Master CPS - Pharmacology
for MSRA

Core Concepts

Pharmacology is the study of how drugs interact with living systems. Key principles include:

• Pharmacokinetics (PK): What the body does to the drug (ADME).
  • Absorption: Bioavailability (fraction of administered drug reaching systemic circulation). Routes: oral, IV, IM, SC, transdermal.
  • Distribution: Volume of distribution (Vd) – extent drug distributes into body tissues. Highly protein-bound drugs have lower free fraction.
  • Metabolism: Primarily liver (CYP450 system) – converts lipid-soluble drugs into water-soluble metabolites for excretion. Phase I (oxidation, reduction, hydrolysis) and Phase II (conjugation). First-pass metabolism significantly reduces oral bioavailability.
  • Excretion: Primarily kidneys (glomerular filtration, tubular secretion, reabsorption). Clearance (CL) – volume of plasma cleared of drug per unit time.
  • Half-life (t½): Time for drug concentration to reduce by half. Determines dosing interval and time to steady state (approx. 4-5 half-lives).
• Pharmacodynamics (PD): What the drug does to the body.
  • Receptors: Target proteins (e.g., GPCRs, ion channels, enzyme-linked, intracellular).
  • Agonist: Binds to and activates a receptor to produce a biological response.
  • Antagonist: Binds to a receptor but does not activate it, blocking agonist action. Competitive vs. Non-competitive.
  • Efficacy: Maximal effect a drug can produce.
  • Potency: Amount of drug needed to produce a given effect.
  • Therapeutic Index: Ratio of toxic dose to therapeutic dose (narrow margin = higher risk, e.g., Warfarin, Lithium, Digoxin).
• Adverse Drug Reactions (ADRs): Harmful or unintended responses.
  • Type A (Augmented): Dose-dependent, predictable (e.g., bleeding with warfarin, bradycardia with beta-blockers).
  • Type B (Bizarre): Dose-independent, unpredictable (e.g., anaphylaxis, SJS).
• Drug Interactions: One drug altering the effects of another.
  • Pharmacokinetic: Altered ADME (e.g., CYP450 induction/inhibition, P-glycoprotein).
  • Pharmacodynamic: Synergistic or antagonistic effects at receptor level (e.g., NSAIDs + ACEi impair renal function).
• Special Populations: Dose adjustments often required for elderly, renally/hepatically impaired, pregnant/lactating patients.

Clinical Presentation

• ADRs: Wide range, from mild (e.g., GI upset, rash, dizziness) to severe (e.g., anaphylaxis, angioedema, organ failure). Presentation depends on drug class and mechanism (e.g., anticholinergic symptoms with TCAs, extrapyramidal symptoms with antipsychotics).
• Drug Toxicity/Overdose: Exaggerated pharmacological effects (e.g., respiratory depression with opioids, prolonged QT interval with macrolides, bleeding with anticoagulants, lactic acidosis with metformin).
• Drug Interactions: Can manifest as increased toxicity (e.g., statin myopathy with macrolides) or reduced efficacy (e.g., rifampicin reducing oral contraceptive efficacy).
• Withdrawal Syndromes: Occur upon abrupt cessation of certain drugs (e.g., benzodiazepines, opioids, corticosteroids), presenting with rebound symptoms, seizures, or cardiovascular instability.
• Therapeutic Failure: Due to inadequate dosing, malabsorption, rapid metabolism, or drug interactions reducing efficacy.

Diagnosis (Gold Standard)

Diagnosis of pharmacology-related issues (ADRs, toxicity, interactions) is primarily clinical, based on a comprehensive drug history and temporal relationship.

• Clinical Suspicion: Correlating symptoms with recently started or changed medications.
• Drug History: Detailed list of all prescribed, OTC, herbal, and illicit drugs.
• Drug Levels (Therapeutic Drug Monitoring - TDM): For drugs with narrow therapeutic indices (e.g., Digoxin, Lithium, Phenytoin, Gentamicin, Vancomycin, Theophylline) to confirm toxicity or sub-therapeutic levels.
• Dechallenge/Rechallenge: Symptoms improve upon stopping the drug (dechallenge) and reappear upon restarting (rechallenge - rarely done if severe).
• Genetic Testing: Pharmacogenomics (e.g., CYP2D6 for codeine metabolism, TPMT for azathioprine).

Management (First Line)

Management principles for pharmacology-related problems are generally supportive and symptom-based.

• Stop/Reduce Offending Drug: Crucial first step for most ADRs and toxicities, if clinically appropriate. Taper slowly if withdrawal risk.
• Supportive Care: Airway, Breathing, Circulation (ABC) management. Symptomatic treatment (e.g., antiemetics for nausea, antihistamines for rash).
• Antidotes: Administer specific antidotes where available (e.g., Naloxone for opioid overdose, Flumazenil for benzodiazepine overdose, N-acetylcysteine for paracetamol overdose, Protamine for heparin, Vitamin K for warfarin).
• Decontamination: Activated charcoal (if within 1 hour for oral overdose), gastric lavage (rare).
• Dose Adjustment: For organ impairment (renal/hepatic) or in special populations (elderly, paediatric).
• Substitute Drug: Switch to an alternative drug with a different mechanism or side-effect profile if the offending drug is essential.
• Patient Education: Explain the ADR and how to avoid it in future.

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