Ketriplin

Uses

Amitriptyline is used for depressive illness, particularly with anxiety and nocturnal enuresis in children.

Ketamine is recommended for:

• As the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Ketamine is best suited for short procedures and it can be used with additional doses, for longer procedures.
• For the induction of anesthesia prior to the administration of other general anesthetic agents.
• To supplement low-potency agents, such as nitrous oxide.

Ketriplin 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 agitationGeneral Anesthesia, Induction and Maintenance of General Anesthesia

How Ketriplin 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 .

Ketamine interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors.

Dosage

Ketriplin dosage

Depression :

• Adults: Initially 50-70 mg a day in divided dose or as a single dose at night at bed time.
• Elderly and adolescents: 25-50 mg daily in divided doses or as single dose at bed time. Dose can be increased gradually as necessary to a maximum of 150-200 mg. Usual maintenance dose is 50-100 mg daily.

Nocturnal enuresis:

• 6-10 years: 10-20 mg at bed time.
• 11-16 years: 25-50 mg at bed time for up to 3 months and gradually withdrawn.

Adult:General Anesthesia-

• IV Induction: 1-4.5 mg/kg single dose
• IM Induction: 6.5-13mg
• IV Infusion: 1-2mg/kg at 0.5mg/kg/min

Maintenance:

The maintenance dose should be adjusted according to the patient's anesthetic needs and whether an additional anesthetic is employed. Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia.Rapid sequence Intubation, Induction - 2mg/kg IV

Pediatric:

General Anesthesia:

• IV Induction: 1-2 mg/kg IV; range: 4-13 mg/kg
• IM Induction: 5-10 mg/kg; range: 0.5-4.5 mg/kg
• Maintenance: 0.01-0.03 mg/kg/min continuous IV infusion

Maintenance:

The maintenance dose should be adjusted according to the patient's anesthetic needs and whether an additional anesthetic is employed. Increments of one-half to the full induction dose may be repeated as needed for maintenance of anesthesia.

Rate of Administration: It is recommended that ketamine should be administered slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.

The 100 mg/ml concentration of ketamine should not be injected intravenously without proper dilution. It is recommended the drug be diluted with an equal volume of either Sterile Water for Injection, USP, Normal Saline, or 5% Dextrose in Water.

Reconstitutions

To prepare a dilute solution containing 1 mg of ketamine per ml, aseptically transfer 10 ml (50 mg per ml vial) to 500 ml of Dextrose Injection, 5% or Sodium Chloride Injection, 0.9% and mix well. The resultant solution will contain 1 mg of ketamine per ml.

Side Effects

• Cardiovascular reactions: Hypotension, syncope, postural hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrythmias, and heart block stroke.
• CNS and neuromuscular: Confusional states, disturbed concentration disorientation, delusions, and hallucinations.
• Anticholinergic: Dry mouth, blurred vision, mydriasis, increased intraoccular pressure, hyperplasia.
• Allergic: Skin rash, urticaria, and photosensitization.
• Haematological: Bone-marrow depression including agranulocytosis, leukopenia, eosinophilia, and thrombocytopenia.
• Gastrointestinal: Nausea, epigastric distress, vomiting anorexia, diarrhoea.
• Endocrine: Testicular swelling, gynaecomastia; breast enlargement, galactorrhoea.
• Other reaction: Dizziness, weakness, fatigue, headache, weight loss

Emergence reactions (e.g. vivid dreams, hallucinations, confusion, irrational behaviour); increased muscle tone sometimes resembling seizures; temporary HTN and tachycardia, hypotension, bradycardia, arrhythmias, apnoea, laryngospasm, resp depression, diplopia, nystagmus, nausea, vomiting, lacrimation, hypersalivation, raised intraocular and CSF pressure, transient rash and pain at inj site, cystitis.

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 .

Preclinical studies related to the blocking of NMDA receptors have shown an increase in apoptosis in the developing brain which results in cognitive deficits when used for longer than 3 hours. Toxicity studies regarding carcinogenesis have not been performed. Regarding mutagenesis and fertility, ketamine showed to be clastogenic and to not have effects on fertility.

Precaution

Schizophrenic patients may develop increased symptoms of psychosis; patients with paranoid symptomatology may have an exaggeration of such symptoms. Depressed patients, particularly those with known manic-depressive illness, may experience a shift to mania or hypomania. In these circumstances the dose of Amitriptyline may be reduced or a major tranquilizer such as perphenazine may be administered concurrently.

The possibility of suicide in depressed patients remains until significant remission occurs. Potentially suicidal patients should not have access to large quantities of this drug. Prescriptions should be written for the smallest amount feasible.

Concurrent administration of Amitriptyline hydrochloride and electroshock therapy may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential.

When possible, the drug should be discontinued several days before elective surgery. Both elevation and lowering of blood sugar levels have been reported. Amitriptyline hydrochloride should be used with caution in patients with impaired liver function.

Patient with cardiac decompensation, chronic alcoholic or acutely alcohol-intoxicated patients, pre-anaesth elevated CSF pressure, globe injuries, increased intraocular pressure (e.g. glaucoma), neurotic traits or psychiatric illness (e.g. schizophrenia, acute psychosis), acute intermittent porphyria, seizures, hyperthyroidism, pulmonary or upper resp infection, intracranial mass lesions, head injury, or hydrocephalus, hypovolaemia, dehydration, cardiac disease esp coronary artery disease (e.g. CHF, myocardial ischaemia, MI). Pregnancy and lactation.

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.

Prolonged recovery time with barbiturates or narcotics. May potentiate neuromuscular blocking effects of atracurium and tubocurarine including resp depression with apnoea. May increase risk of bradycardia, hypotension or decreased cardiac output with halogenated anaesthetics. May potentiate CNS depression and risk of resp depression with CNS depressants (e.g. phenothiazines, sedating H1-blockers, skeletal muscle relaxants). May antagonise hypnotic effect of thiopental. May increase risk of HTN with thyroid hormones. May increase risk of hypotension with antihypertensive agents. Reduction in seizure threshold resulting in unpredictable extensor-type seizures when given concurrently with theophylline.

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 .

The apparent volume of distribution of the central compartment and at steady-state are 371.3 ml/kg and 4060.3 ml/kg, respectively.

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 .

Ketamine absorption is very rapid and the bioavailability is around 93%. After the first pass metabolism, only 17% of the administered dose is absorbed. It distributes very rapidly and presents a distribution half-life of 1.95 min. The Cmax levels at peak reach 0.75 mcg/ml in plasma and 0.2 mcg/ml in cerebrospinal fluid.

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) .

The reported half-life in preclinical studies for ketamine is 186 min.

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 .

The clearance rate of ketamine is high and of around 95 L/h/70kg.

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 .

Pharmacokinetic studies have resulted in the recovery of 85-95% of the administered dose in urine mainly in the form of metabolites. Some other routes of elimination of ketamine are bile and feces. When administered intravenously the resultant recovery is distributed by 91% of the administered dose in urine and 3% in feces.

Pregnancy & Breastfeeding use

Pregnancy Category C. Amitriptyline is not recommended during pregnancy, especially during the first and third trimester because the safety of Amitriptyline has not been established yet.

Amitriptyline is detectable in breast milk. Because of the serious adverse reactions in infants from Amitriptyline, a decision should be made whether to continue breast feeding or discontinue the drug

Pregnancy: The safe use of ketamine in pregnancy has not been established, and such use is not recommended.

Lactation: Ketamine is likely to be excreted in breast milk and therefore breastfeeding should be discontinued when ketamine is in use.

Contraindication

Amitriptyline is contraindicated in myocardial infarction; arrythmias, particularly heartblock of any degree; mania; severe liver disease. Initially sedation may effect the ability to drive or operate machinery. It should be used with caution in patients with a history of epilepsy, glaucoma, urinary retention, prostatic hypertrophy, constipation, cardiac disease, diabetes, pregnancy, hepatic impairment, thyroid disease, increased intraoccular pressure, psychoses (may aggravate mania).

CV disease including severe HTN; patients with increased intraocular or CSF pressure.

Acute Overdose

Symptoms: Resp depression.

Management: Employ supportive ventilation. Mechanical support of respiration is preferred to admin of analeptics.

Storage Condition

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

Storage Conditions

Store between 20-25° C.

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