Ezolent Beta

Uses

Etizolam is a thienodiazepine derivative used to treat anxiety and insomnia.

Indicated for the treatment of generalized anxiety disorder with depression, panic disorder and insomnia.

Propranolol is used for:

• essential and renal hypertension
• angina pectoris
• long term prophylaxis after recovery from acyte myocardial infarction
• cardiac dysrhythmia
• prophylaxis of migraine
• essential tremor
• anxiety and anxiety tachycardia
• adjunctive management of thyrotoxicosis and thyrotoxic crisis
• hypertrophic obstructive cardiomyopathy
• phaeochromocytoma (with α-blocker)

Ezolent Beta is also used to associated treatment for these conditions: Anxiety, InsomniaAkathisia caused by antipsychotic use, Angina Pectoris, Atrial Fibrillation, Cardiovascular Mortality, Gastroesophageal variceal hemorrhage prophylaxis, Hemangiomas, High Blood Pressure (Hypertension), Migraine, Myocardial Infarction, Obstructive Hypertrophic Cardiomyopathy, Performance Anxiety, Pheochromocytomas, Proliferating Infantile Hemangioma, Supraventricular Arrhythmias, Tachyarrhythmia caused by Digitalis intoxication, Tachyarrhythmia caused by catecholamine excess, Thyroid Crisis, Thyrotoxicosis, Tremor caused by lithium, Tremor, Essential, Ventricular Tachycardia (VT)

How Ezolent Beta works

Etizolam is selectively a full agonist at GABA-A receptors to increase GABAergic transmission and enhance GABA-induced Cl- currents . It is reported to bind to the benzodiazepine binding site which is located across the interface between the alpha and gamma subunits. Benzodiazapines are reported to only bind to receptors that contain gamma 2 and alpha 1/2/3/5 subunits . Alpha-1-containing receptors mediate the sedative effects of etizolam whereas alpha-2 and alpha-3 subunit-containing receptors mediate the anxiolytic effect . Etizolam shows high potency and affinity towards GABA-A receptor with alpha 1 beta 2 gamma 2S subunit combination . By binding to the regulatory site of the receptor, etizolam potentiates GABA transmission by facilitating the opening of GABA-induced chloride channels . Etizolam is a specific antagonist at PAFR. It inhibits PAF-induced platelet aggregation by inhibiting PAF binding to the receptors located on the surface of platelets with an IC50 of 22nM .

Propranolol is a nonselective β-adrenergic receptor antagonist. Blocking of these receptors leads to vasoconstriction, inhibition of angiogenic factors like vascular endothelial growth factor (VEGF) and basic growth factor of fibroblasts (bFGF), induction of apoptosis of endothelial cells, as well as down regulation of the renin-angiotensin-aldosterone system.

Dosage

Ezolent Beta dosage

Tablet:

Adults:

• Hypertension: A starting dose of 80 mg twice a day may increased at weekly intervals according to response. The usual dose range is 160-320 mg per day. With concurrent diuretic or other antihypertensive drugs a further reduction of blood pressure is obtained.
• Angina, anxiety, migraine and essential tremor: A staring dose of 40 mg two or three times daily may be increased by the same amount at weekly intervals according to patients response. An adequate response in anxiety, migraine and essential tremor is usually seen in the range 80-160 mg/day and an angina in the range 120-240 mg/day.
• Situational and generalized anxiety: A dose of 40 mg daily may provide short term relief of acute situational anxiety. Generalized anxiety require long term therapy, usually responds adequately to 40 mg twice daily which ,which individual cases, may be increased to 40 mgthree times daily. Treatment should be continued according to responses. Patients should reviewed after 6 to 12 months treatment.
• Dysrhythmias, anxiety tachycardia, hypertrophic obstructive cardiomyopathy and thyrotoxicosis: A dosage range of 10-40 mg three or four times a day usually achieves the required response.
• Post myocardial infarction: Treatment should be started between days 5 and after 21 after myocardial infarction, with an initial dose of 40 mg four times a day for 2 or 3 days. In order to improve compliance the total daily doses three after be given as 80 mg twice a day. Phaeochromocytoma (Used only with an alpha receptor blocking drug).
• Pre-operative: 60 mg daily for three days.
• Non-operable malignant cases: 30 mg daily.
• Migraine: Under 12 years: 20 mg two or three times daily.Over 12 years : The adult dose.

Children:

• Sysrhythmias, Phaeochromocytoma, Thyrotoxicisis: Dosage should be individually determined and the following is only a guide 0.25-0.5 mg/kg three or four times daily as required.

Sustained Release Capsule:

Adult:

• Hypertension: The usual initial dose is 80mg Propranolol SR once daily, whether used alone or added to a diuretic. The usual maintenance dosage is 120 to 160 mg once daily.
• Angina pectoris: Starting with 80mg Propranolol SR once daily, dosage should be gradually increased three to seven day intervals until optimum response is obtained.
• Migraine: The initial oral dose is 80 mg Propranolol SR once daily. T he usual effective dose range is 160 to 240 mg once daily. It may be advisable to withdraw the drug gradually over a period of several weeks.
• Hypertrophic subaortic stenosis: 80 mg Propranolol SR once daily

Injection:

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The usual dose is 1 to 3 mg administered under careful monitoring, such as electrocardiography and central venous pressure. The rate of administration should not exceed 1 mg (1 mL) per minute to diminish the possibility of loweringblood pressureand causing cardiac standstill.

Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present. If necessary, a second dose may be given after two minutes. Thereafter, additional drug should not be given in less than four hours. Additional propranolol hydrochloride should not be given when the desired alteration in rate or rhythm is achieved.

Transfer to oral therapy as soon as possible.

Side Effects

Propranolol is usually well tolerated. Minor side effects such as cold extremities, nausea, diarrhea, sleep disturbances and lassitude are often transient. There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs.

Toxicity

Major adverse effects include drowsiness, sedation, muscle weakness and incoordination, fainting, headache, confusion, depression, slurred speech, visual disturbances and changes in libido and tremor . Flumazenil is a competitive antagonist of GABA-A receptors and can be also used to reverse the effect of etizolam overdosage. Etizolam demonstrates no effects on fertility, development and teratogenicity . LD50 values of etizolam when delivered orally, intraperitoneally, and subcutaneously are 3509mg/kg, 825mg/kg, and >5000mg/kg in rats, respectively, and 3070mg/kg, 783mg/kg and 5000mg/kg in mice, respectively .

Symptoms of overdose include hypotension, hypoglycemic seizure, restlessness, euphoria, insomnia. Patients with asthma may develop bronchospasm. In case of overdose, monitor vital signs, mental status, and blood glucose. Treat hypotension with intravenous fluids, bradycardia with atropine, and isoproterenol and aminophylline for bronchospasm. If patients do not respond to intravenous fluids, follow up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour, followed by catecholamines. Dialysis will not be useful as propranolol is highly protein bound.

Precaution

Beta-adrenoceptor blocking drugs should be avoided in over heart failure. Propranolol modifies the tachycardia of hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.

Interaction

Beta-adrenoceptor blocking drugs interact with clonidine.If beta-adrenoceptor blocking drugs and clonidine are given concurrently, clonidine should be discontinued until several days after withdrawal of beta-adrenoceptor blocking drug. Care should be taken in prescribing a beta-adrenoceptor blocking drugs with class 1 antidysrhythmic agents (disopyramide).Beta-adrenoceptor blocking drugs should be used with caution in combination with verapamil in patients with impaired ventricular function.

Volume of Distribution

Apparent distribution volume was 0.9 ± 0.2 L/kg following a single oral doing of 0.5mg etizolam .

The volume of distribution of propranolol is approximately 4L/kg or 320L.

Elimination Route

Etizolam is well absorbed from the intestines with a biological bioavailability of 93% following oral administration. After a single oral dosing of 0.5mg etizolam, it takes approximately 0.9 hours to reach the peak plasma concentration of 8.3 ng/mL .

Patients taking doses of 40mg, 80mg, 160mg, and 320mg daily experienced C_max values of 18±15ng/mL, 52±51ng/mL, 121±98ng/mL, and 245±110ng/mL respectively. Propranolol has a T_max of approximately 2 hours, though this can range from 1 to 4 hours in fasting patients. Taking propranolol with food does not increase T_max but does increase bioavailability.

Half Life

The average elimination half life of etizolam following a single oral dose of 0.5mg is 3.4 hours but may be increased up to 17 hours depending on the rate of metabolism . The main metabolite α-hydroxyetizolam displays a longer elimination half life of 8.2 hours .

The elimination half life of propranolol is approximately 8 hours. The plasma half life of propranolol is 3 to 6 hours.

Clearance

The clearance of propranolol is 2.7±0.03L/h/kg in infants 90 days. Propranolol clearance increases linearly with hepatic blood flow. Propanolol has a clearance in hypertensive adults of 810mL/min.

Elimination Route

In a rat study, the amounts of etizolam excreted was 30% in urine was 70% in feces, while the values in a mouse study were 40% in urine and 60% in feces .

91% of an oral dose of propranolol is recovered as 12 metabolites in the urine.

Pregnancy & Breastfeeding use

There are no adequate and controlled studies in pregnant women. Propranolol is excreted in human milk. Caution should be exercised when propranolol is administered to a nursing mother.

Contraindication

Propranolol Hydrochloride is contraindicated in patients with known Hypersensitivity to any component of the formulation. If there is a history of bronchial asthma of bronchospasm.

Acute Overdose

The symptoms of over dosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm. Treatment of over dosage include close supervision, treatment in an intensive care ward, he use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Storage Condition

Store in a cool dry place. Protect from light.

Innovators Monograph

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