Master Pharmacology
for FMGE

Core Concepts

Pharmacology is the study of how drugs interact with living systems. Key principles govern their effects:

• Pharmacokinetics (ADME):
  • Absorption: Movement of drug from site of administration into systemic circulation. Influenced by bioavailability (fraction of administered dose reaching systemic circulation), first-pass metabolism (hepatic metabolism reducing bioavailability before systemic distribution).
  • Distribution: Reversible transfer of drug from systemic circulation into tissues. Influenced by Volume of Distribution (Vd), protein binding (e.g., albumin for acidic drugs, alpha-1 acid glycoprotein for basic drugs), tissue permeability.
  • Metabolism (Biotransformation): Chemical modification of drugs by enzymes (primarily in liver via CYP450 system and Phase II conjugation reactions) into more polar, water-soluble forms for excretion. Can lead to active/inactive metabolites.
  • Excretion: Removal of drugs/metabolites from the body, primarily via kidneys (glomerular filtration, tubular secretion, reabsorption), but also bile, faeces, lungs.
• Pharmacodynamics: Study of drug effects on the body and their mechanisms of action.
  • Receptors: Macromolecular targets (proteins) where drugs bind to produce effect (agonists activate, antagonists block). Ligand-gated ion channels, G-protein coupled receptors, enzyme-linked receptors, intracellular receptors.
  • Dose-Response Curve: Relates drug dose to magnitude of effect. Defines efficacy (maximal effect) and potency (dose required to produce 50% of maximal effect, EC50/ED50).
  • Therapeutic Index (TI): Ratio of toxic dose to effective dose (TD50/ED50). A narrow TI indicates a small margin of safety.
• Drug Interactions: Modification of the effect of one drug by another. Can be pharmacokinetic (affecting ADME) or pharmacodynamic (affecting receptor binding or physiological response).
• Adverse Drug Reactions (ADRs): Unintended, undesirable effects occurring at therapeutic doses.
  • Type A (Augmented): Predictable, dose-related, exaggerated pharmacological effect.
  • Type B (Bizarre): Unpredictable, idiosyncratic, often immunological (allergy).
  • Type C (Chronic): After prolonged use (e.g., tolerance, dependence).
  • Type D (Delayed): Occurs after some time (e.g., carcinogenicity, teratogenicity).
• Special Populations: Dose adjustments often needed for pediatric, geriatric, pregnant/lactating patients, and those with renal or hepatic impairment.

Clinical Presentation

• Desired Therapeutic Effects: Symptom improvement, disease control, cure.
• Adverse Drug Reactions (ADRs):
  • Non-specific: Nausea, vomiting, diarrhoea, headache, rash, dizziness.
  • Organ-specific toxicity: Hepatotoxicity (jaundice, abnormal LFTs), nephrotoxicity (elevated creatinine, reduced urine output), ototoxicity (tinnitus, hearing loss), myelosuppression (anaemia, infections, bleeding).
  • Hypersensitivity reactions: Ranging from rash to anaphylaxis.
  • Exaggerated pharmacological effects: E.g., hypotension with antihypertensives, bleeding with anticoagulants.
• Drug Interactions: Can manifest as amplified therapeutic effects/ADRs, or reduced therapeutic effect/treatment failure.
• Drug Toxicity/Overdose: Acute or chronic manifestations often representing an extreme extension of pharmacological effects.
• Therapeutic Failure: Lack of expected response, potentially due to suboptimal dosing, poor adherence, drug resistance, or pharmacokinetic variability.

Diagnosis (Gold Standard)

Diagnosis in pharmacology primarily involves identifying the cause of drug-related issues (ADRs, toxicity, therapeutic failure):

• Detailed Drug History: Comprehensive review of all prescribed, OTC, herbal, and recreational drugs, including adherence, recent changes, and allergies. Crucial for identifying causative agents and interactions.
• Clinical Examination: To identify signs and symptoms consistent with suspected ADRs or toxicity.
• Therapeutic Drug Monitoring (TDM): Measurement of drug concentrations in blood (e.g., peak and trough levels) for drugs with narrow therapeutic windows (e.g., digoxin, lithium, phenytoin, aminoglycosides, warfarin).
• Laboratory Tests: Organ function tests (LFTs, RFTs), CBC (for myelosuppression), specific drug levels (TDM), allergic workup.
• Pharmacogenetic Testing: Increasingly used for specific drugs where genetic polymorphisms affect metabolism or response (e.g., TPMT for azathioprine, CYP2D6 for codeine, HLA-B*1502 for carbamazepine).
• De-challenge/Re-challenge: If ethically permissible and clinically safe, stopping the suspected drug and observing for resolution, then reintroducing to confirm causality (rarely done due to risks).

Management (First Line)

• Manage Adverse Drug Reactions (ADRs) & Toxicity:
  • Identify and Remove/Reduce Offending Agent: Withdraw the drug or reduce its dose.
  • Symptomatic and Supportive Care: Treat symptoms (e.g., antiemetics for nausea, antihistamines for rash). Maintain vital functions.
  • Specific Antidotes: Administer if available (e.g., Naloxone for opioid overdose, Flumazenil for benzodiazepine overdose, N-acetylcysteine for paracetamol toxicity, Vitamin K for warfarin overdose, Atropine/Pralidoxime for organophosphate poisoning).
  • Enhance Elimination: Activated charcoal (for recent oral ingestion), forced diuresis, urinary pH adjustment, hemodialysis (for dialyzable drugs like lithium, salicylates).
• Optimize Drug Therapy:
  • Individualize Dosing: Adjust dose based on patient's age, weight, organ function (especially renal/hepatic impairment), comorbidities, and TDM results.
  • Patient Education: Explain proper drug use, potential side effects, importance of adherence, and drug-food/drug-drug interactions.
  • Monitor for Efficacy and Safety: Regular follow-up for therapeutic response and signs of ADRs.
  • Manage Drug Interactions: Avoid harmful combinations, adjust doses, or monitor closely.
• Prevent ADRs: Review medication list thoroughly, check for allergies, consider comorbidities and genetic factors, use lowest effective dose.