Master Pharmacology
for PMDC NLE Step 1

Core Concepts

Pharmacology is the study of how drugs interact with living systems. It encompasses two main branches:

• Pharmacokinetics (PK): What the body does to the drug.
  • Absorption: Movement of drug from site of administration into bloodstream. Factors include bioavailability (F), route, pH, food, first-pass metabolism (hepatic metabolism before systemic circulation, reducing F).
  • Distribution: Movement of drug from blood to tissues. Factors include volume of distribution (Vd), protein binding (e.g., albumin, alpha-1 acid glycoprotein), blood-brain barrier.
  • Metabolism: Biotransformation of drug by enzymes, primarily in the liver.
    • Phase I (Functionalization): Oxidation (Cytochrome P450 - CYP450), reduction, hydrolysis. Can produce active metabolites. CYP450 enzymes are key for drug interactions (inducers increase metabolism, inhibitors decrease).
    • Phase II (Conjugation): Glucuronidation, sulfation, acetylation. Typically leads to more water-soluble, inactive products for excretion.
    • Prodrugs are inactive compounds metabolized to active drugs.
  • Elimination: Irreversible removal of drug from the body.
    • Renal: Glomerular filtration, tubular secretion, tubular reabsorption. Influenced by renal function, urine pH.
    • Hepatic/Biliary: Excretion into bile, enterohepatic recirculation.
  • Clearance (Cl): Volume of plasma cleared of drug per unit time.
  • Half-life (t½): Time taken for plasma drug concentration to reduce by half. Steady state is typically reached after 4-5 half-lives.
  • Kinetics: First-order (constant *fraction* eliminated per unit time) vs. Zero-order (constant *amount* eliminated per unit time, e.g., phenytoin, aspirin at high doses, ethanol).
• Pharmacodynamics (PD): What the drug does to the body.
  • Receptors: Macromolecules (often proteins) that drugs bind to, initiating a cellular response.
    • Agonists: Bind and activate receptors (full, partial, inverse).
    • Antagonists: Bind to receptors but do not activate them, blocking agonist action (competitive, non-competitive, irreversible).
    • Receptor types: Ligand-gated ion channels, G protein-coupled receptors (GPCRs), enzyme-linked receptors, intracellular receptors.
  • Dose-Response: Relationship between drug dose and magnitude of effect.
    • Potency (EC50/ED50): Concentration/dose causing 50% of maximal effect.
    • Efficacy (Emax): Maximal effect a drug can produce.
    • Therapeutic Index (TI): Ratio of toxic dose (TD50) to effective dose (ED50); a measure of drug safety (higher TI = safer).
• Adverse Drug Reactions (ADRs): Unintended, undesirable effects.
  • Type A (Augmented): Dose-dependent, predictable extensions of therapeutic effect or side effects.
  • Type B (Bizarre): Dose-independent, unpredictable (e.g., allergies, idiosyncratic reactions).
• Drug-Drug Interactions (DDIs): Alteration of drug effect by co-administration of another drug, often involving PK (e.g., CYP450 enzymes) or PD (e.g., additive or antagonistic effects).

Clinical Presentation (of Drug-Related Issues)

• Adverse Drug Reactions (ADRs): Manifest as unexpected symptoms (e.g., rash, organ damage like hepatotoxicity, nephrotoxicity), exaggerated therapeutic effects (e.g., hypotension with an antihypertensive), or predictable side effects (e.g., dry mouth with anticholinergics).
• Drug Overdose/Toxicity: Acute onset of severe, dose-related organ dysfunction (e.g., CNS depression, respiratory failure, cardiac arrhythmias, seizures).
• Drug Withdrawal Syndromes: Appearance of symptoms opposite to the drug's effect upon cessation of chronic use (e.g., rebound hypertension from clonidine, seizures from benzodiazepine withdrawal).
• Therapeutic Failure: Lack of expected clinical improvement, potentially due to non-adherence, inadequate dosing, drug interactions, or incorrect diagnosis.
• Idiosyncratic Reactions: Rare, unpredictable responses often due to genetic predisposition (e.g., G6PD deficiency causing hemolytic anemia with primaquine).

Diagnosis (Gold Standard)

The cornerstone of diagnosing drug-related issues is a comprehensive medication history and reconciliation, including prescription, OTC, and herbal products, to identify potential interactions, non-adherence, or recent changes. Therapeutic Drug Monitoring (TDM) is the gold standard for drugs with narrow therapeutic indices (e.g., digoxin, phenytoin, lithium, aminoglycosides), involving measurement of plasma drug concentrations to optimize dosing and prevent toxicity. Clinical suspicion, symptom correlation, and in some cases, pharmacogenetic testing (e.g., CYP2D6 for codeine response, TPMT for thiopurines) can aid in diagnosis.

Management (First Line)

• Identify and Stop Offending Drug: The most critical initial step for ADRs or toxicity.
• Supportive Care: Prioritize ABCs (Airway, Breathing, Circulation). Provide symptomatic treatment (e.g., IV fluids, antiemetics, anticonvulsants).
• Antidotes: Administer specific antidotes when available (e.g., naloxone for opioids, N-acetylcysteine for acetaminophen, flumazenil for benzodiazepines).
• Dose Adjustment/Optimization: Modify drug dosage based on TDM results, renal/hepatic function, patient age/weight, or identified drug interactions.
• Patient Education: Counsel on proper drug use, potential side effects, and adherence to prevent future issues.
• Management of Drug-Drug Interactions: Avoid combination, adjust doses, monitor closely, or switch to alternative drugs.
• De-prescribing: Systematically discontinue unnecessary or potentially harmful medications, especially in polypharmacy.

Exam Red Flags