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1 General Pharmacology 1.1: PHARMACOKINETICS 1.1.1: ABSORPTION The most common method of drug absorption from gastrointestinal tract (GIT): Passive diffusion (MCQ 39) Other methods: Facilitated diffusion, Active transport Drug absorbed by facilitated diffusion: 5-FU Drugs absorbed by active transport: Levodopa (MCQ 37) and α-methyldopa Rate of passive absorption is directly proportional to: Lipid-water partition coefficient FICK’S LAW: Used to determine the rate of absorption, which is quantified as (C1 – C2) × A × P T where (C1 – C2) = Concentration gradient along the direction of diffusion, A = Area of membrane exposed to absorption, P = Permeability coefficient of the membrane, T = Thickness of the membrane. Out of these, the most important determinant for a drug is P (permeability coefficient) which gives a direct measure of its lipid solubility. Greater the lipid solubility, greater the permeability coefficient. Sites of absorption for a drug depend upon the pH of the gut lumen. Acidic environment Alkaline environment Absorption in the GIT A weak acid will remain undissociated A weak base will remain undissociated The undissociated form being lipophilic is easily absorbed The undissociated form being lipophilic is easily absorbed So, acidic drugs are better absorbed in the stomach (MCQ 46, 72) So, basic drugs are better absorbed in the intestine (MCQ 23) On the contrary, a weak base will completely dissociate On the contrary, a weak acid will completely dissociate The dissociated form being poorly lipophilic is not absorbed The dissociated form being poorly lipophilic is not absorbed Reabsorption in the renal tubules A weak acid will remain undissociated A weak base will remain undissociated So, it is easily reabsorbed and hence excretion is decreased So, it is easily reabsorbed and hence excretion is decreased On the other hand, a weak base will be fully dissociated On the other hand, a weak acid will be fully dissociated The dissociated forms are not lipophilic, hence, reabsorption is less The dissociated forms are not lipophilic, hence, reabsorption is less So, to excrete a weak base, urine is acidified So, to excrete a weak acid, urine is alkalinized Most common site of absorption is: Small intestine (upper duodenum) (MCQ 23) Drugs absorbed in the stomach are: (Mnemonic: SABuN) Sulphonamides Barbiturates (MCQ 72) Alcohol NSAIDs (MCQ 72) Chapter-01.indd 1 Chapter-01.indd 1 10/30/2012 11:29:08 AM 10/30/2012 11:29:08 AM

Transcript of Sample Chapter Smart Study Series Pharmacology, 2e by Krishnamurthy To Order Call Sms at +91...

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1 General Pharmacology

1.1: PHARMACOKINETICS

1.1.1: ABSORPTIONThe most common method of drug absorption from gastrointestinal tract (GIT): � Passive diffusion (MCQ 39)

Other methods: Facilitated diffusion, Active transport �

Drug absorbed by facilitated diffusion: � 5-FU Drugs absorbed by active transport: � Levodopa (MCQ 37) and α-methyldopaRate of passive absorption is directly proportional to: � Lipid-water partition coeffi cient

FICK’S LAW: Used to determine the rate of absorption, which is quantifi ed as

(C1 – C2) × A × PT

where (C1 – C2) = Concentration gradient along the direction of diffusion, A = Area of membrane exposed to absorption, P = Permeability coeffi cient of the membrane, T = Thickness of the membrane.

Out of these, the most important determinant for a drug is � P (permeability coeffi cient) which gives a direct measure of its lipid solubility. Greater the lipid solubility, greater the permeability coeffi cient. �

Sites of absorption for a drug depend upon the pH of the gut lumen.

Acidic environment Alkaline environment

Absorption in the GIT

A weak acid will remain undissociated A weak base will remain undissociated

The undissociated form being lipophilic is easily absorbed The undissociated form being lipophilic is easily absorbed

So, acidic drugs are better absorbed in the stomach (MCQ 46, 72) So, basic drugs are better absorbed in the intestine (MCQ 23)

On the contrary, a weak base will completely dissociate On the contrary, a weak acid will completely dissociate

The dissociated form being poorly lipophilic is not absorbed The dissociated form being poorly lipophilic is not absorbed

Reabsorption in the renal tubules

A weak acid will remain undissociated A weak base will remain undissociated

So, it is easily reabsorbed and hence excretion is decreased So, it is easily reabsorbed and hence excretion is decreased

On the other hand, a weak base will be fully dissociated On the other hand, a weak acid will be fully dissociated

The dissociated forms are not lipophilic, hence, reabsorption is less

The dissociated forms are not lipophilic, hence, reabsorption is less

So, to excrete a weak base, urine is acidifi ed So, to excrete a weak acid, urine is alkalinized

Most common site of absorption is: � Small intestine (upper duodenum) (MCQ 23)

Drugs absorbed in the stomach are: (Mnemonic: SABuN) �

� Sulphonamides � Barbiturates(MCQ 72)

� Alcohol � NSAIDs(MCQ 72)

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Bioavailability (F): Fraction of the administered dose of the drug that enters the systemic circulation in an unchanged form.Bioavailability on administration by various routes:

Route Bioavailability

Intravenous (IV) 100% or 1

Subcutaneous (s.c.) Decreased due to local binding to tissues

Intramuscular (IM) Decreased due to local binding to tissues

Oral Decreased due to • Incomplete/decreased absorption (MCQ 58)

• First-pass metabolism (FPM) (MCQ 58)

A. Incomplete/decreased absorption could be due to 1. Intrinsic property of the drug

Drug is a charged molecule, so cannot easily penetrate the biological membrane for absorption. �

E.g., Aminoglycosides, NeostigmineDrug is susceptible to gastric acid; i.e., it is acid labile, so it is broken down by gastric acid. �

E.g., Penicillin G, ErythromycinDrug is cleaved by proteases in the GIT �

E.g., Insulin, Oxytocin [Note: Drugs can be protected from gastric acid by Enteric coating]

Drug

Enteric (acid-resistant)coating

(a)

(a) The drug is coated with an acid–resistant coat, which protects it from gastric acid.

Drug

Reservoir

Core

Semipermeablemembrane

(b)

(b) The reservoir is impregnated with the drug which gradually diffuses out of the semipermeable membrane at a constant rate.

Fig. 1.1: (a) Enteric-coated and (b) sustained-release formulations of a drug.

The drug is covered by a membrane that is resistant to gastric acid (Fig. 1.1a). �

Upon entry into the small intestine, the membrane dissolves or is digested and the drug is now available for �

absorption. Thus, enteric coating only offers protection against degradation. �

It does not increase the duration of action of a drug. �

Duration of action of a drug can be prolonged by � sustained-release formulation (Fig. 1.1b).Here, there is a reservoir that is impregnated with the drug. �

This is covered by a semipermeable membrane through which the drug diffuses at a constant rate. �

Thus, the absorption of the drug is controlled and predictable. �

By decreasing the rate of absorption, the duration of absorption and hence, the time for which the drug remains in the �

circulation can be prolonged. Thus, the action of a drug can be prolonged. �

2. Drug–drug interaction E.g., Antacids decrease absorption of other drugs. 3. Drug–food interaction

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3GENERAL PHARMACOLOGY

Effect of food on absorption

Food increases the absorption of Food decreases the absorption of

• Carbamazepine

• Chloroquine

• Griseofulvin

• Lithium

• Nitrofurantoin

• Ribofl avin

• Spironolactone

• Ampicillin

• Aspirin

• Captopril

• Digoxin

• Isoniazid

• Levodopa

• Rifampicin

• Tetracyclines

B. FPM: It is the metabolism to which the drug is subjected before entering the systemic circulation. Most common site of FPM: Liver �

Other sites of FPM: � Small intestineDrug undergoing FPM in small intestine: � Levodopa (by the enzyme dopa decarboxylase)

Drugs undergoing high/extensive FPM in the liver

Drugs not given orally (Mnemonic: HILT) Drugs given orally in high doses

• Hydrocortisone • Lignocaine (MCQ 36)

• Isoprenaline • Testosterone• Propranolol (MCQ 36) • Morphine• Alprenolol • Pethidine• Salbutamol (MCQ 36) • Methyltestosterone• Verapamil (MCQ 24) • Propoxyphene• Nitroglycerin

1.1.2: DISTRIBUTION

Redistribution Upon administration, the drug is fi rst distributed to organs with a high blood fl ow, e.g., brain, heart, etc. �

If the site of action of the drug is in one of these organs, then there is a � rapid onset of action.Later, as the blood is drained away from these organs, the drug also leaves the organ. �

Thus, the action of the � drug is terminated rapidly. This phenomenon of � rapid onset of action, termination, followed by a gradual onset of action again as the drug re-enters the organ in the next cycle of blood fl ow is termed as redistribution.

E.g., Thiopentone sodium (MCQ 71)

Volume of distribution (Vd): The total volume in which the drug is supposed to be evenly distributed so as to attain the concentration observed in the plasma.

Vd =Dose administered

Plasma concentration

Condition Vd Examples

Drug is highly bound to plasma proteins = Plasma volume = ~3 L

• Warfarin• Phenylbutazone

Drug is bulky and remains in the vascular compartment = Blood volume = ~5 L

• Heparin• Streptokinase

Drug is lipid soluble and is distributed throughout the ECF = ECF volume = ~15 L

• Streptomycin• Gentamicin

Drug is lipid soluble and gets sequestered in the tissues >ECF volume i.e. >15 L • Digoxin• Morphine• Propranolol

Drug is very highly lipid soluble and gets sequestered in the adipocytes ~1000 L • Chloroquine

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4 SMART STUDY SERIES: PHARMACOLOGY

Chloroquine upon administration gets immediately distributed to �

Liver � (hence, used for treatment of amoebic liver abscess) and Retina � (hence, causes retinopathy as a long term side effect)

Digoxine is distributed in the � skeletal muscle. Amiodarone is distributed in the � cornea (hence, causes corneal microdeposits).

Least leaky barrier in human body to drugs: � Blood-brain barrier.Most leaky � barrier in human body to drugs: Blood-placental barrier. (MCQ 29)

Hemodialysis: Removal of a drug from the vascular compartment. �

For this, the drug has to remain in the vascular compartment. �

Therefore, � hemodialysis is effective only for drugs that have a Vd ≤ 5 LPlasma protein bindingA highly plasma protein–bound drug 1. Is not easily metabolized. 2. Is not easily excreted by kidneys.

Hence, it is usually long acting. By convention:Acidic drugs bind to: Albumin (MCQ 46)

Basic drugs bind to: α1-acid glycoprotein However, this is not a hard-and-fast rule.

Drugs bound to albumin Drugs bound to �1 acid glycoprotein

• In case of chronic liver disease/liver cirrhosis, albumin levels decrease

• Hence, bound form of the drug decreases• Therefore, free form of the drug increases• So, there is increased risk of toxicity• Hence, dose of drug needs to be decreased

• In case of acute infl ammatory states, α1 acid glycoprotein levels increase

• Hence, bound form of the drug increases• Therefore, free form of the drug decreases• So, there is reduced effect of the drug• Hence, dose of drug needs to be increased

Theapeutic drug monitoring (TDM):Indications: 1. Drugs with a low safety margin or a narrow therapeutic index (MCQ 34): (Mnemonic: DAT-LAAT)

D � igoxin � Lithium (MCQ 4, 21, 42)

A � ntiarrhythmics � Aminoglycosides (MCQ 4)

T � heophylline � Antiepileptics (MCQ 18, 42)/Anti-seizure drugs � TCAs (MCQ 21, 42)

2. Drugs with a very high interindividual variation in plasma levels� Lithium � TCAs� Methotrexate � Calcineurin inhibitors (MCQ 4, 18)

3. Potentially nephrotoxic drugs are given in the presence of renal failure� Aminoglycosides � Vancomycin

4. For monitoring patient compliance 5. When there is no response to a drug for no apparent reason 6. In case of poisoning TDM is not required for drugs whose effect can be detected by clinical/laboratory examination.E.g., Antihypertensives (measurement of BP)

Hypoglycemics (measurement of blood sugar) (MCQ 18)

Warfarin (measurement of PT/INR), etc. (MCQ 4)

1.1.3: METABOLISM

Prodrug: Drug, which by defi nition, is inactive by itself, and needs to be converted to an active metabolite. (MCQ 26)

Examples of prodrugs:

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5GENERAL PHARMACOLOGY

Prodrug Active metabolite

Acyclovir Acyclovir triphosphate

Bacampicillin Ampicillin

Cyclophosphamide Aldophosphamide, Phosphoramide mustard, Acrolein

Dipivefrin (MCQ 64) Epinephrine

Enalapril (MCQ 10, 64) Enalaprilat

5-Fluorouracil Fluorouridine monophosphate

Levodopa Dopamine

6-Mercaptopurine (MCQ 64) Methylmercaptopurine ribonucleotide

α-Methyldopa α-Methylnorepinephrine

Prednisone Prednisolone

Proguanil Cycloguanil

Sulfasalazine 5-Aminosalicylic acid

Sulindac Sulfi de metabolite

However, there are certain drugs, which are themselves active and further give rise to active metabolites. As these drugs are inherently active, they cannot be considered as prodrugs. Examples of active drugs and their active metabolites:

Active drug Active metabolite

Allopurinol Alloxanthine

Amitriptyline Nortriptyline

Cefotaxime Desacetyl cefotaxime

Chloral hydrate Trichloroethanol

Codeine Morphine

Diazepam Desmethyldiazepam, Oxazepam

Digitoxin Digoxin

Imipramine Desipramine

Losartan E 3174

Morphine Morphine-6-glucuronide

Primidone Phenobarbitone, Phenylethylmalonamide

Procainamide N-acetylprocainamide

Spironolactone Canrenone

METABOLISM OF DRUGS: is carried out in two phases.

Reactions in Phase I Reactions in Phase II

• Oxidation (MCQ 3) (Most common)• Reduction (MCQ 3)

• Cyclization• Decyclization• Hydrolysis (MCQ 3)

• Glucuronidation (MCQ 43) (Most common)• Acetylation• Methylation (MCQ 43)

• Sulfation (MCQ 43)

• Glycine conjugation (MCQ 3, 20)

• Glutathione conjugation (MCQ 3, 20)

Drugs undergoing acetylation:(MCQ 9,32) (Mnemonic: SHIPP-C)� Sulfonamides + Dapsone (MCQ 9) � Procainamide (MCQ 32)

� Hydralazine (MCQ 9,32) � PAS� Isoniazid (MCQ 9,32) � ClonazepamDrugs are mainly metabolized in the liver by cytochromal enzymes. Enzymes of the cytochromal system and drugs metabolized by them:

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6 SMART STUDY SERIES: PHARMACOLOGY

Enzymes Drugs metabolized by it

CYP3A4 All drugs metabolized by cytochromes other than those listed below

CYP2D6 • TCAs• SSRIs• Neuroleptics• Antiarrhythmics• β-blockers (in particular, carvedilol)• Codeine → Morphine

CYP2C8/9 • Warfarin• Phenytoin

CYP2C19 • Proton pump inhibitors• Clopidogrel• Voriconazole

CYP1A1/2 • Procarcinogens

CYP2E1 • Paracetamol → NABQI

Cytochromal enzyme inducers and inhibitors

Inducers Inhibitors

• Rifampicin(MCQ 12)

• Griseofulvin• All antiepileptics except valproate(MCQ 12)

• Polycyclic hydrocarbons (CYP1A1/2)• Cigarette smoke (CYP1A1/2)• Alcohol (CYP2E1)• INH (CYP2E1)(MCQ 12)

• Erythromycin (MCQ 5)

• Clarithromycin• Ketoconazole (MCQ 12)

• Itraconazole (MCQ 5)

• Verapamil• Diltiazem• Cimetidine• Ranitidine• Valproate• HIV protease inhibitors (MCQ 5)

• Grape fruit juice• Quinine (CYP2D6)• Ranolazine (CYP2D6)• INH (for all enzymes other than CYP2E1)(MCQ 12)

1.1.4: ELIMINATIONRenal elimination: mainly follows two types of kinetics:

First-order kinetics: followed by most of the drugs. Zero-order kinetics: followed by

At all doses Only at higher doses

• Alcohol (MCQ 27) • Phenytoin (MCQ 27, 33)

• Tolbutamide• Theophylline• Warfarin• Cetuximab

Characteristics of the two types of clearances: (MCQ 61)

First-order kinetics Zero-order kinetics

1. What is eliminated in unit time? A constant fraction of drug in the plasma A constant amount of drug in the plasma(MCQ 1)

2. Rate of elimination Proportional to plasma concentration of the drug (MCQ 1, 61)

Constant (independent of plasma concentration of the drug)(MCQ 1)

3. Clearance Constant (MCQ 61) Decreases with increase in dose

4. Half-life Constant (MCQ 61) Increases with increase in dose (MCQ 1)

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7GENERAL PHARMACOLOGY

Clearance: The volume of plasma that is cleared of the drug in unit time. Mathematically, denoted by

CL =UVP

where, U = Concentration of drug in urine V = Urine fl ow rate P = Concentration of drug in plasma

Half-life (T½): Time taken for the original plasma concentration of the drug to be reduced to half. Mathematically,

T½ =0.693

kwhere k = Elimination rate constant.

It is defi ned as the fraction of total amount of drug in plasma that is eliminated in unit time. Therefore,

k =CLVd

Therefore,

T½ = 0.693 ÷CL

=0.693 × Vd

Vd CL

Therefore, elimination of the drug in terms of percentage:

No. of half-lives Percentage of drug eliminated

1 50

2 75

3 87.5

4 93.25 (MCQ 22)

5 96.125

Thus, the elimination of the drug crosses 95% in 5 half-lives, which is considered to be signifi cant. Therefore, a drug is nearly completely eliminated after 5 half-lives.

STEADY-STATE PLASMA CONCENTRATION (Cp): The plasma concentration at which the amount of drug entering the plasma due to administration is equal to the amount �

of drug leaving it due to elimination. This is possible only when the effect of half-life on the plasma concentration has already ended. �

Hence, Cp is attained after � 5 half-lives.

Loading dose =Cp × Vd

F

Therefore, loading dose depends upon volume of distribution (MCQ 11)

Maintenance dose =Cp × CL

FTherefore, maintenance dose depends upon clearance.

1.2: PHARMACODYNAMICS

1.2.1: LOG DOSE–RESPONSE CURVE (DRC)Advantages of a log DRC (Fig. 1.2b) over a normal DRC (Fig. 1.2a): 1. The intermediate portion (25% to 75%) of the graph is a straight line. Hence, with an increase in log of the dose, there is a proportionate increase in response.

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8 SMART STUDY SERIES: PHARMACOLOGY

x

y

Dose

Response

(a)

(a) Dose–response curve.

x

y

Dose

Response

(b)

(b) Log dose–response curve.

Fig. 1.2: (a) Dose–response and (b) Log dose–response curves.

2. A wider range of drug doses can be plotted. 3. Effi cacy and potency of drugs can be compared. 4. Agonists and antagonists can be easily compared. Potency: The dose of the drug at which response begins. Therefore, lesser the dose at which the response begins, more potent the drug. Effi cacy: The maximum response achieved by the drug. Therefore, greater the maximum response achieved by a drug, greater the effi cacy of the drug.

A

B

X

Y

A

B

A BLog dose

Response

Fig. 1.3: Comparison between potency and effi cacy of two drugs: A and B. Note: In the above fi gure, A is more potent, but B is more effi cacious.

In the above fi gure, drug A is more potent while B is more effi cacious. In a clinical scenario, a drug is selected on the basis of its effi cacy. E.g., 1. Aspirin is less potent and less effi cacious than morphine. Hence, morphine is preferred as an analgesic over aspirin for

most clinical conditions. 2. Pethidine is less potent but equally effi cacious than morphine. Hence, morphine is preferred as an opioid analgesic over

pethidine. 3. Furosemide is less potent but more effi cacious than metolazone (thiazide). Hence, furosemide is the preferred diuretic. Considering a drug with more than one action,

If the log DRCs for the two effects of the drug are very close to each other (Fig. 1.4a), then the drug can produce the �

second action at a dose at which it produces the fi rst action. Hence, the drug is said to be nonselective or nonspecifi c.E.g., Propranolol in a nonselective β-blocker. �

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9GENERAL PHARMACOLOGY

Log dose

Response

x

y

1

2

(a)

(a) As the curves for effects (1) and (2) of the drug “A” are close to each other, the drug is nonselective.

Log dose

Response

1

2

x

y

(b)

(b) As the curves for effects (1) and (2) of the drug “B” are far apart from each other, the drug is selective.

Fig. 1.4: Comparison between two different effects of a drug.

If the log DRCs for the two effects of the drug are far away from each other (Fig. 1.4b), then the drug will not produce �

the second action at a dose at which it produces the fi rst action. Hence, the drug is said to be selective or specifi c for that particular action. E.g., Metoprolol is selective for β-1 blockade. �

Considering the therapeutic and toxic actions of a drug,

Rx effect

Toxic effect

Re

sp

on

se

Log dose

(a)

x

y

(a) As the curves for therapeutic and toxic effects of the drug “A” are close to each other, the drug is unsafe.

Log dose

(b)

Re

sp

on

se

Rx effect

Toxic effect

x

y

(b) As the curves for therapeutic and toxic effects of the drug “B” are far away from each other, the drug is safe.

Fig. 1.5: Comparison of therapeutic and toxic effects of a drug.

If the log DRCs for the therapeutic and toxic actions of a drug are very close to each other (Fig. 1.5a), then the drug can �

produce toxicity at a dose at which it produces its therapeutic effect. Hence, the drug is said to be unsafe. If the log DRCs for the therapeutic and toxic actions of a drug are far away from each other (Fig. 1.5b), then the drug will �

not produce toxicity at a dose at which it produces its therapeutic effect. Hence, the drug is said to be safe. Thus, the � distance between the log DRCs for the therapeutic and toxic actions of the drug denotes safety.

Also, in a log DRC, If the curve is steep, then a slight change in dose can lead to a large change in effect. Hence, the drug is to be used �

cautiously. If the curve is not very steep, then a slight change in dose will not affect the response to a great extent. So, the drug is �

relatively safer. Thus, � slope of LDRC denotes safety.

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10 SMART STUDY SERIES: PHARMACOLOGY

1.2.2: QUANTAL DOSE–RESPONSE CURVEEstimates whether effect is produced or not (all or none phenomenon). �

E.g., whether insulin produces hypoglycemia or not, morphine produces analgesia or not, quinine produces death in �

animals or not.Main difference between a log and a quantal DRC:

In a log DRC, the various responses produced at various doses of the drug in a single individual human/animal are �

considered. In a quantal DRC, the proportion of humans/animals in the whole population in which the response is produced is �

considered. Advantages over a log DRC:

Quantal (all-or-none) responses can be measured. �

Takes individual variations into consideration. �

How is a quantal DRC plotted? (Fig. 1.6)

x

y

ED 50 LD 50Dose

100%

50%

0%

Perc

enta

ge o

f popula

tion s

how

ing

response

Fig. 1.6: Quantal dose–response curves for therapeutic and toxic effects of a drug.

A large population is selected. �

Drug at the lowest dose is administered. �

The dose is then sequentially increased. �

Dose of the drug at which response occurs in 10%, 20%, 30%,... of the population is measured. �

A graph is plotted as percentage of population in which response is produced versus dose at which that response is �

produced. Once the therapeutic effect is obtained, the dose is further sequentially increased to reach the toxic effect of the drug. �

Similar to the therapeutic effect, the dose at which toxicity occurs in 10%, 20%, 30%,… of the population is measured �

and plotted as a separate curve. The frequency of patients that show response/toxicity is also determined and plotted alongside. �

Parameters derived from a quantal DRC: 1. ED50

Dose at which therapeutic effect is produced in 50% of the population. �

By defi nition, when a drug is marketed in the community, the therapeutic effect should be produced in at least 50% of �

the population. Therefore, it is considered as � Minimum effective dose. A drug “A” with a lower ED � 50 than drug “B” indicates that the same therapeutic effect is produced by drug “A” at a lower dose than drug “B.” So, drug “A” is considered to be more potent than drug “B.” �

Thus, ED � 50 denotes Potency. (MCQ 16)

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11GENERAL PHARMACOLOGY

2. LD50 (TD50) Dose at which toxic effect is produced in 50% of the population. �

In case of laboratory animals, the toxic effect usually produced is death. So, LD � 50 is preferred over TD50.By defi nition, when a drug is marketed in the community, the toxic effect should not be produced in more than 50% of �

the population. Therefore, it is considered as � Maximum acceptable dose. A drug “A” with a lower LD � 50 than drug “B” indicates that the same toxic effect is produced by drug “A” at a lower dose than drug “B.” So, drug “B” is considered to be more safe than drug “A.” �

Thus, LD � 50 denotes Safety. (MCQ 15)

3. Therapeutic rangeA drug can be administered in the dose range between the minimum effective dose and maximum acceptable dose in �

the community. Therefore, � therapeutic range = ED50 – LD50If the ED � 50 and LD50 are far away from each other, the drug can be safely administered over a wider range.On the other hand, if ED � 50 and LD50 are close to each other, the therapeutic range is narrow and the drug has to be cautiously administered. Therefore, therapeutic range also denotes � safety.

4. Therapeutic indexTherapeutic index � (TI) = LD50/ED50For a drug, TI should be � ≥ 2, i.e., ED50 and LD50 should be far away from each other. Any drug with a TI < 2 is likely to cause toxicity at therapeutic doses and hence is considered as unsafe. �

Therefore, TI also indicates � Safety.(MCQ 15)

To summarize,

Indicator/s of potency Indicator/s of safety

• Potency • Distance between the log DRCs for the therapeutic and toxic effects of a drug • Slope of its log DRC• LD50

• Therapeutic range• Therapeutic index

1.3: CLINICAL TRIALS

Phase Done on Done to assess

Preclinical Animals • Effect of the drug on animals

0 Microdosing (subtherapeutic doses in small group of healthy volunteers)Done only in specifi c cases

• Pharmacokinetics (predominantly bioavailability)

I Small group of healthy volunteers • Safety• Pharmacokinetics• Pharmacodynamics

II Small group of patients • Safety• Effi cacy (MCQ 14)

III Large group of patients • Safety • Effi cacy

IV Postmarketing surveillance • Rare ADRs• Chronic or long-term ADRs• Drug interactions• Effect of the drug on special populations, e.g.,

pregnant females, patients with hepatic failure or renal failure, etc.

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12 SMART STUDY SERIES: PHARMACOLOGY

Phase V: Effectiveness research To determine whether the effect obtained by a drug in a study can be generalized to a larger population, or in other words, �

whether the therapeutic effect of the drug is realized in day-to-day clinical practice. The effects obtained by the drug are compared with the ones found in earlier studies. �

Hence, the signifi cance of the therapeutic effect of the drug in the population can be determined. �

Good clinical practices: Guidelines for conducting clinical trials. �

Required for all phases of clinical trials except � Preclinical studies. (MCQ 13)

Good laboratory practices: Guidelines for conducting laboratory experiments. �

Required for all phases of clinical trials except � Phase IV.

Pharmacovigilance is � Monitoring of ADRs. Hence, it is used for monitoring the toxicity/safety profi le of drugs when used in the general population � . (MCQ 6)

1.4: STRUCTURAL DRUG DESIGNING

Modern computerized method to develop or design new drugs. �

Can be divided into two types: 1. Target-based drug designing (Fig. 1.7): (MCQ 2)

Designedcomplementary

ligand

Target

Fig. 1.7: Target-based drug designing.

The desired molecule to be inhibited, for e.g., a receptor or a growth factor is taken as the target. �

The structure of the target (most commonly a protein) is determined using X-ray crystallography or NMR spectroscopy �

or any such method.Using computerized techniques, a molecule is designed such that its structure is complementary to the target. �

So this molecule can now bind to the target. Hence, it is known as ligand. �

This is known as “target-based drug designing” as the structure of the target forms the basis for designing a drug. �

2. Ligand-based drug designing:The ligand that can bind to the target is already known. �

Using combinatorial chemistry, various modifi cations can be performed in the ligand, e.g., addition or deletion of one/ �

more functional group(s). This can alter the structure of the ligand to produce numerous molecules, up to thousands in number. �

Thus, a ligand library can be constructed. �

The main advantage of this library is that it saves time during high-throughput screening. �

Each of these molecules is a potential ligand and might bind to the target. �

This is known as “ligand-based drug designing” as the structure of the ligand forms the basis for designing new drugs. �

HIGH-THROUGHPUT SCREENING:Each of the molecules derived by modifi cation of the structure of the ligand is a potential ligand. �

Now it is to be evaluated as to which of these can bind to the target. �

This can be done by a method known as “high-throughput screening.” �

In this process, each of the ligand is made to bind with the target one by one and the binding is assessed. �

If the potential ligand binds to the target, then it is known as a “hit.” �

Thus, the hits are identifi ed from the group of potential ligands. �

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13GENERAL PHARMACOLOGY

LEAD IDENTIFICATION:Now the hits are molecules that bind to the target. �

Now it is to be evaluated whether they produce an effect on binding to the target. �

This is assessed and those hits that produce the desired effect are identifi ed. �

These are known as “leads.” �

This process is known as “lead identifi cation.” �

LEAD OPTIMIZATION:Once the leads are identifi ed, they are then evaluated as to which effects are produced at what doses. �

This process is known as “lead optimization.” �

Once the lead is optimized, it is now known as a “potential drug” or an “experimental drug” and is further evaluated in �

animals.

QUESTIONS

1. True about fi rst-order kinetics is [AIIMS MAY 2012]a. A constant amount is eliminated in unit timeb. The half-life increases with an increase in dosec. The rate of elimination is constantd. The rate of elimination is proportional to the plasma

concentration2. Nowadays, the method used for drug designing/drug

discovery is [AI 2012]a. Target structure basedb. Hit and trial methodc. Molecular modeling wayd. High-throughput method

3. In metabolism of xenobiotics, all of the following reactions occur in phase I except

(AI 2012, AIIMS NOV 2008)a. Oxidation b. Reductionc. Conjugation d. Hydrolysis

4. Monitoring of the plasma levels is done for all of the following drugs except [AI 2012]a. Lithium b. Cyclosporinec. Gentamicin d. Warfarin

5. All of the following drugs are CYP3A inhibitors except [AIIMS MAY 2010]a. Erythromycin b. Itraconazolec. Ritonavir d. Saquinavir

6. Pharmacovigilance is done for the monitoring of[AIIMS MAY 2009, 2010]

a. Drug priceb. Unethical practicesc. Drug safety d. Pharmacy students

7. MDR gene acts by [AIIMS MAY 2009]a. Blocking drug activationb. Blocking intracellular DNA synthesisc. Causing effl ux of drugd. DNA repair inhibition

8. All of the following drugs require dose reduction in cirrhosis of liver except [AIIMS NOV 2008]a. Lorazepam b. Diazepamc. Metronidazole d. Rifampicin

9. Which of the following drugs is not acetylated?[AIIMS MAY 2008]

a. INH b. Dapsonec. Hydralazine d. Metoclopramide

10. Which of the following is a prodrug? [AIIMS MAY 2008]

a. Enalapril b. Clonidinec. Salmeterol d. Acetazolamide

11. Loading dose of a drug depends upon [AIIMS MAY 2008]

a. Volume of distribution b. Clearancec. Rate of administration d. Half-life

12. Which of these is a CYP450 inhibitor?[AIIMS MAY 2008]

a. Ketoconazole b. Rifampicinc. Phenytoin d. INH

13. Good clinical practices (GCPs) are seen in all of the following except [AIIMS NOV 2007]a. Preclinical trials b. Phase I trialsc. Phase II trials d. Phase IV trials

14. Phase II in a clinical trial is done to assess [AI 2008]a. Therapeutic effi cacyb. Maximal tolerated dosec. Maximal lethal dosed. Toxicity

15. Therapeutic index is a measure of a drug’s [AI 2008]a. Safety b. Potencyc. Effi cacy d. Toxicity

16. ED50 is a measure of [AI 08]a. Toxicity b. Safetyc. Potency d. Effi cacy

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14 SMART STUDY SERIES: PHARMACOLOGY

17. All of the following enzymes and their reactions are involved in the metabolism of xenobiotics except

[AI 2008]a. Cytochrome oxidase b. Cytochrome P450c. Methylation d. Hydroxylation

18. Therapeutic drug monitoring is advised in all of the following except [AIIMS NOV 2007]a. Metformin b. Phenytoinc. Tacrolimus d. Cyclosporine

19. A substance having affi nity but no instrinsic activity is [Delhi 1988, 1990]a. Agonist b. Partial agonistc. Antagonist d. Physiological antagonist

20. Detoxifi cation or protective synthesis occurs by [AIIMS 1984]a. Oxidation b. Reductionc. Conjugation d. All of the above

21. Estimation of serum levels is essential in treatment with [AIIMS 1982]a. Imipramine b. Chlorpromazinec. Lithium d. Haloperidol

22. Elimination after 4 half-lives in fi rst-order kinetics is [AI 1989]a. 84% b. 93%c. 80.5% d. 4.75%

23. The alkaline drug (amidopyrine) is absorbed from [Al 1991]a. Stomach b. Proximal small intestinec. Distal small intestine d. Colon

24. Which drug has a high fi rst-pass effect?[JIPMER 1991]

a. Amiodarone b. Phenytoinc. Verapamil d. Disopyramide

25. What is the advantage of sublingual route of admin-istration of drugs? [JIPMER 1991]a. Prevents fi rst-pass effectb. Easy to administer c. Lipid solubled. Can be spitted out with signs of toxicity

26. What is a prodrug? [JIPMER 1992]a. Drug which increases effi ciency of another drugb. Metabolic end productc. Inactive drug which gets activated in the bodyd. Drug which competes with another for metabolism

27. Zero-order kinetics is seen in all of the following except [PGI 1993]a. Salicylate b. Phenytoin c. Barbiturates d. Ethanol

28. Which of the following avoids fi rst-pass effect of drugs? [JIPMER 1993]a. Oral ingestion b. Rectal suppositoryc. Intravenous injection d. Intraarterial injection

29. Drug which crosses the placental barrier is[Delhi, 1992]

a. Phenytoin b. Diazepamc. Corticosteroids d. All of the above

30. Which of the following is not a dose-related reaction? [JIPMER 1992]a. Myocardial irritation of quinidine b. Hypoglycemia of tolbutamidec. Digitalis-induced arrythmiad. Drug fever of sulfa

31. The dosage of drugs in renal disease should be changed based on [PGI 1980]a. Urine output b. Blood ureac. Serum creatinine d. Creatinine clearance

32. All of the following drugs are metabolized in body by acetylation except [AI 1996]a. INH b. Hydralazinec. Procainamide d. Dilantin

33. Zero-order kinetics is seen with [All India 1996]a. Phenytoin b. Phenobarbitonec. Erythromycin d. Digoxin

34. Most common indication for therapeutic monitoring of plasma levels of a drug is [AI 1996]a. Hit and run drugsb. Drugs with irreversible actionc. Narrow therapeutic ranged. Failure of response

35. Idiosyncrasy is [Karnataka 1996]a. A genetically determined abnormal reaction to drugsb. A characteristic toxic effect at therapeutic dosesc. An altered physiological state produced by repeated

drug used. An immunologically mediated reaction

36. First-pass metabolism is seen in [PGI 2003]a. Lignocaine b. Propranololc. Salbutamol d. Dipyridamole. Erythromycin

37. Drugs absorbed by active transport is [NIMS 1996]a. Propranolol b. Ergotaminec. Levodopa d. Amantadine

38. Plasma concentration of drug at time 0 is 96 gml. If tI/2 is 2 hours, concentration in plasma at 10 hours will be [MAHE 1998]a. 48 b. 24c. 12 d. 3

39. Drugs mostly cross biological membranes by [Rohtak 1998]

a. Passive diffusion b. Active diffusionc. Active transportd. Carrier-mediated transporte. All of the above

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15GENERAL PHARMACOLOGY

40. Time for peak plasma concentration (Tmax) indicates[Karnataka 2001]

a. The rate of elimination b. The rate of absorptionc. The onset of effect d. The intensity of effect

41. Drug(s) causing nephrotoxicity is/are [PGI 2002]a. Gentamicin b. Cloxacillinc. Phenacetin d. Erythromycin

42. Low theraputic range is seen in [PGI 2002]a. Lithium b. Erythromycinc. Phenytoin d. Propranolole. Tricyclic antidepressants

43. In hepatic metabolism, phase II reactions are[PGI 2002]

a. Dealkylation b. Sulfonationc. Methylation d. Glucuronizatione. Deamination

44. Characteristic feature of agonist is [PGI 1999]a. Has affi nity only b. Has affi nity as well as intrinsic activityc. Has intrinsic activity onlyd. Neither has affi nity nor activity

45. Which of the following is true about dose–response curve? [PGI 1999]a. Cannot determine the potency of a drugb. Log dose–response curve is sigmoid shapedc. Cannot fi nd response to antagonistd. A wide range of doses can not be plotted

46. Which of the following is true about acidic drugs? [PGI 1997]

a. Best absorbed in acidic mediumb. Best absorbed in alkaline mediumc. Not absorbed in acidic mediumd. Binds to α-glycoprotein

47. In which one of the following drugs overdosages is hemodialysis useful? [UPSC 2002]a. Digoxin b. Paracetamolc. Barbiturate d. Diazepam

48. In which of the following phases of clinical trial of drug, ethical clearance is not required? [AI 2004]a. Phase I b. Phase IIc. Phase III d. Phase IV

49. The antagonism of leukotriene by terbutaline is an example of [COMED 2005]a. Pharmacological antagonismb. Physical antagonismc. Physiological antagonismd. Chemical antagonism

50. All of the following are reasons for reducing drug dosage in elders except [MAHE 2005]a. They are lean and their body mass is lessb. Have decreasing renal function with agec. Have increased baroreceptor sensitivityd. Body water is decreased

51. Drug distribution is infl uenced by [PGI JUN 2005]a. Drug binding b. Drug solubilityc. Degree of blood fl ow d. Age

52. Which of the following drugs is given by IV route? [POI JUN 2005]a. Heparin b. Pantoprazolec. Ranitidine d. Sumitriptane. Neomycin

53. What would be the maintenance dose for oral administration of a drug every 8 hours if the calculated dosing rate was 20 mg/hour and the bioavailability was 0.5? [MAHA 2005]a. 40 mg b. 75 mgc. 1l0 mg d. 320 mg

54. Side effects of a drug arise due to the interactions of the drug to molecules other than the target. These effects of a drug can be minimized by its high

[AIIMS Nov 2005)a. Specifi city b. Affi nityc. Solubility d. Hydrophobicity

55. Which of the following properties of drug will enable it to be used in low concentrations? [AIIMS NOV 2005]a. High affi nity b. High specifi cityc. Low specifi city d. High stability

56. A highly ionized drug [AJ 2005]a. Is excreted mainly by the kidneyb. Can cross the placental barrier easilyc. Is well absorbed from the intestined. Accumulates in the cellular lipids

57. When a drug is evaluated for its usefulness in controlled conditions, it is termed as a trial signifying? [AI 2006]a. Effi cacy b. Effectivenessc. Effi ciency d. Effect modifi cation

58. Cause for less bioavailability is [PGI JUN 2006]a. High fi rst-pass metabolismb. Increased absorptionc. IV drug administrationd. High solubility

59. Clearance [Karnataka PG MEE 2006]a. Refers to the effi cacy of elimination of a drug by an

organ or whole bodyb. Cannot be greater than blood fl ow to an organc. Determines the steadiness of the drug concentrationd. All the above

60. Ligand-gated ion channel is [PGMCET 2007]a. GABAA receptor b. GABAB receptorc. VIP receptor d. Somatostatin receptor

61. In case of drug that follows fi rst-order elimination [COMED 2008]a. The rate of elimination is constant b. The elimination half-life varies with dosec. The clearance varies with dose

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16 SMART STUDY SERIES: PHARMACOLOGY

d. The rate of elimination varies directly with dose62. All of the following have receptors which are tran-

scription factors except [AI 2007]a. Insulin b. Estrogenc. Glucocorticoids d. Vitamin D

63. Volume of distribution is affected by all except[UP 2007]

a. Binding to plasma protein b. Drug clearancec. Lipid insolubilityd. Absence of blood–brain barrier

64. Which of the following are prodrugs? [PGI 2003]a. Mercaptopurine b. Dipivefrinec. Enalapril d. Phenytoine. Linezolid

65. Which of the following is true about fi rst-pass metabolism? [PCI JUN 2008]a. Only seen in orally taking drugsb. High rectal administration, less fi rst-pass metabolismc. Vomiting affects fi rst-pass metabolismd. Affected by portal and gastrointestinal endotheliume. Prodrug has low fi rst-pass metabolism

66. Compliance of drug is increased by [PCI DEC 2008]a. Increased number of doseb. Increased duration of treatmentc. Past history of unpleasant events like Myocardial

infarctiond. Less frequent dosee. Involvement of family member

67. Absorption of drug in gut is decreased by[PGI DEC 2008]

a. Food b. Nonionized statec. First-pass metabolism d. Small size of particlee. Increased expression of -glycoprotein

68. Which of the following is/are true about competitive inhibition? [PGI JUN 2009]a. Raise Vmax and Kmb. Inhibitors bind to substance binding site on enzymec. Example is malonated. Inhibitors resemble structurally to the substance

69. Combination of ampicillin and gentamidn is an example of [COMED 2009]a. Indifference b. Synergyc. Antagonism d. Bacterial symbiosis

70. Clinically signifi cant drug interaction occurs between pyridoxine and all the following drugs except [Manipal 2009]a. Isoniazid b. Cyclosporinec. Levodopa d. Hydralazine

71. The effect of thiopentone on the CNS is quickly terminated because of

[Delhi PG MAR 2009]a. Rapid metabolism in the CNSb. Quick fi rst-pass eliminationc. Redistributiond. Rapid metabolism in systemic circulation

72. Acetyl salicylate and phenobarbitone are better absorbed from stomach because they are [PGI 1996]a. Weak acids remaining nonionic in gastric pHb. Weak acids remaining ionic in gastric pHc. Strong acids fully ionized in gastric pHd. Weak bases which are ionized at gastric pH

ANSWERS

Answer 1: d (The rate of elimination is proportional to the plasma concentration) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 31–32.

Answer 2: a (Target structure based) [Please refer text for details]

Reference: http://en.wikipedia.org/wiki/Drug_design

Answer 3: c (Conjugation) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 24–26.

Answer 4: d (Warfarin) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 35.

Answer 5: d (Saquinavir)

Saquinavir is the least potent inhibitor of CYP3A4 among the protease inhibitors.

References: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 31–32; Goodman & Gilman. The Pharmacological Basis of Therapeutics, 12th Ed., Pg. 1647.

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17GENERAL PHARMACOLOGY

Answer 6: c (Drug safety)

Pharmacovigilance has been defi ned by the WHO as the “science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems.” Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 79.

Answer 7: c (Causing effl ux of drug)Most ATP-binding cassettes (ABC) are primary active transporters, which rely on ATP hydrolysis to actively pump their �

substrates across membranes. Among the best recognized transporters in this group are P-glycoprotein, encoded by ABCB1 (also termed MDR1) and �

the cystic fi brosis transmembrane regulator (CFTR, encoded by ABCC7). Reference: Goodman & Gilman. The Pharmacological Basis of Therapeutics, 12th Ed., Pg. 89.

Answer 8: a (Lorazepam)Lorazepam is one of the active metabolites of diazepam � that is produced in the liver. It is metabolized only by conjugation. �

The other three drugs are extensively metabolized by liver � ; hence, warrant dose reduction in case of liver cirrhosis. Reference: Goodman & Gilman. The Pharmacological Basis of Therapeutics, 12th Ed., Pg. 463.

Answer 9: d (Metoclopramide) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 25.

Answer 10: a (Enalapril) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 24.

Answer 11: a (Volume of distribution) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 34.

Answer 12: a (Ketoconazole) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 27.

Answer 13: a (Preclinical trials) [Please refer text for details]

Reference: ICH Topic E 6 (R1) Guideline for Good Clinical Practice. European Medicines Agency.

Answer 14: a (Therapeutic effi cacy)The primary aim of phase II studies is the establishment of therapeutic effi cacy, dose range, and ceiling effect in a controlled setting. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 77.

Answer 15: a (Safety) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 54–55.

Answer 16: c (Potency) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 53–54.

Answer 17: a (Cytochrome oxidase) Cytochrome oxidase is a component of the electron transport chain. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 24–26.

Answer 18: a (Metformin) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 35.

Answer 19: c (Antagonist) Competitive antagonists have affi nity but no intrinsic activity (IA = 0), e.g., propranolol, atropine, chlorpheniramine, naloxone.

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18 SMART STUDY SERIES: PHARMACOLOGY

Affi nity Intrinsic activity

Agonist 1 1

Partial agonist 1 0 to 1

Antagonist 1 0

Inverse agonist 1 �1

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 42.

Answer 20: c (Conjugation) Synthetic/conjugation/phase II reactions: metabolite is mostly inactive; except few drugs, e.g., glucuronide conjugate of �

morphine and sulfate conjugate of minoxidil are active.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 24, 25.

Answer 21: a (Imipramine) and c (Lithium) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 35.

Answer 22: b (93%) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 32.

Answer 23: b (Proximal small intestine) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 16.

Answer 24: c (Verapamil) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 28.

Answer 25: a (Prevent fi rst-pass effect)

The chief advantage of sublingual route is that the liver is bypassed and drugs with high fi rst-pass metabolism can be �

absorbed directly into systemic circulation.However, the disadvantages are that it is not easy to administer, and the drug would have to be spit out if signs of toxicity �

occur.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 7.

Answer 26: c (Inactive drug which gets activated in the body) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 23.

Answer 27: c (Barbiturates) [Please refer text for details]

Some studies show that salicylates may show zero order kinetics.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 31.

Answer 28: c (Intravenous injection) and d (Intraarterial injection) Parenteral route of administration refers to administration by injection which takes the drug directly into the tissue fl uid �

or blood without having to cross the intestinal mucosa. The limitations of oral administration are circumvented. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 9, 28.

Answer 29: d (All of the above) [Please refer text for details]

The placenta does not strictly constitute a barrier, and any drug can cross it to a greater or lesser extent.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 84, 396.

Answer 30: d (Drug fever of sulfa) Dose-related adverse effect of sulphonamides includes crystalluria and hemolysis (in G-6-PD defi ciency). �

Drug fever of sulfa is an allergic reaction. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 684.

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19GENERAL PHARMACOLOGY

Answer 31: d (Creatinine clearance) Clearance of drugs that are primarily excreted unchanged (aminoglycosides, digoxin, phenobarbitone) is reduced parallel to decrease in creatinine clearance (CLcr).Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 66.

Answer 32: d (Dilantin) [Please refer text for details]Dilantin is a brand name of Phenytoin. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 25.

Answer 33: a (Phenytoin) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 31.

Answer 34: c (Narrow therapeutic range) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 35.

Answer 35: a (A genetically determined abnormal reaction to drugs) Idiosyncrasy is genetically determined abnormal reactivity to a chemical. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 81.

Answer 36: a (Lignocaine), b (Propranolol), c (Salbutamol) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 28.

Answer 37: c (Levodopa) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 15.

Answer 38: d (3) Let us calculate the plasma concentrations of the drug with a half-life of 2 hours at various time intervals –

Time Plasma concentration (g/mL)

0 96

2 48

4 24

6 12

8 6

10 3

Hence, the answer is 3 hours. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 32.

Answer 39: a (Passive diffusion) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 12.

Answer 40: b (The rate of absorption)

Bioavailability refers to the rate and extent of absorption of a drug from a dosage form as determined by its concentration–time curve in blood.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 17.

Answer 41: a (Gentamicin) and c (Phenacetin) Nephrotoxicity is an important adverse effect of aminoglycoside group, manifesting as tubular damage resulting in loss �

of urinary concentrating power, low g.f.r., nitrogen retention, albuminuria, and casts.Phenacetin introduced in 1887 was extensively used as analgesic–antipyretic, but is now banned because it was implicated �

in analgesic abuse nephropathy.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 198, 721.

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20 SMART STUDY SERIES: PHARMACOLOGY

Answer 42: a (Lithium), c (Phenytoin), and e (Tricyclic antidepressants) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 35.

Answer 43: b (Sulfonation), c (Methylation), and d (Glucouronidation) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 25-26.

Answer 44: b (Has affi nity as well as intrinsic activity) [Please refer Q. no. 19]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 42.

Answer 45: b (Log dose–response curve is sigmoid shaped)

Generally, the intensity of response increases with increase in dose (or more precisely concentration at the receptor) and �

the dose–response curve is a rectangular hyperbola.If the dose is plotted on a logarithmic scale, the curve becomes sigmoid. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 53.

Answer 46: a (Best absorbed in acidic medium) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 13.

Answer 47: c (Barbiturate) Hemodialysis and hemoperfusion (through a column of activated charcoal or other adsorbents) is highly effective only �

for drugs with a Vd of ≤ 5L. Hence it is useful for removing long-acting as well as short-acting barbiturates which are restricted to the vascular �

compartment. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 392.

Answer 48: d (Phase IV) Phase IV/postmarketing surveillance: After the drug has been marketed for general use, practicing physicians are identifi ed through whom data are collected on a structured proforma about the effi cacy, acceptability, and adverse effects of the drug. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 77.

Answer 49: c (Physiological antagonism) Physiological/functional antagonism: the two drugs act on different receptors or by different mechanisms, but have �

opposite overt effects on the same physiological function, i.e., have pharmacological effects in opposite direction.Pharmacological antagonism: Two substances have opposite effects due to action on the same receptors. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 56, 216-217.

Answer 50: c (Have increased baroreceptor sensitivity)Dosages of drugs need to be decreased in the elderly because of

Progressive decline in renal function � → Reduced renal clearance of drugsReduced hepatic microsomal enzyme activity and hepatic blood fl ow �

Decreased plasma protein levels → Increase in the levels of free forms of drugs �

Decrease in lean body mass → Decrease in total body water �

Decreased response of receptors to drugs �

Presence of other diseases/comorbid conditions �

Intake of multiple medications �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 62.

Answer 51: a (Drug binding), b (Drug solubility), and c (Degree of blood fl ow), and d (Age) Factors governing volume of drug distribution include

lipid: water partition coeffi cient of the drug �

pKa (negative logarithm of acidic dissociation constant of the weak electrolyte) value of the drug �

degree of plasma protein binding �

affi nity for different tissues �

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21GENERAL PHARMACOLOGY

blood fl ow to various organs �

fat (lean body mass ratio, which can vary with � age, sex, obesity, etc.) and diseases like conjestive heart failure (CHF), uremia, cirrhosis. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 19.

Answer 52: a (Heparin), b (Pantoprazole), and c (Ranitidine)Heparin is a large, highly ionized molecule, therefore not absorbed orally.Pantoprazole is also available for i.v. administration.Ranitidine is given by i.v. infusion for prophylaxis of stress ulcers.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 598, 630, 633.

Answer 53: d (320 mg) Maintenance dose rate is computed by the equationDose rate = Target Cpss × CL/FCpss = Steady-state plasma concentrationCL = ClearanceF = Bioavailability

∴ Maintenance dose = 20 mg/hour

0.5 = 40 mg/hour = 40 × 8 mg on 8 hours = 320 mg.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 34.

Answer 54: a (Specifi city) Drugs seldom produce just one action; the Dose–Response Curve (DRC) for different effects of a drug may be different. The extent of separation of DRCs of a drug for different effects is a measure of its selectivity.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 54.

Answer 55: a (High affi nity) The dose of a drug is governed by its inherent potency, i.e., the concentration at which it should be present at the target site and its pharmacokinetics characteristics.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 59.

Answer 56: a (Is excreted mainly by the kidney) Nonlipid soluble drugs are highly ionized drugs and are unable to diffuse back in tubules. Thus, rate of excretion of such drugs, e.g., aminoglycoside antibiotics, quaternary ammonium compounds parallels g.f.r. (or creatinine clearance).Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 30.

Answer 57: a (Effi cacy) Healthy volunteers may be used to determine pharmacokinetic characteristics, tolerability, safety, and for certain type of drugs even effi cacy.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 71.

Answer 58: a (High fi rst-pass metabolism) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 17.

Answer 59: d (All of the above) The clearance of a drug is the theoretical volume of plasma from which the drug is completely removed in unit time (analogy creatinine clearance).

Drug is eliminated only from the central compartment (blood).Cpss (steady state plasma concentration) of a drug attained in a given patient depends on its F (bioavailability), V (volume

of distribution), and CL (clearance) in that patient.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 31, 34.

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22 SMART STUDY SERIES: PHARMACOLOGY

Answer 60: a (GABAA receptor)Receptors which function as ion channels

Nicotinic cholinergic �

GABA � AGlycine (inhibitory) �

Excitatory AA (kainate, NMDA or N-methyl- � D-aspartate, quisqualate) and 5-HT3 receptors �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 48.

Answer 61: d (The rate of elimination varies directly with dose) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 31.

Answer 62: a (Insulin) Hormones with nuclear receptors

Estrogen �

Vitamin D �

Vitamin A �

Thyroxine �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 50.

Answer 63: d (Absence of blood–brain barrier) [Please refer Q no. 51]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 19.

Answer 64: a (Mercaptopurine), b (Dipivefrine), and c (Enalapril) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 24.

Answer 65: d (Affected by portal and gastrointestinal endothelium) and e (Prodrug has low fi rst-pass metabolism) All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall and liver (where they reach �

through portal vein).Prodrug may offer advantages over the active form in being more stable, having better bioavailability, etc. �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 23, 28.

Answer 66: d (Less frequent dose) and e (Involvement of family member] If a drug acts for a longer period, then it improves patient compliance a single morning dose is less likely to be forgotten/omitted than a 6 or 8 hourly regimen.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 35.

Answer 67: a (Food) and e (Increased expression of P-glycoprotein) Presence of food dilutes the drug and retards absorption. Hence, most drugs are absorbed better if taken in empty �

stomach.The oral absorption of certain drugs is low because a fraction of the absorbed drug is extruded back into the intestinal �

lumen by the effl ux transporter P-glycoprotein located in the gut epithelium.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 16.

Answer 68: b (Inhibitors bind to substance binding site on enzyme), c (Example is malonate), and d (Inhibitors resemble structurally to the substance)

Competitive (equilibrium type) inhibition: The drug being structurally similar competes with the normal substrate for the catalytic binding site of the enzyme so that �

the product is not formed or a nonfunctional product is formed. Such inhibitors increase the Km but the Vmax remains unchanged �

In nonequilibrium type, Km is unchanged and Vmax is reduced �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 39.

Answer 69: b (Synergy)

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23GENERAL PHARMACOLOGY

When the action of one drug is facilitated or increased by the other, they are said to be synergistic. In a synergistic pair, both the drugs can have action in the same direction or given alone, one may be inactive but still

enhance the action of the other when given together.E.g., of antimicrobial drug synergism –

Sulfonamide + Trimethoprim to prepare cotrimoxazole �

Penicillin/Ampicillin + Streptomycin/Gentamicin for SABE �

Carbenicillin/Ticarcillin + Gentamicin for � PseudomonasCeftazidime + Ciprofl oxacin for � PseudomonasIsoniazid + Rifampicin for tuberculosis �

Amphotericin- B + 5-FC for cryptococcal meningitis �

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 55-56.

Answer 70: b (Cyclosporine) Isoniazid reacts with pyridoxal to form a hydrazone and thus inhibits generation of pyridoxal phosphate. �

Hydralazine, cycloserine, and penicillamine also interfere with pyridoxine utilization and action. �

Pyridoxine, by promoting formation of dopamine from levodopa in peripheral tissues, reduces its availability in the brain, �

abolishing the therapeutic effect in Parkinsonism.Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 876.

Answer 71: c (Redistribution) [Please refer text for details]Anesthetic action of thiopentone sodium injected i.v. is terminated in few minutes due to redistribution. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 19.

Answer 72: a (Weak acids remaining nonionic in gastric pH) [Please refer text for details]

Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 13.

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