Pharmacology zolpidem

Pharmacology Zolpidem is a nonbenzodiazepine hypnotic. While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. 

Kralic, J. E., O Buckley, T. K., Khisti, R. T., Hodge, C. J., Homanics, G. E., and Morrow, A. L. (2002) GABAa receptor al subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem. Neuropharmacology 43, 685-694. 

Zolpidem (1) is an effective hypnotic agent indicated for the short-term treatment of insomnia. Zolpidem interacts with the GABAa receptor, and its pharmacological effect is blocked by the benzodiazepine-receptor antagonist fiumazenil (Sanger and Depoortere, 1998). Zolpidem displaces benzodiazepines more selectively from the cerebellum than the hippocampus or spinal cord, consistent with preferential interaction with the ajGABAA receptor subtype (sometimes referred to as the benzodiazepine coi receptor). Studies... 

In chnical trials, zolpidem shortened sleep latency, improved the quahty of sleep, and accelerated the restoration of normal sleep patterns (Lee, 2004). In insomniac patients it increased the amount of slow wave, restorative sleep as seen in normal sleepers. Zolpidem has high oral bioavailability (70%), a short duration of action (tj /2 = 2 h), and is relatively highly bound to plasma proteins (92%). The recommended dose is generally 10 mg/day as needed. Zolpidem is extensively metabolized, mainly by CYP3A4 but also by CYP1A2 and CYP2C9, and its major metabolites do not appear to have pharmacological activity. It has minimal daytime residual effects, and a low risk for tolerance and abuse. The safety profile showed a low incidence of adverse events, close to that observed with placebo. The medicine is available in over 80 countries. 

Receptors containing the as subunit are of minor abimdance in the brain (Table 1) but are expressed to a significant extent in the hippocampus, where they comprise 15%-20% of the diazepam-sensitive GABAa receptor population, predominately co-assembled with the Ps and y2 subunits. Pharmacologically, the as receptors are differentiated from aiP2y2> a2Psy2 and asP3y2 receptors by a lower affinity to CL 218,872 and near-insensitivity to zolpidem (Table 1). 

Rudolph U, Crestani F, Mohler H (2001) GABAa receptor subtypes dissecting their pharmacological functions. Trends Pharmacol Sci 22 188-194 Sanger DJ, Morel E, Perrault G (1996) Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and Zolpidem. Eur J Pharmacol 313 35-42... 

Zolpidem (Ambien) and zaleplon (Sonata) are structurally unrelated to the benzodiazepines, but both drugs share pharmacological properties with the benzodiazepines. They bind to benzodiazepine receptors and facilitate GABA-mediated inhibition. 

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. 

In this chapter, we discuss the pharmacology of medications that are classified as anxiolytic, sedative, or hypnotic—primarily the benzodiazepines, buspirone, zolpidem, eszopiclone, and zale-plon. Subsequently, we present diagnosis-specific treatment guidelines (outlined in Table 3-1). The commonly used anxiolytics and hypnotics, together with their usual doses, are shown in Table 3-2. Many antidepressant medications are also effective in the treatment of anxiety disorders. The pharmacology of antidepressants is discussed in Chapter 2 their clinical use in anxiety disorders is addressed in the diagnosis-specific sections later in this chapter. 

Zaleplon s onset time, time to maximal drug effect, and duration of action are shorter than with triazolam. Hence, despite its non-BZD structure and unique BZD receptor binding profile, its behavioral pharmacological profile is similar to that of triazolam ( 157). Like zolpidem, zaleplon in recommended doses decreases sleep latency with minimal effect on sleep stages. Thus, it differs from BZDs, which prolong the first two stages of sleep and shorten stages 3 and 4 REM sleep ( 158). 

Some sedative-hypnotics, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone. 

Nonbenzodiazepine ligands at benzodiazepine sites This is a variation on the theme of partial benzodiazepine agonists, as these agents act at the same or similar site as benzodiazepines but are not structurally related to them. Thus, the pharmacology of nonbenzodiazepines is that of a partial agonist, but their chemistry is different from that of a benzodiazepine. This is similar to the approach that novel sedative-hypnotics such as zaleplon and zolpidem have taken, and perhaps a less sedating nonbenzodiazepine partial agonist could hold promise for the treatment of panic disorder. 

The benzodiazepines, the barbiturates, zolpidem, and many other drugs bind to molecular components of the GABAa receptor present in neuronal membranes in the central nervous system. This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA (see Chapter 21 Introduction to the Pharmacology of CNS Drugs). 

Zolpidem is rapidly absorbed after oral administration. Its bioavailability is approximately 70 %. Peak plasma concentrations are attained 1.0-1.5 h after a single therapeutic dose of 10 mg. The major metabolic routes in man include oxidation and hydroxylation, and none of the metabolites is pharmacologically active. The mean ti/2 of zolpidem in healthy volunteers is 2.0-2.5 h [27] (Tab. 2). 

Holm KJ, Goa KL (2000) Zolpidem - An update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 59 865-889... 

Freeman H, Puech AJ, Roth T (eds) (1996) Zolpidem an update of its pharmacological properties and therapeutic place in the management of insomnia. Elsevier, Paris... 

Rush CR. Behavioral pharmacology of zolpidem relative to benzodiazepines a review. Pharmacol Biochem Behav 1998 61 253-69. 

Case Conclusion Upon a thorough examination and interview, you have ruled out medical and pharmacologic agents as possible causes of DL s insomnia. His major depressive disorder may still be a contributing factor to his sleep problem, but at this time DL may benefit from a short-term use of a hypnotic. Upon further discussion, you decide to try one of the newer agents approved for insomnia. DL is prescribed zolpidem as needed for sleep. 

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