Diazepam pharmacodynamics

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... 

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. 

Cimetidine slows the metabolism of BZs. This slowing causes clinically significant increases in cognitive impairment when coadministerd with midazolam (Chouinard et ah, 1999). Cimetidine increases the levels of diazepam and its metabolite, but no pharmacodynamic effects have been demonstrated (Greenblatt et ah, 1984). 

Freidman, H. et al., Pharmacokinetics and pharmacodynamics of oral diazepam effect of dose, plasma concentration, and time, Clin. Pharmacol. Ther., 52, 139, 1992. 

Mould DR, DeFeo TM, Reele S, Milla G, Limjuco R, Crews T, Choma N, Patel IH. 1995. Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam. Clin Pharmacol Ther 58 35-43. 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (266). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interactions were found of olanzapine with aminophylline, biperiden, diazepam, ethanol, fluoxetine, imipramine, lithium, or R/S-warfarin. 

Bateman DN. The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam. Eur J Clin Pharmacol 1986 30(2) 205-8. 

Biihrer M, Maitre PO, Crevoisier C, Stanski DR. Elec-troencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalo-graphic effects of midazolam and diazepam. Clin Pharmacol Ther 1990 48 555-67. 

Bechgaard E, Gizurarson S, Hjortkjaer RK. Pharmacokinetic and pharmacodynamic response after intranasal administration of diazepam to rabbits. ] Pharm Pharmacol 1997 49(8) 747-750. Nielson HW, Bechgaard E, Twile B, et al. Intranasal administration of different liquid formulations of bumetanide to rabbits. Int J Pharm 2000 204 35-41. 

Pharmacodynamic and pharmacokinetic properties of diazepam in horses. American Journal of Veterinary Research 43 756-1762... 

In an attempt to understand the mechanism whereby diazepam was efficacious, Johnson and co-workers (Johnson and Lowndes, 1974 Johnson and Wilcox, 1975) showed diazepam to counteract the over-activity normally associated with skeletal and heart muscle following soman intoxication. It was also shown, however, that diazepam enhances the respiratory depression produced by soman in the pentobarbitone-anaesthetized rabbit. Boskovid (1981) found that atropine and diazepam increased approximately threefold the survival time of rats poisoned with soman, when given 1 min after poisoning. In addition, there are several pharmacodynamic studies of oximes by the same author, in which diazepam (and frequently atropine) were included, but it is often difficult to separate out the effects of the diazepam from the other drugs used (e.g. BoSkovid etal, 1984). 

In a variety of pharmacodynamic studies on experimental animals, it can be concluded that diazepam adds to the effects of atropine and of the classical combination of atropine and pyridtnium oximes (Bokonjic etal., 1987 Gupta, 1984 Kassa and Bajgar, 1994 Kleinrok and Jagiello-Wojtowicz, 1977 Krutak-Krol and Domino, 1985 Rump and Grudzinska, 1974). There seems to be little douht that in experimental animal models, diazepam can prevent, stop, and/or ameliorate convulsions due to OP pe,sticides and render less severe or even prevent structural changes in the brain, but the effects on lethality are less clear (Marrs, 2003). 

In addition to pharmacokinetic drug-drug interactions, pharmacodynamic effects have been reported as well. Halothane increases the susceptibility to ventricular arrhythmias under theophylline therapy as a result of increased sensitivity of the myocardium to endogenous catecholamine release by theophylUne. Ketamine lowers the theophyUine seizure threshold. Benzodiazepines Uke midazolam, diazepam, lorazepam, and Uurazepam increase the central nervous system concentration of adenosine, a potent central nervous system depressant. As theophyUine also blocks adenosine receptors, it counteracts benzodiazepine-induced sedation, resulting in increased dosage requirements for these compounds. ... 

LaisiU, Linnoila M, SeppalaT, Himberg J-J, MattilaMJ. Pharmacokinetic and pharmacodynamic interactions of diazepam with different alcoholic beverages. Eur J Clin Pharmacol (1979) 16, 263-70. 

KlotzU,ReimannIW. Fliarmacddnetic and pharmacodynamic interaction study of diazepam and meti olol. EurJ Clin Pharmacol (1984) 26,223-6. 

In a crossover study, 6 healthy subjects were given a single 5-mg oral dose of diazepam after taking erythromycin 500 mg three times daily for one week. The diazepam AUC was increased by a modest 15%, but its pharmacodynamic effects were unchanged. ... 

A study in healthy subj ects found that metronidazole 400 mg twice daily for 5 days had no effect on the pharmacokinetics of a single 100-microgram/kg intravenous dose of diazepam. Another study in healthy subjects found that metronidazole 750 mg had no effect on the pharmacokinetics of alprazolam or lorazepam. In vivo and in vitro studies have shown that metronidazole has no effect on the pharmacokinetics or pharmacodynamics of midazolam. Interactions with other benzodiazepines seem unlikely-... 

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