Pregabalin
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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral, DailyMed. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as Pregabalin, Lyrica, Nervalin, pregablinPW
Fatal overdose may occur when gabapentinoids are combined with other depressants such as opiates, benzodiazepines, barbiturates, thienodiazepines, alcohol or other GABAergic substances.[1] It is strongly discouraged to combine these substances, particularly in common to heavy doses.PW
Oral
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 50 mg | 50–225 mg | 225–600 mg | 600–900 mg | 900 mg+ |
| Onset | 30–45 minutes |
|---|---|
| Come-up | 1–2 hours |
| Peak | 4–6 hours |
| Offset | 4–8 hours |
| Total | 9–17 hours |
| After-effects | 4–10 hours |
Bioavailability: 90 %
Rectal
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 40 mg | 40–200 mg | 200–450 mg | 450–600 mg | 600 mg+ |
| Onset | 15–30 minutes |
|---|---|
| Come-up | 30–120 minutes |
| Peak | 2–3 hours |
| Offset | 3–5 hours |
| Total | 5–8 hours |
| After-effects | 6–12 hours |
🧬 Receptor activityPHDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Unchecked | — | Ki 19 nM | CHEMBL | TargetUnchecked Action— AffinityKi 19 nM SourceCHEMBL |
| Voltage-dependent calcium channel subunit alpha-2/delta-1 | — | Ki 19 nM | CHEMBL | TargetVoltage-dependent calcium channel subunit alpha-2/delta-1 Action— AffinityKi 19 nM SourceCHEMBL |
| Voltage-dependent calcium channel subunit alpha-2/delta-2 | — | Ki 99 nM | CHEMBL | TargetVoltage-dependent calcium channel subunit alpha-2/delta-2 Action— AffinityKi 99 nM SourceCHEMBL |
| Sodium-dependent noradrenaline transporter | — | Ki 10000 nM | CHEMBL | TargetSodium-dependent noradrenaline transporter Action— AffinityKi 10000 nM SourceCHEMBL |
| Voltage-dependent calcium channel subunit alpha-2/delta-1 (CACNA2D1) | Modulator | 7.097 IC50 | DRUGCENTRAL | TargetVoltage-dependent calcium channel subunit alpha-2/delta-1 (CACNA2D1) ActionModulator Affinity7.097 IC50 SourceDRUGCENTRAL |
| Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2) | Modulator | 7.26 IC50 | DRUGCENTRAL | TargetVoltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2) ActionModulator Affinity7.26 IC50 SourceDRUGCENTRAL |
| Large neutral amino acids transporter small subunit 1 (SLC7A5) | — | 3.801 IC50 | DRUGCENTRAL | TargetLarge neutral amino acids transporter small subunit 1 (SLC7A5) Action— Affinity3.801 IC50 SourceDRUGCENTRAL |
| Uncharacterized protein; Voltage-dependent calcium channel alpha-2 delta subunit (CACNA2D1) | — | 7.14 IC50 | DRUGCENTRAL | TargetUncharacterized protein; Voltage-dependent calcium channel alpha-2 delta subunit (CACNA2D1) Action— Affinity7.14 IC50 SourceDRUGCENTRAL |
Mechanism of actionPHDM
Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models. By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action. Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or benzodiazepine receptors.
Pregabalin is an anticonvulsant that is structurally related to the inhibitory CNS neurotransmitter gamma-aminobutyric acid (GABA). Pregabalin also has demonstrated analgesic activity. Although pregabalin was developed as a structural analog of GABA, the drug does not bind directly to GABA-A, GABA-B, or benzodiazepine receptors; does not augment GABA-A responses in cultured neurons; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.
Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues. ... In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, including glutamate, norepinephrine, and substance P, possibly by modulation of calcium channel function.
Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
Pregabalin is a potent ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system that exhibits potent anticonvulsant, analgesic, and anxiolytic activity in a range of animal models. ... Potent binding to the alpha-2-delta site reduces depolarization-induced calcium influx with a consequential modulation in excitatory neurotransmitter release. Pregabalin has no demonstrated effects on GABAergic mechanisms. ...
For more Mechanism of Action (Complete) data for PREGABALIN (6 total), please visit the HSDB record page.
PharmacodynamicsPH
Although the structure of pregabalin is similar to gamma-aminobutyric acid (GABA), it does not bind to GABA receptors. Instead, it binds the alpha2-delta subunit of presynaptic voltage-gated calcium channels in the central nervous system. Pregabalin does not modulate dopamine receptors, serotonin receptors, opiate receptors, sodium channels or cyclooxygenase activity.
Pharmacokinetics
Half-lifePH
The elimination half life of pregabalin is 6.3 hours.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function.
AbsorptionPHDM
After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional. Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin can be administered with or without food.
Pregabalin is almost exclusively eliminated in the urine. Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body.
After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg. Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB. In rat models, pregabalin has been shown to cross the placenta.
In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved.
Pregabalin is well absorbed after oral administration ...
Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is >/=90% and is independent of dose. Following single- (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (C max ) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.
MetabolismPH
Less than 2% of pregabalin is metabolized and it is excreted virtually unchanged in the urine.
Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.
Protein bindingPH
Pregabalin is not plasma protein bound.
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External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.