Paper I - General Pharmacology: Complete Answers

1. Advantages and Disadvantages of Different Routes of Drug Administration

Enteral Routes

Parenteral Routes

• Used for allergy testing and desensitization
• Example: BCG vaccine, tuberculin (Mantoux) test

Other Routes

2. Generic and Chemical Name of Drugs

• Chemical name - The precise scientific name describing the molecular structure of the drug (IUPAC nomenclature). Example: Paracetamol = N-(4-hydroxyphenyl)acetamide
• Generic (nonproprietary) name - The official non-brand name approved by regulatory authorities (e.g., INN - International Nonproprietary Name). Example: Paracetamol, Metformin, Atenolol
• Brand (proprietary) name - The trade name given by the manufacturer. Example: Calpol (paracetamol), Glucophage (metformin)

• Generic names are universal and used in prescriptions for interchangeability
• Reduces confusion and costs; ensures pharmacovigilance
• WHO recommends prescribing by generic names

3. Special Drug Delivery Systems Including Transdermal Drug Delivery System

Types:

• Drug releases slowly over hours - reduces dosing frequency and maintains steady plasma levels
• Example: Nifedipine SR, Morphine CR, Metformin XR

• Chemical coating resists gastric acid; dissolves in the alkaline intestine
• Protects acid-labile drugs (omeprazole) and prevents gastric irritation (aspirin EC)

• Drug is delivered across skin for systemic effect
• Components: Drug reservoir, rate-controlling membrane, adhesive, backing layer
• Advantages: Avoids first-pass metabolism; sustained drug delivery; easy to remove if needed; improves compliance
• Disadvantages: Only suitable for highly potent, lipophilic drugs; may cause local skin irritation
• Examples: GTN patch (angina), Nicotine patch (smoking cessation), Fentanyl patch (chronic pain), Clonidine patch, Estradiol patch, Scopolamine patch (motion sickness)

• Phospholipid vesicles that encapsulate drugs; targeted delivery reduces toxicity
• Example: Liposomal amphotericin B (reduced nephrotoxicity), Liposomal doxorubicin

• Sub-micron sized drug carriers for targeted therapy (especially cancer)
• Example: Paclitaxel nanoparticles (Abraxane)

• Drug-containing devices implanted subcutaneously for very long-term delivery
• Example: Etonogestrel implant (Nexplanon) - contraception for 3 years; Leuprolide acetate implant (prostate cancer)

• Tablet with osmotic core; water enters and pushes drug out at constant rate
• Example: Nifedipine GITS (Gastrointestinal Therapeutic System)

4. Management of Anaphylactic Shock

Immediate Steps (ABC):

• Adult: 0.5 mg (0.5 mL of 1:1000) IM into anterolateral thigh
• Child: 0.01 mg/kg IM (max 0.5 mg)
• Can repeat every 5-15 minutes if no improvement
• IV only in cardiac arrest or severe refractory cases

• Chlorpheniramine 10 mg IV (H1-blocker) - reduces urticaria/angioedema
• Ranitidine 50 mg IV (H2-blocker) - adjunct

• Hydrocortisone 200 mg IV or Methylprednisolone 1-2 mg/kg IV
• Prevents biphasic reaction (4-8 hours after initial)
• Slow onset; not first-line for acute resuscitation

5. Teratogenic Drugs

FDA Pregnancy Categories (older system):

Important Teratogenic Drugs and Their Effects:

6. Drug Antagonism

Types:

1. Competitive (Reversible) Antagonism:
   • Antagonist competes with agonist for the same receptor binding site
   • Effect of antagonist can be overcome by increasing agonist concentration (parallel shift of dose-response curve to the right; maximal response unchanged)
   • Example: Atropine vs Acetylcholine (muscarinic), Naloxone vs Morphine (opioid), Propranolol vs Adrenaline (beta-adrenergic)
2. Non-competitive (Irreversible) Antagonism:
   • Antagonist binds irreversibly to receptor or an allosteric site; maximum response is reduced
   • Increasing agonist cannot restore maximal response
   • Example: Phenoxybenzamine (alpha blocker - covalently binds), Aspirin (irreversibly inhibits COX)

• Two drugs act on different receptors but produce opposing physiological effects
• Example: Adrenaline (bronchodilation) vs Histamine (bronchoconstriction)
• Example: Insulin (lowers blood glucose) vs Glucagon (raises blood glucose)

• Antagonist chemically interacts with and inactivates the drug (not at receptor)
• Example: Protamine sulfate neutralizes heparin; Chelating agents (EDTA, dimercaprol) bind heavy metals

• Antagonist reduces plasma concentration of agonist by altering absorption, distribution, metabolism, or excretion
• Example: Phenobarbitone induces metabolism of warfarin, reducing its anticoagulant effect

7. Plasma Protein Binding

Key Concepts:

• Only the free (unbound) fraction is pharmacologically active, able to cross membranes, reach the site of action, and be metabolized/excreted
• The bound fraction acts as a drug reservoir - slowly releases free drug as free concentration falls
• Protein binding is expressed as % bound (e.g., warfarin 99% bound - only 1% is free and active)

Drugs with High Protein Binding:

• Warfarin (~99%), Furosemide (97%), Diazepam (98%), Phenytoin (90%), Digoxin (25%), Ampicillin (15%)

Clinical Significance:

1. Drug interactions: When two highly protein-bound drugs compete for the same binding sites (e.g., sulfonamides displacing warfarin), the displaced drug temporarily rises in free concentration - but the body rapidly compensates by increased elimination (clinically, this mechanism is usually minor)
2. Hypoalbuminemia (liver disease, nephrotic syndrome, malnutrition): Total drug concentration in plasma falls, but unbound (active) concentration may remain normal - can lead to toxicity if dose not adjusted
3. Distribution volume: Highly protein-bound drugs have smaller apparent volume of distribution (confined to plasma)
4. Duration of action: Protein binding prolongs drug action

8. First Pass Metabolism

Mechanism:

• After oral absorption, drug passes through intestinal wall → portal vein → liver → hepatic metabolism (CYP450 enzymes) → reduced amount reaches systemic circulation

Consequences:

• Reduced bioavailability of the drug (oral dose must be much higher than IV dose)
• High inter-individual variability (CYP polymorphism)

Examples of Drugs with High First-Pass Metabolism:

Routes That Bypass First-Pass:

• Sublingual (nitroglycerin)
• Transdermal (GTN patch, fentanyl)
• Intravenous/IM/SC
• Rectal (partially bypasses)
• Inhalation

Why Omeprazole Is Given on Empty Stomach (Q10 connection)

9. Bioavailability

• IV administration = 100% bioavailability (gold standard)
• Oral bioavailability is always ≤100% due to incomplete absorption and first-pass metabolism

Factors Affecting Bioavailability:

1. Drug properties: Solubility, lipophilicity, molecular size, ionization (pKa), chemical stability
2. Formulation: Tablet disintegration, dissolution rate, particle size, excipients
3. First-pass metabolism: Major cause of low oral bioavailability
4. GI factors: pH, motility, food, gut flora, transporters (P-glycoprotein efflux)
5. Patient factors: Age, disease state (liver, gut disease), genetic CYP polymorphisms

Bioavailability and Bioequivalence:

• Bioequivalence: Two formulations of the same drug (e.g., generic vs brand) are bioequivalent if their rate and extent of absorption (AUC, Cmax, Tmax) are within 80-125% of each other
• Used to approve generic drug substitution

10. Why Omeprazole Is Given on Empty Stomach in Morning Hours

11. Zero and First Order Kinetics

First-Order Kinetics (most drugs):

• The rate of drug elimination is proportional to the drug concentration at that time
• A constant fraction (%) of drug is eliminated per unit time
• Formula: dA/dt = -k₁ × A(t) (where k₁ = first-order rate constant, units: time⁻¹)
• Plasma concentration declines exponentially
• Half-life is constant (independent of dose)
• Doubling the dose doubles the plasma concentration
• Examples: Most drugs at therapeutic concentrations (digoxin, propranolol, most antibiotics)

Zero-Order Kinetics:

• The rate of elimination is constant - a fixed amount is eliminated per unit time (NOT a fraction)
• Formula: dA/dt = -k₀ (where k₀ = zero-order rate constant, units: mass/time e.g., mg/hour)
• Occurs when elimination mechanisms are saturated (enzyme saturation)
• Plasma concentration declines linearly (not exponentially)
• Half-life is NOT constant - increases with higher doses
• Small increases in dose can cause disproportionately large rises in plasma concentration (dose-dependent/non-linear kinetics) → toxicity risk
• Examples: Phenytoin (at high doses), Alcohol (ethanol), Aspirin (at high doses), Heparin, Warfarin (at high doses)

Summary Table:

12. Plasma Half-Life (t½)

t½ = 0.693 / k (where k = elimination rate constant) t½ = (0.693 × Vd) / CL (where Vd = volume of distribution, CL = clearance)

Clinical Significance:

1. Time to steady state: Requires 4-5 half-lives to reach steady-state plasma concentration (Css) during repeated dosing
2. Dosing interval: t½ determines how often a drug should be dosed to maintain therapeutic levels
3. Drug washout: ~5 half-lives to completely eliminate a drug from the body
4. Loading dose: Used for drugs with long t½ to quickly reach Css (e.g., digoxin, amiodarone)

Examples:

Factors Affecting t½:

• Liver disease → reduced metabolism → increased t½
• Renal failure → reduced excretion → increased t½ (for renally cleared drugs)
• Age (elderly): reduced hepatic/renal function → prolonged t½
• Drug interactions: enzyme inducers reduce t½ (e.g., rifampicin shortens warfarin t½)

13. Therapeutic Drug Monitoring (TDM)

When TDM is Needed:

1. Drugs with a narrow therapeutic index (small difference between effective and toxic concentrations)
2. Drugs with unpredictable pharmacokinetics (nonlinear, high inter-patient variability)
3. Suspected drug toxicity or treatment failure
4. Special populations (renal/hepatic impairment, extremes of age, pregnancy)
5. Suspected non-compliance

Drugs Commonly Monitored:

Timing of Samples:

• Trough levels: Taken just before the next dose - best reflects minimum concentration
• Peak levels: Taken 1-2 hours post-oral, or 30 min post-IV (for aminoglycosides)
• Samples should be taken at steady state (after 4-5 half-lives)

14. Fixed Dose Combination (FDC)

Advantages:

1. Improved compliance - fewer tablets to take (single pill vs multiple)
2. Synergistic effects - enhanced efficacy when drugs work together
3. Reduced dose of each component - lowers risk of individual dose-related side effects
4. Prevents drug resistance (especially in TB, HIV, malaria)
5. Cost-effective - cheaper than multiple individual drugs
6. Convenience - simplified regimen

Disadvantages:

1. Inflexible dosing - cannot adjust individual components independently
2. Increased risk of adverse effects if patient reacts to one component
3. Different pharmacokinetics of components may be suboptimal
4. Difficult to identify which drug causes adverse effects
5. Not suitable for all patients (e.g., renal/hepatic impairment requiring dose reduction of one component)

Examples of Common FDCs:

15. Clinical Trials

Phases of Clinical Trials:

• Very small sub-pharmacological doses in ~10 healthy volunteers
• Assesses basic pharmacokinetics (ADME); not mandatory

• 20-80 healthy volunteers (or patients for cancer/HIV drugs)
• Determines maximum tolerated dose, pharmacokinetics, dose-response, adverse effects
• Focus: Safety and Pharmacokinetics

• 100-300 patients with the target disease
• Assesses drug efficacy, dose-ranging, and short-term safety
• Focus: Does the drug work? What dose?
• Divided into Phase IIa (dose-finding) and IIb (efficacy)

• 300-3,000+ patients; multi-center, usually randomized, controlled, double-blind
• Compares with placebo or standard treatment
• Establishes efficacy and safety profile for regulatory approval
• Focus: Efficacy vs. comparator; rare adverse effects
• Required for drug registration/marketing approval (FDA, EMA)

• After drug approval and launch
• Conducted in thousands of patients in real-world conditions
• Detects rare, long-term, or population-specific adverse effects
• Example: Rofecoxib (Vioxx) withdrawn in Phase IV after cardiovascular risk identified

Key Terms:

• RCT (Randomized Controlled Trial): Gold standard; subjects randomly assigned to treatment or control
• Double-blind: Neither investigator nor subject knows the treatment allocation - reduces bias
• Placebo: Inert substance given to the control group
• Crossover design: Each subject serves as their own control

16. Adverse Drug Reactions (ADRs)

Classification (WHO / Rawlins & Thompson):

• Predictable, dose-dependent, related to drug's known mechanism of action
• Most common type (~80%)
• Reduced by dose reduction
• Example: Bradycardia with propranolol, hypoglycemia with insulin, bleeding with warfarin

• Unpredictable, NOT dose-dependent, unrelated to known pharmacology
• Due to immunological or pharmacogenetic mechanisms
• Less common but more serious; high mortality
• Example: Penicillin anaphylaxis, malignant hyperthermia with halothane, aplastic anemia with chloramphenicol

• Related to cumulative dose over time
• Example: Adrenal suppression with prolonged corticosteroids, cardiomyopathy with long-term doxorubicin, opioid dependence

• Appear after a long delay after drug use
• Example: Carcinogenesis (cyclophosphamide → bladder cancer), teratogenesis (thalidomide), tardive dyskinesia (antipsychotics)

• Occurs when drug is abruptly discontinued
• Example: Adrenal crisis on stopping steroids, rebound hypertension stopping clonidine, benzodiazepine withdrawal syndrome

• Unexpected failure of drug to achieve intended effect
• Often dose-related; drug interactions, resistance
• Example: Oral contraceptive failure due to enzyme inducers (rifampicin)

Severity Classification:

• Mild: No antidote needed; resolves on stopping drug (e.g., nausea)
• Moderate: Change in therapy or hospitalization needed
• Severe: Life-threatening, disabling, fatal

Pharmacovigilance: