Gabafirst Nt

Uses

Gabapentin is used for-

• Epilepsy
• Neuropathic pain (e.g. postherpetic neuralgia) and other pain conditions
• Bipolar disorder
• Headache syndrome
• Spasticity in multiple sclerosis and spinal cord diseases

Others indication are:

• Alcohol withdrawal
• Schizoaffective disorder
• Post-traumatic stress disorder
• Agitation and behavioural disturbances
• associated with dementia
• Lesch-Nyhan syndrome
• Essential tremor
• Restless legs syndrome
• Brachioradial pruritus
• Hemichorea/hemiballismus
• Hot Flashes

Nortriptyline is used for the treatment of depression and nocturnal enuresis.

Gabafirst Nt is also used to associated treatment for these conditions: Partial-Onset Seizures, Peripheral Neuropathic Pain, Postherpetic NeuralgiaIrritable Bowel Syndrome (IBS), Major Depressive Disorder (MDD), Myofascial Pain Syndrome, Orofacial Pain, Pain, Chronic, Post-Herpetic Neuralgia (PHN)

How Gabafirst Nt works

The precise mechanism through which gabapentin exerts its therapeutic effects is unclear. The primary mode of action appears to be at the auxillary α2δ-1 subunit of voltage-gated calcium channels (though a low affinity for the α2δ-2 subunit has also been reported). The major function of these subunits is to facilitate the movement of pore-forming α1 subunits of calcium channels from the endoplasmic reticulum to the cell membrane of pre-synaptic neurons. There is evidence that chronic pain states can cause an increase in the expression of α2δ subunits and that these changes correlate with hyperalgesia. Gabapentin appears to inhibit the action of α2δ-1 subunits, thus decreasing the density of pre-synaptic voltage-gated calcium channels and subsequent release of excitatory neurotransmitters. It is likely that this inhibition is also responsible for the anti-epileptic action of gabapentin.

There is some evidence that gabapentin also acts on adenosine receptors and voltage-gated potassium channels, though the clinical relevance of its action at these sites is unclear.

Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other receptors.

Dosage

Gabafirst Nt dosage

Neuropathic pain: 300 mg on day-1, then 300 mg twice on day-2, then 300 mg thrice on day-3, then increase the dose according to response in steps of 300 mg daily to maximum 1800 mg daily in three divided doses.

Partial seizure/epilepsy: 300 mg on day-1, then 300 mg twice on day-2, then 300 mg thrice on day-3, then increase the dose according to response in steps of 300 mg daily to maximum 2400 mg daily in three divided doses.

In case of children:

• For 3-12 years: 10 to 15 mg/kg, Incase of titration 25-35 mg/kg daily in 3 divided doses.
• Maintenance dose is 900 mg daily (body weight 26-36 Kg) or 1.2 gm daily (body weight 37-50 Kg).

Depression:

• Adult: Low dose initially increased as necessary to 75-100 mg daily in divided doses or as a single dose (max. 150 mg daily)
• Adolescent & Elderly: 30-50 mg daily in divided doses; Child not recommended for depression

Nocturnal enuresis:

• Child 7 years: 10 mg
• 8-11 years: 10-20 mg
• Over 11 years: 25-35 mg, 30 minutes before bedtime; max period of treatment (including gradual withdrawal) 3 months- full physical examination and ECG before further course.

Gabapentin can be taken orally with or without food.

Side Effects

Generally Gabapentin is well tolerated but a few side effects like fatigue, dizziness , ataxia, weight gain, peripheral edema, dry mouth and somnolence, may occur. Rarely it may cause fulminate hepatic failure, or aplasticanemia.

The most common side effects include dry mouth, sedation, constipation and increased appetite, mild blurred vision, tinnitus, often euphoria and mania. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects and should be avoided.

Toxicity

The oral TDLo of gabapentin in humans is 2.86 mg/kg and the LD₅₀ in rats has been found to be >8000 mg/kg. Symptoms of overdose are consistent with the drug's adverse effect profile and involve CNS depression (e.g. dizziness, drowsiness, slurred speech, lethargy, loss of consciousness) and gastrointestinal symptoms such as diarrhea. Management of overdose should involve symptomatic and supportive treatment. Gabapentin can be removed by hemodialysis - this may be of benefit in some patients, such as those with impaired renal function.

Multi-drug overdoses involving gabapentin, particularly in combination with other CNS depressants such as opioids, can result in coma and death - this possibility should be considered when managing overdosage.

The oral LD50 of nortriptyline in the rat is 405 mg/kg.Symptoms of overdose with nortriptyline include cardiac arrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, coma, and CNS depression. Changes in the electrocardiogram, particularly in QRS segment, may be indicative of tricyclic antidepressant toxicity.

Precaution

Patients should be instructed to take Gabapentin only as prescribed. While using Gabapentin patients should be instructed either not to drive a car or to operate other complex machinery until they have gained sufficient experiences about Gabapentin whether or not it affects their mental and/or motor performance adversely.

Not intended for treatment of bipolar depression. Avoid abrupt withdrawal. Patient at risk of seizures, with DM, narrow angle glaucoma, urinary retention, prostatic hyperplasia, chronic constipation, history of CV disease. Renal and hepatic impairment. Elderly, childn. Pregnancy and lactation.

Interaction

Antacids may reduce the bioavailability of Gabapentin by up to 20%. Cimetidine may alter its reanal excretion. Gabapentin does not interact with other anti-epileptic drug or with oral contraceptive preparations.

Nortriptyline should not be given with adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, phenylpropanolamine, drugs that are metabolized by CYP4502D6, MAOIs, guanethidine, debrisoquine, bethanidine, clonidine and reserpine etc. Barbiturates may increase the rate of metabolism of nortriptyline.

Volume of Distribution

The apparent volume of distribution of gabapentin after IV administration is 58±6 L. The drug is found in the CSF in concentrations approximately 9-20% of the corresponding plasma concentrations and is secreted into breast milk in concentrations similar to that seen in plasma.

The apparent volume of distribution (Vd)β, estimated after intravenous administration is 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver.

Elimination Route

Absorption of gabapentin is thought to occur solely via facilitated transport by the LAT1 transporter within the intestines. As this process is saturable, the oral bioavailability of gabapentin is inversely proportional to the administered dose - the oral bioavailability of a 900mg/day regimen is approximately 60%, whereas a 4800mg/day regimen results in only 27% bioavailability. The T_max of gabapentin has been estimated to be 2-3 hours. Food has no appreciable effect on gabapentin absorption.

Nortriptyline is readily absorbed in the gastrointestinal tract with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%.

Half Life

The elimination t_1/2 of gabapentin in patients with normal renal function is 5-7 hours. In patients with reduced renal function, the elimination t_1/2 may be prolonged - in patients with a creatinine clearance of 16,17

The average plasma half-life of nortriptyline in healthy volunteers is about 26 hours, but is said to range from 16 to 38 hours. One study mentions a mean half-life of about 39 hours.

Clearance

Both the plasma clearance and renal clearance of gabapentin are directly proportional to the patient's creatinine clearance due to its primarily renal elimination.

The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour.

Elimination Route

Gabapentin is eliminated solely in the urine as unchanged drug. Cimetidine, an inhibitor of renal tubular secretion, reduces clearance by approximately 12%, suggesting that some degree of tubular secretion is involved in the renal elimination of gabapentin.

Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.

Pregnancy & Breastfeeding use

Pregnancy: Gabapentin is a pregnancy category C drug; it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: Gabapentin may be secreted through the breast milk like many other drugs , so it should be used in women who are nursing, only if the benefits clearly outweigh the risks.

The safety of nortriptyline for use in pregnancy has not been established. Nortriptyline should only be given during pregnancy when there are no alternatives and benefit outweighs risk.

Contraindication

Gabapentin is contraindicated in patients who have known hypersensitivity to the drug.

Nortriptyline is contraindicated in patients with hypersensitivity to nortriptyline. Concomitant administration with MAOI is contraindicated. Do not use with or within 2 weeks of stopping an MAOI. Nortriptyline is contraindicated during the acute recovery period after myocardial infarction.

Special Warning

Use in Children: Safety and effectiveness of Gabapentin in the management of neuropathic pain in pediatric patients have not been established. Safety and effectiveness of Gabapentin in the management of seizures in pediatric patients below the age of 3 years have not been established.

Renal impaired patient: In case of renal impaired patient Gabapentin doses must be reduced :

• CrCl >60 ml/min: 1200 mg/daily in 3 divided doses
• CrCl 30-60 ml/min: 600 mg/daily in 2 divided doses
• CrCl 15-30 ml/min: 300 mg/daily single dose
• CrCl <15 ml/min: 150 mg/daily single dose or 300 mg/every alternate day
• Heamodialysis: maximum 300 mg after each dialysis Gabapentin can be taken orally with or without food.

Acute Overdose

Symptoms: Severe hypotension, cardiac dysrhythmias, shock, CHF, pulmonary oedema, convulsions, and CNS depression, including coma; changes in ECG.

Management: Symptomatic and supportive treatment. Admin IV Na bicarbonate, benzodiazepines. Admin activated charcoal to reduce absorption. Emesis is contraindicated. Initiate cardiac monitoring and observe for signs of CNS or resp depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures.

Storage Condition

Tablets should be stored below 25° C and protected from light & moisture

Store at 15-30° C. Protect from light and moisture.

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