Tryp C

Uses

Depression with Anxiety, agitation or tension.

Tryp C is also used to associated treatment for these conditions: Acute Depression, Anorexia Nervosa (AN), Attention Deficit Hyperactivity Disorder (ADHD), Bulimia Nervosa, Depression, Diabetic Neuropathies, Insomnia, Irritable Bowel Syndrome (IBS), Major Depressive Disorder (MDD), Migraine, Moderate Depression, Neuropathic Pain, Nocturnal Enuresis, Severe Depression, Sleep disorders and disturbances, Tension Headache, Moderate Agitation, Moderate Anxiety, Severe Anxiety, Severe agitationAlcohol Withdrawal Syndrome, Anxiety, Anxiety Disorders, Depression, Peptic Ulcer Disease, Acute Anxiety, Pyschosomatic disease

How Tryp C works

The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain , . These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects . This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms.

Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown .

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.

Dosage

Tryp C dosage

1 tablet (5 mg chlordiazepoxide and 12.5 mg amitriptyline) three to four times daily; may increase to 6 tablets if necessary

Side Effects

Drowsiness, Dry mouth, Constipation, Blurred vision, Dizziness, Bloating, Vivid dreams, Impotence, Tremor, Confusion, Nasal congestion, Edema, Syncope, Ataxia, EEG abnormalities, Menstrual irregularities, Blood dyscrasias (agranulocytosis), Hepatic dysfunction (jaundice).

Toxicity

Toxicity Data: Oral TDLO (child): 4167 μg/kg; Oral TDLO (man): 714 μg/kg/1D (intermittent); Oral TDLO (woman): 10 mg/kg .

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose are further increased by simultaneous ingestion of alcohol and another psychotropic agent . Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma, among others , .

Use in pregnancy

For amitriptyline, only limited clinical data are available regarding its use in pregnancy. Amitriptyline is not recommended during pregnancy unless clearly required and only after careful consideration of both risks and benefits .

Use in breastfeeding

Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % - 1 % of the maternal dose). A risk to the suckling child must be considered. A decision should be made as to whether it is appropriate to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product, considering the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Effects on fertility

Animal studies have shown reproductive toxicity. No data on the effects of amitriptyline on human fertility are available .

Mutagenesis and carcinogenesis

The genotoxic potential of amitriptyline has been investigated in various in vitro and in vivo studies. Although these investigations showed some contradictory results, a potential of amitriptyline to lead to chromosome abnormalities cannot be excluded. Long-term carcinogenicity studies have not been performed to this date .

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

Precaution

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (age <24 yr) taking antidepressants for major depressive disorders and other psychiatric illnesses.

Caution in BPH, urinary/GI retention, increased IOP, thyroid dysfunction, open-angle glaucoma, seizure disorders, brain tumor, respiratory impairment, respiratory disease. Risk of anticholinergic side-effects. May cause orthostatic hypotension. Paradoxical reactions including hyperactive or aggressive behavior reported.

Both agents may cause sedation and impair ability to perform tasks requiring mental alertness. Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; monitor during the initial 1 -2 months of therapy and dosage adjustments.

Not approved for treatment of dementia-related psychosis.

Interaction

Monoamine oxidase inhibitors can potentiate the effects of Amitriptyline.

Anticholinergic agents: Amitriptylin should not be given with symptomatic agents such as adrenaline, epinephrine, isoprenaline, noradrenaline.

CNS depressant: Amitriptyline may enhance the response to alcohol, barbiturates.

Cemitidine: Cemitidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.

Volume of Distribution

The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg) . It is found widely distributed throughout the body . Amitriptyline and the main metabolite nortriptyline pass across the placental barrier and small amounts are present in breast milk .

Elimination Route

Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration . Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences .

Half Life

The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours) .

24-48 hours

Clearance

The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h) . No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased .

Elimination Route

Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine . 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours . Small amounts are excreted in feces via biliary elimination .

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

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Lactation: Excretion in milk unknown; not recommended

Contraindication

Hypersensitivity. Severe cardiovascular disorders, Angle clossure glaucoma, Within 14 days of MAOIs, Any drugs or conditions that prolong QT interval, Acute recovery post-MI.

Storage Condition

Keep containers well closed and stored below 25˚ C, protected from light.

Innovators Monograph

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