Drug Interactions

Fundamentals of Interactions - The Chemical Tango

• Drug interactions: one drug alters another's clinical effects or concentration.
• Two main types:
  • Pharmacokinetic (PK): Body's effect on drug (ADME).
    • Altered Absorption, Distribution, Metabolism (e.g., CYP450 enzyme induction/inhibition), Excretion.
  • Pharmacodynamic (PD): Drug's effect on body.
    • Receptor binding (synergism/antagonism), or altered signal transduction.
• Clinical impact: ↑toxicity, ↓efficacy, or new adverse effects.
• Risk factors: Polypharmacy, elderly, genetic polymorphisms, hepatic/renal impairment.

⭐ Cytochrome P450 (CYP) enzymes, particularly CYP2D6 and CYP3A4, are central to many psychotropic drug interactions.

CYP450 & PK Interactions - Enzyme Traffic Jams

Cytochrome P450 (CYP450) enzymes in liver metabolize most psychotropics. Interactions via induction (↓ effect) or inhibition (↑ toxicity) alter drug levels.

• CYP Inducers: 📌 "CRAPS" - Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, Smoking.
  • Effect: ↓ levels of substrates (e.g., OCPs, antipsychotics).
• CYP Inhibitors: 📌 Key examples: Valproate, Fluoxetine, Fluvoxamine, Erythromycin, Grapefruit Juice.
  • Effect: ↑ levels of substrates, risk of toxicity.
• Key Psychotropic Pathways:
  • CYP2D6: TCAs, venlafaxine, risperidone, aripiprazole. (SSRIs often inhibit)
  • CYP3A4: Benzodiazepines (alprazolam), quetiapine, lurasidone.
  • CYP1A2: Clozapine, olanzapine. (Smoking induces)
• Other PK: Absorption (antacids), distribution (protein binding), excretion ($Li^+$ & NSAIDs).

⭐ Fluvoxamine is a potent inhibitor of CYP1A2 & CYP2C19, significantly impacting clozapine & olanzapine levels.

Pharmacodynamic Dangers - When Drugs Collide

• Serotonin Syndrome:
  • Cause: SSRI/SNRI + MAOI, triptans, linezolid.
  • Triad: Cognitive (agitation), Autonomic (hyperthermia), Neuromuscular (myoclonus).
  • 📌 Mnemonic: SHIVERS.

  ⭐ MAOIs need a 2-week washout before SSRIs (fluoxetine: 5 weeks) to prevent serotonin syndrome.

• Hypertensive Crisis (MAOIs):
  • Cause: + Tyramine-rich foods (cheese, wine), sympathomimetics.
  • Symptoms: Severe headache, ↑↑BP.
• Additive CNS Depression:
  • Cause: Benzodiazepines + Alcohol, opioids, antihistamines.
  • Effect: ↑Sedation, respiratory depression.
• QTc Prolongation:
  • Drugs: Antipsychotics (haloperidol), TCAs, macrolides.
  • Risk: Torsades de Pointes (TdP).
  • ⚠️ Monitor ECG if QTc > 500 ms.
• Anticholinergic Burden:
  • Drugs: TCAs, 1st gen antipsychotics, antihistamines.
  • Symptoms: Dry mouth, blurred vision, constipation, urinary retention, confusion.
  • 📌 Mnemonic: "Dry as a bone..." oka

Noteworthy Psychiatric Drug Pairs - Risky Mixes

• SSRIs/SNRIs + MAOIs: ⚠️ Serotonin Syndrome (hyperthermia, rigidity, myoclonus). Min 2-week washout (Fluoxetine 5 weeks).
• Lithium + NSAIDs/Thiazides/ACEIs: ↑ Lithium levels → Toxicity. Monitor levels.
• Valproate + Lamotrigine: ↑ Lamotrigine levels (avg. 2x) → ↑ Risk of Stevens-Johnson Syndrome (SJS). (📌 VDL: Valproate Doubles Lamotrigine)
• Clozapine + Carbamazepine: ↑ Risk of agranulocytosis/bone marrow suppression. Avoid.
• Benzodiazepines + Opioids: Severe respiratory depression, coma, death.
• TCAs + MAOIs: Hypertensive crisis, Serotonin Syndrome.

⭐ Valproate inhibits Lamotrigine metabolism (UGT glucuronidation), doubling its levels and SJS risk.

High‑Yield Points - ⚡ Biggest Takeaways

• Serotonin Syndrome: High risk with SSRIs/SNRIs + MAOIs, linezolid, triptans.
• Hypertensive Crisis: From MAOIs + tyramine-rich foods or sympathomimetics.
• CYP450 Inducers (e.g., carbamazepine) ↓ drug levels; Inhibitors (e.g., fluoxetine) ↑ drug levels.
• Lithium Toxicity: Increased by NSAIDs, thiazides, ACE inhibitors.
• Clozapine Levels: Altered by CYP1A2 inhibitors (e.g., fluvoxamine) & inducers (smoking).
• Benzodiazepines + Opioids: Potent risk of severe CNS & respiratory depression.
• Valproate + Lamotrigine: Valproate inhibits lamotrigine metabolism, ↑ SJS risk.