Impress A

Uses

• * Anxiety disorder
• * Short term relief of anxiety
• * Anxiety associated with depression
• * Panic disorder, with or without agoraphobia.

Depression: For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident.

Childhood Enuresis: May be useful as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older, after possible organic causes have been excluded by appropriate tests. In patients having daytime symptoms of frequency and urgency, examination should include voiding cystourethrography and cystoscopy, as necessary. The effectiveness of treatment may decrease with continued drug administration.

Impress A is also used to associated treatment for these conditions: Anxiety, Generalized Anxiety Disorder (GAD), Panic DisorderAttention Deficit Hyperactivity Disorder (ADHD), Bulimia Nervosa, Enuresis, Major Depressive Disorder (MDD), Neuropathic Pain, Panic Disorder, Post Traumatic Stress Disorder (PTSD)

How Impress A works

Alprazolam is a triazolobenzodiazepine used to treat certain anxiety and panic disorders. Alprazolam acts on benzodiazepine receptors BNZ-1 and BNZ-2. The active metabolites 4-hydroxyalprazolam acts on these receptors with 0.20 times the potency of alprazolam and alpha-hydroxyalprazolam acts on these receptors with 0.66 times the potency.

The effect of alprazolam on BNZ-1 mediates the sedation and anti-anxiety effects of the drug while the action on BNZ-2 mediates effects on memory, coordination, muscle relaxation, and anticonvulsive activity.

Alprazolam also couple with GABA-A receptors to enhance GABA binding to its receptor. This interaction mediates inhibition of the nervous system and results in a calming effect.

The molecular mechanisms as well as the clinical effects of alprazolam have both been well demonstrated, however the means by which the molecular mechanism translates to a clinical effect is still not understood.

Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin . It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin . Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression .

Dosage

Impress A dosage

Treatment should be initiated with a dose of 0.25 to 0.5 mg three times daily. Depending on the response, dose may

be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. The maximum dose should not

exceed 4 mg/day. Occasional patients with panic disorder may need as much as 10 mg a day to achieve a

successful response and in these cases periodic reassessment and consideration of dosage adjustment is required.

Dosage should be individualized for maximum beneficial effect with a lowest possible dose. If side-effects occur at

starting dose, dose may be lowered. When discontinuing therapy, dosage should be reduced gradually by no more

than 0.5 mg every three days.

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

daily and may be gradually increased if needed and tolerated. Safety and effectiveness of Alprazolam in individuals

below 18 years of age have not been established.

Alprazolam XR 1 should be administered once daily, preferably in the morning by patients who are on multiple dosage

regimen of Alprazolam 0.25/0.5 mg. The tablets should be taken intact, they should not be chewed, crushed, or broken.

Depression: Initially up to 75 mg daily in divided doses increased gradually to 150-200 mg (up to 300 mg in hospital); up to 150 mg may be given as a single dose at bed time; elderly, initially 10 mg daily, increased gradually to 30-50 mg daily; child not recommended for depression.

Panic attack: Initially 10-25 mg/day, depending on how the medication is tolerated, raise the dose until the desired response is obtained. The daily doses required vary greatly from patient to patient, between 75-150 mg, if necessary it can be increased to 200 mg.Nocturnal enuresis(Child):

• 7 years: 25 mg
• 8 to 11 years: 20-50 mg
• Over 11 years: 50-75 mg at bedtime; max. period of treatment (Including gradual withdrawal) is 3 months; full physical examination is required before further course.

Side Effects

Side effects, if occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. The most frequent side effects are drowsiness and light headedness. The other side effects, that may occur include depression, headache, confusion, dry mouth, constipation etc.

Dry mouth, less sedation, blurred vision (disturbances of accommodation, increased intraocular pressure), constipation, nausea, difficulty with micturation; cardiovascular side-effects, sweating, tremors, rashes and hypersensitivity reaction (including urticaria & photosensitivity), behavioral disturbances (particularly in children) hypomania or mania (particularly in elderly), interference with sexual function; blood sugar changes, increased appetite, weight gain (occasionally weight loss).

Toxicity

Alprazolam overdose can present as sleepiness, confusion, poor coordination, slow reflexes, coma, and death. Taking alprazolam with alcohol lowers the threshold for overdose. Patients should have their respiration, pulse, and blood pressure monitored. Patients can be treated by gastric lavage and intravenous fluids.. If hypotension occurs, patients may be treated with vasopressors. In known, or suspected overdoses, patients can be given the benzodiazepine receptor antagonist flumazenil in addition to other methods of management.

Oral LD50 in rats is 331-2171mg/kg.

Alprazolam is a pregnancy category D teratogen meaning there is evidence of risk to the fetus of a mother taking alprazolam but in some cases the benefit may outweigh the risk. Children born to these mothers are also at risk of withdrawal symptoms, flaccidity, and respiratory issues.

Benzodiazepines are expressed in human breast milk and so nursing is generally not recommended in mothers taking alprazolam.

Alprazolam is not associated with carcinogenicity, mutagenicity, or impairment of fertility.

The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract .

Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations.

Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue.

Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured.

Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention.

Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs.

LD₅₀/> Values

Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg

Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg

Human range of toxicity is considered to include single dosages greater than 5 mg/kg.

Precaution

Because Alprazolam may produce psychological and physical dependence, increment of dose or abrupt discontinuation of Alprazolam therapy should not be done without physician's advice. Duration of therapy must be determined by the physicians. Alprazolam should be administered with caution to patients with hepatic or renal disease, chronic pulmonary insufficiency or sleep apnea.

Cardiac diseases (particularly with arrhythmias), history with epilepsy, pregnancy and breast feeding, elderly, hepatic impairment (avoid if severe), thyroid disease, psychoses, angle-closure glaucoma, history of urinary retention, concurrent electro-convulsive therapy. Drowsiness may affect performances of skilled tasks (e.g. driving), alcohol induced Imipramine effect.

Interaction

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

Imipramine should not be used in combination with Monoamine oxidase inhibitors (MAO), anticholinergic agents, antihypertensive agents, methylphenidate, levodopa, antipsychotic drug, cimetidine, barbiturates, and oral contraceptives.

Volume of Distribution

Volume of distribution following oral administration is 0.8-1.3L/kg. Alprazolam crosses the blood-brain barrier.

Imipramine has a high apparent volume of distribution of 10-20 L/kg . The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation.

Elimination Route

Oral bioavailability of a standard release tablet of alprazolam is 84-91% with a time to maximum concentration of 1.8 hours. A 1mg oral dose of alprazolam leads to a maximum plasma concentration of 12-22mcg/L. Alprazolam is rapidly absorbed in the gastrointestinal tract.

Data for the area under the curve and the effect of taking alprazolam with food are not readily available.

Rapidly and well absorbed (>95%) after oral administration . The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food.

Half Life

11.2 hours in healthy patients. The half life is 16.3h in the elderly, 5.8-65.3h in patients with alcoholic liver disease, 9.9-40.4h in obese patients. The half life is 25% higher in Asian patients compared to Caucasians. Other studies have shown the half life to be 9-16h.

Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h .

Clearance

Oral clearance is 0.90±0.21mL/min/kg but this increases to 2.13±0.54mL/min/kg when given with CYP3A inducers. Other studies have demonstrated a clearance of 0.70-1.5mL/min/kg.

Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg .

Elimination Route

Alprazolam is mainly eliminated in the urine. A large portion of the dose is eliminated as unmetabolized alprazolam. 2

Imipramine is primarily excreted in the urine with less than 5% present as the parent compound

Pregnancy & Breastfeeding use

Pregnancy: Alprazolam has been categorized in pregnancy category D; that means, it should be avoided in pregnancy.

Lactation: Like other benzodiazepines, Alprazolam is assumed to be excreted in breast milk. Therefore, nursing should not be undertaken by mothers who must use Alprazolam.

Pregnancy category D. Limited data suggest that imipramine is likely to be excreted in human breast milk. Known risk of damage to fetus.

Contraindication

Contraindicated in patients with hypersensitivity to alprazolam or other benzodiazepines. Alprazolam is also contraindicated in patients with myasthenia gravis, acute narrow angle glaucoma, during pregnancy and also in infants.

Recent myocardial infarction, arrhythmias (particularly heart block), not indicated in manic phase, severe liver disease.

Special Warning

Use in Children: Safety and efficacy of Alprazolam in patients under the age of 18 years has not been established.

Acute Overdose

Manifestations of Alprazolam over dosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. In such cases of over dosage general supportive measures should be employed along with immediate gastric lavage.

Children have been reported to be more sensitive than adults to an acute overdosage of imipramine. An acute overdose in infants or young children must be considered serious and potentially fatal.

Storage Condition

Alprazolam tablets should be stored in a cool and dry place, protected from light and moisture.

Store in a cool & dry place, protected from light and moisture. Keep all medicines out of the reach of children.

Innovators Monograph

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