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GENERAL PHARMACOLOGY - Complete Question Bank Answers

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LAQs (Long Answer Questions)

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LAQ 1: Classify the Routes of Drug Administration. Discuss Advantages & Disadvantages. Add a note on Special Drug Delivery Systems.

Classification of Routes of Drug Administration

• Oral (per os)
• Sublingual / Buccal
• Rectal

• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Intradermal
• Intrathecal / Intracerebroventricular
• Intraperitoneal
• Intra-arterial
• Intraosseous

• Skin (transdermal)
• Mucous membranes (nasal, conjunctival, vaginal, urethral)
• Inhalation (pulmonary)
• Epidural

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Enteral Routes

• Drug is placed under tongue (SL) or between cheek and gum (buccal)
• Absorbed directly into systemic circulation via sublingual veins
• Advantages:
  • Rapid onset (1-2 min)
  • Bypasses first-pass metabolism
  • Bypasses GIT degradation
  • Absorbed drug directly enters systemic circulation
• Disadvantages:
  • Only lipid-soluble, potent drugs can be given
  • Drug must not be swallowed
• Examples: Glyceryl trinitrate (GTN), buprenorphine, nifedipine (buccal)

• Advantages:
  • Useful when oral route not available (vomiting, unconscious children)
  • Partial bypass of first-pass metabolism (lower rectum drains into inferior rectal veins - systemic; upper rectum drains into portal vein)
  • Avoids gastric acid degradation
• Disadvantages:
  • Erratic and incomplete absorption
  • Patient inconvenience and discomfort
  • Not suitable for irritant drugs
• Examples: Diazepam (rectal), paracetamol suppositories, metronidazole suppositories

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Parenteral Routes

• Injected into skeletal muscle (deltoid, gluteus)
• Onset: 15-30 min
• Advantages: Moderately rapid onset; aqueous and oily preparations can be given; depot preparations possible
• Disadvantages: Painful; risk of nerve injury; not for anticoagulated patients
• Examples: Depot penicillin, haloperidol decanoate

• Injected under the skin
• Slower and more prolonged absorption than IM
• Advantages: Self-administration possible (insulin); sustained absorption
• Disadvantages: Painful; limited volume; not for vasoconstrictors (can cause necrosis)
• Examples: Insulin, heparin, vaccines

• Injected into subarachnoid space
• Bypasses blood-brain barrier
• Used for spinal anaesthesia, intrathecal chemotherapy, antibiotics for CNS infections

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Note on Special Drug Delivery Systems

• Drug is incorporated into a patch applied to skin, providing continuous slow release into systemic circulation
• Components: Drug reservoir, rate-controlling membrane, adhesive, backing membrane
• Advantages: Avoids first-pass metabolism; sustained drug levels; non-invasive; improved compliance; easy to remove if adverse effects occur
• Disadvantages: Only suitable for potent, lipophilic drugs with small molecular weight; skin irritation; expensive
• Examples: GTN patch (angina), fentanyl patch (pain), nicotine patch (smoking cessation), estrogen patch (HRT), clonidine patch (hypertension)
• Penetration enhancers (DMSO) may be used

• Drug pellets implanted subcutaneously for prolonged action (months-years)
• Examples: Norplant (levonorgestrel implant), testosterone pellets

• Drug encapsulated in lipid bilayer vesicles (liposomes) or nanoparticles
• Targeted drug delivery to specific organs (e.g., liposomal amphotericin B, liposomal doxorubicin)
• Reduced toxicity, increased drug concentration at target site

• Drug released at a constant, controlled rate via osmotic pressure
• Examples: Nifedipine OROS, metoprolol XL, oxybutynin OROS

• Ocuserts (pilocarpine ocusert) - slow release into conjunctival sac for 1 week

• Levonorgestrel-releasing IUD (Mirena) - local drug delivery for contraception

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LAQ 2: Define Biotransformation. Explain the Various Mechanisms of Drug Metabolism with Examples.

Definition

Significance:

• Terminates drug action (usually inactivation)
• May activate prodrugs (e.g., enalapril → enalaprilat)
• May produce toxic metabolites (e.g., paracetamol → NAPQI)
• Increases water solubility for renal/biliary excretion

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Mechanisms of Biotransformation

• Mediated by CYP450 enzyme system (NADPH + O2 dependent)
• Examples:
  • Aliphatic hydroxylation: Tolbutamide → Hydroxytolbutamide
  • Aromatic hydroxylation: Phenytoin → Parahydroxyphenytoin
  • N-dealkylation: Morphine → Normorphine; Diazepam → Desmethyldiazepam
  • O-dealkylation: Codeine → Morphine (activation)
  • Epoxidation: Carbamazepine → Carbamazepine-10,11-epoxide
  • Desulfuration: Thiopentone → Pentobarbital
  • Deamination: Amphetamine → Phenylacetone

• Nitro-reduction: Nitrazepam → 7-aminonitrazepam
• Carbonyl reduction: Warfarin (minor pathway)
• Mediated by CYP450 and NADPH

• Ester hydrolysis: Procaine → PABA + diethylaminoethanol; aspirin → salicylate + acetic acid
• Amide hydrolysis: Lignocaine → diethylaminoethanol + xylidide
• Mediated by plasma esterases and microsomal esterases

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LAQ 3: Define Bioavailability. Explain the Factors Affecting Bioavailability.

Definition

• For IV: Bioavailability = 100% (by definition)
• Formula: F = (AUC oral / AUC IV) × (Dose IV / Dose oral) × 100

Measurement:

• Area Under Curve (AUC) of plasma concentration vs. time graph
• Parameters: Cmax, Tmax, AUC

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Factors Affecting Bioavailability

1. Lipid solubility - highly lipid soluble drugs are better absorbed
2. Particle size - smaller particle size = greater surface area = better absorption (e.g., micronized griseofulvin)
3. Salt form - different salts have different solubilities (e.g., erythromycin estolate vs. base)
4. Crystal form (polymorphism) - amorphous > crystalline absorption
5. pKa and ionization - un-ionized form is better absorbed; Henderson-Hasselbalch equation determines ionization

1. Disintegration and dissolution - tablet must first disintegrate, then dissolve; rate-limiting step is dissolution
2. Excipients - binders, fillers, coatings can affect absorption
3. Enteric coating - delays absorption until intestine
4. Formulation type - solution > suspension > capsule > tablet > enteric-coated tablet (order of absorption rate)

1. GI motility:
   • Increased motility (diarrhea) - reduced absorption
   • Reduced motility (metoclopramide increases, atropine decreases) - affects Tmax
2. Gastric pH:
   • Acidic drugs (aspirin) better absorbed in acidic pH (stomach)
   • Basic drugs better absorbed in alkaline pH (intestine)
   • Antacids raise pH - can reduce absorption of iron, ketoconazole
3. Gastric emptying rate:
   • Faster emptying → faster onset; slow emptying delays absorption
   • Food generally slows gastric emptying
4. Splanchnic blood flow: Reduced in shock - reduces absorption from IM/SC sites
5. Intestinal flora: Can metabolize drugs (e.g., digoxin by intestinal bacteria)
6. First-pass metabolism: Single most important factor reducing oral bioavailability
   • Drugs with high hepatic extraction: GTN (bioavailability <1%), morphine (25-30%), propranolol (30%), lignocaine (3%)

• Drug absorbed from GIT enters portal circulation → passes through liver before reaching systemic circulation
• Liver extensively metabolizes some drugs → greatly reduced bioavailability
• Drugs with high first-pass metabolism: GTN, morphine, propranolol, lignocaine, salbutamol, estrogen, testosterone
• Ways to bypass first-pass:
  • SL/buccal route, transdermal, rectal (partial), IV, IM, SC, inhalation

• Chelation: tetracycline + Ca2+/Fe2+/Mg2+ → insoluble complex
• Adsorption: drugs adsorbed on antacids (cholestyramine)
• Enzyme inhibitors/inducers affecting intestinal CYP3A4

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LAQ 4: Describe the Factors Affecting Drug Action. Mention their Pharmacological & Clinical Importance.

1. Absorption:
   • Route of administration alters speed and completeness of absorption
   • Clinical importance: IV route gives fastest and most reliable effect in emergencies
2. Distribution:
   • Plasma protein binding (PPB): Highly bound drugs have smaller free fraction; drug interactions from displacement
   • Volume of Distribution (Vd): Low Vd = drug stays in plasma; High Vd = extensive tissue distribution
   • Blood-brain barrier, placenta, protein binding affect distribution
3. Metabolism (Biotransformation):
   • Liver disease reduces metabolism → drug accumulation → toxicity (e.g., morphine in hepatic failure)
   • Enzyme induction (rifampicin, phenobarbitone): increases metabolism → reduces drug effect
   • Enzyme inhibition (erythromycin, ketoconazole): decreases metabolism → drug accumulation
   • Genetic polymorphism: fast vs slow acetylators (INH); CYP2D6 (codeine, tramadol)
4. Excretion:
   • Renal disease: drugs eliminated by kidney accumulate → dose reduction needed (aminoglycosides, digoxin)
   • Urinary pH manipulation: alkalinization with sodium bicarbonate increases excretion of acidic drugs (aspirin, phenobarbitone) - used in poisoning

1. Age:
   • Neonates/infants: immature drug-metabolizing enzymes, BBB less developed, reduced plasma protein binding → increased sensitivity
   • Elderly: reduced renal and hepatic function, reduced lean body mass, reduced plasma albumin → increased sensitivity and toxicity
   • Clinical: dose reduction needed at extremes of age
2. Body Weight / Body Surface Area:
   • Doses are usually expressed in mg/kg (children)
   • Obese patients: fat-soluble drugs have larger Vd
3. Sex:
   • Women have less body water, more adipose tissue → lipophilic drugs have larger Vd
   • Hormonal differences affect drug response
   • Pregnancy: altered pharmacokinetics and special consideration for teratogenicity
4. Genetic Factors (Pharmacogenomics):
   • Slow acetylators: accumulate INH → peripheral neuropathy; sulfonamides → adverse effects
   • Fast acetylators: INH less effective for TB
   • G6PD deficiency: dapsone, primaquine, nitrofurantoin → hemolytic anemia
   • Pseudocholinesterase deficiency: succinylcholine apnea
   • Porphyria: barbiturates can precipitate acute attacks
   • CYP2D6 poor metabolizers: codeine → no analgesia; cannot convert to morphine
5. Pathological State:
   • Liver disease: impaired metabolism of drugs (morphine, chlorpromazine, diazepam)
   • Renal disease: accumulation of renally-excreted drugs (aminoglycosides, metformin, digoxin)
   • Cardiac failure: reduced hepatic and renal blood flow → reduced drug clearance
   • Thyroid disorders: hyperthyroid patients more sensitive to digoxin; hypothyroid patients more sensitive to CNS depressants
6. Drug Tolerance:
   • Decreased response to a drug after repeated administration
   • Pharmacokinetic tolerance (enzyme induction), pharmacodynamic tolerance (receptor down-regulation)
7. Placebo Effect:
   • Psychological response to an inert substance; ~35% of patients respond to placebo for pain relief
8. Time of Administration:
   • Chronopharmacology: drugs are more effective at certain times of day
   • Example: antihypertensives are more effective when BP is highest (morning)
9. Drug Interactions:
   • Pharmacokinetic (absorption, metabolism) or pharmacodynamic (additive, synergistic, antagonistic) interactions

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SAQs (Short Answer Questions)

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SAQ 1: Transdermal Patch - Advantages, Disadvantages & Examples

• Backing layer (impermeable, protective)
• Drug reservoir (drug in carrier matrix)
• Rate-controlling membrane (microporous - controls release rate)
• Contact adhesive layer
• Protective peel-off strip

1. Avoids first-pass hepatic metabolism - increases bioavailability
2. Maintains constant plasma drug levels (avoids peak-trough fluctuation)
3. Painless and non-invasive
4. Easy to apply and remove
5. Improved patient compliance
6. Prolonged duration of action (12 hrs - 7 days depending on patch)
7. Can be removed immediately if adverse effects occur
8. Useful for patients with swallowing difficulties or vomiting

1. Only suitable for highly potent lipophilic drugs with low molecular weight (<500 Da)
2. Skin irritation and contact dermatitis
3. Rate of absorption can vary with skin condition, body site, and blood flow
4. Expensive
5. Not suitable for large doses
6. Slow onset of action

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SAQ 2: First Pass Metabolism

• Intestinal wall has CYP3A4 and other enzymes
• Liver has CYP450 enzyme system (CYP3A4, CYP2D6, etc.)
• Drug is metabolized before reaching systemic circulation
• Extent of first-pass effect = hepatic extraction ratio (E)
  • High E (>0.7): GTN, morphine, propranolol, lignocaine, salbutamol
  • Low E (<0.3): diazepam, warfarin, theophylline

• GTN (bioavailability <1% oral)
• Morphine (bioavailability ~25%)
• Propranolol (bioavailability ~30%)
• Lignocaine (bioavailability ~3%)
• Salbutamol
• Testosterone, estrogens
• Aspirin
• Naltrexone

1. Oral dose must be much higher than parenteral dose for drugs with high first-pass effect (morphine oral: 30 mg = morphine IV: 10 mg; 3:1 ratio)
2. Liver disease reduces first-pass metabolism → toxicity with usual doses
3. Bypass routes avoid first-pass: sublingual (GTN), transdermal (estrogen, fentanyl), IV, IM, SC
4. Enzyme inducers (rifampicin) increase first-pass → reduce bioavailability
5. Enzyme inhibitors (cimetidine) decrease first-pass → increase bioavailability

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SAQ 3: Prodrug - Advantages with Examples

1. Type I: Biotransformation occurs intracellularly (e.g., acyclovir, statins)
2. Type II: Biotransformation occurs extracellularly (plasma or intestinal lumen)

• Oxidation (enalapril → enalaprilat)
• Hydrolysis (aspirin → salicylate; bambuterol → terbutaline)
• Reduction
• Phosphorylation (acyclovir → acyclovir triphosphate)

1. Improved oral bioavailability - prodrug bypasses poor absorption (e.g., ampicillin prodrug bacampicillin has 100% bioavailability)
2. Avoidance of first-pass metabolism - prodrug itself not metabolized, activated at target site
3. Reduction of adverse effects - inactive prodrug less toxic than active drug (olsalazine for IBD - released in colon only)
4. Improved stability - prodrug more stable than active drug
5. Improved patient compliance - tasteless prodrug (chloramphenicol palmitate)
6. Site-specific drug delivery - activated at target organ (5-ASA released in colon from sulfasalazine)
7. Prolonged duration of action (fluphenazine decanoate IM depot)

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SAQ 4: Microsomal Enzyme Induction & Inhibition and its Significance

• Located on smooth endoplasmic reticulum (SER) of hepatocytes
• Main enzyme: Cytochrome P450 (CYP450) - a superfamily of heme-containing monooxygenases
• Important isoforms: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (most abundant, metabolizes ~50% of drugs)

• Increased synthesis of CYP450 enzymes
• Onset: 7-14 days; Offset: 7-14 days after stopping inducer
• Results in: increased drug metabolism → reduced plasma levels → reduced effect (or increased toxic metabolite)

• Phenytoin
• Carbamazepine
• Barbitones (phenobarbitone)
• Rifampicin (most potent inducer)
• Alcohol (chronic)
• Smoking (induces CYP1A2)
• Griseofulvin, St. John's Wort

• Rifampicin reduces efficacy of: OCP (contraceptive failure), warfarin (increased bleeding risk when rifampicin stopped), corticosteroids, antifungals
• Phenobarbitone induces own metabolism (autoinduction)
• Chronic alcohol: tolerance to drugs via enzyme induction
• INH + rifampicin: rifampicin induces INH metabolism → more toxic hydrazine metabolites

• Decreased CYP450 activity
• Onset: rapid (immediate, competitive inhibition)
• Results in: decreased drug metabolism → increased plasma levels → increased effect or toxicity

• Sodi um valproate
• Isoniazid
• Cimetidine (H2 blocker)
• Ketoconazole / fluconazole (azole antifungals)
• Fluoxetine / fluvoxamine
• Amiodarone
• Chloramphenicol
• Erythromycin, clarithromycin (macrolides)
• Sulfaphenazole; also metronidazole, ritonavir, grapefruit juice (CYP3A4)

• Erythromycin + terfenadine → terfenadine accumulation → fatal cardiac arrhythmia (torsades de pointes)
• Ketoconazole + cisapride → fatal arrhythmia
• Cimetidine + warfarin → excessive anticoagulation → bleeding
• INH inhibits CYP2C9 → phenytoin toxicity
• Grapefruit juice (furanocoumarins inhibit CYP3A4) → increased nifedipine, simvastatin, cyclosporine levels

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SAQ 5: First Order & Zero Order Kinetics with Examples

• A constant fraction (percentage) of the drug is eliminated per unit time
• Rate of elimination is proportional to drug concentration
• Plasma half-life is constant and independent of dose
• Semi-log plot of plasma concentration vs. time gives a straight line
• Most drugs follow first-order kinetics at therapeutic concentrations
• Examples: Paracetamol, most antibiotics, digoxin, most benzodiazepines

• T1/2 is constant
• Time to reach steady state = ~5 half-lives
• Linear pharmacokinetics: doubling dose doubles plasma level

• A constant amount (not fraction) of drug is eliminated per unit time
• Elimination capacity is saturated (enzyme saturation)
• Plasma half-life is not constant - increases with dose
• Plot of plasma concentration vs. time gives a straight line (not semi-log)
• Also called dose-dependent or Michaelis-Menten kinetics
• Dangerous - small dose increase can cause disproportionate increase in plasma levels

• Phenytoin (at therapeutic concentrations - hence narrow therapeutic index)
• Alcohol (ethanol) - eliminated at ~10 mL/hour regardless of concentration
• Aspirin at high (toxic) doses
• Warfarin at high doses
• Theophylline (approaches at high doses)

• Phenytoin: small dose increase can cause toxic plasma levels → nystagmus, ataxia, confusion
• Alcohol: cannot be eliminated faster no matter how much coffee you drink!
• Need therapeutic drug monitoring for zero-order drugs

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SAQ 6: Define Therapeutic Index. Explain Therapeutic Drug Monitoring with its Indications.

• Definition: The ratio of the dose that produces toxicity to the dose that produces the desired therapeutic effect.
• Formula: TI = TD50 / ED50
  • TD50 = Dose lethal/toxic in 50% of population
  • ED50 = Dose effective in 50% of population
• Also expressed as Therapeutic Ratio or Margin of Safety
• More clinically relevant: Therapeutic Window = range between minimum effective concentration (MEC) and minimum toxic concentration (MTC)

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• Trough levels (just before next dose) - for most drugs
• Peak levels (1-2 hrs after dose) - aminoglycosides
• Steady state levels (after 5 half-lives)

1. Narrow therapeutic index drugs - where therapeutic and toxic doses are close (digoxin, lithium, phenytoin, theophylline, aminoglycosides, cyclosporine)
2. Drugs with unpredictable pharmacokinetics - highly variable absorption or metabolism
3. Suspicion of toxicity or therapeutic failure - to distinguish under-dosing from non-compliance vs. true resistance
4. Altered physiological states: renal failure, hepatic failure, cardiac failure (change drug handling)
5. Drug interactions - when enzyme inducers or inhibitors are co-administered
6. Long-term therapy monitoring
7. Checking compliance

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SAQ 7: Fixed Dose Combinations (FDC) - Advantages, Disadvantages & Examples

1. Improved patient compliance (one tablet instead of multiple)
2. Synergistic or additive efficacy (TB treatment: HRZE)
3. Prevention of drug resistance (HIV - HAART; TB)
4. Reduced adverse effects through dose reduction (e.g., co-trimoxazole)
5. Simplified drug regimens
6. Convenient for chronic disease management
7. Cost-effective

1. Fixed ratio may not suit all patients (dose individualization not possible)
2. Adverse effects or contraindications to one component - entire combination must be stopped
3. Difficult to identify which drug causes adverse effects
4. Drug interactions between components
5. Increased risk of polypharmacy
6. Some are irrational combinations

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SAQ 8: Methods to Prolong the Duration of Drug Action

1. Slow-release (sustained-release) formulations: ER/XR/SR tablets (nifedipine SR, metoprolol XL)
2. Enteric-coated preparations: Delays dissolution until intestine
3. Repository / Depot preparations:
   • Oily injections (penicillin G benzathine, haloperidol decanoate, fluphenazine decanoate)
   • Microcrystalline suspensions (insulin NPH)
4. Transdermal delivery systems: GTN patch, fentanyl patch
5. Implants: Norplant, testosterone pellets
6. Plasma protein binding: Maintains drug reservoir; slowly released as free drug falls
7. Prodrugs: Bambuterol (prolonged terbutaline release), dipivefrin
8. Combining with vasoconstrictors: Adrenaline + lignocaine (reduces local blood flow → prolonged local anaesthesia)
9. Combining with enzyme inhibitors: Probenecid + penicillin (blocks tubular secretion → prolonged penicillin levels)
10. Targeted drug delivery: Liposomes, nanoparticles (slow release at target)
11. Osmotic pump systems (OROS): Constant controlled release (nifedipine OROS)
12. Pegylation: PEG-interferon, PEG-asparaginase → prolonged half-life

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SAQ 9: Drug Synergism & Antagonism with Examples

• Two drugs produce an effect greater than either alone
• Types:
  1. Additive: Combined effect = sum of individual effects (1+1=2)
     • Examples: Aspirin + paracetamol for pain; Co-trimoxazole (TMP + SMX - additive antibacterial)
  2. Supraadditive (Potentiation/Supra-additive synergism): Combined effect > sum of individual effects (1+1>2)
     • Examples: Carbidopa + levodopa; clavulanic acid + amoxicillin; probenecid + penicillin; Alcohol + chlorpromazine (CNS depression)

• TB treatment (4-drug regimen)
• HIV HAART (3-drug regimen)
• Antihypertensive combinations
• Cancer chemotherapy combinations

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• One drug reduces or abolishes the effect of another

1. Pharmacological (receptor) Antagonism:
   • Competitive (reversible) antagonism: Antagonist and agonist compete for same receptor; can be overcome by increasing agonist dose; shifts dose-response curve to right (parallel shift) without changing Emax
     • Examples: Atropine vs. Ach; Naloxone vs. morphine; propranolol vs. adrenaline; phentolamine vs. noradrenaline
   • Non-competitive (irreversible) antagonism: Antagonist binds irreversibly or at different site; cannot be overcome; reduces Emax; dose-response curve shifts down
     • Examples: Phenoxybenzamine (irreversible α blocker); aspirin (irreversible COX inhibitor)
2. Physiological (functional) Antagonism:
   • Two drugs act on different receptors producing opposing effects
   • Examples: Adrenaline (bronchodilation via β2) antagonizes histamine (bronchoconstriction via H1) - used in anaphylaxis; glucagon antagonizes insulin
3. Chemical Antagonism:
   • Direct chemical interaction between drugs
   • Examples: Protamine sulfate (+ charge) neutralizes heparin (- charge); chelating agents (EDTA, desferrioxamine, BAL) bind heavy metals; dimercaprol (BAL) binds arsenic, mercury
4. Pharmacokinetic Antagonism:
   • One drug alters pharmacokinetics of another
   • Examples: Activated charcoal reduces drug absorption; enzyme inducers reduce drug levels

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SAQ 10: General Guidelines for Management of a Drug Poisoning Case

1. Identify the poison - history, pill bottles, plasma/urine drug levels
2. Reduce absorption:
   • Emesis (only if conscious, within 1 hour): syrup of ipecac (now rarely used)
   • Gastric lavage (within 1 hour): left lateral position; protect airway
   • Activated charcoal (most useful, within 1-2 hours): 1 g/kg; adsorbs most organic drugs; repeat doses for salicylates, theophylline, phenobarbitone (enterohepatic cycling)
   • Not useful for: iron, lithium, alcohols, alkalis/acids (caustics)
3. Hasten elimination:
   • Forced alkaline diuresis (IV NaHCO3 + IV fluids): for salicylate and phenobarbitone poisoning
   • Acidification of urine (now rarely used): for amphetamine, phencyclidine
   • Hemodialysis/hemoperfusion: lithium, methanol, salicylate, theophylline, barbiturates
4. Specific antidotes:

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SAQ 11: Define Tolerance. Explain the Types of Tolerance with Examples.

• Due to increased drug metabolism (enzyme induction)
• Increased drug elimination → lower plasma levels with same dose
• Examples:
  • Barbiturates (phenobarbitone) - induce CYP450 → auto-induction
  • Carbamazepine - autoinduction
  • Chronic alcohol - induces CYP2E1

• Drug levels remain the same, but response is reduced
• Due to: receptor down-regulation, receptor desensitization, altered second messenger, depletion of mediator
• Examples:
  • Opioid tolerance (morphine) - receptor desensitization
  • Nitrate tolerance (GTN) - depletion of sulfhydryl groups needed for NO generation
  • Benzodiazepine tolerance
  • Beta-agonist tolerance (salbutamol) - β2 receptor down-regulation

• Rapid development of tolerance (within minutes to hours) after a single or few doses
• Examples:
  • Ephedrine - indirect sympathomimetic; depletes noradrenaline stores rapidly
  • Amphetamine
  • Histamine (rapid desensitization)
  • LSD (serotonin receptors)

• Tolerance to one drug confers tolerance to a related drug (same class/receptor)
• Examples:
  • Morphine tolerance → tolerance to other opioids (heroin, codeine)
  • Alcohol tolerance → cross-tolerance to benzodiazepines and barbiturates
  • One nitrate → tolerance to other nitrates

• Drug addicts need escalating doses
• Nitrate-free period (8-12 hrs) restores sensitivity to GTN
• Scheduled ("drug holiday") for beta-agonists in asthma

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SAQ 12: Dose Response Relationship

• Plotted as: Drug effect (y-axis) vs. log dose (x-axis)
• Produces a sigmoid (S-shaped) curve
• Key parameters:
  • Emax (Maximal efficacy): Maximum effect achievable regardless of dose increase
  • EC50: Dose producing 50% of maximal effect (measure of potency)
  • Slope: Steepness indicates how rapidly effect increases with dose

• Full agonist: Produces maximum possible response (Emax = 100%) - e.g., morphine
• Partial agonist: Even at full receptor occupancy, cannot produce 100% Emax - e.g., buprenorphine (may act as antagonist in presence of morphine)
• Inverse agonist: Produces opposite effect to agonist

• Measures frequency of response in population (e.g., % of population showing sleep, analgesia, death)
• Gives normal distribution or cumulative sigmoid curve
• Key derived values:
  • ED50: Dose effective in 50% of population
  • TD50: Dose toxic in 50%
  • LD50: Dose lethal in 50%
  • Therapeutic Index = TD50/ED50

• Potency: Amount of drug needed to produce a given effect (related to EC50) - lower EC50 = more potent
• Efficacy: Maximum effect achievable (Emax) regardless of dose
• Clinically, efficacy is more important than potency
• Example: Furosemide is more efficacious than thiazides (causes greater diuresis) but may be less potent on a mg/mg basis

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SAQ 13: Phases of a Clinical Trial

• Sub-therapeutic doses in 10-15 subjects
• Microdosing studies
• PK/PD assessment
• Very short duration

• Subjects: Healthy volunteers (20-80), exceptions: cancer, AIDS (patients used)
• Objective: Safety, tolerability, pharmacokinetics, maximum tolerated dose, dose escalation
• Duration: Several months
• Blind: Open-label (non-blinded)
• Dropout: ~30% fail here

• Subjects: Patients with target disease (100-300)
• Objective: Efficacy, optimal dose, safety in patients, preliminary PK
• Divided into: Phase IIa (dose-ranging) and Phase IIb (efficacy)
• Duration: Several months to 2 years
• Blind: Randomized controlled (single or double blind)
• Dropout: ~50% fail here

• Subjects: Large number of patients (300-3,000+) in multiple centers
• Objective: Confirm efficacy, monitor adverse effects, compare with existing treatment
• Duration: 1-4 years
• Design: Double-blind, randomized, multicentric, controlled trial
• Outcome: Main basis for regulatory approval (CDSCO in India, FDA in USA, EMA in Europe)
• Dropout: ~25% fail here

• After marketing approval
• Objective: Detect rare adverse effects, long-term safety, efficacy in special populations, new indications, drug interactions
• Examples of post-marketing withdrawals:
  • Thalidomide (teratogenicity discovered post-marketing)
  • Rofecoxib/Vioxx (cardiac events)
  • Cisapride (QT prolongation)
  • Terfenadine (cardiac arrhythmias)
• Includes Pharmacovigilance

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SAQ 14: Pharmacovigilance

1. Early detection of unknown/new adverse drug reactions (ADRs)
2. Detection of increases in frequency of known ADRs
3. Identify risk factors for ADRs
4. Assess pharmacokinetics of a drug in special populations
5. Provide useful information for risk-benefit assessment

1. Spontaneous Reporting System (Yellow Card System in UK; Vigibase of WHO; PvPI in India)
   • Healthcare professionals and patients report suspected ADRs
   • Advantages: inexpensive, covers large population, can detect rare ADRs
   • Disadvantages: under-reporting (only 5-10% of ADRs reported)
2. Prescription Event Monitoring (PEM)
   • All events reported in patients taking a specific drug
   • "Green card" system in UK
3. Record Linkage Studies
   • Link prescription databases with hospital/mortality records
4. Case-Control Studies
   • Compare ADR cases with matched controls
5. Cohort Studies
   • Follow patients taking a drug for development of ADRs

• Launched 2010 by Ministry of Health and Family Welfare
• Coordinating centre: Indian Pharmacopoeia Commission (IPC), Ghaziabad
• ADR reporting through CDSCO via Vigiflow database
• Every hospital should have an ADR Monitoring Centre (AMC)

• WHO-UMC Scale: Certain, Probable, Possible, Unlikely, Unassessable
• Naranjo Scale: Score-based probability scale

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SAQ 15: Adverse Drug Reactions (ADRs)

• Extension of pharmacological effect
• Predictable, common, dose-dependent
• Less severe; reversible on dose reduction
• Examples: Morphine - constipation, respiratory depression; ACE inhibitors - hypotension; warfarin - bleeding; NSAIDs - GI irritation, peptic ulcer

• Not predictable from pharmacological actions
• Rare, severe, possibly fatal
• Examples:
  • Immune-mediated: penicillin anaphylaxis; drug-induced lupus (procainamide, hydralazine)
  • Pharmacogenetic: G6PD deficiency + primaquine → hemolysis; succinylcholine apnea (pseudocholinesterase deficiency); porphyria + barbiturates
  • Idiosyncratic: chloramphenicol - aplastic anemia; halothane - hepatitis

• Due to long-term use
• Examples: Opioid dependence, NSAID-induced renal failure, corticosteroid-induced osteoporosis, tardive dyskinesia (antipsychotics), analgesic nephropathy

• Occur after long latency from drug exposure
• Examples: Carcinogenesis (alkylating agents - leukemia); teratogenicity (thalidomide); tardive dyskinesia

• Occurs on stopping the drug
• Examples: Adrenal insufficiency after corticosteroid withdrawal; clonidine rebound hypertension; beta-blocker withdrawal - angina rebound

• Drug resistance or inadequate drug levels

• Pharmacovigilance
• TDM for narrow TI drugs
• Avoiding known drug interactions
• Pre-treatment screening (G6PD before primaquine)
• Patient education

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SAQ 16: Plasma Half-Life & its Importance

• Vd = Volume of distribution
• CL = Total body clearance

• First-order kinetics: t1/2 is constant regardless of dose or concentration
• Zero-order kinetics: t1/2 is not constant (increases with dose)

1. Dosing frequency: Drugs with short t1/2 require more frequent dosing; drugs with long t1/2 can be given once daily
   • GTN: t1/2 = 1-3 min (needs continuous infusion/patch)
   • Digoxin: t1/2 = 36 hrs (once daily dosing)
   • Amiodarone: t1/2 = 40-55 days (loading dose needed)
2. Time to reach steady state: ~5 half-lives to reach 97% of steady state
   • Clinically important: antidepressants (t1/2 ~24 hrs - steady state in 5 days), digoxin (5-7 days)
3. Duration of drug action: Generally proportional to t1/2
4. Loading dose: Required for drugs with long t1/2 to rapidly achieve therapeutic levels (digoxin, amiodarone, chloroquine)
5. Withdrawal syndrome: Drugs with short t1/2 cause more severe withdrawal (diazepam t1/2 = 20-40 hrs vs. triazolam t1/2 = 2-4 hrs - triazolam causes more severe withdrawal)
6. Drug accumulation and toxicity: Long t1/2 drugs accumulate with repeated dosing; higher risk in elderly (reduced CL)
7. Time for drug to wash out: ~5 half-lives after stopping drug (e.g., fluoxetine t1/2 = ~2 weeks due to active metabolite - drug interactions persist for weeks after stopping)
8. Estimation of dosing interval: Usually dose every 1-2 half-lives to avoid excessive peak-trough fluctuation

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SAQ 17: Define & Classify Receptors. Describe the Different Types of GPCRs.

• Drug binding directly opens ion channel (fastest - milliseconds)
• Examples:
  • Nicotinic ACh receptor (Na+/K+ channel) - skeletal muscle NMJ, autonomic ganglia
  • GABA-A receptor (Cl- channel) - benzodiazepines, barbiturates
  • Glutamate (NMDA, AMPA) receptors (Na+, Ca2+)
  • Serotonin 5-HT3 receptor

• 7-transmembrane domain receptors; signal through heterotrimeric G-proteins
• Response in seconds to minutes
• Most numerous class of drug targets
• Examples: Adrenergic, muscarinic, dopamine, histamine H1/H2, opioid, serotonin (most subtypes)

• Drug binding activates intrinsic enzyme (tyrosine kinase or guanylyl cyclase)
• Response in minutes to hours
• Examples:
  • Insulin receptor (tyrosine kinase) → GLUT4 translocation
  • Growth hormone receptor (JAK-STAT)
  • ANP receptor (guanylyl cyclase - cGMP)

• Ligand-activated transcription factors; drug enters cell and binds intracellular receptor
• Response in hours to days (gene transcription)
• Examples:
  • Glucocorticoid receptor (prednisolone)
  • Thyroid hormone receptor (T3/T4)
  • Estrogen, progesterone, androgen receptors
  • PPAR receptors (thiazolidinediones - pioglitazone)
  • Retinoic acid receptor

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• cAMP (via Gs): β-receptor activation → ↑heart rate, bronchodilation
• IP3/DAG/Ca2+ (via Gq): α1 activation → vasoconstriction
• cGMP (via NO): GTN → smooth muscle relaxation, vasodilation

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VSAQs (Very Short Answer Questions)

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VSAQ 1: Apparent Volume of Distribution (Vd)

• Large Vd → high tissue binding → hard to remove by dialysis
• Small Vd → can be removed by hemodialysis (useful in poisoning)
• Vd is used to calculate Loading dose: Loading dose = Vd × Target plasma concentration

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VSAQ 2: Plasma Protein Binding & its Clinical Importance

• Only free (unbound) drug crosses membranes, exerts effect, is metabolized, and excreted
• Drug-protein binding is reversible (equilibrium maintained)
• Most drugs bind albumin: acidic drugs bind albumin; basic drugs bind α1-acid glycoprotein

1. Drug displacement interactions:
   • A drug with higher affinity can displace another → sudden increase in free (active) drug → toxicity
   • Example: Sulfonamides displace warfarin → bleeding; aspirin displaces methotrexate → methotrexate toxicity; sulfonamides displace bilirubin in neonates → kernicterus
2. Hypoalbuminemia:
   • Liver disease, nephrotic syndrome, malnutrition → reduced albumin → more free drug → toxicity
   • Important for: phenytoin, warfarin (dose reduction needed)
3. Competition between drugs:
   • Aspirin displaces urate → may worsen gout transiently
4. Reduced distribution into tissues:
   • Highly protein-bound drugs have low Vd, remain in vascular compartment
5. TDM considerations:
   • Total plasma level (bound + free) may be normal, but free (active) level elevated in hypoalbuminemia → toxicity

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VSAQ 3: Anaphylactic Reactions & Idiosyncrasy - Give Examples

• Type I hypersensitivity (IgE-mediated)
• Mechanism: Prior sensitization → IgE antibodies on mast cells → re-exposure to drug → mast cell degranulation → histamine, leukotrienes, prostaglandins → systemic vasodilation, bronchoconstriction
• Drug causes: Penicillin (most common), sulfonamides, radiocontrast media, aspirin, vaccines, blood products
• Features: Urticaria, angioedema, bronchospasm, hypotension, cardiovascular collapse (within minutes)
• Treatment: Adrenaline (epinephrine) 0.5 mg IM - first line; antihistamines + corticosteroids; IV fluids

• Abnormal (qualitatively different) drug response due to genetic variation
• Not dose-related; not immunological
• Examples:
  • G6PD deficiency + primaquine/dapsone/nitrofurantoin → hemolytic anemia
  • Pseudocholinesterase deficiency + succinylcholine → prolonged apnea
  • Porphyria + barbiturates → acute porphyric attack
  • Malignant hyperthermia + halothane/succinylcholine → dangerous hyperthermia
  • Acute intermittent porphyria + sulfonamides → attack

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VSAQ 4: Drug Dependence

• Strong desire/craving to repeat drug use for pleasure or to avoid discomfort
• No physical withdrawal symptoms
• Most powerful form of dependence
• Examples: Cannabis, cocaine, amphetamine

• Physiological adaptation to drug presence; abrupt stopping causes withdrawal syndrome
• Withdrawal syndrome is opposite to the drug's effect
• Examples:
  • Opioids: withdrawal → yawning, lacrimation, diarrhea, muscle cramps, piloerection
  • Benzodiazepines: withdrawal → anxiety, tremors, seizures
  • Alcohol: withdrawal → delirium tremens, seizures

• Tolerance: Need for more drug for same effect
• Dependence: Need for drug to feel "normal"
• Both often occur together (morphine, alcohol)

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VSAQ 5: Teratogenicity & Teratogenic Drugs

• 0-2 weeks: All-or-nothing effect (implantation failure or normal development)
• 3-8 weeks (organogenesis): Most critical - major structural malformations
• 9 weeks - term: Growth, functional development (CNS, reproductive system most vulnerable)

• A: Safe (folic acid)
• B: No proven risk in humans (paracetamol)
• C: Risk cannot be ruled out
• D: Positive evidence of risk (dilantin/phenytoin)
• X: Contraindicated in pregnancy (thalidomide, warfarin, isotretinoin)

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VSAQ 6: Tachyphylaxis

1. Depletion of endogenous mediator stores - most common mechanism
   • Indirect sympathomimetics (ephedrine, amphetamine) cause release of stored noradrenaline → stores depleted → subsequent doses produce less effect
2. Receptor desensitization: Rapid uncoupling of receptor from effector pathway
3. Down-regulation of receptors

• Ephedrine - classic example (releases NA from stores; stores become depleted)
• Amphetamine - depletes catecholamine stores
• Histamine - rapid desensitization
• LSD (lysergic acid diethylamide) - serotonin receptor tachyphylaxis
• Nitrites (amyl nitrite) - rapid tolerance
• Serotonin - rapid desensitization

• Tachyphylaxis: RAPID (minutes to hours, few doses)
• Tolerance: GRADUAL (days to weeks, repeated dosing)

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VSAQ 7: Phase III Clinical Trial

• Stage: Third stage of drug development, after Phase I (safety) and Phase II (preliminary efficacy)
• Subjects: Large patient population (300-3,000+ patients) across multiple centers (multicentric)
• Objectives:
  1. Confirm therapeutic efficacy in a large population
  2. Identify adverse effects (including less common ones)
  3. Compare with existing standard treatment (active control)
  4. Establish appropriate dosing regimen
  5. Gather data for regulatory submission
• Design: Randomized, double-blind, controlled trial (placebo or active comparator)
• Duration: 1-4 years
• Outcome: Provides the pivotal evidence for regulatory approval (FDA, EMA, CDSCO)
• Ethical requirement: Informed consent from all patients
• Phase IIIb: Post-approval studies done to expand indications or support labeling changes

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VSAQ 8: Pharmacogenomics & Pharmacogenetics

• Study of the influence of single gene variations on drug response
• Focus on individual genes (e.g., CYP2D6, NAT2)
• Examples:
  • CYP2D6 polymorphism: poor metabolizers of codeine (no analgesia), tramadol, tricyclic antidepressants
  • NAT2 (N-acetyltransferase): slow acetylators → INH toxicity (peripheral neuropathy)
  • Pseudocholinesterase: succinylcholine apnea
  • HLA-B*5701: abacavir hypersensitivity
  • HLA-B*1502: carbamazepine - Stevens-Johnson syndrome (in Asian populations)
  • TPMT (thiopurine methyltransferase): azathioprine/6-MP toxicity in TPMT-deficient patients

• Broader term - studies how the entire genome influences drug response
• Uses genome-wide association studies (GWAS) and genomic profiling
• Aims to identify genetic biomarkers for drug efficacy and toxicity
• Foundation of personalized/precision medicine

• Oncology: KRAS mutation testing before cetuximab in colorectal cancer; HER2 testing before trastuzumab
• Warfarin dosing: CYP2C9 and VKORC1 genotyping
• Clopidogrel: CYP2C19 genotyping (reduced efficacy in poor metabolizers)
• HIV: HLA-B*5701 before abacavir

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VSAQ 9: Saturation Kinetics

• Also called zero-order kinetics or Michaelis-Menten kinetics
• When drug concentration exceeds the metabolic capacity of enzymes → enzymes become saturated
• A constant amount (not fraction) of drug eliminated per unit time
• Results in non-linear (dose-dependent) pharmacokinetics
• Small dose changes → disproportionately large changes in plasma levels
• t1/2 is not constant → increases with increasing dose/concentration
• Clinical danger: At therapeutic doses, minor dose increase can cause toxicity
• Examples:
  • Phenytoin (most important example - saturates CYP2C9 at therapeutic doses)
  • Ethanol (alcohol, oxidized at ~10 mL/hr by ADH regardless of blood level)
  • Aspirin at high doses (saturates glycine conjugation pathway)
  • Theophylline at high doses

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VSAQ 10: Hoffman Elimination

• A non-enzymatic, spontaneous chemical degradation that occurs at normal body temperature and pH
• Not dependent on organ function (kidney or liver)
• Drug spontaneously degrades in plasma/body
• Examples:
  • Atracurium (neuromuscular blocker) - undergoes Hofmann elimination at body pH/temperature to laudanosine
  • Cisatracurium (another NMBA) - undergoes Hofmann elimination (less laudanosine production)
• Clinical importance:
  • Safe in hepatic and renal failure - does not accumulate
  • Preferred NMBAs in patients with liver failure or renal failure (Atracurium > Vecuronium in these patients)
  • No need for dose adjustment in organ failure

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VSAQ 11: Drug Redistribution

• Given IV → rapidly enters well-perfused brain → induces anaesthesia
• Then redistributes from brain to less perfused tissues (muscle, then fat)
• Brain concentration falls rapidly → patient regains consciousness
• Drug not metabolized quickly - merely redistributed
• Clinical use: Explains why thiopentone has a short duration of action (5-10 min) despite a long half-life (11 hrs)

• Fentanyl (high lipophilicity) - rapid redistribution from brain to adipose tissue explains short action
• Diazepam single IV dose - fast redistribution into fat

• Explains ultrashort action of thiopentone, ketamine
• Repeated dosing or infusion → fat saturation → much longer duration of action (accumulation)
• Important for IV anaesthetics

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VSAQ 12: Define Drug, Pharmacokinetics & Pharmacodynamics

• A - Absorption
• D - Distribution
• M - Metabolism (Biotransformation)
• E - Excretion

• Drug-receptor interactions
• Dose-response relationships
• Mechanisms of drug action
• Signal transduction pathways

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VSAQ 13: OTC Drugs

• Drugs that can be purchased without a prescription
• Self-diagnosis and self-medication
• Deemed safe for use without medical supervision
• Characteristics: Low toxicity, wide therapeutic index, simple conditions they treat are self-diagnosable
• Examples: Paracetamol, aspirin, ibuprofen (low dose), antihistamines (cetirizine, loratadine), antacids, ORS, OCP (in some countries), topical antifungals (clotrimazole cream), povidone-iodine, cough syrups (some)
• Advantages: Convenient, reduces burden on healthcare system, patient autonomy
• Disadvantages: Risk of overuse, drug interactions, masking of serious illness, adverse effects without monitoring

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VSAQ 14: Orphan Drugs

• 7-year market exclusivity
• Tax credits for clinical trials
• Fast-track regulatory review
• Grants for research

• Imatinib (Gleevec) - CML (BCR-ABL inhibitor)
• Nusinersen - Spinal muscular atrophy
• Idursulfase - Hunter syndrome
• Ivacaftor - Cystic fibrosis (specific mutations)
• Thalidomide (second life) - Multiple myeloma, leprosy ENL

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VSAQ 15: P Drug

• Concept introduced by WHO to improve rational prescribing
• A P-drug is a drug that a physician/prescriber has personally selected as the first-choice drug for a given indication, based on careful analysis of efficacy, safety, cost, and suitability (ESCO criteria)
• Builds personal formulary for common conditions
• Benefits:
  • Improves prescribing efficiency
  • Reduces irrational prescribing
  • Cost-effective prescribing
  • Consistent clinical practice
• Selection criteria (WHO - 6 steps):
  1. Define the diagnosis
  2. Specify therapeutic objective
  3. Make an inventory of effective drugs
  4. Choose an effective drug
  5. Start treatment
  6. Give information, instructions, and warnings

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VSAQ 16: Placebo & its Uses

• ~35% of patients respond to placebo for pain, anxiety, nausea
• Mediated by release of endogenous opioids (endorphins) and psychological factors
• Higher with: injections > tablets, branded > generic, larger pills, more frequent dosing

1. In clinical trials: Control arm - to separate drug effect from placebo effect; determines true drug efficacy
2. Therapeutic use:
   • Mild anxiety, insomnia, psychosomatic symptoms
   • When patient insists on treatment but no drug is indicated
3. Research: To study placebo mechanisms, pain pathways
4. To reduce negative anticipatory effects in some patients

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VSAQ 17: Loading Dose & Maintenance Dose

• An initial larger dose given to rapidly achieve the desired therapeutic plasma concentration (especially for drugs with long t1/2 where reaching steady state would take too long)
• Formula: Loading Dose = Vd × Target plasma concentration / Bioavailability (F)
• When needed: Long t1/2 drugs where waiting for steady state (5 half-lives) is clinically unacceptable
• Examples:
  • Digoxin: t1/2 = 36 hrs; without loading dose → 7 days to reach steady state; give loading dose 1-1.5 mg in divided doses
  • Amiodarone: t1/2 = 40-55 days; give 800 mg/day loading for 1 week, then reduce
  • Chloroquine (malaria): loading dose 10 mg/kg then maintenance
  • Lidocaine (arrhythmia): IV bolus loading dose then infusion

• Dose given at regular intervals to maintain plasma drug concentration within the therapeutic window (replace drug eliminated between doses)
• Formula: Maintenance Dose = CL × Css × τ / F
  • CL = Clearance, Css = Target steady-state concentration, τ = Dosing interval
• Adjusted in renal/hepatic failure (reduced CL → reduce maintenance dose or extend dosing interval)

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VSAQ 18: Classify the Drug Dosage Forms

• Tablets (plain, enteric-coated, film-coated, dispersible, effervescent, modified-release)
• Capsules (hard gelatin, soft gelatin)
• Powders
• Granules
• Lozenges / Troches
• Suppositories (rectal)
• Pessaries (vaginal)

• Solutions (syrups, elixirs, linctus, drops)
• Suspensions
• Emulsions
• Injections (ampoules, vials, IV bags)

• Ointments (oil-based)
• Creams (water-in-oil or oil-in-water emulsions)
• Gels
• Pastes

• Inhalations (aerosols, nebulizer solutions, dry powder inhalers)
• Anaesthetic gases

• Patches

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VSAQ 19: Essential Medicines

• First published 1977; updated every 2 years
• Current list has ~560 medicines
• Divided into: Core list and Complementary list

• Currently NLEM 2022 with ~400 medicines
• Forms the basis for drug procurement in government hospitals
• Drugs on NLEM are eligible for price regulation under DPCO

• Evidence-based efficacy and safety
• Cost-effectiveness
• Disease burden in population
• Public health relevance
• Quality assurance

• Rational drug use promotion
• Price regulation and affordability
• Guides government drug procurement
• Reduces polypharmacy and irrational prescribing

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VSAQ 20: Schedule H Drugs

• Drugs that cannot be sold without a prescription from a registered medical practitioner
• Governed by Drugs and Cosmetics Act, 1940 (India) and Rule 65(11)(h) of D&C Rules 1945
• Label must bear "Rx" symbol and "Schedule H Drug - To be sold by retail on the prescription of a Registered Medical Practitioner only"

• More restrictive sub-category for specific high-risk drugs
• Includes: Antibiotics (Third-generation), antiretrovirals (ARVs), anti-TB drugs, habit-forming drugs
• Pharmacist must maintain a separate record of sales
• More stringent monitoring to prevent antibiotic resistance

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VSAQ 21: Drugs that can be used in Pregnancy & Lactation

• Antibiotics: Penicillins, cephalosporins, azithromycin (with caution), erythromycin base
• Antihypertensives: Methyldopa (drug of choice), hydralazine, nifedipine, labetalol
• Analgesics: Paracetamol (Category B; avoid in third trimester), low-dose aspirin (for pre-eclampsia prophylaxis)
• Antiemetics: Ondansetron, promethazine, metoclopramide
• Antidiabetics: Insulin (all types - drug of choice)
• Anticoagulant: Heparin (does not cross placenta; safe)
• Antiepileptics: No antiepileptic is completely safe, but if needed: lamotrigine (safest), with folic acid supplementation
• Antacids: Magnesium/aluminum hydroxide (avoid high dose)

• Paracetamol, ibuprofen (short-term)
• Penicillins, cephalosporins
• Methyldopa, labetalol
• Heparin, warfarin (low level in breast milk)
• Insulin (not absorbed orally by infant)

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VSAQ 22: Therapeutic Window

• Below MEC: Drug is sub-therapeutic (ineffective)
• Between MEC and MTC: Therapeutic range - optimal effect
• Above MTC: Toxic/adverse effects

• Wide TI (penicillin): large difference between MEC and MTC; easy to maintain in therapeutic window
• Narrow TI (digoxin, lithium, phenytoin, aminoglycosides, warfarin): small window; TDM needed

• Guides dosing decisions (adjust dose to keep in therapeutic window)
• Forms the basis for TDM
• Important for narrow TI drugs in altered physiological states

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VSAQ 23: Drugs given by Sublingual Route & its Advantages

1. Glyceryl trinitrate (GTN) - acute angina attack (onset 2 min)
2. Isosorbide dinitrate (ISDN) - acute angina
3. Buprenorphine - pain, opioid maintenance therapy
4. Nifedipine (buccal, for hypertensive urgency)
5. Ergotamine (migraine)
6. Apomorphine (Parkinson's disease rescue therapy)
7. Captopril (hypertensive urgency in some protocols)

1. Rapid onset (1-2 minutes) - useful in emergencies
2. Avoids first-pass metabolism - highly bioavailable (GTN would have <1% oral bioavailability but ~100% SL)
3. Avoids GI degradation by acid and enzymes
4. Drug enters systemic circulation via sublingual veins → superior vena cava (bypasses portal circulation)
5. Can be removed if adverse effects → stop further absorption
6. Non-invasive
7. Suitable for drugs that are well-absorbed across mucosa

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VSAQ 24: Pharmacological Basis of Drug Addiction & Drug De-addiction

• Compulsive drug use despite harm
• Involves: reward pathway (mesolimbic dopamine pathway), compulsion, loss of control

• Dopamine reward pathway: Drugs activate mesolimbic dopamine system (VTA → Nucleus accumbens → prefrontal cortex)
• All addictive drugs increase dopamine in the nucleus accumbens (reward center)
• Opioids: activate μ-opioid receptors → inhibit GABA interneurons → increased dopamine release
• Cocaine/amphetamine: block dopamine reuptake (cocaine = DAT blocker; amphetamine = reverse transport)
• Alcohol: acts on GABA-A (CNS depression) + NMDA antagonism + dopamine release
• Nicotine: nicotinic receptor (α4β2) activation → dopamine release
• Cannabis: THC → CB1 receptor → dopamine release

• Chronic drug use → down-regulation of dopamine receptors → need higher doses for same effect (tolerance)
• Abrupt cessation → below-normal dopamine activity → withdrawal syndrome (opposite of drug effect)

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Summary - What Was Covered

Topics Covered:

1. Routes of Drug Administration (with Special Drug Delivery Systems)
2. Biotransformation - Phase I & Phase II reactions with examples
3. Bioavailability - definition, factors, and clinical significance
4. Factors Affecting Drug Action - pharmacokinetic and pharmacodynamic

1. Transdermal Patch - advantages, disadvantages, examples
2. First Pass Metabolism
3. Prodrug - advantages with examples
4. Enzyme Induction & Inhibition (CYP450) - clinical significance
5. First Order & Zero Order Kinetics with examples
6. Therapeutic Index & Therapeutic Drug Monitoring (TDM)
7. Fixed Dose Combinations (FDC)
8. Methods to Prolong Drug Action
9. Drug Synergism & Antagonism - all types with examples
10. Management of Drug Poisoning
11. Drug Tolerance - types with examples
12. Dose Response Relationship - graded vs quantal
13. Phases of Clinical Trial (Phase 0 through IV)
14. Pharmacovigilance (including PvPI India)
15. Adverse Drug Reactions - ABCDE classification
16. Plasma Half-Life & its Importance
17. Receptors - classification and GPCRs