HOW MANY BENZODIAZEPINES ARE NEEDED IN CLINICAL PRACTICE? The use of the benzodiazepines is more than a medical practice, it has reached the scale of a mass cultural phenomenon. The first step in correct therapeutic use is to consider carefully, medical needs vs fashion vs abuse [For a special report on the recommended useofbenzodiazepines see Inpharma 232: 11 (f2Apr 1980)). All benzodiazepines are quite rapidly and almost completely absorbed after oral administration. Maximum absorption occurs within 30 to l80 minutes. They are highly bound to plasma proteins but this property has never been found to have any clinical implications. All benzodiazepines are highly lipid soluble and are readily distributed in body tissues. Two kinetic properties define the clinical profile of the various benzodiazepines: the formation of pharmacologically active metabolites, and the length of elimination half-lives of the administered drug and its active metabolite(s). The benzodiazepines which yield nordiazepam as their metabolite (bromazepam , clorazepate, chlordesmethyldiazepam, chlordiazepoxide, clobazam, desmethyldiaiepam, diazepam, fiurazepam, medazepam, pinazepam and prazepam) first undergo hepatic N-dealkylation to nordiazepam or its halogenated homologues, then hydroxylation of the N-deaIkyl derivatives to oxazepam or its halogenated homologues. Conjugation with glucuronic acid is followed by excretion. The nitrobenzodiazepines (clonazepam, flunitrazepam, nimetazepam and nitrazepam) have a different metabolic pathway with no important known active metabolites. Within the 'short-acting' benzodiazepine group, lorazepam and oxazepam have no active metabolites and are directly conjugated with glucuronic acid, while temazepam is partIy demethylated to oxazepam and partly directly conjugated. Their short half-liVes suggest potential advantages for their routine use. Therapeutic indications and general use
Their use in anxiety or sleep disturbance appears to depend more on dose than on selectivity of pharmacological action. Lorazepam and oxazepam, first marketed as antianxiety agents, have been found effective, at higher doses, for sleep induction. Temazepam, used in the UK as a hypnotic with a recommended dose of 10 to 30mg has been used in Italy as an antianxiety agent, in 5 mg tablets. On the other hand, benzodiazepines currently utilised as 'pure' hypnotics (flurazepam and nitrazepam) have not been studied with a view to their clinical use in anxiety states. Recommendations for use of benzodiazepines in depression seem to be somewhat inappropriate. They have been shown as 'inferior' and 'equal to' other antidepressants but never 'superior'. In acute withdrawal in alcoholism IV diazepam is the treatment of choice and for longer term treatment of withdrawal, chlordiazepoxide I 00-400mg/ day is suggested. They have failed to prove their efficacy in prevention of relapse into alcoholism. As muscle relaxants they (usually diazepam) may be of value for symptomatic relief of muScle spasms and spasticity and for pre-anesthetic procedures where the combined sedative effect is of particular value. There is also a role for some of them (mainly clonazepam and intravenous diazepam) in anticonvulsive treatment. Use of benzodiazepines in particular conditions and age groups Until the results of a large study become available the controversial findings on the risk of congenital malformations (cleft lip and/ or palate) suggest a cautious attitude in the prolonged use of benzodiazepines in the first trimester of pregnancy. Furthermore, even the use ofbenzodiazepines in the latter part of pregnancy (specifically in eclampsia and pre-eclampsia) and during labor needs to be approached with caution because: • Benzodiazepines accumulate in the fetuS and might explain the hypothermia, poor sucking, hypotonia, asphyxia, and respiratory depression sometimes seen in neonates. The drug may remain in the neonate for up to. I 0 days, and withdrawal symptoms in neonates have been reported. When treatment is medically necessary, recent data suggest a more favourable benefit/risk ratio, for 'short-acting' benzodiazepines such as oxazepam, where even a 3-fold prolongation in half-life still gives a mean value of only 22 hours. All benzodiazepines are likely to be excreted into breast milk and therefore to become available to the breast fed infant but up to 10mg daily should not produce clinically important milk levels. In pediatrics the main indication is for control of febrile convulsions. Intravenous diazepam is the drug of choice. In the elderly an increased incidence of side effects (mainly excessive or delayed sedation, drowsiness, postural hypotension) has been reported. Elimination half-lives are significantly longer in the elderly, leading to accumulation of the parent compound and its active metabolite(s). Possible advantages ofbenzodiazepines with shorter half-lives in aged persons have been recently stressed. Liver disease involving impairment of metabolic processes such as dealkyiation and hydroxylation may cause notable changes in disposition patterns ofbenzodiazepines. This has been shown for diazepam and chlordiazepoxide in patients with cirrhosis or acute viral hepatitis. Hypoalbuminemia has been associated with a higher incidence of side effects of diazepam. In both of these disease states, lower doses should be used to avoid accumulation. In renal disease no change of drug disposition has been seen although some claims have been made for a higher frequency of side effects as the BUN increases.
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Acute toxicity and side effects
Benzodiazepines are commonly considered very safe drugs. Their record of no fatalities and their low potential for toxicity emerges clearly from many overdose histories. Benzodiazepines do not cause severe respiratory, cardiovascular ,or CNS depression; clinical manifestations include only sleep drowsiness and stupor. In therapeutic use benzodiazepines are reported to cause side effects which appear to be simply a more intense expression of their desired pharmacological effects. Age- and doserelated drowsiness appears consistently to prevail over the range of other side effects, which are often paradoxical and opposite (e.g. confusion, ataxia, excitement, agitation, transient hypotension, vertigo, drug fever, gastrointestinal distress) but whose incidence is always low (well below I %). Of more doubtful interpretation are the occasional reports of other side effects including skin reactions, ovulation suppression, galactorrhea, liver damage, leukopenia and pancytopenia. Impairment of performance and morning-after residual effects ('hangover') are well known. A specific and important cause of side effects due to use of benzodiazepines is their interaction with alcohol in an additive or synergistic manner. There is widespread agreement that tolerance develops to the sedative effects. The most impressive evidence comes from clinical conditions where benzodiazepines are used in very high daily dosages (up to 300mg/ day) with no documentable oversedation. Development of tolerance to the antianxiety and hypnotic effects is more difficult to assess. Tne risk of dependence is low but nevertheless benzodiazepines can produce psychological and physical dependence if given in excessive doses over a prolonged period, particularly to patients with unstable personality. Some guidelines are called for
In conclusion, for sleep induction short-acting benzodiazepines seem preferable as fewer hangovers and oversedation effects can be expected, particularly in elderly people. The use oflong-acting benzodiazepines as hypnotics appears unjustified, as unwanted effects (mainly oversedation) due to their accumulation in chronic treatment are likely. Pro-nordiazepam benzodiazepines should be reserved for patients for whom sedation is desired over the following day. For the treatment of anxiety a single daily dose of a long-acting pro-nordiazepam benzodiazepine should suffice. The effect should also cover the need for sleep-inducing activity, which is frequently sought by anxious persons. When more than a once daily drugtaking routine is regarded as more suitable, short-acting benzodiazepines are a better choice. The frequently encountered practice of repeated daily doses of medium- to long-acting benzodiazepines should be avoided. If such recommendations are accepted, no more than 2 or 3 benzodiazepines should suffice in medical practice to fulfil all clinical needs. How different this proposal is from the current market situation. Bellantuono.c.etal.: Drugs 19: 195-219(Mar 1980)
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INPHARMA 3 May 1980
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