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=Ambien (Zolpidem tartrate) = == toc ==

Alternate Names:
Ambien CR (diphasic extended release tablet) Zolpimist (oromucosal spray) Edluar (sub-lingual tablet)[2]

IUPAC: N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide [3]

Class/Indications:
Zolpidem is a non-benzodiazepine sedative-hypnotic of the imidazopyridine class. It has a molecular weight of 764.9g/mol and a pKa of 6.14.[7]

Its pharmacological indications include short-term treatment of insomnia [4]. While Zolpidem has anti-convulsant and muscle relaxant effects, the beneficial actions require doses up to twenty times the sedative dose, which is impractical and potentially toxic for patients.

Sedative effects for insomnia occur quickly, with sedation usually occurring fifteen minutes after oral administration and with the effects lasting between two and three hours, due to its short half-life. These effects may take longer to see when zolpidem is taken with food, as discussed in the Distribution section.

Absorption
Absorption differs by dosage form. Immediate and extended release tablets are dissolved in the stomach at different rates and are absorbed both in the stomach to a small extent and in the small intestine, directly through the lumen thanks to its highly nonpolar structure. Extended-release tablets have an outer layer that dissolves quickly to put the patient to sleep, and then the larger interior dose dissolves later keeping plasma levels high allowing patients to stay asleep longer. The immediate release tablets have approximately the same time to max concentration, but as you can see in Graph 1 below, the extended-release tablets have higher concentrations later on in the drug's life cycle. This dose is more highly absorbed after the stomach. The oral spray dose has very similar bioavailability thanks to its absorption rate in the oral and nasal mucosa, and it avoids first pass metabolism for a period of time. Based on the pKa at 6.14, we would expect to see the drug more highly absorbed in the intestine, as we indeed do. [7]

===Absorption of a 12.5mg Oral dose Stat === Average peak concentration (C max ): 134ng/mL Time to peak concentration (T max ): 1.5 hours Average AUC: 740ng*hr/mL

Food-effect:
C max : decreased 30% T max : 2 to 4 hours Average AUC: decreased 23%

Graph 1 is an example of a plasma concentration verses time curve. [10]

Distribution
<span style="font-family: Arial,Helvetica,sans-serif;">The volume of distribution (Vol <span style="font-family: Arial,Helvetica,sans-serif; font-size: 80%; vertical-align: sub;">D <span style="font-family: Arial,Helvetica,sans-serif;">) of zolpidem in a healthy patient is 0.54 L/kg. It is extensively distributed into the body including the brain and in breast milk with between 0.004 and 0.019% of a 20mg oral dose found in the milk.[7]

<span style="font-family: Arial,Helvetica,sans-serif;">The time to peak plasma concentrations varies based on the formulation and in some instances whether the dose was administered with or without food. The immediate release tablets peak at 1.6 hours without meal and approximately 2.2 hours when taken with a meal. Peak plasma concentrations for other formulations can be found in Table 1 below.[8] <span style="font-family: Arial,Helvetica,sans-serif;">

<span style="font-family: Arial,Helvetica,sans-serif;">Once in the plasma zolpidem is approximately 92.5% bound to plasma protein .[9]

Geriatric patient variability
According to drugs.com, zolpidem has been found to have a longer half-life, a higher peak plasma concentration, and an increased AUC on a plasma concentration time curve when studied in geriatric patients. This correlates to marked increases in undesirable side effects such as confusion and falls. It is suggested that initial doses be lower than what would normally be considered a therapeutic dose to monitor these effects prior to increasing dosage if needed. [7]

<span style="font-family: Arial,Helvetica,sans-serif;">Mechanism of Action
<span style="font-family: Arial,Helvetica,sans-serif;">Zolpidem acts by selectively binding the α1 subunit of an alpha <span style="font-family: Arial,Helvetica,sans-serif;">gamma-aminobutyric acid (GABA A ) receptor, thereby potentiating the effects of the inhibitory GABA receptors.[1]

<span style="font-family: Arial,Helvetica,sans-serif;">There are two members of the GABA family of receptors, the GABA A and the GABA B as seen in Figure 2. While the GABA B receptors are metabotropic or G-coupled protein complexes, the GABA A receptors are ionotropic or ligand gated ion channels. The GABA A receptors have five subunits: two alphas, two betas, and one gamma as seen in Figure 3. When bound by an agonist the GABA A receptors open to increase the influx of chloride ions causing hyperpolarization of the cell. [4]

<span style="font-family: Arial,Helvetica,sans-serif;">The mechanism of action for Zolpidem differs from other agonists of the GABA receptor based on it's ability to more specifically bind to one of the α1 subunits. In comparison, benzodiazepines tend to bind non-specifically to each of the alpha subunits.[4]

<span style="font-family: Arial,Helvetica,sans-serif;">Metabolism
<span style="font-family: Arial,Helvetica,sans-serif;">Zolpidem undergoes phase I metabolism in the liver by the following cytochrome p450 enzymes: <span style="font-family: Arial,Helvetica,sans-serif;">CYP1A2 (14% clearance) <span style="font-family: Arial,Helvetica,sans-serif;">CYP3A4 (61% clearance) <span style="font-family: Arial,Helvetica,sans-serif;">CYP2C9 (22% clearance) <span style="font-family: Arial,Helvetica,sans-serif;">CYP2C19 (<3% clearance) <span style="font-family: Arial,Helvetica,sans-serif;">CYP2D6 (<3% clearance)

<span style="font-family: Arial,Helvetica,sans-serif;">These enzymes inactivate the drug via parallel hydroxylation creating 3 inactive alcohol derivatives. These alcohol derivatives are then further metabolized by alcohol dehydrogenase to form aldehyde derivatives. Then aldehyde dehydrogenase metabolizes the aldehyde derivatives to form carboxylic acid derivative. The acid derivatives are then readily excreted via urine.

<span style="font-family: Arial,Helvetica,sans-serif;"> <span style="font-family: Arial,Helvetica,sans-serif;">There are 3 inactive primary metabolites:

<span style="font-family: Arial,Helvetica,sans-serif;">M-3 metabolite (84%) <span style="font-family: Arial,Helvetica,sans-serif;">IUPAC:N,N-dimethyl-2-(6-hydroxymethyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide

<span style="font-family: Arial,Helvetica,sans-serif;">M-4 metabolite (12%) <span style="font-family: Arial,Helvetica,sans-serif;">IUPAC:N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-hydroxymethyll)acetamide

<span style="font-family: Arial,Helvetica,sans-serif;">M-11 metabolite (4%) <span style="font-family: Arial,Helvetica,sans-serif;">IUPAC:N-hydroxymethyl, N-methyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide



<span style="font-family: Arial,Helvetica,sans-serif;">In addition, because CYP3A4 is the main enzyme that metabolizes zolpidem, the inhibition of the CYP3A4 enzymes by azole antifungals (ketoconazole is particularly potent) causes significant inhibition of the breakdown of zolpidem. Also, a CYP2C9 inhibitor sulfaphenazole has an effect on the metabolism of Zolpidem, but to a much less extent due to the fact that the bulk of the metabolism is done by CYP3A4.

<span style="font-family: Arial,Helvetica,sans-serif;">Excretion
//<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">Excreted in: // <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">-Urine (48% to 67%) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> -Feces (29% to 42%) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> -Unchanged zolpidem is present in trace amounts in urine and feces (<1%)

//Half-life elimination:// -Immediate release, Extended release: ~2.5-2.8 hours (range 1.4-4.5 hours) -Cirrhosis: Up to 9.9 hours; -Elderly: Prolonged up to 32%

//<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;">Breast Feeding and Pregnancy // <span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> -Between 0.004 and 0.019% of the total administered dose is excreted into milk

//<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;">Pregnancy Category C // <span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> -Children born to mothers using sedatives are shown to suffer withdrawal symptoms and flaccidity. <span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> -It is not known exactly how zolpidem effects infant. <span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> -The benefits of zolpidem for the mother should outweight the possible harm caused to the child.

<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 12px;">Possible effect on urinary system:
Recent research has shown that zolpidem increases bladder capacity (through increasing aldosterone concentration) and suppresses urine excretion. The exact pathway for this response is not fully known. This could be used clinically to treat nocturia.

<span style="font-family: Arial,Helvetica,sans-serif;">References
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">1. Crestani F, Martin J, Möhler H, Rudolph U. Mechanism of action of the hypnotic zolpidem in vivo. //British Journal Of Pharmacology// [serial online]. December 2000;131(7):1251-1254. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed October 15, 2011 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">2. Clinical Pharmacology Online Website. http://clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=656&sec=monsup. Accessed October 15, 2011 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">3. Wikipedia.org Online Website. http://en.wikipedia.org/wiki/Zolpidem. Accessed October 15, 2011 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">4. PharmGKB Online Website. http://pharmgkb.com/drug/PA451976#tabview=tab1&subtab=31. Accessed November, 8, 2011 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">5. Lecture Notes for Pharmacy Students Online Website. http://marufahmed.blogspot.com/2010/04/gamma-amino-butyric-acid-gaba-and-its.html. Accessed November 10, 2011. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">6. Looking for Diagnosis Online Website.[|http://www.lookfordiagnosis.com/mesh_info.php?term=Receptores+Gaba&lang=2] Accessed November 10, 2011. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">7.http://www.drugs.com/ppa/zolpidem-tartrate.html. Accessed November 13, 2011. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">8. http://teach.belmont.edu:2491/crlsql/servlet/crlonline. Accessed November 13, 2011. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">9. Monti, J.M, Spence, D. Warren, et al. (2009). Pharmacotherapy of Insomnia: Focus on Zolpidem Extended Release. //Clinical Medicine: Therapeutics//. I, 123-140. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> 10. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=34409. Accessed November 27, 2011. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">11. von Moltke L, Greenblatt D, Shader R, et al. Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, andin vivo correlations. //British Journal Of Clinical Pharmacology// [serial online]. July 1999;48(1)Available from: Academic Search Premier, Ipswich, MA. Accessed November 29, 2011. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;"> 12. Langtry HD, Benfield P. Zolpidem: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990; 40(2): 291-313. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12px;">13. Matsuta, Yosuke. Zolpidem increases bladder capacity and decreases urine excretion in rats. Neurourology and Urodynamics. http://dx.doi.org/10.1002/nau.2079710.1002/nau.20797 Accessed November 2010.