Pharmacokinetic Interactions

PK Interactions Overview - ADME Dance Moves

• PK interactions: One drug changes how another "dances" through the body via Absorption, Distribution, Metabolism, Excretion (ADME).
• Key "Dance Steps" altered:
  • Absorption: GI pH, motility, chelation (tetracycline + antacids).
  • Distribution: Protein binding (warfarin).
  • Metabolism: CYP450 induction (rifampicin) or inhibition (ketoconazole).
  • Excretion: Renal clearance (probenecid + penicillin).
• Outcome: Altered drug levels → therapeutic failure or toxicity.

⭐ The liver's CYP450 enzyme system is a major "dance floor" for metabolic drug interactions, impacting many medications.

Absorption Interactions - Entry Blockers

• Mechanisms affecting drug transfer from gastrointestinal tract to systemic circulation.
• Chelation & Complexation:
  • Forms non-absorbable complexes.
  • E.g., Tetracyclines/Quinolones + divalent/trivalent cations ($Ca^{2+}$, $Fe^{2+}$, $Al^{3+}$) in antacids, dairy, iron supplements → ↓ antibiotic absorption.
  • Cholestyramine (bile acid sequestrant) binds Warfarin, Digoxin → ↓ their absorption.
• Transport Protein Interactions:
  • P-glycoprotein (P-gp) Inhibition:
    • P-gp (efflux pump in enterocytes) inhibition → ↑ absorption of P-gp substrates (e.g., Digoxin, Dabigatran).
    • Inhibitors: Verapamil, Amiodarone, Clarithromycin, Ketoconazole, Ritonavir, Grapefruit juice. 📌 VACK-RG Juice.
  • OATP Inhibition:
    • Organic Anion Transporting Polypeptide (e.g., OATP1A2) inhibition by some fruit juices (apple, orange) → ↓ absorption of substrates.
    • E.g., ↓ Fexofenadine absorption.

⭐ Grapefruit juice, a P-gp/CYP3A4 inhibitor, can ↑ Felodipine bioavailability >200%, risking toxicity.

Distribution Interactions - Protein Binding Battles

• Drugs compete for plasma protein binding (e.g., albumin).
• Displacement ↑ free concentration of affected drug.
• Clinically vital for drugs:
  • Highly protein-bound (>90%).
  • Narrow Therapeutic Index (NTI).
  • Small Volume of Distribution (Vd).
• Examples: Aspirin displaces Warfarin → ↑ bleeding risk.
  • Sulfonamides displace Tolbutamide → hypoglycemia.

⭐ Displacement of NTI drugs (e.g., Warfarin, Phenytoin) is critical; ↑ free drug causes immediate toxicity before elimination adjusts.

Metabolism Interactions - Enzyme Wars

• Cytochrome P450 (CYP) Enzymes: Primary site for metabolic drug interactions. Located mainly in liver & gut wall.
• Enzyme Induction:
  • Mechanism: ↑ Enzyme synthesis → ↑ metabolic rate of substrate drugs.
  • Effect: ↓ Plasma concentration of substrate → potential therapeutic failure.
  • Onset: Gradual (days to weeks).
  • 📌 Inducers: CRAP GPS (Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbital, St. John's Wort).
• Enzyme Inhibition:
  • Mechanism: ↓ Enzyme activity → ↓ metabolic rate of substrate drugs.
  • Effect: ↑ Plasma concentration of substrate → ↑ risk of toxicity.
  • Onset: Rapid (hours to days).
  • 📌 Inhibitors: SICKFACES.COM G (Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Chloramphenicol, Erythromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole, Grapefruit juice).

⭐ Rifampicin, a potent CYP3A4 inducer, can significantly reduce the efficacy of oral contraceptives, potentially leading to unintended pregnancies.

Excretion Interactions - Renal Roadblocks

• Altered renal handling: impacts drug $t_{1/2}$ & effects.
• Mechanisms:
  • Tubular secretion competition (Probenecid ↓ Penicillin via OAT).
  • Urine pH changes → altered reabsorption. 📌 Ionized = Trapped & Excreted.
• Key Examples:
  • NSAIDs + Methotrexate → ↑ MTX toxicity.
  • Thiazides + Lithium → ↑ Li toxicity.
  • NaHCO₃ (alkalinization) → ↑ acidic drug (aspirin) excretion.

⭐ Competition for OAT/OCT transporters (e.g., probenecid-penicillin) is a major site of renal drug interactions.

High‑Yield Points - ⚡ Biggest Takeaways

• CYP450 inducers (e.g., Rifampicin, Phenytoin) ↓ drug levels, leading to treatment failure.
• CYP450 inhibitors (e.g., Ketoconazole, Erythromycin) ↑ drug levels, leading to increased toxicity.
• P-gp inducers (e.g., Rifampicin) ↓ drug absorption/bioavailability, reducing efficacy.
• P-gp inhibitors (e.g., Verapamil) ↑ drug absorption/bioavailability, increasing toxicity.
• Chelation (e.g., Tetracyclines + antacids) or gastric pH changes significantly ↓ drug absorption.
• Protein binding displacement (e.g., Warfarin + Aspirin) ↑ free drug concentration, risking adverse effects.
• Altered renal excretion (e.g., Probenecid blocks Penicillin secretion) ↑ drug half-life and effect.