Drug Interactions

Intro & Classification - Friendly Fire?

• Drug Interaction (DI): Modification of a drug's effect by another drug, food, or herbal product.
• Significance: May ↑ or ↓ therapeutic effects or ↑ adverse effects (ADRs).
• Types:
  • Pharmacokinetic (PK): Body's handling of drug (ADME) altered.
    • E.g., enzyme induction/inhibition affecting metabolism.

    ⭐ Grapefruit juice is a potent inhibitor of CYP3A4, increasing levels of many drugs.

  • Pharmacodynamic (PD): Drug's action on body altered.
    • E.g., synergistic or antagonistic effects at receptors.
  • Pharmaceutical: In vitro incompatibility (e.g., IV admixture).

Pharmacokinetic (PK) Interactions - ADME Antics

Alters drug conc. via Absorption, Distribution, Metabolism, Excretion (ADME).

• Absorption (A):

  • pH changes: Antacids ↓ketoconazole.
  • Chelation: Tetracycline + $Ca^{2+}$ ↓absorption.
  • Motility: Metoclopramide ↑, anticholinergics ↓.
  • Gut flora: Antibiotics ↓OCP/digoxin efficacy.

• Distribution (D):

  • Protein binding: Aspirin displaces warfarin → ↑free warfarin, ↑bleed risk.

• Metabolism (M): (Mainly Cytochrome P450)

  • Induction: ↑Metabolism → ↓drug effect (e.g., Rifampicin + OCPs → OCP failure).

  • Inhibition: ↓Metabolism → ↑drug toxicity (e.g., Erythromycin + Warfarin → ↑bleeding).

  • CYP450 Enzyme Interactions:

    Enzyme	Inducers (📌 G P S C R I B S Cell Phone)	Inhibitors (📌 SICKFACES.COM Group + Grapefruit)	Key Substrates (Examples)
    CYP3A4	Carbamazepine, Rifampicin, Phenytoin, St. John's Wort	Macrolides, Azoles, Ritonavir, Grapefruit Juice	Statins (Simva), Ca-blockers, Warfarin, Cyclosporine
    CYP2D6	(Few potent)	SSRIs (Fluoxetine), Quinidine, Bupropion	β-blockers (Metoprolol), Codeine, TCAs
    CYP2C9	Rifampicin, Barbiturates	Fluconazole, Amiodarone, Sulfamethoxazole	Warfarin (S), Phenytoin, NSAIDs
    CYP2C19	Rifampicin, Carbamazepine	Omeprazole, Fluconazole	Clopidogrel (prodrug), Diazepam
    CYP1A2	Smoking, Char-meat	Ciprofloxacin, Fluvoxamine	Theophylline, Caffeine

  ⭐ Grapefruit juice (CYP3A4 inhibitor) ↑levels of nifedipine, simvastatin, cyclosporine.

• Excretion (E):

  • Urinary pH: $NaHCO_3$ ↑aspirin excretion; $NH_4Cl$ ↑amphetamine excretion.
  • Tubular secretion: Probenecid ↓penicillin excretion (↑effect), ↑MTX toxicity.

Pharmacodynamic (PD) Interactions - Receptor Riot

• Drugs clash at receptors or common pathways, altering patient response. Plasma levels unaffected.
• Synergism: Enhanced combined effect.
  • Additive ($1+1=2$): e.g., Aspirin + Paracetamol.
  • Potentiation ($1+1>2$): e.g., Levodopa + Carbidopa (Carbidopa inhibits peripheral metabolism of Levodopa, ↑ CNS availability). 📌 Synergy Potentiates Action (SPA).
• Antagonism: One drug blocks or reduces another's effect.
  • Physiological (Functional): Opposite actions via different receptors (e.g., Histamine vs Adrenaline on bronchi).
  • Receptor Blockade:
    • Competitive: Reversible binding to agonist site. Shifts Dose-Response Curve (DRC) right (↓potency, $E_{max}$ unchanged). (e.g., Naloxone vs Morphine).
    • Non-competitive: Irreversible or allosteric binding. ↓ $E_{max}$ (↓efficacy). (e.g., Phenoxybenzamine vs Noradrenaline).

⭐ Naloxone competitively antagonizes Morphine at opioid receptors, reversing respiratory depression without affecting Morphine's $E_{max}$ if sufficient agonist is present.

Clinically Significant Interactions - Danger Duos

• Warfarin (NTI):
  • • Amiodarone, Macrolides, Azoles (inhibitors) → ↑INR, ↑Bleeding.
  • • Rifampicin, Carbamazepine (inducers) → ↓INR, ↑Clots.
• Digoxin (NTI):
  • • Diuretics ($K^+\downarrow$), Amiodarone, Verapamil → ↑Digoxin toxicity.
• Lithium (NTI):
  • • NSAIDs, Thiazides, ACEIs → ↑Lithium toxicity.
• Statins + Macrolides/Azoles/Fibrates → ↑Rhabdomyolysis risk.
• Serotonin Syndrome: MAOIs + SSRIs/SNRIs/Tramadol → Hyperthermia, rigidity. 📌 SHIVERS.
• QT Prolongation: Macrolides + Azoles + Class IA/III Antiarrhythmics → ↑Torsades de Pointes.
• Sildenafil + Nitrates → Severe hypotension ⚠️.

⭐ Grapefruit juice (CYP3A4 inhibitor) ↑ levels of Statins, calcium channel blockers, Cyclosporine.

High‑Yield Points - ⚡ Biggest Takeaways

• Pharmacokinetic interactions alter ADME (Absorption, Distribution, Metabolism, Excretion); pharmacodynamic interactions alter drug action/effect.
• Enzyme induction (e.g., Rifampicin, Phenytoin) ↓ drug levels, reducing efficacy.
• Enzyme inhibition (e.g., Ketoconazole, Erythromycin) ↑ drug levels, increasing toxicity.
• Cytochrome P450 (CYP450) enzymes are key in metabolic drug interactions.
• Grapefruit juice inhibits CYP3A4, significantly ↑ levels of susceptible drugs.
• Warfarin has critical interactions, notably with antibiotics, antifungals, and NSAIDs.
• Risk of serotonin syndrome with multiple serotonergic drugs; risk of Torsades de Pointes with multiple QT-prolonging drugs.