Neuropax

Uses

Diazepam is used for the management of anxiety disorders or for the shortterm relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. In acute alcohol withdrawal, Diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.

Diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, and stiff-man syndrome.

Oral Diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.

The effectiveness of Diazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

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)

Neuropax is also used to associated treatment for these conditions: Alcohol Withdrawal Syndrome, Anxiety, Anxiety Disorders, Refractory Epilepsy, Intermittent distinct from a patient’s usual seizure pattern, stereotypic episode Epileptic seizure, Refractory seizure disorders, Skeletal muscle spasm, Sedation, Perioperative management therapyAkathisia 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 Neuropax works

Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties .

Benzodiazepines, such as diazepam, bind to receptors in various regions of the brain and spinal cord. This binding increases the inhibitory effects of gamma-aminobutyric acid (GABA) . GABAs functions include CNS involvement in sleep induction. Also involved in the control of hypnosis, memory, anxiety, epilepsy and neuronal excitability .

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

Neuropax dosage

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects.

ADULTS:

Management of Anxiety Disorders and Relief of Symptoms of Anxiety: Depending upon severity of symptoms 2 mg to 10 mg, 2 to 4 times daily

Symptomatic Relief in Acute Alcohol Withdrawal: 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed

Adjunctively for Relief of Skeletal Muscle Spasm: 2 mg to 10 mg, 3 or 4 times daily

Adjunctively in Convulsive Disorders: 2 mg to 10 mg, 2 to 4 times daily

Geriatric Patients, or in the presence of debilitating disease: 2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated

PEDIATRIC PATIENTS:

Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in pediatric patients under 6 months: 1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated

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

Drowsiness and light headedness the next day; confusion and ataxia (specially in the elderly); amnesia may occur; dependence; paradoxical increase in aggression; occasionally headache, vertigo, hypotension, gastrointestinal disturbances, visual disturbances, dysarthria, tremor, changes in libido, incontinence, urinary retention, blood disorders and jaundice reported.

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

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation . In most cases only observation of vital functions is required .

Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support) .

Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease . Severe effects in overdose also include rhabdomyolysis and hypothermia . Overdose of benzodiazepines in combination with other CNS depressants (including alcohol) may be fatal and should be closely monitored .

In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus . The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus . Patients should also be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physician about the desirability of discontinuing the drug .

Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonates . With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants) .

Diazepam passes into breast milk . Breastfeeding is therefore not recommended in patients receiving diazepam .

Safety and effectiveness in pediatric patients below the age of 6 months have not been established .

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated) . Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function . Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function .

Decreases in clearance and protein binding, and increases in volume of distribution and half-life has been reported in patients with cirrhosis . In such patients, a 2- to 5- fold increase in mean half-life has been reported . Delayed elimination has also been reported for the active metabolite desmethyldiazepam . Benzodiazepines are commonly implicated in hepatic encephalopathy . Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronic hepatitis .

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

Diazepam is not recommended for use in patients with depressive disorders or psychosis. Patients should be advised against the concurrent use of alcohol and other CNS depressant drugs. Patients with known or presumed dependence from alcohol or drugs should not take benzodiazepines.

Since Diazepam has a CNS depressant effect, patients should be warned against driving, operating dangerous machinery, or engaging in other hazardous activities requiring mental alertness and physical coordination.

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

Diazepam may potentiate or interact with the effects of other CNS acting drugs such as alcohol, narcotics, hypnotics, sedative antihistamines, antipsychotics, anxiolytics/ sedatives, anesthetics, antidepressants and anticonvulsants. Besides these diazepam may interact with phenytoin, cimetidine, levodopa, lithium.

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

In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg .

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

Elimination Route

After oral administration, it is considered that diazepam is rapidly and completely absorbed from the gastrointestinal tract as >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours .

Absorption is delayed and decreased when administered with a moderate fat meal . In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting . There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting . This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food .

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

Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principal active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration . The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease .

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 diazepam is 20 to 30 mL/min in young adults .

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

Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates .

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

Pregnancy & Breastfeeding use

Category D: The use of Diazepam during the first trimester of pregnancy should almost always be avoided as it bears a risk of congenital malformation.

Diazepam has been detected in breast milk. If possible the use of diazepam should be avoided during lactation.

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

Patients with known hypersensitivity to benzodiazepines, & myasthenia gravis are contraindicated to diazepam.

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

Symptoms: Somnolence, ataxia, confusion, dysarthria, little or no resp depression, hypotension, muscular weakness, deep coma, severe depression, diminished reflexes.

Management: Symptomatic and supportive treatment. Empty stomach by vomiting or gastric lavage. Activated charcoal may help reduce absorption. Flumazenil may be used for the complete or partial reversal of the sedative effects but there is a risk of seizure esp in long-term benzodiazepine users and in cyclic antidepressant 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 between 15-30°C. Protect from light. Inj: Avoid freezing.

Store in a cool dry place. Protect from light.

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