Chapter 16  ·  Module 2  ·  Introduction to Medical Pharmacology

First-Generation Antipsychotics

Potency classification, key agents, extrapyramidal syndromes, and serious adverse effects

Potency Classification and Adverse Effect Profile

Agent Dose Range Extrapyramidal Symptom Risk Sedation Anticholinergic Orthostatic Hypotension
High-Potency Agents — selective D2 blockade
Haloperidol 2–20 mg/day High Low Low Low
Fluphenazine 2–20 mg/day High Low Low Low
Perphenazine 8–64 mg/day Moderate Moderate Low Moderate
Low-Potency Agents — broad receptor blockade (D2 + H1 + M1 + alpha-1)
Chlorpromazine 200–1000 mg/day Low–Moderate High High High
Thioridazine 200–800 mg/day Low High Highest High

Extrapyramidal Syndromes — Time Course and Management

Onset: Hours to Days

Acute Dystonia

  • Sustained muscle contractions, abnormal postures
  • Oculogyric crisis, torticollis, opisthotonus
  • Laryngeal dystonia — airway emergency
  • Risk: young males, antipsychotic-naive patients
  • Treat: Benztropine or diphenhydramine intramuscularly or intravenously — rapid effect
  • Mechanism: Relative cholinergic excess from acute D2 blockade

Onset: Days to Weeks

Akathisia

  • Subjective inner restlessness, urge to move
  • Pacing, inability to sit still
  • Leading cause of non-adherence
  • Danger: mistaken for worsening psychosis → dose escalation worsens it
  • Treat: Propranolol first-line; dose reduction; short-term benzodiazepines
  • Note: Anticholinergics not first-line for akathisia

Onset: Weeks

Drug-Induced Parkinsonism

  • Bradykinesia, rigidity, resting tremor
  • Indistinguishable from Parkinson disease at examination
  • Higher risk in elderly patients
  • Dose-dependent; reversible with dose reduction
  • Treat: Dose reduction preferred; benztropine or amantadine if needed
  • Caution: Anticholinergics worsen cognition in elderly patients

Serious Adverse Effects — Neuroleptic Malignant Syndrome and Tardive Dyskinesia

Neuroleptic Malignant Syndrome

  • Timing: Acute — days to weeks from initiation
  • Tetrad: Hyperthermia + Lead-pipe rigidity + Autonomic instability + Altered consciousness
  • Lab: Markedly elevated creatine kinase (rhabdomyolysis)
  • vs. Serotonin syndrome: Rigidity + bradyreflexia (not hyperreflexia/clonus)
  • Treatment: Stop antipsychotic immediately; dantrolene; bromocriptine; intensive care unit support
  • Incidence: 0.01–0.02% — rare but life-threatening

Tardive Dyskinesia

  • Timing: Late — months to years of exposure
  • Movements: Repetitive, involuntary orofacial movements (lip smacking, tongue protrusion); choreiform limb movements
  • Mechanism: D2 receptor upregulation (supersensitivity) from chronic blockade
  • Risk factors: Older age, female sex, high-potency agents, longer duration
  • Treatment: Minimize dose or switch; vesicular monoamine transporter 2 inhibitors (valbenazine, deutetrabenazine) for established cases
  • May be irreversible — prevention is the goal

Potency Rule: High-potency agents (haloperidol, fluphenazine) = high extrapyramidal symptom risk, low sedation/anticholinergic burden. Low-potency agents (chlorpromazine, thioridazine) = lower extrapyramidal symptom risk, high sedation/anticholinergic/orthostatic burden. Potency predicts adverse effect profile, not antipsychotic efficacy.

Unique to thioridazine: QTc prolongation / torsades de pointes (hERG blockade) + pigmentary retinopathy at high doses. Last-resort agent requiring baseline electrocardiogram.