Fluphenazine
Fluphenazine
Generic Name
Fluphenazine
Mechanism
Fluphenazine is a first‑generation (typical) antipsychotic that acts primarily as a potent, high‑affinity antagonist of presynaptic dopamine D₂ receptors in the mesolimbic pathway. By blocking these receptors, it reduces the excitatory dopaminergic signaling responsible for psychotic symptoms.
Pharmacokinetics
- Absorption: Rapid oral absorption; peak plasma levels 30–60 min post‑dose.
- Distribution: Highly lipophilic; ~80 % protein‑bound, crosses the blood‑brain barrier.
- Metabolism: Hepatic N‑dealkylation (CYP3A4) → desalkyl‑fluphenazine; conjugation via glucuronidation.
- Elimination: Renal excretion of metabolites; half‑life 18–24 h (oral), 30–48 h (long‑acting IM).
- Drug interactions: CYP3A4 inhibitors (ketoconazole) ↑ plasma levels; CYP3A4 inducers (rifampin) ↓ efficacy.
Indications
- Acute or maintenance treatment of schizophrenia (primarily in patients resistant to atypical agents).
- Acute manic episodes in bipolar disorder (short‑term or adjunctive therapy).
- Psychotic disorders with comorbid agitation where rapid symptom control is needed.
Contraindications
- Absolute contraindications: hypersensitivity to phenothiazines; severe renal/hepatic impairment; uncontrolled Parkinsonian tremor.
- Warnings: QT prolongation, hepatotoxicity, nephrogenic diabetes insipidus, severe hypotension, and neuroleptic malignant syndrome (NMS).
- Caution: Use in elderly with dementia‑related psychosis (increased mortality risk).
- Pregnancy: Category D; avoid unless benefits outweigh risks.
Dosing
| Formulation | Loading Dose | Maintenance Dose | Notes |
| Oral (tablet) | 2–4 mg once daily (start low) | 4–24 mg/day in divided doses | Titrate over 2–4 weeks. |
| Long‑acting IM (Depot) | 5 mg IM once | 10–15 mg IM every 4–6 weeks | Requires 2‑week overlap with oral. |
| Oral/Depot combined | 2–4 mg PO + 5 mg IM | 4–24 mg PO + 10–15 mg IM | Bridging strategy. |
• Administration tips: Oral dose before bedtime to reduce daytime extrapyramidal symptoms.
• Depot injection: Dilute in 0.9 % saline; deliver into gluteal or anterolateral thigh muscle.
Adverse Effects
Common (≥10 %)
• Extrapyramidal symptoms (EPS): dystonia, parkinsonism, akathisia, tardive dyskinesia.
• Anticholinergic: dry mouth, constipation, blurred vision.
• Sedation, orthostatic hypotension.
Serious (rare)
• Neuroleptic malignant syndrome (NMS) – hyperthermia, rigidity, autonomic instability.
• Severe QT prolongation → torsades de pointes.
• Nephrogenic diabetes insipidus → polyuria, polydipsia.
• Hepatotoxicity (↑AST/ALT, bilirubin).
Monitoring
| Parameter | Frequency | Rationale |
| Baseline labs – CBC, LFTs, electrolytes, renal function | Before initiation | Detect pre‑existing abnormalities |
| Recheck LFTs | 1 month, then quarterly | Early detection of hepatotoxicity |
| ECG | Baseline in patients >65 or on QT‑prolonging drugs | Detect QT interval changes |
| Weight/BMI | Every visit | Track metabolic effects |
| EPS assessment | At each clinic visit | Early intervention with anticholinergics |
| Tachycardia/Hypertension | Monitor BP with dosing | Manage orthostatic effects |
Clinical Pearls
- Titration strategy matters: Start at the lowest dose (2 mg PO) and double every 5–7 days until symptoms resolve, minimizing EPS.
- Depot vs. oral: Long‑acting IM improves adherence in chronic schizophrenia but still requires an oral bridge for rapid symptom control.
- EPS mitigation: If dystonia appears, give benztropine 1–2 mg PO/IV; akathisia can respond to propranolol 10–40 mg PO QID.
- Drug interactions: Co‑administration with macrolide or fluoroquinolone antibiotics may synergistically increase QT risk; consider alternative antipsychotics if possible.
- Elderly caution: Use lower maintenance doses (≤8 mg/day) and monitor for falls, orthostatic hypotension, and cognitive decline.
- Nephrogenic DI prevention: Maintain adequate hydration; consider desmopressin if polyuria persists.