Pharmacology - Flunitrazepam (Rohypnol)

[Jatelka]

Flunitrazepam is 6-(2-fluorophenyl)-2-methyl-9-nitro-
2,5-diazabicyclo[5.4.0]undeca-
5,8,10,12-tetraen-3-one.

It has the chemical formula C16H12FN3O and a molecular mass of 313.3.



Flunitrazepam is a pale yellow crystalline solid, slightly soluble in water and slightly soluble in alcohol. It’s melting point is 166-167 C.

Pharmacokinetics

80% of an oral dose is absorbed. There is a significant first-pass effect of 10-15%. Bioavailability is 64-77%. Peak plasma levels occur at 45 minutes.It is 80% protein bound.

Flunitrazepam has a half-life of 18-26 hours. It is metabolized by CY3PA to two major active metabolites: 7-amino-flunitrazepam and N-desmethyl-flunitrazepam. Elimination half life for the 7-amino is 10-16 hours, and for the N-desmethyl 23-33 hours. Both are excreted as glucuronides by the kidney.

Flunitrazepam accumulates with chronic administration, and steady state levels are achieved in 3-5 days.

Indications

Short-term treatment of severe insomnia, unresponsive to other therapies. Usual therapeutic dose is 1mg at night. The dose should be reduced to 0.5mg in elderly/debilitated patients, or those with renal or hepatic disease.

Contraindications

Hypersensitivity, severe respiratory, hepatic or renal disease, pregnancy and lactation, and acute narrow-angle glaucoma (because of atropine-like adverse effects).

Interactions

The usual additive sedative effect when taken with other CNS depressants (including alcohol).

Disulfiram and Cimetidine both inhibit oxidative metabolism of Flunitrazepam, and plasma Flunitrazepam levels may be increased by co-administration.

The anti-cholinergic adverse effects of atropine-like drugs, antihistamines and certain anti-depressants may be potentiated.

Flunitrazepam may interact with anti-convulsants, requiring a dose titration. It is recommended that plasma anti-convulsant levels are monitored.

Cisapride leads to a temporary increase in flunitrazepam levels via increased absorption rates.

Adverse Effects

It is estimated that 13% of people taking Flunitrazepam experience adverse effects. As with all benzodiazepines adverse effects are more likely in higher doses and in the elderly.

Common: Headache, low blood pressure, GI upset, dry mouth, hangover effect, ataxia, confusion, tremor, double vision, changes in libido.

Uncommon: Tachycardia, orthostatic hypotension (postural drop in blood pressure), hiccups, muscle weakness, skin rashes and excessive sweating.

Rare: Anaphylaxis, anxiety, hallucinations and paradoxical excitation, somnambulism and other complex sleep-behaviours (including sleep-driving and sleep-sex), delusions, psychosis and suicidal ideation.

Overdosage

All the usual benzodiazepine effects.

Oral LD50 (rat): 7060mg/kg. Oral LD50 (mouse): 3450mg/kg