Alprazolam

Alprazolam is an Antidepressant agent belonging to the Benzodiazepine class.

Alprazolam is a tri-azolobenzodiazepine with intermediate onset commonly used to treat panic disorders and generalized anxiety in addition to anxiety associated with depression.

Alprazolam is Readily absorbed Its Bioavailability is 84-92% for immediate-release and approximately 90% for extended-release. Time to reach peak plasma concentration is 1-2 hours for immediate-release, approximately 9 hours (extended-release), and 1.5-2 hours (orally disintegrating tab). Alprazolam is having Volume of distribution of about 0.84-1.42 L/kg (immediate release). Alprazolam is ~80% protein-bound in serum. The majority of this protein binding is to serum albumin. Alprazolam is metabolized to fewer effective metabolites by various CYPs including CYP3A4, CYP3A5, CYP3A7, and CYP2C9.The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As.4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha- hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity. It is excreted mainly via urine, as an unchanged drug.

Alprazolam shows side effects like Drowsiness, light-headedness, headache, tiredness, dizziness, irritability, talkativeness, difficulty concentrating etc.

Alprazolam is available in the form of Oral Tablets and oral solutions.

Alprazolam is available in India, US, Canada, Japan, China, France, Italy, Singapore, Germany, Australia, and Malaysia.

Alprazolam belongs to Benzodiazepine class and acts as Antidepressant Agent.

Alprazolam binds stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors.

The Onset of action of Alprazolam is not clinically established.

The Time to peak plasma concentration of Alprazolam is approximately 1-2 hours for immediate-release, approximately 9 hours (extended-release), and 1.5-2 hours (orally disintegrating tablets).

Alprazolam is available in the form of Oral Tablets and oral solutions.

Alprazolam tablet and solution are taken orally, usually in divided dose.

Alprazolam is used to treat panic disorders and anxiety, like unexpected extreme fear and tension due to stress. It is recommended to start with a small dosage and increase it gradually. Do not stop taking this medicine suddenly as it may cause withdrawal symptoms like seizures, aggressive behavior, blurred vision, etc.

Alprazolam is an Antidepressant agent belonging to the Benzodiazepine class.

Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.

Alprazolam is approved for use in the following clinical indications

• Alprazolam is indicated for the acute treatment of generalized anxiety disorder in adults. Alprazolam is also indicated, either as a standard or extended-release formulation, for the treatment of panic disorder with or without agoraphobia in adults.
• Alprazolam may also be prescribed off-label for insomnia, premenstrual syndrome, and depression.

• Anxiety

Anxiety disorders (adjunctive therapy or monotherapy) (alternative agent):

Immediate release:

Oral: Initial: 0.25 mg 3 to 4 times daily; may increase dose based on response and tolerability in increments ≤1 mg/day at intervals ≥3 days up to a usual dose of 2 to 6 mg/day in 3 to 4 divided doses. Some patients may require up to 8 mg/day for optimal response; maximum: 10 mg/day. With doses >4 mg/day, increase more gradually to minimize adverse effects; periodically reassess and consider dosage reduction.

Extended release (panic disorder labeled use):

Oral: Initial: 0.5 to 1 mg once daily; may increase dose based on response and tolerability in increments ≤1 mg/day at intervals ≥3 days up to a usual dose of 2 to 6 mg/day. Some patients may require up to 8 mg/day for optimal response; maximum: 10 mg/day. With doses >4 mg/day, increase more gradually to minimize adverse effects; periodically reassess and consider dosage reduction. Administration in 2 divided doses may be considered to maximize efficacy.

Procedural anxiety (premedication) (off-label use):

Immediate release:

Oral, Sublingual: 0.5 mg 30 to 90 minutes before procedure; if needed due to incomplete response and/or duration of procedure, may repeat the dose (usually at 50% of the initial dose) after 30 to 60 minutes.

• Vertigo, acute episodes

Immediate release: Oral: Initial: 0.5 mg every 8 hours as needed for up to 48 to 72 hours.

Alprazolam is available in various strengths as 0.25 mg; 0.5 mg; 1 mg; 2 mg; 3 mg; 0.5 mg/5 mL; 1 mg/mL.

Alprazolam is available in the form of Oral Tablet, oral solution.

• Dosage Adjustment in Kidney Patient

CrCl ≥10 mL/minute: No dosage adjustment necessary.

CrCl <10 mL/minute: No dosage adjustment necessary; use with caution as enhanced pharmacodynamic effects (eg, psychomotor and memory impairment) may be observed in patients with end-stage kidney disease.

• Dosage Adjustment in Hepatic impairment Patient

Advanced liver disease:

IR tablet, oral concentrate, orally disintegrating tablet: 0.25 mg 2 to 3 times daily.

Extended release: 0.5 mg once daily.

Alprazolam is contraindicated in patients with

• Alprazolam Tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam is contraindicated with ketoconazole and itraconazole since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A).

• Depression: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus).
• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.

Consumption of alcohol with this medicine is not recommended as it increases the risk of severe respiratory depression and breathlessness.

Alprazolam are known to be excreted in human milk. It should be assumed that alprazolam chronic administration like that of diazepam to nursing administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use Alprazolam.

Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

Common

Drowsiness, light-headedness, headache, tiredness, dizziness, irritability, talkativeness, difficulty concentrating, dry mouth, increased salivation, changes in sex drive or ability, nausea, constipation, changes in appetite, weight changes, difficulty urinating, joint pain

Rare

Shortness of breath, seizures, severe skin rash, yellowing of the skin or eyes, confusion, problems with speech, problems with coordination or balance.

• Opioids: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma aminobutyric acid (GABAA) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
• CNS Depressants: The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.
• Strong Inhibitors of CYP3A (except ritonavir): Concomitant use of ALPRAZOLAM with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions.
• Moderate or Weak Inhibitors of CYP3A: Concomitant use of ALPRAZOLAM with CYP3A inhibitors may increase the concentrations of ALPRAZOLAM, resulting in increased risk of adverse reactions of alprazolam.
• CYP3A Inducers: Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.
• Ritonavir: Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir.
• Digoxin: Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age).

The common side effects of Alprazolam include the following

Common side effects

Drowsiness, light-headedness, headache, tiredness, dizziness, irritability, talkativeness, difficulty concentrating, dry mouth, increased salivation, changes in sex drive or ability, nausea, constipation, changes in appetite, weight changes, difficulty urinating, joint pain.

Rare side effects

Shortness of breath, seizures, severe skin rash, yellowing of the skin or eyes, confusion, problems with speech, problems with coordination or balance.

• Pregnancy

Pregnancy Category D

Teratogenic Effects

Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

• Nursing Mothers

Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use Alprazolam.

• Pediatric Use

Safety and effectiveness of Alprazolam in individuals below 18 years of age have not been established.

• Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of Alprazolam should be used in the elderly to preclude the development of ataxia and oversedation.

Symptoms: Mild cases: Drowsiness, mental confusion, lethargy, impaired coordination, diminished reflexes, slurred speech, dilated pupils, absent bowel sounds, tachycardia. Serious cases: Ataxia, hypotonia, hypotension, hypothermia, rhabdomyolysis, atrioventricular block, coma.

Management: Supportive treatment with respiration, pulse rate and blood pressure monitoring. Induce vomiting (within 1 hour of ingestion) if the patient is conscious or perform gastric lavage if unconscious. Activated charcoal may be given to reduce absorption if gastric emptying is of no advantage. Administer IV fluids and maintain an adequate airway. Flumazenil may be considered with close monitoring for re-sedation, respiratory depression and other residual benzodiazepine effects.

• Pharmacodynamic

Alprazolam is a benzodiazepine that binds γ-aminobutyric acid (GABA) type-A receptors (GABAARs) to enhance their inhibitory effect on neurotransmission, specifically in the brain. Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death; patients taking benzodiazepines and opioids concurrently may require lower doses of one or both medications, depending on their clinical situation. Patients with pre-existing impaired respiratory function are at increased risk of adverse effects including death during treatment with benzodiazepines. In addition, due to its CNS depressant effects, patients taking alprazolam should avoid operating heavy machinery or driving and should avoid other CNS depressants such as alcohol. As with other benzodiazepines, alprazolam carries a risk of abuse, misuse, and addiction, which is higher in predisposed individuals and may require strict monitoring. Cessation of therapy may result in acute or protracted withdrawal symptoms, which may be life-threatening; the patient dose should be gradually tapered whenever discontinuation or reduced dosage are necessary. Newborns born to mothers using alprazolam later in pregnancy may suffer from sedation and withdrawal symptoms. As CYP3A is required for the initial step in alprazolam metabolism, alprazolam is contraindicated in patients taking strong CYP3A inhibitors, such as ketoconazole and itraconazole; milder CYP3A inhibitors still necessitate alprazolam dosage adjustments. Lastly, benzodiazepines may have negative effects, such as panic disorders, increased suicide incidence, and episodes of mania/hypomania, in patients suffering from depression.

• Pharmacokinetics

Absorption

Alprazolam is Readily absorbed Its Bioavailability is 84-92% for immediate-release approximately and 90% for extended-release. Time is taken to reach peak plasma concentration and 1-2 hours for immediate-release, approximately 9 hours (extended-release), and 1.5-2 hours (orally disintegrating tab).

Distribution

Alprazolam is having Volume of distribution of about 0.84-1.42 L/kg (immediate-release). Alprazolam is ~80% protein-bound in serum.18,19 The majority of this protein binding is to serum albumin.

Metabolism and Excretion

Alprazolam is metabolized to fewer effective metabolites by various CYPs including CYP3A4, CYP3A5, CYP3A7, and CYP2C9.The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As.4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha- hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity. It is excreted mainly via urine, as unchanged drug.

• https://www.uptodate.com/contents/alprazolam-drug-information#F132002
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018276s055lbl.pdf
• https://reference.medscape.com/drug/xanax-niravam-alprazolam-342896#5
• https://medlineplus.gov/druginfo/meds/a684001.html
• https://www.drugs.com/alprazolam.html
• https://www.rxlist.com/alprazolam/generic-drug.htm#what_are_warnings_and_precautions_for_alprazolam_xanax
• https://go.drugbank.com/drugs/DB00404