Alprazolam, half-life

Alprazolam Increased AUC of alprazolam by 96°/o, increased alprazolam half-life by 71°/o increased psychomotor impairment... 

Another study in healthy subjects found that dextropropoxyphene 65 mg every 6 hours prolonged the alprazolam half-life from 11.6 to 18.3 hours, and decreased the clearance from 1.3 to 0.8 mL/minute per kg. The pharmacokinetics of single doses of diazepam and lorazepam were not significantly affected. It would seem that dextropropoxyphene inhibits the metabolism (hydroxylation) of the alprazolam by the liver, thereby reducing its loss from the body, but has little or no effect on the A/-demethylation or glucuronidation of the other two benzodiazepines. The clinical importance of this is uncertain, but the inference to be drawn is that the CNS depressant effects of alprazolam will be increased, over and above the simple additive CNS depressant effects likely when other benzodiazepines and dextropropoxyphene are taken together. More study is needed. 

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). 

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. 

The withdrawal syndrome occurred earlier and was more severe for short half-life (alprazolam, lorazepam) than for long half-life drugs (diazepam, clorazepate). 

In the management of anxiety, the cumulative effects of longer half-life BZDs often result in excessive sleepiness, apathetic states, and confusion (with or without paradoxical agitation). Thus, short- and intermediate-acting agents such as oxazepam, lorazepam, and alprazolam are preferable. Lower doses (e g., 0.5 to 1.0 mg of lorazepam 0.25 to 0.5 mg of alprazolam) are preferable. Agents with very short half-lives, such as midazolam and triazolam, are not well tolerated, especially in those with more severe neurocognitive disruption. In this context, low-dose antipsychotics were found more effective than lorazepam in the treatment of AIDS-related delirium (495). 

Alprazolam has been researched more extensively than any other benzodiazepine in panic disorder, and is very effective. Because of its short duration of action, it generally must be administered in three to five daily doses. Clonazepam, which has a longer duration of action than alprazolam, has also been investigated in panic disorder. It can generally be administered twice a day. Clonazepam is reported to have less abuse potential than alprazolam and to be easier to taper during discontinuation owing to its longer half-life. 

Insomnia is a common complaint in the elderly. As people age they require less sleep, and a variety of physical ailments to which the elderly are subject can cause a change in the sleep pattern (e.g. cerebral atherosclerosis, heart disease, decreased pulmonary function), as can depression. Providing sedative hypnotics are warranted, the judicious use of short half-life benzodiazepines such as temazepam, triazolam, oxazepam and alprazolam for a period not exceeding 1-2 months may be appropriate. Because of their side effects, there would appear to be little merit in using chloral hydrate or related drugs in the treatment of insomnia in the elderly. It should be noted that even benzodiazepines which have a relatively short half-life are likely to cause excessive day-time sedation. The side effects and dependence potential of the anxiolytics and sedative hypnotics have been covered elsewhere in this volume (Chapter 9). 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

AUC) and increases in peak plasma concentration (Cmax) of triazolam (73,74) (Fig. 2). Cotreatment of ketoconazole with alprazolam, also a CYP3A substrate, produced a large increase in AUC for alprazolam (74). However, alprazolam is a low-extraction compound with bioavailability ordinarily in the range of 90% (75). As such, the reduction in alprazolam clearance caused by ketoconazole was evident mainly as prolonged elimination half-life but without a significant change in Cmax. 

The inhibitory effect of ritonavir (a viral protease inhibitor) on the metabolism of alprazolam, a CYP3A-mediated reaction, has been investigated in a doubleblind study (44). Ten subjects took alprazolam 1.0 mg plus either low-dose ritonavir (four doses of 200 mg) or placebo. Ritonavir reduced alprazolam clearance by 60%, prolonged its half-life, and magnified its benzodiazepine agonist effects, such as sedation and impairment of performance. 

A within-subject, double-bhnd, placebo-controlled, parallel design has been used to measure the effects of citalo-pram (20 mg/day) and fluoxetine (20 mg/day) on the pharmacokinetics and pharmacodynamics of alprazolam (1 mg/day) (45). Fluoxetine significantly impaired the metabolism of a single oral dose of alprazolam 1 mg, leading to prolongation of the half-life and an increased AUC, whereas citalopram did not. Neither SSRI significantly affected the pharmacodynamic effects of alprazolam. This experiment suggests differential effects of citalopram and fluoxetine on alprazolam kinetics. 

Clinical duration of action may be shorter than plasma half-life, leading to dosing more frequently than 2-3 times daily in some patients, especially for immediate release alprazolam... 

Via CYP450 3A4 inhibition, nefazodone may increase the half-life of alprazolam and triazolam, so their dosing may need to be reduced by half or more... 

These inhibit oxidative metabolism and at the same time enhance glucuronidation. Consequently, the half-lives of benzodiazepines such as alprazolam, chlordiazepoxide, diazepam, and triazolam were found to be increased, and the half-life of Iorazepam, and to a lesser extent that of oxazepam, can be significantly reduced. 

A Pu. 70% protein bound, half-life = 11 hrs. More rapid onset than tricyclic antidepressants. Some argue that Alprazolam has high dependency/abuse potential and a severe withdrawal syndrome. Few interactions. Additive with other CNS depressants. ... 

I. Itraconazole. A single 800-microgram dose of alprazolam was given to 10 healthy subjects before and after a 6-day course of itraconazole 200 mg daily. The itraconazole increased the AUC and the half-life of alprazolam nearly threefold, and psychomotor function was impaired. ... 

Ketoconazole. A study in healthy subjects found that ketoconazole 200 mg twice daily decreased the clearance of alprazolam 1 mg by about two-thirds, and prolonged its half-life fourfold, but the maximum serum levels remained unchanged. ... 

In a randomised study 12 healthy subjeets were given erythromycin 400 mg three times daily for 10 days with a single 8(X)-mierogram dose of alprazolam on day 8. The alprazolam AUC0.48 was inereased by 61% and the half-life inereased from 16 to 40.3 hours. However, no inerease in sedation was seen. The manufaeturers prediet that other maerolides will in-teraet similarly, and they speeifieally name erythromycin and troleandomycin. ... 

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