AKUGABA-M 150 150/1000mcg CAPSULE

Indications

• Neuropathic pain
• Postherpetic neuralgia
• Partial seizures (as adjunctive therapy)

Dosage

Children: For children aged 3 to 12 years, the initial dose is typically 10 mg/kg/day, which can be increased based on clinical response

Adults: The usual starting dose for adults is 300 mg on day one, increasing to 600 mg on day two and 900 mg on day three, with a maximum dose of 3600 mg per day, divided into three doses.

Mechanism of action

Gabapentin primarily acts on the auxiliary α2δ-1 subunit of voltage-gated calcium channels, reducing the release of excitatory neurotransmitters by decreasing the density of presynaptic calcium channels. This action is associated with its therapeutic effects in managing neuropathic pain and seizure disorders. Additionally, gabapentin may interact with adenosine receptors and voltage-gated potassium channels, although the clinical significance of these interactions remains unclear.

Pharmacodynamics

Gabapentin inhibits the release of excitatory neurotransmitters, mitigating pathological neurotransmission common in neuropathic pain and seizure disorders. It possesses a wide therapeutic index, and high doses have not demonstrated fatal reactions in animal studies. However, gabapentin is not effective for absence seizures and should be used with caution in patients with mixed seizure disorders. Adverse reactions can include drug reaction with eosinophilia and systemic symptoms (DRESS), which necessitate prompt medical evaluation.

Pharmacokinetics

Gabapentin is absorbed from the gastrointestinal tract and exhibits linear pharmacokinetics. Peak plasma concentrations are typically reached within 2 to 3 hours post-administration. It is not extensively metabolized and is primarily excreted unchanged in the urine, necessitating dosage adjustments in patients with renal impairment. The drug has a bioavailability that decreases with increasing doses, and its elimination half-life is approximately 5 to 7 hours.

Contra-indications

• Hypersensitivity to gabapentin or any of its components
• History of drug reaction with eosinophilia and systemic symptoms (DRESS)

Adverse effects

• Drowsiness
• Dizziness
• Fatigue
• Ataxia
• Nausea
• Vomiting
• Peripheral edema
• Weight gain
• Visual disturbances
• Mood changes
• Euphoria
• Depression
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Interactions

• Caution should be exercised with other CNS depressants, as gabapentin may enhance their effects
• Antacids can reduce the bioavailability of gabapentin if taken simultaneously; it is advisable to separate dosing

Precautions

• Use with caution in patients with renal impairment
• Caution in patients with a history of substance abuse
• Monitor for signs of mood changes, suicidal thoughts, or behavior
• Taper dose gradually if discontinuing treatment to avoid rebound seizures

Pregnancy

Gabapentin is classified as category C. There are no adequate and well-controlled studies in pregnant women. Gabapentin should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Gabapentin is excreted in human milk. Caution is advised when administering to nursing women.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral capsules
• Oral tablets
• Oral solution

Indications

• Vitamin B12 deficiency
• Megaloblastic anemia
• Peripheral neuropathy
• Neuropathic pain
• Multiple sclerosis

Dosage

Children: For paediatric patients, refer to the BNF for Children for appropriate dosing guidelines.

Adults: The typical adult dosage for methylcobalamin is 500 micrograms to 1,000 micrograms administered intramuscularly or subcutaneously, usually once daily for the initial treatment, followed by maintenance doses as needed.

Mechanism of action

Methylcobalamin serves as a cofactor for the enzyme methionine synthase, which catalyzes the conversion of homocysteine to methionine. This reaction is crucial in the synthesis of S-adenosylmethionine (SAMe), an important methyl donor in numerous methylation reactions within the body. Methylcobalamin also plays a role in myelin formation and the maintenance of nerve cells.

Pharmacodynamics

Methylcobalamin exhibits neuroprotective effects, promoting nerve regeneration and repair in peripheral neuropathy. It is believed to enhance nerve conduction and improve neurological function. The physiological effects are primarily attributed to its role in methylation processes and the synthesis of neurotransmitters.

Pharmacokinetics

Methylcobalamin is water-soluble and is absorbed in the intestine. The bioavailability can be affected by gastrointestinal health, and intrinsic factor is not required for its absorption. It is distributed throughout the body, with high concentrations in the liver, kidneys, and brain. The elimination half-life of methylcobalamin is approximately 6 hours, and it is excreted primarily in the urine.

Adverse effects

• Nausea
• Diarrhea
• Headache
• Dizziness
• Anxiety
• Rash
• Pruritus

Precautions

• Monitor patients with Leber's disease due to potential optic nerve damage.
• Caution in patients with allergies to cobalt or vitamin B12.
• Use with caution in patients with renal impairment.

Pregnancy

Methylcobalamin is classified as a category A drug. It is generally considered safe during pregnancy, but consultation with a healthcare provider is recommended.

Breast-feeding

Methylcobalamin is excreted in breast milk. It is generally considered safe during breastfeeding, but consultation with a healthcare provider is recommended.

Storage

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

Formulations

• Tablets
• Injections
• Sublingual tablets
• Oral solutions

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.