Pharmacology & Drug Interactions

# Pharmacology & Drug Interactions Knowledge Pack

## Pharmacokinetics Fundamentals

### ADME — Absorption, Distribution, Metabolism, Excretion

**Absorption**: The process by which a drug moves from its site of administration into systemic circulation. Oral bioavailability (F) is the fraction reaching systemic circulation after oral administration. F depends on: fraction absorbed from GI tract (dissolution, permeability across intestinal epithelium), first-pass metabolism in gut wall (CYP3A4 expressed in enterocytes) and liver (portal circulation delivers all absorbed drug to liver before systemic circulation).

Factors affecting oral absorption: gastric pH (PPIs increase pH → reduce absorption of pH-dependent drugs like ketoconazole, iron, and some HIV protease inhibitors; increase absorption of drugs degraded by acid), gastric emptying rate (faster emptying → faster absorption for most drugs; food slows emptying), intestinal motility, drug interactions at transporter level (Pgp efflux pumps in enterocytes actively expel substrates back into GI lumen — inhibiting Pgp increases absorption of its substrates).

**Distribution**: After reaching systemic circulation, drugs distribute to tissues based on blood flow, permeability, and binding. Vd indicates the apparent volume into which a drug distributes. Low Vd (~0.1 L/kg = plasma volume) means drug stays in blood — highly protein-bound, large molecular weight. Examples: warfarin (Vd 0.14 L/kg, 99% protein-bound). High Vd (>1 L/kg) means extensive tissue distribution — lipophilic drugs accumulate in fat, muscle, organs. Examples: amiodarone (Vd 60 L/kg, distributes into fat with t½ of 40-55 days).

Protein binding: Only unbound (free) drug is pharmacologically active, can cross membranes, and is available for metabolism/excretion. Albumin binds acidic drugs (warfarin, phenytoin, NSAIDs), alpha-1 acid glycoprotein binds basic drugs (lidocaine, propranolol). Displacement interactions are rarely clinically significant for drugs with large Vd (the displaced drug distributes into tissues, increasing Vd and CL proportionally — free concentration normalizes). Clinically significant for drugs with small Vd, narrow therapeutic index, and high protein binding — primarily warfarin.

**Metabolism**: Phase I reactions (CYP enzymes: oxidation, reduction, hydrolysis) create or expose functional groups. Phase II reactions (conjugation: glucuronidation via UGT, sulfation, acetylation, glutathione conjugation) attach polar molecules to increase water solubility for excretion. Most metabolism occurs in the liver; some in gut wall, kidneys, lungs.

Key CYP enzymes and their substrates:
- **CYP3A4** (metabolizes ~50% of all drugs): statins (atorvastatin, simvastatin — NOT pravastatin or rosuvastatin), calcium channel blockers (amlodipine, felodipine), benzodiazepines (midazolam, triazolam — NOT lorazepam, oxazepam), calcineurin inhibitors (tacrolimus, cyclosporine), many HIV protease inhibitors.