Principles of Psychopharmacology

PK Essentials - Drug's Grand Tour

• Absorption: Bioavailability (F); IV = 100%. First-pass metabolism impacts F.
• Distribution: Volume of Distribution ($V_d = \text{Dose} / C_0$). Protein binding (unbound drug active). BBB crossing (lipophilic drugs).
• Metabolism: Hepatic. Phase I (CYP450: oxidation, reduction, hydrolysis), Phase II (conjugation).
  • CYP Inducers: 📌 CRAP GPS (e.g., Carbamazepine, Rifampicin). ↓ drug effect.
  • CYP Inhibitors: 📌 SICKFACES.COM (e.g., Valproate, Fluconazole). ↑ drug effect/toxicity.
• Excretion: Primarily renal. Clearance (CL). Half-life ($t_{1/2} = (0.693 \times V_d) / CL$). Steady state: 4-5 $t_{1/2}$.
• Special Populations: Elderly (↓ clearance, altered $V_d$), Pediatrics (enzyme immaturity).

⭐ Most psychotropics are lipophilic and highly protein-bound, influencing $V_d$ and duration of action.

PD Unveiled - Brain's Chat Room

• Core Principle: Drug binds to target (e.g., receptor) → alters cellular function → therapeutic/adverse effect.
• Receptor Interactions:
  • Agonist: Activates receptor (e.g., SSRIs ↑ 5-HT effect indirectly).
  • Antagonist: Blocks receptor (e.g., antipsychotics block D₂ receptors).
    • Competitive: Reversible; overcome by ↑ agonist concentration.
    • Non-competitive: Irreversible/allosteric; ↓ Emax.
  • Partial Agonist: Submaximal response (e.g., aripiprazole at D₂).
  • Inverse Agonist: Effect opposite to agonist (e.g., some antihistamines).
• Dose-Response: Relationship between drug dose & effect.
  • Potency: Dose for 50% maximal effect (ED₅₀).
  • Efficacy: Maximum possible effect (Emax).
  • Therapeutic Index (TI): $TI = TD₅₀/ED₅₀$ (Ratio of toxic dose to therapeutic dose; safety margin).
• Key Neurotransmitters (NTs): Dopamine (DA), Serotonin (5-HT), GABA, Norepinephrine (NE).

⭐ Receptor occupancy by a drug does not always correlate linearly with clinical response due to factors like spare receptors, signal amplification, and individual patient variability in downstream pathways and metabolism.

ADRs & Alerts - Safety First Crew

• Serotonin Syndrome: Triad (Cognitive, Autonomic, Neuromuscular - myoclonus, hyperreflexia, tremor). Manage: Stop agent, Cyproheptadine.
• NMS (Neuroleptic Malignant Syndrome): 📌FEVER (Fever, Encephalopathy, Vitals unstable, Enzymes ↑CPK, Rigidity "lead-pipe"). Manage: Stop antipsychotic, Dantrolene/Bromocriptine.
• Lithium Toxicity: Levels > 1.5 mEq/L (Therapeutic $0.6-1.2$ mEq/L). GI, neuro (ataxia, confusion). Dialysis if > 2.5 mEq/L or severe.
• Clozapine: Agranulocytosis (ANC < 1500/µL), myocarditis, seizures, metabolic syndrome.
• Lamotrigine: Stevens-Johnson Syndrome (SJS)/TEN. ⚠️ Slow dose titration essential to minimize risk.
• TCAs: Cardiotoxicity (QRS > 100ms), anticholinergic, orthostasis. 📌 "Tri-C's": Coma, Convulsions, Cardiotoxicity.
• General: Monitor vitals, labs (LFT, KFT, CBC), ECG. Beware CYP450 Drug-Drug Interactions (DDI).

⭐ Clozapine: Risk of agranulocytosis (ANC < 1500/µL or WBC < 3000/µL). Strict ANC monitoring vital.

Clinical Pearls - Pro Prescribing

⭐ Rational combinations: Maximize synergy (e.g., SSRI + Mirtazapine), minimize antagonism. Key for treatment resistance.

• Special Populations: Pregnancy (risk-benefit), elderly (↓dose, monitor), hepatic/renal (dose adjust).

High‑Yield Points - ⚡ Biggest Takeaways

• Pharmacokinetics (ADME) governs drug movement; lipid solubility aids CNS penetration.
• Pharmacodynamics describes drug actions; receptor affinity and intrinsic activity are key.
• CYP450 enzymes (e.g., 2D6, 3A4) are crucial for drug metabolism and interactions.
• Half-life (t½) determines dosing interval and time to steady state (4-5 t½).
• Therapeutic Index (TI) indicates drug safety; narrow TI drugs (Lithium) need TDM.
• Serotonin syndrome and MAOI-tyramine reactions are critical drug interactions.
• Consider age and pregnancy for dose adjustments and drug selection in psychopharmacology.