GABANORT-400

Indications

• Epilepsy
• Focal seizures with or without secondary generalization
• Neuropathic pain
• Spasticity in multiple sclerosis
• Muscle symptoms in motor neurone disease

Dosage

Adults: Initially 300 mg once daily for 1–2 weeks, then 300 mg twice daily for 1–2 weeks, followed by 300 mg 3 times a day for 1–2 weeks. Adjustments should be made according to response; maximum usual dose is 0.9–3.6 g daily in 3 divided doses (

Mechanism of action

Gabapentin primarily acts on the auxiliary α2δ-1 subunit of voltage-gated calcium channels, inhibiting their action and subsequently reducing the release of excitatory neurotransmitters. This mechanism is thought to contribute to its efficacy in treating neuropathic pain and seizures. Gabapentin may also influence adenosine receptors and voltage-gated potassium channels, although the clinical significance of these effects remains unclear.

Pharmacodynamics

Gabapentin is classified as an anticonvulsant that inhibits the release of excitatory neurotransmitters. Its wide therapeutic index makes it safer in overdoses, with high doses not leading to fatal outcomes in animal studies. While effective in treating neuropathic pain and seizure disorders, it is not effective for absence seizures and should be used cautiously in patients with mixed seizure disorders. Gabapentin has been associated with serious hypersensitivity reactions, including DRESS syndrome.

Pharmacokinetics

Gabapentin is absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 2 to 3 hours post-administration. It does not bind significantly to plasma proteins and is eliminated primarily through renal excretion. The drug's half-life is approximately 5 to 7 hours, necessitating multiple daily doses for therapeutic effect. Dose adjustments may be required in patients with renal impairment.

Adverse effects

• Dizziness
• Somnolence
• Fatigue
• Ataxia
• Nausea
• Vomiting
• Peripheral edema
• Visual disturbances
• Mood changes
• Respiratory depression

Interactions

• Opioids (increased risk of respiratory depression)
• CNS depressants (increased sedation)
• Antacids (may decrease gabapentin absorption if taken concurrently)

Precautions

• Use with caution in patients with compromised respiratory function
• Use with caution in patients with renal impairment
• Monitor for signs of suicidal thoughts or behavior
• Monitor for signs of hypersensitivity reactions (DRESS)

Pregnancy

Gabapentin should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Consult a healthcare professional for individual assessment.

Breast-feeding

Gabapentin is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Capsules
• Tablets
• Oral solution

Indications

• Depressive illness
• Neuropathic pain

Dosage

Children: For children aged 12–17 years, treatment should begin at a low dose, increasing if necessary to 30–50 mg daily in divided doses or alternatively taken once daily. The maximum dose is 150 mg per day.

Adults: Initially, 10 mg once daily, preferably at night, which may be increased to 75 mg daily if necessary, with the maximum dose being 150 mg per day.

Mechanism of action

Nortriptyline is thought to inhibit the reuptake of serotonin and norepinephrine at neuronal membranes, with a more selective action on norepinephrine. This action enhances mood and alleviates depressive symptoms. Additionally, it interacts with various other receptors including muscarinic acetylcholine receptors and histamine receptors, which may contribute to both its therapeutic effects and side effects.

Pharmacodynamics

Nortriptyline exhibits antidepressant effects primarily through the inhibition of serotonin and norepinephrine reuptake, leading to increased levels of these neurotransmitters in the synaptic cleft. It also has antimuscarinic properties which can lead to side effects such as dry mouth and urinary retention. The drug's affinity for multiple receptors may influence its overall therapeutic efficacy and side effect profile.

Pharmacokinetics

Nortriptyline is well absorbed following oral administration, with peak plasma concentrations typically occurring within 4 to 8 hours. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, and has a half-life of about 18 to 44 hours. The drug is mostly excreted as metabolites in the urine. Dosing adjustments may be necessary in patients with hepatic impairment. Regular monitoring of plasma levels may be warranted in patients receiving higher doses.

Contra-indications

• Arrhythmias during the manic phase of bipolar disorder
• Heart block
• Immediate recovery period after myocardial infarction

Adverse effects

• Dry mouth
• Drowsiness
• Constipation
• Urinary retention
• Hypotension
• Cardiac conduction defects
• Arrhythmias
• Dilated pupils
• Suicidal tendencies
• Neurological effects
• Increased risk of fracture
• Photosensitivity reaction
• Respiratory disorders
• Thrombocytopenia
• Anticholinergic syndrome

Interactions

• Severe: dacomitinib increases exposure
• Moderate: eliglustat increases exposure
• Unknown: valproate increases concentration

Precautions

• Caution in patients with cardiovascular disease
• Caution in patients with chronic constipation
• Caution in patients with diabetes
• Caution in patients with epilepsy
• History of bipolar disorder
• History of alcohol dependence
• History of hyperthyroidism (risk of arrhythmias)
• Elderly patients may be particularly susceptible to side effects

Pregnancy

Use only if potential benefit outweighs risk.

Breast-feeding

The amount secreted into breast milk is too small to be harmful.

Storage

Store in a cool, dry place away from light.

Formulations

• Nortriptyline (as Nortriptyline hydrochloride) 10 mg/5 ml oral solution
• Nortriptyline tablets 10 mg
• Nortriptyline tablets 25 mg
• Nortriptyline capsules 10 mg
• Nortriptyline capsules 25 mg

Mechanism of action

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. Although the exact mechanism by which gabapentin exerts its analgesic effects is not known, the drug has been shown to prevent allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several models of neuropathic pain. Gabapentin also has been shown to decrease pain-related responses after peripheral inflammation in animals; however, the drug has not altered immediate pain-related behaviors. The clinical relevance of these findings is not known. In vitro studies demonstrate that gabapentin binds to the alpha2delta subunit of voltage-activated calcium channels; however, the clinical importance of this effect is not known. Gabapentin is an anticonvulsant agent structurally related to the inhibitory CNS neurotransmitter gamma-aminobutyric acid (GABA). Gabapentin enacarbil is a prodrug of gabapentin that is rapidly converted to gabapentin following oral administration; the therapeutic effects of gabapentin enacarbil are attributed to gabapentin. Although gabapentin was developed as a structural analog of GABA that would penetrate the blood-brain barrier (unlike GABA) and mimic the action of GABA at inhibitory neuronal synapses, the drug has no direct GABA-mimetic action and its precise mechanism of action has not been elucidated. Results of some studies in animals indicate that gabapentin protects against seizure and/or tonic extensions induced by the GABA antagonists picrotoxin and bicuculline or by GABA synthesis inhibitors (e.g., 3-mercaptopropionic acid, isonicotinic acid, semicarbazide). However, gabapentin does not appear to bind to GABA receptors nor affect GABA reuptake or metabolism and does not act as a precursor of GABA or of other substances active at GABA receptors. Gabapentin also has no affinity for binding sites on common neuroreceptors (e.g., benzodiazepine; glutamate; quisqualate; kainate; strychnine-insensitive or -sensitive glycine; alpha1-, alpha2-, or beta-adrenergic; adenosine A1 or A2; cholinergic [muscarinic or nicotinic]; dopamine D1 or D2; histamine H1; type 1 or 2 serotonergic [5-HT1 or 5-HT2]; opiate mc, delta, or k) or ion channels (e.g., voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20alpha-benzoate). Conflicting results have been reported in studies of gabapentin affinity for and activity at N-methyl-d-aspartic acid (NMDA) receptors. Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kina

Pharmacodynamics

Gabapentin is an anti-convulsant medication that inhibits the release of excitatory neurotransmitters, allowing for its use against pathologic neurotransmission such as that seen in neuropathic pain and seizure disorders. It has a wide therapeutic index, with doses in excess of 8000 mg/kg failing to cause a fatal reaction in rats. Gabapentin is ineffective in absence seizures and should be used in caution in patients with mixed seizure disorders involving absence seizures. Gabapentin has been associated with drug reaction with eosinophilia and systemic symptoms (DRESS), otherwise known as multi-organ hypersensitivity. This reaction can prove fatal and early symptoms such as fever, lymphadenopathy, and rash should be promptly investigated.

Mechanism of action

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. The mechanism of adverse imipramine-induced reactions ... was investigated by precipitating such reactions in rats with three injections (ip) of imipramine (5-40 mg/kg) at 24, 5, and 1 hr before testing, and comparing their occurrence with comparable treatments using specific noradrenergic and serotonergic reuptake inhibitors (nortriptyline (10 or 30 mg/kg, ip), citalopram (0.5-5.0 mg/kg, ip)). This initial study indicated that these reactions were mediated by imipramine's noradrenergic effects. The effect of equal-dose regimens of amitriptyline and nortriptyline on the concn of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline incr to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs incr serotonin levels but decr cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential incr in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an incr in dopamine turnover particularly in brain areas assoc with motor function and posture which may account for tricyclic antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition. Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through beta2-adrenoceptors (beta2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor a (TNFa) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on beta2-ARs expressed by non-neuronal satellite cells. This stimulation of beta2-ARs decreases the neuropathy-induced production of membrane-bound TNFa, resulting in relief of neuropathic allodynia. This indirect anti-TNFa action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the beta2-AR agonist terbutali

Pharmacodynamics

Nortriptyline exerts antidepressant effects likely by inhibiting the reuptake of serotonin and norepinephrine at neuronal cell membranes. It also exerts antimuscarinic effects through its actions on the acetylcholine receptor.