Clonazepam
Clonazepam
Generic Name
Clonazepam
Mechanism
Clonazepam is a long‑acting benzodiazepine that potentiates GABA_A receptor activity.
• Enhances the frequency of chloride channel opening → hyperpolarization of neuronal membranes.
• Produces net inhibition in limbic and cortical circuits, reducing neuronal excitability.
• Key for its anticonvulsant, anxiolytic, muscle‑relaxant, and sedative properties.
Pharmacokinetics
| Parameter | Typical Values | Notes |
| Absorption | Oral bioavailability ≈ 90% | Peak plasma 30–120 min. |
| Distribution | Volume of distribution ~ 1 L/kg | Highly lipophilic → crosses BBB rapidly. |
| Metabolism | Hepatic CYP3A4 → 2‑hydroxy metabolites | Metabolites inactive, not a major route. |
| Elimination | Half‑life 18–50 h (depends on age & hepatic function) | Renal excretion negligible. |
| Food effect | Minor | Can be taken with food. |
| Drug interactions | CYP3A4 inhibitors ↑ levels; alcohol ↓ metabolism | Caution with CNS depressants, opioids. |
Indications
- Seizure disorders: Lennox‑Gastaut, absence, myoclonic, and generalized tonic‑clonic seizures (add‑on therapy).
- Benzodiazepine withdrawal: prolonged taper or bridge.
- Obsessive‑compulsive disorder (off‑label, low‑dose).
- Short‑term treatment of panic disorder (when benzodiazepines are preferred).
- Anxiety and seizure prophylaxis in pregnancy – limited evidence, but may be used if benefits outweigh risks.
Contraindications
- Absolute contraindications: severe respiratory insufficiency, acute asthma, acute hypersensitivity to benzodiazepines.
- Caution:
- Pregnancy – category D; use only if benefit > risk.
- Elderly & geriatric patients – increased sensitivity, risk of encephalopathy.
- Recent alcohol withdrawal – risk of precipitating seizures.
- Depressive disorders with suicidality – possible exacerbation.
Warnings
• Anticholinergic burden may worsen cognitive decline.
• Cumulative CNS depression with opioids, alcohol, or other sedatives.
• Physical dependence and tolerance can develop within weeks.
Dosing
| Age/Criterium | Initial Dose | Titration | Maintenance | Max Daily Dose |
| Adults | 0.25–0.5 mg BID (or PRN) | Increase 0.25 mg every 3–5 days | 1–4 mg/day | 8 mg/day |
| Children (≥ 6 yrs) | 0.125 mg every 12 h | Increase 0.125 mg every 5 days | 0.25–2 mg/day | 4 mg/day |
| Elderly | 0.125 mg BID | Slow titration 0.125 mg every 7 days | 0.25–1 mg/day | 4 mg/day |
| Pregnant (2nd–3rd trimester) | 0.25 mg BID | Use lowest effective dose | Maintain at lowest dose | N/A |
• Formulations: Immediate‑release tablets 0.125–4 mg; sublingual tablets 0.5 mg (rapid onset for acute seizures).
• Administration: Oral or sublingual; keep bottles upright, protect from moisture.
Adverse Effects
| Common | Serious |
| Somnolence, dizziness, headache, mild memory impairment. | Respiratory depression (especially with opioids), severe hypotension. |
| Ataxia, incoordination, blurred vision. | Severe CNS depression, seizures (paradoxical). |
| Dry mouth, constipation. | Anticholinergic crisis in susceptible patients. |
| Mood changes – irritability or agitation. | Dependence syndrome; withdrawal seizures. |
Monitoring
- Clinical:
- Seizure frequency & severity.
- Anxiety scales (HAM-A, GAD‑7).
- Cognitive function (Mini‑MOCA in elderly).
- Signs of withdrawal (cramp, tremor, agitation).
- Laboratory (if chronic therapy or high dose):
- Liver function tests (ALT, AST) quarterly.
- CBC if progressive anemia or thrombocytopenia suspected.
- Safety:
- Monitor respiratory status in opioid co‑therapy.
- Educate on avoidance of alcohol & driving.
- Pregnancy: repeat fetal ultrasound if therapy >3 months.
Clinical Pearls
- Delayed‑onset anxiety: a single 0.5 mg dose can be taken *before* a predictable trigger; avoid extra dosing beyond 1 yr without taper.
- Add‑on therapy for refractory myoclonic seizures: start at 0.25 mg BID; titrate to 1 mg/day—helps avoid high doses of sodium‑valproate.
- Sublingual route: ideal for status epilepticus or children who cannot swallow. Rapid absorption (~ 30 min).
- Withdrawal bridge: if a patient stops benzodiazepines suddenly, start 2 mg/day of clonazepam and taper by 0.5–1 mg every 3–4 days.
- Elderly dosing: begin at 0.125 mg BID, a 20‑30 % lower target than younger adults; monitor for ataxia and cognitive slowing.
- Drug–Drug Interaction: Phenobarbital and rifampin ↓ clonazepam levels; consider dose increase to maintain therapeutic effect.
- Metoclopramide & fluoxetine can ↓ clearance → increase risk of NMS‑like features; titrate cautiously.
- Pregnancy: If treatment is essential, use the lowest effective dose and monitor maternal gamma‑glutamyl transferase (GGT) to track potential fetal exposure.
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• *This drug card is intended for educational purposes and should not replace individualized clinical judgment or institutional formularies.*