Benzodiazepine Antagonist

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Chapter: Essential pharmacology : Sedative -Hypnotics

Flumazenil : It is a BZD analogue which has little intrinsic activity (practically no effect on normal subjects), but competes with BZD agonists as well as inverse agonists for the BZD receptor and reverses their depressant or stimulant effects respectively.


BENZODIAZEPINE ANTAGONIST

 

Flumazenil

 

It is a BZD analogue which has little intrinsic activity (practically no effect on normal subjects), but competes with BZD agonists as well as inverse agonists for the BZD receptor and reverses their depressant or stimulant effects respectively.

 

Flumazenil abolishes the hypnogenic, psychomotor, cognitive and EEG effects of BZDs. At higher doses it has some week BZD agonist like as well as inverse agonist like activity in animal models, but these are of no clinical significance.

 

Flumazenil is absorbed orally; oral bioavailability is ~16%, but it is not used orally. On i.v. injection, action of flumazenil starts in seconds and lasts for 1–2 hr; elimination t½ is 1 hr, due to rapid metabolism.

 

Uses

 

1. To Reverse BZD Anaesthesia

 

Patients anaesthetized/sedated with a BZD wakeup, get oriented and regain motor control within 1 min of an i.v. injection of 0.3–1 mg of flumazenil. Resedation generally occurs after 1–2 hr (more with diazepam than with midazolam): supplemental doses of flumazenil may be given. It allows early discharge of patients after diagnostic procedures and facilitates post-anaesthetic management.

 

2. BZD Overdose

 

Majority of patients of BZD overdose require only supportive measures like patent airway, maintenance of BP, cardiac and renal function, etc. In addition, flumazenil 0.2 mg/min may be injected i.v. till the patient regains consciousness. Practically all patients intoxicated with a BZD alone respond within 5 min. However, reversal of respiratory depression is incomplete. Flumazenil blocks the hypnotic effect of zolpidem-like non-BZDs as well. In mixed CNS depressant poisoning, whatever sedation is not abolished by 5 mg of flumazenil should be taken to be due to a non-BZD/non-Zolpidem-like depressant. It thus helps in differential diagnosis of such patients.

 

Adverse Effects

 

Flumazenil is safe and well tolerated.

Agitation, discomfort, tearfulness, anxiety, coldness and withdrawal seizures are the occasional side effects.

 

Melatonin

 

It is N-acetyl-5methoxy tryptamine, the principal hormone of the pineal gland which is secreted at night and has been found to play an important role in entraining (synchronizing) the sleep-wakefulness cycle with the circadian rhythm. Though high doses (80 mg) of melatonin can induce sleep, low doses (2–10 mg) do not depress the CNS, but probably increase the propensity of falling asleep. Started before the flight it has been shown to reduce jetlag symptoms and to hasten re-entrainment with daynight cycle of the new place in intercontinental travellers. Beneficial effects in shift workers and in individuals with delayed sleep phase syndrome have also been reported. It has improved sleep quality in elderly insomniacs and has helped weaning off regular BZD users of their hypnotic. However, melatonin is not a dependable hypnotic; has little effect on latency and duration of sleep, especially in nonelderly insomniacs. Though it is unlikely to have the disadvantages of conventional hypnotics, its long-term safety is not known. Lowering of seizure threshold at night has been related to melatonin peak and psychiatric changes due to melatonin are apprehended. Use may therefore be restricted to treatment of jetlag, shift workers and elderly hypnotic dependent insomniacs.

 

Since melatonin secretion declines with age, it has been argued that melatonin supplementation might retard ageing. Though there is no proof of benefit melatonin (2–5 mg/day) is being consumed as a health food in USA and some other countries. It has also been tried in cluster headache. In India it is marketed as a remedy for disturbed biorhythms and degenerative diseases.

 

MELOSET 3 mg tab, ZYTONIN, ETERNEX melatonin 3 mg + pyridoxine 10 mg tab; one tab at evening daily.

 

Ramelteon

 

It is a melatonin receptor agonist introduced in some countries as a novel hypnotic for sleep onset insomnia, that does not produce the usual BZD-like side effects.

 


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