Meigabalin Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin binds to an auxillary subunit (α₂-δ protein) of voltage-gated calcium channels in the central nervous system.
Evidence from animal models with nerve damage has shown that pregabalin reduces calcium dependent release of pronociceptive neurotransmitters in the spinal cord possibly by disrupting calcium trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage suggest the antinociceptive activities of pregabalin may also be mediated through interactions with the descending noradrenergic and serotonergic pathways.
Pharmacokinetics: Absorption: Bioavailability: ≥90%.
Distribution: V_d: 0.56 L/kg.
Protein binding: Pregabalin is not bound to plasma proteins.
Metabolism: Negligible.
Half-life elimination: 6.3 hours.
Time to peak, plasma: within 1 hour (2.5 hours with food).
Excretion: Urine (98% as unchanged pregabalin, The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine for 0.9% of the dose).
Linearity/Non-linearity: Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%). Multiple-dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
Pharmacokinetics in special patient groups: Gender: Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of pregabalin.
Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (following a 4-hour hemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dosage reduction in patients with renal impairment and dosage supplement following hemodialysis is necessary.
Hepatic impairment: No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Elderly (over 65 years of age): Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decrease in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Breast-feeding mothers: The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating woman who were at least 12 weeks postpartum. Lactation had little to no influence on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose.