Pharmacology - Alprazolam

[Jatelka]

Alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-I] [1,4] benzodiazepine. It is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH. Its formula is C17H13ClN4 and it’s molecular mass is 308.765



Pharmacokinetics

Alprazolam is readily absorbed following oral administration. Peak concentrations occur at 1 to 2 hours. Levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL are observed. The mean plasma elimination half-life is about 11.2 hours (range: 6.3-26.9 hours) in healthy adults. Alprazolam is approximately 80% protein bound, with albumin accounting for the majority of binding.

Metabolism/Elimination

Alprazolam is metabolized primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites, 4-hydroxyalprazolam and α-hydroxyalprazolam.. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration are less than 4%. It is not thought that these metabolites contribute to the biological action of alprazolam.
Alprazolam and its metabolites are excreted primarily in the urine.

Special Populations

Changes in the pharmacokinetics and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired liver function and impaired renal function. Changes have also been demonstrated in older patients.

The mean half-life of alprazolam in older subjects (> 65) is 16.3 hours (range: 9.0-26.9 hours)

In patients with alcoholic liver disease the half-life of alprazolam ranges between 5.8 and 65.3 hours (mean: 19.7 hours)

A study done in an obese group of subjects demonstrated a half-life ranging between 9.9 and 40.4 hours (mean=21.8 hours)

Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

Interactions

Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied, along with their effect on increasing alprazolam concentrations, are as follows: Ketoconazole, 3.98 (AUC) fold; Itraconazole, 2.70 (AUC) fold; Nefazodone, 1.98 (AUC) fold; Fluvoxamine, 1.96 (AUC) fold; and erythromycin 1.61 (AUC) fold.

CYP3A inducers would be expected to decrease alprazolam concentrations and this has been demonstrated in vivo: The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90 ± 0.21 mL/min/kg to 2.13 ± 0.54 mL/min/kg and the elimination t½ was shortened (from 17.1 ± 4.9 to 7.7 ± 1.7 h) following administration of 300 mg/day carbamazepine for 10 days. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000-1200 mg/day); the effect at usual carbamazepine doses is unknown.

The ability of alprazolam to induce human hepatic enzymes has not been determined. However, this is not a property of benzodiazepines in general. Alprazolam does not effect anticoagulation in individuals on Warfarin

Clinical Studies

Anxiety Disorders

Although Alprazolam has been shown to be effective in randomized, double-blind, placebo controlled trials, these were only 4 week studies.

Panic Disorder

Again, although Alprazolam has been shown to be effective in placebo-controlled studies, these only lasted 10 weeks.

Animal Studies

When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment

Indications

Management of anxiety disorders and panic disorder, with or without agoraphobia

Anxiety Disorders and Transient Symptoms of Anxiety

Initial therapeutic dose is 0.25 to 0.5 mg three times a day. The dose is increased, at intervals of 3 to 4 days (depending on effect on symtoms) to a maximum of 4 mg daily, in divided doses, given in divided doses. The risk of dependence increases with dose and duration of treatment.
As with all benzodiazepines, dependence can occur with as little as 14 days continuous treatment. Alprazolam should not be discontinued abruptly.
It is recommended that the daily dosage be decreased by no more than 0.5 mg every 3 days.

Panic Disorder

In panic disorder, higher doses of alprazolam are often required. Generally in the range of 1 to 10 mg daily. Mean dose used in clinical trials was 5 to 6mg.

Dose Titration

Treatment is usually initiated with a dose of 0.5 mg three times daily. Depending on the response, it may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day.

Dose Maintenance

In a dose-response study, patients treated with doses of alprazola greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit.

Dosing in Special Populations

In elderly patients, or in patients with liver disease, the usual starting dose is 0.25 mg, given two or three times daily.

Side Effects & Drug Interactions

Side effects are most likely during the first few weeks of treatment (as with all benzodiazepines)

Common: Drowsiness, anterograde amnesia, changes in appetite, changes in libido, light-headedness/dizziness, depression, headache, confusion, rebound insomnia and anxiety, dry mouth, GI disturbance, palpitations, blurred vision, tremor, urinary symptoms, nasal congestion and rashes

Rare: Menstrual irregularity, anaphylaxis, paradoxical excitation (including agitation, anxiety and hallucinations), syncope, disinhibition (and inappropriate sexual behaviour), derealization/depersonalization, night terrors and sleep paralysis, impotence, alterations in taste and oedema.

Discontinuation-Emergent Symptoms

Insomnia, light-headedness, nausea/vomiting, diarrhea, abnormal involuntary movements, dry mouth, headache, reduced appetite/weight loss, sweating, anxiety, fatigue, tachycardia, depression, confusion and blurred vision

Physical and Psychological Dependence

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (up to 4 mg/day). The risk of withdrawal seizures may be increases at doses above 4 mg/day

Use with Other CNS Depressants and More Interactions

Alprazolam produces additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

The steady state plasma concentrations of imipramine and desipramine are increased on average by 31% and 20%, respectively, when given concomitantly with alprazolam doses of up to 4mg

Co-administration of fluoxetine increases plasma concentrations of alprazolam by 46%, decreases clearance by 21% and increases half-life by 17%

Co-administration of propoxyphene decreases plasma concentrations of alprazolam by 6%, decreases clearance by 38%, and increases half-life by 58%

Co-administration of oral contraceptives increases plasma concentrations of alprazolam by 18%, decreases clearance by 22%, and increases half-life by 29%

Co-administration of fluvoxamine approximately doubles the concentration of alprazolam, decreases clearance by 49% and increases half-life by 71%

Co-administration of cimetidine increases the plasma concentration of alprazolam by 86%, decreases clearance by 42%, and increases half-life by 16%.

There are possible interactions with: diltiazem, isoniazid, antibiotics such as erythromycin and clarithromycin, grapefruit juice, sertraline, paroxetine, ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine.

Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.

Ketoconazole and itraconazole are potent enzyme inhibitors and have been shown to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively.

Risk of Foetal Harm

There is an increased risk of congenital abnormalities when alprazolam is administered during the first trimester

Carcinogenesis, Mutagenesis and Impairment of Fertility

No evidence of carcinogenic potential was observed during 2-year studies of in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).

Alprazolam is not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day.

Alprazolam produces no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.

Pregnancy and Lactation

Children born of mothers who are receiving benzodiazepines are at some risk for withdrawal symptoms during the postnatal period. Flaccidity and respiratory depression have been reported in children born of mothers who have been taking alprazolam. Alprazolam is excreted in breast milk, and may cause lethargy in infants, as well as failure to thrive.

Overdose

The acute oral LD50 in rats is 331-2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following intravenous doses of alprazolam over 195 mg/kg; 975 times the maximum recommended daily human dose.

Sources: rxlist, inchem, bnf