typical Dose: Half-Life Therapeutic Adverse Effects Drug

168
Dose Interval Range Neurologic Systemic Interactionsa
Phenobarbital Luminal Tonoclonic 60-180 m^a: 90h 10-40 µg/mL Sedation Skin rash Level increased
Focal-onset qHd Ataxia by valproic
Contusion acid, piienytoin
Dizziness
Decreased
libido
Depression
Phenytoin Dilantin Tonic-clonic 300-400 mg/d 24 h (wide 10-20 µg/mL Dizziness Gingival Level increased
| Pharmacology

(diphenyl Focal-onset (3-6 rng/kg. variation, dose- Diplopia hyperplasia by isoniazid,

hydantoin) adult 4-8mg/kg. dependent) Ataxia LymphadenofHttiy sulfonamides,
child); qd-tid Incoordination Hirsutism fluoxetine
Confusion Osteomalacia Level decreased
Facial coarsening ty enzyme-
Skin rash inducing drugsb
Altered folate
metabolism
Primidone Mysoline Tonic-clonic 750-1000 mg/d: Primidone. Primidone, Same as Level increased
Focal-onset bid-tid 8-15h 4-12 µg/mL phenobarbital by valproic acid
Phenobarbital, Phenobarbital, Level decreased
90 h 10-40 µg/mL by phenytoin
(increased
conversion to
phenobarbital)
Rufinamide Banzal Lenrrox- 3200 mg/d (45 6-10 h Not established Sedation Gastrointestinal Level decreased

AfraTafreeh.com
Gastaut mg/kg, child); Fatigue irritation by enzyme-
syndrome bid Dizziness Leukopenia: inducing drugsb
Ataxia Cardiac Level increased
Headache conduction by valproic acid
Diplopia (QT interval May increase
shortening) phenytoin
Generic Name Trade Name Principal Uses Typical Dose: Half-Life Therapeutic Adverse Effects Drug
Dose Interval Range Neurologic Systemic Interactionsa
Tiagabine Gabitril Focal-onset 33-56 mg/d; 2-5 h (witti Net established Confusion Gastrointestinal Level decreased
bid-bid (as enzyme Sedation irritation by enzyme-
adjunct to inducing
inducer!, Depression
enzyme- drugs’1
inducing 7-9 h (without Dizziness
antiepiieotic enzyme Speech or
Aug teg; men) inducer) language
prat) Ferns
Paresthesias
Psychosis
Topiramate Topamax Focal-onset 200-400 mg/d: 20 fl 2-20 µg/mL Psychomotor Renal stones Level decreased
Toni&clonic bid (immediate I immediate siowng (avoid use with coenzyme-
Lenwu- Gastaut please), daily releases 30 other cardan inducing
Sedation
syn<fctiroe (extended fi (extended ic anhydiase drugs’*
please) Speech or inhibitors)
release*
language Glaucoma weight
problems loss Hyoohurosis
Fatigue
Paresthesias
valproic acid Depakene Tonic-clonic 760-2000 mg/d 15 h 50-125 µg/mL Ataxia Hepatotomaty Level decreased
(valproate Depalotec Absence (20-60 mg/ Sedation Thrombocytopenia ty enzyme-
sodium, Atypical kg); bid-qid Gastrointestinal Inducing drugs”
Tremor
divalproex (immediate and Irritation weight
absence

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sodium) delayed release, gam Transient
Myoclonic daily (extended alopecia
Focal-onset release) Hyperammonemia
Atonic
Zonisamide Zonegran Focal-onset 200-400 mg/d; 50-68 h 10-40 µg/mL Sedation Anorexia Level decreased
Tonic-clonic qd-bid Dizziness Renal stones by enzyme-
Hypohidrosis inducing drugsb
Confusion
Headache
Central Nervous System

Psychosis
|
169
170 | Pharmacology

NON EPILEPTIC USES OF PHENYTOIN-

Tigeminal neuralgia, Digoxin INDUCED VT, Wound healing

Carbamazepine- First line DOC for tem- poral lobe eiplesy, Trigeminal neuralgia. Carbamazepine
has SIADH adverse effect.

Broad spectrum antiepileptic – sodium valproate (multiple mechanism of action- GABA agonism,Anti
glutamate NMDA blocker,Na channel block, T- CCB).
Valproate is DOC for- Myoclonic/ atonic/ clonic and tonic Absence /Lennox gestaut synd.

Valproate useful for prophylaxis of chronic migraine, Bipolar disorder, very effective in rapid
cyclers(>4episodes of maniaand depression /year).
Valproate most teratogenic, highly hepatotoxic.

• Phenytoin follows zero order kinetics at plasma levels – >10 µg/mL.

• Phenytoin toxicity occurs at plasma levels – >20 µg/mL.
• DOC for Rolandic epilepsy – Carbamazepine.
• DOC for trigeminal neuralgia – Oxcarbazepine.
• Antiepileptic drugs that can aggravate juvenile myoclonic epilepsy – Phenytoin and Carbamazepine
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(hence, contraindicated).
• All anti-epileptics are enzyme inducers except – Valproate.
• Anti-epileptic causing weight loss – Topiramate, zonisamide, felbamate.
• Anti epileptic causing weight gain- valproate, gabapentin.
• DOC for infantile spasms – ACTH.
• DOC for infantile spasms associated with tuberous sclerosis – Vigabatrin.
• Visual field contraction is a side effect of – Vigabatrin.
• DOC for status epilepticus – Lorazepam.
• DOC for emergency control of seizures – Lorazepam.
• Anti-epileptics contraindicated in porphyria – Barbiturates.
• Felbamate is on the verge of withdrawl due to – Aplastic anemia and Hepatotoxicity.
• Acetazolamide is effective in – Catamenial epilepsy at a dose of 10 mg/kg/d (Maximum: 1000 mg/d).

Newer antiepileptic drugs

Stiripentol – GABA transmission enhancer for severe myoclonic epilepsy in infants
(SMEI) / Dravet’s syndrome.
Retigabine (ezogabine)- potassium channel opener- useful in partial seizure.
 Central Nervous System | 171
Anti epileptics causing:
Weight gain Weight loss Eye problem
Sod valproate, gabapentin Topiramate, zonisamide, Vigabatrine- visual field defect
felbamate Topiramate- angle closure
glaucoma
ezogabine – retinal
degeneration

Anti epileptic useful

Prophylaxis of chronic migraine Bipolar disorder
Valproate Carbamazepine
Topiramate Valproate
Gabapentin Lamotrigine

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172 | Pharmacology

Worksheet
To do
Drug Mechanism of Action Uuses ADR

Topiramte

Retigabine

Vigabatrine

Ethosuximide
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Fosphenytoin

Oxcarbazepine

Acetazolamide
 Central Nervous System | 173
Concept 8.4 : Drugs Useful In Parkinson’s Disease
Learning objectives:
• To know the classification of anti Parkinson drugs
• To know the drugs useful for other movement disorder

Time Needed
1 reading
st
30 mins
2 reading
nd
20 mins

Classification of Antiparkinson Drugs:

Mechanism Examples
1 Dopamine precursors • Levo dopa
2 Dopamine receptor agonists • ERGOT
• Bromocriptine
• Cabergoline
• Pergolide
• NON ERGOT-
• Ropinirole
• Pramipexole
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• Rotigotine
• (trans dermal patch)
• Apomorphine (D4 agonist)
3 Peripheral dopa decarboxylase inhibitors • Carbidopa
• Benserazide
4 COMT inhibitors • Tolcapone (central + peripheral action, highly hepato
toxic, causing habidomyolysis and severe diarrhea)
• Entacapone (only peripheral)
5 MAO-B inhibitors • Selegiline
• Rasagiline
• Safenamide
6 Dopamine facilitator • Amantadine
7 Central anticholinergics • Trihexyphenidyl (Benzhexol)
• Benztropine
• Biperiden
• Procyclidine
• Promethazine
• (H1 antihistaminic)
• Orphenadrine
• (H1 antihistaminic)
174 | Pharmacology

One-liners:
• Single most effective drug for PD – Levodopa.
• Percentage of administered levodopa penetrating the blood-brain barrier – 1-3%.
• Oral bioavailability of levodopa can be decreased by – Pyridoxine.
• Drug used to treat vomiting due to levodopa- Domperidone.
• Somnolence is a side effect of – Dopamine receptor agonists.
• Chronic therapy of levodopa may cause on and off phenomina.
• Apomorphine (D4 agonist) useful in treatment of of phenomina.
• Levodopa contra indicated in malignant melanoma (levodopa is precursor or
melanin).
• Peripheral vasospasm can occur (ERYTHROMELALGIA) as a side effect of –
Bromocriptine.
• Dopamine receptor agonist withdrawn due to cardiac valvular fibrosis – Pergolide.
• Drug available as a transdermal patch applied over cranium – Rotigotine.
• Vomiting due to apomorphine (useful in off phenomina) can be prevented or treated by
– Trimethobenzamide.
• Orange discolouration of urine can be seen with – COMT inhibitors.
• Livedo reticularis is a side effect of – Amantadine and Bromocriptine.
• Ropinirole useful in restless leg syndrome.

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Drugs useful for on and off phenomena
• Entacapone (COMT inhibitor)
• Selegiline (MAO-B inhibitor)
• Istradefylline – adenosine (A2) block
• Rescue therapy – S/C APOMORPHINE (D4 agonist)

Newer Drug
Pemavanserin - 5HT2A inverse agonist useful for treatment of Parkinson disease
psychosis

Drugs for Multiple Sclerosis (MS):

Drug Mechanism of action

1 Interferons Bind to VLA-4 on T cells

(IFNβ-1a, IFNβ-1b) ↓
Interfere with adhesion of T cells to endothelium
and decrease T cell activation

2 Glatiramer acetate Induces Th2 cells

↓
Mediates bystander suppression of inflammation
 Central Nervous System | 175

3 Mitoxantrone Intercalates DNA and suppresses humoral

(antibiotic anti cancer drug) and cell-mediated responses

4 Natalizumab Monoclonal antibody against α4β1integrin

ADR- Progressive multifocal leuco ↓
encphalopathy Inhibits T cell trafficking into CNS

5 Fingolimod Sphingosine-1-phosphate receptor agonist

↓
ADR- bradycardia Sequesters lypmhocytes in lymph nodes

6 Teriflunomide (active metabolite of Dihydroorotate dehydrogenase inhibitor

leflunomide) ↓
Inhibits de novo pyrimidine synthesis

7 Dalfampridine Kv1 potassium channel blocker

↓
Increases duration of neurotransmitter release
at the neuromuscular junction

8 Dimethyl fumarate Activates Nrf-2 pathway

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One-liners:
• Only drug useful in secondary progressive multiple sclerosis (SPMS) – Mitoxantrone.
• Drug found to improve walking in patients with multiple sclerosis – Dalfampridine.
• Decreased progression of disease on EDSS seen with – Mitoxantone andNatalizumab.
• Naltalizumab given once in a month, not more than 18 months (due to risk of progressive
leuco encephalopathy).
• Drug useful for Huntington’s chorea and Tourette syndrome – Tetrabenazine
(dopaimine depletory). Chlorpromazine, Haloperidol (D2 antagonists).

Huntington’s chorea
Treatment DOC
D2 blockers

Chlorpromazine Tetrabenazine
Haloperidol Deutetrabenazine
(dopamine depletor)
176 | Pharmacology
Tourette syndrome Associated Tics
Treatment Non Responders
Alpha 2 agonist-
Clonidine Atypical antipsychotics
Guanafacine (Aripipraole)
Drugs useful for Amyotrophic lateral sclerosis
Riluzole- NMDA blocker
Edaravone- anti oxidant

New Drugs under Investigation for Alzheimer’s Disease (AD):

Drug Mechanism of action
1 Etazolate Positive allosteric modulator of the GABAA receptor at the barbiturate binding site;
Adenosine receptor antagonist; Selective PDE4 inhibitor.
2 Semagacestat γ-secretase inhibitor (Trials have been abandoned due to lack of efficacy).
3 Bapineuzumab Antibody against Aβ; Binds to Aβ and helps in its clearance (Trials have been
abandoned again due to lack of efficacy).
4 Gantenerumab Also an antibody against Aβ; Binds to Aβ and helps in its clearance.
5 Aducanumab Antibody against aggregated forms of β-amyloid; helps in amyloid clearance.
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 Central Nervous System | 177

Worksheet
To do
Drug useful for Parkinson disease psychosis

Drugs useful for restless leg syndrome

Drugs useful for on and off phenomena

AfraTafreeh.com
Anti viral drug useful in Parkinson disease

Antioxidant useful in ALS

MABs useful in multiple sclerosis

178 | Pharmacology
Concept 8.5 : Antipsychotic Drugs
Learning objectives:
• To know the classification of typical antipsychotic drugs
• To know the actions and adverse effects of typical antipsychotic agent
• To know the examples for atypical antipsychotic agents
• To know the uses and adverse effects of atypical antipsychotic agents
• To know the comparison between typical and atypical antipsychotic agents

Time Needed
1 reading
st
40 mins
2nd reading 25 mins

Examples of Typical Antipsychotics (Neuroleptics):

1. Phenothiazines

Aliphatics • Chlorpromazine
• Trifluopromazine

Piperidines • Thioridazine
• Mesoridazine
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Piperazines • Trifluoperazine
• Prochlorperazine
• Fluphenazine

2. Butyrophenones • Haloperidol
• Droperidol
• Trifluperidol

3. Diphenylbutylpiperidines • Penfluridol
• Pimozide

4. Thioxanthenes • Chlorprothixene
• Thiothixene
• Flupenthixol
• Zuclopenthixol

5. Dihydroindoles • Molindone

6. Dibenzoxapines • Loxapine
 Central Nervous System | 179
Typical antipsychotic drugs actions
D2 block Anti histaminergic Anticholinergic action Alpha blocking action
action

Anti psychotic action, Side effects Side effects like Side effects like
anti emetic action Sedation Dryness of mouth, Hypotension
Side effects Increase in appetite, constipation, urinary
EPS causing weight gain retension
galactorrhoea Lowering seizure
threshold, causing
seizure

One-liners:
• Antipsychotic used in Gilles de la Tourette syndrome – Haloperidol.
• Neurolept anesthesia – Droperidol + Fentanyl.
• Autonomic side effects are maximum with – Chlorpromazine (due to maximum
anticholinergic action).
• Autonomic side effects are minimum with – Haloperidol (due to minimum anticholinergic
action).
• Most potent D2 blocking antipsychotics are- butryphenones (haloperidol).
• AfraTafreeh.com
Mydriasis is maximum with – Thioridazine.
• Impaired ejaculation is seen with – Thioridazine.
• Ocular side effects maximum with – Thioridazine.
• Sedation is maximum with – Chlorpromazine.
• Seizures is maximum with – Chlorpromazine.
• Cholestatic jaundice side effect of – chlorpromazine.
• Blue-gray metallic discolouration of skin is seen with – Chlorpromazine.

Examples of Extrapyramidal Reactions:

• Parkinsonian features (Drug-induced Parkinsonism).
• Akathisia (most common type of EPS).
• Rabbit syndrome (peri-oral tremors).
• Acute dystonia.
• Tardive dyskinesia.
• Neuroleptic malignant syndrome.
180 | Pharmacology

One-liners:
• Extrapyramidal side effects maximum with – Haloperidol (due to minimum anticholinergic
action).
• Extrapyramidal reaction which may worsen with drug discontinuation – Tardive
dyskinesia.
• Most fatal of the extrapyramidal reactions – Neuroleptic malignant syndrome.
• Specific treatment of drug- induced parkinsonism – Central anticholinergics.
• Specific treatment of akathisia –
• Propranolol.
• Specific treatment of neuroleptic malignant syndrome – Dantrolene and Bromocriptine.
• VALBENAZINE (VMAT inhibitor)- approved for Tardive dyskinesia.

Examples of Atypical Antipsychotics:

• Clozapine. • Amisulpride.
• Olanzapine. • Levosulpride.
• Risperidone. • Quetiapine.
• Paliperidone. • Ziprasidone.
• Sulpride. • Aripiprazole.
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Asenapine
Paliperidone – active metabolite of risperidone, Approved for schizoaffective
disorder
Atypical antipsychotic drug causing metabolic Atypical antipsychotic drug no risk of metabolic
syndrome syndrome
• Clozapine • Ziprasidone
• Olanzapine • Aripiprazole
• Quetiapine • Asenapine

Long-acting injectable preparations

(risperidone, paliperidone, olanzapine, aripiprazole)
Drug Adverse effects
Clozapine Granulocytosis, seizure, cataract, myocarditis, metabolic syndrome
Quetiapine Cataract, priapism, metabolic syndrome
Olanzapine Metabolic syndrome, EPS
Risperidone EPS
Ziprasidone QT prolongation
 Central Nervous System | 181

Worksheet
To do
Most potent typical antipsychotic

Most oculo toxic antipsychotic drug

Atypical antipsychotic drug causing metabolic

syndrome

Atypical antipsychotic causing long QT

AfraTafreeh.com

Antipsychotic drug given sublingually

Atypical antipsychotic drug useful in schizoaffective

disorder
182 | Pharmacology
Concept 8.6 : Anti Manic Drugs
Learning objective
• To know the drugs useful for bipolar disorder
• To know the adverse effects and contra indications of lithium

Time Needed
1 reading
st
25 mins
2 reading
nd
15 mins

Drug useful for bipolar disorder:

Drugs useful for prophylaxis Drugs for mania Drugs for depression
(maintenance)

Lithium (has anti suicidal valproate, Carbamazepine, Lamotrigine

activity) Haloperidol, olanzapine,
quetiapine, ziprasidone,
risperidone, Aripiprazole
diazepam, Endoxifen

Therapeutic Plasma Levels of Lithium:

Maintenance of bipolar disorder
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0.5 – 0.8 mEq/L

Acute mania 0.8 – 1.2 mEq/L

Toxicity > 1.5 mEq/L

Hemodialysis is effective at > 4 mEq/L

Adverse effects Contra indications Drug interactions

Leucocytosis Pregnancy NSAID, DIURETICS aggravates

Tremor (most common) Sick sinus syndrome lithium toxicity
Hypothyroidism (inhibits release Lithium aggravate the action of
of T3 & T4 from thyroid follicle) non depolarising SMR
Increase urination( treated by
amiloride a Enac inhibitor)
Teratogenicity (Epstein
anomalies)
Cardio toxicity
Aggravation of psoriasis
 Central Nervous System | 183

One-liners:
• DOC for bipolar disorder –Lithium.
• DOC for rapid cyclers of bipolar disorder – Valproate.
• Lithium is used in Felty syndrome as it – Increases neutrophil count.
• Acute mania- valproate, Carbamazepine, haloperidol, olanzapine, aripiprazole
diazepam.
• Depressive phase - lamotrigine.
• Half life of lithium is 20 - 24hrs, lithium should be stopped 2 days before surgical
procedure

Incidences of Various Side Effects of Lithium:

1 Overt hypothyroidism 7 – 10%

2 Reversible T wave flattening ~ 20%

3 Polyuria / Diabetes insipidus ~ 60%

4 Fine tremors 15 – 70%

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• Amiloride is the DOC for treating
• lithium indued DI.
• Lithium contraindicated in pregnancy and in sick sinus syndrome.

One-liners:
• Frequency of fine tremors due to lithium – 8-12 Hz.
• Teratogenic effect of lithium – Ebstein’s anomaly.
184 | Pharmacology

Worksheet
To do
Half life of lithium

Anti epileptic drugs useful for mania

Most common side effect of lithium

Drug of choice for lithium induced DI

AfraTafreeh.com

Contra indication for lithium

Toxic plasma level of lithium

Drug aggravating lithium toxicity

 Central Nervous System | 185
Concept 8.7 : Antidepressants
Learning objectives:
• To the classification of antidepressants
• To know the uses and adverse effects of SSRI, TCA and other reuptake inhibitors
• To know the uses and adverse effects of MAO inhibitors
• To know the newer antidepressants

Time Needed
1st reading 40 mins
2 reading
nd
25 mins

Classification
1 Tricyclic antidepressants • Imipramine (useful in nocturnal enuresis, DOC-
desmopressin).
• Trimipramine.
• Clomipramine –approved for OCD.
• Desipramine.
• Amitriptyline- useful in prophylaxis of chronic migraine,
peripheral neuropathy.
• Nortriptyline.
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• Protriptyline.
• Doxepin- has high antihistamine action useful to control
itching in atopic dermatitis, lichen simplex.
• Dothiepin.
2 Tetracyclic antidepressants • Mianserin.
• Maprotiline.
• Amoxapine.
3 Bicyclic antidepressants • Viloxazine.
4 Selective serotonin reuptake • Fluoxetine- longest acting.
inhibitors (SSRIs) • Fluvoxamine.
• Paroxetine.
• Sertraline.
• Citalopram.
• Escitalopram- highly selective SSRI.
• Dapoxetine.
5 Serotonin norepinephrine reuptake • Venlafaxine (side effect- sustained hypertension)
inhibitors (SNRI) • Milnacipram.
• Duloxetine (useful in stress incontinence, fibromyalgia,
• diabetic neuropathy pain).
• Levo-milnacipram, vilazodone.
• vortioxetine.
186 | Pharmacology

6 Norepinephrine serotonin reuptake • Tianeptine.

enhancer (NSRE)
7 Norepinephrine dopamine • Bupropion (useful in smoking control, causing weight
reuptake inhibitor(NDRI) loss- useful in obesity, important adverse effect- seizure).
8 Noradrenergic and specific • Mirtazapine.
serotonergic antidepressant
(NaSSA)
9 Serotonin antagonists and reuptake • Trazodone.
inhibitor (SARI) • Nafazodone.
Serotonin antagonists and reuptake • Tianeptine.
enhancer • Amineptine.
10 Norepinephrine antagonists • Reboxetine.
and reuptake inhibitors (NARI)
11 Monoamine oxidase (MAO- A) • Moclobemide.
inhibitors • Clorgiline.
12 Herbal product ( st johns wort) • Inhibits the reuptake of NE. 5HT.
Active compound – Hyperphorin

SSRI-
SSRI
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USES Adverse Effects Drug interaction
• Fluoxetine- longest • Depression • Nausea, vomiting, • Risk of causing
acting(least chance of • OCD diarrhoea serotonin syndrome
causing withdrawal • Anxiety • Insomnia when given with
manifestation) • Anxiety MAO inhibitor
• Post traumatic stress
• Fluoxamine- shortest disorder • Delay in orgasm • Fluoxetine is the
acting CYP2D6 inhibitor,
• Premature ejaculation • bleeding thereby interfere
• Paroxetine- may
cause weight gain, • Bulimia nervosa the activation of
approved for post • Post menopausal tamoxifen
menopausal tension stress syndrome
syndrome, teratogen
• Citalopram- may
cause QT prolon­
gation
• Es citalopram- highly
selective SSRI
• Sertraline- safe in
elderly person and
cardiac patients
• Depoxetine –
approved for treating
premature ejaculation
 Central Nervous System | 187
TCA-
TCA MOA & other Uses Adverse effects TCA poisoning TCA poisoning
actions symptoms treatment
Clomipramine MOA- inhibits Depression Sedation Altered level of Sodium
Imipramine reuptake of both Nocturnal Weight gain consciousness bicarbonate
NE & 5HT enuresis Cardiotoxicity Lignocaine
Doxepine Seizure
Other action (imipramine) Convulsion or bretylim
Amytriptiline Cardiotoxicity
Alpha blocking, Lichen simplex, for treating
Nortriptyline Dryness Metabolic
anti cholinergic, atopicdermatitis- arrhythmia (
of mouth, acidosis
Amoxapine and anti doxepine don’t use class Ia
constipation, drug for treating
Desipramine histamergic action Diabetic urinary retension TCA induced
Meproteline neuropathy,
Postural arrhythmia
Reboxetine migraine
hypotension Diazepam for
prophylaxix-
amytriptiline treating seizure
Psychosis-
amoxapine No role for
dialysis
No specific
antidote for TCA
poisoning

SNRI
SNRI AfraTafreeh.com USES
Venlafaxine- Duloxetine, Milnacipram Depression
Levo-milnacipram, vilazodone, vortioxetine Duloxetine-
Neuropathy pain
Fibromyalgia
Stress incontinence

NDRI
NDRI USES
Bupropion Depression
ADHD
Obesity
Smoking control
Solriamfetol Narcolepsy

Other Anti Depressants

Serotonin reuptake Presynaptic alpha 2 Presynaptic alpha 2 & Herbal medicine
enhancer antagonist 5HT1 antagonist
Tianeptine, amineptine Mianserine Mirtazapine At john’s wort
188 | Pharmacology

One-liners:
• Longest acting SSRI – Fluoxetine (due to formation of an active metabolite).
• SSRI having least chance of producing discontinutation symptom on withdrwal-
fluoxetine( due to longer duration of action).
• SSRI least likely to cause withdrawl symptoms – Fluoxetine (due to formation of an
active metabolite).
• Antidepressant with antipsychotic properties – Amoxapine.
• Antidepressant used for aggression in elderly – Trazodone.
• DOC for endogenous depression – SSRI .
• DOC for neurotic disorders – SSRI .
• SSRI are drug of choice for- OCD, PTSD, anxiety with panic attack.
• DOC for acute exacerbations of neurotic diseases – Benzodiazepines.
• Avoid class Ia anti arrhythmic drug for treating TCA induced cardiotoxicity.
• FDA approved TCA for OCD is clomipramine but DOC is SSRI.

Drugs that can precipitate serotonin syndrome:

Drugs that Drugs that Drugs inhibits Drugs inhibits Drugs that act as
increase serotonin increase serotonin reuptake of 5HT metabolism of serotonin agonists
synthesis release 5HT
Tryptophan AmphetaminesAfraTafreeh.com
Dextromethorphan MAO inhibitors Buspirone
Cocaine Pentazocine Triptans
Ecstasy Pethidine Ergot alkaloids
(Methylenedioxy SSRIs Lithium
methamphetamic SNRIs LSD
acid)
TCAs Piperazine
Sibutramine
SARIs
Tramadol

MAO inhibitors
Selective MAO A inhibitors Selective MAO-B inhibitors Nonselective MAO inhibitors
Moclobamide Selegeline Phenelzine
Clorgiline Rasagiline Tranylcypromine
Safinamide Isocarboxazid

One-liners:
• Selective MAO B inhibitors useful for Parkinson disease
• MAO inhibitors aggravates the adverse effects of pethidine
 Central Nervous System | 189
Drugs that can precipitate cheese reactions with MAOi
• Amphetamines • Phenylpropanolamine
• Ephedrine • Tyramine
• Pseudoephedrine • Linezolid
• Phenylephrine • INH

AfraTafreeh.com
190 | Pharmacology

Worksheet
To do
Longest acting SSRI

SSRI approved for premature ejaculation

TCA approved for OCD

TCA approved for nocturnal enuresis

AfraTafreeh.com
Uses of duloxetine

Antidepressant useful for controlling smoking

Most anxiogenic antidepressant

MAO inhibitor useful for treating depression

 Central Nervous System | 191
Concept 8.8 : Anti anxiety drugs
Learning objectives:
• To now the drugs useful for various type of anxiety disorder

Time Needed
1 reading
st
10 mins
2nd reading 5 mins

Examples of Anti-anxiety Drugs:

1 SSRIs- Fluoxetine, paroxetine, and sertraline
2 SNRIs- Venlafaxine
3 Benzodiazepines- Clonazepam /alprazolam/lorazepam
4 Azapirones: 5HT1A AGONIST- non sedative, non habit forming
• Buspirone
• Gepirone
• Ipsapirone
5 H1 antihistaminics
• Hydroxyzine (cetirizine is the active metabolite)
6 β-blockers AfraTafreeh.com
• Propranolol (DOC for performance anxiety)

One-liners:
• In general Anti depressantare the – FIRST LINE rugs useful for treating anxiety
disorder
192 | Pharmacology

Worksheet
To do
I general first line drugs useful for anxiety disorder
are

Preferred drug for performance anxiety

AfraTafreeh.com
Anti histamine having anti anxiety activity

5HT1A agonist useful for anxiety disorder are

 Central Nervous System | 193
Concept 8.9 Opioids
Learning objective:
• To know the action of opioid based on opioid receptors
• To know the classification of opioid drugs
• To know the drugs useful for opioid poisoning and opioid deaddiction
• To know newer opioids

Time Needed
1st reading 30 mins
2 reading
nd
20 mins

Actions of various opioid receptors:

µ κ δ
• Physical dependence • Physcial dependence • Analgesia (spinal + affective
(morphine type) (nalorphine type) supraspinal component)
• Miosis • Miosis (low- er ceiling) • Respiratory depression
• Constipation (µ2) • Constipation • Affective behavior
• Analgesia • Analgesia • Reinforcing actions
• Supraspinal – µ1 • Supraspinal – κ3 • Constipation
• Spinal – µ2 AfraTafreeh.com
• Spinal – κ1
• Respiratory depression (µ2) • Respiratory depression (lower
• Euphoria ceil- ing)
• Sedation • Dysphoria
• Sedation
• Diuresis
All the actions of morphine may develops tolerance on repeated administration except-
constriction of pupil(miosis), constipation, convulsion.
Morphine causes convulsion due to formation of metabolite M3G (morphine 3
glucoronide).
Pethidine causes convulsion de to formation of NORPETHIDINE.
Morphine has histamine releaseing property – causing vasodilatation – useful in LVE.

Classification
Pure agonist
Natural Semi synthetic Synthetic
• Morphine. • Heroin ( diacetyl morphine). • Pethidine (Meperidine).
• Codeine. • Pholcodeine. • Methadone (longest acting).
• Thebaine. • Levorphanol. • Fentanyl.
• Papaverine. • Dextropropoxyphene.
• Noscapine. • Tramadol.
• Tapentadol.
194 | Pharmacology
Opioid agonists and antagonists:
Drug µ κ δ
Morphine Agonist (Strong) Agonist (Weak) Agonist (Weak)
Nalorphine Antagonist (Strong) Agonist (Moderate) -
Pentazocine Partial ago- nist (Weak) Agonist (Moderate) -
Butorph- anol Partial ago- nist (Weak) Agonist (Strong) -
Buprenor- phine Partial agonist Antagonist (Moderate) -
Naloxone Antagonist (Strong) Antagonist (Moderate) Antagonist (Weak)
Naltrexone Antagonist (Strong) Antagonist (Strong) Antagonist (Weak)

Peripheral opioid antagonist

• Methyl Naltrexone • Naloxegol
• Alvemopan • Naldemedine

Potency comparison of opioids:

Morphine 1
Codeine 0.1
Pethidine
AfraTafreeh.com
0.1
Heroin 3
Fentanyl 80-100
sufantanyl 1000 times > than morphine

Half-lives of various opioids:

Drug Half-life
Remifentanil (rapid metabolism by pseudocholinesterase- useful in day care surgery) 8-20 min
Alfentanil 1-2 h
Morphine 3-4 h
Fentanyl 4-5 h
Sufentanil 4-5 h
Methadone 24-36 h

Drugs for Opioid Deaddiction:

Deaddiction To treat withdrawal symptom To prevent relapse
• Methadone • Clonidine • Naltrexone
• burenorphine • Lofexidine
 Central Nervous System | 195

One-liners:
• ALVIMOPEN- peripheral opioid antagonist- useful for treating opioid induced
constipation and for treatment of Post op ileus.

Fentanyl + Droperidol= Neuroleptic analgesia

Fentanyl + Droperidol + N2O = N
 euroleptic anaesthesia post op truncal regidity
(max alfentanil)
Thorax mus regidity- wooden chest syndrome

Newer opioids
• Peripheral κ - antagonist ASIMADOLINE – usefil in IBS.
• Peripheral µ and κ - agonist, delta antagonist- Eluxadoline -useful in IBS
• Peripheral κ - antagonist-NALFURAFINE – Anti pururitic- CKD.

AfraTafreeh.com
196 | Pharmacology

Worksheet
To do
Opioid contra indicated for treating MI pain

Example for mu agonist kappa antagonist

Day analgesic useful in surgery

Peripheral opioid antagonists

AfraTafreeh.com

Drugs useful for deaddiction of opioid

Ant diarrhoeal opioid

Cough suppressant
 Central Nervous System | 197
Concept 8.10 Newer drugs:
Time Needed
1 reading
st
10 mins
2 reading
nd
5 mins

Drug Mechanism Indication

1 Topiramate Predominantly blocks sodium channels Partial onset and primary generalized
tonic-clonic seizures;
Lennox-Gastaut syndrome.

2 Brivaracetam Binds to synaptic vesicle 2A (SV2A) Partial seizures in patients >16 years of
glycoprotein age.

3 Brexpiprazole Atypical antipsychotic – SDAM (Sero- Schizophrenia;

tonin-dopamine activity modulator) Depression.

4 Pimavanserin Inverse agonist at 5-HT2A> 5-HT2C Hallucinations and delusions associated

with Parkinson’s disease.

5 Suvorexant AfraTafreeh.com
Blocks both orexin receptors (OX1 and Insomnia.
OX2)

6 Tasimelteon Melatonin (MLT-1 and MLT-2) receptor Non 24-hour sleep-wake disorder in to-
agonist tally blind.

7 Alemtuzumab Monoclonal antibody against CD52 Relapsing multiple sclerosis.

8 Daclizumab Monoclonal antibody against CD25 Relapsing multiple sclerosis.

9 Droxidopa Synthetic amino acid precursor (metabo- Neurogenic orthostatic hypotension;

lized to norepinephrine and epinephrine) Hemodialysis-induced hypotension.

10 Eteplirsen Triggers excision of exon 51 of dystro- Duchenne muscular dystrophy.

phin mRNA, restoring the reasing frame
of dystrophin
9 Endocrine System

CONCEPTS
 Concept 9.1 Pituitary hormones

 Concept 9.2 AfraTafreeh.com

Antithyroid hormones

 Concept 9.3 Antidiabetic drugs

 Concept 9.4 Corticosteroids

 Concept 9.5 Sex hormones

 Concept 9.6 Drugs useful for bone health

 Endocrine System | 199
Concept 9.1 : Pituitary Hormones
Learning objectives:
• To know the GnRh analogue and antagonist
• To know the drugs useful for acromegaly and dwarfism

Time Needed
1 reading
st
20 mins
2 reading
nd
10 mins

GnRH Agonists: Gn RH Antagonists ADR

• Leuprolide. • Ganirelix. Hot flush, loss of libido,
• Goserelin. • Cetrorelix. impotence, sarcopenia (reduced
• Busorelin. • Abarelix. muscle mass), osteoporosis
• Naferelin. • Degarelix
• Desorelin.
• Histrelin.
• Tritprelin.

Drugs used for treating acromegaly

Growth hormone release inhibitors (S/C) Octreotide Lanreotide Vapreotide Seglitide
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Growth hormone receptor blocker (S/C) Pegvisomant
Dopamine analogues (oral) Bromocriptine Cabergoline

Drugs useful in treating dwarfism:

Growth hormone release factors Sermorelin Hexarelin
Tesamorelin
Recombinent GH- Somatrem
Somatropin
recombinent human IGF-1 + IGF binding protein 3 Mecasermin

Tesamorelin: GHRF, Reduces abdominal fatin HIV with lipodystrophy

• Atosiban- oxytocin receptor antagonist

• Ergometrine – useful in PPH
• Carboprost PGF@α- useful in PPH
200 | Pharmacology

One-liners:
• DOC for central DI – Desmopressin.
• Treatment of nephrogenic DI – Thiazides and NSAIDs.
• DOC for SIAD – Vaptans > Demeclocycline.
• Mecasermin – recombinant IGF-1 approved for growth failure in children with severe
primary IGF-1 deficiency (administered subcutaneously).

AfraTafreeh.com
 Endocrine System | 201
Concept 9.2 Anti-Thyroid Drugs
Learning objective:
• To know the classification of antithyroid drugs
• To know the drugs useful for thyrotoxicosis

Time Needed
1 reading
st
25 mins
2 reading
nd
15 mins

Classification of anti-thyroid medications

1 Thyroid hormone synthesis inhibitors (Thioamides)
Propylthiouracil
Carbimazole
Methimazole
2 Iodide trapping inhibitors
Thiocyanates
Perchlorates
Nitrates
Fluoroborates
3
AfraTafreeh.com
Thyroid hormone release inhibitors
Iodides
4. Peripheral T4 to T3 conversion inhibitors
propranolol, amiodarone, propyl thiouracil, dexamethasone, ipodate
5. Radioactive iodine

Propylthiouracil v/s Carbimazole / Methimazole:

Propylthiouracil Carbimazole / Methimazole
1 Plasma protein binding High (75%) Absent
2 Vd ~ 20 L ~ 40 L
3 T½ ~ 75 min ~4–6h
4 Dosing frequency 1 – 4 times a day 1 – 2 times a day
5 Efficacy Lower Higher
6 Inhibition of peripheral T4 → T3 Present Absent
conversion
7 Use in thyroid storm Effective Not effective
8 Side effects Higher Lower
202 | Pharmacology

One-liners:
• DOC for Graves’ disease – Methimazole.
• DOC for hyperthyroidism / thyrotoxicosis in 1st trimester of pregnancy – Propylthiouracil.
• DOC for hyperthyroidism / thyrotoxicosis in 2nd / 3rd trimester of pregnancy –
Methimazole > Carbimazole.
• Most common side effect of antithyroid drugs – Urticarial papular rash.
• Most serious side effect of antithyroid drugs – Agranulocytosis.

Half-lives of radioactive iodine isotopes:

Isotope Half-life
123
I 8 days
125
I 13 hours
131
I 60 days

One-liners:
• Radioactive iodine is contraindicated in – Pregnancy.
• Thyroid constipation is seen with – Iodides.

AfraTafreeh.com
Drugs for thyroid storm (Acute thyrotoxic crisis):
• Propylthiouracil.
• Propranolol.
• Hydrocortisone.
• Saturated solution of potassium iodide (SSKI).

One-liners:
• DOC for thyroid storm (Acute thyrotoxic crisis) – Propylthiouracil.
 Endocrine System | 203
Concept 9.3 : Drugs for Diabetes Mellitus:
Learning objective:
• To know the classification of anti diabetic dugs
• To know the classification insulin analogue
• To know the action and adverse effects of oral antidiabetic drugs
• To know the action adverse effects of newer antidiabetic drugs

Time Needed
1st reading 1 hr
2 reading
nd
30 mins

Classification of anti-diabetic drugs:

Parenteral
1. Isulin
2. GLP-1 analogues • Exenatide
• Liraglutide
3. Amylin analogues • Pramlintide

Oral antidiabetic drugs AfraTafreeh.com

Sulfonylureas
Meglitinide analogues • Repaglinide
• Nateglinide
Thiazolidinediones • Pioglitazone
α-glucosidase inhibitors • Acarbose
• Miglitol
• Voglibose
Biguanides (AMPK activators) • Metformin
DPP-IV inhibitors • Sitagliptin
• Vildagliptin
• Saxagliptin
• Alogliptin

Classifications of Insulins:
Type Onset (h) Peak (h) Duration (h) Can be mixed with
A: RAPID / ULTRA-SHORT ACTING
Insulin lispro 0.2 – 0.3 1 – 1.5 3–5 Regular, NPH
Insulin aspart 0.2 – 0.3 1 – 1.5 3–5 Regular, NPH
Insulin glulisine 0.2 – 0.4 1–2 3–5 Regular, NPH
204 | Pharmacology

B: SHORT-ACTING
Regular (soluble) 0.5 – 1 2–3 6–8 All except insulin
insulin glargine / detemir
C: INTERMEDIATE ACTING
Insulin zinc sus- 1–2 8 – 10 20 – 24 Regular
pension (Lente)
Neutral protamine 1 – 2 8 – 10 20 – 24 Regular
hagedorn (NPH)
D: LONG ACTING
Insulin glargine 2–4 - 24 None
Insulin detemir 1–4 - 24 None

One-liners:
• 1U insulin activity reduces blood glucose of a fasting rabbit to – 45 mg/dL
• 1 mg of International Standard of Insulin = 28U
• Degludec - longest acting insulin

• Lente = 7:3 mixture of ultralente (crystalline) and semilente (amorphous) insulin zinc suspension.
• Mixtard (30/70) = 30% regular insulin + 70% isophane insulin.
•
AfraTafreeh.com
Mixtard (50/50) = 50% regular insulin + 50% isophane insulin.
• Actrapid = Regular insulin.

One-liners:
• DOC for T1DM – Insulin.
• All insulin preparations are clear except –
• Lente and NPH (which are cloudy).
• Peakless absorption insulins – Glargine and Detemir.
• Insulin whose absorption is not affected by exercise – Glargine.
• Insulins that cannot be mixed with others –
• Glargine and Detemir.
• Insulin that is stable at acidic pH – Glargine
• Fastest subcutaneous absorption of insulin occurs at – Anterior abdominal wall.
• Absorption is usually most rapid from the abdominal wall, followed by the arm, buttock, and
thigh. If a patient is willing to inject into the abdomen.
• Most commonly insulin is injected subcutaneously over the – Thigh (due to lipodystrophy at the
injection site).
• Inhalational insulin – AFREZZA was approved in June-July 2014.
• Earlier inhalational preparation Exubera has been withdrawn due to – Lack of cost- effectiveness.
• Possible risk of inhalational insulin – Lung cancer.
 Endocrine System | 205
Amino acid modification in various insulin
Insulin Position Original amino acid Substituent amino acid

Lispro B28 Proline Lysine

B29 Lysine Proline

Aspart B28 Proline Aspartate

Glulisine B3 Aspartate Lysine

B29 Lysine Glutamate

Glargine A21 Asparagine Glycine

B chain Two additional arginine residues

Detemir B29 Lysine Additional myristic acid

Degludec B29 Lysine Additional hexadec­anedioic acid

B30 Threonine Deleted

One-liners:
•
AfraTafreeh.com
Lispro, aspart, glulysine are monomer rapid in onset of action.
• Regular insulin hexamer, take 30-40 minutes to become monomer.
• Detemir – Myristic acid is added to insulin → Increases binding to albumin and hence,
duration of action.
• Duration of action of insulin degludec – 42 hours.

Drug interactions of insulin:

Action antagonized by (Decreased effect of Increased risk of hypoglycemia with
insulin seen with)
• Thiazides • Sulfonylureas
• Loop diuretics • β-blockers
• Corticosteroids • Salicylates
• Oral contraceptives • Lithium
• β-agonists • Theophylline

One-liners:
• Most common side effect of insulins – Hypoglycemia
• Non-diabetic use of insulin – Hyperkalemia (IV insulin + Glucose) → Causes shift of
potassium into the cells
206 | Pharmacology

Sulfonyureas
Classification:
1st Generation 2nd Generation

Longer acting Shorter acting

Decrease both basal and post-prandial Decrease only post-prandial hyperglycemia

hyperglycemia

Usually given once or twice a day Usually given before each meal

Greater incidence of hypoglycemia Lesser incidence of hypoglycemia

E.g: E.g:
• Tolbutamide • Glibenclamide (Glyburide)
• Tolazamide • Glimepiride
• Chlorpropamide • Glipizide
• Gliclazide

One-liners:
• Longest acting sulfonylurea – Chlorpropamide.
•
•
AfraTafreeh.com
Most common side effect of sulfonylureas – Hypoglycemia.
Sulfonlyurea with maximum risk of hypoglycemia – Chlorpropamide.
• Chlorpropamide- cause cholestatic jaundice, SIADH.
• Glyburide can be used in GDM

Pharmacokinetic properties of sulfonylureas

Drug Plasma T½ (h) Duration of Daily dose No. of doses per
action (h) day
Tolbutamide 6 6-8 0.5-3 g 2-3
Glibenclamide 2-4 24 2.5-15 mg 1-2
Glipizide 3-5 12 5-20 mg 1-2
Gliclazide 8-20 12-24 40-240 mg 1-2
Glimepiride 5-7 24 1-6 mg 1-2

Additional properties of chlorpropamide

• Syndrome of inappropriate antidiuresis (SIAD)
• Agranulocytosis
• Cholestatic jaundice
• Disulfiram-like reaction
 Endocrine System | 207

Meglitinides
Pharmacokinetics of meglitinide analogues:
Drug Plasma T½ (h) Duration of ac- Daily dose No. of doses per
tion (h) day
Repaglinide ≤1 3-5 1-8 mg 3-4
Nateglinide 1.5 2-4 180-480 mg 3-4

One-liners:
• Binding site of meglitinide analogues on SUR – Kir6.1
• Flu-like symptoms is a side effect of – Nateglinide

Thiazolidinediones
Thiazolidinediones withdrawn:
Drugs withdrawn Reason
1 Troglitazone Hepatotoxicity (Acute fulminant hepatitis)
2 Rosiglitazone AfraTafreeh.com
Increased risk of precipitation of congestive heart failure

One-liners:
• Pioglitazone has also been withdrawn in most of the Western countries due to – increased
risk of urinary bladder cancer

Pharmacokinetics
Drug Plasma T½ (h) Duration of Daily dose No. of doses per
action (h) day
Pioglitazone 3-5 24 15-45 mg 1

One-liners:
• Onset of action of thiazolidinediones – 2-3 months.
• Weight gain is maximum with – Thiazolidinediones (due to fluid retention and edema).
• Thiazolidinediones- activates PPAR γ.
• TELMISARTAN – PPAR γ agonism property.
• Increased risk of pathological fractures is seen with – Thiazolidinediones.
208 | Pharmacology
Alpha-Glucosidase Inhibitors
• Absorption of miglitol from GIT – 50%.
• Only oral antihyperglycemic effective in T1DM – α-glucosidase inhibitors.
• But FDA approved drugs for type 1 & 2 DM are- Insulin and pramlintide.
• Antidiabetic that can reduce fibrinogen levels – Acarbose.
• Abdominal distension and flatulence is a side effect of – α-glucosidase inhibitors

Biguanides
Pharmacokinetics of metformin
Drug Plasma T½ (h) Duration of Daily dose No. of doses per
action (h) day

Metformin 1.5-3 6-8 0.5-2.5 g 1-2

Contraindications to metformin: (factors precipitating lactic acidosis)

• Renal failure (S. creatinine > 1.5 mg/dL for males, 1.4 mg/dL for females).
• Severe liver disease.
• AfraTafreeh.com
Severe pulmonary disease, including COPD.
• Decompensated heart failure.
• Chronic alcohol abuse.

Metformin to be discontinued if patient is:

• Severely ill.
• Not taking anything orally.
• Requiring administration of radiological contrast media (Metformin increases the nephrotoxicity
of radiological contrast agents).
• One day before and after the radiological procedure metformin should be stopped.

One-liners:
• Maximum daily dose of metformin – 2250 mg.
• Antidiabetic effective in polycystic ovarian disease – Metformin (It can both
regularize menses and increase chances of ovulation).
• Antidiabetic that may be effective in cancers – Metformin (It is under evaluation for
breast and colon cancers).
• Metformin is a AMPK activator.
• Megaloblastic anemia is a side effect of – Metformin.
• Phenformin has been withdrawn due to – Lactic acidosis.
 Endocrine System | 209
Mechanisms of GLP-1 based action
• Increased insulin secretion from pancreas (glucose-dependent).
• Decreased glucagon secretion from pancreas (glucose-dependent).
• Suppression of appetite.
• Delayed gastric emptying.

One-liners:
• Exenatide is – Synthetic exendin-4 derived from the saliva of Gila monster (Heloderma
suspectum).
• Exenatide shares ~ 50% homology with human GLP-1.
• Liraglutide is – recombinant human GLP-1
• Liraglutide shares ~97% homology with human GLP-1.
• GLP-1 analogues cause nausea as a side effect in – 40-50% of cases at the initiation of
therapy.
• Pancreatitis is a side effect of – GLP-1 analogues.
• Increased risk of medullary thyroid carcinoma is seen with – Liraglutide.
• GLP=1 analogues will cause weight loss, Liraglutide is FDA approved drug of
obesity.

AfraTafreeh.com
Pharmacokinetics of DPP-IV inhibitors:
Drug Plasma T½ (h) Dura- tion of action (h) Daily dose
Sitagliptin ~12 24 100 mg
Vildagliptin 2-4 12-24 50-100 mg

One-liners:
• Reversible DPP-IV inhibitors – Sitagliptin and Alogliptin.
• Irreversible DPP-IV inhibitors – Vildagliptin and Saxagliptin.
• All DPP-IV inhibitors are metabolized by CYP enzymes in liver except – Saxagliptin.
• Recent side effect reported with DPP-IV inhibitors – Joint pain.
• All DDP- IV inhibitors are unsafe in kidney failure except- LINAGLIPTIN.
• VILDAGLIPTIN- cause hepatotoxicity.
• Most common side effect of DPP-IV inhibitors will be upper respiratory infection.

Mechanism of action of pramlintide

• Decreased glucagon secretion from pancreas (glucose-dependent).
• Suppression of appetite.
• Delayed gastric emptying.
• Pramlintide acts on amylin receptors in – Hind brain.
• Pramlintide is stable at pH of – 4.
• Pramlintide is approved for – both T1 and T2 DM; only in combination with insulin.
210 | Pharmacology
Drugs affecting basal and post-prandial hyperglycemia
Both basal and post prandial Only post-prandial
• Intermediate acting insulins • Ultra-short acting insulins
• Long acting insulins • Short-acting insulins
• 1st generation sulfonylureas • 2ndgeneration sulfonylureas
• Thiazolidinediones • Meglitinide analogues
• Biguanides • α-glucosidase inhibitors
• GLP-1 analogues
• DPP-IV inhibitors

Newer antidiabetics
Class (Mechanism) Examples

1 Sodium glucose translocase-2 (SGLT-2) inhibitors (Decrease the • Canagliflozin

proximal tubular reabsorption of glucose) • Dapagliflozin
• Empagliflozin
• Sergliflozin

2 Bile acid binding resins (Decrease the absorption of glucose from the • Colesevelam
GIT)
AfraTafreeh.com
3 D2 receptor agonist (Resets the hypothalamic glucose control • Bromocriptine
mechanism and reduce plasma glucose levels)

4 Aldose reductase inhibitor (Reduces the conversion of glucose to • Epalrestat

sorbitol; hence, decreases the occurrence of diabetic complications)

5 Dual PPAR agonists (Reduce both lipid and glucose levels; hence • Saroglitazar
effective in diabetic dyslipidemia)

6 Newer GLP-1 analogues • Albiglutide

• Semaglutide
• Taspoglutide
• Lixisenatide
 Endocrine System | 211

One-liners:
• Recent side effect with SGLT2 inhibitors – Diabetic ketoacidosis.
• Epalrestat has been specifically approved for – Diabetic neuropathy.
• Saroglitazar has been specifically approved for – Diabetic dyslipidemia.
• Saroglitazar was approved on – 5th June, 2013
• Ruboxistaurin – Protein kinase C-β inhibitor under investigation for diabetic peripheral
retinopathy.

Effect of drugs on blood glucose

Drugs causing hyperglycemia Drugs causing hypoglycemia
• Glucocorticoids • β-blockers
• Antipsychotics • Ethanol
• Protease inhibitors • NSAIDs
• β-agonists • Pentamidine
• Thiazides • ACE inhibitors
• Loop diuretics • Lithium
• Phenytoin • Theophylline
• Opioids • Bromocriptine
• Diazoxide AfraTafreeh.com • Mebendazole
• Nicotinic acid
• Pentamidine
• Epinephrine
• Interferons
• Amphotericin B
• L-asparaginase
• Acamprosate
• Basiliximab
• Thyroid hormones

Indications of glucagon:
• Hypoglycemia.
• Cardiogenic shock due to β-blockers (stimulates the heart).
• To facilitate radiographic examination of upper / lower GIT (by relaxing the stomach and intestines).
212 | Pharmacology

Worksheet
To do
Longest acting isulin analogue

Insulin prepared in acidic pH

Safer DPP4 inhibitor safe in renal failure

AfraTafreeh.com
Most common side effect of SGLT 2 inhibitor

Most common side effect of alpha glucosidase

inhibitor

Antidiabetic drug approved for treating obesity

 Endocrine System | 213
Concepts 9.4 : Corticosteroids
Learning objective:
• To know the classification of steroids
• To know the side effects and contra indications of steroids

Time Needed
1 reading
st
30 mins
2 reading
nd
15 mins

Potency Gradation of Systemic Steroids

Classification Compound Gluco-corticoid Mineralo- Equivalent
potency corticoid potency dose (mg)

Short-acting Hydrocortisone (Cortisol) 1 1 20

(T½ < 12 h)
Cortisone 0.8 0.8 25

Intermediate-acting Deflazacort 3–4 0 6

(T½ 12-36 h)
Prednisone 4 0.8 5

Prednisolone
AfraTafreeh.com
4 0.8 5

Methylpredni-solone 5 0.5 4

Triamcinolone 5 0 4

Long-acting Dexamethasone 25 0 0.75

(T½ > 36 h)
Betamethasone 25 0 0.75

Mineralo-corticoids Desoxy-corticosterone 0 100 2.5

acetate (DOCA)

Fludricortisone 10 150 0.2

Aldosterone 0.3 3000 Not used

clinically

One-liners:
• DOCA is administered – Sublingually.
• Most potent mineralocorticoid – Aldosterone.
• Most potent clinically used mineralocorticoid – Fludricortisone.
214 | Pharmacology
Potency gradation of topical steroids
Class Compound and formulation
1 (Most potent) • Betamethasone dipropionate (cream, ointment: 0.05%).
• Clobetasol propionate (cream, ointment: 0.05%).
• Halobetasol propionate (ointment: 0.05%).
• Diflorasone diacetate (ointment: 0.05%).
2 • Desoximetasone (cream, ointment: 0.25%, gel: 0.05%).
• Amcinonide (ointment: 0.1%).
• Fluocinonide (cream, ointment, gel: 0.05%).
• Halcinonide (cream, ointment 0.1%).
3 • Betamethasone valerate (ointment: 0.1%).
• Diflorasone diacetate (cream: 0.05%).
• Triamcinolone acetonide (ointment: 0.1%, cream: 0.5%).
4 • Amcinonide (cream: 0.1%).
• Desoximetasone (cream: 0.05%).
• Fluocinolone acetonide (cream: 0.2%, ointment 0.025%).
• Flurandrenolide (ointment: 0.05%, tape 4 µg/cm2).
• Hydrocortisone valerate (ointment: 0.2%).
• Triamcinolone acetonide (ointment: 0.1%).
•
AfraTafreeh.com
Mometasone furoate (cream, ointment: 0.1%).
5 • Betamethasone dipropionate (lotion: 0.05%).
• Betamethasone valerate (cream, lotion: 0.1%).
• Fluocinolone acetonide (cream: 0.025%).
• Flurandrenolide (cream: 0.05%).
• Hydrocortisone butyrate (cream: 0.1%).
• Hydrocortisone valerate (cream: 0.2%).
• Trimacinolone acetnoide (cream, lotion: 0.1%).
6 • Alclometasone dipropionate (cream, ointment: 0.05%).
• Desonide (cream: 0.05%).
• Fluocinolone acetonide (cream, solution: 0.01%).
7 (Least potent) • Dexamethasone sodium phosphate (cream: 0.1%).
• Hydrocortsione (cream, ointment, lotion: 0.5%, 1%, 2%).

One-liners:
• Topical steroid is most potent as – Ointment.
• For exuding lesions – Cream is preferred, as it allows evaporation of the exudates and
dries the lesion .
• For dry and scaly lesions – Ointment is preferred, as it forms an occlusive cover around
the lesion and retains moisture.
• Steroid topical spray is preferred on – Hairy regions.
 Endocrine System | 215
Effects of glucocorticoids on blood cells
Increased levels of Decreased levels

• RBCs • Eosinophils
• Platelets • Basophils
• Neutrophils • Lymphocytes

Side effects of steroids

• Hypothalamo-pituitary adrenal axis suppression
• Cushingoid features – Moon face, Buffalo hump, Lemon-on-sticks (or orange-on sticks) appearance due
to lipid redistribution.
• Hyperglycemia.
• Myopathy.
• Osteoporosis.
• Thinning of skin.
• Easy bruisability.
• Telangiectasiae.
• Hypertension.
• Immunosuppression and increased risk of opportunistic infections.
• Peptic ulcer disease. AfraTafreeh.com
• Euphoria and psychosis.
• Glaucoma and cataract.
• Topical steroids in eye cause – Glaucoma.
• Systemic steroids in eye cause – Cataract.

Contra indication of steroids

• Peptic ulcers.
• Diabetes mellitus.
• Hypertension.
• Viral and fungal infections.
• Intestinal tuberculosis.
• Osteoporosis.
• Herpes simplex keratitis.
• Psychosis.
• Epilepsy.
• Congestive heart failure.
• Renal failure.
• Steroids are contraindicated in – Intestinal tuberculosis, as they increase the risk of perforation.
216 | Pharmacology
Inhibitors of steroid synthesis
• Metyrapone – Inhibits 11-β-hydroxylase.
• Aminoglutethimide.
• Trilostane.
• mitotane.
• High doses of ketoconazole.
• Pesireotide.
• Etomidate.

Maximum glucocarticoid action Dexamethasone

Maximum mineralocorticoid action Aldosterone

Glucocarticoid with Maximum Minerlocarticoi action Hydrocartisone

Lest potent Glucocarticoid action Cortisone

Most potent Glucocarticoid action Betamethasone

Maximum topical action

AfraTafreeh.comTriamcinolone
One-liners:
• ACTH- drug of choice for Infantile spasm
• Vigabatrine- drug of choice for infantile spasm with tuberous sclerois
 Endocrine System | 217

Worksheet
To do
Most potent glucocarticosteroid

Glucocorticoid having highest mineralocorticoid

action

Example for mineralocarticod antagoists

AfraTafreeh.com

Drugs inhibiting glucocorticoid synthesis

Example for glucocorticoid receptor blocker

218 | Pharmacology
Concept 9.5 : Gonadal Steroids:
Learning objectives:
• To know the estrogen and progesterone preparations
• To know the different methods of contraception
• To know the uses of selective estrogen receptor modulator & selective progesterone
receptor modulators

Time Needed
1 reading
st
30 mins
2 reading
nd
20 mins

Examples of androgens:
Natural (Endogenous) Synthetic
• Testosterone • Methyltestosterone
• Dihydrotestosterone • Fluoxymesterone
• Dehydroepiandreosterone • Testosterone undecanoate
• Androstenedione • Mesterolone
• Androsterone

Examples of estrogens: AfraTafreeh.com

Natural (Endogenous) Synthetic
• Estradiol Steroidal –
• Estriol • Ethinyl estradiol
• Estrone • Mestranol
• Tibolone
Non-steroidal –
• Diethylstilbestrol (Stilbestrol)
• Hexestrol
• Dienestrol

Examples of progestogens:
Progesterone derivatives 19-nortestosterone derivatives
Older compounds – Older compounds –
• Medroxyprogesterone acetate • Norethisterone (Norethindrone)
• Hydroxyprogesterone caproate • Lynestrenol (Ethinyl estrenol)
• Megesterol acetate • Allylestranol
• Dydrogestrone • Levonorgestrel (It is also included under gonanes)
Newer compounds – Newer compounds (Gonanes) –
• Nomegestrol ­acetate • Desogestrel
• Norgestimate
• Gestodene
 Endocrine System | 219

One-liners:
• Gestodene inhibits ovulation at doses as low as – 40µg/d.
• Examples of pure progesterone antagonists – Onapristone and Gestinone.

Examples of oral contraceptive preparations:

Progestin Estrogen Trade Name

Combined Pills

Norgestrel 300µg Ethinyl estradiol 30µg Mala-D (21 tabs

+ 7 tabs of ferrous
sulphate 60mg)

Norgestrel 500µg Ethinyl estradiol 50µg Ovral-G

Levonorgestrel 250µg Ethinyl estradiol 50µg Ovral, Duoluton-L

Levonorgestrel 150µg Ethinyl estradiol 30µg Ovral-L, Ovipauz

Levonorgestrel 100µg Ethinyl estradiol 20µg Loette, Ovilow,

Combee

Desogestrel 150µg AfraTafreeh.com

Ethinyl estradiol 30µg Novelon

Desogestrel 150µg Ethinyl estradiol 20µg Femilon

Phased Pills

Levonorgestrel 50-75-125µg Ethinyl estradiol 30-40-30µg Triquilar (6+5+10)

Norethindrone 500-750-1000µg Ethinyl estradiol 35-35-35µg Orthonovum 7/7/7

(7+7+7)

Post-Coital Pills

Levonorgestrel 250µg Ethinyl estradiol 50µg Ovral, Duoluton-L

(2+2 tablets)

Levonorgestrel 750µg, 1500µg - - Norlevo, Ecee2

(1+1 tablets)
iPill, Nofear-72, Oh
God (1 tablet)

Mini Pills (Progesterone-Only Pills)

Norethindrone 350µg - - Micronor, Nor-QD

Norgestrel 75µg - - Ovrette

220 | Pharmacology
Effects of different forms of contraception:
Effect Combined E+P Minipill Post-coital pill Injections
(Only P) (Only P) (Only P)
FSH inhibition ++ - - +
LH inhibition +++ + + +++
Anti-ovulatory effect +++ + +,- ++
Hostile cervical mucus +++ +++ - +++
Endometrium Hyper-secretory Out of phase Unfavour-able Atrophic
Failure rate (pregnancy 0.1-0.3 2-3 2-4 < 0.5
per 100 women years)
Contraceptive efficacy ++++ +++ ++ ++++

One-liners:
• Gossypol – Non-steroidal male contraceptive obtained from cotton seed, studied in China.
• Ulipristal – Selective progesterone receptor modulator (SPRM) approved as an
emergency contraceptive – 30 mg taken within 72 hours of intercourse.
• Bazedoxifene – Third generation SERM approved in combination with estrogen for
prevention and treatment of postmenopausal osteoporosis.

• SERM for breast cancer- Tamoxifen, Toremifen, Doloxifen, Raloxifene.

• AfraTafreeh.com
SERD for breast cancer- Fulvestrant.
• SERM for DUB- Ormeloxifene.
• Centchromin- Contraception (Twice in wk with the gap of four days- first 3 months, Latter - once
in a wk).
• SERMs For Dyspareunia-Ospemifene.
• Ulipristal.
• Asoprisnil.
• Telapristone- uterine fibroid, endometriosis.

• SPRM.
• Ulipristal- emergency contraceptive,
• effective upto five days.
• Asoprisnil.
• Telapristone- uterine fibroid, endometriosis.

Aromatase Inhibitors:
Aminoglutethimide, Formestane
Exemestane
Vorozole
Fadrozole
Letrozole
Anastrazole
 Endocrine System | 221

Worksheet
To do
SERM useful for dyspareunia

SERM useful for ovulation induction

What is ulipristal

AfraTafreeh.com
Adverse effects of tamoxifen

Mechanism of action finesteride

Examples for aromatase inhibitors

222 | Pharmacology
Concept 9.6 : Drugs useful for maintaining bone health
Learning objectives:
• To know the drugs useful in osteoporosis
• To know action, uses and adverse effects of bisphosphonates
• To know the vit D analogues and their uses
• To know the parathormone analogues
• To know the drugs useful for hypercalcemia

Time Needed
1 reading
st
30 mins
2nd reading 20 mins

Inhibiting osteoclast Promoting osteoblast Dual action( promoting

osteoblast & inhibiting
osteoclast)

Bisphosphonates Calcitriol Strontium

Estrogen & Serm Calcium ranelate
Cinacalcet Parathormone
Calcitonin - teriparatide, Abaloparatide
AfraTafreeh.com
Thiazide Diuretics
Denosumab- Rank L antibody Anti sclerotic antibody
Romosozumab
Blosozumab

Bisphosphonates
Genera rations Examples

First generation- • Medronate

• Etidronate
• Clodronate
• Tiludronate

Sec generation- • Alendronate

• Pamidronate (IV)
• Ibadronate

Third generation- • Risedronate

• Zoledronate (IV) (most potent)
 Endocrine System | 223
Mechanism of action
• Accelerating apoptosis of osteoclast reducing their number
• Detect osteoclast precursors and inhibit their differentiation (by inhibiting IL-6)
• Inhibit G protein involved in activation of osteoclast

Uses ADR
Osteoporosis Erosive esophagitis
Hypercalcemia Flu like symptoms
Paget’s Disease Renal toxicity
Antitumor action Osteonecrosis of jaw
(breast cancer) stress fractures in the lateral cortex of the femoral
shaft

Cinacalcet, Etelcalcetide
• Activates the calcium sensing receptor in the parathyroid inhibits PTH secretion indication
USES-
• Sec hyper parathyroidism Hypercalcemia

Teriparatide, Abaloparatide AfraTafreeh.com

Mechanism of action ADR AVOID IN
Recombinent PTH Paresthesia Pagets disease
Approved for treatment of severe osteoporosis Hypercalcemia Hypercalcemia
Low & pulsatile dose (s/c) Nephrolithiasis Thiazides, steroids
Stimulate Bone Formation Risk of osteosarcoma Risk of osteosarcoma
Improves bone density in most of bones
except – distal radius

Vitamin D Analogs
Dihydrotachysterol Hypoparathyroidism
Ergocalciferol (calciferol) vitamin D deficiency treatment of familial
hypophosphatemia, hypoparathyroidism
vitamin D–resistant rickets type II
Alpha calcidol Renal osteodystrophy
Calcipotriol (Calcipotriene) Psoriasis (topical)
Paricalcitol Sec.Hyperparathyroidism
Doxercalciferol (1α-hydroxyvitamin D2)
Maxacalcitol
224 | Pharmacology
Uses of vit D
• Hypocalcemia
• CRF, intestinal osteodystrophy
• Nutritional Rickets&osteomalacia
• Hypoparathyroidism
• Osteoporosis
• Fanconi syndrome
• PSORIASIS

Calcitonin
Uses ADR
Pagets disease (S/C-Salcatonin) nausea, flushing, altered taste sensation
Hypercalcemia
Osteoporosis (Intra nasal- Salcatonin)
Diagnostic marker in medullary ca of thyroid

One-liners:
• BUROSUMAB - Acting against FGF23
• AfraTafreeh.com
USE - X linked hypophospataemia

Drug Therapy for Hyper Phosphatemia Drug Therapy for Hypercalcemia

Sevelamer hydrochloride Hydration with saline
Sevelamer carbonate Forced diuresis (saline + loop diuretic)
Lanthanum carbonate Corticosteroids calcitonin
Sucroferric oxyhydroxide Plicamycin
Ferric citrate IV bisphosphonates (pamidronate, zoledronate) dialysis

Uses of calcium
• hypocalcemic tetany
• Hyperkalemia
• black widow spider envenomation
• MgSO4 toxicity

Denosumab
Target uses Avoid in
Against RANKL Osteoporosis
Giant cell tumor
 Endocrine System | 225

Worksheet
To do
Mechanism of action of bisphosphonates

Target for denosumab

Analogues PTH

Diuretic useful for treating hypercalcemia

AfraTafreeh.com

Uses of calcitonin

Burosumab useful in

Topical vit d useful in psoriasis

10 Gastro Intestinal System

CONCEPTS
 Concept 10.1 Drugs for Peptic Ulcer Disease
AfraTafreeh.com
 Concept 10.2 Antiemetics

 Concept 10.3 Drugs useful for constipation,

diarrhea and IBS
 Gastro Intestinal System | 227
Concept 10.1 : Drugs useful for Peptic Ulcer Disease
Learning objective:
• To know the classification of drugs useful in APD
• To know the action uses and adverse effects of PPIs
• To know the actions adverse effects of H2 blockers
• To know the drugs useful in H pylori disease

Time Needed
1st reading 30 mins
2 reading
nd
20 mins

1 Proton pump inhibitors (PPIs) • Omeprazole

• Esomeprazole (Esmoprazole)
• Rabeprazole
• Dexrabeprazole
• Lansoprazole
• Dexlansoprazole
• Pantoprazole
• Iloprazole
2 H2 receptor antagonists
AfraTafreeh.com
• Cimetidine
• Ranitidine
• Famotidine
• Roxatidine
• Nizatidine
3 Prostaglandin (PGE1) analogues • Misoprostol
4 Anticholinergics • Pirenzepine
• Telenzepine
5 Antacids • Sodium bicarbonate
• Magnesium hydroxide
• Magnesium trisilicate
• Aluminium hydroxide
• Hydroxy magnesium aluminate (Magaldrate)
• Calcium carbonate
6 Ulcer protectives • Sucralfate
• Colloidal bismuth subcitrate
• Dimethylpolysiloxane
• Dimethicone
• Simethicone
228 | Pharmacology

7 Drugs for H. pylori eradication • Amoxicillin

• Tetracyclines
• Clarithromycin
• Metronidazole
• Tinidazole
• Omeprazole
• Lansoprazole
• Bismuth subcitrate

Proton Pump Inhibitors (PPIs):

Drug Dose (mg/d)

Iloprazole 5

Dexrabeprazole 10

Lansoprazole 15-30

Omeprazole 20

Esomeprazole 20
AfraTafreeh.com
Rabeprazole 20

Dexlansoprazole 30

Pantoprazole 40

One-liners:
• PPIs are available as enteric coated formulations – To prevent degradation from
gastric acid.
• Active metabolite of PPIs – Sulfenamide
• T½ of PPIs – 1 – 2 h.
• Duration of action of PPIs – 1 – 2 days
• PPIs are - irreversible inhibition of proton pump - Hit and run drug.
• Most potent PPI – Iloprazole.
• Least potent PPI – Pantoprazole.
• Fastest acting PPI – Rabeprazole.
• DOC for NSAID-induced ulcer – PPIs.
• Specific drug for NSAID-induced ulcer – Misoprostol.
• Teratogenic effect associated with misoprostol – Mobius syndrome.
 Gastro Intestinal System | 229
H2 Receptor Antagonists: Intravenous doses of H2 Receptor Antagonists
Cimetidine Ranitidine Famotidine

Intermittent bolus 300 mg every 6-8 h 50 mg every 6-8 h 20 mg every 12 h

Continuous infusion 37.5-100 mg/h 6.25-12.5 mg/h 1.7-2.1 mg/h

One-liners:
• Ranitidine is – 5 times more potent than cimetidine.
• Famotidine is – 5-8 times more potent than ranitidine.
• Ranitidine absorption is reduced by – Antacids and Sucralfate.
• DOC for stress ulcers – Ranitidine.
• Drug interactions among H2 blockers are maximum with – Cimetidine.
• Cimetidine – microsomal enzyme inhibitior.
• Cimetidine - causes gyenecomastia.
• H2 antagonist maximally reduces nocturnal gastric acid output (better given at
night time).
• H2 antagonist undergoes renal route of excretion.

AfraTafreeh.com
Antacids: 1g of Antacid Neutralizes How Much of mEq of HCl
Antacid (1g) Neutralizes HCl (mEq)

Magnesium hydroxide 30

Magaldrate 28

Calcium carbonate 20

Sodium bicarbonate 12

Sodium citrate 10

Magnesium trisilicate 10

Aluminium hydroxide 1 – 2.5

One-liners:
• Encephalopathy is a side effect of – Aluminium salts.
• Milk alkali syndrome can occur due to excessive ingestion of – Calcium carbonate.
• Ulcer Protective-Sucralfate (Acts only in acid medium pH below 4), BISMUTH
(can cause black stool, tongue)
• Ulcer Healingng- Carbenoloxone- Epithelisation of ulcer without- decreasing acid
production.
230 | Pharmacology
Drugs Active Against H.pylori
• Amoxicillin • Tinidazole
• Tetracyclines • Omeprazole
• Clarithromycin • Esomeprazole
• Levofloxacin • Lansoprazole
• Metronidazole • Colloidal bismuth subcitrate (CBS)

Regimens Against H.pylori:

1st line: PPI-based Triple Therapy × 10-14 days:
PPI – Standard dose OD/BD
Clarithromycin – 500 mg BD
Amoxicillin – 1 g BD OR Metronidazole 500 mg BD
OR
Bismuth-based Quadruple Therapy x 10-14 days:
PPI – Standard dose OD/BD OR H2 receptor antagonist – Standard dose OD/BD
Bismuth subcitrate – 525 mg QID
Metronidazole – 250-500 mg QID
Tetracycline – 500 mg QID AfraTafreeh.com
OR
Sequential Therapy x 10 days
Days 1 – 5:
PPI – Standard dose OD/BD + Amoxicillin – 1 g BD
Days 6 – 10:
PPI – Standard dose OD/BD + Metronidazole – 250-500 mg BD + Clarithromycin – 250-500 mg BD
2nd line:
If Amoxicillin is used in 1st line → Bismuth- based quadruple therapy × 10-14 days
(same as above)
If metronidazole is used in 1st line → Levofloxacin­based triple therapy × 10-14 days
PPI – Standard dose OD/BD
Amoxicillin – 1 g BD
Levofloxacin 250 mg BD
 Gastro Intestinal System | 231

Worksheet
To do
PPI having interaction with clopidogrel

Adverse effects of PPIs

DOC for stress ulcer

AfraTafreeh.com

H2 blocker having microsomal enzyme inhibitory

action

Anti ulcer drug causing black colour stool is

232 | Pharmacology
Concept 10.2 : Antiemetics
Learning objective:
• To know the classification of anti emetics
• To know the examples for prokinetic agents

Time Needed
1 reading
st
25 mins
2 reading
nd
15 mins

Classification of Antiemetics
1 5-HT3 antagonists • Ondansetron
• Granisetron
• Tropisetron
• Dolasetron
• Palonosetron
• Ramosetron

2 D2 antagonists • Metoclopromide
• Domperidone
• Itopride
AfraTafreeh.com
3 Anticholinergics • Hyoscine (Scopol- amine)
• Dicyclomine

4 Antihistaminics • Promethazine
• Diphenhydramine
• Dimenhydrinate
• Doxylamine
• Cyclizine
• Meclizine
• Cinnarizine

5 Neuroleptics • Chlorpromazine
• Trifluopromazine
• Prochlorperazine
• Haloperidol

6 NK-1 receptor antag- onist • Aprepitant

• Fosaprepitant
• Netupitant

7 CB-1 receptor ago- nists • Dronabinol

• Nabilone
 Gastro Intestinal System | 233

8 5-HT4 agonists • Cisapride

• Mosapride
• Tegaserod

9 Miscellaneous • Dexamethasone
• Benzodiazepines

One-liners:
• Highly selective 5HT3 antagonist – Palanosetran.
• Most common side effect of ondensetran – Headache.
• 5-HT3 antagonists are not effective in – Apomorphine-induced vomiting and Motion
sickness.
• Metoclopromide has additional – 5-HT4 agonistic and 5-HT3 antagonistic actions.
• Most common drug for treating anticancer drug induced vomiting – ondansetran +
dexamethasone.
• Amti emetic used for treating delayed vomiting due to anticander drug – apprepitant.

Prokinetics: Examples of Prokinetics:

1 D2 antagonists AfraTafreeh.com
• Metoclopromide
• Domperidone
• Itopride

2 5-HT4 agonists • Cisapride

• Mosapride
• Tegaserod
• Prucalopride

3 5-HT3 antagonists • Ondansetron

• Granisetron
• Tropisetron
• Dolasetron
• Palonosetron
• Ramosetron

4 Miscellaneous • Erythromycin
Motilin receptor stimulant
234 | Pharmacology

Worksheet
To do
5HT3 antagonist having longer duration

NK1 blockers useful for treating anticancer drug

induced vomiting are

AfraTafreeh.com
Adverse effect of metoclopromide

Antibiotic having prokinetic activity

 Gastro Intestinal System | 235
Concept 10.3 : Drugs for Diarrhoea, Constipation and IBS
learning objective:
• To know the drugs useful in treating diarrhoe and constipation
• To know the drugs useful in IBS and IBD

Time Needed
1 reading
st
30 mins
2 reading
nd
30 mins

Drugs Useful for Diarhoea

A: ANTISECRETORY AGENTS
1 Racecadotril – For short-term management of acute secretory
diarrhea.
2 5-ASA agents – For diarrhea due to IBD.
3 Bismuth subsalicylate – For Traveler’s diarrhea.
4 Atropine and its derivatives – For nervousness or drug-induced
diarrhea.
5 Octrotide – For secretory diarrheas.
B: ANTIMOTILITY AGENTS
AfraTafreeh.com
1 Loperamide (Opioid µ receptor agonist)
2 Diphenoxylate + Atropine
3 Difenoxin (Metabolite of diphenoxylate)
4 Codeine – For Traveler’s diarrhea
5 Paregoric – Camphorated opium tincture for diarrhea in children.
C: ADSORBENTS
1 Bile acid sequestrants Cholestyramine Colestipol
Colesevelam
2 Bulk-forming laxatives Bran
Psyllium (Plantago) Methylcellulose Calcium polycarbophil
Isapghol

New -WHO Formula ORS (Oral Rehydration Salt):

Content Concentrations
NaCl 2.6 g Na+ 75 mM
KCl 1.5 g K
+ 20 mM
Trisodium citrate 2.9 g Cl -
65 mM
Water 13.5 g Citrate 10 mM
Water 1L Glucose 75 mM
236 | Pharmacology

One-liners:
• Atropine is added to diphenoxylate – To discourage addiction.

Drugs for Constipation

1 Bulk-forming laxatives • Bran
• Psyllium
• Methylcellulose
• Calcium polycarbophil
• Isapghol

2 Surfactant laxatives • Docusates

• Poloxamers
• Lactulose

3 Stimulant laxatives • Phenolphthalein

• Bisacodyl
• Sodium picosulfate
• Oxyphenisatin

4 Osmotic laxatives AfraTafreeh.com

• Magnesium sulfate
• Magnesium citrate
• Magnesium hydroxide
• Milk of Magnesia
• Sodium sulfate
• Sodium phosphate
• Sodium potassium tartarate
• Castor oil

5 Anthraquinone derivatives • Senna

• Cascara sagrada

Types of Stools and Latency of Action of Purgatives in Usually

Recommended Doses
Soft, formed faeces Semifluid stools Watery evacuation
(takes 1-3 days) (takes 6-8 hours) (within 1-3 hours)

Bulk-form- ing laxa- tives Phenol- phthalein Saline pur- gatives

Docusates Bisacodyl Castor oil
Liquid Sodium picosulfate
paraffin Senna
Lactulose
 Gastro Intestinal System | 237

One-liners:
• Laxative useful in hepatic encephalopathy – Lactulose
• Phenolphthalein has been withdrawn due to – Potential carcinogenecity
• Oxyphenisatin has been withdrawn due to – Hepatotoxicity
• Castor oil is derived from seeds of – Ricinuscommunis

Drugs for Inflammatory Bowel

Disease (IBD):
1 Glucocorticoids

2 5-ASA agents • Sulfasalazine

• Mesalazine
• Olsalazine
• Balsalazide

3 Immunosuppres- sants • Azathioprine

• 6-Mercaptopurine
• Methotrexate
AfraTafreeh.com • Cyclosporine
• Tacrolimus

4 Biologicals (Anti TNF-α) • Infliximab

• Adalimumab
• Certolizumabpegol

5 Antibiotics • Metronidazole
• Ciprofloxacin

One-liners:
• DOC for acute exacerbation of IBD – Glucocorticoids.
• Only drug more effective in ulcerative colitis than Crohns’ disease – Sulfasalazine.
• Active metabolite of sulfasalazine – 5-ASA (Acts locally).
• Sulfasalazine – 5-ASA +Sulfapyridine
• Mesalazine – Delayed release preparation of 5-ASA coated with a pH sensitive acrylic
polymer.
• Olsalazine– 2 molecules of 5-ASA joined by an azo bond
• Balsalazide– 5-ASA linked to 4-aminobenzyl-β-alanine
238 | Pharmacology
Drugs for Irritable Bowel Syndrome:
A: CONSTIPATION-PREDOMINANT IBS

1 Bulk-forming laxatives • Bran

• Psyllium
• Methylcellulose
• Calcium polycar- bophil
• Isapghol

2 Osmotic purgatives • Lactulose syrup

• Sorbitol
• Polyethylene glycol
• Magnesium hy- droxide

3 5-HT4 agonists • Prucalopride

4 Lubiprostone

B: DIARRHOEA-PREDOMINANT IBS

1 Loperamide

2 Cholestyramine AfraTafreeh.com
3 5-HT3 antagonist • Alosetron

C: ABDOMINAL PAIN-PREDOMINANT IBS

1 Antispasmodics • Dicyclomine
• Hyoscine butyl bromide
• Mebeverine

2 TCAs

3 SSRIs

One-liners:
• Lubiprostone – CLC-2 (Type 2 chloride channel activator), Cyclic prostaglandin
derivative
• Linaclotide - (guanylatecyclase-C activator) Cystic fibrosis transmembrane
conductance regulator (CFTR) activator- increases chloride rich secretion-
Increases bowl movement.
• Crofelemer - Inhibitor of CFTR, USE- HIV drug induced diarrhoea.
 Gastro Intestinal System | 239
Miscellaneous:
Gallstone Dissolving Drugs:
Chenodeoxycholic acid (Chenodiol) Ursodeoxycholic acid (Ursodiol)
Acts primarily by inhibiting cholesterol synthesis in Acts primarily by inhibiting intestinal cholesterol
the liver absorption
Raises plasma LDL cholesterol by reducing LDL Does not raise plasma LDL cholesterol
receptors in the liver
Reduces cholesterol secretion in bile after prolonged Reduces cholesterol secretion in bile immediately
administration upon administration
Generates a more litholytic bile acid pool Itself lowers cholesterol saturation index of bile
Promotes micellarsolubilization of cholesterol Promotes solubilization of cholesterol by liquid
crystal formation

Prebiotics v/s Probiotics

Prebiotics Probiotics
Special forms of dietary fibers that nourish and Live bacteria that are supplemented from outside
enhance the growth of beneficial bacteria in the gut
Not affected by heat, cold, acid or time Can be destroyed by heat, cold, gastric acid or
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storage for prolonged periods

Indications of Prebiotics and Probiotics:

• Acute infectious diarrhea
• Antibiotic-associated diarrhea (Pseudomem branous enterocolitis)
• Neonatal necrotizing enterocolitis
• Lactase deficiency
• Irritable bowel syndrome
• Inflammatory bowel disease
• Celiac disease
• Food protein hypersensitivity
• H. pylori infection

Newer drugs
Drug Mechanism Indication

1 Vono- prazan Potassium-com- petitive acid Peptic ulcer disease and reflux esophagitis
blocker (approved only in Japan)

2 Vedoli- zumab Monoclonal an- tibody against Inflammatory bowel

α4β7 integrin disease in adults
240 | Pharmacology

3 Rifaxi- min Inhibits bacterial RNA Diarrhea-predomi- nant irritable bowel

polymerase syndrome

4 Eluxad- oline µ and κ opioid receptor agonist Diarrhea-predomi- nant irritable bowel
and δ-opioid receptor antag- onist syndrome

5 Naloxe- gol Pegylatednal- oxol (opioid Opioid-induced con- stipation in adults

receptor antag- onist)

6 Obeti- cholic acid Semi-synthetic bile acid ana- Primary biliary cholangitis
logue

7 Yosprala Fixed drug combination (FDC) of Patients who require aspirin for second-
Aspi- rin + Omepra- zole ary prophylaxis of cardio-vascular and
cerebro-vascular events and who are at risk
for develop- ing aspirin-associat- ed gastric
ulcers

AfraTafreeh.com
 Gastro Intestinal System | 241

Worksheet
To do
Examples for antimotility drugs

Lubiprostone mechanism of action

AfraTafreeh.com

What is croflemer
11 Antimicrobials

CONCEPTS
 Concept 11.1 General considerations
 Concept 11.2 Sulfonamides, Cotrimaxazole and
Quinolones
 Concept 11.3 
Cell wall inhibitors (beta lactum
antibiotics, glycopetides)
 Concept 11.4 Protein Synthesis Inhibitors
(Aminoglycosides, Macrolides,
Linocsamide)
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 Concept 11.5 
Broad spectrum antibiotics
(Tetracyclines & Chloramphenicol)
 Concept 11.6 Antitubercular Drugs
 Concept 11.7 Antileprotic Drugs
 Concept 11.8 Antifungal Drugs
 Concept 11.9 Antiviral Drugs (Retro & Non Retro
Viral)
 Concept 11.10 Antimalaria Drugs
 Concept 11.11 Ant Amoebic Drugs
 Concept 11.12 Anthelminthic Drugs
 Antimicrobials | 243
Concept 11.1 : General Considerations
Learning objectives: Contribution of scientist
• To know the classifications on antimicrobial agents
• To know the problems that arise with the use of antimicrobial agents
• To understand the concept antimicrobial agents resistance
• To know the factors governing selection of antimicrobial agents
• To know the categories of antimicrobial therapy

Time Needed
1 reading
st
45 mins
2nd reading 30 mins

1 Paul Ehrlich Developed arsphenamine (Salvarsan) and neoarsphenamine for syphilis.

Developed atoxyl for sleeping sickness.
Coined the term ‘chemotherapy’.
2 Gerhard Domagk Used prontosil (a dye) for treatment of streptococcal infections.
Sulphonamides were later developed from these dyes.
Was awarded the Nobel Prize for Medicine in 1938.
3 Louis Pasteur Demonstrated the phenomenon of antibiosis by showing that the growth
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of anthrax bacilli in urine can be inhibited by exposure to air- borne
bacteria.
4 Alexander Fleming Discovered penicillin in 1928.
5 Howard Florey and Ernst Isolated penicillin.
Chain Shared the Nobel Prize with Alexander Fleming for development of
penicillin.
6 Selman Waksman Isolated streptomycin from soil actinomycetes.
and colleagues
7 Brotzu Isolated Cephalosporium fungus, the source of cephalosporins in 1948.

Classification of antimicrobial agents

Based on source:
Drug Microbial source
Drugs obtained from bacteria
1 Polymyxin B Bacillus polymyxa
2 Colistin Bacillus (Aerobacillus) colistinus
3 Bacitracin Bacillus subtilis (Tracy-I strain)
4 Tyrothricin Bacillus bravis
5 Aztreonam Chromobacterium violaceum
244 | Pharmacology

6 Vancomycin Streptococcus orientalis

7 Teicoplanin Actinoplanes teichomyetius
8 Mupirocin Pseudomonas fluorescens
Drugs obtained from fungi
1 Penicillins Originally isolated from– Penicillium notatum
Nowadays, commercially prepared from a mutant of – Penicillium
chrysogenum
2 Cephalosporins Cephalosporium acremonium
3 Griseofulvin Penicillium griseofulvum
4 Caspofungin Glarea lozoyensis
Micafungin Coleophoma empedri
Anidulafungin Aspergillus nidulans
Drugs obtained from actinomycetes
1 Streptomycin Streptomyces griseus
Gentamicin, Netilmicin Micromonospora
Tobramycin Streptomyces tenebrarius
Remaining aminoglycosides are semi-synthetic derivatives
2 Oxytetracycline
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Streptomyces rimosus
Demeclocycline Streptomyces aureofaciens
Remaining tetracyclines are semi-synthetic derivatives
3 Chloramphenicol Streptomyces venezuelae
4 Erythromycin Streptomyces erythreus
Remaining macrolides are semi-synthetic derivatives
5 Amphotericin B Streptomyces nodosus
Nystatin Streptomyces noursei
Hamycin Streptomyces pimprina
Natamycin Streptomyces natalensis
6 Imipenem Derivative of thienamycin, obtained from Streptomyces cattleya.
7 Clavulanic acid Streptomyces clavuligerus
8 Streptogramins (Quinupristin / Streptomyces pristinaespiralis
Dalfepristin)
9 Spectinomycin Streptomyces spectabilis
10 Daptomycin Streptomyces roseosporus
11 Rifampicin Derivative of Rifamycin B obtained from Streptomyces
meditteranei
 Antimicrobials | 245
Based on mechanism of action-
Cell wall Cell membrane Protein synthesis Nucleic acid Folic acid Microtuble
inhibitors inhibitors inhibitor synthesis synthesis inhibitors
inhibitor inhibitors

Beta-lactam 1. Polypeptide By acting on 30s Metronidazole Sulfonamide Griseofulvin

antibiotics – Polymyxin-B ribosomes Rifampicin Trimethoprim
Vancomycin / – Polymyxin-E Aminoglycoside Nitrofurantoin Pyrimethamine
Teicoplanin (Colistin) Tetracycline
Bacitracin 2. Polyene By acting on 50s
(polypeptide) Antifungals ribosomes
Cycloserine – Amphotericin B Chloramphenicol
Fosfomycin 3. Azole Antifungal Macrolides
– Ketoconazole Liconsanamide
4. Allylamime (clindamycin)
– Terbinafine Streptogramin
Linezolid

Bases on bacteriostatic or bactericidal

Bacteriostatic Bactericidal

• Protein synthesis Inhibitors (except • Cell Wall Inhibitors

aminoglycosides, streptogramins)
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• Cell membrane inhibitors
• Those affecting “Folate Pathway” • Those affecting nucleic acid synthesis
(sulfonamides / trimethoprim) • First line ATT (Except ethambutol)
• Affecting DNA- nitrofurantoin, novobiocin • Cotrimoxazole
• Aminoglycosides
• Streptogramins

Classification of Antimicrobials Based on their Action

and Post-Antibiotic Effect:
Time-dependent Concentration-dependent Time-dependent,
(with minimal or no PAE) (with prolonged PAE) concentration-enhanced
(with PAE)

• β-lactams • Aminoglycosides • Clarithromycin

• Vancomycin • Daptomycin • Clindamycin
• Fluoroquinolones • Erythromycin
• Metronidazole • Linezolid
• Azithromycin • Streptogramins
• Ketolides • Tetracyclines
• Tigecycline
246 | Pharmacology
Adverse effects of antimicrobial agents (AMA)
General Aminoglycoside Tetracyckine Chloramphenicol Vancomycin Amphotericin B
Hypersensititivy Ototoxic Pseudotumor Bone marrow Redman Allergy
Anaphylaxis Nephrotoxic cerebri suppression syndrome Nephrotoxic
Skeletal muscle Outdated drugs Grey baby Ototoxic Anemia
paralysis -fnaconis syndrome Nephrotoxic Neurological
syndrome damage
Teratogenicity

Phototoxicity Ototoxicity nephrotoxicity Disulfiram like Hemolysis in G6PD

reaction deficiency
Sulfonamides Aminoglycoside Aminoglycosides Cephalosporins Sulfonamide
Tetracyclines Vancomycin Tetracyclines Metronidazole Primaquine,
Demeclocyline Macrolides -outdated Chloramphenicol chloroquine, quinine
Fluroquinolone Demeclocycline Griseofulvin Chloramphenicol
Sparfloxacin Sulfonamides Nitrofurantoin
Azithromycin Penicillin Fluroquinolones
(methicillin)

Antimicrobial Resistance
Inability to reach target Insensitive target Drug inactivation / Through alternative
site Modification pathways
Decreased influx- AfraTafreeh.com
Quinolone Rifampicin
- β-lactam Sulphonamides,
Aminoglycosides, penicillin antibiotics Trimethoprim
Tetracycline Increased (β lactamase)
efflux – tetracyc, Aminoglycosides
Erythromycin, Quinolone Chloramphenicol (acetyl
transferase)

Choice of antimicrobial agents

Patient Factors Drug Factor Micro Organism Factors
Age- Spectrum of activity (BROAD/ Bacteriological/diagnostic services
Gray baby syndrome.- NARROW) are not available-
CHLORAMPHENICOL Type of activity (CIDAL/ STATIC) EMPIRICAL THERAPY to cover
Jaundice (kernicterus) - Sensitivity of the organism all likely organisms with a broad-
SULPHONAMIDES Relative toxicity spectrum drug
Bone & teeth defect- Pharmacokinetic profile Bacteriological services are
TETRACYCLINES (CONCENTRATION/ TIME available & treatment can be
Renal & hepatic functions DEPENDENT) delayed for a few days-
H/O allergy to AMA host defence Cost It is BETTER TO WAIT FOR The
culture & sensitivity report
Local factors- Presence of pus and
secretions, pH Bacteriological /diagnostic services
are available. But treatment cannot
Supha&cotrimoxazole-Kernicterus
be delayed:
Tetracycline-Teeth & bone defect
EMPIRICAL THERAPY started
Aminoglycoside –ototoxicity provisionally-
Quinolones-arthropathy AMA should be changed later in the
Clarithromycin-teratogenic light of bacteriological findings
Chloramphenicol- grey baby
 Antimicrobials | 247
Antimicrobials in Renal Disease:
Drugs to be completely avoided Dose reduction even Dose reduction only in
in mild failure moderate-to-severe renal
failure

• Nalidixic acid • Aminoglycosides • Aztreonam

• Nitrofurantoin • Amphotericin B • Carbenicillin
• Talampicillin • Cephalosporins • Clarithromycin
• Tetracyclines • Ethambutol • Cotrimoxazole
(except doxycycline) • 5-Flucytosine • Fluoroquinolones
• Vancomycin • Imipenem
• Meropenem
• Metronidazole

Antimicrobials in Liver Disease:

Drugs to be avoided Dose reduction needed

• Erythromycin esteolate • Chloramphenicol

• Nalidixic acid • Clindamycin
• Pefloxacin • Isoniazid
• Pyrazinamide AfraTafreeh.com • Metronidazole
• Talampicillin • Rifampicin
• Tetracyclines

Combination of Antimicrobial Agents

Advantages Disadvantages

Synergism Increased incidence ADR (vancomycin + tobramycin

Prevention of resistance – more nephrotoxic)
Broadening of spectrum Increased risk of superinfections (pseudomembranous
Initial therapy for severe infection colitis)
If inadequate doses- risk of resistance
Higher cost

Examples of Antimicrobial Synergistic Combinations:

• Penicillin + Tetracycline for Pneumococci.
• Penicillin + Chloramphenicol for Pneumococci.
• Penicillin + Erythromycin for Group A Streptococcus.
• Nalidixic acid + Nitrofurantoin for E.coli.
248 | Pharmacology
Examples of Antimicrobial Antagonistic Combinations:
• Penicillin / Ampicillin + Streptomycin / Gentamicin for enterococcal SABE.
• Vancomcyin + Gentamicin for enterococcal SABE.
• Carbenicillin / Ticarcillin + Gentamicin for Pseudomonas infections, especially in neutropenic patients.
• Ceftazidime + Ciprofloxacin for Pseudomonas infected orthopedic prosthesis.
• Penicillin + Sulfonamide for actinomycosis.
• Streptomycin + Tetracycline for brucellosis.
• Streptomycin + Chloramphenicol for K. pneumoniae infection.
• Rifampicin + Isoniazid for tuberculosis.
• Rifampicin + Dapsone for leprosy.

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Fig. 11.1

Chemoprophylaxis
DISEASE DRUGS
CHOLERA Tetracycline/ doxycycline
Bacterial Conjunctivitis Erythromycin ophthalmic ointment
Diphtheria Erythromycin &1st dose of vaccine
Influenza Oseltamivir
Plaque Tetracycline
Leprosy Dapsone
Meningococcal meningitis rifampin/ciprofloxacin/ ceftriaxone
Rheumatic fever Benzathine penicillin
TB- INH -6months
MAC azithromycin/ clarithromycin
Gonorrhoea/syphilis ampicillin/ceftriaxone
Rickettsial tetracycline
Malaria chloroquine/ mefloquine
 Antimicrobials | 249
Antimicrobials for Surgical Prophylaxis
Oral (single dose given 1 hour before procedure)
• Amoxicillin – 2g (50mg/kg)
• Cephalexin – 2g (50mg/kg)
• Cefadroxil – 2g (50mg/kg)
• Clindamycin – 600mg (20mg/kg) – for penicillin allergic patients
• Azithromycin – 500mg (15mg/kg) – for penicillin allergic patients
• Clarithromycin – 500mg (15mg/kg) – for penicillin allergic patients
Parenteral (single injection given just before procedure)
• Ampicillin – 2g (50mg/kg) IM/IV
• Cefazolin – 1g (25mg/kg) IV
• Vancomycin – 1g (20mg/kg) IV – in MRSA prevalent areas and/or penicillin allergic patients
• Clindamycin – 600mg (20mg/kg) IV – for penicillin allergic patients
• Cefuroxime – 1.5g (30mg/kg) IV + Metronidazole – 0.5g (10mg/kg) IV – for gut and biliary tract surgery
• Gentamicin – 160mg (3mg/kg) IV + Metronidazole – 0.5g (10mg/kg) IV – for gut and biliary tract
surgery

Antimicrobials for Surgical Prophylaxis in Case of dirty Contaminated

Wounds:
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• Cefazolin – 1g IV 8 hourly + Vancomycin – 1g IV 12 hourly.
• Cefoxitin – 1g IV 6 hourly.
• Ceftizoxime – 1g IV 12 hourly.
• Clindamycin – 0.6g IV 8 hourly + Gentamicin – 80mg IV 8 hourly.
• Ampicillin – 2g IV 6 hourly / Vancomycin – 1g IV 12 hourly + Gentamicin – 80mg IV 8 hourly +
Metronidazole – 0.5g IV 8 hourly.
• Amoxicillin – 1g + Clavulanate – 0.2g IV 12 hourly.

Duration of Surgical Prophylaxis:

Dirty contaminated wounds 5 days

All other cases 3 hours

250 | Pharmacology

Worksheet
To do
Antibiotic inhibiting cell wall synthesis

Antibiotic following concentration dependent killing

Mechanism of resistance of antimicrobial agents

Antimicrobial to be avoided in renal failure

AfraTafreeh.com
antimicrobial to be avoided in liver failure

Antibiotic causing red man syndrome

Antimicrobials causing ototoxicity

Antibiotics inhibiting protein synthesis

 Antimicrobials | 251
Concept 11.2 : Sulfonamides, Cotrimaxazole and Quinolones
Learning objectives:
1. To study the mechanism of actions of sulfonamide and cotrimaxazole
2. To know the classification and clinical uses of sulfonamides
3. To the adverse effects of sulfonamides
4. To know the classification and clinical uses of quinolones
5. To know the adverse effects & withdrawn quinolones

Time Needed
1 reading
st
30 mins
2nd reading 15 mins

Antimetabolites:
Pathway of folate metabolism:
Pteridine + PABA

Dihydropteroate synthase

Dihydropteroic acid

Dihydrofolate synthase AfraTafreeh.com

Dihydrofolic acid

Dihydrofolate reductase

Tetrahydrofolic acid

Mechanism of action of antibacterial antimetabolites:

Sulfonamides Dihydropteroatesynthase inhibitors
Dapsone
Trimethoprim Dihydrofolate reductase inhibitors
Pyrimethamine

Sulfonamides:
Short-acting (4 – 8 h) Sulfadiazine
Intermediate acting (8 – 12 h) Sulfamethoxazole
Long acting (~ 7 days) Sulfadoxine
Sulfamethopyrazine
Topical Sulfacetamide sodium Silver sulfadiazine Mafenide
Sulfasalazine (eye)
252 | Pharmacology

One-liners:
• Sulfonamides and Dapsone are structural analogues of – PABA.
• Increased bacterial production of PABA
• can lead to resistance to – Sulfonamides.
• Sulfonamide which is a carbonic anhydrase inhibitor – Mafenide.

Adverse effectsof sulfonamides–(Mnemonic: CAR-PHEK).

• Crystalluria. • Hypersensitivity reactions – SJS and TEN.
• Acute hemolysis. • Erythema multiforme.
• Rashes. • Kernicterus.
• Photosensitivity.

One-liners:
• Sulfonamides cause kernicterus due to – Displacement of bilirubin from plasma
protein binding sites.
• Co trimaxazole Sulfamethaxazole 400mg + Trimethoprime 80mg, 5: 1 ratio) .
• DOC- pneumocystis carinii Co trimaxazole DS.
• Sulfasalazine- (5ASA (ulcerative colitis) + Sulfapyridine (RA) ) .
•
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For Toxoplasmosis- Sulfadiazine + Pyrimethamine+ Folinic acid.
• Toxoplasmosis in pregnancy- spiramycin (macrolide) .
• Domagk (1938) - invented sulfonamide compound.

Cotrimoxazole:
Trimethoprim + sulfamethoxazole in the ratio of –
1:5 in the tablet
1:20 in the tissues

One-liners:
• Cotrimazine – Trimethoprim + Sulfadiazine.

Cotrimoxazole is the DOC in:

• Nocardiosis
• Cryptosporidiasis
• Isosporiasis
• Pneumocystis jiroveci pneumonia
 Antimicrobials | 253
DNA Gyrase Inhibitors-
Examples for quinoles
Quinolones Fluoroquinolones
1 generation (Mnemonic: N-COP) 2 generation (Rest all)
st nd

Nalidixic acid Norfloxacin Levofloxacin

Ciprofloxacin Lomefloxacin
Ofloxacin Sparfloxacin
Pefloxacin Moxifloxacin
Gatifloxacin
Prulifloxacin

Fluoroquinolones that have been withdrawn:

Drug Reason
Trovafloxacin Hepatotoxicity
Grepafloxacin Cardiotoxicity (Adverse cardiac events)
Clinafloxacin Phototoxicity
Temafloxacin Immune hemolytic anemia
Gatifloxacin (systemic AfraTafreeh.com
Pancreatic damage
preparation) → Hypoglycemia f/b
hyperglycemia

One-liners:
• Nalidixic acid was obtained as a by - product of – Chloroquine synthesis.
• Most potent 1st generation fluoroquinolone – Ciprofloxacin.

Pharmacokinetics of fluoroquinolones:
Drug Oral F (%) PPB (%) % Metabolized
Norfloxacin 35–45 15 25
Ciprofloxacin 60–80 20–35 20
Ofloxacin 85–95 25 5–10
Pefloxacin 90–100 20–30 85
Levofloxacin ~ 100 25 5
Gemifloxacin 70 55–73 –
Moxifloxacin 85 40 70–80
Prulifloxacin 90 45 > 90
254 | Pharmacology

One-liners:
• Pefloxin injection should be diluted in – Glucose (as it precipitates in the presence of
Cl- ions.
• Pefloxin, gemifloxacin has high CNS penetration power.
• Antimicrobials that get concentrated in prostrate – Fluoroquinolones and trimethoprim.
• Fluoroquinolones detected in ascitic fluid – Ofloxacin and Pefloxacin.
• Fluoroquinolones detected in breast milk – Ciprofloxacin, Ofloxacin and Pefloxacin.
• Fluoroquinolones that do not require dose reduction in renal failure – Pefloxacin,
trovafloxacin and Moxifloxacin.
• Trovafloxacin highly hepatotoxic.

Fluoroquinolones effective against tuberculosis:

• Ciprofloxacin. • Levofloxacin.
• Ofloxacin. • Moxifloxacin.

One-liners:
• Best fluoroquinolone against tuberculosis – Moxifloxacin.
•
penetration).
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Fluoroquinolone preferred in bacterial meningitis – Pefloxacin (due to good BBB

• Strength of ciprofloxacin eye drops: 3 mg/mL.

• Strength of ofloxacin eye drops: 0.3%.
• Strength of levofloxacin eye drops: 0.5%.
• Most important toxicity of nalidixic acid – Neurotoxicity.
• Nalidixic acid is contraindicated in Infants (due to greater risk of neurotoxicity) .
• Most common adverse reaction to fluoroquinolones – GI symptoms.
• Most common fluoroquinolone increasing the risk of Cl. difficile infection – Ciprofloxacin.
• Highest phototoxic quinolone- sparfloxacin.
• Risk of tendon damage due to fluoroquinolones is higher in patients – less than 6yr age
and above 60 years of age.
• Most common tendon ruptured due to fluoroquinolones – Achilles tendon.
• QTc interval prolongation is seen with– Sparfloxacin, Moxifloxacin and Gatifloxacin.
• Quinolone useful in TB­Ciprofloxacin, Levofloxacin, Moxifloxacin.
• Purulifloxacin­ Ulifloxacin­ Broad spectrum.
• Quinolones are microsomal enzyme inhibitors.

Achilles tendon rupture due to fluoroquinolones is more common in:

• Age > 60 years. • Solid organ transplant recipients.
• Patients on corticosteroids. • Renal insufficiency.
 Antimicrobials | 255

Worksheet
To do
Drugs useful for toxoplasmosis

First line DOC for enteric fever

Withdrawn quinolone & the reason for withdrawal

AfraTafreeh.com

Most common adverse effects of sulfonamde

Cotrimaxazole is the DOC for

256 | Pharmacology
Concept 11.3 : Cell wall Inhibitors (beta-lactum antibiotics, glycol
petides)
Learning objectives:
1. To know the classification of penicillin
2. To know the spectrum and adverse effects of penicillin
3. To know the classification of cephalosporine
4. To know the spectrum and adverse effects of cephalosporines
5. To the uses and adverse effects of atypical beta lactam antibiotics
6. To know the uses and adverse effects of vancomycin
7. To know the drugs useful for treatment of MRSA & VRSA

Time Needed
1 reading
st
45 mins
2 reading
nd
20 mins

Examples of Bacterial Cell Wall Synthesis Inhibitors:

Enzyme Drug Inhibiting
Alanin Ligase (Alanin Racemase) Cycloserine
Enol Pyruate Transferase Fosphomycin
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Dephosporylation of bactophrenol Bacitracin
Trnasglycosilase Glycopepitide (Vancomycin)
Transpeptitase Beta lactum antibioitics

β-lactams (Bind to penicillin-binding Glycopeptides (Bind to Miscellaneous

proteins or PBPs) transpeptidase D-Alanyl-D-Alanine)
Transglycosylase
Penicillins Vancomycin Bacitracin
Cephalosporins Teicoplanin
Carbapenems
Monobactams

Penicillins:
Classification according to Source:
Natural Synthetic
• Penicillin G (also known as Benzyl penicillin / Crystalline penicillin / Rest all
Aqueous penicillin)
• Procaine penicillin G
• Benzathine penicillin
 Antimicrobials | 257

One-liners:
• Purpose of conjugating penicillin with procaine and benzathine – Prolong half-life and
hence, duration of action.
• Longest acting penicillin – Benzathine penicillin.
• 1 U of crystalline penicillin (Penicillin G) sodium = 0.6 µg of the standard preparation.
• Hence, 1 g of Penicillin G sodium = 1667 U.
• However, 1 g of Penicillin G potassium = 1595 U.

Route of administration:
Oral (acid resistant) Parenteral (acid labile)
Mnemonic: VODKAA • Rest all
• Penicillin V (Phenoxymethyl penicillin)
• Oxacillin
• Dicloxacillin
• C (K) loxacillin
• Amoxicillin
• Ampicillin

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One-liners:
• Tubular secretion of penicillins and cephalosporins is inhibited by – Probenecid.
• Hence, it can increasethe plasma levels of penicillins and cephalosporins.

Spectrum of action of penicillins:

Extended-spectrum penicillins Narrow-spectrum penicillins
Cover – Almost all Gram +ve and Gram –ve organisms Cover – Only Gram +ve organisms,
Neisseria and spirochaetes
Aminopenicillins: Rest all
Becampicillin (prodrug)
Amoxicillin
Ampicillin
Carboxypenicillins – Pseudomonal infection
Carbenicillin
Ticarcillin
Ureidopenicillins – pseudomonal + klebsiella infection
Piperacillin
Azlocillin
Mezlocillin
258 | Pharmacology

One-liners:
• DOC for leptospirosis – Penicillin G.
• DOC for actinomycosis – Penicillin G.
• DOC for rat bite fever – Penicillin G.
• DOC for syphilis (except neurosyphilis) – Benzathine penicillin.
• Benzathine penicillin is contraindicated in neurosyphilis as – it worsens the neurological
features.
• Treatment for neurosyphilis – Penicillin G / Procaine penicillin.
• Jarisch herxheimer reaction-side effect of penicillin in syphilitic patient.
• Amino penicillin (Ampicillin) contra indicted in infectious mononeculeosis (due to risk
of skin allergy) .
• DOC for prophylaxis of rheumatic carditis – Benzathine penicillin.
• Dose of benzathine penicillin for prophylaxis of rheumatic carditis – 1.2MU (12 lac units)
IM every 3-4 weeks.
• DOC for listeriosis – Ampicillin.
• Anti-pseudomonal penicillin – (carboxypenicillin and urediopenicillin) Piperacillin >
Carbenicillin.
• Most common mechanism of penicillin resistance – β-lactamase production.
• Most common mechanism of methicillin resistance – Alterations in penicillin-binding
proteins.
• METHICILLIN- causes intertitial nephritis.
•
•
AfraTafreeh.com
PROCAINE PENICILLIN-causes seizure.
OXACILLIN- side effects-hepatitis.
• NAFCILLIN- side effect-neutropenia.
• CARBENICILLIN- causes bleeding.
• Resistance to methicillin is primarily – chromosome mediated.

Susceptibility of Penicillins To β-Lactamase:

Penicillinase-resistant Penicillinase-susceptible

• Methicillin • Rest all

• Nafcillin
• Oxacillin
• Cloxacillin
• Dicloxacillin

Examples for beta lactamase inhibitors

• Sulbactum
• Clavulanic acid
• Tozabactam
 Antimicrobials | 259

One-liners:
• Usually beta lactamase inhibitors as such has no anti bacterial action.
• β-lactamase inhibitor exhibiting direct activity against Acinetobacter – Sulbactam
• The purpose of additing beta lactamase inhibitor with beta lactum antibiotic is to prevent
resistance.
• β-lactams show cross-allergy with each other except – Aztreonam.
• Aztreonam shows cross-allergy only with – Ceftazidime.
• Aztreonam effective for aerobic gram negative infection.
• Aztreonam spectrum is simillr to aminoglycosides.

Cephalosporins:
Classification:
Generation of cephalopsorins Examples Route
1st generation cephalosporins Cefalothin Parenteral
(Mnemonic: LO-ZO-LEX-RA-DROXIL) Cefazolin
Cefalexin Oral
Cefradine
AfraTafreeh.com Cefadroxil
2nd generation cephalosporins Cefaclor Oral
(Mnemonic: as a FACt, MAN kills FOX for FUR) Cefamandole Parenteral
Cefoxitin
Cefuroxime
Cefuroxime axetil Oral
3 generation cephalosporins
rd
Ceftriaxone Parenteral
Mnemonics: TRI-ZI-PER-TAX-ZOX; Cetazidime
FIX-PODO-MET-BUT-NIR) Cefoperazone
Cefotaxime
Ceftizoxime
Cefixime Oral
Cefpodoxime
Ceftamet
Ceftibuten
Cefdinir
4th generation cephalosporins Cefepime Parenteral
Cefpirome
Cefclidine
5th generation cephalosporins Ceftobipirole parenteral
Ceftaroline
260 | Pharmacology
Indications:
1st generation cephalosporins Prophylaxis of surgical infections

2nd generation cephalosporins Anaerobic bacterial infections

3rd generation cephalosporins Gram-ve bacterial infections

Cefoperazone and ceftazidime- anti pseudomanal activity

4th generation cephalosporins Reserve drugs for nosocomial infections

5th generation cephalosporins Reserve drugs for nosocomial infections; also effective against
MRSA

One-liners:
• DOC for gonorrhea – Ceftriaxone.
• DOC for meningococcal meningitis – Ceftriaxone.
• DOC for prophylaxis of meningococcal meningitis – Ceftriaxone.
• Most reliable drug for enteric fever – Ceftriaxone.
• Fastest acting bactericidal drug for typhoid fever – Ceftriaxone.
• DOC for Pseudomonas infection – Ceftazidime.
• Only cephalosporins with anti-MRSA activity – 5th generation cephalosporins.
• Cephalosporins can cause bleeding due to – Hypoprothrombinemia (Cefoperazone,
AfraTafreeh.com
Ceftriaxone, Cefotetan, Cefomondole, Moxolactam.
• Cefoperazone may cause disulfiram like reaction.
• Fifthe generation cephalosporins useful-MRSA, Community acquired pneumonia.
• Ceftazidime,Cefoperazone useful in psudomonal infection.

Atypical Beta Lactum Antibiotic (Cabapenam. Monobactam)

Carbapenems:
• Imipenem. • Ertapenem.
• Meropenem. • Faropenem.
• Doripenem.

One-liners:
• Orally active carbapenem – Faropenem.
• Imipenem is metabolized by – dipeptidase enzyme on the renal proximal tubular brush
border; hence, combined with dipeptidase inhibitor – Cilastatin.
• β-lactam effective against ESBL producing strains – Imipenem.
• High doses of imipenem can cause – Seizures.
• Carbapenem resistance is seen due to production of – metallo-beta lactamase
(carbapenemase) enzyme. E.g.: NDM-1 (New Delhi metallo-beta lactamase-1) also
known as ‘superbug’.
 Antimicrobials | 261

Monobactams:
Aztreonam - Effective against aerobic Gr(-)ve infection.
• β-lactam used in penicillin allergy cases.

Glycopeptides:
Examples:
• Vancomycin. • Dalbavancin.
• Teicoplanin. • Oritavancin.
• Telavancin.

One-liners:
• Glycopeptides are only effective against – Gram+ve organisms as D-Ala-D-Ala is absent
in Gram-ve organisms.

Vancomycin:
One-liners:
One-liners:
• AfraTafreeh.com
Vancomycin is orally – not absorbed; hence given IV.
• BBB penetration is – Poor.
• T½: ~ 6 hours.
• Dose: 500 mg QID.
• Use- orally for pseudo memberanous colitis, intra venously for MRSA (DOC).
• Most common side effect – Red man syndrome ( due to release of histamine).
• Dose needs to be reduced in renal failure, as it is excreted unchanged by kidney.

Drugs Effective against MRSA:

• Glycopeptides. • 5th generation cephalosporins.
• Linezolid. • Tigecycline.
• Quinupristin / Dalfepristin (Streptogramins). • Cotrimoxazole.
• Daptomycin. • Ciprofloxacin.
• Mupirocin.

Drugs effective against VRSA:

• Linezolid(common side effects- thrombocytopenia, neuropathy both peripheral ad optic, has MAO
enzyme ibhibitory action).
• Quinupristin / Dalfepristin (Streptogramins) (common side effect- infusion reaction, arthralgia).
• Daptomycin ( side effect- myopathy).
• Tigecycline( intravenous tetracycline, resistant to efflux pump, excreted via bile, safe in renal failiure).
262 | Pharmacology

One-liners:
• DOC for MRSA – Vancomycin.
• Route of vancomycin in pseudomembranous enterocolitis (drug-induced colitis) – Oral.
• Most common side effect due to vancomycin – Maculopapular rash.
• Red man syndrome is seen with – Vancomycin.

Red man syndrome:

• Infusion reaction due to vancomycin.
• Widespread histamine release due to non-specific mast cell degranulation.
• Appearance – 4–10 min after the commencement or soon after the completion of an infusion.
• Erythema of the peri-oral region and upper trunk.
• Prevention – Slow IV infusion of a diluted solution over 60 minutes.

Pseudomembranous Colitis:
• Caused by bacterium Clostridium difficile.
• Most commobly caused by 3rd gen cephlosporins.
• Treated by Metronidazole (firstline DOC), Vancomycin, Rifaximin, Fidaxomicin.
AfraTafreeh.com
 Antimicrobials | 263

Worksheet
To do
Jarisch herxheimer reaction is the adverse effect
of

Cephalosporines causing disulfiram like reactions

Redman syndrome is the adverse effects of

AfraTafreeh.com
Drugs useful for VRSA

Antimicrobial causing cheese reaction

Anti pseudomanla penicillins are

264 | Pharmacology
Concept 11.4 : Protein Synthesis Inhibitors
Learning objectives:
• To know the various mechanism of actions of protein synthesis inhibitors
• To study the uses and adverse effects of aminoglycosides
• To know the uses and adverse effects of macrolides
• To know the uses and adverse effects of clindamycin (lincosanamide)

Time Needed
1st reading 40 mins
2 reading
nd
20 mins

Mechanisms of Action of Protein Synthesis Inhibitors:

Aminoglycosides • Prevent formation of polysomes
(binds with 30S ribosome) • Promote disaggregation of already formed polysomes
• Cause misreading of mRNA code
↓
Freeze the initiation of protein synthesis
Tetracyclines Inhibit the binding to aminoacyl-tRNA to A site on ribosomes
(binds with 30S ribosome)
Chloramphenicol Inhibit peptidyltransferase enzyme
(binds with 50S ribosome)
AfraTafreeh.com
Macrolides Clindamycin Lincomycin Inhibit the process of translocation
(binds with 50S ribosome)

One-liners:
• Puromycin – Structural analogue of tyrosinyl-tRNA. It gets incorporated into the
carboxy-terminal position of the peptide at the A site of ribosome and causes premature
release of the peptide, thus prematurely terminating protein synthesis.
• Retapamulin – Topical antibiotic belonging to pleuromutilin class; approved for skin
infections due to Gram+ve bacteria such as impetigo. Also binds to 50S and inhibits
protein synthesis

Binding sites of Protein Synthesis Inhibitors:

30S 30S-50S interface 50S
Streptomycin All aminogly­cosides except Rest all
Tetracyclines streptomycin

Aminoglycosides:
• Streptomycin • Capreomycin • Neomycin (topical)
• Gentamicin • Tobramycin • Framycetin (topical)
• Kanamycin • Netilmicin • Paromomycin (topical)
• Amikacin • Sisomicin
 Antimicrobials | 265
Nomenclature:
Source – Streptomyces Source – Micromonospora

Add –_mycin Add – _micin

E.g.: Streptomycin E.g.: Gentamicin

One-liners:
• Aminoglycosides are not absorbed orally due to – Polar nature.
• BBB penetration of aminoglycosides – Poor.
• Aminoglycosides require dose reduction in – Renal failure as they are primarily
excreted unchanged by the kidney.

Guidelines for dose adjustment of gentamicin in renal insufficiency:

Creatinine clearance (mL/min) Dose adjustment needed

70 70 % of daily dose

50 50 % of daily dose

30
AfraTafreeh.com
30 % of daily dose

20 – 30 80 % on alternate days

10 – 20 60 % on alternate days

< 10 40 % on alternate days

Aminoglycosides Effective in Tuberculosis:

• Streptomycin. • Capreomycin.
• Amikacin. • Kanamycin (Mnemonic: SACK) .

One-liners:
• Aminoglycoside used in hepatic encephalopathy – Neomycin.
• Intrinsic aminoglycoside resistance – Anaerobes, as penetration of aminoglycosides into
bacterial cells is an aerobic process.
• Aminoglycoside showing least cross- resistance – Amikacin (effective even when
organism is resistant to other aminoglycosides) .
• Most common cause for resistance of mahority of aminoglycoside is due to enzymatic
degradation.
• Outstanding aminoglycosides not yet developed resistance are amikacin and netilmicin.
266 | Pharmacology
Comparison of Toxicities of Aminoglycosides:
Ototoxicity Nephrotoxicity
Vestibular Cochlear
Streptomycin ++ ± +
Gentamicin ++ + ++
Kanamycin + ++ ++
Amikacin + ++ ++
Tobramycin +± + +
Sisomycin ++ + ++
Netilmicin +± + ++

One-liners:
• Hearing loss due to aminoglycosides is – Irreversible.
• Least ototoxic aminoglycoside – Netilmicin.
• Most vestibulotoxic aminoglycoside – Streptomycin.
• Least nephrotoxic aminoglycoside – Streptomycin.
• Most nephrotoxic aminoglycoside – Neomycin.
• AfraTafreeh.com
Most skeletal muscle relaxing drug – neomycin

One-liners:
• Aminoglycoside follows concentration dependent killing.
• Aminoglycosides has long post antibiotic effect.
• Aminoglycoside effective for kala azar – paramomycin.
• Aminoglycosides effective for pseudomonal infection - Toramycin, Amikacin, -
gentamicin.
• Gentamicin PMMA (poly methyl methacrylate) - given as an implantation into the bone in
case of osteomyelitis.
• DOC- plague- streptomycin (for mass prophylaxis- doxycycline).
• Aminoglycosides when combine with beta lactam antibiotic produces synergestic effect

Macrolides :
Examples of Macrolides:
• Erythromycin. • Roxithromycin.
• Clarithromycin. • Spiramycin.
• Azithromycin. • Tacrolimu.
 Antimicrobials | 267

One-liners:
• Erythromycin was isolated in – 1952.
• Telithromycin is a – Ketolide.

Azithromycin is Doc in:

• Whooping cough. • Chancroid.
• Atypical pneumonia. • Donovanosis.
• Trachoma. • Goncoccal and non gonococal urethritis.

Azithromycin is preferred over erythromycin today for most of the

indications due to:
• Higher efficacy.
• Better gastric tolerance.
• Convenient once daily dosing regimen.

One-liners:
• DOC for prophylaxis of rheumatic carditis in penicillin-allergic patients – Erythromycin.
• AfraTafreeh.com
DOC for atypical mycobacterial infections – Clarithromycin.
• DOC for toxoplasmosis in pregnancy – Spiramycin.
• Macrolides exhibit cross-resistance with – Clindamycin and Lincomycin.
• Biliary excretion is the major route for elimination of – Erythromycin and Azithromycin.
• Ototoxicity due to macrolides manifests as – Transient auditory impairment /
Reversible hearing loss.
• Telithromycin is contraindicated in – Myasthenia gravis (due to exacerbation of
symptoms).
• Erhtromycin estolate – unsafe in pregnancy (causing cholestatic jaundice to
mother).
• Clarithromycin useful in Mycobacteium Avium Complex.
• Clarithromycin useful in H. pylori induced gastric ulcer.
• Azithromycin has largve valume of distribution.
• Azithromycin may cause QT prolongation.
• Erythromycin may aggrevate congenital pyloric stenosis.
• Macroline by acting on motilin receptor in GIT acting as proinetic.

Lincosanmide (clindamycin)
• Useful In anaerobic infection
• Common side effect is pseudomembranous colitis
268 | Pharmacology

Worksheet
To do
Aminoglycosides useful In TB

Most nephrotoxic aminoglycosides

Antimicrobial group having prokinetic property

AfraTafreeh.com
Macrolide having immunosuppressant property

Example for ketolide

 Antimicrobials | 269
Concept 11.5 : Broad Spectrum Antibiotics
(Tetracyclines & Chloramphenicol)
Learning objectives:
• To know the uses and adverse effects of tetracycline
• To know the uses and adverse effects of chloramphenicol

Time Needed
1st reading 25 mins
2 reading
nd
10 mins

Tetracyclines:
Examples of Tetracyclines:
• Tetracycline. • Demeclocycline.
• Chlortetracycline. • Doxycycline.
• Oxytetracycline. • Minocycline.
• Methacycline.

AfraTafreeh.com
One-liners:
• Oral absorption of tetracyclines is reduced by – Food, milk and cations.
• Tetracycline that can be given in full doses in renal failure – Doxycycline, tigecycline
(as it is excreted in bile).

Doxycycline is DOC in:

• Brucellosis (along with rifampicin) . • Relapsing fever.
• Cholera. • LGV.
• Rickettsial infections. • Prophylaxis of leptospirosis.
• Lyme’s disease.

Doxycycline Useful for Prophylaxis of:

• Brucellosis (along with rifampicin) . • Plague.
• Cholera., Malaria • Prophylaxis of leptospirosis.
270 | Pharmacology

One-liners:
• Most potent tetracycline – Minocycline.
• All tetracyclines are nephrotoxic except – Doxycycline , tigecycline.
• Tetracycline with highest phototoxicity – Demeclocycline> Doxycycline.
• Tetracycline exhibiting vestibular toxicity – Minocycline.
• Fanconi’s syndrome is seen with – Outdated / Expired tetracyclines.
• Pseudo tumor cerebri (elevation intracranial pressure) – side effect of tetracycline.

Tigecycline:
• Glycylcycline.
• Tetracycline derivative.
• Given intravenously.
• Mechanism similar to tetracyclines.
• Resistant to efflux pump.
• Reserve drug for resistant infections including
• MRSA.
• Tetracycline useful in leprosy- Minocycline.
• Demeclocycline because of causing DI can be useful in SIADH.
AfraTafreeh.com
Newer tetracyclines
Drug Uses
Eravacycline complicated intra abdominal infection
Omadacycline Community-acquired bacterial pneumonia, skin and skin structure infections
Sarecycline moderate to severe acne vulgaris

Chloramphenicol:
• Bone marrow suppression due to chloramphenicol occurs regularly if plasma concentrations are – ≥
25 µg/mL.
• Grey baby syndrome is a side effect of – Chloramphenicol.
• Grey baby syndrome is more common in – Preterm infants.
• Most common antibiotic causing aplatsti anemia – Chloramphenicol.
• Most common reason for resistance of chloramphenicol is due to enzymatic degradation (acetyl
transferase).
 Antimicrobials | 271

Worksheet
To do
Doxycycline useful prophylactically for

Safer tetracycline in renal failure includes

Grey baby syndrome is the side effect of

AfraTafreeh.com
Fancony syndrome is the side effect of

Tetracycline resistant to efflux pump is

Most common cause for chloramphenicol resistant is

272 | Pharmacology
Concept 11.6 : Antitubercular Drugs
Learning objectives:
• To know the first line and second lines drugs useful in TB
• To know the adverse effects of anti TB drugs
• To know the newer drugs for resistant TB

Time Needed
1 reading
st
35 mins
2 reading
nd
20 mins

Antimycobacterials:
Contributions of various scientiststo treatment of tuberculosis:
1 Lehman Developed para-amino salicylic acid (PAS)
2 Domagk Developed thiacetazone
3 Kushner and colleagues Developed pyrazinamide
4 Sensi and Margalith Isolated rifampicin

One-liners:
• AfraTafreeh.com
The first ever drug for TB was – PAS in 1943.

Conventional 1st line drugs for TB:

• Isoniazid. • Ethambutol.
• Rifampicin. • Streptomycin.
• Pyrazinamide.

Chanisms of action of 1st line anti-TB drugs:

Cell wall synthesis inhibitors 1. Isoniazid Inhibits mycolic acid synthesis
2. Pyrazinamide Inhibits arabino- galactan synthesis
3. Ethambutol
Protein synthesis inhibitors 1. Rifampicin Inhibits DNA-de- pendent RNA polymerase
2. Streptomycin (Transcription inhibitor)
Freezes initia- tion of protein synthesis

Mechanisms of resistance for 1st line anti-TB drugs:

Drug Gene
Isoniazid KatG > InhA > KasA
Rifampicin rpoB
Pyrazinamide pncA
Ethambutol embB
 Antimicrobials | 273
Prevalence of drug resistance:
• Isoniazid: 1 in 106 bacilli. • Rifampicin: 1 in 107 – 108 bacilli.

One-liners:
• Resistance to anti-TB drugs is most commonly encountered with – Isoniazid.
• Overexpression of inhA may lead to cross-resistance of isoniazid with – Ethionamide.

Isonaizid (H) :
One-liners:
• Apart from tuberculosis, isoniazid is effective in – M.kansasii infection.
• INH not effective in MAC infection.

Peripheral neuropathy due to INH is more common in:

• Slow acetylators. • Poor nutrition.
• Diabetes mellitus. AfraTafreeh.com
• Anemia.

Indian population:
60 – 70 % - Slow acetylators of INH.
30 – 40% - Fast acteylators of INH.

One-liners:
• Peripheral neuropathy due to isoniazid is because of deficiency of – Pyridoxine.
• Dose of pyridoxine for prevention of peripheral neuropathy – 10 mg/d.
• Dose of pyridoxine for treatment of peripheral neuropathy – 100 mg/d.
• Antidote for isoniazid poisoning – Pyridoxine.
• Fast acetylators of isonazid are supposed to be more prone to – Hepatotoxicity (due to
formation acety hydrazine heoatotoxic metabolite) (not definitely proven) .
• INH may CNS side effects like memory loss, seizure, psychosis.
• Rarely causes shoulder hand syndrome.
• Safest anti-TB drug in pregnancy – Isoniazid.
• Isoniazid safe in renal faiure.
• Isoniazid is a microsomal enzyme inhibitor.
• Isoniazid is most effective aginst rapidly multiplying organism.
274 | Pharmacology

Rifampicin:
Indicationsof rifampicin:
Therapeutic –
• All mycobacterial infections.
• Brucellosis.
• Legionellosis.
• Staphylococcal endocarditis and osteomyelitis.
Prophylactic –
• Meningococcal meningitis
• H.influenzae meningitis

One-liners:
• Anti-TB drug penetrating caseous material – Rifampicin
• Rifampicin penetrates BBB but – effluxed out by p­gp. Hence, net rifampicin inside CNS
is zero
• Anti-TB drug penetrating caseous material – Rifampicin.
• Rifampicin penetrates BBB but – effluxed out by p­gp. Hence, net rifampicin inside CNS
is zero.

AfraTafreeh.com
Drugs causing intersitital nephritis as a side effect:
Antimicrobials • β-lactams
• Sulfonamides
• Quinolones
• Vancomycin
• Minocycline
• Rifampicin
• Isoniazid*
• Ethambutol
• Acyclovir
Diuretics • Thiazides
• Loop diuretics
• Triamterene
Anticonvulsants • Phenytoin
• Carbamazepine
• Valproate
• Phenobarbitone
 Antimicrobials | 275

Miscellaneous • NSAIDs
• PPIs
• H2 blockers
• Captopril
• Mesalazine
• Indinavir
• Allopurinol

Pyrazinamide:
• Pyrazinamide gets activated in – Acidic environment.
• Most heaptotoxic antitubercular – Pyrazinamide.
• Hyperuricemia and arthralgias are seenwith – Pyrazinamide.
• Unsafe in renal failure.

Ethambutol:
One-liners:
• Ethambutol is effective in all mycobacterial infections excluding – Leprosy.
• Optic neuritis is seen with – Ethambutol.
• AfraTafreeh.com
Red-green colour blindness is seen with – Ethambutol.
• Optic neuritis due to ethambutol may be minimied by supplementing with Vit
B12.

Drugs causing colour vision abnormalities:

Ethambutol Red-green colour blindness
Sildenafil Blue-green colour blindness
Digoxin Yellow vision
Thioridazine Brown vision

Streptomycin – previously discussed under aminoglycosides

Use of 1st line antituberculars in renal and liver disease
How to use Liver failure Renal failure
Full doses Ethambutol Rifampicin
Streptomycin
Reduced doses Isoniazid Isoniazid
Rifampicin Pyrazin- amide
Avoided Pyrazinamide Ethambutol
Strepto- mycin
276 | Pharmacology

One-liners:
• Rifabutin and Rifapentine have been re-grouped as – Extended 1st line drugs.
• Terizidone is a conjugate of – 2 molecules of cycloserine.

Newer drugs for tuberculosis:

1 Bedaquiline F0/F1 ATP synthase inhibitor (inhibits aerobic respiration)

2 Delamanid Inhibits mycolic acid synthesis; cell wall synthesis inhibitor.

3 Pretomanid Inhibits both mycolic acid synthesis and F0/F1 ATP synthase

4 Sutezolid Congener of linezolid; protein synthesis inhibitor

Classification of antitubercular drugs into cidal and static drugs:

Tuberculocidal Tuberculostatic
• Isoniazid • Rest all
• Rifamycins (Rifampicin, Rifabutin, Rifapentine)
• Pyrazinamide
• Aminoglycosides
• Fluoroquinolones AfraTafreeh.com
• Bedaquiline

One-liners:
• Antitubercular drug causing hypothyroidism – Ethionamide, Para-amino salicylic
acid.
• Anti TB drugs causing psychosis- INH, cycloserine.
• Anti TB drug causing uveitis- rifanutin.
• Antitubercular abosultely contrain - dicated in immunocompromised – Thiacetazone (due
to a high incidence of fatal hypersensitivity reactions) .
• Anti TB drugs useful for MAC- rifabutin, ethambutol, clarithromycin (REC).

Indications for chemoprophylaxis of TB

• Contacts of open TB with recent Mantoux conversion.
• Children with positive Mantoux test and a TB patient in the family.
• Patients of leukemia, diabetes or silicosis with a positive Mantoux test.
• Patients with old inactive disease with a recent Mantoux conversion.
• Neonates of tubercular mothers.

One-liners:
• Isoniazid monotherapy: 10­20 mg/ kg/d x 6 months.
 Antimicrobials | 277

Worksheet
To do
Anti TB drugs causing memory loss

First line anti TB drug having microsomal enzyme

induction property

Non tuberculous uses of rifampicin

Anti TB drug acting by inhibiting arabinogalaton

synthesis

AfraTafreeh.com
Optic neuritis is the adverse effect

First line Anti TB drug very safe in renal failure

patient is

Anti TB drugs causing hypothyroidism includeds

Ant TB drug causing uveitis is

278 | Pharmacology
Concept 11.7 : Antileprotic Drugs
Learning objectivs:
• To know the drugs useful in paucibacillary and in multibacillary leprosy
• To know the drugs useful for treating lepra reaction
• To know the drugs useful in atypical mycobacterium infections

Time Needed
1 reading
st
15 mins
2 reading
nd
10 mins

Treatment of leprosy:
Paucibacillary (Duration: 6 months) Multibacillary (Duration: 12 months)

Drug Dose Drug Dose

Rifampi- cin 600 mg on D1 Rifampi- cin 600 mg on D1

Dapsone 100 mg/d everyday Dapsone 100 mg/d everyday

Clofazi- mine 300 mg on D1

50 mg/d on re- maining
days
AfraTafreeh.com
• Anti TB drug useful in leprosy – Rifampicin, ethionamide.
• Antibiotics useful in leprosy – Ofloxacin, Minocycline, Clarithromycin.

• Most common adverse effect oo dapsone – skin rashes, hemolytic anemia.

• INJ. Acadapsone – given intra muscularly, long acting.

One-liners:
• Dapsone is also useful in ulcers caused by – Brown recluse spider.
• Dapsone produces hemolysis in G6PD deficient cases at doses of – > 50 mg/d.
• Sulfone syndrome develops – 4-6 weeks after starting dapsone.
• Main side effect of clofazimine – Reddish black discolouration of skin and body
secretions.
• C;pfazimine due its anti inflammatory action useful in type 2 lepra reaction.
• Most potent drug against leprosy – Rifampicin.
• Most potent fluoroquinolone against M. leprae – Moxifloxacin
 Antimicrobials | 279
ROM therapy:
Rifampicin 600 mg single dose
Ofloxacin 400 mg single dose
Minocycline 100 mg single dose
Originally employed for single lesion leprosy
Abandoned now

Treatment of Lepra reactions:

Type 1 Steroids
Type 2 (Erythema nodosum leprosum) Steroids
Recurrent and persistent cases of Type 2 Thalidomide, clofazimine, chloroquine

Treatment of atypical mycobacterial infections:

Clarithromycin + Azithromycin + Ethambutol + Rifampicin / Rifabutin

One-liners:
• DOC for atypical mycobacteria – Clarithromycin
AfraTafreeh.com
280 | Pharmacology

Worksheet
To do
Quinolone useful in leprosy

Drug useful for both type and type 2 lepra reaction

Anti TB drugs having antileprosy activitiy

AfraTafreeh.com

Most common adverse effect of clofazimine

 Antimicrobials | 281
Concept 11.8 : Antifungal Drugs
Learning objectives:
• To know the classification and mechanism of antifungal agents
• To know the drugs useful for superficial and deep mycosis
• To know the uses and adverse effects of azole antifungal agent
• To know the uses and adverse effects of ecchinocandins

Time Needed
1st reading 30 mins
2 reading
nd
15 mins

1 Antibiotics

• Polyenes • Echinocan- dins • Hetero- cyclic benzofu- rans

• Amphotericin B • Caspo- fungin • Gris- eo- ful- vin

• Nystatin • Mica- fungin
• Hamycin • Anidu- lafungin
• Natamycin

2 Antimetabolites AfraTafreeh.com
• 5-Flucytosine

3 Azoles

• Imidazoles • Triazoles

• Clotrimazole • Fluconazole
• Econazole • Itraconazole
• Miconazole • Voriconazole
• Oxiconazole • Posaconazole
• Butaconazole • Isavuconazole
• Tioconazole • Ternazole
• Sulconazole
• Sertconazole
• Ketoconazole

4 Allylamines

• Terbinafine
• Butenafine
• Naftifine
282 | Pharmacology

5 Miscellaneous

• Tolnaftate
• Undecylenic acid
• Benzoic acid
• Quinodochlor
• Ciclopirox olamine
• Sodium thiosulphate
• Haloprogin

One-liners:
• Whitfield’s ointment – 3% Salicylic acid + 5% Benzoic acid (It is named after Arthur
Whitfield, a British dermatologist) .

Mechanisms of action of antifungals:

Polyenes Bind to ergosterol on the fungal cell membrane
↓
Disorientation of the cell mem- brane
AfraTafreeh.com
Echinocan- dins Inhibit the synthesis of 1,3-β-D-glucan
↓
Reduce the structural integrity of the fungal cell wall

Griseofulvin Binds to β-tubulin

↓
Disorientation of microtubules

5- Flucyto- sine Inhibits DNA and RNA synthesis

Azoles Inhibit 14-α-sterol demethylase enzyme

Allylamines Inhibit squalene epoxidase enzyme

All antifungals are fungicidal except:

• Griseofulvin.
• 5-Flucytosine.
• Azole antifungals.
 Antimicrobials | 283

Polyenes:
Examples:
• Amphotericin B. • Hamycin.
• Nystatin. • Natamycin.

One-liners:
• Only polyene that can be used systemically – Amphotericin B (Others are too toxic,
hence used only topically).

Special formulations of amphotericin B:

• Amphotericin B lipid complex (ABLC).
• Amphotericin B colloidal dispersion (ABCD) .
• Amphotericin B deoxycholate salt.
• Liposomal amphotericin B.

One-liners:
• AfraTafreeh.com
Special formulations of amphotericin B are required because – It is water insoluble.
• Liposomal amphotericin B is usually preferred as it is – Better tolerated or less toxic.
• Amphotericin B is usually preferred for – Disseminated fungal infections.
• Only fungal infection that does not respond to Amphotericin B – Maduramycosis.
• DOC for Kala-azar – Amphotericin B.
• DOC for cryptococcal meningitis – Amphotericin-B + 5-Flucytosine (followed by long-
term treatment with Fluconazole).
• Amphotericin B causes loss of – Potassium and calcium ions.
• Patient on amphotericin B requires – Potassium supplementation.
• Oral nystatin is used for – Esophageal candidiasis.
• DOC for Fusarium solanii keratitis – Natamycin.

Echinocandins:
Examples- Caspofungin, Micafungin, Anidulafungin
Mechanism of action- Beta-1,3-glucan synthase inhibition
Administered as IV infusion due to short half-lives
Approved for invasive candidiasis and invasive aspergillosis
Never the DOC due to high cost
Concomitant administration of cyclosporine / tacrolimus is contraindicated due to
increase in levels
284 | Pharmacology

One-liners:
• Dose of caspofungin – 50 mg/d
• Dose of micafungin and anidulafungin – 100 mg/d

Griseofulvin:
Acts by binding to β-tubulin
Oral absorption is increased by fatty foods
Not used much due to high incidence of side effects and drug interactions

One-liners:
• Antifungal that gets deposited in keratin precursor cells – Griseofulvin.
• Only fungal infection in which Griseofulvin is effective – Dermatophytosis.
• Disulfiram-like reaction in caused by – Griseofulvin.

Azoles:
Fluconazole is DOC in:
• Candidiasis AfraTafreeh.com
• Coccidioidal meningitis
• Esophageal candidiasis. • Cryptococcal meningitis
• Localized (pulmonary) cryptococcosis.

Itraconazole is DOC in:

• Histoplasmosis • Localized (pulmonary) aspergillosis.
• Blastomycosis • Sporotrichosis.
• Sporotichosis • Maduramycosis.

Voriconazole is DOC in:

• Invasive aspergillosis.
• Persistent febrile neutropenia.
• Side effects- phototoxicity, visual toxicity, QT prolongation

• Ketoconazole- useful for Cushing syndrome

• Side effect- gynecomastia,
 Antimicrobials | 285

One-liners:
• Only triazole antifungal that can be administered topically – Fluconazole.
• Triazoles effective in mucormycosis – Posaconazole and Isavuconazole.
• Posoconazole – useful in mucormycosis
• Isavuconazole – useful for Candidiasis, aspergillus, mucormycosis.

One-liners:
• Single agent 5-Flucytosine is used in – Chromoblastomycosis.

AfraTafreeh.com
286 | Pharmacology

Worksheet
To do
Mechanism of action of griseofulvin

Dose limiting adverse effect of amphotericin B

Mechanism ofaction of azole antifungal agent is

Anti fungal drug very useful for candidiasis

AfraTafreeh.com
Azole antifungal agent causing QT prolongation is

Terbinafine acts by

Antimetabolite having antifungal acticity is

Echinocandine useful for

 Antimicrobials | 287
Concept 11.9 : Antiviral Drugs (Retro & Non Retro Viral)
Learning objectives: To know the classification of anti retroviral drugs based on their
mechanism of action

Time Needed
1 reading
st
45 mins
2 reading
nd
25 mins

Classification of Antiretrovirals
1 Nucleoside reverse transcriptase inhibitors (NRTIs) • Zidovudine
• Lamivudine
• Stavudine
• Didanosine
• Zalcitabine
• Emtricitabine
• Abacavir
• Festinavir
2 Nucleotide reverse transcriptase inhibitor • Tenofovir
3 AfraTafreeh.com•
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine
• Efavirenz
• Etravirine
• Delavirdine
• Rilpivirine
• Lersivirine
4. Protease inhibitors • Ritonavir
• Saquinavir
• Indinavir
• Nelfinavir
• Amprenavir
• Fosamprenavir
• Lopinavir
• Atazanavir
• Tipranavir
• Darunavir
5. Entry inhibitors / Fusion inhibitors • Maraviroc- CCR 5 blocker
• Enfuvirtide
• Cenicriviroc
• Ibalizumab
288 | Pharmacology

6. Integrase inhibitors • Raltegravir

• Elvitegravir
• Dolutegravir
7 Maturation inhibitors • Bevirimat
• Viveron

• Dose limiting side effect of zidovudine – Myelosuppression.

• Dose limiting side effect of didanosine – Pancreatitis.
• Stavudine- causes severe Neuropathy, Lactic acidosis, Lipodystrophy.
• Abacavir may cause SJS in apatient with HLA B 5701 allele, so genetic screening should be done
before administration of abacavir.
• Lamivudine,tenofovir useful in HBV infection.

• Common side effect of NNRTI – skin rashes.

• Specific side effect of nevirapine­hepatotoxicity.
• Specific side effect of efavirenz­psychosis.
• Indinavir- causes nephrolithiasis.
• Ritonavir – most potent microsomal enzyme inhibitor.
• Lipodystrophy least with atozanavir.
• AfraTafreeh.com
Tipranavir- can cause intracranial hemorrhage.
• Common side effects of protease inhibitors - hyperglycemia, hyperlipidemia, fat redistribution .

• Tesamorelin- GHRF- Reduces abdominal fat in HIV patient with lipodystrophy.

• CROFELEMER-Inhibitor of CFTR, USE- HIV drug induced diarrhoea.

One-liners:
• NRTIs are active against both – HIV-1 and HIV-2.
• Oldest antiretroviral drug – Zidovudine.
• Zidovudine should not be combined with – Stavudine as both compete for intracellular
phosphorylation.
• Stavudine should not be combined with – Didanosine due to increased risk of
severe peripheral neuropathy and potentially fatal pancreatitis.
• Peripheral neuropathy is maximum with – Stavudine.
• Pancreatitis is maximum with – Didanosine.
• Festinavir has been shown to be effective in – Resistant infections.
• NNRTIs are only active against – HIV-1.
• Teratogenic antiretroviral – Efavirenz.
• Lersivirine is effective against HIV with – Y181C mutation.
• 1st HIV protease inhibitor to be clinically approved – Saquinavir.
• Most potent protease inhibitor – Ritonavir.
• Least potent protease inhibitor – Saquinavir.
 Antimicrobials | 289

• Boosted PI regimen: PIs are combined with low dose (100 – 200 mg) ritonavir. Ritonavir
inhibits metabolism of the PI, thus increasing its bioavailability.
• PI not to be combined with ritonavir in boosted PI regimen – Nelfinavir (as it is
metabolized by CYP2C19, which is not inhibited by ritonavir).
• Renal stones are seen with – Indinavir.
• Skin eruptions and hyperglycemia are seen with – Fosamprenavir.
• Enfuvirtide is always administered – subcutaneously.
• Most prominent side effect with enfuvirtide – Injection site reactions.
• Antiretroviral drug that can bind to both CCR2 and CCR5 – Cenicriviroc.
• Ibalizumab– Monoclonal antibody against CD4.
• Elvitegravir is approved for initial treatment / naïve cases.
• Dolutegravir is approved for raltegravir-resistant infections.
• Maturation inhibitors bind to – gag protein.
• Cobicistat- booster for elvitegravir.

Prevention of parent-to-child transmission of HIV:

• Most effective drug for preventing parent-to-child transmission of HIV – Zidovudine.
• Drug most commonly used for preventing parent-to-child transmission of HIV in developing countries
– Nevirapine.
AfraTafreeh.com
Constituents of combined pill for HIV – STRIBILD
• Elvitegravir. • Cobicistat (acts as a bioenhancer;
• Tenofovir. • inhibits the metabolism of elvitegravir) .
• Emtricitabine.

Drugs for Herpes Virus Infections:

Drugs for human herpes virus infections:
• Acyclovir. • Cidofovir.
• Valacyclovir. • Foscarnet.
• Famciclovir • Idoxuridine.
(prodrug, active form penicyclovir) . • Trifluridine.
• Penciclovir. • Docosanol
• Ganciclovir. (entry inhibitor, given topically) .
• Valganciclovir. • Fomivirsen.
290 | Pharmacology

One-liners:
• Acyclovir is a – Nucleoside analogue.
• DOC for herpes simplex infections – Acyclovir.
• DOC for varicella zoster virus infections – Acyclovir.
• Dose of acyclovir for herpes simplex infections – 200 mg five times a day OR 400 mg
three times a day.
• Dose of acyclovir for varicella infections 800 mg five times a day.
• Advantage of valacyclovir over acyclovir Better oral bioavailability.
• DOC for CMV infections – Gancyclovir.
• Dose limiting side effectof gancyclovir – Myelosupression.
• DOC for acyclovir / gancyclovir resistant infections – Foscarnet.
• Foscarnet- side effect – acute renal failure, external genitalia ulcer.
• Fomivirsen – Antisense oligonucelotide against CMV mRNA.

Drugs for Hepatitis C:

Targets Drugs inhibiting
Viral Targets
1 NS3-NS4a • Telaprevir
(protease) AfraTafreeh.com • Boceprevir
• Danoprevir
2 NS5a • Daclatasvir
(participates in formation of membrane- • Ladipasvir
bound replication complex • Ombitasvir
3 NS5b (RNA • Sofosbuvir
polymerase) • Dasabuvir
Host Targets
1 Cyclophilin A • Alisporivir
2 miR-122 (micro- RNA 122) • Miravirsen (antisense oligonucleotide)

One-liners:
• Drug whose approval has been kept on hold due to reports of severe pancreatitis –
Alisporivir
• Ladipasvir is given – Orally
• Viramidine (under trail)
 Antimicrobials | 291

Drugs for Hepatitis B

• First­line: Entecavir, Tenofovir
• Second­line: lamivudine Adefovir Telbivudine Injectable therapy- Interferons and Pegylated interferons

One-liners:
• Serum creatinine monitoring is required for – Adefovir and Tenofovir (due to
nephrotoxicity) .
• Drugs common to both HIV and HBV – Lamivudine and Tenofovir.
• Drug ommon to both HBV and HCV is INF-α.
• Costliest treatment for Hep-B – Pegylated interferons.

Drugs for Viral Respiratory Infections:

Drugs for Influenza:
Drug Mechanism
1 Amantadine Bind to M2 protein on influenza virus
2 Rimantadine ↓
Prevent viral uncoating and replication
3 Oseltamivir AfraTafreeh.com
Bind to viral neuraminidase enzyme
4 Zanamivir ↓
Prevent aggregation of virus at the cell surface
5 Peramivir
↓
Reduce the release of virus from infected cells

One-liners:
• DOC for influenza – Oseltamivir (given orally).
• Route of administration of zanamivir - intra nasal.

Drugs for respiratory syncytial virus (RSV) :

• Ribavarin (aerosolized).
• Palivizumab (Once monthly IM injection) – Monoclonal antibody against an antigen on the F surface
protein on RSV.
292 | Pharmacology

Worksheet
To do
NRTI causing myelosuppression is

NRTI causing dose dependent pancreatitis

NRTI safe in renal failure

Anti retro viral having anti hepatitis activity includes

Specific side effect of nevirapine

AfraTafreeh.com
Examples for integrase inhibitors

Anti retro viral causing cerebral hemorrhage is

Dose limiting side effect of acyclovir

Common side effect of ganciclovir

Sofosbuvir is useful in

Anti viral drug useful in both influenza A and B virus

 Antimicrobials | 293
Concept 11.10 : Antimalaria Drugs
Learning objectives
• To know the classification of antimalarial drug
• To know the actions and adverse effects of antimalarial drugs
• To the artemisinin combination therapy
• To know the chemoprophylaxis of malaria

Time Needed
1st reading 000000 mins
2 reading
nd
000000 mins

Classification of antimalarial drugs

4-aminoquinolines • Chloroquine
• Amodiaquine
• Piperaquine
Quinoline-methanol • Mefloquine
Cinchona alkaloids • Quinine
• Quinidine
Biguanide • Proguanil (Chloroguanide)
Diaminopyrimidine
AfraTafreeh.com
• Pyrimethamine
8-aminoquinolines • Primaquine
• Tafenoquine
Sulfonamides and sulfones • Sulfadoxine
• Sulfamethopyrazine
• Dapsone
Antibiotics • Tetracycline
• Doxycycline
• Clindamycin
Sesquiterpine lactones • Artemisinins
Amino alcohols • Halofantrine
• Lumefantrine
Naphthyridine • Pyronaridine
Naphthoquinone • Atovaquone
Effects of antimalarials on various developmental stages of parasite:
Gp Drug Liver stages Blood stages
Sporozoite Primary Hypnozoite Asexual Gametocyte
1 Artemisinins - - - + +
Chloroquine - - - + ±
294 | Pharmacology

Mefloquine - - - + -
Quinine / Quinidine - - - + ±
Pyrimethamine - - - + -
Sulfadoxine - - - + -
Tetracyclines - - - + -
2 Atovaquone / - + - + ±
Proguanil
3 Primaquine - + + - +

One-liners:
• Quinine was isolated from – Cinchona bark in 1820
• Chloroquine was originally marketed as – Resochin
• Proguanil was introduced in – 1945
• Fastest onset of action – Artemisinins
• Most toxic antimalarial – Quinine

Chloroquine:
Indications of chloroquine: (Mnemonic: RED LIP Mahathma Ganthi) :
AfraTafreeh.com
• Rheumatoid arthritis.
• Extra-intestinal amoebiasis (Amoebic liver abscess) .
• Discoid lupus erythematosus (DLE) .
• Lepra reaction Type 2 (Erythema nodosum leprosum or ENL) .
• Infectious mononucleosis.
• Photodermatitis.
• Malaria.
• Giardiasis.

One-liners:
• MOA: Binds to heme and prevents its degradation.
• Plasma protein binding – 50%.
• Therapeutic plasma levels – 15­30 ng/mL.
• Vd = 1200 – 1500 L.
• Mainly gets concentrated in – Liver and Retina.
• Loading dose: 600 mg stat.
• Loading dose of chloroquine is needed because of – Large Vd.
• Chloroquine may precipitate / exacerbate – Porphyria and Psoriasis.
• Bull’s eye macula / Retinopathy is seen with – Chloroquine.
• Retinopathy due to chloroquine is – Irreversible.
 Antimicrobials | 295
Risk factors for retinopathy due to chloroquine:
• Age > 60 years.
• Duration of use > 5 years.
• Daily dose > 3 mg/kg for Chloroquine and > 6.5 mg/kg for Hydroxychloroquine.
• Cumulative dose > 100g.
• Renal disease.
• Liver disease.
• Pre-existing / Concomitant retinal disease.
• Obesity.

One-liners:
• Hydroxychloroquine is mainly used in – RA and SLE.

Artemisinin Derivatives:
Examples:
• Dihydroartemisinin. AfraTafreeh.com
• Arteether.
• Artesunate. • Arterolane.
• Artemether.

One-liners:
• Artemisinin is derived from – Artemisia annua (Quinghasou) mentioned in Chinese
traditional medicine.
• Artemisinin cannot be directly used in humans as – It is insolublein both water and oil
(Hence, derivatives of artemisinin are used).
• Artemisinin derivative developed in India – Arteether.

Routes of administration:
Dihydroartemisinin Oral

Artesunate Oral, IM, IV, rectal

Artemether Oral, IM

Arteether IM

Arterolane Oral
296 | Pharmacology
Artemisinin-Combination therapies (ACTs) :
• Artesunate + Mefloquine.
• Artesunate + Sulfadoxine / Pyrimethamine.
• Artesunate + Amodiaquine.
• Artesunate + Pyronaridine.
• Artemether + Lumefantrine- available as FDC (fixed dose comibination).
• Arterolane + Piperaquine.
• Dihydroartemisinin + Piperaquine.

One-liners:
• Artemisinin monotherapy is contraindicated due to rapid development of – Resistance
and Recrudescence.

Drugs of choice for malaria:

Normal scenario In pregnancy
DOC for uncompli- cated malaria Chloro - quine Chloroquine
DOC for compli- cated malaria ACT 1st trimester – Quinine
AfraTafreeh.com 2nd / 3rd trimes- ter – ACT
DOC for chloro- quine-resistant malaria ACT 1st trimester – Quinine
(both un- complicated and complicated) 2nd / 3rd trimes- ter – ACT

One-liners:
• Quinine is also useful in – Nocturnal muscle cramps.

Chemoprophylaxis of malaria:
1 CQ-sensitive area Chloroquine: 300 mg or 5 mg/ kg weekly.
Started 1 week before travel and continued up to 4 weeks after
return from endemic area.
2 CQ-resistant area > 6 weeks stay Mefloquine: 250 mg.
Started 1 – 2 weeks before travel and continued up to 4 weeks after
return from endemic area.
3 CQ-resistant area < 6 weeks stay Doxycycline: 100 mg.
Started 1 day before travel and continued up to 4 weeks after return
from endemic area.
4 Alternative Proguanil: 200 mg daily + Chloroquine 300 mg weekly.
 Antimicrobials | 297

One-liners:
• DOC for chemoprophylaxis – Chloroquine.
• DOC for chemoprophylaxis for chloroquine-resistant endemic area; Stay < 6 weeks –
Doxycycline.
• DOC for chemoprophylaxis for chloroquine-resistant endemic area; Stay < 6 weeks –
Doxycycline.
• DOC for chemoprophylaxis for chloroquine-resistant endemic area for a pregnant female
– Mefloquine.
• Neuropsychiatric reactions are a side effect of – Mefloquine.

Mefloquine:
• Basic drug – binds with α1 acid glycoprotein.
• Long half life (20days).
• Side effect – Nueropsychosis.
• When givn with Halofantrine, quinine – risk of QT prolongation.

Primaquine:
• Gametocidal.
• Vivax curative.
• AfraTafreeh.com
In G6PD deficiency patiens – causes hemolyticmanemia.
• C/I= Pregnancy.

Intermittent preventive therapy for malaria

Single dose of Pyrimethamine (75 mg) / Sulfadoxine (1500 mg) each in 2nd and 3rd
trimester (with a gap of not less than 1 month) is recommended for pregnant women
in high P. falciparum endemic areas.
298 | Pharmacology

Worksheet
To do
Anti malarial drug used for radical cure of vivax
infection

Antimalarial drug causing neuropsycosis

Indications of ACT

AfraTafreeh.com
DOC for cerebral malaria

Drug effective only for extra intestinal amoebiasis

Black water fever is the adverse effect of

 Antimicrobials | 299
Concept 11.11 : Ant Amoebic Drugs
Learning objective : T
 o know the drugs useful in amoebiasis and other protozoal
infections

Time Needed
1 reading
st
20 mins
2 reading
nd
15 mins

Drugs for Amoebiasis:

Tissue Amoebicides
1 Nitroimidazoles • Metronidazole
• Tinidazole
• Ornidazole
• Secnidazole
• Satranidazole
• Nimorazole
2 Alkaloids • Emetine
• Dehydroemetine
3 Chloroquine
Luminal Amoebicides
AfraTafreeh.com
• Paromomycin
• Diloxanide furoate
• Nitazoxanide
• Quinidochlor (Clioquinol)
• Diiodohydroxyquin (Iodoquinol)
• Tetracyclines

One-liners:
• DOC for amoebiasis – Metronidazole.
• DOC for extra-intestinal amebiasis – Metronidazole.
• Chloroquine is effective only in – Amoebic liver abscess.
• Dose of metronidazole for intestinal amebiasis – 400 mg TDS × 5-7 days.
• Dose of metronidazole for extra- intestinal amebiasis – 800 mg TDS × 7-10 days.
• Luminal amebicide of choice / DOC to eradicate asymptomatic cyst passer state –
Paromomycin.
• Dose of paromomycin as a luminal amebicide – 25­35 mg/kg/d oral in three divided
doses.
• Subacute myelo-optic neuropathy (SMON) is a side effect of – Clioquinol and Iodoquinol.
• Flatulence is th common side effect of Diloxanide furoate.
• For Guinea worm infection – NIRIDAZOLE is the Drug of choice.
300 | Pharmacology
Other Protozoal Infections:
DOC for other protozoal infections:
Infection DOC
Giardiasis Tinidazole
Trichomoniasis Metronidazole
Visceral leishmaniasis (Kala azar) (Liposomal) Amphotericin B
Cutaneous leishmaniasis (Oriental sore) Sodium stibogluconate
Chagas’ disease (American sleeping sickness) Benznidazole > Nifurtimox
Toxoplasmosis Pyrimethamine/ Sulfadiazine + Folinic acid
Cryptosporidiasis Nitazoxanide
Isosporiasis Cotrimoxazole
Cyclosporiasis Cotrimoxazole
Babesiosis Clindamycin + Quinine
Balantidiasis Tetracyclines
Naegleria Amphotericin B (High dose) + Rifampicin

Drugs For African Sleeping Sickness:

AfraTafreeh.com
Treatment of African sleeping sickness:
Early stage (Haemo-lym- phatic Late stage (Neurolog- ical /
stage / No CNS involvement) CNS involvement)
West African Pentamidine Eflornithine
(T. brucei gambiense)
East African Suramin Melarsopol
(T. brucei rhodesiense)

Treatment of South American Trypnosomiasis (Chagas disease) -

Benznidazole (DOC), Nifutrimox
One-liners:
• Dose of metronidazole for giardiasis and trichmononiasis – 400 mg TDS x 7-10 days.
• DOC for Giardiasis in pregnancy – Paromomycin.
 Antimicrobials | 301

Worksheet
To do
Common side effect of metronidazole

Aminoglycoside useful for amoebiasis

AfraTafreeh.com
Drug useful in toxoplasmosis in pregnancy

Common side effect of diloxanide furoate

302 | Pharmacology
Concept 11.12 : Anthelminthic Drugs
Learning objective:
• To know the examples for various anthelminthic agents
• To know appropriate choice of drugs for helminthic infections

Time Needed
1 reading
st
30 mins
2 reading
nd
15 mins

Examples for anthelminthic agents

• Mebendazole • Diethylcarbazine citrate (DEC)
• Albendazole • Ivermectin
• Thiabendazole • Levamisole
• Pyrantel pamoate • Niclosamide
• Piperazine • Praziquantel

One-liners:
• Ivermectin is a semi-synthetic derivative of active principle obtained from – Streptomyces
avermitilis.
AfraTafreeh.com
DOC for Helminthic Infestations:
Helminthic infestation DOC Other alternatives
Ascariasis (Round worm) Albendazole • Mebendazole
• Pyrantel pamoate
Hookworm Albendazole Mebendazole
Enterobiasis (Pin worm or Seat worm) Mebendazole • Albendazole
• Pyrantel pamoate
Trichuriasis (Whip worm) Mebendazole Albendazole
Trichinellosis Albendazole + Steroids Mebendazole + Steroids
Stronglyoidiasis Ivermectin Albendazole
Lymphatic filariasis DEC Ivermectin
Loiasis DEC Ivermectin
River blindness (Onchocerciasis) Ivermectin
Dracunculosis (Guinea worm) Metronidazole Mebendazole
Visceral larva migrans Albendazole Steroids
Cutaneous larva migrans Albendazole • Thiabendazole
• Mebendazole
• Ivermectin
 Antimicrobials | 303

Taenia saginata (Beef tape- worm) Praziquantel Niclosamide

Taenia solium (Pork tapeworm) other Praziquantel Niclosamide
than neurocysticercosis
Neurocysticercosis Albendazole + Steroids Praziquantel + Steroids
Diphyllobothriasis (Fish tape- worm) Praziquantel
Hymenolepis nana (Dwarf tapeworm) Praziquantel Albendazole
Hydatid disease Albendazole Praziquantel
Schistosomiasis Praziquantel • Oxamniquine
• Artemether
Paragonimiasis Praziquantel Triclabendazole
Clonorchis sinensis Praziquantel
Opistorchis viverinii Praziquantel
Fasciola hepatica (Liver fluke) Triclabendazole
Other intestinal nematodes Praziquantel

• Broad spectrum anti helminthic for Trematodes – Doc Praziquantel (Exception- Fasiola hepatica-
Triclobendazole, Bithional) .
AfraTafreeh.com
• Broad spectrum anti helminthic for Cystodes- – Doc Praziquantel (Exception Echi- nococcus
granulosa- -Neurocysticerscosis-Albendazole.
• Broad spectrum anti helminthic forNematodes- Doc Albendazole (Exception for Ochocerca
volvulus- Ivermectin, for W. bancrofti—DEC) .

One-liners:
• Pyrantel pamoate acts by causing – Spastic paralysis.
• Piperazine acts by causing – Flaccid paralysis.
• DOC for worm infestation in pregnancy – Piperazine.
• Dose of albendazole in worm infestation – 400 mg single oral dose for adults and
children > 2 years; 200 mg oral single dose for children < 2 years.
• Dose of mebendazole in pin worm infestation – 100 mg oral single dose.
• Dose of mebendazole in trichinellosis – 200 mg BD x 4 days.
• Dose of mebendazole in other worm infestations – 100 mg BD x 3 days.
• Dose of ivermectin in strongyloidiasis and onchocerciasis – 150­200 µg/kg single oral
dose.
• Dose of DEC in filariasis – 2 mg/kg TDS (6 mg/kg/d) x 21 days.
• Dose of albendazole in neurocysticercosis – 400 mg BD x 8-30 days for adults; 15 mg/
kg/d in 2 divided doses x 8­30 days for children.
• Levamisole is now only used as an anthelminthic; not as an immunomodulator.
304 | Pharmacology
Scabicides:
Scabicide Method of use

Permethrin (5%) Single application

Benzene hexachloride (BHC) Single application

Benzyl benzoate 3 applications at 12 hourly intervals

Crotamiton (10%) 2 applications daily for 14 days

Ivermectin Single oral dose (200 µg/kg)

Drugs used for viscereal leishmanisis-

• Amphotericin B (DOC) .
• Pentamidine.
• Paromomycin.
• Miltefosine.
• Sitamaquine.
for all forms of leishmaniasis: Sodium stibogluconate.
AfraTafreeh.com
 Antimicrobials | 305

Worksheet
To do
Anthelminthic drug causing spastic paralysis

Uses of ivermectin

Broad spectrum drug useful for majority of

nematodes AfraTafreeh.com

DOC for neurocysticercosis

306 | Pharmacology
Recent FDA approved drugs:
Drug Mechanism Indication

1 Ceftazidime + 3rd gen cephalosporin + Non-β- Complicated intra-abdominal and

Avibactam lactam β-lactamase inhibitor urinary tract infections

2 Obiltoxaximab Monoclonal antibody targeting Inhalational anthrax

Bacillus anthracis toxin

3 Dalbavancin 2nd generation lipoglycopeptide; Acute bacterial skin and skin

inhibits bacterial cell wall synthesis structure infections

4 Oritavancin Glycopeptide; inhibits bacterial cell Acute bacterial skin and skin
wall synthesis structure infections

5 Tedizolid Oxazolidinone; inhibits bacterial Acute bacterial skin and skin

protein synthesis structure infections

6 Finafloxacin Fluoroquinolone; inhibits bacterial Acute otitis externa

DNA gyrase

7 Atazanavir HIV protease inhibitor HIV-1 infection

8 Darunavir HIV protease inhibitor HIV-1 infection

9 Cobicistat AfraTafreeh.com
Inhibits the CYP metabolism of
HIV-1 infection
elvitegravir

10 Elbasvir Inhibits NS5a protein; prevents HCV genotypes 1-4 infection

formation of membrane replication
complex

11 Velpatasvir Inhibits NS5a protein; prevents HCV genotypes 1-6 infection

formation of membrane replication
complex

12 Daclatasvir Inhibits NS5a protein; prevents HCV genotype 3 infection

formation of membrane replication
complex

13 Ombitasvir Inhibits NS5a protein; prevents HCV genotype 4 infection

formation of membrane replication
complex

14 Paritaprevir NS3-NS4a protease inhibitor HCV genotype 4 infection

15 Grazoprevir NS3-NS4a protease inhibitor HCV genotype 1-4 infection

16 Dasabuvir NS5b RNA polymerase inhibitor HCV infection

17 Peramivir Neuraminidase inhibitor Acute uncomplicated influenza in

adults
 Antimicrobials | 307

18 Tavaborole Inhibits leucyl-tRNA synthetase; Onychomycosis of toe nails

inhibits fungal protein synthesis

19 Efinaconazole Inhibits lanosterol 14-α demethylase Onychomycosis of toe nails

(14-α sterol demethylase) enzyme in
fungi

20 I s a v u c o n a z o n i u m Inhibits lanosterol 14-α demethylase Invasive aspergillosis; Invasive

sulphate (prodrug of (14-α sterol demethylase) enzyme in mucormycosis
isavuconazole) fungi

21 Miltefosine Disturbs alkyl-phospholipid Leishmaniasis

metabolism and synthesis of
glycolipids and glycoproteins in
Leishmania donovani.

AfraTafreeh.com
12 Anticancer Drugs

CONCEPTS
 Concept 12.1 Classification of Cytotoxic Agents
(Cell Cycle Specific and Cell Cycle
Non Specific)

 Concept 12.2 Antimetabolites

 Concept 12.3 Antibiotic Anticancer Drugs

 Concept 12.4 Alkylating and Related Anticancer

Drugs
AfraTafreeh.com
 Concept 12.5 Vinca Alkaloids, Taxanes

 Concept 12.6 Topoisomerase Inhibitors

 Concept 12.7 Hormonal Agents Used in Cancer

 Concept 12.8 Tyrosine Kinase & other Small

Molecule Inhibitors

 Concept 12.9 Monoclonal Antibodies

 Concept 12.10 Chemotherapy

 Concept 12.11 Anticancer Drugs ADR &

Management of Adverse Drug
Reaction
 Anticancer Drugs | 309
Concept 12.1 : Classification of Cytotoxic Anticancer Drug
Learning objective : T
 o know the classification anticancer drugs according to cell cycle
specific or cell non specific

Time Needed
1 reading
st
10 mins
2 reading
nd
5 mins

AfraTafreeh.com

Fig. 12.1

Cell cycle non specific agents

Alkylating agents
Cisplatin
Antibiotic anticancer except Bleomycin

Natural Sources of Anti-Cancer Drugs:

Drug Natural source

A: DRUGS OBTAINED FROM PLANTS

1 Vinca alkaloids Catharanthus roseus / Vinca rosea (Madagascar periwinkle)

2 Taxanes Bark of Taxus brevifolia (Western yew / Pacific yew tree)

3 Camptothecin analogues Camptotheca acuminata

4 Epipodophyllotoxins Podpohyllum peltatum, (Mandrake plant / Mayapple)

310 | Pharmacology

B: DRUGS OBTAINED FROM MICRO-ORGANISMS

1 Epothilones Sorangium cellulosum, a mycobacterium

2 Actinomycin D Streptomyces spp.

3 Anthracyclines Streptomyces peuceticus var. caesius

4 Bleomycin Streptomyces verticillus

5 Mitomycin C Streptococcus caespitosus

6 Trabectedin Ecteinascidin turbinate (Marine tunicate)

7 L-asparaginase Escherichia coli

AfraTafreeh.com
 Anticancer Drugs | 311

Worksheet
To do
Methotrexate acts on which phase of cell cycle

Antibiotic anticancer drug acts on G2 phase of cell

cycle is

AfraTafreeh.com
Paclitaxel acts on which phase of cell cycle

Cyclophosphamide is cell cycle specific or cell cycle

non specific
312 | Pharmacology
Concept 12.2 : Antimetabolites
Learning objectives:
• To know the classification of antimetabolites
• To know the uses and adverse effects of antimetabolites

Time Needed
1 reading
st
15 mins
2 reading
nd
10 mins

Classification:
Folic acid / Folate antagonists Methotrexate (Amethopterin)
Pemetrexed
Trimetrexate
Pralatrexate
Lometrexol
Raltitrexed

Pyrimidine analogues 5-Fluorouracil (5-FU)

Capecitabine
AfraTafreeh.com
Floxuridine
Cytarabine (Ara-C)
Azacytidine
Decitabine
Gemcitabine

Purine analogues 6-Mercaptopurine (6-MP)

6-Thioguanine (6-TG)
Fludarabine
Cladribine
Clofarabine
Nelarabine
Pentostatin
 Anticancer Drugs | 313

One-liners:
• DMARD of choice for rheumatoid arthritis – Methotrexate.
• Starting dose of Methotrexate in RA – 7.5 – 15 mg oral once a week.
• Dose of methotrexate for psoriasis – 2.5 mg/d x 5 days in a week OR 10 – 25 mg IV
once a week.
• Dose of intrathecal methotrexate for leukemic meningitis and meningeal carcinomatosis
in < 3 years of age – 12 mg repeated every 4 days until malignant cells are no longer
evident in CSF.
• Glucarpidase –Recombinant carboxypeptidase G2, that cleaves methotrexate. When
given IV, methotrexate levels fall by ≥ 99% within 5 – 15 minutes.
• Erythematous pruritic rash is seen with – Pemetrexed.
• Pemetrexed toxicity can be ameliorated by – Dexamathasone + Folic acid + Vitamin
B12.
• Indication of trimetrexate – Pneumocystis jiroveci pneumonia.
• Genetic deficiency of dihydropyrimidine dehydrogenase (DPD) can lead to increased
toxicity with – 5-FU.
• Capecitabine – Prodrug of 5-FU.
• Gemcitabine- DOC for pancreatic cancer.
• Gemcitabine is the radio sensitizer.
• Most common drug useful for colorectal cancer – 5FU.
• Hand-foot syndrome is a side effect of – Capecitabine > 5-FU.
• Cerebellar toxicity is a side effect of – Cytarabine.
•
AfraTafreeh.com
Drugs that act by causing global hypomethylation of DNA – Azacytidine and Decitabine.
• While co-administering with allopurinol, the oral dose of 6-MP should be reduced by –
75%.
• DOC for hairy cell leukemia –Cladribine.
• Capillary leak syndrome is a side effect of – Clofarabine.
• Pentostatin inhibits – Adenosine deaminase (ADA).
314 | Pharmacology

Worksheet
To do
Antidote of methotrexate

Cerebellar ataxia is the adverse effect of

6MP inactivated by

Drugs causing hand foot syndrome are

AfraTafreeh.com

Anticancer drugs causing radio sensitizer

Pentostatin acts by inhibiting

Drug of choice for pancreatic cancer is

 Anticancer Drugs | 315
Concept 12. 3 : Antibiotic Anticancer Drugs
Learning objectives:
• To know the examples of anticancer antibiotics
• To know the uses and adverse effects of anticancer antibiotics

Time Needed
1 reading
st
10 mins
2 reading
nd
5 mins

Anthracyclines • Doxorubicin (Adriamycin).

• Donorubicin (Rubidomycin).
• Epirubicin.
• Idarubicin.
• Valrubicin.
Mitoxantrone.
Mitomycin C.
Actinomycin D (Dactinomycin) .
Bleomycin.
AfraTafreeh.com
One-liners:
• Pericarditis-myocarditis syndrome can be caused by – Doxorubicin.
• Antidote for doxorubicin- DEXRAZOXANE+ Alpha tocopherol.
• Mithramycin (Plicamycin)-useful for treatment of hypercalcemia.
• Adriamycin flare – Erythematous streaking near the site of doxorubicin infusion.
• Mitomycin was isolated by – Wakaki and co-workers in 1958.
• Mitomycin C can be used topically for – Laryngotracheal stenosis.
• Actinomycin D was first isolated by – Selman Waksman and H. B. Woodruff in 1940.
• DOC for Wilms’ tumour – Actinomycin D.
• Radiation recall phenomina side effect of Actinomycin D.
• Bleomycin mainly accumulates in – Lungs and Skin.
• Flagellate dermatitis can be caused by – Bleomycin.
• Treatment of flagellate dermatitis – Topical steroids.
• Radio protector – Amifostine.
• Radio sensitizer – Gemcitabine.
• Radiation recall phenomina – Dactinomycin.
316 | Pharmacology

Worksheet
To do
Anti cancer drugs causing lung fibrosis

Flagellate dermatitis can be caused by

Anticancer drug useful for hypercalcemia

AfraTafreeh.com
Drug useful for laryngo treacheal stenosis is

Radiation recall reactions are seen with

Antidote for doxorubicin

 Anticancer Drugs | 317
Concept 12.4 : Alkylating agents
Learning objective:
• To know the examples for alkylating anticancer drugs
• To know the general properties of alkylating agents
• To know the uses and adverse effects of alkylating agents

Time Needed
1 reading
st
25 mins
2 reading
nd
15 mins

Nitrogen mustards • Mechlorethamine (Mustine HCl)

• Cyclophosphamide
• Ifosfamide
• Glufosfamide
• Melphalan
• Chlorambucil
• Bendamustine

Ethylenimines • ThioTEPA
AfraTafreeh.com
• Altreatamine

Alkyl sulfonates • Busulfan

Nitrosoureas • Carmustine (BCNU)

• Lomustine (CCNU)
• Semustine
• Streptozotocin

Methylhydrazines • Procarbazine

Triazines • Dacarbazine
• Temozolomide

Platinum coordination complexes • Cisplatin (1st generation)

• Carboplatin (2nd generation)
• Oxaliplatin (3rd generation)
318 | Pharmacology

One-liners:
• The first clinically used nitrogen mustard Mustine HCl.
• Most reactive of the nitrogen mustards Mustine HCl.
• Vesication due to Mustine HCl can be treated with – Sodium thiosulphate.
• DOC for Wegener’s granulomatosis Cyclophosphamide.
• DOC for steroid-dependent nephritic syndrome – Cyclophosphamide.
• MESNA – Mercaptoethane sulfonate sodium
• Most preferred route for administering Mesna – Intravenous.
• Glufosfamide – β-D-glucose + Ifosforamide mustard (A metabolite of ifosfamide).
• Myelosuppression due to nitrosoueas is Delayed (Onset around 6 weeks after institution)
and prolonged.
• Anti-CA drug which is a MAO inhibitor – Procarbazine.
• Anti-CA drug causing disulfiram-like reactions – Procarbazine.
• Diuretic used with cisplatin – Mannitol (to establish a chloride diuresis).
• While administering cisplatin infusion, infusion equipment should not be made of aluminium
(Since cisplatin reacts with Aluminium).
• Amifostine is the antidote for cisplatin.
• Dose limiting side effect of oxaliplatin is Peripheral neuropathy.
• Site of action of alkylating agents – N7 GUANINE RESIDUE.
• VENO OCCLUSIVE DISEASE OF LIVER side effects of alkylating agents, which can be
minimized by (Budd–Chiari syndrome) – DEFIBROTIDE.
• AfraTafreeh.com
Secondary cancer produced maximally by procarbazine.
• Chemical pancreatectomy – Streptozocin.

Cisplatin • OTOTOXIC
• NEPHROTOXIC-
• NEUTORTOXIC
• Highest emetogenic
• Hypo Mg, Cal, K &
• Hypophosphatemia

Carboplatin • Myelosuppression

Oxaliplatin • Neurotoxic
• PharyngoIaryngeal
• paraesthesias
 Anticancer Drugs | 319

Worksheet
To do
Antidote for cyclophosphamide

Amifostine is the antidote for

Chemical pancreatectomy agent is

AfraTafreeh.com
Antithrombotic drug useful for treating veno
occlusive disease of liver is

Most emetogenic anticancer drug is

Anticancer drug having MAO enzyme inhibitory

action is
320 | Pharmacology
Concept 12.5 : Vinca Alkaloid & Taxanes
Learning objectives: To know the action and adverse effects of vinca alkaloid & taxanes

Time Needed
1st reading 10 mins
2 reading
nd
5 mins

Vinca alkaloids • Vincristine (Oncovin)

• Vinbastine
• Vinorelbine
Taxanes • Paclitaxel
• Docetaxel
Epothilones • Ixabepilone
• Patupilone
• Sagopilone
• 21-aminoepothilone-B
Estramustine

One-liners: AfraTafreeh.com
• Bone marrow sparing cytotoxic agent – Vincristine
• Taxol – Brand name of Paclitaxel.
• Stocking and glove neuropathy seen with – Paclitaxel
• Docetaxel is administered with – Polysorbate 80
• Ixabepilone is indicated in – Metastatic breast cancer
• Estramustine = Estradiol (Hormone) + Normustine (Nornitrogen mustard).
• Estramustine is indicated in – Hormone refractory prostate cancer
 Anticancer Drugs | 321

Worksheet
To do
Anticancer drugs acting on M phase

Anticancer drugs causing skin vesicant

Ixabepilone useful in AfraTafreeh.com

Estramustine useful in
322 | Pharmacology
Concept 12.6 : Drugs Inhibiting Topo isomerase Enzyme
Learning objective: To study the uses and adverse effects of topoisomerase inhibitors

Time Needed
1st reading 00000 mins
2 reading
nd
00000 mins

Classification:
Camptothecin analogues (Topoisomerase-I inhibitors) • Topotecan
• Irinotecan
Epipodophyllotoxins • Etoposide
(Topoisomerase-II inhibitors) • Teniposide

One-liners:
• Active metabolite of irinotecan – SN-38.
• Dose-limiting toxicity of irinotecan – Delayed diarrhea.
• Toxicity of irinotecan is increased in – Gilbert’s syndrome.
• Irinotecan has anti cholinesterase property.

Enzymes
AfraTafreeh.com
• L-asparaginase is synthesized from – E.coli.
• L-asparaginase is used in – ALL.
• Hypercoagulability is a side effect of – L-asparaginase.
• Pegasparaginase is administered – IM once every 14 days.

Miscellaneous
Examples:
• Hydroxyurea. • Mitotane.
• Trabectedin. • Tretinoin (all-trans retinoic acid).
• Arsenic trioxide. • Romidepsin.
• Vorinostat.

One-liners:
• Hydroxyurea inhibits – Ribonucleoside diphosphate reductase.
• Hydroxyurea can also be used as a – Radiosensitizer and Inducer of fetal hemoglobin.
• DOC for sickle cell anemia – Hydroxyurea.
• Mitotane is used for – Palliation in inoperable adrenocortical carcinoma.
• Tretinoin and arsenic trioxide are used in – Acute promyelocytic leukemia.
• Romidepsin and vorinostate inhibit – Histone deacetylase, Romidepsin and vorinostat are
used in – Cutaneous T cell lymphomas.
 Anticancer Drugs | 323

Worksheet
To do

AfraTafreeh.com
324 | Pharmacology
Concept 12.7 : Hormonal Therapy for Cancer
Learning objectives: To know the classification hormonal agents useful in cancer

Time Needed
1st reading 25 mins
2 reading
nd
15 mins

Selective Estrogen Receptor • Tamoxifen • Breast cancer

Modulators (SERMs) • Toremifene
• Raloxifene

Selective Estrogen Receptor • Fulvestrant • Breast cancer

Downregulator (SERDs)

Aromatase inhibitors • 1st generation: • Breast cancer

• Aminoglutethimide
• 2nd generation:
• Formestane
• 3rd generation:
• Letrozole
AfraTafreeh.com
• Anastrozole
• Exemestane

GnRH Analogues • Nafarelin

• Buserelin
• Goserelin
• Histrelin
• Deslorelin
• Triptorelin
• Leuprolide

GnRH Antagonists • Abarelix

• Degarelix

Antiandrogens • Flutamide
• Bicalutamide
• Nilutamide
• Enzalutamide

Glucocorticoids
 Anticancer Drugs | 325
Anti-androgens:
Steroidal Non-steroidal
• Danazol • Flutamide
• Cyproterone acetate • Bicalutamide
• Nilutamide
• Enzalutamide
Not used nowadays Used in CA prostate

Malignancies in which Glucocorticoids are Useful / Effective

• ALL • Non-Hodgkin’s lymphoma
• CLL • Multiple myeloma
• Hodgkin’s disease

Newer Drugs for Prostate Cancer

1 Abiraterone 17-α hydroxylase inhibitor

2 Galeterone Androgen receptor inhibitor + 17-α hydroxylase inhibitor

3 Erismodegib SMO antagonist (Hedgehog pathway antagonist)

AfraTafreeh.com
One-liners:
• Advantage of raloxifene over tamoxifen – Antagonist at uterus; hence minimal risk
of endometrial carcinoma.
• Ormeloxifene (Centchroman) – non-steroidal SERM used as oral contraceptive
(marketed as Saheli).
• Steroidal inhibitors of armoatase – Formestane and Exemestane (Rest are non-
steroidal).
• Irreversible inhibitors of armoatase – Formestane and Exemestane.
• Ganirelix and Cetrorelix are GnRH antagonists mainly for – Ovarian hyperstimulation.
• OSPEMIFENE - is a SERM useful in DYSPAREUNIA.
326 | Pharmacology

Worksheet
To do
Side effects of tamoxifen

Advantage of raloxifene over tamoxifen

Example for SERD

AfraTafreeh.com

Examples for steroidal aromatase inhibitors

Androgen receptor blockers useful cancer prostate

are
 Anticancer Drugs | 327
Concept 12.8 : Tyrosine Kinase Inhibitors
Learning objectives: To know the uses of tyrosine kinase inhibitors

Time Needed
1st reading 30 mins
2 reading
nd
15 mins

PDGFR • Imatinib • CM;

• GIST
EGFR1 • Erlotinib • Useful in Metastatic non small
specific • Gefitinib cell lung cancer
• Afatinib
VGEFR • Sunitinib • Sunitinib- RCC, HCC
• Sorafenib • Sorafenib- RCC, GIST
Dual EGFR1 and EGFR2 • Lapatinib • Breast cancer
specific

Indications of imatinib-
• AfraTafreeh.com
CML (Almost all cases are bcr-abl +ve).
• ALL (bcr-abl +ve).
• CMML (EVT6-PDGFR +ve).
• GIST.
• Dermatofibrosarcoma protuberans

One-liners:
• The first tyrosine kinase inhibitor to be approved by FDI – Imatinib.
• DOC for CML – Imatinib.
• Dasatinib and Nilotinib. - Treatment of imatinib-resistant CML – Dasatinib.
• Side effect of dasatinib – Pleural effusion.
• Treatment of dasatinib – resistant CML Nilotinib.
• Side effect of nilotinib – QTc prolongation.
• Erlotinib and geftnib are approved for Refractory non-small cell lung cancer.
• Erlotinib- causesdysmorphic eyelashes.
• Bioavailability of erlotinib is – Increased by food (67% → 100%); hence not combined
with food to prevent toxicity.
• Treatment of imatinib-resistant GIST – Sunitinib.
• Only drug approved for metastatic hepatocellular carcinoma – Sorafenib.
• The most common side effect of sunitinib and sorafenib – Fatigue.
328 | Pharmacology
Newer Tyrosine Kinase Inhibitors:
Drug Target Indication

1 Cabozantinib c-Met and VEGFR2 tyrosine kinases Medullary thyroid cancer

2 Masitinib Multiple tyrosine kinases (c-Kit, PDGFR Mast cell tumours, specifically in dogs
and FGR tyrosine kinases)

3 Semaxanib VEGFR tyrosine kinase (antiangiogenic) Advanced colorectal cancer (Trials

discontinued due to lack of efficacy)

4 Ruxolitinib Janus kinase Myelofibrosis (Intermediate or high-risk)

5 Ibrutinib Bruton’s tyrosine kinase Mantle cell lymphoma &

Chronic lymphoid leukemia

6 Vemurafenib B-raf enzyme Late stage melanoma

Dabraenib
dramtenib

7 Ponatinib bcr-abl fusion protein CML &

Philadelphia chromosome +ve ALL

8 Ceritinib ALK ALK +ve metastatic non small cell lung

AfraTafreeh.com
cancer

9 Vandetanib Multiple (VEGFR, EGFR, Ret) tyrosine Late stage medullary thyroid cancer
kinase

10 Regorafenib Multiple Metastatic colorectal cancer

Advanced gastrointestinal stromal
tumours

One-liners:
• Sales of ponatinib were temporarily suspended in 2013 due to – the risk of life-threatening
blood clots and severe narrowing of blood vessels.
• 1 drug approved by FDA for late stage (metastatic) medullary thyroid cancer – Vandetanib.
st

• Vandetanib is contraindicated in – Congenital long QT syndrome.

• Regorafenib is anti-angiogenic due to – Dual VEGFR2-TIE2 tyrosine kinase inhibition.
• Side effect of regorafenib – Hepatotoxicity.
• Tofacitinib - janus kinase blocker - useful in rheumatoid arthritis.
 Anticancer Drugs | 329

Worksheet
To do
Doc for CML

Examples for VGFR blocking tyrosine kinase

inhibitors

TKI useful in medullary cancer of thyroid

AfraTafreeh.com
Janus kinase inhibitor useful in myelofibrosis

TKIs useful in breast cancer

330 | Pharmacology
Concept 12.9 : Monoclonal Antibodies
Learning objectives: To know the MABs target and their indications

Time Needed
1st reading 30 mins
2 reading
nd
20 mins

Examples:
Target Drug (Antibody) Indication
CD 20 Rituximab • B-cell neoplasms
• Autoimmune disorders
Ofatumumab CLL (not responding to fludarabine and
alemtuzumab)
EGFR1 Cetuximab • Metastatic colorectal cancer
• Palliative treatment of head and neck squamous
cell cancer
Panitumumab Metastatic colorectal cancer
EGFR2 (HER2/neu) Trastuzumab HER2-neu +ve breast cancer
VEGF
AfraTafreeh.com
Bevacizumab • Renal cell carcinoma
• Nitrosourea-resistant glioblastoma
• Metastatic breast cancer
• Metastatic colorectal cancer
• Non small cell lung cancer
• Wet Age-related macular degeneration (ARMD)
Ranibizumab Wet ARMD
TNF-α Adalimumab • RA
Infliximab • Ankylosing spondylitis
Golimumab • Psoriatic arthritis
Certolizumab pegol • Crohn’s disease
IL-6 Tocilizumab RA
CD 25 (IL-2 receptor) Basilixmiab Prophylaxis of acute transplant rejection
Daclizumab
CD 52 Alemtuzumab CLL not responding to fludarabine
RANKL Densoumab Osteoporosis
Proteasome Bortezomib • Multiple myeloma
• Relapsed / Refractory mantle cell lymphoma
 Anticancer Drugs | 331

IL-12 and IL-23 Ustekinumab Psoriasis

Lymphocyte function Efalizumab Psoriasis
associated antigen-1
(LFA-1)
C5 complement Eculizumab Paroxysmal nocturnal hemoglobinuria
component
CD38 Daratumumab Multiple myeloma

Side Effects of Bevacizumab:

• Pulmonary hemorrhages.
• Arterial thromboembolic events.
• Hypertension. If poorly controlled → Reversible posterior leukoencephalopathy.
• GI perforation.
• Asymptomatic proteinuria.

One-liners:
• Autoimmune disease in which rituximab is not effective – Paroxysmal nocturnal
hemoglobinuria. AfraTafreeh.com
• Eculizumab- targeting against complement component C5- useful in paroxysmal
nocturnal hemoglobinuria.
• Rituximab may be associated with – Reactivation of BK and JC virus infections.
• Ocrelizumab – anti-CD 20 that entered trials for RA and SLE but was suspended due to
increased risk of deaths due to opportunistic infections (presently under trial for multiple
sclerosis).
• Bevacizumab may restore hearing in patients with – NF-2 related tumours.
• Asymptomatic proteinuria due to bevacizumab is more common in patients with – ovarian
cancer and primary colon cancer.
• Pegaptanib – A pegylated single strand of nucleic acid that binds to 165 isoform of VEGF;
approved for wet ARMD.
• VEGFR blocking MABs useful in ARMD- Bevacizumab, Ranizumab.
• Etanercept – Recombinant fusion protein containing two soluble TNF p75 receptor
moieties linked to Fc portion of human IgG1.
• All anti-TNF-α are administered subcutaneously except – Infliximab (which is
administered IV).
• Most common s/e of Bortezomib – Thrombocytopenia.
• Most chronic s/e of Bortezomib – Peripheral neuropathy.
• Bortezomib(proteasome inhibitor) – DOC multiple myeloma.
• BELIMUMAB – useful in SLE MABs for specific conditions
332 | Pharmacology

CONDITION DRUG NAMES TARGET

Mycosis Fungoides Mogamulizumab CCR- 4
Rheumatoid Arthritis Infliximab, Adalimumab, TNF - alpha
Certolizumab, Golimumab

Rheumatoid Arthritis Tocilizumab, Sarilumab IL-6

Gout Canakinumab IL- 1
Osteoporosis Denosumab RANKL
Osteoporosis Bolosozumab Sclerostin
Romosozumab
X Linked Hypophosphatemia Burosumab FGF 23

PLAQUE PSORIASIS
Brodalumab IL 17
Secukinumab
Ixekizumab

Guselkumab IL-23
Tildrkizumab AfraTafreeh.com
Ustekinumab IL 12, 23

Efalizumab CD11a

Multiple sclerosis
Natalizumab (α4β1 - integrin)

Ocrelizumab CD20

Alentuzumab CD 52

Bronchial Asthma
Oma li zu mab Ig E

Res li zu mab IL- 5

Mepo li zu mab
Benralizumab

Tralokinumab IL-13
Lebrikizumab

Dupilumab IL- 4, Atopic Dermatitis

 Anticancer Drugs | 333
Migraine
Erenumab CGRP antagonist
Fremanezumab
Galcanezumab

Programmed Death Receptor-1 (PD-1) Inhibitors

Malignant melanoma
Ipilimumab Cytotoxic T Lymphocyte–Associated Protein 4
(CTLA- 4)

Nivolumab immune check point inhibitor, Programmed Death-1

Pembrolizumab (PD-1)

Atezolizumab, Durvalumab – targeting Against programmed death ligand-1 (PDL1), useful in urothelial
carcinoma
AVELUMAB - Programmed Death Ligand- 1 (PDL-1 useful in merkel cell carcinoma

BI PHASIC MABs
Catumaxomab AfraTafreeh.com
Epithelial Cell Adhension
Molecule Malignant ascities
(EpCAM) + CD 3

Ertumaxomab HER 2 + CD 3 Breast Cancer

Blinatumomab CD19 B CELL +CD3 T CELL Philadelphia Chromosome Negative

Refractory All

Solitomab EpCAM + CD 3T CELL Solid Tumors

Duligotuzumab HER 1 + HER 3 Head And Neck Cancer

TNF α + Human Serum Albumin Rheumatoid Arthritis

334 | Pharmacology
Concept 12.10 : Chemotherapy
Learning objective : to know the various regimen useful for cancer chemotherapy

Time Needed
1st reading 00000 mins
2 reading
nd
00000 mins

MOPP Mustine HCl. Oncovin (Vincristine). Hodgkin’s lymphoma (Not used nowadays).
Procarbazine.
Prednisolone.
ABVD Adriamycin (Doxorubicin) Hodgkin’s lymphoma
Bleomycin Vinblastine Dacarbazine
CHOP-R Cyclophosphamide Non- Hodgkin’s lymphoma
Hydroxydaunorubicin (Doxorubicin)
Oncovin (Vincristine) Prednisolone
Rituximab
BEP Bleomycin Etoposide Testicular cancers
Platinum (Cisplatin)
FOLFOX Folinic acid Colorectal cancer
AfraTafreeh.com
5-Fluorouracil Oxaliplatin
FOLFIRI Folinic acid Colorectal cancer
5-Fluorouracil Irinotecan
VAMP Vincristine Acute leukemia
Amethopterin (Methotrexate)
6-MP
Prednisolone

One-liners:
• T-10 protocol is used for – Osteosarcoma.

• PD-L1 inhibitors (programmed death-ligand).

• Atezolizumab –urothelial carcinoma. Avelumab – Merkel cell carcinoma. Durvalumab- urothelial
bladder cancer.
 Anticancer Drugs | 335
Concept 12.11 : Adverse effects of anticancer drug
Learning objective:
• To know the common adverse effects and specific adverse effects of anti cancer drugs
• To know the treatment available for preventing and treating anticancer drug induced
toxicities

Time Needed
1 reading
st
40 mins
2nd reading 20 mins

• Myelosuppression – Granulocytopenia, Agranulocytosis, Aplastic anemia, Thrombocytopenia

(myelosupprssion less with busulphan, vincristine, L- asparaginase).
• Lymphoctyopenia and inhibition of lymphocyte function → Immunosuppression and increased risk of
opportunistic infections.
• Oral mucositis and stomatitis.
• Diarrhoea.
• GI hemorrhages.
• Nausea and vomiting.
• Alopecia.
• Dermatitis. AfraTafreeh.com
• Oligospermia and impotence in males.
• Inhibition of ovulation and amenorrhea in females.
• Fetal death and abortions.
• Teratogenesis.
• Increased risk of secondary malignancies.
• Hyperuricemia and tumour lysis syndrome.

Emetogenic Potential of Cytotoxic Drugs:

High Moderate Mild
• Cisplatin(most emetogenic) • Carboplatin • Bleomycin
• Carmustine • Cytarabine • Chlorambucil
• Cyclophosphamide • Procarbazine • Busulfan
• Actinomycin D • Vinblastin • 5-Fluorouracil
• Dacarbazine • Doxorubicin • 6-Thioguanine
• Lomustine • Daunorubicin • Hydroxyurea
• Ifosfamide • Vincristine
• 6-Mercaptopurine • Methotrexate
• Paclitaxel • Etoposide
• L-asparaginase
336 | Pharmacology

One-liners:
• Most serious side effect of cytotoxic drugs – Myelosuppression.
• Most emetogenic anti-cancer drug – Cisplatin.

Anti-Cancer Drugs Causing Cardiotoxicity as a Side Effect:

• Anthracycline antibiotics. • Cyclophosphamide.
• Mitoxantrone. • 5-Fluorouracil.
• Trastuzumab.

Anti-Cancer Drugs Causing Peripheral Neuropathy as a Side Effect:

• Vinca alkaloids. • Thalidomide.
• Taxanes. • Bortezomib.
• Platinum co-ordination complexes.

Salvage Therapy:
Specific treatments for side effects of anticancer drugs
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Hemorrhagic cystitis due to cyclophosphamide and ifosfamide Mesna

Cisplatin-induced nephrotoxicity Amifostine

Methotrexate toxicity Folinic Acid( Leucovorin)

Anthracycline- induced cardiotoxicity Dexrazoxane (Iron Chelator)

Chemotherapy- induced hyperuricemia Allopurinol

Hypercalcemia of malignancy Bisphosphonates

Amifostine:
• Chemoprotectant + Radioprotectant.
• MOA – Free radical scavenger.
• Short acting(T½ = 8 min).
• Prevents nephrotoxicity due to cisplatin.
• Cannot protect CNS as it does not cross blood brain barrier.
• Reduces the incidence of xerostomia.
 Anticancer Drugs | 337
Doses for Treatment of Chemotherapy-Induced Neutropenia:
G-CSF (Filgrastim) 5 mg/kg/d s.c
GM-CSF 250 mg/m2 s.c
(Sargramostim) Molgrasmstim lenogramstim
Pegfilgrastim 1 dose of 6 mg 24 hours after institution of
chemotherapy
Continue till absolute neutrophil count is 10,000 / µL

• Recombinant- erythropoietin- Epoietin, Darbopoietin Oprelvekin (interleukin- 11analogue)-

thrombopoietic factor.
• Other thrombopoietic factors - Romiplostim, Eltrombopag.

One-liners:
Most common manifestation of chemotherapy- induced myelosuppression – Neutropenia (since
WBCs have the shortest life span) f/b Thrombocytopenia f/b Anemia.

Drugs used to Treat Chemotherapy Induced Nausea and Vomiting:

1 5-HT3 antagonists • Ondansetron (DOC).
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• Granisetron.
• Tropisetron.
• Dolasetron.
• Palonosetron- (longest acting, highly selec-
tive 5HT 3 blocker, can be used for delayed
phase vomiting also).
2 NK-1 / Substance P antagonists • Aprepitant (DOC for delayed vomiting).
• fosaprepitant.
• Netupitant.
3 D2 antagonists • Metoclopramide
• Promethazine
• Haloperidol
• Droperidol
4 Steroids • Dexamethasone
• Methylprednisolone
5 Cannabinoid agonists (anti emetic + • Dronabinol
appetite stimulant) • Nabilone
6. Palifermin • Mucosal ulcer
338 | Pharmacology

Worksheet
To do
Antidote for doxorubicin

Anti emetic useful for anticancer drug induced

vomiting

Examples for granulocyte CSF

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Il 11 analogue useful for treating thrombocytopenia
is

Radioprotector

MESNA useful for

13 Immunomodulators

CONCEPTS
 Concept 13.1 Immunomodulators
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340 | Pharmacology
Concept 13.1 : Immunomodulators
Learning objectives:
• To know the classification of immunosuppressants
• To know the uses and adverse effects of immunosuppressants
• To study the uses and adverse effects of immunostimulants
• To know the uses and adverse effects of INF

Time Needed
1st reading 45 mins
2 reading
nd
25 mins

Classification of Immunosuppressants
1 • Glucocorticoids
2 • Calcineurin Inhibitors
• Cyclosporine
• Tacrolimus (FK-506)
3 • Antiproliferative And Antimetabolic Drugs
• Sirolimus
• Temsirolimus
• Everolimus
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• Azathioprine
• Mycophenolate mofetil
• Leflunomide
• Fingolimod
4 • Biologicals (Monoclonal Antibodies and Receptor Fusion Proteins)
• Muromonab CD3.
• Antithymocyte globulin.
• Anti-Rho immunoglobulin.
• Infliximab.
• Adalimumab.
• Etanercept.
• Canakinumab.
• Daclizumab.
• Basiliximab.
• Inolimomab.
• Alemtuzumab.
• Efalizumab.
• Alefacept.
• Rilonacept.
• Tofacitinib.
 Immunomodulators | 341
Side Effects of Calcineurin Inhibitors
Cyclosporine > Tacrolimus Tacrolimus > Cyclosporine

Hirsutism. Nephrotoxicity.
Hyperplasia of gums. Neurotoxicity.
Hypertension. Hepatotoxicity.
Hyperglycemia and diabetes mellitus.
Diarrhea.
Alopecia.

One-liners:
• Tacrolimus is a – Macrolide.
• Cyclosporine binds to – Cyclophilin.
• Tacrolimus binds to – FKBP (FK-506 binding protein).
• Calcineurin inhibitors inhibit the lymphocyte production of – IL-2.
• Steroids inhibits IL17 & IL6.
• Voclosporine – Congener of cyclosporine; evaluated for prevention of anterior uveitis in
LUMINATE programme.
• Pimecrolimus – Congener of tacrolimus; approved for topical treatment of atopic
dermatitis in children > 2 years of age.
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Mechanisms of Antimetabolites:
1 Sirolimus (Rapamycin) Inhibit mTOR (mammalian target of rapamycin)

2 Temsirolimus

3 Everolimus

4 Azathioprine Inhibits T lymphocyte proliferation(Anti metabolites)

5 Mycophenolate mofetil Inhibits inosine monophosphate dehydrogenase (IMP)

dehydrogenase enzyme

6 Leflunomide Inhibits dihydro-orotate dehydrogenase enzyme

7 Fingolimod Activates sphingosine-1- phosphate receptors

Triple Therapy Regimen for Induction of Immunosuppression in Renal

Transplant Recipients
• Cyclosporine
• Azathioprine
• Prednisolone (±Muromonab CD3
342 | Pharmacology
Indications apart from Prophylaxis of Transplant Rejection:
1 Temsirolimus Renal cell carcinoma.
Hepatocellular carcinoma.
2 Everolimus
Mantle cell lymphoma.

3 Azathioprine RA.

4 Mycophenolate mofetil SLE.

5 Leflunomide RA.

6 Fingolimod Multiple sclerosis.

One-liners:
• DOC to prevent acute transplant rejection – Corticosteroids (IV methylprednisolone).
• Progressive multifocal leuknoence- phalopathy is a side effect of – Mycophenolate mofetil.
• Hepatotoxicity is a side effect of –
• Leflunomide.
• Anakinra – Anti IL-1 for RA.
• Abatacept – T-cell co-stimulation inhibitor (Anti CD80/CD86); approved for RA.
• Tofacitinib – Janus kinase inhibitor for
• RA (also under evaluation for psoriasis).
• AfraTafreeh.com
Alefacept – LFA-3-IgG1 fusion protein targeting CD2; approved for psoriasis.

Examples of Immunostimulants:
• Thalidomide and its congeners • Interferons.
• (Lenalidomide and Pomalidomide). • IVIg.
• Levamisole. • Aldesleukin.
• BCG vaccine.

Mechanism of Action of Thalidomide at The Molecular Level

1 Promotes apoptosis by inhibiting anti- apoptotic proteins:
• Inhibits NF-κB.
• Inhibits A1/Bfl-1.

2 Inhibits angiogenesis:
• Inhibits IL-6.

3 Inhibits tumour cell growth and survival:

• Inhibits interaction of cells with adhesion molecules.

4 Enhances T-cell mediated cytotoxicity.

 Immunomodulators | 343
Peripheral neuropathy due to thalidomide:
• Most serious side effect of thalidomide.
• Occurs in 10-30% of cases.
• Predominantly sensory.
• Asymmetrical, painful, peripheral paresthesia with sensory loss.
• Commonly presents with numbness of toes and feet, muscle cramps, weakness, signs of pyramidal tract
involvement and carpal tunnel syndrome.
• Increases with higher cumulative doses, especially in elderly.
• Symptoms improve upon discontinuation, but long-standing sensory loss may not reverse.

TNF-α blockers
• Infliximab • Golimumab
• Adalimumab • Certolizumab
• Eternacept

TNF-α blockers side effects-

Anti drug antibody formation, allergic reaction
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Activation of latent infection,hepatotoxicity, heart failure, secondary cancer

Contraindications to anti-TNF-α agents:

• Hepatitis B. • Systemic lupus erythematosus.
• HIV and other immunocompromised states. • Pregnancy.
• Active tuberculosis. • Lactation.
• Multiple sclerosis.

IL- modifiers:
Anakinra Analogue of IL 1 receptor Antagonist Useful In rheumatoid arthritis

Pitrakinra IL 3 & 4 Antagonist Under clinical trial for bronchial asthma

Aldeslukin Analogue- IL 2 Useful In RCC, malignant melanoma

Basiliximab, Il-2 receptor blockers immunosupressants

Daclizumab

Denilukin diftitox Combination of IL 2 + Diftheria toxin- Useful in Cutaneous T cell lymphoma

Resilzumab Il5 blocker Useful in bronchial asthma

344 | Pharmacology

Mepolizumab IL 5 blocker Hypereosinophiic synd, churg- strauss

syndrome

Tocilizumab IL- 6 blocker Useful in rheumatoid arthritis

Operlvikin Analogue of IL-11 Useful for treatment of anticancer drug

induced Thrombocytopenia

Ixekizumab IL- 17 Blocker Plaque psoriasis

Brodalumab

One-liners:
• Most common side effect of thalidomide – Sedation f/b Constipation.
• Most serious side effect of thalidomide
• Peripheral neuropathy.
• Thalidomide: Renantiomer is responsible for sedation; S enantiomer for biological
effects and teratogenicity (Mnemonic: S is not S).
• Teratogenic effects due to Thalidomide – Phocomelia and Mobius syndrome.
• Lenalidomide is indicated in – Multiple myeloma and Myelodysplastic syndrome
(especially in patients with 5q deletion).
• Myelosuppression is a side effect of – Lenalidomide.
• Pomalidomide is approved in – Multiple myeloma.
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Indications of interferons
IFN-α-2b • Hairy cell leukemia.
• Follicular lymphoma.
• Malignant melanoma.
• AIDS-related Kaposi’s sarcoma.
• Condyloma acuminata.
• Chronic hepatitis B & C.

IF N -β-1a, IFN-β-1b • Multiple sclerosis.

IFN-γ • Chronic granulomatous disease.

Indications of Intravenous Immunoglobulin (IVIG)

• Kawasaki’s disease.
• Idiopathic thrombocytopenic purpura (ITP).
• Guillain-Barre syndrome (GBS).
• Myasthenic crisis.
• Agammaglobulinemia (as replaceent therapy
 Immunomodulators | 345

One-liners:
• Fatal agranulocytosis is a side effect of
• – Levamisole.
• Imiquimod acts as a ligand for – Toll- like receptor-7 (TLR-7).
• Imiquimod is used for – Genital warts.
• BCG vaccine is used for – Superficial bladder cancer.
• DOC for Kawasaki’s disease – IVIg.
• Aldesleukin – Recombinant IL-2 for metastatic renal cell carcinoma and malignant
melanoma.
• Denileukin diftitox – Recombinant IL-2 + Diphtheria toxin for cutaneous T cell lymphomas.

Newer drugs:
Drug Mechanism Indication

1 Blinatumomab Monoclonal antibody targeting CD19 Philadelphia chromosome –ve relapsed

and CD3 or refractory B cell precursor ALL

2 Venetoclax Inhibits Bcl-2 (anti-apoptotic protein) Chronic lymphocytic leukemia (CLL)

3 Ibrutinib Inhibits Bruton’s tyrosine kinase

Chronic lymphocytic leukemia (CLL)
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4 Idelalisib Inhibits phosphoinositide-3-kinase-δ Relapsed CLL

5 Belinostat Inhibits histone deacetylase Relapsed or refractory peripheral T cell

lymphoma

6 Panobinostat Inhibits histone deacetylase Multiple myeloma

7 Siltuximab Monoclonal antibody targeting IL-6 Multicentric Castleman’s disease

8 Palbociclib Inhibits CDK-4 and CDK-6 ER +ve and HER-2 –ve breast cancer

9 Lenvatinib Inhibits VEGFR2 and VEGFR3 tyrosine Thyroid cancer resistant to radio-iodine
kinases

10 Nivolumab Monoclonal antibody targeting Metastatic squamous non-small cell

programmed cell death-1 (PD-1) carcinoma lung;
receptor on T cells Unresectable / metastatic melanoma

11 Ceritinib Inhibits ALK (tyrosine kinase) ALK +ve metastatic non-small cell lung
cancer

12 Ramucirumab Monoclonal antibody targeting VEGFR2 Gastric cancer

13 Dinutuximab Monoclonal antibody targeting GD2 High-risk neuroblastoma

(glycolipid disialoganglioside)
346 | Pharmacology

14 Olaparib Inhibits PARP (poly ADP ribose Previously treated BRCA mutated
polymerase) enzyme involved in DNA advanced ovarian cancer
repair

15 Atezolizumab Monoclonal antibody targeting PDL-1 Locally advanced/metastatic urothelial

(Programmed cell death ligand-1) carcinoma refractory to chemotherapy
and / or radiotherapy

16 Fluciclovine 18F labeled synthetic L-leucine analogue Diagnostic agent for PET imaging for
prostate cancer

17 Sonidegib Inhibits smoothened receptor pathway Locally advanced basal cell carcinoma
(Hedgehog signalling pathway)

18 Pembrolizumab Monoclonal antibody targeting Unresectable / metastatic melanoma

programmed cell death-1 (PD-1)
receptor on T cells

19 Netupitant Neurokinin-1 (NK-1) receptor antagonist Prevention of chemotherapy-induced

/ Substance P antagonist nausea and vomiting

20 Apremilast Selective PDE-4 inhibitor Moderate – severe plaque psoriasis;

Psoriatic arthritis
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21 Secukinumab Monoclonal antibody targeting IL-17A Plaque psoriasis

22 Ixekizumab Monoclonal antibody targeting IL-17A Plaque psoriasis

23 Ivermectin Anti-inflammatory and anti-parasitic Inflammatory lesions of rosacea

action against Demodex mites

24 Lifitegrast Inhibits binding o f Keratoconjunctivitis sicca (dry eye

lymphocyte function-associated antigen disease)
1 (LFA-
1) to intercellular adhesion molecule 1
(ICAM-1)

25 Aflibercept Inhibits VEGF Wet macular degeneration

 Immunomodulators | 347

Worksheet
To do
Most common side effect of cyclosporine

Mechanism of action of mycophenolate mofetil

Examples for mTOR inhibitors

Most common side effect of thalidomide

AfraTafreeh.com
Tyrosine kinase inhibitor useful for thyroid
cancer

VGFR blocking MABs example

MABs useful in multiple sclerosis

Examples for immunostimulants

14 Special Topics
Drugs Useful for Obesity

CONCEPTS
 Concept 14.1 
Special Topics Drugs Useful for
Obesity
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 Special Topics Drugs Useful for Obesity | 349
Concept 14.1 : Special Topics Drugs Useful for Obesity
1. Drugs for Medical Management of Obesity:
Drug Mechanism of action

1 Orlistat Inhibits pancreatic lipase (ADR-Steatorhoea)

Olestra Sucrose polyester, cooking medium

Rimonabant CB-1 antaonist (withdrawn due to psychiatry problem)

2 Lorcaserin 5-HT2C agonist (Anorectic), withdrawn because of gastric cancer

GLP-1-analogue LIRAGLUTIDE

3 Phentermine + Topiramate Phentermine – α1 agonist; Topiramate – Anti-epileptic

Bupropion + Naltrexone Bupropion- NADRI Naltrexonep opioid antagonist Zonisamide-
Bupropion + Zonisamide antiepileptic

One-liners:
• Tesofensine – Serotonin-noradrenaline-dopamine reuptake inhibitor (SNDRI) for obesity.
• Cetilistat – Pancreatic lipase inhibitor (Similar to Orlistat) for obesity.Sibutramine has been
withdrawn due to – Stroke
• AfraTafreeh.com
Sibutramine has been withdrawn due to – Stroke

2.
Condition Drug Useful

ADHD • DOC for ADHD in children – Methylphenidate (metabolite name is Ritalinic acid)
• DOC for ADHD in adults – Atomoxetine
• Other drugs useful in ADHD are
• Clonidine
• Guafacine, guanabenz
• Modafinil

Narcolepsy • MODAFINIL
• SOLRIAMFETOL- NDRI
• PITOLISANT / TIPROLISANT - H3 Inverse agonist (orphan drug status)

Drug Uses

Modafinil • Narcolepsy
• Shift workers
• Obstructive sleep apnoea syndrome
• ADHD ( not approved by FDA)
350 | Pharmacology
3. Drugs useful for Glaucoma
Agents Decreasing Aqueous Secretion
Alpha agonist Beta blockers Carbonic anhydrase inhibitors

Selective ∝2 Beta blockers- Brinzolamide

Agonists Timolol Dorzolamide
Apraclonidine Betaxolol Oral- Acetazolamide
Brimonidine Carteolol
Levobunolol
Metipranolol

Agents Promoting Drianage of Aqueous

Trabecular outflow
Cholinomimetics Rho kinase inhibitors

Pilocarpine (direct acting, short acting) Netarsudil

Ecothiophate- long acting- ADR- Cataract Repasudil –

Uveoscleral outflow AfraTafreeh.com

PGF2∝ (Agonist) Non selective ∝ agonists

• Latanoprost • Epinephrine
• Bimatoprost • Dipivefrine
• Tafluprost
• Travoprost
• Unoprostone

Adverse effects of antiglaucoma drugs

Lid lag Apraclonidine

Anterior uveitis Brimonidine

Bronchospasm Non selective beta blockers

Iris pigmentation Latanoprost, bimatoprost

Hypertrichoisis of eye lash Bimatoprost

cataract Echothiophate
 Special Topics Drugs Useful for Obesity | 351
4. Antismoking drugs
First line therapy
• Varenicline- (α4β2) nicotinic agonist
• Nicotine
• Bupropion - NDRI
Cystine
Second line therapy-
• Clonidine
• Nortriptyline
Miscellaneous-
• Rimonabant- IInverse agonist of Cannabinoid 1 receptor, eight loss (obesity),
Prevents craving of alcohol, ADR- Psychiatry problems (withdrawn)
• Topiramate
• Mecamylamine – ganglionic blocker

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