Self Assessment and Review Pharmacology Hira Bhalla, Yogesh Gulati, Deepak Mishra
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General PharmacologyChapter 1

All India
2008–1995
AIIMS
2008–1995
PGI
2007–1997
Chapter Review
2008–1990
Rising Topic
Questions
Answers
References
Explanation
23
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PHARMACODYNAMICS : Pharmacodynamics refers to the action of the drug at the cellular level. The binding of a drug to its receptor or binding site, the relationship of dose and therapeutic level to the physiologic response, and the relationship of drug action and efficacy to dosage interval.
TARGETS FOR DRUG ACTION (Most drug targets are proteins)
Receptors : Sensing elements of chemical communication that coordinates the overall function of the body. The majority of drug receptors are regulatory proteins. The classification includes:
  1. Extracellular receptors, which work through a second messenger E.g. Muscarinic and Nicotinic receptors
  2. Intracellular receptors, which alter gene expression by altering the configuration of structural proteins regulating DNA transcription.
Other targets include:
Ion channels
Enzymes
Carriers
Cl GABA
Acetylcholinesterase
Choline Carrier
Hemicholinium
Na+ – Antiarrhythmics
Tyrosine kinase
Noradrenaline uptake 1
TCA, Cocaine
K+ channels
MAO, DHFR,
Na+ / K+/Cl co transporter
Loop diuretics
Ca++
H+ / K+ ATPase,
Serotonin Re-uptake
SSRIs
Na+ / K+ ATPase etc.
COX, Thymidine kinase (Acyclovir),
Reverse transcriptase
Molecules such as enzymes, transport proteins or structural proteins (e.g., histone, tubulin) may also be classified as drug targets:
  • Structural proteins (Tubulin, Vinca alkaloids, and Colchicine)
  • DNA : Alkylating agents
  • Immunophylins : Cyclosporine, FK-506 (Sirolimus)
  • Therapeutic antibodies e.g. Abciximab / Adalimumab
  • Cell wall constituentsAntibiotics – Penicillins / Cephalosporins / Amphotericin-B
Other non-proteins:
• Digitalis
– Digibind (antibody)
• Metals
– Chelating agents
• HCl
– Oral antacids
 
TRANSDUCER MECHANISMS
SIGNAL TRANSDUCTION : The processes which take place between Drug-receptors interactions and the effect at cellular level.4
Depending upon the molecular structure and nature of the linkage, 4 different receptor super families are identified:
  1. Ligand Gated Ion-channel receptor (Inotropic – located in the neurons)
    • – Receptors are directly linked to an ion-channel without the intervention of second messenger
    • – Drug – Receptor interaction → Depolarization / Hyperpolarization ? of cell Effect (milliseconds)
      E.g. :
      INHIBITORY
      EXCITATORY
      – Nicotinic cholinergic
      – Kainate
      – GABAA
      – NMDA
      – Glycine
      – Aspartate
      – Glutamate
      – 5-HT3
      MOA : Once the ligand binds to the receptor, there is opening of ion-channel, thus causing inflow / outflow of ions (depending upon the nature of channel).
    • Important for moment-to-moment transfer of information across the synapses.
  2. G – Protein coupled Receptor (they interact with GTP & GDP; also called as metabotropic or transmembrane spanning receptors)
    Examples of GPCR: Muscarinic, Adrenergic, Dopaminergic, 5-HT (except 5-HT3), Opioids, Odorant etc.
    • Most abundant type of receptors
    • All are single polypeptide chains having GTPase activity
    Three major effectors pathways:
    1. Adenylyl cyclase cAMP pathway
    2. Channel regulation Ca++, Na+, K+
    3. Phospholipase C: IP3- DAG pathway
    • Activated G : Protein then changes the concentration of second messenger, cAMP, Calcium, PIP.
      Several kinds of G – proteins are described.
      Gs-
      Gi-
      Adenylyl cyclase → ↑ cAMP
      adenylyl cyclase – ↓ cAMP
      Examples:
      β adrenergic amines
      α – adrenergic
      Glucagon
      Muscarinic (M2)
      Histamine
      Opioids
      Gt-
      Gq-
      cGMP Phosphodiesterase → ↓cGMP
      ↑ PLC ↑ IP3, DAG, Ca++
      Examples:
      photons (on Retinal Rods and Cones)
      5 HTIC, M3 Acetylcholine
  3. Enzyme linked Receptor (cytokine receptors)
    • Membrane bound receptors one extra-cellular and the other intracellular terminal
    • The Intracellular terminal binds to a kinase and activates it when binds to a ligand
    • Kinases are mainly involved in cell growth and differentiation
    • Two important effector pathways include:
      • – Ras / Raf / MAP kinase pathway – involved in cell growth, division and differentiation
      • – JAK / STAT pathway activated by cytokines involved in control and synthesis of many inflammatory mediators
        Eg: Growth Hormone, erythropoietin, IFNs, Insulin, ANP, cytokines, EGF
  4. Nuclear Receptors
    Receptor mediated DNA transcription
    Eg: Glucocorticoids, mineralocorticoids, sex – steroids, Vit. A, retinoic acid, Vit. D, glilazones, fibrates etc.5
    • – Receptors are intranuclear (except steroids which are cytoplasmic)
    • – The ligand enters the cell to bind to receptor to form complex
    • – Receptor ligand complex cause gene transcription causing protein synthesis
      E.g. :
      – Glucocorticoids → Lipocortin
      – Mineralocorticoids – water channel proteins and other transport proteins
      – Retinoic acid → regulates protein synthesis during fetal life
 
DRUG – RECEPTOR INTERACTIONS
Agonist
Affinity + Intrinsic activity [e.g. Adrenaline on beta adrenergic receptors]
Antagonist
Affinity + No Intrinsic activity [Propranolol on Beta receptors]
Partial agonist
Affinity + Intrinsic activity < 100%; In the presence of full agonist, PA behaves as an antagonist [naloxone, buprenorphine on µ receptors], A partial agonist (e.g. pindolol, pentazocine) is that which has the ability to stimulate the receptor, but has less potency at the receptor than the endogenous ligand.
The endogenous ligand is always in the body and competes with the drug for receptor binding sites. When centrations of the endogenous ligand are low, the partial agonist acts as an agonist, because it binds and stimulates unbound receptors, albeit with decreased potency. However, when endogenous ligand concentrations are high, the drug competes for binding sites on the receptors, and because of the drug's decreased activity at the receptor, effectively blocks the binding sites for the more potent endogenous ligand. In this case, the drug is effectively acting as an antagonist.
Inverse Agonist
– Affinity + Intrinsic activity in the negative direction to that of the agonist
The Beta carboline on Benzodiazepine receptors
Competitive Antagonism
  • Reversibility
  • Surmountability
  • Parallel shift of DRC to right
E.g. : propranolol, atropine, pheniramine
A drug receptor antagonist binds to an endogenous receptor and does not elicit a response, no intrinsic activity; the antagonistic drug prevents the binding of the endogenous agonist, resulting in decreased activation of the receptor.
A competitive antagonist binds and dissociates from the receptor, in accordance with the binding affinity of the drug for the receptor.
Once a drug molecule binds to the receptor, produces activation, and dissociates, the opportunity exists for a second drug molecule to occupy the binding site on the receptor. If this molecule is a receptor agonist, continued stimulation occurs. If, however, the molecules is an antagonist, or is decreased in potency with regards to the endogenous agonist, stimulation decreases and pharmacologic effect is impaired.
6
 
Other types of Antagonism
Physical Antagonism
:
Universal antidote
Chemical Antagonism
:
NaHCO3 + HCI, Heavy metal + chelating agent
Physiological Antagonism
:
Adrenaline in Anaphylaxis
Pharmaceutical Interaction
:
Occurs outside the body to drug with other agent
Eg: IV phenytoin glucose bolus (Precipitation)
Pharmacokinetic antagonism
:
Enzyme inducers decreasing activation of substrate
 
Tolerance
When a drug is given over time, the effects may decrease accordingly. This may be the consequence of, for example, desensitization of receptors or depletion of neurotransmitter stores.
Requirement of higher quantity of drug to produce the desired pharmacological effect.
– Pharmacokinetic Tolerance
:
Eg. Alcohol, phenobarbitone, carbamazepine inducing their own metabolism
– Pharmacodynamic Tolerance
:
Drug induced changes in receptors density (down regulation)
Impairment in receptor coupling to signal transduction pathway
Eg. Tolerance to Dopamine agonists, Benzodiazepines
Tachyphylaxis : If a drug is administered and produces a response that diminishes with subsequent doses, the effect is termed tachyphylaxis. This phenomenon is a rapid development of tolerance with subsequent dosage.
Eg. Indirect acting sympathomimetics like ephedrine, amphetamine, tyramine, nicotine.
 
Factors that result in variation in drug responsiveness
  • idiosyncratic drug response
  • tachyphylaxis
  • hypersensitivity response
  • alteration in concentration of drug that reaches the receptor (pharmacokinetic effect)
  • variation in endogenous receptor ligand concentration
  • alteration in the number or function of receptors
 
PHARMACOKINETICS (PK)
PK concerns with dose and concentration while PD concerns with concentration and subsequent effect.
 
Components of PK (ADME)
Absorption
:
into the systemic circulation
Distribution
:
from plasma to other organs
Metabolism
:
chemical alteration of the drug
Elimination
:
from the body
Before absorption one-step takes place (All except IV) i.e. Liberation i.e. liberation of the active drug from the formulation
  1. Liberation
    • First step that determines the onset intensity & duration of drug action.
    • Liberation takes place in all routes except i.v. route and oral use of True solutions.
    • Liberation is controlled by the characteristics of the drug product.
    • Disintegration and dissolution are essential components of liberation. Disintegration is the smallest detectable particle. Disintegration time and dissolution practically determine onset/intensity and duration of drug action.
  2. Absorption : Unless the drug is present in the solution form, it won't be absorbed (except i.v.) therefore dissolution becomes the first and rate-limiting step in absorption. After dissolution the drug diffuses to the site of absorption. Except i.v., from all other routes the drug has to pass biological membranes. Among various routes of absorption, passive diffusion accounts for the maximum, which depends on the pH and pKa and the lipid solubility of the unionized from. The pH of a physiologic compartment in relation to the pKa of a particular drug and the classification of the drug as a weak base determine the amount of drug that will be absorbed in that compartment. Because drugs can only pass through cell membranes in nonionized (neutral) form, optimizing the pH of the compartment of the pKa of the drug will result in more drug particles existing in nonionized form (as calculated using the Henderson-Hasselbalch equation). This will result in a greater absorption of drug in that compartment.7
    E.g. Ingestion of an antacid results in an increase in the pH of the gastric milieu. Because the pKa aspirin (a weak acid) is 3.5, and therefore exist mainly in nonionized form in the gastric milieu, an increase in gastric pH would shift the equilibrium to the right, resulting in an increase in the ionized form and decreased absorption of the drug.
    To change urinary pH:
    Acidify
    :
    NH4CL, Vitamin C, cranberry juice
    Alkalinize
    :
    NaHCO3, acetazolamide
    Partition coefficient measure the lipophilic characteristic of drug. The more lipophic a drug is, the higher is its partition coefficient.
First Pass metabolism can occur in g.i.t mucosa / blood vessel / liver (maximum in liver).
During absorption from oral and rectal route, the same amount of drug may be destroyed before reaching the central compartment. In the central compartment, the same amount of drug is bound to proteins & the same amount remains free.
Only the free fraction of the drug is therapeutically active.
There is a fixed ratio between the free and bound fraction. As the free fraction of drug is absorbed, drug from the bound form gets released only to act therapeutically.
 
Modes of absorption
The major transport mechanism are as under :
• Passive Diffusion (Non-ionic or simple diffusion)
• Carrier Mediated Transport :
Facilitated diffusion / Symport
Active transport
• Pinocytosis / Phagocytosis and Filtration.
 
BIOAVAILABILITY
This is the fraction of administered drug that reaches the systemic circulation in the unchanged from. In general, food retards absorption of most orally administered drugs except: beta-blockers, griseofulvin, nitrofurantoin, ketoconazole, probucol.
Bioavailability has 2 components:
Rate of absorption, Tmax, the time to achieve maximum concentration, Cmax is the maximum concentration achieved
Extent of absorption, AUC = reflects the extent of absorption
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Factors affecting bioavailability
  • ▪ First Pass metabolism
    • – CCBs / B.B./ Nitrates / Lignocaine / L – Dopa
  • ▪ Solubility of the drug.
    • – for a drug to be absorbed, it should be largely hydrophobic, yet have some aqueous solubility.
  • ▪ Chemical instability: drugs such as penicillin, insulin, peptide hormones are unstable in stomach pH or degraded by intestinal enzymes
  • ▪ Nature of Formulation: Particle size / salt form presence of excipients affects bioavailability
Steady-State concentration : when a drug is administered at regular intervals, there is a time when the rate of administration is equal to the rate of elimination. The drug concentration varies in a very narrow range. When a fixed dose is administered at each half life interval it takes 5–6 half- lives.
When a drug is administered by continuous administration, it takes one half-life to saturate 50% steady – steady concentration, 2 half lives 75% and 3 half lives 87.5% and so on.
Bioequivalence : When the bioavailability of 2 pharmaceutical equivalent drug products of same drug is similar, they are said to be bioequivalent.
Therapeutic Equivalence : When 2 different formulations have similar safety & efficacy. They may not be bioequivalent.8
 
DRUG DISTRIBUTION
It depends on :
  • – Blood flow
  • – Permeability
  • – Degree of binding to plasma or tissue proteins
  • – Relative hydrophobicity of the drug
Volume of distribution : It is a hypothetical volume of fluid that would accommodate all the drug in the body, if the concentration throughout was the same as in plasma.
A VD = 5L means the drug is confined to plasma volume; this the minimum volume of distribution.
E.g. Heparin / Aminoglycoside antibiotics / Mannitol / Hippurate / Urea etc.
If VD is 10–20L : Extra cellular fluid.
40L = Total body water – e.g. alcohol.
If more than that, it means the drugs is sequestered elsewhere: e.g. digoxin /chloroquine / vit. B12
 
Clinical Significance of VD
In case of drug overdose, dialysis can be life saving if the drug has low VD.
Larger the VD, larger is the T½
BINDING of drugs :
Albumin
Acidic drugs bind to albumin
Has multiple sites for it
Competitive displacement e.g. Tolbutamide/sulfa drugs
The basic groups in albumin are Arginine, Histidine, Lysine → which bind to Acidic drugs
Acidic groups are Aspartic acid / Glutamic acid / Tyrosine. Bind to basic drugs
(Binding of basic drugs to albumin has less significance)
Very lipophilic drugs bind to erythrocyte membranes than to plasma proteins.
  • Displacement interactions are important in case of Narrow therapeutic index drugs.
  • Only the free fraction of the drug is pharmacologically active
  • Hypoalbuminemia can cause decreased protein binding. Since the free fraction of the drug is pharmacologically active it has little significance (Unless plasma albumin falls below 2.5 gm/dl)
  • α1 – acidic glycoprotein acts as binder for BASIC DRUGS, whose levels increases in pregnancy, rheumatoid arthritis, nephritis, surgery, trauma, chronic stress etc.
  • Sex hormones bind to GLOBULINS : (Sex hormones binding Globulin – SHBG).
 
DRUG METABOLISM
AIMS of metabolism are to make the substance les reactive and/or more water soluble to be eliminated from the body easily.
Purpose:
1. Active drug
Active metabolite (Diazepam → desmethyl Diazepam → oxazepam)
2. Inactive drug
Active metabolite (Azathioprine – Mercaptopurine)
3. Active drug
Inactive metabolite (Most drugs)
 
Biotransformation
  • Phase I Reactions
  • Degradative reactions
  • Microsomal reactions
  • Non microsomal reactions :
    Oxidation
    Reduction
    Hydrolysis
 
Microsomal reactions
  • Associated primarily with smooth surface endoplasmic reticulum of liver.
  • Principal enzymes involved are mixed function oxidases and cytochrome P450 (absorption peak is at 450 cm−1)
  • Non specific in action, can be induced or activated.9
  • Only metabolize lipid soluble drugs.
    E.g. – Can metabolize lipid soluble amphetamine, but cannot metabolize less lipid soluble natural amines like tyramine or nor-epinephrine which are mainly metabolize by non-microsomal enzymes like Monoamine oxidase (MAO) and catechol-o-methyl transferase.
Phase I :
Reactions not involving CYP
Amine oxidation (Histamine / catecholamines)
Dehydrogenation – (Alcohol)
Hydrolysis – (procainamide)
Major human CYP enzymes inducing metabolism: CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4
CYP 3A4 is the most common drug metabolizing enzyme, which metabolizes about 50% of drugs used in man.
CYP enzymes are inducible and also inhibited by drugs.
Common Enzyme Inducers
:
Rifampicin, Carbamazepine, Phenobarbitone, Nevirapine, Ethanol
Common Enzyme Inhibitors
:
Macrolides, Ketoconazole, Metronidazole, Griesofulvin
 
Phase II reactions
  • Synthetic reaction
  • Mainly non microsomal reactions; Exception only one unique microsomal enzyme system e.g.:- the glucuronic acid conjugation.
    1. Being microsomal, it is soluble and intact its activity in soluble form.
    2. It can form glucuronide conjugates with a range of natural metabolites also e.g. -bilirubin.
Prosthetic groups arc added to the drug to make it more water soluble to facilitate its elimination.
E.g. : glucuronidation / sulfate / acetate / amino acid conjugation.
By far, glucuronidation is most common and most important of all conjugations.
Reversal: Not all drugs undergo phase I followed by phase II.
For INH, it is first acetylated (Phase II reaction) then hydrolysed to isonicotinic acid (phase I).
 
Non microsomal enzymes :
  • As soluble cell fractions and can still retain their catalytic activity.
  • Present in cytoplasm, mitochondria of hepatic cells and in plasma.
  • E.g.: -MAO, esterases, amidases, transferases and conjugases.
  • Non – inducible
  • Show genetic variation (eg. Pseudocholinesterase and acetyl transferase etc.)
 
Kinetics of Metabolism
  • 1st order (Rate of metabolism is directly proportional to substrate concentration).
  • 0 order (Rate of metabolism is constant despite increased substrate concentration).
  • Pseudo zero order – Rate of metabolism is depressed as substrate concentration increases.
 
FACTORS AFFECTING DRUG METABOLISM
  • Genetic influence : Acetylation of INH, Procainamide / Hydralazine
Genetic factors play a role in determining dosage and dosage frequency. An example is acetylation-patients may be classified into “fast” and slow acetylators, depending on the level of expression and activity of acetylases. It is considered when prescribing a drug such as isoniazid. The same is true for persons expressing decreased levels or defective pseudocholinesterases, which would affect the clearance of drugs such as succinylcholine.
  • Age : Neonate : slow metabolism in neonates, 1st week peak. 1–5 years saturated to adult values.
    • – Elderly: Minor changes occur but liver / kidney function ↓ ↓
  • Pregnancy : clearance of some drugs increased (metoprolol)
  • Liver disease : ↓ ↓ ↓ drug metabolism
  • Time of day : Ampicillin, steroids, digoxin, lithium, Indomethacin, AUC increases 23%, given at 9.00 pm than at 9.00 am
  • Diet : Charcoal, brilled beef / alcohol / grape fruit juice inhibit microsomal enzyme
  • Malnutrition : ↓ ↓ ↓10
  • Alcohol
    Acute : ↓ ↓
    Chronic : ↑ ↑
  • Other drugs : drugs can interact to increases or decreased drugs clearances
  • Cigarette smoking : ↑ metabolism of theophylline/caffeine and clozapine
  • Disease states, Hyperthyroidism, Acromegaly, enhance drug metabolism
  • CHF, Hypothyroidism chronic malnutrition decreases drug metabolism
 
ELIMINATION OF DRUGS
Clearance : Amount of unchanged drug cleared from the VD per unit time. It is rate of elimination / concentration.
So rate of elimination – CL X C
Clearance of a drug can occur in kidney, liver and lungs & other tissues, so Cl total = CLR + CLH + CLp + CL other.
Half-life : Time taken attains 50% of steady state. This is only valid when the drug follows 1st order kinetics
1st order kinetics : Rate of drug elimination is directly proportional to the plasma concentration i.e. if plasma concentration is increased or decreased by 50%; the rate of elimination is increased or decreased by 50%.
0 order Kinetics : When the drug metabolism & elimination reach a saturation point so that further increase in plasma concentration cannot lead to further increase in drug elimination i.e. a fixed quantity of drug is eliminated per unit time.
Pseudo zero order kinetics : Phenytoin / Ethanol / Aspirin
As the concentration increases, the increases in the elimination becomes less and less
In general : Lipid soluble drugs are predominantly excreted in the bile, while water soluble drugs are primarily excreted in urine.11
 
ALL INDIA
  1. Which of the following reaction is not involved in detoxification of drugs ? [AI 08]
    1. Cytochrome oxidase
    2. Cytochrome P450
    3. Methylation
    4. Sulfate conjugation
  1. ED50 is a measure of : [AI 08]
    1. Toxicity
    2. Safety
    3. Potency
    4. Efficacy
  1. Therapeutic index for a drug is a measure of : [AI 08]
    1. Safety
    2. Potency
    3. Efficacy
    4. Toxicity
  1. Phase II drug trials are done to find : [AI 08]
    1. Efficacy
    2. Lethal dose
    3. Maximal tolerated dose
    4. Safety index
  1. Forced Alkaline Diuresis of Alkanization of urine is used in Poisoning with : [AI 08]
    1. Barbiturates
    2. Amphetamina
    3. Alcohol
    4. Datura
  1. G6PD enzyme deficiency does not cause hemolysis in treatment with : [AI 08]
    1. Quinine
    2. Pyrimethamine
    3. Chloroquine
    4. Primaquine
  1. Which one of the following antiplatelet is a prodrug: [AI 07]
    1. Aspirin
    2. Dipyridamole
    3. Ticlopidine
    4. Abciximab
  1. In unconjugated hyperbilirubinemia, the risk of kernicterus increases with the use of : [AI 05]
    1. Ceftriaxone
    2. Phenobarbitone
    3. Ampicillin
    4. Sulphonamide
  1. A highly ionized drug : [AI 05; 04]
    1. Is excreted mainly by the kidney
    2. Can cross the placenta easily
    3. Is well absorbed from the intestine
    4. Accumulates in the lipids
  1. In which of the following phases of clinical trial of drug ethical clearance is not required? [AI 04]
    1. Phase I
    2. Phase II
    3. Phase III
    4. Phase IV
  1. The extent to which ionisation of a drug takes place is dependent upon pKa of the drug and the pH of the solution in which the drug is dissolved. Which of the following statements is not correct :
    1. pKa of a drug is the pH at which the drug is 50% ionized [AI 03]
    2. Small changes of pH near the pKa of a weak acidic drug will not affect its degree of ionization
    3. Knowledge of pKa of a drug is useful in predicting its behaviour in various body fluids
    4. Phenobarbitone with a pKa of 7.2 is largely ionized at acid pH and will be about 40% nonionised in plasma
  1. Presence of food might be expected to interfere with drug absorption by slowing gastric emptying. or by altering the degree of ionisation of the drug in the stomach. Which of the following statements is not correct example : [AI 03]
    1. Absorption of digoxin is delayed by the presence of food
    2. Concurrent food intake may severely reduce the rate of absorption of phenytion
    3. Presence of food enhances the absorption of hydrochlorthiazide
    4. Antimalarial drug halofantrine is more extensively absorbed if taken with food
Answer
1. a. Cytochrome …
2. c. Potency
3. a. Safety
4. a. Efficacy
5. a. Barbiturates
6. b. Pyrimethamine
7. c. Ticlopidine
8. d. Sulphonamide
9. a. Is excreted …
10. d. Phase IV
11. b. Small changes …
12. c. Presence of…
12
  1. All of the following statements regarding bioavailability of a drug are true except : [AI 03]
    1. It is the proportion (fraction) of unchanged drug that reaches the systemic circulation
    2. Bioavailability of an orally administered drug can be calculated by comparing the Area Under Curve (0-α. after oral and intravenous(iv) administration
    3. Low oral bioavailability always and necessarily mean poor absorption
    4. Bioavaialabilty can be determined from plasma concentration or urinary excretion data
  1. Regarding efficacy and potency of a drug, all are true, except : [AI 02; PGI Dec. 04]
    1. In a clinical setup, efficacy is more important than potency
    2. In the log dose response curve, the height of the curve corresponds with efficacy
    3. ED50 of the drug corresponds to efficacy
    4. Drugs that produce a similar pharmacological effect can have different levels of efficacy
  1. True statement regarding first order kinetics is :
    1. Independent of plasma concentration
    2. A constant proportion of plasma concentration is eliminated [AI 01; PGI Dec. 04]
    3. T ½ increases with dose
    4. Clearance decreases with dose
  1. All are reasons for reducing drug dosage in elderly except : [AI 01]
    1. They are lean and their body mass is less
    2. Have decreasing renal function with age
    3. Have increased baroceptor sensitivity
    4. Body water is decreased
  1. True statement regarding inverse agonists is : [AI 01]
    1. Binds to receptor and causes intended action
    2. Binds to receptor and causes opposite action
    3. Bind to receptor and causes no action
    4. Bind to receptor and causes submaximal
  1. All are pharmacogenetic conditions, except : [AI 00; AIIMS June 99; PGI Dec. 06]
    1. Adenosine deaminase deficiency
    2. Malignant hyper-pyrexia
    3. Coumarin insensitivity
    4. G6PD deficiency
  1. Which of the following is true : [AI 00]
    1. As the concentration of drug increases over the therapeutic range, the bound form of the drug increases
    2. The bound form is not available for metabolism but is available for excretion
    3. Acidic drug binds to albumin; and basic drug binds β globulin
    4. Binding sites are non-specific and one drug can displace the other
  1. True about teratogenicity of a drug is all except : [AI 00]
    1. It is genetically predetermined
    2. Environment influences it
    3. Related to the dose of the teratogenic drug
    4. Affects specially at a particular phase of development of foetus
  1. Which of the following is not an example of cytochrome p450 dehydrogenase inducer : [AI 98; PGI Dec. 06; PGI June 05]
    1. Phenobarbitone
    2. Rifampicin
    3. Phenytoin
    4. Ketoconazole
  1. Drug, which is contraindicated in pregnancy is:
    1. Tetracycline [AI 95; AIIMS Feb. 97]
    2. Erythromycin
    3. Ampicillin
    4. Chloroquine
 
AIIMS
  1. Which drug is not acetylated ? [AIIMS May 08]
    1. NH
    2. Dapsone
    3. Hydralazine
    4. Metoclopropamide
  1. Which is a prodrug ? [AIIMS May 08]
    1. Enalapril
    2. Clonidine
    3. Captopril
    4. Lisinopril
  1. Loading dose depends on : [AIIMS May 08]
    1. Volume of distribution
    2. Clearance
    3. Rate of administration
    4. Half life
Answer
13. c. Low oral
14. c. ED50 of …
15. b. A constant …
16. c. Have …
17. b. Binds …
18. a. Adenosine …
19. d. Binding …
20. a. It is genetically …
21. d. Ketocon …
22. a. Tetracycline
23. d. Metoclopropa …
24. a. Enalapril
25. a. Volume …
13
  1. Which is CPY P450 inhibitor ? [AIIMS May 08]
    1. Ketoconazole
    2. Rifampicin
    3. Phenytoin
    4. INH
  1. Therapeutic monitoring is done for all of the following except : [AIIMS Nov. 07]
    1. Tacrolimus
    2. Metformin
    3. Cyclosporine
    4. Phenytoin
  1. Good clinical practices (GCPs) are not a part of : [AIIMS Nov. 07]
    1. Preclinical studies
    2. Phae I studies
    3. Phase II studies
    4. Phase IV studies
  1. The following are contraindicated in pregnancy except : [AIIMS May 07]
    1. Sodium nitroprusside
    2. Labetalol
    3. Spironolactone
    4. ACE inhibitors
  1. The following drug is contraindicated in pregnancy: [AIIMS May 07]
    1. ACE inhibitor
    2. Calcium channel blocker
    3. Beta blocker
    4. Penicillin
  1. Maternal carbimazole intake causes all except : [AIIMS May 07]
    1. Choanal atresia
    2. Cleft lip and cleft palate
    3. Fetal goitre
    4. Scalp defects
  1. Loading dose depends on : [AIIMS Nov. 06]
    1. Half life
    2. Plasma volume
    3. Volume of distribution
    4. Rate of clearance
  1. Which of the following is a prodrug ? [AIIMS Nov. 06]
    1. Clonidine
    2. Enalapril
    3. Salmeterol
    4. Acetazolamide
  1. Drugs undergoing acetylation include except : [AIIMS Nov. 06]
    1. Dapsone
    2. Metoclopramide
    3. Procainamide
    4. INH
  1. Side effects of a drug arise due to the interactions of the drug of molecules other than the target. These effects of a drug can be minimized by its high : [AIIMS Nov. 05]
    1. Specificity
    2. Affinity
    3. Solubility
    4. Hydrophobicity
  1. Which of the following property of drug will enable it to be used in low concentrations : [AIIMS Nov. 05]
    1. High affinity
    2. High specificity
    3. Low specificity
    4. High stability
  1. Which of the following drugs can be safely prescribed in pregnancy ? [AIIMS May 05]
    1. Warfarin
    2. ACE inhibitors
    3. Heparin
    4. β – blockers
  1. Km of an enzyme is : [AIIMS May 03]
    1. Dissociation constant
    2. The normal physiological substrate concentration
    3. The substrate concentration at half maximal velocity
    4. Numerically identical for all isozymes that catalyze a given reaction
  1. For drugs with first order kinetics the time required to achieve steady state levels can be predicted from : [AIIMS May 03]
    1. Volume of distribution
    2. Half life
    3. Clearance
    4. Loading dose
Answer
26. a. Ketoconazole
27. b. Metformin
28. a. Preclinical …
29. b. Labetalol
30. a. ACE …
31. b. Cleft …
32. c. Volume …
33. b. Enalapril
34. b. Metoclopra …
35. a. Specificity
36. a. High …
37. c. Heparin
38. c. The substrate …
39. b. Half life
14
  1. All of the following drugs are metabolised by acetylation except : [AIIMS May 03]
    1. INH
    2. Sulfonamides
    3. Ketoconazole
    4. Hydralazine
  1. The lymphocytopenia seen a few hours after administration of a large dose of prednisone to a patient with lymphocytic leukemia is due to : [AIIMS Nov. 02]
    1. Massive lymphocytic apoptosis
    2. Bone marrow depression
    3. Activation of cytotoxic cells
    4. Stimulation of natural killer cell activity
  1. The substrate concentration used for determining the activity of an enzyme having Km=x µm will be: [AIIMS Nov. 02]
    1. 2xµm
    2. 4xµm
    3. 8xµm
    4. 10xµm
  1. Racemic mixture of two enantiomers with different pharmacokinetic and pharmacodynamic properties is seen in : [AIIMS May 02]
    1. Dilantin
    2. Digoxin
    3. Verapamil
    4. Octreotide
  1. A drug is more likely to cause toxicity in elderly patients due to all of the following reasons except: [AIIMS May 02]
    1. Decreased renal excretion of drugs
    2. Decreased hepatic metabolism
    3. Increased receptor sensitivity
    4. Decreased volume of distribution
  1. Which of the following can be given with dose adjustment : [AIIMS June 00]
    1. Levodopa + metoclopramide
    2. Gentamicin + Furosemide
    3. Ferrous sulphate + Tetracycline
    4. Clonidine + Chlorpromazine
  1. Alcohol intake during pregnancy causes, all, except : [AIIMS Nov. 99]
    1. Brachycephaly
    2. Microcephaly
    3. Hyperkinetic movements
    4. Congenital anomalies
  1. New drug study and development can be done by: [AIIMS Nov. 99]
    1. Pharmacogenetics
    2. Molecular modelling
    3. Pharmacolibrary
    4. Neopharmacy
  1. Concentration of a drug in blood is 40 microgm/ml. Dose of the drug is 200mg. Volume of distribution of the drug assuming minute elimination is : [AIIMS June 99]
    1. 5 litre
    2. 0.5 litre
    3. 2.5 litre
    4. 3 litre
  1. All of the followings can cause hemolytic anaemia except : [AIIMS June 99, Dec. 95; PGI Dec. 04]
    1. Isoniazid
    2. Rifampicin
    3. Co – trimoxazole
    4. Propranolol
  1. A drug X has affinity to bind with albumin and Y has 150 times more affinity to bind with albumin than X. TRUE statement is : [AIIMS June 99]
    1. Drug X will available more in tissues
    2. Drug Y will be more available in tissues
    3. Free conc. of drug X in blood will be more
    4. Toxicity of Y will be more
  1. Drug, not metabolised by liver is : [AIIMS June 98]
    1. Penicillin G
    2. Phenytoin
    3. Erythromycin
    4. Cimetidine
  1. Which of the following is not an example of cytochrome P450 dehydrogenase inducer : [AIIMS June 97]
    1. Phenobarbitone
    2. Rifampicin
    3. Phenytoin
    4. Ketoconazole
Answer
40. c. Ketoconazole
41. a. Massive …
42. a. 2xµm
43. c. Verapamil
44. d. Decreased …
45. c. Ferrous …
46. a. Brachycephaly
47. b. Molecular …
48. a. 5 litre
49. d. Propranolol
50. a. Drug X …
51. a. Penicillin G
52. d. Ketoconazole
15
 
PGI
  1. Physiological antagonism found in : [PGI Dec. 07]
    1. Isoprenaline and Salbutamol
    2. Isoprenaline and Adrenalin
    3. Isoprenaline and Propanolol
    4. Adrenaline and Histamine
  1. Drug dependence is characterized by : [PGI Dec. 07]
    1. Takes it daily
    2. Tolerance
    3. Withdrawal symptoms occurs
    4. Uses despite knowing harmful effects
  1. Which is a pro-dug : [PGI Dec. 07]
    1. Cyclophosphamide
    2. Lisinopril
    3. Metochlorpramide
    4. Ranitidine
    5. Eptifibatide
  1. Narrow therapeutic index seen in : [PGI Dec. 07]
    1. Metformin
    2. Phenytoin
    3. Cyclosporin
    4. Digitalis
  1. In G6PD deficiency, drugs contraindicated are : [PGI Dec. 07]
    1. Primaquine
    2. Chloroquine
    3. Hydralazine
    4. Losartan
  1. Advantages of fixed drug combinations : [PGI Dec. 07]
    1. Decrease cost
    2. Increase efficacy
    3. Increase compliance
    4. Decrease resistance
    5. Dose titration can be done
  1. Drugs which cause fetal renal anomalies : [PGI Dec. 06]
    1. Enalapril
    2. Furosemide
    3. Angiotensin receptor blocker
    4. Amlodipine
    5. Phenytoin
  1. On I.V. drug administration elimination of a drug depend on : [PGI Dec. 06; June 06]
    1. Lipid solubility
    2. Volume of distribution
    3. Clearance
    4. Drug concentration
  1. A 70 kg man was given a drug with dose of 100mg/kg bd. wt t1/2 is 10 hours, plasma concn is 1.9 mg/ml clearance is : [PGI Dec. 06]
    1. 0–02 liter/hr
    2. 20 liter/hr
    3. K is 0.0693
    4. K is 6.93
    5. 0.2 liter/hr
  1. True about tachyphylaxis : [PGI Dec. 06]
    1. Direct sympathomimetic involved
    2. Mechanism clearly understood
    3. Ephedrine tachyphylaxis reversed with noradrenaline
    4. Indirect sympathomimetics involved
    5. It is an anaphylaxis reaction
  1. Drug transport mechanism include : [PGI June 06]
    1. Active transport
    2. Passive transport
    3. Lipid solubility
    4. Facilitated diffusion
    5. Symport
  1. Causes for less bioavailability : [PGI June 06]
    1. High first pass metabolism
    2. Increased absorption
    3. IV drug administration
    4. High solubility
  1. Drugs inducing CYP3A4 include : [PGI Dec. 06]
    1. Fexofenadine
    2. Phenytoin
    3. Carbamazepine
    4. Rifampin
    5. Glucocorticoid
  1. Which of the following statement is not true ? [PGI Dec. 06]
    1. If drug is administered rectally it follow first order
    2. If drug is administered IM it follow zero order
    3. If drug is administered IV it follow first order
    4. Bioavailability is irregular after oral administration
    5. In acute renal failure, renally excreted drug follow zero order kinetics
Answer
53. d. Adrenaline …
54. a, b, c and d
55. a. Cyclophosph …
56. b, c and d
57. a and b
58. a, b, c and d
59. a and c
60. a, b, c and d
61. e. 0.2 liter/hr
62. d. Indirect …
63. a, b, c, d and e
64. a. High first …
65. b, c, d and e
66. a, b and c
16
  1. Pharmacogenetics is associated with : [PGI Dec. 06]
    1. Variability of enzyme action
    2. Environmental influence
    3. Individual variability in oral absorption
    4. Different MAO in different individual
    5. Different dose response curve in different individual
  1. Drug synergism is seen in all except : [PGI June 05]
    1. Flucytosine and amphotericin B for cryptococcal
    2. Trimethoprim and sulphamethoxazole for UTI
    3. Penicillin and aminoglycoside
    4. Chlortetracycline + penicillin
  1. Drugs given by I.V. route : [PGI June 05]
    1. Heparin
    2. Pantoprazole
    3. Ranitidine
    4. Sumatriptan
    5. Neomycin
  1. True about efficacy and potency of drugs : [PGI Dec. 04]
    1. Efficacy is clinically more important than potency
    2. Height of DRC corresponds to efficacy
    3. The amount of drugs to produce certain response is called efficacy
    4. Drugs having similar pharmacological action may have different efficacy
  1. True about routes of drug administration : [PGI June 04]
    1. 80% bioavailability by I.V. injection
    2. I.M. administration needs sterile technique
    3. I.D. injection produces local tissue necrosis and irritation
    4. Inhalation produces delayed systemic bioavail-ability
  1. Volume of distribution of drugs altered in : [PGI June 04]
    1. Obesity
    2. Athletes
    3. Pregnancy
    4. Older age
    5. Neonate
  1. Dose adjustment is needed if bilirubin is >1.5mg/dl in : [PGI June 04]
    1. Methotrexate
    2. Ansacrine
    3. Rifampicin
    4. Tolcapone
  1. First pass metabolism is seen in : [PGI Dec. 03]
    1. Lignocaine
    2. Propranolol
    3. Salbutamol
    4. Dipyridamole
    5. Erythromycin
  1. Most important side effect of dapsone is hemo-lytic anaemia, the next adverse effect : [PGI June 03]
    1. G – 6 – PD deficiency
    2. Infectious mononucleosis like syndrome
    3. Agranulocytosis
    4. Lichenoid eruption
    5. Skin pigmentation
  1. Blood brain barrier crossed by : [PGI Dec. 02]
    1. Dopamine
    2. Propranolol
    3. Glycopyrrolate
    4. Physostigmine
    5. Streptomycin
  1. Low therapeutic range is seen in : [PGI Dec. 02]
    1. Lithium
    2. Erythromycin
    3. Phenytoin
    4. Propranolol
    5. Tricyclic antidepressant
  1. In hepatic metabolism phase II reactions are : [PGI Dec. 02]
    1. Dealkylation
    2. Sulfonation
    3. Methylation
    4. Glucuronization
    5. Deamination
  1. Drug safely given in pregnancy : [PGI Dec. 02]
    1. Antifolate
    2. Quinine
    3. Chloroquine
    4. Primaquine
    5. Tetracycline
Answer
67. a and d
68. d. Chlortetra …
69. a, b and c
70. a, b and d
71. b and c
72. a, c, d, and e
73. a, c and d
74. a, b and c
75. c and e
76. b and d
77. a and c
78. b, c and d
79. c. Chloroquine
17
  1. High hepatic excretion ratio seen in : [PGI June 02]
    1. Propranolol
    2. Lidocaine
    3. Ampicillin
    4. Imipramine
    5. Theophylline
  1. Drugs which cause malformation in the foetal include : [PGI Dec. 01]
    1. Heparin
    2. Warfarin
    3. Valproic acid
    4. Steroids
    5. Phenytoin
  1. Which of the following drugs are secreted in breast milk : [PGI June 01]
    1. Antihistaminics
    2. Antithyroid drugs
    3. Penicillin
    4. Diazepam
    5. Antiepileptics
  1. Displacement of protein bound drug : [PGI June 00]
    1. ↑↑ Drug plasma level
    2. ↑↑ Side effects
    3. ↓ Free levels
    4. ↓ Effect
  1. Which is true about Max. distribution : [PGI June 00]
    1. Highly lipophilic
    2. Blood brain barrier
    3. ↓ Excretion
    4. ↓ Receptor
  1. At pharmacological doses unwanted unavoidable effects are called : [PGI Dec. 99]
    1. Side effects
    2. Idiosyncratic reaction
    3. Toxicity
    4. Pharmacogenetics
  1. Characteristic feature of agonist is : [PGI Dec. 99]
    1. Has affinity only
    2. Has affinity as well as intrinsic activity
    3. Has intrinsic activity only
    4. Neither has affinity nor activity
  1. True regarding dose-response curve is : [PGI June 99]
    1. Cannot determine the potency of a drug
    2. Log dose response curve is sigmoid shaped
    3. Cannot find response to antagonist
    4. A wide range of doses can not be plotted
  1. Mechanism of action of GABA is on : [PGI Dec. 99]
    1. G protein
    2. Tyrosine kinase
    3. PIP / DAG
    4. 5 – HT
  1. The maximum effect of a drug is defined by its : [PGI Dec. 98]
    1. Therapeutic index
    2. Potency
    3. Efficacy
    4. Adversity
  1. Alkalinity of urine is done in : [PGI June 97]
    1. Barbiturate poisoning
    2. Lithium toxicity
    3. Alprazolam overdone
    4. Diazepam toxicity
  1. About acidic drug true is : [PGI June 97]
    1. Best absorbed in acidic medium
    2. Best absorbed in alkaline medium
    3. Not absorbed in acidic medium
    4. Binds to alpha glycoprotein
Answer
80. a, b, d and e
81. b, c, d and e
82. a, b, c, and d
83. a. ↑↑ free …
84. a. Highly …
85. a. Side …
86. b. Has affinity …
87. b. Log dose …
88. a. G-protein
89. c. Efficacy
90. a. Barbiturate …
91. a. Best …
18
 
ANSWERS, REFERENCES, EXPLANATIONS WITH INFORMATIVE ILLUSTRATIONS
1. Ans. is a i.e. Cytochrome oxidase
Ref. KDT 6/e, p 25 – 26
Cytochrome oxidase is the enzyme for final component of electron transport chain, but not for chemical pathways of drug biotransformation.
Xenobiotics are metabolized by monooxygenases like CYP P-450.
Drug biotransformation is commonly grouped into two types, which is depicted below as Phase I (non-synthetic reaction) and Phase II (synthetic reaction).
Biotransformation occurs as follows :
zoom view
19
Mnemonics
• All reactions starting with ‘De’ are phase – I reactions
Dealkylations
Deaminations
Desulphuration
Dechlorination
Decyclization
• All the reactions starting with ‘G’ are phase – II reactions
Glucoronide conjugation
Glycine conjugation
Glutathione conjugation
2. Ans. is c i.e. Potency
Ref. KDT 6/e, p 55
  • ED50 means effective dose which can provide 50% of the maximal response.
  • Smaller the ED50, more potent is the drug, which is shown in log dose response (LDR) curve below.
zoom view
This graph shows that the drug A is more potent because its ED50 is comes at vary low dose as compared to ED50 of drug B.
The potency of the drug tells us nothing about its efficacy and safety and therefore a relatively unimportant characteristic for therapeutic purposes.
3. Ans. is a i.e. Safety
Ref. Rang & Dale KDT 55, 5/e, p 89; KDT 6/e, p 55; Katzung 10/e, p 30 – 31
Therapeutic index of a drug in terms of ratio between the average minimum effective dose and the average maximum tolerated dose in group of subjects:
zoom view
LD50 is the dose that is lethal in 50% of the population and ED50 is the dose that is effective in 50% for a safe drug, the TI should be at least more than one and hence or drug having larger value of LD50 but smaller value of ED50 is considered to be more safe.20
Limitation of TI:
  • LD50 does not reflect toxicity in the therapeutic setting, where unwanted effects are common, but rarely death.
  • ED50 is often not definable for e.g. – the ED50 for aspirin used for a mild headache is much lower than for aspirin as an antirheumatic drug.
4. Ans. is a i.e. Efficacy
Ref. Goodman & Gilman 11/e, p 133 – 134; KDT 6/e, p 77
In Phase II drug is studied for first time in patients with target disease to determine its efficacy.
Clinical Testing has four phases
Phase I
Non-blind or Open label
Number of subjects 20 – 25 healthy volunteers.
i. Determines – Pharmacokinetic differences in animals and humans
ii. Determines safe and tolerated dose
iii. Determines any predictable toxicity
iv. Determines Pharmacokinetics of the drugs in humans
Phase II
Single or Double blind
First time in patients with target disease
Determines efficacy and safety
Early phase – 20 – 200 patients, single blind
Late phase – 50 – 300 patients, double blind.
Phase III
Double blind
Are large scale randomized control trials in patients (250 – 1000 plus).
Determines safety and efficacy
Designed to minimise error in information gathered in P – I and P – II.
Phase IV
Post-licensing phase-field trials.
No fixed duration (it is the surveillance phase during post marketing clinical use)
5. Ans. is a i.e. Barbiturates
Ref. KDT 6/e, p 13, KDT 6/e, p 392
Alkalisation of urine is done therapeutically for salicylate or barbiturate poisoning.
Since the pH of the urine is acidic, all acidic drugs (e.g. salicylates, barbiturates and sulfonamides) remain predominantly noninonised and have more changes of their reabsorption than excretion.
On the contrary, if the pH of the urine is made alkaline by giving sodium bicarbonate or sodium citrate, the ionization of acidic drugs would increase. As a result their reabsorption would be retarded while excretion facilitated.
Drugs working effectively at alkaline pH (basic drug)
Cotrimoxazole
Gentamicin
Cephalosporins
Fluroquinolones
Drugs that work effectively better at Acidic pH (acidic drug)
Nitrofurantoin
Tetracyclin
Methicillin
Cloxacillin
21
6. Ans. is b i.e. Pyrimethamine
Ref. Harrison 17/e, p 657
Drugs that carry risk of clinical hemolysis in persons with G6PD deficiency new list included in Harrison 17 edition
Groups
Definite risk
Possible risk
Doubtful risk
Antimalarials
Primaquine
Dapsone/chlorproguanil
Chloroquine
Quinine
Sulphonamidex/sulphones
Sulphametoxazole
Others
Dapsone
Sulfasalazine
Sulfadimidine
Sulfisoxazole
Sulfadiazine
Antibacterial/antibiotics
Cotrimoxazole
Nalidixic acid
Nitrofurantoin
Niridazole
Ciprofloxacin
Norfloxacin
Chloramphenical
p-Aminosalicylic acid
Antipyretic/analgesics
Acentanilide
Phenazopyridine (Pyridium)
Acetylsalicylicacid high dose (3 g/d)
Acetylsalicylic acid <3 g/d
Acetaminophen
Phenacetin
Other
Naphthalene
Methylene blue
Vitamin K analogues
Ascorbic acid >1g
Rasburicase
Doxorubicin
Probenecid
7. Ans. is c i.e. Ticlopidine
Ref. Goodman & Gilman 11/e, p 1482; KDT 6/e, p 23 – 24
“Ticlopidine is a prodrug that requires conversion to the active thiol metabolite by a hepatic cytochrome P450 enzyme.”
… Goodman & Gilman
Clopidogrel is closely related to Ticlopidine but has more favorable toxicity profile-less thrombocytopenia and leukopenia.
  • Both the drugs are inhibitors of Purinergic receptors present on the platelets
Thienopyridine drugs Ticlopidine and Clopidogrel are prodrugs.
Prodrug
  • Few drugs are inactive as such and need conversion in the body to one or more active metabolites such a drug are called prodrugs.
  • The prodrug may offer advantages over the active form in being :
    • – More stable
    • – Having better bioavailability
    • – Other desirable pharmacokinetic properties
    • – Less side effects and toxicity.
Prodrug
Active form
Prodrug
Active form
Azathioprine
Mercaptopurine
Dipivefrine
Epinephrine
Bacampicillin
Ampicillin
Enalapril
Enalaprilat
Benyrolate
Aspirin + Paracetamol
Levodopa
Dopamine
Cortisone
Hydrocortisone
Proguanil
Proguanil triazine
22
Cyclophosphamide
Aldophosphamide
Sulindac
Sulfide metabolite
Sulfasalazine
5 Aminosalicylic acid
Zidovudine (All NRTI's)
Zidovudine triphosphate
Mercaptopurine
Methylmercaptopurine
Flourouracil
Flourouridine mono PO4− − −
Prednisone
Prednisolone
ALL ACE inhibitors are Prodrugs except :
C
-
Captopril
L
-
Lisinopril
8. Ans. is d i.e. Sulphonamide
Ref. KDT 6/e, p 684
Kernicterus in Neonates
Sulphonamide can precipitate kernicterus in the newborn, specially if premature, by displacement of bilirubin from plasma protein binding sites and more permeable blood brain barrier (causing unconjugated hyperbilirubinemia).
Common adverse effects of sulphonamide
• Nausea, vomiting and epigastric pain
Crystalluria – dose related
• Hypersensitivity reactions
• Hepatitis – dose unrelated
Hemolysis in individuals with G-6-PD deficiency
Kernicterus in the new born
Mnemonic :
5S – Sulfonamide major side effects
Sulfonamide side effects :
Steven-Johnson syndrome
Skin rash
Solubility low (causes crystalluria)
Serum albumin displaced (causes newborn kernicterus and potentiating of other serum albumin binders like warfarin)
9. Ans. is a i.e. Is excreted mainly by the kidney
Ref. KDT 6/e, p 16, 30
A highly ionized drug is not reabsorbed by the tubules and is easily excreted by the kidneys because it is lipid insoluble.
Ionization increases renal clearance of drugs :
  • Only free, unbound drug is filtered
  • Only nonionized forms undergo active secretion and active or passive reabsorption.
  • Ionized forms of drug are “trapped” in the filtrate.
Non Ionized Drugs
Ionized Drugs
Non ionized drugs are lipid soluble
Ionized drugs are lipid insoluble
Rapidly pass across placenta
Poorly pass across placenta
Rapidly absorbed from GIT
Poorly absorbed from GIT
23
10. Ans. is d i.e. Phase IV Ref. Goodman & Gilman 11/e, p 133 – 134; KDT 6/e, p 77
Conducted by large number of clinicians at different centers.
  • Looking at the flowchart below, we can easily conclude that phase 4 of clinical testing is a phase of post marketing surveillance after reviewing the results of phase 1, 2 and 3 of clinical testing. This phase occurs only after FDA safety review, NDA submission and NDA approval, so it does not require ethical clearance anymore.
zoom view
Clinical Testing has four phases
Phase I
Non-blind or Open label
• Number of subjects 20 – 25 healthy volunteers.
i. Determines – Pharmacokinetic differences in animals and humans
ii. Determines safe and tolerated dose
iii. Determines any predictable toxicity
iv. Determines Pharmacokinetics of the drugs in humans
24
Phase II
Single or Double blind
First time in patients with target disease
Determines efficacy and safety
Early phase – 20 – 200 patients, single blind
Late phase – 50 – 300 patients, double blind.
Phase III
Double blind
Are large scale randomized control trials in patients (250 – 1000 plus).
Determines safety and efficacy
Designed to minimise error in information gathered in P – I and P – II.
Phase IV
Post-licensing phase-field trials.
No fixed duration (it is the surveillance phase during post marketing clinical use)
11. Ans. is b i.e. Small changes of pH near the pKa of a weak acidic drug will not affect its degree of ionization
Ref. KDT 6/e, p 12 – 13
  • Lets take each option separately :
Option ‘a’
Drugs are weak acids or weak bases and can exist in either nonionised (HA) or ionised (A) forms in an equilibrium, depending on pH of the environment and their pKa (pKa is numerically equal to the pH at which the molecule is 50% ionised and 50% nonionised.)
Option ‘b’
One scale change in pH causes a ten fold change in ionisation. With the change of pH, the rate of change of ionisation is greatest at pH value near pKa.
Option ‘c’
Non ionized form of the drug cross biological membranes and enters different body fluids. pKa of the drug therefore, is useful in predicting its behaviour in various body fluids.
Option ‘d’
Phenobarbitone is a weakly basic drug with a pKa of 7.2. It will, thus be largely ionised at acidic pH.
An example of a case in which this is an issue is the use of:
  • Weak basis local anesthetic (e.g., lidocaine prilocaine) when an infection or inflammation is present.
  • Altered gastric pH. An acidic drug may be incompletely absorbed if gastric pH is increased. This may occur through the use of antacids, H2-receptor antagonists, or the use of proton pump inhibitors, or in conditions where vomiting is present. This may result in systemic alkalosis, which further lowers drug potency.
12. Ans. is c i.e. Presence of food enhances the absorption of hydrochlorthiazide Ref. KDT 6/e, p 16, 461, 748; Katzung 10/e, p 855
Food in general reduced absorption rate of drug.
  • Presence of food in stomach delays absorption of digoxin as well as digitoxin.
  • Oral absorption of halofantrine is variable and is enhanced with food but because of toxicity concerns, it should however not be taken with meals.
  • Food ingested has not been found to affect the absorption of hydrochlorthiazide.
  • Absorption of phenytoin by oral route is slow, mainly because of its poor oral solubility. We could not find any reference of the effect of food on phenytoin absorption.25
    Empty stomach favoured the absorption of drug.
    For E.g.
    Rifampin rate and extent of absorption reduced after meal.
    Absorption of tetracycline's is also markedly reduced if taken with milk and milk products.
Exceptions
  • Absorption of certain antifungal drugs (e.g. griseofulvia) is enhanced by administering the drug with fatty diet.
  • Vitamin C, iron in its ferrous form therefore, increase its bioavailability.
  • Bioavailability of phenytoin improves after meals by its better dissolution due to food-induced bile secretion.
13. Ans. is c i.e. Low oral bioavailability always and necessarily means poor absorption Ref. KDT 6/e, p 17
The absorbed drug may undergo first pass metabolism in the intestinal wall / liver or be excreted in bile. So, drug can absorbed from intestine and before reaching the target organ it get metabolized in liver (MC) not means that it is not or poorly absorbed.
Term bioavailability is used to indicate the proportion of unchanged drug that passes into the systematic circulation after oral administration, taking into account both absorption and local metabolic degradation.
Clearance can markedly affect the extent of availability because it determines the extraction ratio. (Option “d”).
  • Bioavailability is determined by the area under the plasma concentration time curve. (Option “b”)
  • Area under the curve of an orally administered drug when compared to the area under the curve for an IV administered drug (100%) can certainly give an idea of its bioavailability.
  • Importance of Bioavailability : Bioavailability greater concern with drugs that shows narrow margin of safety (e.g, antiarrhythmics, antidiabetics etc.).
  • Let's look in to bioavailability of a drug administered by different routes :
    IV / IA > TD > IM / SC > Rectal > Oral / Inhalational.
Route
Bioavailability (%)
IV / IA
100
IM
75 to ≤ 100
SC
75 to ≤ 100
Oral (PO)
5 to < 100
Rectal (PR)
30 to < 100
Inhalation
5 to < 100
Transdermal (TD)
80 to < 100
14. Ans. is c i.e. ED50 of the drug corresponds to efficacy Ref. Katzung 10/e, p 28; KDT = 54, 55
  • ED50 means effective dose which can provide 50% of the maximal response.
  • Smaller the ED50 more potent is the drug and hence, it tells about potency of drug.26
Efficacy denotes the maximal response as reflected by the height of the Log dose response curve on its ordinate i.e. Y axis (height of curve).
The curve for the drug with greater affinity (i.e., acting at the lower concentration), will lie close to the ordinate, while the curve for the drug with lesser affinity will lie farther towards right (drug B in figure).
  • – Potency means the dose of a drug required to produce a standard effect.
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  • For analysing the options clearly, let's go through the salient features of potency and efficacy in the following table :
Potency
Efficacy
Potency refers to the amount of drug needed to produce a certain response.
Efficacy refers to the maximal response that can be elicited by the drug. It refers to the maximum height of the curve.
Competitive antagonist acts by decreasing the potency of a drug, such that maximal response (efficacy) can still be attained by increasing dose of agonist. Causes rightward shift of DRC.
Non competitive antagonist acts by decreasing the efficacy of a drug. Maximal response is suppressed and unsurmountable. Causes flattening of DRC.
Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produced 50% of that drugs maximal effect.
The efficacy of a drug is obviously crucial for making clinical decisions when a large response is needed. It is a more decisive factor in the choice of a drug.
• Potency of a drug depends in part on the affinity of receptors for binding the drug and in part on the efficiency with which drug receptor interaction is coupled to response.
• It may be determined by the drug's mode of interactions with receptors or by characteristics of the receptor effector system involved.
15. Ans. is b i.e. A constant proportion of plasma concentration is eliminated Ref. K DT 6/e, p 31 – 32
Before coming to answer read following facts about First order and Zero order Elimination Rate.27
First Order elimination Rate
Zero order Elimination Rate
• Rate of elimination is directly proportional to plasma concentration or the amount present. The higher the concentration, the more rapid the elimination. For eg.,
• Rate of elimination is independent of plasma concentration (or amount in the body)
A constant fraction of the drug is eliminated per unit time
A constant amount of the drug is eliminated per unit time.
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Graphically, first order elimination follows an exponential decay versus time.
Graphically, zero order elimination follows a straight-line decay versus time.
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T½ always remain constant irrespective of dose
Drugs with zero-order of elimination have no fixed half life.
Most of the drugs in pharmacology follow first order kinetics
Eg. : Ethanol, Phenytoin, Salicylates, Tolbutamide, Theophylline, Warfarin, Dicumerol
28
Mixed order of Kinetics (or mixed order kinetics or saturation kinetics, Pseudo zero order).
Michaelis-Menten Kinetics : Some important drugs, like phenytoin, digoxin, warfarin, dicumarol, tolbutamide and aspirin (higher doses) obey mixed order elimination kinetics.
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16. Ans. is c i.e. Have increased baroreceptor sensitivity
Ref. KDT 62, Katzung 10/e, p 984
  • Baroreceptor sensitivity does not increase with age. On the contrary it tends to decrease with age. This leads to impaired blood pressure response to standing and volume depletion. Therefore dosage should be increased in this situation.
  • The most important of these is the decrease in Renal function.
Changes related to aging that affect pharmacokinetics of drugs
Variable
Young Adults (20–30yrs)
Older Adults (60–80 yrs)
Body water (%of body weight)
61
53
Lean body mass (% of body weight)
19
12
Body Fat (% of body weight)
26–33 (Female)
18–20 (Male)
38–45
36–38
Serum albumin (g/dl)
4.7
3.8
Kidney weight (% of young adult)
(100)
80
Hepatic blood flow (% of young adult)
(100)
55–60
17. Ans. is b i.e. Binds to receptor and causes opposite action Ref. K DT 6/e, p 42
Inverse Agonist (Negative Antagonists)
These have full affinity towards the receptor, but their intrinsic activity ranges between ‘zero to minus one’. They stabilise the receptor from undergoing the productive conformational change. Consequently, they will produce an effect opposite to that of an agonist even in its absence.
For Eg., β-carbolines act as a inverse agoinsts at benzodiazepine receptor and produce the effects like, anxiety, awakening and seizures, which are just the opposite of the effects of benzodiazepines (antianxiety, sedation, anticonvulsant).29
The Two State Receptor Model Theory
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18. Ans. is a i.e. Adenosine deaminase deficiency
Ref. KDT 6/e, p 63 – 64
Pharmacogenetic is the study of the genetic basis for variation in drug response. Pharmacogenetics encompasses pharmacogenomic, which employs tools for surveying the entire genome to assess multigenic determinants of drug response.
Examples :
  • Atypical Pseudocholinesterase
    • – Prolonged succinylcholine Apnoea.
  • G-6 PD deficiency
    • Hemolysis with primaquine and other oxidizing drugs like Sulfonamides, Dapsone, Quinine, Chloroquine, Nalidixic acid, Nitrofurantoin and menadione.
  • Acetylators polymorphism
    • – Isoniazid neuropathy, Procainamide and hydralazine induced lupus in slow acetylators.
  • Acute intermittent porphyria
    • – Precipitated by barbiturates due to genetic defect in repression of porphyrin synthesis.
  • CYP2D6 abnormality causes poor metoprolol / debrisoquin metaboliser status.
  • Malignant hyperthermia after halothane.
  • Inability to hydroxylate phenytoin toxicity at usual doses.30
  • Resistance to coumarin anticoagulants due to an abnormal enzyme (that regenerates the reduced form of Vit. K) which has low affinity for the coumarins.
  • Precipitation of an attack of angle closure glaucoma by mydriatics in individuals with narrow iridocorneal angle.
19. Ans. is d i.e. Binding sites are non-specific and one drug can displace the other Ref. KDT 6/e, p 21; Goodman & Gilman 11/e, p 8
Considering each option separately :
Option ‘a’
:
As concentration of drug increases over the therapeutic range, it is the free form of the drug that increases (because most protein binding sites are already saturated).
Option ‘b’
:
Protein binding of drug affects : Metabolism of drug and Elimination of drug.
Protein binding limits the glomerular filtration of drug but dose not affect the renal tubular secretion. Protein bounded drugs excreat via renal by Tubular secretion.
Option ‘c’
:
Plasma protein binding of drug
Albumin
α−1 acid glycoprotein
All the acidic drugs bind to plasma protein Albumin
All the basic drugs bind to α-1 acid glycoprotein
• Ex. : Valproic acid, Phenytion, Barbiturates Benzodiazipines, Sulphonamides, Tetracycline, Tolbutamide, Warfarin NSAIDs
• Ex. : Beta Blocker, Prazosin, Bupivacaine Lignocaine, Verapamil, Disopyramide Imipramine, Methadone
Option ‘d’
:
Binding sites are nonspecific and one drug can displace the other at therapeutic plasma concentration. Only a tiny fraction is unbounded. Sulphonamides are an exception because they occupy 50% of binding sites at therapeutic concentration and so can cause unexpected effect by displacing other drugs. … KDT 6/e, p 684
20. Ans. is a i.e. It is genetically predetermined Ref. Katzung 10/e, p 975; KDT 6/e, p 84 – 85
Defining a teratogen :
  • Results in a characteristic set of malformations, indicating selectivity for certain target organs.
  • Exert its effects at a particular stage of foetal development i.e. during the limited period of organogenesis of the target organs.
Drugs can affect the foetus at 3 stages :
  • Fertilization and implantation - conception to 17 days, failure of pregnancy which often goes unnoticed.
  • Orgamogenesis - 18 to 55 days of gestation, most vulnerable period, deformities are produced.
  • Growth and development - 56 days onwards, development and functional abnormalities can occur, e.g., ACE inhibitors can cause hypoplasia of organs, specially lungs and kidneys; NSAIDs may induce premature closure of ductus arteriosus.31
21. Ans. is d i.e. Ketoconazole
Ref. Katzung 10/e, p 61 – 62,; KDT = 892 – 894
Drugs that enhance drug metabolism in humans.
Inducer
Drug whose metabolism is enhanced
Benzo[a]pyrene
Theophylline
Carbamazepine
Carbamazepine, clonazepam, itraconazole
Glutethimide
Antipyrine, glutethimide, warfarin
Griseofulvin
Warfarin
Phenobarbital & other barbiturates
Barbiturates, chloramphenicol, chlorpromazine, cortisol, coumarin anticoagulants, digitoxin, doxorubicin, itraconazole, phenylbutazone, phenytoin, quinine, testosterone
Phenylbutazone
Aminopyrine, cortisol, digitoxin
Phenytoin
Cortisol, dexamethasone, digitoxin, itraconazole, theophylline
Rifampin
Saquinavir Coumarin, digitoxin, glucocorticoids, itraconazole, oral contraceptive
Ritonavir
Midazolam
St. John's wort
Alprazolam, cyclosporine, digoxin, indinavir, oral contraceptives, ritonavir, simvastatin, tacrolimus, warfarin
Drugs that inhibit drug metabolism in humans.
Inhibitor
Drug whose metabolism is inhibited
Ketoconazole
Astemizole, cyclosporine, terfenadine
Allopurinol, chloramphenicol, Isoniazid
Antipyrine, dicumarol, probenecid, tolbutamide
Chlorpromazine
Propranolol
Cimetidine
Chlordiazepoxide, diazepam, warfarin
Dicumarol
Phenytoin
Disulfiram
Antipyrine, ethanol, phenytoin, warfarin
Grapefruit juice
Alprazolam atorvastatin, cisapride, cyclosporine
Oral contraceptives
Antipyrine
Phenylbutazone
Phenytoin, tolbutamide
Ritonavir
Amiodarone, cisapride, itraconazole, midazolam, triazolam
Saquinavir
Cisapride, ergot derivatives, midazolam, triazolam
Secobarbital
Secobarbital
Spironolactone
Digoxin
Itraconazole
Alfenatanil, astemizole, buspirone, cisapride, cyclosporine, delavirdine, diazepam, digoxin, felodipine, loratidine, phenytoin, quinidine, indinavir
Proteas inhibiters, sildenafil, statins, sirolimus, tacrolimus, verapamil, warfarin
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22. Ans. is a i.e. Tetracycline
Ref. KDT 6/e, p 714
Tetracycline causes temporary separation of bone growth when given during late pregnancy. So it is contraindicated in pregnancy.
  • Chloroquine is antimalarial of choice in pregnancy.
  • Erythromycin and Ampicillin : there is no teratogenicity seen with these drugs.
Mnemonic : TEtracycline is a TEratogen that causes staining of TEeth in the newborn.
23. Ans. is d i.e. Metoclopropamide
Ref. KDT 6/e, p 25
Drugs metabolised by Acetylation : N-Acetyl Conjugations
All the drugs having amino or hydrazine residues e.g. :
• Hydralazine
• Histamine
• INH (Isoniazid)
• Procainamide
• PAS
• Sulphonamides
• Dapsone
24. Ans. is a i.e. Enalapril
Ref. Goodman & Gilman 11/e, p 1482; KDT 6/e, p 23
ALL ACE inhibitors are Prodrugs except :
C
-
Captopril
L
-
Lisinopril
Prodrug - Few drugs are inactive as such and need conversion in the body to one or more active metabolites such a drug are called prodrugs list given in answer 7 of all india 07
25. Ans. is a i.e. Volume of distribution
Ref. KDT 6/e, p 34
Loading dose (or priming dose) is given to reduce the time needed to reach the steady state plasma concentration. The loading dose can be calculated by the following formula :
Loading dose = Desired plasma conc. (mg/L) x aVd (L/kg body weight)
So loading directly proportional to aVd ie volume of distribution
Since five half lives are needed to reach the steady state plasma concentration, several days would be wasted in obtaining the desired therapeutic effect. So, if there is a clinical emergency, like congestive heart failure with atrial fibrillation or hyperpyrexia due to malaria, we use drugs in loading dose to reach steady state in single short which is depicted in the figure below.
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33
26. Ans. is a i.e. Ketoconazole
Ref. Katzung 10/e, p 61 – 62
Already explained, refer answer no. 21
27. Ans. is b i.e. Metformin
Ref. KDT 6/e, p 35
Therapeutic drug monitoring is defined as the science that combines the measurement of serum drug concentrations with respect to clinical pharmacokinetics and pharmacodynamics.
Therapeutic drug monitoring (TDM) is particularly useful in the following situations :
  • Drugs with low safety margin – digoxin, anticonvulsants, antiarrhythmics, theophylline, aminoglycoside antibiotics, lithium, and tricyclic antidepressants.
  • If individual variations are large – antidepressants, lithium.
  • Potentially toxic drugs used in the presence of renal failure – aminoglycoside antibiotics, vancomycin.
  • In case of poisoning.
  • In case of failure of response without any apparent reason – antimicrobials.
  • The check patient compliance – psychopharmacological agents.
Commonly monitored drugs
Aminoglycosides
Antiarrhythmics
Antiepileptic
Antidepressants
Antipsychotics
Others
Amikacin
Amiodarone
Carbamazepine
Amitriptyline
Haloperidol
Digoxin
Gentamicin
Disopyramide
Clonazepam
Imipramine
Lithium
Salicylates
Netilmicin
Flecainide
Ethosuximide
Nortriptyline
Theophylline
Tobramycin
Lidocaine
Phenobarbitol
Cylosporin
Mexiletine
Phenytoin
Vancomycin
Procainamide
Valproic acid
Tacrolimus
Quinidine
Sotalol
28. Ans. is a i.e. Preclinical studies
Ref. KDT 6/e, p 76 – 77
Good clinical practice is a set of guidelines for biomedical studies which encompasses the design, conduct, termination audit, analysis, reporting & documentation of the studies involving human subjects.
For preclinical studies subjects are animals & the that according to GLP Good Laboratory Practice during which a wide range of non human studies e.g. toxicity testing pharmacokinetics analysis, formulation, etc are performed.
29. Ans. is b i.e. Labetalol
Ref. KDT 6/e, p 909 – 910
Choice of drugs for common problems during pregnancy.
Drug class
Unsafe
Safe
Antihypertensives
ACE inhibitors (X), Angiotensin antagonists (X), Thiazide diuretics, Furosemide, Propranolol, Nitroprusside
Methyldopa, Hydralazine, Atenolol, Metoprolol, Pindolol, Nifedipine, Prazosin, Clonidine labetalol
34
Antibacterials
Cotrimoxazole, Fluoroquinolones (X), Tetracycline (X), Doxycycline (X), Chloramphenicol (X), Gentamicin, Streptomycin (X), Kanamycin (X), Tobramycin (X), Clarithromycin, Azithromycin, Clindamycin, Vancomycin, Nitrofurantoin
Penicillin G, Ampicillin, Amoxicillin-Clavulanate, Cloxacillin, Pipera-cillin, Cephalosporins, Erythromycin
Antitubercular
Pyrazinamide, Ethambutol Streptomycin (X)
Isoniazid, Rifampicin
Antiamoebic
Tinidazole (X), Quiniodochlor
Metronidazole
Antimalarial
Quinine (X), Mefloquine Pyrimethamine + sulfadoxine (X), Artemether, Artesunate, Primaquine (X)
Chloroquine, Proguanil
Antiretrovial
Didanosine, Abacavir, Indinavir, Ritonavir, Efavirenz
Zidovudine, Lamivudine, Nevira-pine, Nelfinavir, Saquinavir
Antidiabetics
Sulfonylureas (X), Metformin (X), Pioglitazone, Rosiglitazone, Repaglinide, Nateglindie, Acarbose (X)
Insulin (preferably human insulin)
Corticosteroids
Betamethasone, Dexamethasone (high dose & prolonged use
Inhaled corticosteroids, Topical corticosteroids, Prednisolone oral (low dose)
Antithyroid drugs
Carbimazole, Radioactive iodine (X), Iodide
Propylthiouracil
Anticoagulants
Warfarin (X), Acenocoumarol, Phenindione (X)
Heparin (unfractionated) Heparin (LMW)
Drugs marked (X) are contraindicated during pregnancy.
30. Ans. is a i.e. ACE inhibitor
Ref. KDT 6/e, p 909 – 910; Katzung 10/e, p 975
Antihyperensive avoided in pregnancy are :
  • Diuretics
  • ACE inhibitors, causes renal damage
  • Reserpine
  • Nonselective β blockers
  • Sodium nitroprusside
For more details, refer answer no. 29
31. Ans. is b i.e. Cleft lip and cleft palate
Ref. Drugs in Pregnancy & Lactation, KDT 85, 6/e, p 888
Foetal aplasia cutis caused by carbimazole teratogenecity.
Congenital malformations secondary to exposure to carbimazole during gestation are :
• Scalp or patchy hair defect
• Choanal atresia
• Esophageal atresia
• Tracheo-esophageal fistula
• Minor facial anomalies
• Hypoplastic or absent phalanges
• Psychomotor delay
35
Drugs and their congenital malformation when taken in pregnancy are given below :
Drugs
Congenital malformation
• Penicillamine
• Cutis lexa
• Warfarin
• Contradi syndrome
• Chlorambucil
• Genitourinary anomaly (Renal agenesis)
• Valproic acid
• Neural tube defect
• Carbamezapine
• Cleft lip and palate, Cardiac defect
• Costicosteroid
• Congenital heart disease, cleft lip and palate
• Barbiturates
• Respiratory depression
• Carbimazole
• Foetal Aplasia Cutis
• Lithium
• Ebstein anomaly, Foetal goiter.
• DES
• Vaginal adenosis (Clear cell Ca)
• Thalidomide
• Phocomelia
• Chloramphenicol
• Grey baby syndrome
• Androgens
• Virilization; Limb, oesophagus and cardiac defects
• Isotretinoin
• Craniofacial defect, Heart anomaly, Abortion
• Indomethacin
• Premature closure of DA
• Tamoxifen
• Risk of Abortion and Foetal damage
32. Ans. is c i.e. Volume of distribution
Ref. Goodman & Gilman 11/e, p 730; KDT 6/e, p 18 – 19
When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the target concentration.
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Volume of drug distribution depends on :
• Lipid solubility
• Ionisation at physiological pH (dependent on pka).
• Differences in regional blood flow.
• Affinity for different tissues.
• Fat : lean body mass ratio.
• Diseases like CHF, uremia, cirrhosis.
• Extent of plasma and tissue protein binding.
33. Ans. is b i.e. Enalapril
Ref. KDT 6/e, p 23
All ACE inhibitor are prodrug except Captopril and Lasinopril.
For more details, refer answer no. 7
34. Ans. is b i.e. Metoclopramide
Ref. KDT 6/e, p 25
Drugs metabolised by Acetylation (N-Acetyl Conjugations) are the drugs having amino or hydrazine residues e.g. :
• Hydralazine
• Histamine
• INH (Isoniazid)
• Procainamide
• PAS
• Sulphonamides
• Dapsone
36
35. Ans. is a i.e. Specificity
Ref. Lawrence 9/e, p 93
Side effects of a drug arise due to the interactions of the drug molecules other than the target can be minimized by making the drug more specific eg., as we used cardioselective β−blocker have less side effect on respiratory system so side effects will be minimized by this process.
Lawrence States
“The pharmacologist who pruduces a new drug and the doctor who gives it to a patient share the desire that it should possess a selective action, so that additional and unwanted adverse effects do not complicate the management of the patient”
Affinity
Will enable drug to be used in low concentrations
Solubilty & Hydrophobicity
It will determine drugs capability to cross barriers in the body and act on target organ
36. Ans. is a i.e. High affinity
Ref. Rang & Dale 5/e, p 11, KDT 6/e, p 92
Affinity is the ability of the drug to bind with the receptor and is determined by the interaction of the molecular structures of the receptor and the drug.
Affinity
  • Affinity relates the drug concentration to the functional receptor occupancy.
  • The receptor occupancy by the drug is needed to elicit a response, so drug with hyper affinity will occupy larger number of receptor and produce more response at a given concentration than drug with lower affinity.
  • The drug which has more affinity will occupy more receptor at a given concentration and the drug which has low affinity will occupy lower number of receptor at a given concentration.
Efficacy (Intrinsic activity)
  • It is the ability of the drug to activate (induce a conformational change in) the receptor consequent to receptor occupation.
  • The two properties of affinity and intrinsic activity (IA) are independently variable, i.e. drugs with the same affinity can possess different degrees of intrinsic activity.
37. Ans. is c i.e. Heparin
Ref. Katzung 9/e, p 995
  • Heparin is a very large polar molecule, so unable to cross the placenta It is the drug of choice for the management and prophylaxis of venous thromboembolism in pregnancy
Drugs SAFE & UNSAFE in pregnancy Already explained, refer answer no. 29
Placental drug transport depends upon
Lipid solubility :
Unionized drug transportation > Ionized drug like thiopentone > Highly ionized drugs (SCh, d-tubocurarine).
Exception – Salicylates are almost completely ionized at physiological pH, even then foetal level is high because the small amount of salicylate which is not ionized is highly lipid soluble.
Molecular Size :
• Molecular size :
  • – 250–500 – Cross placenta easily, depending upon their lipid solubility and degree of ionization
37
  • – 500–1000 – Cross placenta more difficulty
  • – > 1000 – Cross very poorly
Membrane Transporters :
• P- glycoprotein transporter pumps back into the maternal circulation a variety of drugs, including cancer drugs (vinblastine, doxorubicin) and other agent (digoxin). Inhibition of this transporter may cause drug accumulation in the fetus.
Protein Binding, Placental and Foetal drug metabolism
38. Ans. is c i.e. The substrate concentration at half maximal velocity Ref. Lippincot's Biochem 2/e, p 53
  • Km is Michaleis-Menten constant. It is the characteristic of an enzyme and a particular substrate and it reflects the affinity of the enzyme for that substrate.
  • Km is numerically equal to the substrate concentration at which the reaction velocity is equal to ½ Vmax.
  • Numerically, small Km reflects a high affinity of the enzyme for substrate because a low concentration of the substrate is needed to half saturate the enzyme.
  • A numerically large Km reflects a low affinity of enzyme for substrate because a high concentration of substrate is needed to half saturate the enzyme.
  • The rate of the reaction is directly proportional to the enzyme concentration at all substrate concentration.
  • First order reaction - when substrate concentration is much less than Km, the velocity of the reaction is roughly proportional to the substrate concentration. The rate of the reaction is then said to be of first order.
  • Zero order reaction - When substrate concentration is much greater than Km, the velocity is constant and equal to Vmax. The rate of reaction is then independent of substrate concentration and said to be of the zero order.
39. Ans. is b i.e. Half life
Ref. Lippincott's Pharmacology 2/e, p 18; KDT 6/e, p 34
For all drugs with first order kinetics, the time required to achieve steady-state levels can be predicted from the half life. The steady state is reached in 3–5 half lives unless dose interval is very much longer than t½.
As regarding other options affecting steady state level
Clearance
• Clearance affects the steady state plasma concentration (Css) of the drug. There is no effect on the time required to achieve the steady level.
• Clearance is inversely proportional to the steady state concentration (Css).
Volume of distribution
• Volume of distribution is inversely proportional to Css. There is no relation to the time required to achieve the level.
• If the volume of distribution is increased, the Css level falls.
Rate of drug infusion
• If rate of drug infusion is increased, the Css increases but the time required to achieve the steady state level remains the same.
38
The following figure shows the rate of attainment of steady state concentration of drug in plasma and the rate of wash-out of drug when the drug infusion is stopped.
zoom view
40. Ans. is c i.e. Ketoconazole
Ref. KDT 6/e, p 25
Drugs metabolised by Acetylation (N-Acetyl Conjugations) are the drugs having amino or hydrazine residues e.g. :
• Hydralazine
• Histamine
• INH (Isoniazid)
• Procainamide
• PAS
• Sulphonamides
• Dapsone
Synthetic / Phase – II Biotransformation reactions :
Glucoronide conjugation : Microsomal conjugation
• All compounds having hydroxyl or carboxylic acid groups :
  • – Chloramphenicol
  • – Aspirin
  • – Phenacetin
  • – Morphine
  • – Metronidazole
  • – Endogenous substrates :
  • – Bilirubin
  • – Thyroxine
Non-Microsomal conjugation
Glycine conjugation :
  • – Salicylates
  • – Other drugs having carboxylic acid group
Glutathione conjugation :
  • It inactivate highly reactive quinone or epoxide intermediates formed during metabolism of certain drugs, e.g.
  • – Paracetamol
39
Methylation :
  • Amines and phenols are methylated e.g.
  • – Histamine
  • – Epinephrine
  • – Nicotinic acid
  • Mnemonic : HEN – Meat
Sulphate Conjugation :
  • Phenolic compounds and steroids are sulphated e.g.
  • – Chloramphenicol
  • – Adrenal and Sex steroids
41. Ans. is a i.e. Massive lymphocytic apoptosis
Ref. Goodman & Gilman 11/e, p 1599
Glucoconticoids Limited the recruitment of inflaumatory cells at the loca site KDT 6/e, p 278–79
Action of Glucocorticoids
Lymphoid malignancies
Activation of programmed cell death (apoptosis) in certain lymphoid tissues
Normal tissues
Redistribution of lymphocytes, eosinophils, monocytes and basophils away from the periphery. It leads to decrease in these cell counts within 4–6 hours.
Increased release of neutrophils from marrow diminished rate of removal from the circulation and increased demargination from vascular walls.
42. Ans. is a i.e. 2xµm
Ref. Lippincot's Biochem 2/e, p 53, KDT 6/e, p 32–33
  • Km is Michaleis Menten constant. It is numerically equal to the substrate concentration at which the reaction velocity is equal to ½ Vmax.
  • Now, in the question,
    Km = xµm and
    Km is the substrate concentration at which reaction velocity is ½ Vmax.
So, the maximum activity of the enzyme would be at a substrate concentration of 2xµm.
43. Ans. is c i.e. Verapamil
Ref. Goodman & Gilman 11/e, p 949; KDT 6/e, p 529
  • Goodman and Gillman describe Verapamil as :
  • For this reason, a given concentration of verapamil prolongs the PR interval to a greater extent when the drug is administered intravenously (where conc. of l- and d- enantiomers are equivalent) that when it is administered orally.
44. Ans. is d i.e. Decreased volume of distribution
Ref. KDT 6/e, p 62
There is increased volume of distribution for fat soluble drugs in elderly individuals. This results in decreased elimination of the drug which leads to increased toxicity.40
Other important changes seen in elderly which lead to increased toxicity of drugs
• Decreased renal excretion of drugs
• Decreased lean body mass
• Decreased hepatic metabolism of drugs
• Decreased total body water
• Increased receptor sensitivity in the target organs
• Increase in body fat
• Decrease plasma albumin
• Increase in α-1 acid glycoprotein
• Decrease GFR
• Decrease Tubular secretion
45. Ans. is c i.e. Ferrous sulphate + Tetracycline
Ref. KDT 6/e, p 712
  • Tetracyclines have chelating property – forms insoluble and unabsorbable complexes with calcium and other metals. Milk, iron preparations, nonsystemic antacids and sucralfate reduce their absorption. Administration of these substances and tetracyclines should be staggered.
  • Now looking at the other options :
    About clonidine + chlorpromazine : Chlorpromazine abolishes the antihypertensive action of clonidine probably by blocking the α (alpha) receptors on which it acts.
    About Gentamicin + Furosemide : High ceiling diuretics (Furosemide) and Aminoglycoside antibiotics are both ototoxic, produce additive toxicity should not be used together.
    Levodopa and Metoclopramide : Metoclopramide reverse the therapeutic effect of Levodopa by blocking DA receptors.
46. Ans. is a i.e. Brachycephaly
Ref. Katzung 9/e, p 372; KDT 6/e, p 85
Alcohol intake during pregnancy cause Foetal Alcohol syndrome.
The abnormalities that have been characterized as Foetal Alcohol syndrome include :
• Intrauterine growth retardation
• Microcephaly
• Poor coordination
• Minor joint anomalies
• Hyperkinetic movements
• Underdevelopment of midfacial region
• Cardiac malformation (ASD, PDA)
“Alcohol-related neurodevelopmental disorder” may also occur and its incidence is about three times more than foetal alcohol syndrome. it is characterised by behavioural as well as cognitive and motor deficits. This ethanol then triggers apoptotic neurodegeneration in CNS. Alcohol is easily secreted through breast milk which may delay motor development in the child
  • Molecular modelling allows new drug designing and development by the process of conceptualising for the performance of required function based on essential characteristics (pharmacopores), including idealized structural and physical properties.
  • Molecular modelling / computational chemistry is the science or art of representing molecular structure numerically and simulating their behaviour with the equation of quantum and classical physics.41
  • The development of molecular modelling programs and their application in pharmaceutic research has been formalised as a field of study known as computer assisted drug design (CADD) or computer assisted molecular design (CAMD).
48. Ans. is a i.e. 5 litre
Ref. KDT 6/e, p 19
zoom view
49. Ans. is d i.e. Propranolol
Ref. Harrison 17/e, p 657
Drugs that carry risk of clinical hemolysis in persons with G6PD deficiency.
Groups
Definite risk
Possible risk
Doubtful risk
Antimalarials
Primaquine
Dapsone/chlorproguanil
Chloroquine
Quinine
Sulphonamidex/sulphones
Sulphametoxazole
Others
Dapsone
Sulfasalazine
Sulfadimidine
Sulfisoxazole
Sulfadiazine
Antibacterial/antibiotics
Cotrimoxazole
Nalidixic acid
Nitrofurantoin
Niridazole
Ciprofloxacin
Norfloxacin
Chloramphenical
p-Aminosalicylic acid
Antipyretic/analgesics
Acentanilide
Phenazopyridine (Pyridium)
Acetylsalicylicacid high dose (3 g/d)
Acetylsalicylic acid <3 g/d
Acetaminophen
Phenacetin
Other
Naphthalene
Methylene blue
Vitamin K analogues
Ascorbic acid >1g
Rasburicase
Doxorubicin
Probenecid
50. Ans. is a i.e. Drug X will be available more in tissue
Ref. KDT 6/e, p 20
In the question drug X has 150 times lower affinity to bind with albumin than drug Y and it is clearly given in the book that highly plasma protein bound drugs are largely restricted to the vascular compartment and tend to have lower volume of distribution.
  • Option ‘c’ is confusing but the fact is that free concentration of the drug does not depend upon the plasma protein binding.42
Other important aspects of plasma protein binding :
  • The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma and dissociates when the concentration of the latter is reduced due to elimination. Plasma protein binding thus implies to temporary storage of the drug.
  • High degree of protein binding generally makes the drug long acting, because bound fraction is not available for metabolism or excretion, unless it is actively extracted by liver or kidney tubules.
  • Generally expressed plasma concentrations of the drug refer to bound as well as free drug.
  • One drug can bind to may sites on the albumin molecule. Conversely, more than one drug can bind to the same site. This can give rise to displacement interactions among drugs bound to the same site.
  • In nephrotic syndrome, binding may be reduced and high concentrations of free drug may be attained, e.g. phenytoin and furosemide.
51. Ans. is a i.e. Penicillin G
Ref. KDT 6/e, p 696
  • Penicillin G is metabolized mainly in kidney Pharmacokinetics of PnG is dominated by very rapid renal excretion (10%), by glomerular filtration and rest by tubular secretion (90%).
  • Rest of the drugs given in the question erythromycin cimetidine and phenytoin are metabolized in the liver.
52. Ans. is d i.e. Ketoconazole
Ref. KDT 6/e, p 27 – 28
Ketoconazole is microsomal enzyme inhibitors (not inducer).
Microsomal enzyme Induction :
• Anticonvulsant
– Phenobarbitone
– Phenytoin
– Glucocorticoids
• Antitubercular
– Rifampicin
– Isoniazid
• Steroid
– Glucocorticoids
• Others
– Chloral hydrate
– Phenylbutazone
– Griseofulvin
– DDT
53. Ans. is d i.e. Adrenaline and Histamine
Ref. KDT 6/e, p 56
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. has pharmacological effects in opposite direction, e.g.
  • Histamine and adrenaline on bronchial muscles and BP.
  • Hydrochlorothiazide and triamterene on urinary K+ excretion.
  • Glucagon and insulin on blood sugar level.
Other types of Antagonism
• Physical Antagonism
:
Universal antidote
43
• Chemical Antagonism
:
NaHCO3 + HCI, Heavy metal + chelating agent
• Pharmaceutical Interaction
:
Occurs outside the body to drug with other agent
Eg: IV phenytoin glucose bolus (Precipitation)
• Pharmacokinetic antagonism
:
Enzyme inducers decreasing activation of substrate
54. Ans. is a, b, c and d i.e. All are correct options
Ref. KDT 6/e, p 83
Drug dependence is a state in which use of drugs for personal satisfaction is accorded a higher priority than other basic needs, often in the face of known risks to health. Dependency includes both addiction and habituation.
  • Reinforcement is the ability of the drug to produce effects that make the user wish to take it again or to induce drug seeing behaviour. The frequency of use of drugs is usually daily and duration is inevitably greater than 2–3 weeks. (Option “a”)
  • Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome. (Option “c”)
55. Ans. is a i.e. Cyclophosphamide
Ref. Goodman & Gilman 11/e, p 1482; KDT 6/e, p 24
Prodrug
  • Few drugs are inactive as such and need conversion in the body to one or more active metabolites such a drug is called prodrugs.
  • The prodrug may offer advantages over the active form in being :
    • – More stable
    • – Having better bioavailability
    • – Other desirable pharmacokinetic properties
    • – Less side effects and toxicity.
Prodrug
Active form
Prodrug
Active form
Azathioprine
Mercaptopurine
Dipivefrine
Epinephrine
Bacampicillin
Ampicillin
Enalapril
Enalaprilat
Benyrolate
Aspirin + Paracetamol
Levodopa
Dopamine
Cortisone
Hydrocortisone
ProguanilProguanil
triazine
Cyclophosphamide
Aldophosphamide
Sulindac
Sulfide metabolite
Sulfasalazine
5 Aminosalicylic acid
Zidovudine (All NRTI's)
Zidovudine triphosphate
Mercaptopurine
Methylmercaptopurine
Flourouracil
Flourouridine mono PO4−−−
Prednisone
Prednisolone
ALL ACE inhibitors are Prodrugs except :
C
-
Captopril
L
-
Lisinopril
56. Ans. is b, c and d i.e. Phenytoin; Cyclosporin; and Digitalis
Ref. Katzung 10/e, p 377; KDT 6/e, p 405
The therapeutic plasma level of phenytoin for most patient is between 10 and 20 µg/ml.
Therapeutic level of some important drugs characterized by their low therapeutic index.
Digoxin
– 0.8 – 2 ng/ml
Clonidine
– 0.2 – 2.0 ng/ml
Phenytoin
– 10–20 µg/ml
Lithium
– 0.6 – 1.2 mEq/L (for prophylaxis)
Primidone
– 10–40µg/ml
– 0.8 – 1.2 mEq/L (for maintenance)
44
Theophyline
– 5 – 20 µg/ml
Quinidine
– 2 – 6 µg/ml
Valproic acid
– 50 – 100 µg/ml
Mnemonic :
Therapeutic dosage – toxicity values for most commonly monitored medications.
“The magic 2s”–
Digitalis (.5 – 1.5) toxicity
=
2
Lithium (.6 – 1.2) toxicity
=
2
Theophylline (10 – 20) toxicity
=
20
Dilantin (10 – 20) toxicity
=
20
57. Ans. is a and b i.e. Primaquine and Chloroquine
Ref. Harrison 17/e, p 657
Drugs that carry risk of clinical hemolysis in persons with G6PD deficiency.
Groups
Definite risk
Possible risk
Doubtful risk
Antimalarials
Primaquine
Dapsone/chlorproguanil
Chloroquine
Quinine
Sulphonamidex/sulphones
Sulphametoxazole
Others
Dapsone
Sulfasalazine
Sulfadimidine
Sulfisoxazole
Sulfadiazine
Antibacterial/antibiotics
Cotrimoxazole
Nalidixic acid
Nitrofurantoin
Niridazole
Ciprofloxacin
Norfloxacin
Chloramphenical
p-Aminosalicylic acid
Antipyretic/analgesics
Acentanilide
Phenazopyridine (Pyridium)
Acetylsalicylicacid high dose (3 g/d)
Acetylsalicylic acid <3 g/d
Acetaminophen
Phenacetin
Other
Naphthalene
Methylene blue
Vitamin K analogues
Ascorbic acid >1g Rasburicase
Doxorubicin
Probenecid
58. Ans. is a, b, c and d i.e. Decrease cost; Increase efficacy; Increase compliance; and Decrease resistance Ref. KDT 6/e, p 60
Advantage of fixed dose combination
  • Convenience and better patient compliance. It is cost saving compared to both / all the components administered separately.
  • Certain drugs combination are synergistic e.g., sulfamethoxazole + trimethoprim; levodopa + carbidopa / benserazide; combination oral contraceptives.
  • The therapeutic effect of two components being same may add up while the side effect being different may not add up e.g. amlodipine + atenolol.
  • The side effect of one component may be counteracted by other, e.g., thaizide + K+ sparing diuretics.
  • Combination drugs may decrease resistant to microbiological agents e.g. 1 + IV and tuberculosis.45
Disadvantage of fixed dose combination
  • The patient may not actually need all the drugs present in a combination. The patient is subjected to additional side effect and expense.
  • The dose of the most drugs needs to be adjusted as individualized; when a combined formulation is used, thus can not be done without alteration of the dose of the components.
  • The time course of action of the components may be different administering them at the same interval may be inappropriate.
  • Altered renal or hepatic function of the patient may differently affect the pharmacokinetics of the components.
  • Adverse effect, when it occurs, can not easily ascribe to the particular drug causing it.
  • Contraindication to one component (allergy / other conditions) contraindicates the whole preparation.
  • Confusion of therapeutic aims and false sense of superiority of two drugs over is fostered, especially in case of antimicrobials whose combinations should be avoided. Corticosteroids should never be combined with any other meant for internal use.
59. Ans. is a and c i.e. Enalapril; and Angiotensin receptor blocker Ref. Katzung 10/e, p 975
Enalapril and Angiotensin receptor blocker causes Renal damage when given during all course of pregnancy.
Drugs safe and unsafe during pregnancy given in Ans. 29.
60. Ans. is a, b, c and d i.e. Lipid solubility; Volume of distribution; Clearance; and Drug concentration Ref. KDT 6/e, p 31 – 32; Katzung 10/e, p 35
Clearance, the measure of the ability of the body to eliminate the drug.
Elimination of drug depends upon :
– Bioavailability
– Volume of distribution
– Clearance
  • Drug injected intravenously are completely absorbed and rapidly distributed, as they reach the blood stream directly without crossing any membrane.
  • Absorption occurs by passive diffusion from the injection site to the plasma or lymph.
  • Filtration through channels in the endothelial capillary membrane.
61. Ans. is e i.e. 0.2 liter/hr
Ref. KDT 6/e, p 18, 30
zoom view
Plasma volume of distribution.
zoom view
46
62. Ans. is d i.e. Indirect sympathomimetics involved Ref. KDT 6/e, p 68, Goodman & Gilman's 11/e, p 31, 162, 170
  • Tachyphylaxis is acute development of tolerance after a rapid and repeated administration of a drug at shorter intervals.
  • Tachyphylaxis is seen with indirectly acting sympathomimetics like ephedrine, amphetamine and tyramine.
  • These drugs act by releasing catecholamines (from the storage sites), the synthesis of which is unable to match its release.
Reason :
There is gradual depletion of the agonist from the storage sites with no chances of its replenishment because of the repeated administration of the drug at short intervals.
Tachyphylaxis may also occur as a result of a change in the sensitivity of target cells (pharmacodynamic reasons).
63. Ans. is a, b, c, d and e i.e. Active transport; Passive transport; Lipid solubility; Facilitated diffusion; and Symport
Ref. KDT 6/e, p 12
The major transport mechanism are as under :
• Passive Diffusion (Non-ionic or simple diffusion)
• Carrier Mediated Transport :
Facilitated diffusion / Symport
Active transport
• Pinocytosis / Phagocytosis and Filtration.
Modes of absorption
  1. Passive diffusion (Most common Mode)
    • Passage though semi-permeable membrane
    • Concentration dependent
    • Does not involve a carrier
      • – It is not saturable
      • – Lipid soluble drugs readily penetrate the biological membranes
      • – Water-soluble drugs penetrate through the water channels
      • – The unionized moiety is lipid soluble. E.g. Weak organic bases / acids alcohol, urea, glycosides
      • – pKa of the drugs and pH of surrounding medium determines the degree of ionization and hence the degree of absorption
  2. Convective transport : Drug soluble dissolved in the aqueous medium move along with the solvent through the pore. Since the diameter of the water filled pores is 7–10 A, only drugs having diameter <7A can pass through. In general globular molecules having molecules wt of 150 can pass (or chain like e.g. organic & inorganic electrolytes compounds having M.W < 400).
  3. Active transport :
    • Utilization of ATP and carrier molecule
    • Drugs having higher affinity can displace the drug having lower affinity for it
    • Drug can move against a concentration gradient
    • The process shows saturation kinetics for the carrier
      E.g. Monosaccharides / Amino Acids / cardiac glycosides / sex hormones47
  4. Facilitated transport :
    • This process utilizes a carrier and no energy but does not move against a concentration gradient.
      E.g. : Vit. B12 (+ intrinsic factor) ? absorption of B12
64. Ans. is a i.e. High first pass metabolism
Ref. KDT 6/e, p 28 – 29; Katzung 10/e, p 40
  • First pass (presystemic) metabolism refers to metabolism of a drug during its passage from the site of absorption in to the systemic circulation.
  • All orally administered drugs are exposed to drug metabolising enzymes in the intestinal wall and liver (where they first reach through the portal vein.
For a drug administered orally the bioavailability is < 100% due to because, incomplete extent of absorption and first pass metabolism.
Drugs may not be absorbed because of a reverse transporter associated with P-glycoprotein efflux pump.
65. Ans. is b, c, d and e i.e. Phenytoin; Carbamazepine; Rifampin; and Glucocorticoid Ref. KDT 6/e, p 24
Cytochrome P-450–3A4 carry out biotransformation of largest number of drugs. It is found in liver, intestine and kidney.
Inducers :
• Carbamazepine
• Glucocorticoids
• Rifampin
• Macrolide antibiotics
• Phenytoin
For more details about List of Enzyme induces and Inhibitors, refer answer no. 21
66. Ans. is a, b and c i.e. If drug is administered rectally it follow first order; If drug is administered IM it follows zero order; and If drug is administered IV it follows first order Ref. KDT 6/e, p 17 – 18, 28; Katzung 10/e, p 40
Bioavailability defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route.
For a drug administered orally bioavailability is < 100% due to incomplete extent of absorption and first pass metabolism.
Drugs may not be absorbed because of a reverse transporter associated with P-glycoprotein.
Mode of administration
Bioavailability
Oral
Irregular (different brands of same drug have different bioavailability)
Sublingual
Relatively good
Rectal
Relatively poor metabolized in liver
Inhalational
Relatively good
Parenteral (IV, IM, S/C)
–100%
Now come to pharmacokinetics
Zero order kinetics = Capacity limited = Saturable48
  • Rate of elimination remains constant irrespective of drug
  • Clearance decrease with increase in dose. E.g., Ethanol, Methanol.
1st order kinetics = Linear kinetics
  • Rate of elimination increase with increase in dose of drug
  • Clearance is constant
Note :
Few drugs, when given in high doses or in case of failure of excretion begin to show zero order kinetics (pseudozero order kinetics) eg. Phenytoin, Tolbutamide, Theophylline, Warfarin, Clarithromycin, Dicoumarol, Heparin, Salicylates.
67. Ans. is a and d i.e. Variability of enzyme action; and Different mechanism of action in different individual Ref. Katzung 10/e, p 58; KDT 6/e, KDT 6/e p 63
Cause of Variations in Action of Drugs :
  • The variations are mainly because of different rates of drugs metabolism due to different enzyme levels contributed by genetic factors.
  • The dose of drug to produce the same affect may vary by 4 – 6 fold so dose response curve may be different.
  • Example of genetically determined variations are :
    • Slow and fast acetylators for isoniazid
    • Atypical pseudocholinesterase resulting in prolongation of succinyl choline action.
68. Ans. is d i.e. Chlortetracycline + penicillin
Ref. KDT 6/e, p 55, 685, 723
Drug Synergism
:
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.
Now, considering each option separately.
Option ‘a’
Flucytosine has supra-additive action with amphotericin-B (AMB) in the case of fungi sensitive to both, e.g. Cryptococcoses, Coccidioidomycosis. (AMB increases the penetration of 5-FC into the fungus).
Option ‘b’
Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t½ (∼ 10hr). Optimal synergy in case of most organisms is exhibited at a concentration ratio of sulfamethoxazole 20 : trimethoprim 1, the minimum inhibitory concentration (MIC) of each component may be reduced by 3–6 times.
Option ‘c’
Penicillin/ampicillin + streptomycin/gentamicin is combined. Penicillin disrupts the bacterial cell wall, over come resistance.
Option ‘d’
This is the wrong answer. No synergism is reported for chlortetracycline + penicillin.
Other important antimicrobial combinations
  • Carbenicillin/ticarcillin + gentamicin for pseudomonas infection, specially neutropenic patients.
  • Ceftazidime + ciprofloxacin for pseudomonas infected orthopaedic prosthesis.
  • Rifampicin + INH in tubercular infection.49
69. Ans. is a, b and c i.e. Heparin; Pantoprazole; and Ranitidine Ref. KDT 5/e, p 178, 562, 591, 593, 702
  • Heparin is a large ionized molecule, therefore not absorbed orally. Injected I.V. it acts instantaneously but after s/c injection, anti coagulant effect develops after 60min. It does not cross Blood brain barrier or placenta It is the anticoagulant of choice during pregnancy.
  • Pantoprazole is a newer H+ K+ ATPase inhibitor. It is the only proton pump inhibitor available for I/V administration.
  • Ranitidine is H2 blocker which can be given orally, I/M or I/V.
  • Sumatriptan can be used by oral, nasal spray or subcutaneous route.
  • Neomycin is highly toxic drug, can be used orally or topically.
70. Ans. is a, b and d i.e. Efficacy is clinically more important than potency; Height of DRC corres-ponds to efficacy; and Drugs having similar pharmacological action may have different efficacy Ref. Katzung 9/e, p 28
Potency
Efficacy
Potency refers to the amount of drug needed to produce a certain response.
Efficacy refers to the maximal response that can be elicited by the drug. It refers to the maximum height of the curve.
Competitive antagonist acts by decreasing the potency of a drug, such that maximal response (efficacy) can still be attained by increasing dose of agonist. Causes rightward shift of DRC.
Non competitive antagonist acts by decreasing the efficacy of a drug. Maximal response is suppressed and unsurmountable. Causes flattening of DRC.
Potency refers to the concentration (EC50) or dose (ED50) of a drug required to clinical decisions when a large response is needed.
The efficacy of a drug is obviously crucial for making produced 50% of that drugs maximal effect. It is a more decisive factor in the choice of a drug.
• Potency of a drug depends in part on the affinity of receptors for binding the drug and in part on the efficiency with which drug receptor interaction is coupled to response.
• It may be determined by the drug's mode of interactions with receptors or by characteristics of the receptor effector system involved.
71. Ans. is b and c i.e. I.M. administration needs sterile technique; and I.D. injection produces local tissue neurosis and irritation
Ref. KDT 6/e, p 10
Let's analyse each option one by one.
Option ‘a’
• Through i.v. route, the drug directly reaches the systemic circulation and effects are produced immediately (great value in emergency).
Bioavailability is 100%.
• The intima of veins is insensitive and drug gets diluted with blood, Therefore, even highly irritant drugs can be injected I.V.
• Only aqueous solutions (not suspensions) can be injected I.V. and there are node pot preparations for this route.
50
• Dose of the drug required is smallest.
Option ‘b’ & ‘c’
• Not only i.m., but all the parenteral routes such as subcutaneous (S.C.), intramuscular (I.M.) intravenous (I.V.) and intradermal (I.D.) have the following disadvantages :
  • Preparation and technique needs to be sterile.
  • – It is costlier.
  • It is invasive, painful and can cause local tissue necrosis and irritation.
  • – Assistance of another person is mostly needed.
  • – There are chances of local tissue injury.
  • – It is in general, more risky.
Option ‘d’
In inhalation, absorption takes place from the vast surface of alveoli – immediate systemic bioavailability and very rapid action.
• Volatile liquids and gases are given by inhalation for systemic action e.g., amylnitrate.
• When administration is discontinued, the drug diffuses back and is rapidly eliminated in expired air.
72. Ans. is a, c, d, and e i.e. Obesity; Pregnancy; Older age; and Neonate Ref. KDT 6/e, p 19 – 20, 38; Katzung 10/e, p 40
Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route.
  • In obese patient, because of greater than normal adipose tissue content, Vd is increased Option ‘a’.
  • In pregnancy, blood volume increased by 30–40%. Although total protein is increased, but plasma protein concentration is decreased, thus altering Vd Option ‘c’.
  • In elderly, Vd is more because of increased total body fat content and decreased plasma protein binding of drugs Option ‘d’.
  • In neonates, because of greater volume of e.c.f, it provides a larger Vd of highly ionized drugs Option ‘e’.
Volume of drug distribution depends on :
• Lipid solubility
• Ionisation at physiological pH (dependent on pka).
• Differences in regional blood flow.
• Affinity for different tissues.
• Fat : lean body mass ratio.
• Diseases like CHF, uremia, cirrhosis.
• Extent of plasma and tissue protein binding.
There is increased volume of distribution for fat soluble drugs in elderly individuals. This results in decreased elimination of the drug which leads to increased toxicity.
73. Ans. is a, c and d i.e. Methotrexate; Rifampicin; and Tolcapone
Ref. Harrison 17/e, p 1951
Drugs which can cause diffuse hepatocellular damage have to be used cautiously in hepatic disease. So, if biluribuin is more than 1.5 mg/dl, the dose adjustment of the following drugs is needed :
• Acetaminophen
• Acebutolol
• Allopurinol
• Amiodarone
• Dapsone
• Erythromycin estolate
• Halothane
• Isoniazid
• Methotrexate
• Minocycline
• Nifedipine
• Quinidine
51
• Rifampicin
• Salicylates
• Tolcapone
• Verapamil
• Valproate
• Zidovudine
• Flutamide
• Nitrofurantoin
• Troafloxacin
• Phenytoin
• Carbamazine
• Nefazodone
• Methyldopa
• Oxyphenisatin
• Troglitazone
74. Ans. is a, b and c i.e. Lignocaine; Propranolol; and Salbutamol
Ref. KDT 6/e, p 28 – 29
  • First pass (presystemic) metabolism refers to metabolism of a drug during its passage from the site of absorption in to the systemic circulation.
  • All orally administered drugs are exposed to drug metabolising enzymes in the intestinal wall and liver (where they first reach through the portal vein).
Extent of first pass metabolism of important drugs :
Low
Intermediate
High
Not given orally
Given orally
– Phenobarbitone
– Aspirin
– Isoprenaline
Propranolol
– Phenylbutazone
– Quinidine
Lignocaine
– Alprenolol
– Tolbutamide
– Desipramine
– Hydrocortisone
– Verapamil
– Theophylline
– Nortriptyline
– Testosterone
Salbutamol
– Pindolol
– Chlorpromazine
– Nitroglycerine
– Pentazocine
– Morphine
– Metoprolol
– Pethidine
– Methyltestosterone
– Propoxyphene
75. Ans. is c and e i.e. Agranulocytosis; and Skin pigmentation
Ref. KDT 6/e, p 752
  • Dapsone is the simplest, cheapest and most active use antileprotic drug.
  • It is generally well tolerated at doses 100mg/day or less.
Adverse effects of Dapsone
Most common
• Hemolytic anaemia
• Methemoglobinemia
Cutaneous
• Allergic rashes
• Hypermelanosis
• Exfoliative dermatitis
• Fixed drug eruption
• Phototoxicity
Others
• Agranulocytosis
• Neuropathy
• Headache
• Psychosis
• Hepatitis
• Gastrointestinal intolerance
• Rash
• Lepra reaction
76. Ans. is b and d i.e. Propranolol; and Physostigmine
Ref. KDT 6/e, p 20, 101
  • The blood brain barrier is formed by capillary endothelial cells in brain having tight junctions and lacking large intercellular pores.
  • Both blood brain barrier and blood CSF barrier are lipoidal and limit the entry of non-lipid soluble drugs.52
  • Lipid soluble drugs are able to cross the blood-brain barrier such as :
    – Levodopa
    – Physostigmine
    – Propranolol
    – Organophosphates
  • Lipid insoluble drugs are not able to cross the blood-brain barrier such as :
– Streptomycin
– Neostigmine
– Hexamethonium
– Dopamine
– Glycopyrrolate
77. Ans. is a and c i.e. Lithium; and Phenytoin
Ref. KDT 6/e, p 35
Low therapeutic range is seen in following drugs :
• Lithium
• Digoxin
• Lignocaine
• Aminoglycosides
• Theophylline
• Anticonvulsants e.g. phenytoin
Fore more detail refer answer no. 27
78. Ans. is b, c and d i.e. Sulfonation; Methylation; and Glucuronization Ref. KDT 6/e, p 22 – 26
Biotransformation occurs as follows :
zoom view
Mnemonics
All reactions starting with ‘De’ are phase – I reactions
Dealkylations
Deaminations
Desulphuration
Dechlorination
Decyclization
All the reactions starting with ‘G’ are phase – II reactions
Glucoronide conjugation
Glycine conjugation
Glutathione conjugation
53
zoom view
79. Ans. is c i.e. Chloroquine
Ref. Katzung 10/e, p 975, KDT 909, 910
Already explained, refer answer no. 29
80. Ans. is a, b, d and e i.e. Propranolol; Lidocaine; Imipramine; and Theophylline Ref. KDT 5/e, p 126, 203, 409, 659
Option ‘a’
Propranolol is well absorbed after oral administration, but has low bioavailability due to high first pass metabolism in liver. Oral : parenteral dose ratio of up to 40:1 has been found.
Option ‘b’
Lidocaine also undergoes high first pass metabolism in the liver.
Option ‘c’
Ampicillin is partly excreted in bile and reabsorbed – entero hepatic circulation occurs. However, primary channel of excretion is kidney.
Option ‘d’
Tricyclic antidepressant (Imipramine) are extensively metabolized in the liver, the major route for Imipramine and Amitriptyline is demethylaton whereby active metabolites-desipramine and nortriptyline respectively are formed.
Option ‘e’
Theophyline is extensively metabolized in liver by demethylation and oxidation.
81. Ans. is b, c, d and e i.e. Warfarin; Valproic acid; Steroids; and Phenytoin Ref. KDT 6/e, p 85; Drugs in Pregnancy & Lactation 6/e, p 888
Already explained, refer answer no. 3154
82. Ans. is a, b, c, and d i.e. Antithistaminics; Antithyroid drugs; Penicillin; and Diazepam Ref. KDT 6/e, p 912 – 914
There is a huge list of the drugs which are secreted in breast milk in small to large amounts and may cause harm to foetus but we are highlighting a select few :
– Acyclovir
Benzodiazepenes
– Iodine/ Iodides
– Alcohol
– Chloramphenicol
– Metformin
– Amiodarone
– Ciprofloxacin
– Metronidazole
– Amphetamines
– Cyclosporine
Penicillins
– Androgens
– Dapsone
– Streptomycin
– Anticancer drugs
– Diltiazem
– Tetracyclines
Antihistaminics (H1)
– Ergotamine
Antithyroid drugs (Carbimazole)
– Estrogens
– Azathioprine
These are the drugs which are either contraindicated in breast feeding or are secreted in significant amounts to cause harm to the foetus.
83. Ans. is a i.e. ↑↑ free drug plasma level
Ref. KDT 6/e, p 20 – 21
There are certain concepts relating to drugs with plasma protein binding.
  • Displacement of protein bound drugs leads to increased free drug plasma level.
    • – One drug can bind to many sites on albumin molecule Conversely, more than one drug can bind to the same site.
      This can give rise to displacement interactions among drugs bound to the same site.
      Drugs bound with higher affinity will displace that bound with lower affinity.
    The concentration of free (displaced drug) is increased but is transient and achieves a steady level of free drug concentration which is only marginally higher unless displacement extends to tissue binding or there is concurrent inhibition of metabolism or excretion. E.g. Phenylbutazone and salicylates displace tolbutamide Indomethacin, phenylbutazone displace tolbutamide Sulphonamide and vit. K displace bilirubin (Kernicterus in neonates).
  • Highly plasma protein bound drugs are largely restricted to the vascular compartment and thus, have lower volumes of distribution.
  • The bound fraction is not available for action.
    The bound fraction is in equilibrium with the free drug plasma and dissociates when the concentration of latter is reduced.
    Protein bound drug is thus equivalent to temporary storage of the drug.
  • High degree of protein binding generally makes the drug long acting, because fraction is not available for metabolism or excretion.
  • Generally expressed plasma concentrations of the drug refer to bound as well as free drug.
  • In hypoalbuminemia (nephrotic syndrome), binding may be reduced and high concentrations of free drug may be attained (e.g, phenytoin and furosemide).55
84. Ans. is a i.e. Highly lipophilic
Ref. KDT 6/e, p 18 – 19
  • One of the most important factor responsible for maximum distribution is lipid solubility of a drug.
  • The extent of distribution of a drug depends upon :
    – Lipid solubility
    – Ionisation at physiological pH (dependent on pka)
    – Differences in regional blood flow
    – Extent of binding to plasma and tissue proteins
85. Ans. is a i.e. Side effects
Ref. KDT 6/e, p 78–80
Both side effects and toxicity are Type – A – ADR. But side effect are seen at therapeutic doses while toxicity is due to prolonged use or overdose.
zoom view
86. Ans. is b i.e. Has affinity as well as intrinsic activity
Ref. KDT 6/e, p 42
Agonists
have both affinity and maximal intrinsic activity (IA = 1), e.g. adrenaline, histamine, morphine.
Competitive antagonists
have affinity but no intrinsic activity (IA = 0), e.g. propranolol, atropine, chlorpheni-ramine, naloxone.
Partial agonists
have affinity and submaximal intrinsic activity (IA between 0 to 1), e.g. dichloroisoproterenol, nalorphine.
Inverse agonists
have affinity but intrinsic activity with a minus sign (IA between 0 to − 1), e.g. DMCM.
87. Ans. is b i.e. Log dose response curve is sigmoid shaped
Ref. KDT 6/e, p 52 – 53
  • The dose response curve (DRC) is a rectangular hyperbola but if the dose is plotted on logarithmic scale, the curve becomes sigmoid as is evident in figure below :56
    zoom view
  • The advantages of plotting log dose – response curves are :
    • A wide range of drug doses can be easily displayed on a graph.
    • Comparison between agonists and study of antagonists become easier.
  • The position of DRC on the dose axis is the index of drug potency which refers to the amount of drug needed to produce a certain response.
  • The upper limit of DRC is the index of drug efficacy and refers to the maximal response that can be elicited by the drug.
88. Ans. is a i.e. G-protein
Ref. KDT 6/e, p 48, 349
GABA acts through its specific receptors GABAA and GABAB which are characterized as follows :
GABAA receptor
GABAB receptor
– Intrinsic ion channel receptor
– G-protein coupled receptor
– Increases Cl conductance
– Not antagonized by Bicuculline
– Blocked by Bicuculline
– Blocked by saclofen
– Facilitated by benzodiazepenes
– Hyperpolarises neurons by increasing K+ conductance and altering Ca++ flux
89. Ans. is c i.e. Efficacy
Ref. KDT 6/e, p 53 – 54; Katzung 10/e, p 28
Efficacy
– The upper limit of Dose response curve (DRC) is the index of drug efficacy and refers to the maximal response that can be elicited by the drug.
Potency
– The position of DRC of the dose axis is the index of drug potency which refers to the amount of drug needed to produce a certain response.
90. Ans. is a i.e. Barbiturate poisoning
Ref. KDT 6/e, p 30
  • Acidic drugs such a Barbiturates and Salicylates ionize more and are less reabsorbed in alkaline urine. Therefore, urine is alkalinised in barbiturate poisoning.
  • On the other hand, basic drugs such as morphine and amphetamine ionise more and are less reabsorbed in acidic urine. Thus, urine is acidified in their poisoning.57
91. Ans. is a i.e. Best absorbed in acidic medium
Ref. KDT 6/e, p 15
  • Acidic drugs e.g., salicylates, barbiturates etc. are predominantly unionised in acid gastric juice and are absorbed from the stomach.
    because acidic drugs ionise in alkaline medium in the small intestines; and once ionised, the ions being lipid insoluble, do not diffuse across gastric mucosal cells.
  • Basic drugs, on the other hand, like morphine, quinine etc. are largely ionised and are absorbed only on reaching the duodenum.
  • Acidic drugs bind to albumin wile basic drugs bind to α1-acid glycoprotein.58
 
CHAPTER REVIEW
  • This section includes questions of Various Other PGMEES from 1990 – 2008.
  • Questions are arranged in increasing order of page sequence of KDT 6 Edition. This is done to make referral system more easy and uncomplicated to save the precious time of PGMEE Aspirant.
  1. All are inhibitors of cytochrome P-450 enzymes except : (Manipal 07)
    1. Amiodarone
    2. Disulfiram
    3. Fluoxetine
    4. Rifampicin
      [Ref. KDT 6/e, p 27]
  1. When causes least “gain in weight”? (NIMHANS 06)
    1. Olanzapine
    2. Risperidone
    3. Quetiapine
    4. Ziprasidone
      [Ref. CMDT, p 1063]
  1. Loading dose depends on the following factors except : (APPG 06)
    1. Drug concentration to be achieved
    2. Volume of distribution
    3. Clearance of the drug
    4. Bioavailability of drug
      [Ref. KDT 6/e, p 34]
  1. How long does the protection from passive immunization using an immune globulin preparation typically last ? (MAHE 05)
    1. 1 to 3days
    2. 1 to 3 weeks
    3. 1 to 3 months
    4. 1 to 3 years
      [Ref. KDT 6/e, p 886]
  1. Half life does not help in estimating : (SGPGI 05)
    1. Margin of safety
    2. Time taken to eliminate the drug completely from the body
    3. Dosing schedule
    4. Cone, of drug in body at a particular time after its administration
      [Ref. Katzung 10/e, p 38 – 39]
  1. Therapeutic index of a drug is an indicator of : (J & K 05)
    1. Potency
    2. Safety
    3. Action
    4. Efficacy
      [Ref. KDT 6/e, p 55]
  1. All are reasons for reducing drug dosage in elderly except : (MAHE 05)
    1. They are lean and their body mass is less
    2. Have decreasing renal function with age
    3. Have increased baroreceptor sensitivity
    4. Body water is decreased
      [Ref. KDT 6/e, p 52]
  1. The drugs that does not cause Raynaud's phenomenon: (APPG 05)
    1. Vincristine
    2. Bleomycin
    3. Vinblastin
    4. Cisplatin
      [Ref. Laurence 9/e, p 613, 614; Goodman & Gilman 10/e, p 1435]
  1. Competitive inhibition : (Manipal 05)
    1. Response depends on antagonist concentration
    2. Antagonist binds to same receptor as agonist
    3. Binds to different sites
    4. Reduces intrinsic activity of agonist
      [Ref. KDT 6/e, p 57]
  1. Which one of the opioids has maximum plasma protein binding capacity ? (Jipmer 05)
    1. Morphine
    2. Sulfentanil
    3. Fentanyl
    4. Pethidine
      [Ref. KDT 6/e, p 458]
Answer
1. d. Rifampicin
2. d. Ziprasidone
3. c. Clearance of …
4. c. 1 to 3 months
5. a. Margin of …
6. b. Safety
7. c. Have increased …
8. a and c
9. b. Antagonist …
10. d. Pethidine
59
  1. Which of the following given in pregnancy has teratogenic effects : (APPGE 04)
    1. Vit. B6
    2. Vit. B3
    3. Folic acid
    4. Vit. D
      [Ref. KDT 6/e, p 85; Katzung 10/e, p 975]
  1. Clearance means : (Manipal 04)
    1. Rate of elimination/plasma concentration
    2. Plasma concentration/half life
    3. Time taken for the plasma concentration of the drug to be reduced to half its original value
    4. Rate of elimination X plasma concentration
      [Ref. KDT 6/e, p 31]
  1. Steady state means : (Manipal 04)
    1. Dose rate X clearance
    2. Dose rate/clearance
    3. Clearance/dose rte
    4. Rate of elimination/plasma concentration
      [Ref. KDT 6/e, p 33]
  1. Drugs which cannot be safely used in pregnancy all except ? (Manipal 03)
    1. Tetracycline
    2. Sulphonylurea
    3. Heparin
    4. Warfarin
      [Ref. KDT 6/e, p 598]
  1. The antibiotic which cannot be safely used in pregnancy are all except : (Manipal 03)
    1. Tetracycline
    2. Ampicillin
    3. Streptomycin
    4. Sulphonamides
      [Ref. KDT 6/e, p 85]
  1. Zero order kinetics is not followed by : (Manipal 03)
    1. Phenytoin
    2. Ethanol
    3. Barbiturates
    4. Salicylates
      [Ref. KDT 6/e, p 31]
  1. If a drug is given repeatedly at approximately the same time as its half life, after how many dosages will the drug achieve a steady a state in plasma : (Manipal 03)
    1. 2 – 3
    2. 4 – 5
    3. 8 – 9
    4. 6 – 8
      [Ref. KDT 6/e, p 33]
  1. To increase the fetal lung maturity the drug to be used is : (Manipal 03)
    1. Methyldopa
    2. Propranolol
    3. Insulin
    4. Betamethasone
      [Ref. KDT 6/e, p 284]
  1. True regarding “Plasma half life” of drugs :
    1. Maximum effective dose of drug
    2. Max. lethal effect (Manipal 02)
    3. Potency of drug
    4. Dose frequency interval
      [Ref. KDT 6/e, p 33–34]
  1. Downgrading of receptors is due to : (Manipal 01)
    1. Increased uptake of agonist by them
    2. Increased interaction with antagonist
    3. Both of the above
    4. None of the above
      [Ref. KDT 6/e, p 68]
  1. Which of the following does not cross placenta ? (Manipal 00)
    1. 131I
    2. Heparin
    3. Warfarin
    4. Dicoumarol
      [Ref. KDT 6/e, p 85]
  1. All are examples of prolong except : (Up 01)
    1. Enalapril
    2. Cortisone
    3. Azathioprine
    4. Mercaptopurine
      [Ref. KDT 6/e, p 23 – 24]
  1. True about partial agonist is : (Up 01)
    1. Produces maximal effect
    2. Supramaximal effect
    3. Produces submaximal effect
    4. Effect in opposite direction
      [Ref. KDT 6/e, p 40 – 41]
  1. Basic drug binds to : (Up 00)
    1. α-acidic glycoprotein
    2. Albumin
    3. Lipoprotein
    4. Mucoprotein
      [Ref. KDT 6/e, p 13 – 14]
  1. Km value indicates : (Up 00)
    1. Purity of enzyme
    2. Physiological role
    3. Half life enzyme drug complex
    4. Affinity
      [Ref. KDT 6/e, p 31 – 34]
Answer
11. d. Vit. D
12. a. Rate of …
13. b. Dose rate/ …
14. c. Heparin
15. b. Ampicillin
16. c. Barbiturates
17. b. 4 – 5
18. d. Betamethasone
19. d. Dose …
20. a. Increased …
21. b. Heparin
22. c. Azathioprine
23. c. Produces …
24. a. α-acidic …
25. c. Half life …
26. b. Psychological
60
  1. Placebo effect is : (UP 99)
    1. Pharmacological
    2. Psychological
    3. Trial of drug effect
    4. Drug dependence
      [Ref. KDT 6/e, p 65]
  1. Generic drug true is : (UP 99)
    1. High cost
    2. Increased bioavailability
    3. Low cost
    4. Reduced clearance
      [Ref. KDT 6/e, p 63]
  1. Oxidative elimination of drug : (UP 99)
    1. Conjugation
    2. Azo reduction
    3. Acetylation
    4. Sulfoxide
      [Ref. KDT 6/e, p 35]
  1. Monitoring of plasma level is required in : (UP 99)
    1. Carbamazepine
    2. Diazepam
    3. Valproic acid
    4. Phenytoin
      [Ref. KDT 6/e, p 35]
  1. Which of the following drug has high first pass metabolism : (UP 98)
    1. Propranolol
    2. Phenytoin
    3. Doxycycline
    4. Pentazocine
      [Ref. KDT 6/e, p 28]
  1. All are examples of microsomal inducers except : (UP 98)
    1. Phenytoin
    2. Ethanol
    3. Cimetidine
    4. Rifampicin
      [Ref. KDT 6/e, p 27]
  1. All are examples of prodrug except : (UP 98)
    1. Enalapril
    2. Bacampicillin
    3. Levodopa
    4. Phenylbutazone
      [Ref. KDT 6/e, p 24]
  1. Following drugs are hepatic microsomal inducers except : (UP 97)
    1. Alcohol
    2. Cimetidine
    3. Phenyramine
    4. Sulphonamides
      [Ref. KDT 6/e, p 26 – 27]
  1. All drug can cross placenta except : (UP 95)
    1. Heparin
    2. Diazepam
    3. Theophylline
    4. Warfarin
      [Ref. KDT 6/e, p 598]
  1. Drug contraindicated with pregnancy : (UP 95)
    1. Hydralazine
    2. Propranolol
    3. Methyldopa
    4. Magnesium sulphate
      [Ref. KDT 6/e, p 553]
  1. The advantages of transdermal delivery system are a/e : (UP 95)
    1. High peak plasma level
    2. Slow releasing
    3. Continuous
    4. Effect comes late
      [Ref. KDT 6/e, p 9]
  1. Which drug causes hyperuricemia is : (UP 94)
    1. Pyrazinamide
    2. Rifampicin
    3. Ethambutol
    4. Streptomycin
      [Ref. KDT 6/e, p 742]
  1. Which is not prodrug : (UP 94)
    1. Oxyphenbutazone
    2. Azathioprine
    3. Cholecaflciferol
    4. Sulindac
      [Ref. KDT 6/e, p 24]
  1. Plasma monitoring is essential in therapy of : (UP 94)
    1. Ethosuccimide
    2. Phenobarbitone
    3. Phenytoin
    4. Sodium valproate
      [Ref. KDT 6/e, p 404]
  1. Which of the following avoids lst bypass effect of drug : (UP 93)
    1. Intra-arterial injection
    2. Rectal suppositories
    3. Intravenous injection
    4. Oral insertion
      [Ref. KDT 6/e, p 28]
Answer
27. c. Low cost
28. d. Sulfoxide
29. d. Phenytoin
30. a. Propranolol
31. c. Cimetidine
32. d. Phenylbutazone
33. b. Cimetidine
34. a. Heparin
35. b. Propranolol
36. a. High peak …
37. a. Pyrazinamide
38. a. Oxyphenbu ….
39. c. Phenytoin
40. a. Intra-arterial …
61
  1. Serum level measurement of a drug is not useful in : (AIIMS Dec. 94)
    1. Large person to person difference in serum levels
    2. Drug with low margin of safety
    3. Drug activated in body
    4. To check compliance
      [Ref. KDT 6/e, p 35]
  1. Cy-GMP is the second messenger of : (AIIMS May 94)
    1. Growth hormone
    2. Follicle stimulating hormone (FSH.-with AMP)
    3. Insulin -Phosphorylate
    4. Thyroxin-at nuclear receptor
      [Ref. KDT 6/e, p 48]
  1. All induce liver microsomal enzyme except : (AIIMS May 94)
    1. Metyrapone
    2. Carbamazepine
    3. Glutethimide
    4. Phenobarbitone
      [Ref. KDT 6/e, p 419]
  1. All are nephrotoxic, except : (AIIMS Nov. 93)
    1. Lithium
    2. Gentamicin
    3. Chlorpromazine
    4. Cephalosporin
      [Ref. KDT 6/e, p 428]
  1. Half-life of a drug is a good indicator of the following, except : (AIIMS June 92)
    1. Time required to reach steady state
    2. Time for a drug to be removed from the body
    3. Appropriate dosing interval
    4. Margin of safety
      [Ref. KDT 6/e, p 32 – 35]
  1. All of following cross plasma membrane, except: (June 1991)
    1. Androstenodione acts on cytoplasmic steroid hormone or receptors
    2. M- Dopa
    3. Epinephrine
    4. Thyroxine
      [Ref. KDT 6/e, p 805]
  1. Which of the following is not an inducer of hepatic microsomal enzymes : (AIIMS June 91)
    1. Phenytoin
    2. Meprobamate
    3. Tolbutamide
    4. Rifamipicin
      [Ref. KDT 6/e, p 26 – 27]
  1. Which is the advantage of sublingual route of administration of drugs : (Jipmer 91)
    1. Prevents first pass effect
    2. Easy to administer
    3. Lipid soluble
    4. Can be spitted out with signs of toxicity
      [Ref. KDT 6/e, p 7]
  1. Drugs mostly cross biological membranes by : (ROHTAK 98)
    1. Passive diffusion
    2. Active diffusion
    3. Active transport
    4. Carrier mediated transport
    5. All of the above
      [Ref. KDT 6/e, p 12]
  1. The alkaline drug (Amidopyrine) is absorbed from: (AI 91)
    1. Stomach
    2. Proximal small intestine
    3. Distal small intestine
    4. Colon
      [Ref. KDT 5/e, p 16]
  1. All of the following are protein bound except : (Delhi 92)
    1. Propranolol
    2. Atenolol
    3. Phenylbutazone
    4. Warfarin
      [Ref. KDT 6/e, p 20]
  1. What is prodrug : (Jipmer 91)
    1. Drug which increase efficiency of another drug
    2. Metabolic end product
    3. Inactive drug which gets activated in the body
    4. Drug which competes with another for metabolism
      [Ref. KDT 6/e, p 23]
  1. Prodrugs are : (NIMHANS 01)
    1. Lisinopril
    2. Ramipril
    3. Enalapril
    4. Captopril
      [Ref. KDT 6/e, p 24]
  1. Which cytochrome is responsible for drugs metabolism? (TN 95)
    1. P-450
    2. C-3b
    3. C-3A
    4. C-2a
      [Ref. KDT 6/e, p 24]
Answer
41. c. Drug activated …
42. None
43. a. Metyrapone
44. c. Chlorpromazine
45. d. Margin of …
46. b. M- Dopa
47. b and c
48. a. Prevents …
49. a. Passive …
50. b. Proximal …
51. b. Atenolol
52. c. Inactive …
53. b and c
54. a. P-450
62
  1. Which of the following statements is correct ?
    1. Most drugs are absorbed in ionised form
    2. Basic drugs are generally bound to plasma albumin (Karn 94)
    3. Microsomal enzymes are located in the mitochondria of hepatic cells
    4. Blood brain barrier is deficient at the chemoreceptor trigger zone
      [Ref. KDT 5/e, p 14, 12, 18, 23]
  1. Enzyme cytochrome p450 inhibitors are : (NIMHANS 01)
    1. Sodium valproate
    2. INH
    3. Rifampicin
    4. Ethambutol
      [Ref. KDT 6/e, p 27]
  1. Drug with extensive first pass metabolism : (Jipmer 91)
    1. Propranolol
    2. Digoxin
    3. Quinidine
    4. Chlorpromazine
      [Ref. KDT 6/e, p 28]
  1. Which of the following shows high first pass metabolism : (ROHTAK 98)
    1. Propranolol
    2. Phenobarbitone
    3. Phenylbutazone
    4. Phenytoin
      [Ref. KDT 6/e, p 28]
  1. Substrate concentration and velocity curve indicates : (PGI 96)
    1. Michelis – Mentons equation
    2. Inverse relation
    3. Zero order kinetics
    4. All of the above
      [Ref. KDT 6/e, p 33; Harper 24/e, p 83]
  1. Plasma concentration of drug at time 0 is 96 g/ml. If tl/2 is 2 hours concentration in plasma at 10 hours will be : (MAHE 98)
    1. 4
    2. 24
    3. 12
    4. 3
      [Ref. KDT 6/e, p 32]
  1. T 1/2 of a drug can determine all the following except : (AIIMS 90)
    1. Dosing interval
    2. Elimination time
    3. Steady plasma concentration
    4. Therapeutic dosage
      [Ref. Katzung 10/e, p 38–39]
  1. Indiosyncrasy is : (Karnat 96)
    1. A genetically determined abnormal reaction drugs
    2. A characteristic toxic effect at therapeutic doses
    3. An altered physiological state produced by repeated drugs use
    4. An immunologic ally mediated reaction
      [Ref. KDT 6/e, p 81]
  1. Drug which crosses the placental barrier is : (DELHI 84, 92)
    1. Phenytoin
    2. Diazepam
    3. Corticosteroids
    4. All of the above
      [Ref. KDT 6/e, p 85; Katzung 10/e, p 975]
  1. The effects of hypoglycemia is marked by : (TN 90)
    1. Warfarin
    2. Beta blockers
    3. Calcium channel blockers
    4. Aminoglycosides
      [Ref. KDT 6/e, p 138]
  1. The intake of which of the following is associated with an increase in weight : (CUPGEE 96)
    1. Chlorpromazine
    2. Methyldopa
    3. OCP
    4. Thyroxine
      [Ref. KDT 6/e, p 315]
  1. Gout is precipitated by all except : (MP 98)
    1. Furosemide
    2. Vincristine
    3. Penicillin
    4. Sulfinpyrazone
      [Ref. KDT 6/e, p 205]
  1. Which of the following drugs causes post anaesthetic muscle stiffness : (AI 91)
    1. Fentanyl
    2. Pyridostigmine
    3. Suxamethonium
    4. Gallamine
      [Ref. KDT 6/e, p 346]
  1. Drugs absorbed by active transport is : (NIMS 96)
    1. Propranolol
    2. Ergotamine
    3. Levodopa
    4. Amantidine
      [Ref. KDT 6/e p 417]
Answer
55. d. Blood …
56. d. Ethambutol
57. a. Propranolol
58. a. Propranolol
59. a. Michelis …
60. d. 3
61. d. Therapeutic …
62. a. A genetically …
63. d. All of the above
64. b. Beta blockers
65. c. OCP
66. d. Sulfinpyrazone
67. c. Suxamethonium
68. c. Levodopa
63
  1. Drug with extensive first pass metabolism : (Jipmer 92)
    1. Propranolol
    2. Haloperidol
    3. Diazepam
    4. Acetazolamide
      [Ref. KDT 6/e, p 28]
  1. Cough is an adverse reaction with intake of : (PGI 93)
    1. Captopril
    2. Prazosin
    3. Nifedipine
    4. Thiazide
      [Ref: KDT 6/e, p 484]
  1. Cough is an adverse reaction seen with intake of: (PGI 93)
    1. Thiazide
    2. Nifedipine
    3. Enalapril
    4. Prazosin
      [Ref: KDT 6/e, p 485]
  1. Which of the following is not a dose related reaction : (JIPMER 92)
    1. Myocardial irritation of quinidine
    2. Hypoglycemia of tolbutamide
    3. Digitalis induced arrhythmia
    4. Drug fever of sulpha
      [Ref. KDT 5/e, p 643, 476, 248, 462]
  1. Which dose not cross placental barrier : (AIIMS 90)
    1. Diazepam
    2. Pethidine
    3. Atropine
    4. Dicoumerol
      [Ref. Goodman & Gilman 10/e p 594]
  1. Urine is coloured due to the intake of : (UPSC 97)
    1. Phenindione
    2. Phenobarbitone
    3. Phenytoin
    4. Quinine
      [Ref. KDT 6/e, p 601]
  1. Not a prodrug : (JIPMER 99)
    1. Lisinopril
    2. Enalapril
    3. Ramipril
    4. Famotidine
      [Ref. KDT 6/e p 24]
  1. Which drug has a high first pass effect : (Jipmer 91)
    1. Amiodarone
    2. Phenytoin
    3. Verapamil
    4. Disopyramide
      [Ref. KDT 6/e, p 28]
  1. Urine is coloured due the intake of : (CUPGEE 96)
    1. Phenindione
    2. Phenobarbitone
    3. Phenytoin
    4. Quinine
      [Ref. KDT 6/e, p 601]
  1. Drugs which increase the metabolism of warfarin in/are : (PGI 90)
    1. Rifampicin
    2. Septran
    3. Phenylbutazone
    4. Phenobarbitone
      [Ref. KDT 6/e, p 28, 603; Katzung 10/e, p 55, table 4–2]
  1. Which one of the following drugs dose not exhibit zero order kinetics : (CUPGEE 96)
    1. Phenytoin
    2. Ethanol
    3. Salicylate
    4. Ranitidine
      [Ref. KDT 6/e, p 31]
  1. All the prodrugs except : (Jipmer 95)
    1. Enalapril
    2. Paracetamol
    3. Sulphamethoxazole
    4. Trimethoprim
      [Ref. KDT 6/e, p 24]
  1. One of the following in high doses can cause convulsions : (AI 90)
    1. Penicillin
    2. Sulphonamides
    3. Aminoglycosides
    4. Erythromycin
      [Ref. KDT 6/e, p 697]
  1. Canrenone is the prodrug of : (APPGE 04)
    1. Ampicillin
    2. Spironolactone
    3. Frusemide
    4. Acetazolamide
      [Ref. KDT 6/e, p 24]
  1. Which is used in drug induced ulcers : (UP 2K)
    1. Antacids
    2. Ranitidine
    3. Omeprazole
    4. Misoprostol
      [Ref. KDT 6/e, p 632]
Answer
69. a. Propranolol
70. a. Captopril
71. c. Enalapril
72. d. Drug fever …
73. c. Atropine
74. a. Phenindione
75. a. Lisinopril
76. c. Verapamil
77. a. Phenindione
78. a and d
79. d. Ranitidine
80. b, c and d
81. a. Penicillin
82. b. Spironolactone
83. c. Omeprazole
64
  1. The following is a prodrug : (JIPMER 02)
    1. Lovastatin
    2. Pravostatin
    3. Cetrivastatin
    4. Fluvastatin
      [Ref. KDT 5/e, p 578]
  1. The following has maximum propensity for photodermatitis : (JIPMER 98)
    1. Oxytetracycline
    2. Doxycycline
    3. Minocycline
    4. Beta 2 agonist
      [Ref. KDT 6/e, p 713]
  1. Chronic ulceration would most likely occur following administration of : (DNB 91)
    1. Carbenicillin
    2. Clindamycin
    3. Chloramphenicol
    4. Colistin B
      [Ref: KDT 6/e, p 731]
  1. Which is an Ototoxic drug : (MP 98)
    1. Tetracycline
    2. Vincristine
    3. Penicillin
    4. Sulphonamide
      [Ref. KDT 6/e, p 825]
  1. Psychosis can be caused by : (JIPMER 91)
    1. Steroids
    2. INH
    3. Chloroquine
    4. All of above
      [Ref. KDT 6/e, p 286, 786, 741]
  1. Drug which increases absorption of oral iron : (Orissa 04)
    1. Folic acid
    2. Nalidixic acid
    3. Vitamin C
    4. Tetracycline
      [Ref. KDT 6/e, p 878]
  1. In G-6 PD deficiency, hemolysis occurs most commonly with : (JIPMER 91)
    1. Sulphonamide
    2. INH
    3. Amphotericin B
    4. Primaquine
      [Ref. Harrison 17/e, p 657, table (101–5]
  1. Which of the following are the recognised causes of rapidly progressive glomerulonephritis : (UPSC 97)
    1. Indomethacin
    2. Penicillamine
    3. Lead
    4. Rifampicin
      [Ref. Harrison 17/e, p 1787–1788]
  1. All of the following drug can cause photo-dermatitis except : (UPSC 97)
    1. Griseofulvin
    2. Chloroquine
    3. Captopril
    4. Oral contraceptive
      [Ref. Harrison 17/e, p 343–353]
  1. All the following drugs cause hirsutism except : (TN 01)
    1. Phenytoin
    2. Minoxidil
    3. Corticosteroids
    4. Heparin
      [Ref. Harrison 17/e, p 301, table (50–1)]
  1. The following cause macrocytic anemia except : (AI 92)
    1. Pyrimethamine
    2. Methotrexate
    3. Pentamidine
    4. Trimethoprim
      [Ref: Harrison 17/e, p 649–650]
  1. Hypersensitive cholestatic jaundice is caused by: (AI 92)
    1. Chlorpromazine
    2. Rifampicin
    3. Halothane
    4. Tetracycline
      [Ref: Harrison 17/e, p 265]
  1. All cause hyperprolactinemia except : (MAHE 98)
    1. Metoclopramide
    2. Haloperidol
    3. Trifluperazine
    4. Lasix
      [Ref. Harrison 17/e, p 2205]
  1. Hirsutism is caused by : (MAHE 98)
    1. Minoxidil
    2. Phenytoin
    3. Hydralazine
    4. All
      [Ref. Harrison 17/e, p 301, table (50–1)]
Answer
84. a. Lovastatin
85. b. Doxycycline
86. b. Clindamycin
87. b. Vincristine
88. d. All of above
89. c. Vitamin C
90. a. Sulphonamide
91. d. Rifampicin
92. d. Oral contrace …
93. d. Heparin
94. c. Pentamidine
95. a and b
96. d. Lasix
97. a and b
65
  1. Drug induced hypothermia is caused by all the drugs, except : (Orissa 98)
    1. Phenothiazines
    2. Barbiturates
    3. MAO-inhibitors
    4. Ethanol
      [Ref. Harrison 17/e, p 135, table (20–1)]
  1. Drug implicated in the causation of pancreatitis : (PGI 96)
    1. L- Asparaginase
    2. Cyclophosphamide
    3. Cyclosporine
    4. Methotrexate
      [Ref. Harrison 17/e, p 2007 KDT 6/e p 827]
  1. Galactorrhea is caused by all except : (Orissa 00)
    1. Metoclopramide
    2. Digitalis
    3. Reserpine
    4. Methyldopa
      [Ref. Harrison 17/e, p 2205]
  1. Cholestatic jaundice occurs with intake of all except : (AI 93)
    1. Erythromycin
    2. INH
    3. O.C. pills
    4. Nifedipine
      [Ref: Harrison 17/e, p 265]
  1. All of the following are hepatotoxic except : (A.P. 97)
    1. Erythromycin
    2. Tetracycline
    3. Choloroquine
    4. Rifampicin
      [Ref. Harrison 17/e, p 1951, table (299–2)]
  1. The following drug is used for osteoporosis : (JIPMER 02)
    1. Ranitidine
    2. Raloxifene
    3. Ramipril
    4. Riclopride
      [Ref. Harrison 17/e, p 2404–2406; Goodman & Gilman 10/e, p 1738]
  1. Fanconi's syndrome is caused by : (JIPMER 91)
    1. Cephalosporins
    2. Chloramphenicol
    3. Deceased pseudocholinesterase
    4. Old and degraded tetracyclines
      [Ref: Harrison 17/e, p 1807, KDT 6/e, p 713]
  1. Agranulocytosis is common with : (KERAL 94)
    1. Chloramphenicol
    2. Methotrexate
    3. Sulpha drugs
    4. Amikacin
      [Ref. Harrison 17/e, p 668]
  1. Gynecomastia is caused by : (AP 97)
    1. Phenytoin
    2. Cushing's syndrome
    3. Conn's syndrome
    4. None
      [Ref. Harrison 17/e, p 2318]
  1. Drug which is not a cause of a chronic active hepatitis : (PGI 96)
    1. INH
    2. Methyldopa
    3. Chlorpromazine
    4. Oxyphenacetin
      [Ref. Harrison 17/e, p 1951, table (299–2)]
  1. Not an ototoxic drug : (PGI 96)
    1. Neosporine
    2. Amikacin
    3. Vincristine
    4. Aminoglycoside
      [Ref. Harrison 17/e, p 202]
  1. Non ischaemic chest pain is caused by : (KERALA 97)
    1. Bleomycin
    2. Vincristine
    3. Cyclophosphamide
    4. Cisplatinum
      [Ref. Harrison 17/e, p 525]
  1. Leukoencephalopathy is seen with use : (PGI 93, 81)
    1. Vincristine
    2. Cyclophosphamide
    3. Methotrexate
    4. 5-FU
      [Ref: Harrison 17/e, p 2080]
Answer
98. c. MAO-inhibitors
99. a. L- Asparaginase
100. b. Digitalis
101. b. INH
102. c. Choloroquine
103. b. Raloxifene
104. d. Old and …
105. a and d
106. a. Phenytoin
107. c. Chlorpromazine
108. a. Neosporine
109. a. Bleomycin
110. c. Methotrexate
66
NOTES
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