ZOLARAM 0.5MG TABLETS

Indications

• Anxiety disorders
• Panic disorders
• Short-term relief of anxiety symptoms

Dosage

Adults: For anxiety, adults typically start with 10 mg taken 3 times

Mechanism of action

Alprazolam enhances the inhibitory effect of γ-aminobutyric acid (GABA) at GABA type-A receptors (GABA_ARs), which are crucial for mediating phasic and tonic inhibition of neurotransmission in the brain. By binding to specific sites on these receptors, alprazolam increases the frequency of chloride ion channel opening, leading to hyperpolarization of neurons and resulting in a calming effect.

Pharmacodynamics

Alprazolam exhibits anxiolytic, sedative, muscle relaxant, anticonvulsant, and amnesic properties due to its action on GABA_A receptors. The drug is effective in reducing anxiety and panic attacks but carries a risk of respiratory depression, especially when combined with other CNS depressants such as opioids. Patients with compromised respiratory function are at a heightened risk of severe adverse effects, including fatality. The potential for abuse and dependence necessitates careful patient monitoring and appropriate tapering upon discontinuation.

Pharmacokinetics

Alprazolam is well absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-2 hours after oral administration. It has a half-life of approximately 6-12 hours, allowing for once or twice daily dosing in most cases. The drug is extensively metabolized in the liver, with a significant portion undergoing conversion to active metabolites. Renal and hepatic impairment can alter the pharmacokinetics of alprazolam, necessitating dose adjustments. The drug is excreted primarily in urine, mostly in the form of metabolites.

Contra-indications

• Chronic psychosis
• Respiratory depression

Adverse effects

• Menstruation irregularities
• Urinary incontinence
• Decreased alertness
• Anxiety
• Ataxia
• Confusion
• Depression
• Dizziness
• Drowsiness
• Hyperprolactinaemia
• Peripheral oedema
• Dysarthria
• Fatigue
• Headache
• Hypotension
• Mood alterations
• Photosensitivity reactions
• Psychosis
• Suicidal thoughts
• Muscle weakness
• Nausea
• Respiratory depression
• Abnormal behaviour
• Hallucinations
• Libido disorder
• Rash
• Aggression
• Delusions
• Jaundice
• Restlessness
• Urinary retention

Interactions

• Clarithromycin (severe - increases exposure)
• Miconazole (moderate - increases exposure)
• Mitotane (moderate - decreases exposure)
• Monoclonal antibodies (moderate - decreases exposure)
• Tocilizumab (moderate - decreases exposure)
• Rifampicin (moderate - decreases exposure)
• Fluvoxamine (moderate - increases exposure)
• Dronedarone (unknown - increases exposure)
• Antifungals, azoles (unknown - increases exposure)
• Cobicistat (unknown - increases exposure)

Precautions

• Risk of dependence
• Caution in elderly patients
• Caution in patients with hepatic impairment
• Caution in patients with renal impairment
• Avoid use with other CNS depressants
• Gradual tapering recommended upon discontinuation
• Monitor for withdrawal symptoms

Pregnancy

Risk of neonatal withdrawal symptoms if used during pregnancy; avoid regular use, and use only if clearly indicated such as for seizure control.

Breast-feeding

Benzodiazepines are present in breast milk; should be avoided if possible during breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight. Keep out

Mechanism of action

Neurotransmission relies on excitatory and inhibitory signalling. γ-aminobutyric acid (GABA) type-A receptors (GABA_ARs) are members of the pentameric ligand-gated ion channel (PLGIC) superfamily located synaptically and perisynaptically to mediate phasic inhibition and extrasynaptically to mediate tonic inhibition. GABA_ARs comprise a variety of subunits from a homologous family whose members are named based on sequence identity as one of α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3. Each subunit possesses an extracellular (ECD), transmembrane (TMD), and intracellular (ICD) domain; inter-subunit interfaces are the primary points of neurotransmitter and modulator binding, described by coordination of the principal (+) and complementary (-) sites in each subunit. Binding of GABA to GABA_ARs induces pore opening, rapid flow of chloride ions, and synaptic hyperpolarization, which in turn manifests as an inhibitory signal. The most prevalent GABA_ARs _in vivo_ are the α1β2γ2 receptors, which contain both GABA (β+/α-) and benzodiazepine (BZD, α+/γ-) binding sites in the intersubunit interfaces of the relevant subunits. In general, any receptors containing an α_x/γ_z interface, where x = 1-3,5 and z = 1-3, have potential high-affinity BZD binding sites, although small sequence differences between subunits may alter binding affinity to individual molecules. The α4 and α6 subunits, in which an otherwise conserved histidine is replaced by arginine, do not bind traditional BZD ligands such as diazepam and hence are considered "diazepam-insensitive". GABA binding results in a series of conformational changes in the ECDs of GABA_AR β subunits, "locking" each to its neighbouring α- interface. The binding of alprazolam in the high-affinity BZD site stabilizes the α+/γ- interface and facilitates the conformational changes that lead to pore opening, hence functioning as a positive allosteric modulator. The exact manner in which GABA_AR allosteric modulation mediates the therapeutic and unwanted effects of benzodiazepines remains unclear. Earlier studies suggested that the primary factor was the α subunit composition, with α1-containing receptors mediating the sedative effects, α2/3-containing receptors the anxiolytic effects, and α5-containing receptors the memory effects of benzodiazepines. More recent studies suggest a more complex set of factors including subunit composition, physiological location, neuronal circuit, and nerve cell type. To further complicate matters, there may be up to five distinct BZD binding sites on GABA_ARs, with site 1 corresponding to the classical high-affinity α+/γ- interface. The effects of binding at sites 2-4 are not fully understood and likely impart greater complexity to benzodiazepine pharmacological action. In animals, benzodiazepines protect against seizures induced by electrical stimulation and by pentylenetetrazol; benzodiazepines appear to act, at least partly, by augmenting presynaptic inhibition. The drugs suppress the spread of seizure activity but do not abolish the abnormal discharge from a focus in experimental models of epilepsy. In usual doses, benzodiazepines appear to have very little effect on the autonomic nervous system, respiration, or the cardiovascular system. /Benzodiazepines/ CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis. Anxiolytic and possibly paradoxical CNS stimulatory effects of benzodiazepines are postulated to result from release of previously suppressed responses (disinhibition). After usual doses of benzodiazepines for several days, the drugs cause a moderate decrease in rapid

Pharmacodynamics

Alprazolam is a benzodiazepine that binds γ-aminobutyric acid (GABA) type-A receptors (GABA_ARs) 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.