Pregabalin

Absorption

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.

Toxicity

In a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation .
The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures.
Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway).
Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone.

Description

Pregabalin is structurally similar to gamma-aminobutyric acid (GABA) - an inhibitory neurotransmitter. It may be used to manage neuropathic pain, postherpetic neuralgia, and fibromyalgia among other conditions. Although as per the FDA Label the mechanism of action has not been definitively defined, there is evidence that pregabalin exerts its effects by binding to the α2δ subunit of voltage-dependent calcium channels. Pregabalin is marketed by Pfizer under the trade name Lyrica and Lyrica Cr (extended release). It may have dependence liability if misused but the risk appears to be highest in patients with current or past substance use disorders.

Chemical properties

Off-White Solid

Originator

Warner-Lambert (US)

The Uses of Pregabalin

Pregabalin was originally FDA approved in 2004 as an anti-epileptic drug, also called an anticonvulsant. It works by slowing down impulses in the brain that cause seizures. Pregabalin is used to treat pain caused by fibromyalgia, or nerve pain in people with diabetes (diabetic neuropathy), herpes zoster (post-herpetic neuralgia), or spinal cord injury.

The Uses of Pregabalin

Pregabalin is an anticonvulsant drug used for neuropathic pain, as an adjunct therapy for partial seizures, and in generalized anxiety disorder. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade nam

Indications

Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, neuropathic pain associated with spinal cord injury, and as adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older.

Definition

ChEBI: Pregabalin is a gamma-amino acid that is gamma-aminobutyric acid (GABA) carrying an isobutyl substitutent at the beta-position (the S-enantiomer). Binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. It has a role as an anticonvulsant and a calcium channel blocker. It is functionally related to a gamma-aminobutyric acid.

brand name

Lyrica (CP).

General Description

Pregabalin, marketed as the anticonvulsant drug Lyrica, is used in the treatment of epilepsy and generalized anxiety disorder. Along with other anticonvulsants such as gabapentin and levetiracetam, pregabalin is also used to treat neuropathic pain. This certified reference standard is suitable for pregabalin GC/MS or LC/MS applications from forensic analysis, clinical toxicology and pain prescription monitoring to urine drug testing.

Biochem/physiol Actions

Pregabalin is a lipophilic GABA analog/ligand at α2δ subunit of voltage-dependent Ca2+ channels. Pregabalin is an anticonvulsant, anxiolytic analgesic used to treat peripheral neuropathic pain and fibromyalgia.

Pharmacokinetics

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.

Clinical Use

Antiepileptic
Neuropathic pain
Generalised anxiety disorder

Synthesis

Several syntheses of pregabalin (X) have been disclosed in the literature, including process scale-up comparison of several different routes. The most cost efficient route as described in the publication is shown in the Scheme. Condensation of diethyl malonate 69 in the presense of diisopropyl amine in acetic acid gave a,b-unsaturated diester 70 in high yield. Reaction of the enone diester with potassium cyanide gave cyano diester 71 in 95% yield. In a remarkable three step, one pot process, the nitrile in 71 was hydrolyzed followed by decarboxylation of one of the esters to provide 72 in 73% yield. Resolution of the two enantiomers was achieved using (S)-(+)-mandellic acid, one of the best acid found after many salt screening, to give, after two recrystallization, a 99:1 ratio of the desired diastereomer.Removal of the acid was done with wet THF instead of base separation, to avoid salt impurities, and one recrystallization in ethanol gave 100% ee diastereomer in 25 ¨C 29% overall yield.
It?ˉs worth noting that the Pfizer group have come up with a new process of preparing pregabalin (X) via enantioselective reduction, that promises to further reduce cost and waste associated with the manufacture of this drug.

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: anticonvulsant effect antagonised.
Antimalarials: anticonvulsant effect antagonised by mefloquine.
Antipsychotics: anticonvulsant effect antagonised.
Orlistat: possible increased risk of convulsions.

Metabolism

Less than 2% of pregabalin is metabolized and it is excreted virtually unchanged in the urine.

Metabolism

Pregabalin undergoes negligible metabolism, and about 98% of a dose is excreted in the urine as unchanged drug.