GABAPRO

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

Dosage

Children: Refer to specific formulation guidelines as excipients are not dosed individually.

Adults: Refer to specific formulation guidelines as excipients are not dosed individually.

Mechanism of action

Excipients do not have a pharmacological mechanism of action in the way active drugs do; instead, they facilitate the delivery and absorption of the active pharmaceutical ingredients (APIs) in the body, improving the overall pharmacokinetics and bioavailability of the medication.

Pharmacodynamics

As excipients are inactive, they do not have pharmacodynamic properties. However, the choice of excipient can influence the release profile of the active ingredient, alter the drug's stability, and affect the solubility and bioavailability of the drug, which are critical for ensuring that the intended therapeutic effects are achieved.

Pharmacokinetics

Excipients generally do not undergo pharmacokinetic processes like absorption, distribution, metabolism, and excretion as active drugs do. They are usually considered inert, but their physical and chemical properties can influence the pharmacokinetics of the active ingredients they accompany. For example, some excipients may enhance the solubility of the active ingredient, facilitating better absorption in the gastrointestinal tract.

Pregnancy

Safety during pregnancy has not been established for all excipients. Some may pose risks while others are generally considered safe. Consultation with healthcare professionals is advised.

Breast-feeding

The safety of excipients during breastfeeding varies depending on the specific excipient. It is essential to consult healthcare professionals.

Storage

Excipients should be stored according to the specific requirements of the formulation they are a part of. Generally, they should be kept in a cool, dry place away from light.

Dosage

Children: Refer to specific BNF for Children guidelines for the medication contained within the film formulation, as dosing will depend on the active ingredient and the patient's age and weight.

Adults: Refer to specific BNF guidelines for the medication contained within the film formulation, as dosing will vary widely based on the active ingredient.

Mechanism of action

The mechanism of action for drugs delivered via film formulations varies depending on the active pharmaceutical ingredient contained within the film. Generally, the drug is absorbed through the mucosal membranes in the mouth or gastrointestinal tract, leading to systemic circulation. This can enhance the onset of action compared to traditional solid dosage forms.

Pharmacodynamics

Pharmacodynamics will vary based on the specific drug contained in the film formulation. In general, pharmacodynamics refers to the biochemical and physiological effects of the drug on the body, including its mechanism of action, therapeutic effects, and side effects. Film formulations may provide rapid onset of action due to faster dissolution and absorption of the drug.

Pharmacokinetics

Pharmacokinetics, which includes absorption, distribution, metabolism, and excretion (ADME), will also vary by the specific active ingredient in the film formulation. In general, films may exhibit faster absorption rates due to their design, leading to quicker peak plasma concentrations. The distribution will depend on the lipophilicity of the drug, while metabolism will occur primarily in the liver, and excretion can be renal or fecal, depending on the drug's characteristics.

Pregnancy

The safety of film in pregnancy has not been well established. Use only if clearly needed.

Breast-feeding

It is unknown if film is excreted in human milk. Use with caution while breastfeeding.

Storage

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

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.