Sample Chapter Smart Study Series Pharmacology, 2e by Krishnamurthy To Order Call Sms at +91 8527622422

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  • 1. 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 The dissociated forms are not lipophilic, hence, reabsorption is less 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 10/30/2012 11:29:08 AM
  • 2. 2 SMART STUDY SERIES: PHARMACOLOGY 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, Neostigmine Drug is susceptible to gastric acid; i.e., it is acid labile, so it is broken down by gastric acid. E.g., Penicillin G, Erythromycin Drug is cleaved by proteases in the GIT E.g., Insulin, Oxytocin [Note: Drugs can be protected from gastric acid by Enteric coating] Drug Reservoir Drug Core Enteric (acid-resistant) Semipermeable coating membrane (a) (b) (a) The drug is coated with an acid–resistant coat, which (b) The reservoir is impregnated with the drug which gradually protects it from gastric acid. 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 interactionChapter-01.indd 2 10/30/2012 11:29:09 AM
  • 3. GENERAL PHARMACOLOGY 3 Effect of food on absorption Food increases the absorption of Food decreases the absorption of • Carbamazepine • Ampicillin • Chloroquine • Aspirin • Griseofulvin • Captopril • Lithium • Digoxin • Nitrofurantoin • Isoniazid • Riboflavin • Levodopa • Spironolactone • 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 intestine Drug 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) • Propranolol (MCQ 36) • Morphine • Isoprenaline • Testosterone • Alprenolol • Pethidine • Salbutamol (MCQ 36) • Methyltestosterone • Verapamil (MCQ 24) • Propoxyphene • Nitroglycerin 1.1.2: DISTRIBUTION Redistribution Upon administration, the drug is first distributed to organs with a high blood flow, 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 flow 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. Dose administered Vd = Plasma concentration Condition Vd Examples Drug is highly bound to plasma proteins = Plasma volume • Warfarin = ~3 L • Phenylbutazone Drug is bulky and remains in the vascular compartment = Blood volume • Heparin = ~5 L • Streptokinase Drug is lipid soluble and is distributed throughout the ECF = ECF volume • Streptomycin = ~15 L • 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 • ChloroquineChapter-01.indd 3 10/30/2012 11:29:09 AM
  • 4. 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 L Plasma protein binding A 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 • In case of acute inflammatory states, α1 acid glycoprotein decrease levels increase • Hence, bound form of the drug decreases • Hence, bound form of the drug increases • Therefore, free form of the drug increases • Therefore, free form of the drug decreases • So, there is increased risk of toxicity • So, there is reduced effect of the drug • Hence, dose of drug needs to be decreased • 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) Digoxin Lithium (MCQ 4, 21, 42) Antiarrhythmics Aminoglycosides (MCQ 4) Theophylline 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 definition, is inactive by itself, and needs to be converted to an active metabolite. (MCQ 26) Examples of prodrugs:Chapter-01.indd 4 10/30/2012 11:29:09 AM
  • 5. GENERAL PHARMACOLOGY 5 Prodrug Active metabolite Acyclovir Acyclovir triphosphate Bacampicillin Ampicillin Cyclophosphamide Aldophosphamide, Phosphoramide mustard, Acrolein Dipivefrin (MCQ 64) Epinephrine (MCQ 10, 64) Enalapril 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 Sulfide 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) • Glucuronidation (MCQ 43) (Most common) • Reduction (MCQ 3) • Acetylation • Cyclization • Methylation (MCQ 43) • Decyclization • Sulfation (MCQ 43) • Hydrolysis (MCQ 3) • 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) (MCQ 9,32) Hydralazine PAS Isoniazid (MCQ 9,32) Clonazepam Drugs are mainly metabolized in the liver by cytochromal enzymes. Enzymes of the cytochromal system and drugs metabolized by them:Chapter-01.indd 5 10/30/2012 11:29:09 AM
  • 6. 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 (MCQ 12) • Rifampicin • Erythromycin (MCQ 5) • Griseofulvin • Clarithromycin • All antiepileptics except valproate(MCQ 12) • Ketoconazole (MCQ 12) • Polycyclic hydrocarbons (CYP1A1/2) • Itraconazole (MCQ 5) • Cigarette smoke (CYP1A1/2) • Verapamil • Alcohol (CYP2E1) • Diltiazem • INH (CYP2E1)(MCQ 12) • 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: ELIMINATION Renal 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 (MCQ 27) • Alcohol • 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 Constant (independent of plasma concentration of of the drug (MCQ 1, 61) the drug)(MCQ 1) 3. Clearance Constant (MCQ 61) Decreases with increase in dose (MCQ 61) 4. Half-life Constant Increases with increase in dose (MCQ 1)Chapter-01.indd 6 10/30/2012 11:29:09 AM
  • 7. GENERAL PHARMACOLOGY 7 Clearance: The volume of plasma that is cleared of the drug in unit time. Mathematically, denoted by UV CL = P where, U = Concentration of drug in urine V = Urine flow 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, 0.693 T½ = k where k = Elimination rate constant. It is defined as the fraction of total amount of drug in plasma that is eliminated in unit time. Therefore, CL k= Vd Therefore, CL 0.693 × Vd T½ = 0.693 ÷ = 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 significant. 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. Cp × Vd Loading dose = F Therefore, loading dose depends upon volume of distribution (MCQ 11) Cp × CL Maintenance dose = F Therefore, 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.Chapter-01.indd 7 10/30/2012 11:29:10 AM
  • 8. 8 SMART STUDY SERIES: PHARMACOLOGY y y Response Response x x Dose Dose (a) (b) (a) Dose–response curve. (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. Efficacy 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. Efficacy: The maximum response achieved by the drug. Therefore, greater the maximum response achieved by a drug, greater the efficacy of the drug. Y B B A A Response X Log dose A B Fig. 1.3: Comparison between potency and efficacy of two drugs: A and B. Note: In the above figure, A is more potent, but B is more efficacious. In the above figure, drug A is more potent while B is more efficacious. In a clinical scenario, a drug is selected on the basis of its efficacy. E.g., 1. Aspirin is less potent and less efficacious than morphine. Hence, morphine is preferred as an analgesic over aspirin for most clinical conditions. 2. Pethidine is less potent but equally efficacious than morphine. Hence, morphine is preferred as an opioid analgesic over pethidine. 3. Furosemide is less potent but more efficacious 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 first action. Hence, the drug is said to be nonselective or nonspecific. E.g., Propranolol in a nonselective β-blocker.Chapter-01.indd 8 10/30/2012 11:29:10 AM
  • 9. GENERAL PHARMACOLOGY 9 2 y y 2 1 1 Response Response x x Log dose Log dose (a) (b) (a) As the curves for effects (1) and (2) of the drug “A” are (b) As the curves for effects (1) and (2) of the drug “B” are far close to each other, the drug is nonselective. 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 first action. Hence, the drug is said to be selective or specific for that particular action. E.g., Metoprolol is selective for β-1 blockade. Considering the therapeutic and toxic actions of a drug, y y Rx effect Rx effect Toxic effect Toxic effect Response Response x x Log dose Log dose (a) (b) (a) As the curves for therapeutic and toxic effects of the drug (b) As the curves for therapeutic and toxic effects of the drug “B” “A” are close to each other, the drug is unsafe. 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.Chapter-01.indd 9 10/30/2012 11:29:10 AM
  • 10. 10 SMART STUDY SERIES: PHARMACOLOGY 1.2.2: QUANTAL DOSE–RESPONSE CURVE Estimates 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 100% Percentage of population showing response 50% 0% y ED 50 LD 50 Dose 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 definition, 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 ED50 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, ED50 denotes Potency. (MCQ 16)Chapter-01.indd 10 10/30/2012 11:29:10 AM
  • 11. GENERAL PHARMACOLOGY 11 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, LD50 is preferred over TD50. By definition, 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 LD50 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, LD50 denotes Safety. (MCQ 15) 3. Therapeutic range A drug can be administered in the dose range between the minimum effective dose and maximum acceptable dose in the community. Therefore, therapeutic range = ED50 – LD50 If the ED50 and LD50 are far away from each other, the drug can be safely administered over a wider range. On the other hand, if ED50 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 index Therapeutic index (TI) = LD50/ED50 For 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 • Pharmacokinetics (predominantly bioavailability) healthy volunteers) Done only in specific cases I Small group of healthy volunteers • Safety • Pharmacokinetics • Pharmacodynamics II Small group of patients • Safety • Efficacy (MCQ 14) III Large group of patients • Safety • Efficacy 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.Chapter-01.indd 11 10/30/2012 11:29:10 AM
  • 12. 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 significance 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 profile 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) Target Designed complementary ligand 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 modifications 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 modification 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 identified from the group of potential ligands.Chapter-01.indd 12 10/30/2012 11:29:10 AM
  • 13. GENERAL PHARMACOLOGY 13 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 identified. These are known as “leads.” This process is known as “lead identification.” LEAD OPTIMIZATION: Once the leads are identified, 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 first-order kinetics is [AIIMS MAY 2012] 8. All of the following drugs require dose reduction in a. A constant amount is eliminated in unit time cirrhosis of liver except [AIIMS NOV 2008] b. The half-life increases with an increase in dose a. Lorazepam b. Diazepam c. The rate of elimination is constant c. Metronidazole d. Rifampicin d. The rate of elimination is proportional to the plasma 9. Which of the following drugs is not acetylated? concentration [AIIMS MAY 2008] 2. Nowadays, the method used for drug designing/drug a. INH b. Dapsone discovery is [AI 2012] c. Hydralazine d. Metoclopramide a. Target structure based 10. Which of the following is a prodrug? b. Hit and trial method [AIIMS MAY 2008] c. Molecular modeling way a. Enalapril b. Clonidine d. High-throughput method c. Salmeterol d. Acetazolamide 3. In metabolism of xenobiotics, all of the following 11. Loading dose of a drug depends upon reactions occur in phase I except [AIIMS MAY 2008] (AI 2012, AIIMS NOV 2008) a. Volume of distribution b. Clearance a. Oxidation b. Reduction c. Rate of administration d. Half-life c. Conjugation d. Hydrolysis 12. Which of these is a CYP450 inhibitor? 4. Monitoring of the plasma levels is done for all of the [AIIMS MAY 2008] following drugs except [AI 2012] a. Ketoconazole b. Rifampicin a. Lithium b. Cyclosporine c. Phenytoin d. INH c. Gentamicin d. Warfarin 13. Good clinical practices (GCPs) are seen in all of the 5. All of the following drugs are CYP3A inhibitors following except [AIIMS NOV 2007] except [AIIMS MAY 2010] a. Preclinical trials b. Phase I trials a. Erythromycin b. Itraconazole c. Phase II trials d. Phase IV trials c. Ritonavir d. Saquinavir 14. Phase II in a clinical trial is done to assess [AI 2008] 6. Pharmacovigilance is done for the monitoring of a. Therapeutic efficacy [AIIMS MAY 2009, 2010] b. Maximal tolerated dose a. Drug price c. Maximal lethal dose b. Unethical practices d. Toxicity c. Drug safety 15. Therapeutic index is a measure of a drug’s [AI 2008] d. Pharmacy students a. Safety b. Potency 7. MDR gene acts by [AIIMS MAY 2009] c. Efficacy d. Toxicity a. Blocking drug activation 16. ED50 is a measure of [AI 08] b. Blocking intracellular DNA synthesis a. Toxicity b. Safety c. Causing efflux of drug c. Potency d. Efficacy d. DNA repair inhibitionChapter-01.indd 13 10/30/2012 11:29:10 AM
  • 14. 14 SMART STUDY SERIES: PHARMACOLOGY 17. All of the following enzymes and their reactions are 29. Drug which crosses the placental barrier is involved in the metabolism of xenobiotics except [Delhi, 1992] [AI 2008] a. Phenytoin b. Diazepam a. Cytochrome oxidase b. Cytochrome P450 c. Corticosteroids d. All of the above c. Methylation d. Hydroxylation 30. Which of the following is not a dose-related reaction? 18. Therapeutic drug monitoring is advised in all of the [JIPMER 1992] following except [AIIMS NOV 2007] a. Myocardial irritation of quinidine a. Metformin b. Phenytoin b. Hypoglycemia of tolbutamide c. Tacrolimus d. Cyclosporine c. Digitalis-induced arrythmia 19. A substance having affinity but no instrinsic activity d. Drug fever of sulfa is [Delhi 1988, 1990] 31. The dosage of drugs in renal disease should be a. Agonist b. Partial agonist changed based on [PGI 1980] c. Antagonist d. Physiological antagonist a. Urine output b. Blood urea 20. Detoxification or protective synthesis occurs by c. Serum creatinine d. Creatinine clearance [AIIMS 1984] 32. All of the following drugs are metabolized in body by a. Oxidation b. Reduction acetylation except [AI 1996] c. Conjugation d. All of the above a. INH b. Hydralazine 21. Estimation of serum levels is essential in treatment c. Procainamide d. Dilantin with [AIIMS 1982] 33. Zero-order kinetics is seen with [All India 1996] a. Imipramine b. Chlorpromazine a. Phenytoin b. Phenobarbitone c. Lithium d. Haloperidol c. Erythromycin d. Digoxin 22. Elimination after 4 half-lives in first-order kinetics is 34. Most common indication for therapeutic monitoring [AI 1989] of plasma levels of a drug is [AI 1996] a. 84% b. 93% a. Hit and run drugs c. 80.5% d. 4.75% b. Drugs with irreversible action 23. The alkaline drug (amidopyrine) is absorbed from c. Narrow therapeutic range [Al 1991] d. Failure of response a. Stomach b. Proximal small intestine 35. Idiosyncrasy is [Karnataka 1996] c. Distal small intestine d. Colon a. A genetically determined abnormal reaction to drugs 24. Which drug has a high first-pass effect? b. A characteristic toxic effect at therapeutic doses [JIPMER 1991] c. An altered physiological state produced by repeated a. Amiodarone b. Phenytoin drug use c. Verapamil d. Disopyramide d. An immunologically mediated reaction 25. What is the advantage of sublingual route of admin- 36. First-pass metabolism is seen in [PGI 2003] istration of drugs? [JIPMER 1991] a. Lignocaine b. Propranolol a. Prevents first-pass effect c. Salbutamol d. Dipyridamol b. Easy to administer e. Erythromycin c. Lipid soluble 37. Drugs absorbed by active transport is [NIMS 1996] d. Can be spitted out with signs of toxicity a. Propranolol b. Ergotamine 26. What is a prodrug? [JIPMER 1992] c. Levodopa d. Amantadine a. Drug which increases efficiency of another drug 38. Plasma concentration of drug at time 0 is 96 gml. If b. Metabolic end product tI/2 is 2 hours, concentration in plasma at 10 hours will c. Inactive drug which gets activated in the body be [MAHE 1998] d. Drug which competes with another for metabolism a. 48 b. 24 27. Zero-order kinetics is seen in all of the following c. 12 d. 3 except [PGI 1993] 39. Drugs mostly cross biological membranes by a. Salicylate b. Phenytoin [Rohtak 1998] c. Barbiturates d. Ethanol a. Passive diffusion 28. Which of the following avoids first-pass effect of b. Active diffusion drugs? [JIPMER 1993] c. Active transport a. Oral ingestion b. Rectal suppository d. Carrier-mediated transport c. Intravenous injection d. Intraarterial injection e. All of the aboveChapter-01.indd 14 10/30/2012 11:29:10 AM
  • 15. GENERAL PHARMACOLOGY 15 40. Time for peak plasma concentration (Tmax) indicates 51. Drug distribution is influenced by [PGI JUN 2005] [Karnataka 2001] a. Drug binding b. Drug solubility a. The rate of elimination b. The rate of absorption c. Degree of blood flow d. Age c. The onset of effect d. The intensity of effect 52. Which of the following drugs is given by IV route? 41. Drug(s) causing nephrotoxicity is/are [PGI 2002] [POI JUN 2005] a. Gentamicin b. Cloxacillin a. Heparin b. Pantoprazole c. Phenacetin d. Erythromycin c. Ranitidine d. Sumitriptan 42. Low theraputic range is seen in [PGI 2002] e. Neomycin a. Lithium b. Erythromycin 53. What would be the maintenance dose for oral c. Phenytoin d. Propranolol administration of a drug every 8 hours if the calculated e. Tricyclic antidepressants dosing rate was 20 mg/hour and the bioavailability 43. In hepatic metabolism, phase II reactions are was 0.5? [MAHA 2005] [PGI 2002] a. 40 mg b. 75 mg a. Dealkylation b. Sulfonation c. 1l0 mg d. 320 mg c. Methylation d. Glucuronization 54. Side effects of a drug arise due to the interactions of e. Deamination the drug to molecules other than the target. These 44. Characteristic feature of agonist is [PGI 1999] effects of a drug can be minimized by its high a. Has affinity only [AIIMS Nov 2005) b. Has affinity as well as intrinsic activity a. Specificity b. Affinity c. Has intrinsic activity only c. Solubility d. Hydrophobicity d. Neither has affinity nor activity 55. Which of the following properties of drug will enable 45. Which of the following is true about dose–response it to be used in low concentrations? [AIIMS NOV 2005] curve? [PGI 1999] a. High affinity b. High specificity a. Cannot determine the potency of a drug c. Low specificity d. High stability b. Log dose–response curve is sigmoid shaped 56. A highly ionized drug [AJ 2005] c. Cannot find response to antagonist a. Is excreted mainly by the kidney d. A wide range of doses can not be plotted b. Can cross the placental barrier easily 46. Which of the following is true about acidic drugs? c. Is well absorbed from the intestine [PGI 1997] d. Accumulates in the cellular lipids a. Best absorbed in acidic medium 57. When a drug is evaluated for its usefulness in b. Best absorbed in alkaline medium controlled conditions, it is termed as a trial signifying? c. Not absorbed in acidic medium [AI 2006] d. Binds to α-glycoprotein a. Efficacy b. Effectiveness 47. In which one of the following drugs overdosages is c. Efficiency d. Effect modification hemodialysis useful? [UPSC 2002] 58. Cause for less bioavailability is [PGI JUN 2006] a. Digoxin b. Paracetamol a. High first-pass metabolism c. Barbiturate d. Diazepam b. Increased absorption 48. In which of the following phases of clinical trial of c. IV drug administration drug, ethical clearance is not required? [AI 2004] d. High solubility a. Phase I b. Phase II 59. Clearance [Karnataka PG MEE 2006] c. Phase III d. Phase IV a. Refers to the efficacy of elimination of a drug by an 49. The antagonism of leukotriene by terbutaline is an organ or whole body example of [COMED 2005] b. Cannot be greater than blood flow to an organ a. Pharmacological antagonism c. Determines the steadiness of the drug concentration b. Physical antagonism d. All the above c. Physiological antagonism 60. Ligand-gated ion channel is [PGMCET 2007] d. Chemical antagonism a. GABAA receptor b. GABAB receptor 50. All of the following are reasons for reducing drug c. VIP receptor d. Somatostatin receptor dosage in elders except [MAHE 2005] 61. In case of drug that follows first-order elimination a. They are lean and their body mass is less [COMED 2008] b. Have decreasing renal function with age a. The rate of elimination is constant c. Have increased baroreceptor sensitivity b. The elimination half-life varies with dose d. Body water is decreased c. The clearance varies with doseChapter-01.indd 15 10/30/2012 11:29:10 AM
  • 16. 16 SMART STUDY SERIES: PHARMACOLOGY d. The rate of elimination varies directly with dose a. Food b. Nonionized state 62. All of the following have receptors which are tran- c. First-pass metabolism d. Small size of particle scription factors except [AI 2007] e. Increased expression of -glycoprotein a. Insulin b. Estrogen 68. Which of the following is/are true about competitive c. Glucocorticoids d. Vitamin D inhibition? [PGI JUN 2009] 63. Volume of distribution is affected by all except a. Raise Vmax and Km [UP 2007] b. Inhibitors bind to substance binding site on enzyme a. Binding to plasma protein c. Example is malonate b. Drug clearance d. Inhibitors resemble structurally to the substance c. Lipid insolubility 69. Combination of ampicillin and gentamidn is an d. Absence of blood–brain barrier example of [COMED 2009] 64. Which of the following are prodrugs? [PGI 2003] a. Indifference b. Synergy a. Mercaptopurine b. Dipivefrine c. Antagonism d. Bacterial symbiosis c. Enalapril d. Phenytoin 70. Clinically significant drug interaction occurs between e. Linezolid pyridoxine and all the following drugs except 65. Which of the following is true about first-pass [Manipal 2009] metabolism? [PCI JUN 2008] a. Isoniazid b. Cyclosporine a. Only seen in orally taking drugs c. Levodopa d. Hydralazine b. High rectal administration, less first-pass metabolism 71. The effect of thiopentone on the CNS is quickly c. Vomiting affects first-pass metabolism terminated because of d. Affected by portal and gastrointestinal endothelium [Delhi PG MAR 2009] e. Prodrug has low first-pass metabolism a. Rapid metabolism in the CNS 66. Compliance of drug is increased by [PCI DEC 2008] b. Quick first-pass elimination a. Increased number of dose c. Redistribution b. Increased duration of treatment d. Rapid metabolism in systemic circulation c. Past history of unpleasant events like Myocardial 72. Acetyl salicylate and phenobarbitone are better infarction absorbed from stomach because they are [PGI 1996] d. Less frequent dose a. Weak acids remaining nonionic in gastric pH e. Involvement of family member b. Weak acids remaining ionic in gastric pH 67. Absorption of drug in gut is decreased by c. Strong acids fully ionized in gastric pH [PGI DEC 2008] d. 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.Chapter-01.indd 16 10/30/2012 11:29:10 AM
  • 17. GENERAL PHARMACOLOGY 17 Answer 6: c (Drug safety) Pharmacovigilance has been defined 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 efflux 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 fibrosis 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 efficacy) The primary aim of phase II studies is the establishment of therapeutic efficacy, 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 affinity but no intrinsic activity (IA = 0), e.g., propranolol, atropine, chlorpheniramine, naloxone.Chapter-01.indd 17 10/30/2012 11:29:10 AM
  • 18. 18 SMART STUDY SERIES: PHARMACOLOGY Affinity 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 first-pass effect) The chief advantage of sublingual route is that the liver is bypassed and drugs with high first-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 fluid 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 deficiency). Drug fever of sulfa is an allergic reaction. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 684.Chapter-01.indd 18 10/30/2012 11:29:10 AM
  • 19. GENERAL PHARMACOLOGY 19 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.Chapter-01.indd 19 10/30/2012 11:29:11 AM
  • 20. 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 affinity 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 identified through whom data are collected on a structured proforma about the efficacy, 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 drugs Reduced hepatic microsomal enzyme activity and hepatic blood flow 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 flow), and d (Age) Factors governing volume of drug distribution include lipid: water partition coefficient of the drug pKa (negative logarithm of acidic dissociation constant of the weak electrolyte) value of the drug degree of plasma protein binding affinity for different tissuesChapter-01.indd 20 10/30/2012 11:29:11 AM
  • 21. GENERAL PHARMACOLOGY 21 blood flow 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 equation Dose rate = Target Cpss × CL/F Cpss = Steady-state plasma concentration CL = Clearance F = Bioavailability 20 mg/hour ∴ Maintenance dose = 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 (Specificity) 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 affinity) 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 (Efficacy) Healthy volunteers may be used to determine pharmacokinetic characteristics, tolerability, safety, and for certain type of drugs even efficacy. Reference: Tripathi. Essentials of Medical Pharmacology, 6th Ed., Pg. 71. Answer 58: a (High first-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.Chapter-01.indd 21 10/30/2012 11:29:11 AM
  • 22. 22 SMART STUDY SERIES: PHARMACOLOGY Answer 60: a (GABAA receptor) Receptors which function as ion channels Nicotinic cholinergic GABAA Glycine (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 first-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 efflux 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)Chapter-01.indd 22 10/30/2012 11:29:11 AM
  • 23. GENERAL PHARMACOLOGY 23 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 Pseudomonas Ceftazidime + Ciprofloxacin for Pseudomonas Isoniazid + 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.Chapter-01.indd 23 10/30/2012 11:29:11 AM