Benzodiazepines half-lives

Bromazepam, a moderately short-acting benzodiazepine (half-life about 12 hours), has been used in the treatment of anxiety states and has the usual effects of benzodiazepines, for example amnesia and depressed psychomotor... 

Indications Anxiety, depression, panic attacks Category Benzodiazepine Half-life 11-16 hours... 

Trade names Corax Huberplex Libritabs (Valeant) Librium (Valeant) Limbitrol (Valeant) Medilium Mitran Multum Novopoxide Psicofar Reposans-10 Solium Tropium Indications Anxiety Category Benzodiazepine Half-life 6-25 hours... 

Indications Petit mal and myoclonic seizures Category Benzodiazepine Half-life 18-50 hours... 

Trade names Gen-XENE Novoclopate Transene Tranxal Tranxen Tranxene (Ovation) (Abbott) Tranxilen Tranxilium Indications Anxiety and panic disorders Category Benzodiazepine Half-life 48-96 hours... 

Indications Preoperative sedation Category Benzodiazepine Half-life 1-4 hours... 

Trade names Dumozolam Halcion (Pfizer) Novo-Triolam Nu-Triazo Nuctane Somese Somniton Songar Trialam Indications Insomnia Category Benzodiazepine Half-life 1.5-5.5 hours... 

Medical use of benzodiazepines has been declining. Prescribing trends show an overall decline in the number of all benzodiazepine prescriptions written, with a market shift to increased prescribing of short elimination half-life agents (lorazepam, alprazolam), compared with long-elimination half-life agents (diazepam, chlordiazepoxide) (Ciraulo et al. 2004). In 2001, alprazolam was the most widely prescribed benzodiazepine (Ciraulo et al. 2004), and it also was the most widely prescribed psychiatric medication in that year for mood and anxiety disorders (Stahl 2002). 

White et al. 1982). Benzodiazepines may be useful, particularly if agitation is present, although clinicians must be mindful of a possible interaction leading to a prolonged half-life for ketamine (Lahti et al. 1995 Lo and Gumming 1975). In general, because of the short half-life of ketamine, patients usually require observation only for several hours and can then be released home (Koesters et al. 2002). 

AUC, area under the plasma concentration curve BZ, benzodiazepine Cl, clearance t1/2, elimination half-life. 

The answer is a. (Hardman, p 373. Katzung, pp 430-431.) Midazolam is useful for sedation because it produces a higher incidence of amnesia and has a more rapid onset of action and a shorter half-life than other benzodiazepines used in anesthesia... 

AUC, area under the plasma concentration cuive BZ, benzodiazepine Cl, clearance t, elimination half-life Vd, volume of distribution. Data from Benzodiazepines. Fads and Comparisons 4.0 Online. Wolters Kluwer Health, Inc. 2005, http //online.factsandcomparisons.com and Madabushi R, Frank B, DrewelowB, etal. Hyperforinin St. John s wort drug interactions. Fur J Gin Pharmacol 2006 62 225-233. 

There is an association between falls and hip fractures and the use of long-elimination half-life benzodiazepines thus, flurazepam and quazepam should be avoided in the elderly. 

Since the volume of distribution is increased, the elimination half-life of lipid-soluble drugs is increased. This affects for example medium- and long-acting benzodiazepines as well as i.e. verapamil that can accumulate in the body. 

Wang PS, Bohn RL, Glynn RJ et al. (2001) Hazardous benzodiazepine regimens in the elderly effects of half-life, dosage, and duration on risk of hip fracture. Am J Psychiatry 158(6) 892-898... 

Ultimately, it is a drug s half-life combined with its potency that dictates its utility as a sedative-hypnotic. Like other benzodiazepines, clonazepam (Klonopin) can be used to treat insomnia, but its long duration of action renders it prone to hangover effects at doses needed to treat insomnia. Nevertheless, low doses of clonazepam (0.25-2 mg) are a treatment for PLMD and are also used to treat RLS. When hangover effects of even low doses of clonazepam are a problem, other benzodiazepines can be used. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

The half-life of a benzodiazepine is not predictive either of its onset of action or of the therapeutic response of the patient. However, the rate of absorption and distribution within the body are important parameters in determining the pharmacod)mamic response. The period for maximal response to treatment may be as long as 6 weeks, and there is no evidence... 

Q68 Benzodiazepines with a short elimination half-life present a less severe withdrawal after drug discontinuation than drugs with a long elimination half-life. Symptoms of benzodiazepine withdrawal syndrome include anxiety, depression, insomnia and headache. 

Benzodiazepines with a short half-life are excreted more rapidly than benzodiazepines with a long half-life and hence the risk of severe withdrawal side-effects is higher. Withdrawal symptoms include anxiety, depression, insomnia, headache and hallucinations. 

The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area)... 

The duration and degree of reversal of benzodiazepine effects are related to the dose and plasma concentrations of flumazenil. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Within 3 minutes, 80% response will be reached, with the peak effect occurring at 6 to 10 minutes. Pharmacokinetics After IV administration, flumazenil has an initial distribution half-life of 7 to 15 minutes and a terminal half-life of 41 to 79 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. After redistribution the apparent volume of distribution ranges from 0.77 to 1.6 L/kg. Protein binding is approximately 50%. 

Discontinuation of a hypnotic after a month of continued use can cause a rebound of REM (rapid eye movement) sleep. The duration of action of a hypnotic is determined not only by the half-life of the mother substance but especially by their biological half-life determined by the half-life of the mother substance and the biological active metabolites. On this basis the benzodiazepines can be divided in four different groups ultra short-acting with a half-life < 6 hours such as midazolam and triazolam, short-acting with half-lives between 6 and 12 hours like lormetazepam, loprazolam, oxazepam and temazepam. Alprazolam, bromazepam... 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

---