Master Clinical Pharmacology & Therapeutics
for MRCP Part 1

Core Concepts

Clinical Pharmacology & Therapeutics explores drug mechanisms, actions, efficacy, safety, and use in patients. Understanding these principles is vital for safe and effective prescribing.

• Pharmacokinetics (PK): What the body does to the drug
  • Absorption: Bioavailability (F), first-pass metabolism. Routes: oral, IV, IM, SC, topical.
  • Distribution: Volume of Distribution (Vd) - relates total drug in body to plasma concentration. Protein binding (acidic drugs bind albumin, basic drugs bind alpha-1-acid glycoprotein).
  • Metabolism: Primarily liver. Phase I (oxidation, reduction, hydrolysis - CYP450 enzymes). Phase II (conjugation - glucuronidation, sulfation, acetylation). CYP450 System: Key for drug interactions (inducers e.g., rifampicin, carbamazepine; inhibitors e.g., macrolides, grapefruit juice, cimetidine, amiodarone).
  • Excretion: Primarily renal (glomerular filtration, tubular secretion, tubular reabsorption). Also hepatic (biliary), pulmonary, faecal. Clearance (Cl): Volume of plasma cleared of drug per unit time.
  • Half-life (t½): Time for plasma concentration to halve. Determines dosing frequency and time to steady state (~4-5 half-lives).
  • Steady State: Rate of drug administration equals rate of elimination. Achieved after ~4-5 half-lives.
• Pharmacodynamics (PD): What the drug does to the body
  • Receptors: Target macromolecules (GPCRs, ligand-gated ion channels, enzyme-linked, intracellular).
  • Agonist: Binds receptor and produces an effect (full, partial, inverse).
  • Antagonist: Binds receptor but does not produce an effect (competitive, non-competitive, irreversible).
  • Dose-Response Curves: Potency (EC50) and Efficacy (Emax).
• Adverse Drug Reactions (ADRs):
  • Type A (Augmented): Predictable, dose-related, exaggerated pharmacology (e.g., bradycardia with beta-blocker). Common.
  • Type B (Bizarre): Unpredictable, non-dose related, idiosyncratic (e.g., anaphylaxis, SJS). Rare but severe.
  • Type C (Chronic): Occurs with long-term use (e.g., steroid dependence).
  • Type D (Delayed): Occurs after drug cessation (e.g., teratogenicity, carcinogenicity).
  • Type E (End of Use): Withdrawal syndromes.
• Drug Interactions:
  • Pharmacokinetic: Altered ADME (e.g., CYP inhibition/induction, absorption interference, protein binding displacement).
  • Pharmacodynamic: Additive, synergistic, or antagonistic effects (e.g., CNS depression with alcohol + benzodiazepine).
• Special Populations:
  • Renal Impairment: Dose reduction for renally cleared drugs (e.g., gentamicin, digoxin, many antibiotics). GFR is key.
  • Hepatic Impairment: Dose reduction for hepatically metabolised drugs (e.g., opioids, benzodiazepines). Child-Pugh score can guide.
  • Elderly: Polypharmacy, reduced renal/hepatic function, altered Vd (less lean mass, more fat), increased sensitivity to CNS drugs. Start low, go slow.
  • Pregnancy/Lactation: Teratogenicity risks (FDA/TGA categories), drug transfer to breast milk. Avoid non-essential drugs.
  • Paediatrics: Weight-based dosing, different metabolism/excretion pathways.
• Therapeutic Drug Monitoring (TDM): Used for drugs with narrow therapeutic index, variable PK, or poor concentration-effect relationship (e.g., lithium, digoxin, phenytoin, gentamicin, vancomycin, ciclosporin, tacrolimus).

Clinical Presentation

• Drug Toxicity: Dose-dependent symptoms specific to the drug (e.g., visual disturbances with digoxin, ototoxicity/nephrotoxicity with aminoglycosides, confusion/ataxia with phenytoin).
• Adverse Drug Reactions (ADRs): Range from mild rashes (Type B) to anaphylaxis (Type B), organ damage (e.g., hepatitis with paracetamol OD, interstitial nephritis with NSAIDs), or electrolyte disturbances (e.g., hyperkalemia with ACEi).
• Therapeutic Failure: Persistent or worsening symptoms despite treatment, potentially due to sub-therapeutic dosing, non-compliance, drug interactions, or inappropriate drug choice.
• Withdrawal Syndromes: Symptoms upon cessation of certain drugs (e.g., tremors, seizures with alcohol/benzodiazepine withdrawal; rebound hypertension with clonidine cessation).
• Hypersensitivity Reactions: Urticaria, angioedema, bronchospasm, hypotension (anaphylaxis).

Diagnosis (Gold Standard)

Diagnosis of drug-related problems relies on a comprehensive approach:

• Detailed Drug History: Current medications (prescription, OTC, herbal), recent changes, allergies, adherence, recreational drug use. Essential for identifying culprit agents and interactions.
• Clinical Assessment: Thorough physical examination to identify signs and symptoms of toxicity or ADRs.
• Laboratory Tests:
  • Therapeutic Drug Monitoring (TDM): Measuring plasma drug levels (e.g., lithium, digoxin, phenytoin) to confirm toxicity or sub-therapeutic levels.
  • Organ Function Tests: Renal function (urea, creatinine, eGFR), liver function (LFTs), electrolytes to assess organ damage or guide dose adjustments.
  • Specific Toxicity Markers: e.g., paracetamol level for overdose, troponins for cardiotoxicity.
• Electrocardiogram (ECG): For cardiotoxic drugs (e.g., QT prolongation with amiodarone, tricyclic antidepressants).
• De-challenge/Re-challenge: Stopping the suspected drug (de-challenge) and observing symptom resolution; cautiously re-administering (re-challenge) if ethical, to confirm causality (Naranjo scale for ADR causality).

Management (First Line)

• Identify & Stop/Reduce Offending Drug: Crucial first step.
• Supportive Care: Maintain ABCs (Airway, Breathing, Circulation). Symptomatic treatment.
• Antidotes/Reversal Agents: Specific where available (e.g., naloxone for opioid overdose, flumazenil for benzodiazepine overdose, N-acetylcysteine for paracetamol overdose, atropine for organophosphate poisoning).
• Activated Charcoal: May be considered for recent (within 1-2 hours) oral ingestions, if drug binds charcoal. Contraindicated in reduced GCS or caustic ingestions.
• Enhance Elimination:
  • Forced Diuresis: Rarely used.
  • Alkalinization of Urine: For acidic drugs like salicylates.
  • Haemodialysis: For dialysable drugs in severe toxicity (e.g., lithium, methanol, ethylene glycol, high salicylate).
• Dose Adjustment: For renal/hepatic impairment based on clearance and drug properties.
• Manage Specific ADRs: e.g., antihistamines for mild allergic reactions, corticosteroids for severe inflammatory reactions.
• Patient Education: Regarding adherence, potential side effects, lifestyle modifications, and avoiding future interactions.
• Pharmacovigilance: Report serious or unexpected ADRs.