Mechanisms of Drug Interactions

Mechanisms: Overview - Med Mixology 101

• Drug Interaction (DI): Drug's effect modified by another substance (drug, food, herb).
• Primary Mechanisms:
  • Pharmacokinetic (PK): Body's action on drug altered ("ADME").
    • Absorption: e.g., Chelation, pH changes.
    • Distribution: Protein binding displacement.
    • Metabolism: CYP450 enzyme induction/inhibition.
    • Excretion: Altered renal/biliary clearance.
  • Pharmacodynamic (PD): Drug's action on body modified.
    • Receptor interactions (synergism, antagonism).
    • Post-receptor effects.
  • Pharmaceutical: Physical/chemical incompatibility (e.g., IV admixtures).
• Key Outcomes: ↑Toxicity or ↓Efficacy.

⭐ Most clinically significant drug interactions involve alterations in drug metabolism via CYP450 enzyme induction or inhibition (Pharmacokinetic).

Mechanisms: PK (AD) - Entry & Spread Sabotage

• Absorption (Entry Sabotage)
  • Altered Gastric pH:
    • Antacids (↑pH) ↓ absorption of acidic drugs (e.g., ketoconazole, iron).
    • Acidic environment (stomach) favors acidic drug absorption.
  • Chelation/Complexation:
    • Tetracyclines, Fluoroquinolones + Ca²⁺, Mg²⁺, Fe²⁺/³⁺, Al³⁺ (in antacids, dairy, iron preps) → ↓ absorption. 📌 "TFs bind Cations" (Tetracyclines, Fluoroquinolones bind Cations).
  • Altered Gut Motility:
    • Prokinetics (e.g., metoclopramide): ↑ motility → ↓ absorption of slowly absorbed drugs (e.g., digoxin); ↑ for rapidly absorbed (e.g., paracetamol).
    • Anticholinergics: ↓ motility → opposite effects.
  • P-glycoprotein (P-gp) Efflux Pump Modulation:
    • Inducers (e.g., rifampicin): ↑ P-gp efflux → ↓ absorption of substrates (e.g., digoxin).
    • Inhibitors (e.g., verapamil): ↓ P-gp efflux → ↑ absorption of substrates (e.g., digoxin).
• Distribution (Spread Sabotage)
  • Protein Binding Displacement:
    • Highly protein-bound drugs (e.g., warfarin, phenytoin, sulfonamides) can displace each other from albumin.
    • Aspirin displaces warfarin → ↑ free warfarin → ↑ bleeding risk.
    • ⭐ > Displacement is clinically significant mainly for drugs with >90% protein binding, small Volume of Distribution (Vd), and narrow therapeutic index.
  • Altered Tissue Uptake/Binding:
    • Digoxin + Quinidine: Quinidine displaces digoxin from tissue binding sites & inhibits P-gp → ↑ plasma digoxin levels → toxicity.

Mechanisms: PK (ME) - Metabolism & Exit Mayhem

Metabolism (Biotransformation): Primarily hepatic; alters drug structure.

• Enzyme Induction: ↑Metabolism. Effect: ↓Drug levels/failure or ↑Toxic metabolite. Onset: Slow.
  • 📌 Inducers: CRAP GPS (Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Griseofulvin, Phenobarbitone, Sulfonylureas/Smoking/St. John's Wort).
• Enzyme Inhibition: ↓Metabolism. Effect: ↑Drug levels/toxicity. Onset: Rapid.
  • 📌 Inhibitors: SICKFACES.COM Group (Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Chloramphenicol, Erythromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole, Grapefruit juice).
• CYP450: Main system; CYP3A4 for ~50% drugs. Genetic variants (CYP2D6, CYP2C19) → varied response.

⭐ Grapefruit juice (CYP3A4 inhibitor) ↑ levels & toxicity of statins, Calcium channel blockers, cyclosporine.

Excretion (Elimination): Primarily renal.

• Renal:
  • Filtration: unbound drug.
  • Secretion: active; competition (Probenecid + Penicillin → ↑Penicillin).
  • Reabsorption: pH-dependent ion trapping.
    • Acidic drugs (Aspirin): Alkalinize urine (NaHCO₃) for ↑Excretion.
    • Basic drugs (Amphetamine): Acidify urine (NH₄Cl) for ↑Excretion.
• Biliary & Enterohepatic Circulation:
  • Bile excretion, gut reabsorption → prolongs action (Digoxin, OCPs).
  • Antibiotics may ↓ OCP efficacy.

Mechanisms: PD - Target Site Tussles

• Drugs interact at same/related target sites, altering cellular/physiological response.
• Receptor Site Competition:
  • Competitive Antagonism: Naloxone (antagonist) displaces morphine (agonist) at µ-opioid receptors.
  • Partial vs. Full Agonist: Buprenorphine (partial agonist) can ↓ efficacy of morphine (full agonist) if co-administered.
• Allosteric Modulation:
  • Drugs bind to different sites on one receptor complex, modifying the primary ligand's effect.
  • E.g., Benzodiazepines & Barbiturates on GABA-A receptor (enhance GABAergic inhibition, ↑Cl⁻ influx).
• Physiological (Functional) Antagonism:
  • Two drugs act on different receptors/pathways, producing opposing physiological effects on the same system.
  • E.g., Histamine (H1; bronchoconstriction) vs. Adrenaline (β2; bronchodilation).

⭐ Co-administration of Sumatriptan (5-HT1D agonist) and Ergotamine derivatives is contraindicated due to synergistic vasoconstriction (risk of severe coronary/cerebral ischemia); allow at least a 24-hour interval between them.

High‑Yield Points - ⚡ Biggest Takeaways

• Pharmacokinetic (PK) interactions alter drug ADME (Absorption, Distribution, Metabolism, Excretion).
• Pharmacodynamic (PD) interactions at target sites: synergism, antagonism, additive effects.
• CYP450 enzyme induction (e.g., rifampicin) ↓ drug levels, reducing efficacy.
• CYP450 enzyme inhibition (e.g., ketoconazole) ↑ drug levels, increasing toxicity risk.
• P-glycoprotein (P-gp) modulation impacts drug absorption and cellular efflux.
• Altered absorption: chelation (e.g., tetracyclines + antacids) or pH changes reduce bioavailability.
• Protein binding displacement (e.g., warfarin by NSAIDs) ↑ free drug concentration and effect.