Benzodiazepines are by far the most frequently used sedatives. All benzodiazepines share powerful anticonvulsant, muscle-relaxant, hypnotic, sedative, and tranquilizing properties. Their mechanism of action is identical; they interact with a specific binding site, termed the benzodiazepine receptor, which is located on the receptor complex of the important endogenous inhibitory neurotransmitter GABA. The benzodiazepine binding augments or facilitates GABA binding, and vice versa, opening chloride channels and thereby producing sedation and an anticonvulsant activity. Some other nervous system effects, such as muscle relaxation and anxiolysis, are probably due to augmentation of glycinergic neurotransmission in the brainstem and the spinal cord.
Parenterally available benzodiazepines commonly used in the ICU are diazepam, lorazepam, and midazolam. Diazepam and lorazepam are insoluble in aqueous fluids and therefore the parenteral preparation contains propylene glycol and benzyl alcohol. These solvents may cause local irritation at the injection site and sometimes subsequent phlebitis. The commercial formulation of midazolam is soluble in water and causes less local discomfort.
All benzodiazepines are extensively metabolized in the liver. The metabolites of diazepam (desmethyldiazepam and oxazepam) are pharmacologically active and accumulate when repeated doses of diazepam are administered. The active metabolite of midazolam (a-hydroxy-midazolam) makes an important contribution to the effects of midazolam in long-term sedation. It has recently been shown that even glucuronidated a-hydroxy-midazolam has benzodiazepine-like properties; hence renal failure may lead to accumulation of this active metabolite ( Bauerefa/ 1995). Lorazepam is directly glucuronidated, and this metabolite has not yet been shown to be pharmacologically active.
Pharmacokinetic interactions between benzodiazepines and other drugs play no role in clinical practice. Except for additive effects with other central nervous system depressants such as neuroleptics, antidepressants, opioid analgesics, and alcohol, relevant pharmacodynamic interactions do not occur.
Owing to the wide interindividual variability in the potency, efficacy, and pharmacokinetics of benzodiazepines ( Table 1), standard dose schemes are not established and the dose should be determined by the sedative effect. Patients with hepatic or renal insufficiency require lower doses, whereas previous benzodiazepine abuse makes the necessity for higher doses likely. The time to the maximum sedative effect of an intravenous benzodiazepine bolus varies considerably betwen different benodiazepines (Table.,!). A prolonged recovery time, sometimes lasting for several days, may occasionally occur after long-term sedation, even in the absence of liver or kidney dysfunction. Although the elimination half-life of lorazepam is much longer than that of midazolam, lorazepam does not require more recovery time after discontinuation (P,0,h!m.a,DD,eí,,,a.|; 1994). Owing to its slow elimination and the accumulation of even longer-lasting metabolites, diazepam should not be used for long-term sedation.
Table 1 Pharmacokinetics, dosage, and costs of commonly used sedatives
Benzodiazepines are generally among the safest central nervous system active medications. They cause severe central nervous system depression and marked respiratory and cardiovascular dysfunction only when they are heavily overdosed. All these symptoms are reversible. Partly due to reduced metabolism, benzodiazepines can induce or augment symptoms of hepatic encephalopathy in patients with liver cirrhosis and therefore should be avoided in such cases. Anterograde amnesia is a commonly seen and sometimes even opportune side-effect, particularly with midazolam. Withdrawal symptoms including insomnia, anxiety, dysphoria, unpleasant dreams, and sweating may occur after long-term adminstration. Hence it is prudent not to discontinue benzodiazepine medication abruptly but to reduce the dosage gradually over some days if possible.
Since a specific benzodiazepine antagonist (flumazenil) is available, all effects of benzodiazepines can readily be reversed. Because the effect of a single dose of flumazenil lasts for only about 1 h, repeated injections or a continuous infusion may be required in benzodiazepine overdose. Because flumazenil may precipitate the onset of seizures, repeated small injections are preferred to a single large bolus injection.
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