Benzodiazepines pharmacodynamics

Pharmacodynamic tolerance to the psychomotor effects of benzodiazepines has been demonstrated after single or multiple doses (File 1985 Greenblatt and Shader 1978 Rosenberg and Chiu 1985). Pharmacodynamic tolerance to the anxiolytic effect (over a 6-month period) has not been demonstrated (Rickels et al. 1983), and clinical experience supports the view that many patients with anxiety disorders require long-term therapy with benzodiazepines or alternative antianxiety agents. An important clinical consequence of tolerance to sedative effects is observed in benzodiazepine overdoses, when patients may initially be... 

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

Sporadic use (e.g., for the induction of sleep after a psychostimulant binge) does not require specific detoxification. Sustained use can be treated as described in the previous sections on detoxification from therapeutic or high dosages but with added caution. In mixed opioid and benzodiazepine abuse, the patient should be stabilized with methadone (some clinicians use other oral preparations of opioids) and a benzodiazepine. Buprenorphine should not be administered with benzodiazepines, because a pharmacodynamic interaction is possible (Ibrahim et al. 2000 Kilicarslan and Sellers 2000) and fatalities have been reported with the combination (Reynaud et al. 1998). Sedative-hypnotic withdrawal is the more medically serious procedure, and we usually... 

Arendt RM, Greenblatt DJ, dejong RH, et al In vitro correlates of benzodiazepine cerebrospinal fluid uprake, pharmacodynamic action and peripheral disrriburion. J Pharmacol Exp Ther 227 98—106, 1983... 

Ciraulo DA, Sands BE, Shader RI Critical review of liability for benzodiazepine abuse among alcoholics. Am J Psychiatry 145 1501-1506, 1988b Ciraulo DA, Barnhill JG, Ciraulo AM, et al Parental alcoholism as a risk factor in benzodiazepine abuse a pilot smdy. Am J Psychiatry 146 1333-1335, 1989 Ciraulo DA, Antal EJ, Smith RB, et al The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol 10 27—32, 1990 Ciraulo DA, Sarid-Segal O, Knapp C, et al Liability to alprazolam abuse in daughters of alcoholics. Am J Psychiatry 153 956-958, 1996 Ciraulo DA, Barnhill JG, Ciraulo AM, et al Alterations in pharmacodynamics of anxiolytics in abstinent alcoholic men subjective responses, abuse liability, and electroencephalographic effects of alprazolam, diazepam, and buspirone. J Clin Pharmacol 37 64-73, 1997... 

Greenblatt DJ, Shader RI Long-term administration of benzodiazepines pharmacokinetic versus pharmacodynamic tolerance. Psychopharmacol Bull 22 416 23, 1986... 

Sonne J, Loft S, Dossing M et al. (1991) Single dose pharmacokinetics and pharmacodynamics of oral oxazepam in very elderly institutionalised subjects. Br J Chn Pharmacol 31(6) 719-722 Taylor S, McCracken CF, Wilson KC et al. (1998) Extent and appropriateness of benzodiazepine use. Results from an elderly urban community. Br J Psychiatry 173 433—438... 

Benzodiazepines are virtually identical from a pharmacodynamic standpoint (refer to Chapter 2 for a comprehensive discussion of pharmacodynamics and pharmacokinetics). Specifically, they all act by activating the GABA-A receptor complex. Despite their similarity, the benzodiazepines are not wholly interchangeable as a... 

Q65 All benzodiazepines have similar pharmacological profiles. Benzodiazepines have similar pharmacodynamic spectra and pharmacokinetic properties. 

Benzodiazepines have similar pharmacological properties and are used in anxiety and insomnia. The choice of which benzodiazepine to use usually lies with the pharmacodynamic and pharmacokinetic properties, which vary across the class. For example, diazepam, flurazepam and nitrazepam have a prolonged duration of action whereas lorazepam and temazepam have a shorter duration of action. 

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. 

Benzodiazepines are very important drugs from a turnover point of view. A large number of these compounds has been synthesized, developed and marketed (about thirty have been launched), a dozen of which contain fluorine atoms. Specific clinical indications for each compound do not result from a difference in the mechanism but from the pharmacokinetic and pharmacodynamic behavior of each one. 

In the treatment of children and adolescents with anxiety disorders clinicians have a wide variety of pharmacologic options beyond the antidepressants (Shader and Greenblatt, 1995 Lydiard et ah, 1996 Riddle et ah, 1999). The benzodiazepines (BZs), with their favorable safety profile and quick onset of action, are attractive alternatives for the treatment of acute anxiety. While the clinical effectiveness of buspirone has not been proven in children, buspirone is used alone or in combination with other drugs in the treatment of anxiety disorders. The antihistamines are often used to treat insomnia and may reduce acute mild agitation. Zolpidem (Ambien) is occasionally used for its sedative properties. This chapter reviews the structure, proposed mechanisms of action, pharmacodynamic principles, and pharmacokinetic principles of these drugs. 

DeVane, C.L., Ware, M.R., and Lydiard, R.B. (1991) Pharmacokinetics, pharmacodynamics, and treatment issues of benzodiazepines alprazolam, adinazolam, and clonazepam. Psychophar-macol Bull 27 463-473. 

Exogenous progesterone and benzodiazepines may have important pharmacodynamic interactions in that cognitive impairment to benzodiazepines may be enhanced with exogenous progesterone (Kroboth et al. 1985 McAuley et al. 1995). 

Krieger C, Jones K, Kim SU, et al The role of intracellular free calcium in motor-neuron disease. J Neurol Sci 124 27-32, 1994 Kroboth PD, Smith RB, Stoehr GP, et al Pharmacodynamic evaluation of the benzodiazepine—oral contraceptive interaction. Chn Pharmacol Ther 38 525-532, 1985... 

Vgontzas AN, Kales A, Bixler EO. Benzodiazepine side effects role of pharmacokinetics and pharmacodynamics. Pharmacology 1995 51 205-223. 

An interaction between G. biloba administered as 80 mg leaf extract twice a day and low-dose trazodone (20 mg twice daily) was suspected in a patient with Alzheimer s disease, who took the two products together. It is postulated that a pharmacodynamic (increased gamma-aminobutyric acid-ergic activity) and pharmacokinetic mechanisms [increased metabolism of trazodone to w-chlorophenylpiperazine (w -CPP), which acts on the benzodiazepine-binding sites and releases gamma-aminobutyric acid] contribute to the observed effect (32). Table 2 provides a list of reported pharmacodynamic and pharmacokinetic interactions involving ginkgo. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

The newer sedative-hypnotics that are not benzodiazepines are rapidly becoming the first-line treatment for insomnia. These agents not only have pharmacodynamic advantages over benzodiazepines in terms of their mechanism of action, but perhaps more importantly, pharmacokinetic advantages as well. Three nonbenzodiazepine sedative-hypnotic agents that are now available are zaleplon (a pyrazolopyrimidine), zopiclone (a cyclopyrrolone not available in the United States), and zolpidem (an imidazopyridine) (Figs. 8—28-8—30 Table 8—4). 

Pharmacodynamics of Benzodiazepines Barbiturates Molecular Pharmacology of the GABAa Receptor... 

Kaplan SA, Jack ML (1983) Metabolism of benzodiazepines Pharmacokinetic and pharmacodynamic considerations. In E Costa (ed) The Benzodiazepines From Molecular Biology to Clinical Practice. Raven Press, New York, 173-199... 

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

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