Polytab

Uses

Chlordiazepoxide is a benzodiazepine used to treat the withdrawal symptoms of acute alcoholism, to treat preoperative anxiety, and to treat anxiety over a short term period.

For the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety.

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.

Anxiety states: It controls excessive anxiety, tension, and agitation seen in neuroses or associated with somatic conditions. The treatment or prevention of nausea and vomiting of various causes. The management of psychotic disorders, such as acute or chronic catatonic, hebephrenic and paranoid schizophrenia; psychosis due to organic brain damage, toxic psychosis, and the manic phase of manic-depressive illness.

Trihexyphenidyl Hydrochloride is used for an adjunct treatment of all forms of parkinsonism (postencephalitic, arteriosclerotic & idiopathic). Additionally, it is used for the control of extrapyramidal disorders caused by central nervous system drugs such as dibenzoxazepines, phenothiazines, thioxanthenes & butyrophenones.

Polytab is also used to associated treatment for these conditions: Alcohol Withdrawal Syndrome, Anxiety, Anxiety Disorders, Depression, Peptic Ulcer Disease, Acute Anxiety, Pyschosomatic diseaseAttention Deficit Hyperactivity Disorder (ADHD), Bulimia Nervosa, Enuresis, Major Depressive Disorder (MDD), Neuropathic Pain, Panic Disorder, Post Traumatic Stress Disorder (PTSD)Agitation, Psychosis, Schizophrenia, Acute non-psychotic AnxietyExtrapyramidal disorder, Extrapyramidal symptoms caused by butyrophenones, Extrapyramidal symptoms caused by dibenzoxazepines, Extrapyramidal symptoms caused by phenothiazines, Extrapyramidal symptoms caused by thioxanthenes, Idiopathic Parkinson's Disease, Parkinsonism post encephalitic, Arteriosclerotic Parkinsonism

How Polytab works

Chlordiazepoxide binds to stereospecific benzodiazepine (BZD) binding sites on GABA (A) receptor complexes at several sites within the central nervous system, including the limbic system and reticular formation. This results in an increased binding of the inhibitory neurotransmitter GABA to the GABA(A) receptor. BZDs, therefore, enhance GABA-mediated chloride influx through GABA receptor channels, causing membrane hyperpolarization. The net neuro-inhibitory effects result in the observed sedative, hypnotic, anxiolytic, and muscle relaxant properties.

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 .

Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

Trihexyphenidyl is a non-selective muscarinic acetylcholine receptor antagonist but binds with higher affinity to the M1 subtype. In vivo studies have shown that trihexyphenidyl demonstrates higher affinity for central muscarinic receptors located in the cerebral cortex and lower affinity for those located peripherally. Other studies suggest that trihexyphenidyl may modify nicotinic acetylcholine receptor neurotransmission, leading indirectly to enhanced dopamine release in the striatum. Although the anticholinergic has proven to be useful in the treatment of symptoms associated with Parkinson’s disease or other movement disorders, its mechanism of action has yet to be fully elucidated.

Dosage

Polytab dosage

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.

Schizophrenia and other psychoses:

• Adults and child over 12 years: Recommended starting dose is 2-5 mg b.i.d, increased by 5 mg daily after 1 week then at interval of 3 days, according to response.
• Children (6-12 years): Dosage should be adjusted to the weight of the child and severity of the symptoms. The starting dosage is 1 mg b.i.d. Dosage may be increased gradually until symptoms are controlled or until side effects become troublesome. While it is usually not necessary to exceed dosages of 15 mg daily.
• Elderly: Reduce initial dose by at least half

Short-term management of severe anxiety:

• Adult and child over 12 years: 1-2 mg b.i.d, increased if necessary to 6 mg daily.
• Child (3-5 years): 1 mg daily
• Child (6-12 years): Up to 4 mg daily in divided dose.
• Elderly: Reduce initial dose by at least half

Antiemetic:

• Adult: 2-4 mg daily in divided doses; max. 6 mg daily;
• Child 3-5 years: up to 1 mg daily, 6-12 years up to 4 mg daily.

Dosage should be individualized. The initial dose should be low and then increased gradually, especially in patients over 60 years of age. Whether Trihexyphenidyl may best be given before or after meals should be determined by the way the patient reacts.

Idiopathic Parkinsonism: 1 mg of Trihexyphenidylmay be administered the first day. The dose may then be increased by 2 mg increments at intervals of three to five days.

Drug-Induced Parkinsonism: Commence therapy with a single 1 mg dose increase the total daily dosage to 5-15 mg range if the extrapyramidal manifestations are not controlled.

Concomitant Use with Levodopa: When Trihexyphenidyl is used concomitantly with levodopa, the usual dose is 3-6 mg daily.

Side Effects

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).

Common side effects are transient restlessness, dystonias or may resemble parkinsonism. Other CNS Reactions are drowsiness, dizziness, fatigue, blurred vision, seizures. Without these Peripheral oedema, blood dyscrasias, jaundice may occasionally occur. Tachycardia, constipation, urinary hesitancy and retention and hyperpyrexia have been reported very rarely.

Minor side effects such as dryness of the mouth, blurring of vision, dizziness, mild nausea or nervousness. Patients with arteriosclerosis or with a history of idiosyncrasy to other drugs may exhibit reactions of mental confusion, agitation, disturbed behavior, or nausea and vomiting. Potential side effects are constipation, drowsiness, urinary hesitancy or retention, pupil dilation, increased intraocular tension, vomiting and headache.

Toxicity

LD₅₀=537 mg/kg (Orally in rats). Signs of overdose include respiratory depression, muscle weakness, somnolence (general depressed activity).

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.

Symptoms of overdose include agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and restlessness.

Symptoms of overdose include mydriasis, dryness of mucous membranes, red face, atonic states of bowels and bladder, and hyperthermia in high doses. Trihexyphenidyl causes agitation, confusion, and hallucinations due to its effects on the central nervous system. Untreated overdose may result in death, especially in children. Respiratory depression and cardiac arrest may be seen as premortal signs.

Patients experiencing an overdose of trihexyphenidyl may experience dry mouth, anhidrosis, mydriasis, nausea, vomiting, tachycardia, hyperpyrexia, reduced gastrointestinal motility, urinary hesitancy or retention, rash, hyperthermia, confusion, restlessness, agitation, poor coordination, paranoia, psychosis, delirium, hallucinations, coma, respiratory failure, circulatory failure, and death. Patients should be treated with symptomatic and supportive care which may include airway maintenance and the use of physostigmine.

Precaution

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.

Care should be taken when treating elderly patients, and initial dosage should be reduced. Such patients can be specially sensitive, particularly to extra pyramidal and hypotensive effects. Patients with cardiovascular disease including arrhythmias should also be treated with caution. Care should be taken in patients with angina pectoris.

Patients with cardiac, liver, or kidney disorders, or with hypertensioon, should closely be monitored. Since trihexyphenidyl has parasympatholytic activity, it should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Trihexyphenidyl is not recommended for use in patients with tardive dyskinesia unless they have concomitant Parkinson’s disease. Abrupt withdrawal of treatment for parkinsonism may result in acute exacerbation of parkinsonism symptoms; therefore, abrupt withdrawal should be avoided.

Interaction

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.

Trifluoperazine may diminish the effect of oral anticoagulants. Concomitant administration of propranolol with trifluoperazine results in increased plasma levels of both drugs. Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concurrently. Potentiation may occur if antipsychotic drugs are combined with CNS depressants such as alcohol. hypnotics and anticonvulsant.

Cannabinoids, barbiturates, opiates, and alcohol may have additive effects with trihexyphenidyl, and thus, an abuse potential exists. Concurrent use of alcohol or other CNS depressants with trihexyphenidyl may cause increased sedative effects. It may be contraindicated in patients taking monoamine oxidase inhibitors & tricycllic antidepressants.

Volume of Distribution

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

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.

Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a C_max of 7.2 ng/mL, with a T_max of 1.3 hours, and an AUC of 201 ng*h/mL.

Half Life

24-48 hours

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

10-20 hours

The mean elimination half life of trihexyphenidyl is 3.2 ± 0.3 hours.

Clearance

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

Chlordiazepoxide is excreted in the urine, with 1% to 2% unchanged and 3% to 6% as conjugate.

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

Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine.

Pregnancy & Breastfeeding use

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

Pregnancy: Safety for the use of trifluoperazine during pregnancy has not been established. Therefore, it is not recommended that the drug be given to pregnant patients except when, in the judgement of the physician, it is essential. The potential benefits should clearly outweigh possible hazards. There are reported instances of prolonged jaundices, extrapyramidal signs, hyperreflexia or hypoflexia in newborn infants whose mother received phenothiazines.

Lactation: Adequate human data are not available in case of lactation.

Pregnancy Category C. It is not known whether the drug is excreted in human milk and therefore trihexyphenidyl should only be used if the expected benefit to the mother outweighs the potential risk to the infant.

Contraindication

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

Do not use Trifluoperazine in comatose patients, or in those with existing blood dyscrasias or known liver damage, or in those hypersensitive to the active ingredient or related compounds.

Trihexyphenidyl is contraindicated in patients with hypersensitivity in patients to trihexyphenidyl HCl or to any of the tablet or elixir ingredients. Trihexyphenidyl is also contraindicated in patients with narrow angle glaucoma. Blindness after long-term use due to narrow angle glaucoma has been reported.

Acute Overdose

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.

Signs and symptoms will be predominantly extrapyramidal; hypotension may occur. Treatment consists of gastric lavage together with supportive and symptomatic measures. Do not induce vomiting. Extra pyramidal symptoms may be treated with an anticholinergic, antiparkinsonism drug. Treat hypotension with fluid replacement; if severe or persistent. nor adrenaline may be considered. Adrenaline is contraindicated.

Overdosage with trihexyphenidyl produces typical central symptoms of atropine intoxication ( the central anticholinergic syndrome). Signs & symptoms are: dilated and sluggish pupils, warm, dry skin, facial flushing, decreased secretions of mouth, pharynx, nose and bronchi, foul smelling breath, tachycardia etc. Neuropsychiatric signs such as delirium, disorientation, anxiety, hallucinations etc. The condition can progress to stupor, coma, paralysis, cardiac, respiratory arrest and death.

Storage Condition

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

It should be store at room temperature between 15-30° C away from light and moisture.

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