Benzodiazepines (BZDS)

BENZODIAZEPINES (BZDS)

Chlordiazepoxide and diazepam were introduced around 1960 as antianxiety drugs. Since then this class has proliferated and has gained popularity over barbiturates as hypnotic and sedative as well, because—

1.   BZDs have a high therapeutic index. Ingestion of even 20 hypnotic doses does not usually endanger life—there is no loss of consciousness (though amnesia occurs) and patient can be aroused; respiration is not so depressed as to need assistance.

2.   Hypnotic doses do not affect respiration or cardiovascular functions. Higher doses produce mild respiratory depression and hypotension which is problematic only in patients with respiratory insufficiency and cardiac/haemodynamic abnormality.

3.   BZDs have practically no action on other body systems. Only on i.v. injection the BP falls (may be marked in an occasional patient) and cardiac contractility decreases. Fall in BP in case of diazepam and lorazepam is due to reduction in cardiac output while that due to midazolam is due to decrease in peripheral resistance. The coronary arteries dilate on i.v. injection of diazepam.

4.   BZDs cause less distortion of sleep architecture; rebound phenomena on discontinuation of regular use are less marked.

5.   BZDs do not alter disposition of other drugs by microsomal enzyme induction.

6.   They have lower abuse liability: tolerance is mild, psychological and physical dependence and withdrawal syndrome are less marked.

7.   A specific BZD antagonist flumazenil is available which can be used in case of poisoning.

CNS actions The overall action of all BZDs is qualitatively similar, but there are prominent differences in selectivity and timecourse of action: different members are used for different purposes. In contrast to barbiturates, they are not general depressants, but exert relatively selective anxiolytic, hypnotic, muscle relaxant and anticonvulsant effects in different measures. Even when apparently anaesthetic dose of diazepam is administered i.v., some degree of awareness is maintained, though because of anterograde amnesia (interference with establishment of memory trace) the patient does not clearly recollect the events on recovery. The antianxiety action of BZDs is probably not dependent on their sedative property; with chronic administration relief of anxiety is maintained, but drowsiness wanes off due to development of tolerance.

While there are significant differences among different BZDs, in general, they hasten onset of sleep, reduce intermittent awakening and increase total sleep time (specially in those who have a short sleep span). Time spent in stage 2 is increased while that in stage 3 and 4 is decreased. They tend to shorten REM phase, but more REM cycles may occur so that overall effect on REM sleep is less marked than with barbiturates. Nitrazepam has been shown to actually increase REM sleep. Night terrors and body movements during sleep are reduced and stage shifts to stage 1 and 0 are lessened. Most subjects wake up with a feeling of refreshing sleep. Some degree of tolerance develops to the action of BZDs on sleep after repeated nightly use.

BZDs produce centrally mediated skeletal muscle relaxation without impairing voluntary activity. Clonazepam and diazepam have more marked muscle relaxant property. Very high doses depress neuromuscular transmission.

Clonazepam, diazepam, nitrazepam and flurazepam have more prominent anticonvulsant activity than other BZDs. However, their utility in epilepsy is limited by development of tolerance to the anticonvulsant action.

Given i.v., diazepam (but not others) causes analgesia. In contrast to barbiturates, BZDs do not produce hyperalgesia.

Other actions Diazepam decreases nocturnal gastric secretion and prevents stress ulcers. BZDs do not significantly affect bowel movement.

Shortlasting coronary dilatation is produced by i.v. diazepam.

Site And Mechanism Of Action

Benzodiazepines act preferentially on midbrain ascending reticular formation (which maintains wakefulness) and on limbic system (thought and mental functions). Muscle relaxation is produced by a primary medullary site of action and ataxia is due to action on cerebellum.

BZDs act by enhancing presynaptic/postsynaptic inhibition through a specific BZD receptor which is an integral part of the GABA_A receptor–Cl¯ channel complex. The subunits of this complex form a pentameric transmembrane anion channel (Fig. 29.3) gated by the primary ligand (GABA), and modulated by secondary ligands which include BZDs. Only the α and β subunits are required for GABA action, and most likely the binding site for GABA is located on the subunit, while the α/γ subunit interface carrys the BZD binding site. The modulatory BZD receptor increases the frequency of Cl¯ channel opening induced by submaximal concentrations of GABA. The BZDs also enhance binding of GABA to GABA_A receptor. The GABA_A antagonist bicuculline antagonizes BZD action in a noncompetitive manner. It is noteworthy that the BZDs do not themselves increase Cl¯ conductance; have only GABA facilitatory but no GABA mimetic action. This probably explains the lower ceiling CNS depressant effect of BZDs.

The BZD receptor exhibits a considerable degree of constitutive activation. As such, it is capable of fine tuning GABA action in either direction. While the BZD-agonists enhance GABA induced hyperpolarization (due to influx of Cl¯ ions), and decrease firing rate of neurones, other compounds called BZD-inverse agonists like dimethoxy ethyl-carbomethoxyβcarboline (DMCM) inhibit GABA action and are convulsants. The competitive BZD-antagonist flumazenil blocks the sedative action of BZDs as well as the convulsant action of DMCM.

The GABA_A-BZD receptor-Cl– channel complex is composed of five α, β, γ, and in some cases δ, ε, θ or π subunits. Several isoforms of α, β and γ subunits have been cloned. The subunit composition of the complex differs at different sites, i.e. there are multiple subtypes of BZD receptor. The ( α₁2 β₂ 2 γ₂ ) pentamer appears to be the most commonly occurring BZD receptor isoform. Based on studies conducted in genetically mutated mice, it has been suggested that BZD receptor isoforms containing the α₁ subunit are involved in mediating sedative, hypnotic, amnesic and possibly anticonvulsant actions of BZDs, while those containing α₂ subunits mediate anxiolytic and muscle relaxant actions. Diazepam has similar affinity for BZD receptor containing different (α₁, α₂, α₃ or α₅) subunits, and has broad spectrum action. Receptor inhomogeneity may provide an explanation for the pharmacological diversity of other BZDs. The newer non BZD hypnotics zaleplon, Zolpidem, etc. have high affinity for α₁ subunit isoform of BZD receptor and exert selective hypnotic-amnesic effect, but have little antiseizure or muscle relaxant property.

At high concentrations BZDs also potentiate the depressant action of adenosine by blocking its uptake. Certain actions of BZDs are countered by the adenosine antagonist theophylline. Thus, BZDs could be acting through other mechanisms as well.

Pharmacokinetics

There are marked pharmacokinetic differences among BZDs because they differ in lipid-solubility by > 50 fold. Oral absorption of some is rapid while that of others is slow. Absorption from i.m. sites is irregular except for lorazepam. Plasma protein binding also varies markedly (flurazepam 10% to diazepam 99%). BZDs are widely distributed in the body. The more lipid soluble members enter brain rapidly and have a two phase plasma concentration decay curve; first due to distribution and later due to elimination. A relatively short duration of action is obtained with single dose of a drug that is rapidly redistributed, even though it may have a long elimination t½. Using the elimination t½ alone to predict duration of action may be misleading. However, elimination t½ determines duration of action in case of drugs whose elimination is by far the dominant feature or when the drug is given repeatedly.

Benzodiazepines are metabolized in liver by dealkylation and hydroxylation to many metabolites, some of which may be active. The biological effect half-life of these drugs may be much longer than the plasma t½ of the administered compound. Some BZDs (e.g. diazepam) undergo enterohepatic circulation. BZDs and their phase I metabolites are excreted in urine as glucuronide conjugates. BZDs cross placenta and are secreted in milk.

Drugs with a long t½ or those which generate active metabolites cumulate on nightly use; their action may then extend into the next day. Some features of BZDs used as hypnotic are given in Table 29.1.

BZDs may be categorized according to their pharmacokinetic profile into:

1. Slow Elimination Of Parent Drug Or Active Metabolite

Flurazepam Produces an active metabolite which has a long t½, residual effects are likely next morning; cumulation occurs on daily ingestion peaking after 3–5 days; suitable for patients who have frequent nocturnal awakenings and in whom some day time sedation is acceptable.

NINDRAL, FLURAZ 15 mg cap.

2. Relatively Slow Elimination But Marked Redistribution

Diazepam Generates active metabolites (des-methyl-diazepam, oxazepam). On occasional use it is free of residual effects. With regular use accumulation occurs and prolonged anxiolytic effect may be obtained. It is less likely to cause rebound insomnia on discontinuation of chronic use. Withdrawal phenomena are mild.

VALIUM 2, 5, 10 mg tab., 10 mg/2 ml inj., CALMPOSE 5, 10 mg tab, 2 mg/5 ml syr, 10 mg/2 ml inj.

Nitrazepam Accumulation and residual effects can be avoided only if ingestion is occasional. Good for patients with frequent nocturnal awakenings, when some day time sedation is acceptable.

SEDAMON, HYPNOTEX, NITRAVET 5 mg tab., 5, 10 mg cap.

3. Relatively Rapid Elimination And Marked Redistribution

Alprazolam The primary indication of this intermediate acting BZD is anxiety disorder (see Ch. No. 33), but is also being employed as nighttime hypnotic with few residual effects the next day. Discontinuation after regular use has produced relatively marked withdrawal phenomena.

Temazepam It is an intermediate acting BZD. Absorption is slow in case of tablet but fast when used in soft gelatin capsule. Good for sleep onset difficulty, free of residual effects. Accumulation can occur on daily ingestion. Does not produce active metabolites.

4. Ultrarapid Elimination

Triazolam Very potent, peak effect occurs in < 1 hour; good for sleep induction but poor for maintaining it. Patient may wake up early in the morning and feel anxious. This may be a withdrawal phenomenon. Rebound insomnia may occur when it is discontinued after a few nights of use. It does not accumulate on repeated nightly use and no residual effects are noted in the morning. However, higher doses can alter sleep architecture, produce anterograde amnesia and anxiety the following day. Some cases of paranoia and other psychiatric disturbances have been noted—withdrawn from U.K., but is employed in other countries for elderly patients, shift workers, travellers, etc.

Midazolam Extremely rapid absorption—peak in 20 min. It can cause problems in the elderly (ataxia, blackouts); more liable for abuse. Therefore, it is not available now for oral use as a hypnotic. Mainly used as an i.m. premedicant or an i.v. anaesthetic.

Adverse Effects

Benzodiazepines are relatively safe drugs. Side effects of hypnotic doses are dizziness, vertigo, ataxia, disorientation, amnesia, prolongation of reaction time—impairment of psychomotor skills (should not drive). Hangover is less common, but may be noted if larger doses are used, especially of longer acting drugs. Weakness, blurring of vision, dry mouth and urinary incontinence are sometimes complained. Older individuals are more susceptible to psychomotor side effects. Like any hypnotic, BZDs can aggravate sleep apnoea.

Paradoxical stimulation, irritability and sweating may occur in an occasional patient, especially with flurazepam. Some patients experience increase in nightmares and behavioural alterations, especially with nitrazepam.

Tolerance to the sedative effects develops gradually, but there is little tendency to increase the dose. Cross tolerance to alcohol and other CNS depressants occurs.

The dependence producing liability of BZDs is low. They are seldom abused alone. Drug abusers find them rather bland (except rapidly absorbed midazolam) and prefer other CNS depressants. Withdrawal syndrome is generally mild; may be more intense in case of ultrarapid elimination drugs. Drugseeking behaviour is not prominent. Anxiety, insomnia, restlessness, malaise, loss of appetite, bad dreams is all that occurs in most cases. Agitation, panic reaction, tremors and delirium are occasional; convulsions are rare.

An earlier report of increased birth defects on use of diazepam during pregnancy has been disputed. Administration during labour may cause flaccidity and respiratory depression in the neonate.

Interactions

BZDs synergise with alcohol and other CNS depressants leading to excessive impairment. Concurrent use with sod. valproate has provoked psychotic symptoms.

Drug interactions due to displacement from protein binding or microsomal enzyme induction are not significant.

Since CYP 3A4 isoenzyme plays important role in metabolism of several BZDs, their action can be prolonged by CYP 3A4 inhibitors like ketoconazole, erythromycin and others. Cimetidine, isoniazid and oral contraceptives also retard BZD metabolism.

Non-Benzodiazepine Hypnotics

Zopiclone This newer cyclopyrrolone hypnotic is an agonist at a subtype of BZD receptor involved in the hypnotic action. The effect on sleep resemble those of BZDs, but it does not alter REM sleep and tends to prolong stages 3 and 4. It is reported not to disturb sleep architecture or produce hangover or withdrawal phenomena on discontinuation; but some degree of next morning impairment can occur. Zopiclone has been used to weanoff insomniacs taking regular BZD medication. Its t½ is 5–6 hours.

Zopiclone is indicated for short term (< 2 weeks) treatment of insomnia. Side effects are metallic or bitter aftertaste, impaired judgement and alertness, psychological disturbances, dry mouth and rarely dependence. Safety in overdose is similar to BZDs.

ZOPITRAN, ZOPICON, ZOLIUM, 7.5 mg tab, one tab at bedtime for not more than 2–4 weeks (elderly 3.75 mg).

Zolpidem An imidazopyridine which preferentially acts on the α₁ subunit containing subtype of BZD receptors that are important in mediating the hypnotic effect. Hypnotic effect is pronounced: sleep latency is shortened, sleep duration is prolonged in insomniacs, but anticonvulsant, muscle relaxant and antianxiety effects are not evident. Its advantages are: relative lack of effect on sleep stages (REM suppression is slight); minimal residual day time sedation or fading of hypnotic action on repeated nightly use; no/little rebound insomnia on discontinuation; near absence of tolerance or physical dependence and low abuse potential combined with safety in overdose like BZDs.

Zolpidem is nearly completely metabolized in liver (t½ 2 hr), and has short duration of action. It is indicated for short term (1–2 weeks) sleep onset insomnia. Because the plasma t½ is short, next day sedation is minimal, but morning sedation or prolongation of reaction time can occur if it is taken late at night. Side effects are few. Even large doses do not markedly depress respiration. Currently, it is one of the most commonly prescribed hypnotics.

Dose: 5–10 mg (max 20 mg) at bedtime; ½ dose in elderly and liver disease patients.

NITREST, ZOLDEM, DEM 5, 10 mg tabs.

Zaleplon This is the shortest acting of the newer non-BZD hypnotics that selectively act on a subset of BZD receptors containing the α₁ subunit which appear to mediate the hypnotic action. It is rapidly absorbed; oral bioavailability is ~30% due to first pass metabolism; is rapidly cleared by hepatic metabolism with a t½ of 1 hour. No active metabolite is produced. As such it is effective only in sleep-onset insomnia; does not prolong total sleep time or reduce the number of awakenings. Because of brevity of action, it can be taken late at night (> 4 hour before waking time) without causing morning sedation. Surprisingly, despite very short action, no daytime anxiety or rebound insomnia has been observed. No tolerance or dependence has been reported and hypnotic effect does not fade on nightly use. However, its use should be limited to 1–2 weeks. The hypnotic efficacy of zaleplon is rated similar to zolpidem. Like the latter, effect on sleep stages and REM sleep are less than that of BZDs.

Dose: 5–10 mg (max 20 mg) at bed time.

ZAPLON, ZALEP, ZASO 5, 10 mg tabs.

Uses

Currently, BZDs are one of the most frequently prescribed drugs. They have also been combined with many other categories of drugs with a view to improve efficacy by relieving attendant anxiety.

1. As Hypnotic

A hypnotic should not be casually prescribed for every case of insomnia. Understanding the cause of insomnia and use of a variety of other measures can avoid unnecessary hypnotic medication. When indicated, BZDs or the newer non-BZDs like zolpidem, zaleplon, zopiclone are the hypnotic of choice. A wide range of compounds have been developed to suit specific requirements. Some important points are outlined below:

A hypnotic may be used to shorten sleep latency, to reduce nocturnal awakenings, or to provide anxiolytic effect the next day when insomnia is accompanied with marked element of anxiety.

In the use of hypnotics, consideration must be given to onset and duration of action of the drug. The most suitable pharmacokinetic profile drug should be chosen for a given case.

Impaired performance the next day is largely related to the dose and pharmacokinetic profile of the drug. The next day effects are either due to prolonged sedation (longer acting drugs) or rebound anxiety (shorter acting drugs).

Any hypnotic (probably except zolpidemlike drugs) becomes useless after regular use for a few days; may actually be harmful.

Though effect of drugs on the EEG stages of sleep, including REM sleep, could be physiologically relevant, most important is the subject’s own assessment of having slept restfully and with no impairment the following day. This probably correlates more closely with effect of the hypnotic on the cyclic alternating pattern (CAP) of sleep.

Insomnia arises under a variety of circumstances. It could be a long-term (monthsyears), shortterm (weeks) or transient (a day or two, mostly situational) problem.

Chronic Insomnia (> 3 weeks) Uncertainty exists about the use of hypnotics in this situation. The patient may have a personality disorder, but often there is no specific stress factor; may have used hypnotics for long periods, may be alcoholic or have some somatic disease—gastroesophageal reflux, pain, COPD, etc. Measures like aerobic exercise, training at mental relaxation, avoiding anxiety about past/future performance at bedtime, attempting sleep when sleepiness is maximum, avoiding napping at daytime, coffee/ alcohol restriction, treatment of concurrent somatic illness, psychotherapy and controlled sleep curtailment may succeed. Good nightly sleep improves the quality of daytime wakefulness. Patients of obstructive sleep apnoea have poor sleep and feel sleepy during the day. All hypnotics aggravate apnoea and are contraindicated.

Intermittent use of a hypnotic, say once every 3 days, may be tried. Risk of tolerance and abuse are maximum among chronic insomniacs. A slowly eliminated drug is preferable because rebound insomnia and withdrawal symptoms are least marked with these drugs.

Short-term Insomnia (3–21 days) Emotional problem (occupational stress, bereavement) and physical illness are the usual causes. Patient may

have induction difficulty or may be waking up early. Cautious use of low doses of an appropriate drug for the type of sleep disturbance may be made. Generally a hypnotic, free of residual effects should be selected, but when anxiety is a dominant feature, a BZD whose action extends into the next day may be better. Short acting drugs are preferable in the elderly. Intermittent hypnotic use should be limited to 2–3 weeks.

Transient Insomnia (1–3 days) Due to alterations in the circumstances of sleep, e.g. on an overnight train, new place, unusual pattern of work, shift workers, intercontinental travel–jetlag, etc. A rapidly eliminated hypnotic or one with marked distribution is to be preferred to avoid residual effects the next morning. However, night before surgery—a long acting drug is better.

2. Other uses

•       As anxiolytic and for daytime sedation (see Ch. No. 33).

•  As anticonvulsant, especially emergency control of status epilepticus, febrile convulsions, tetanus, etc. (see Ch. No. 30).

•       As centrally acting muscle relaxant (see Ch. No. 25).

•       For preanaesthetic medication, i.v. anaesthesia and conscious sedation (see Ch. No. 27).

•   Before ECT, electrical cardioversion of arrhythmias, cardiac catheterization, endoscopies, in obstetrics and many minor procedures— diazepam i.v. has gained popularity because of its calmingamnesicanalgesic and muscle relaxant properties and relative safety.

•       Alcohol withdrawal in dependent subjects.

•       Along with analgesics, NSAIDs, spasmolytics, antiulcer and many other drugs.

Fixed dose combinations of sedative/hypnotic/anxiolytic drugs with analgesicantipyretics has been banned in India.