Gabapentin Chemical Properties

Melting point:

162°C

Boiling point:

314.4±15.0 °C(Predicted)

Density 

1.058±0.06 g/cm3(Predicted)

Flash point:

9℃

storage temp. 

2-8°C

solubility 

H₂O: 10 mg/mL

form 

solid

pka

pKa1 (25°) 3.68; pKa2 10.70

color 

off-white

Merck 

14,4319

BRN 

2359739

BCS Class

3

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in distilled water may be stored at -20°C for up to 3 months.

InChIKey

UGJMXCAKCUNAIE-UHFFFAOYSA-N

CAS DataBase Reference

60142-96-3(CAS DataBase Reference)

EPA Substance Registry System

Cyclohexaneacetic acid, 1-(aminomethyl)- (60142-96-3)

Safety Information

Hazard Codes 

T,Xi,F

Risk Statements 

61-36/37/38-39/23/24/25-23/24/25-11

Safety Statements 

53-26-36/37/39-45-36-36/37-16

WGK Germany 

3

RTECS 

GU6496000

HazardClass 

IRRITANT

HS Code 

29224999

Hazardous Substances Data

60142-96-3(Hazardous Substances Data)

MSDS

• Language:English Provider:1-(Aminomethyl)cyclohexaneacetic acid
• Language:English Provider:SigmaAldrich

Gabapentin Usage And Synthesis

Description

Gabapentin is a second- generation antiepileptic drug (AED) known under the proprietary brand name of Neurontin® (Pfizer, New York, NY) in the UK and USA.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

• It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.

Indications

Epilepsy: monotherapy or adjunctive therapy of focal seizures with or without secondary generalization. Recommendations summarized from NICE (2012)

• Seizure types: adjunctive (focal seizures), contraindicated (generalized tonic- clonic seizures generalized tonic- clonic seizures if there are absence or myoclonic seizures, or if juvenile myoclonic epilepsy is suspected, tonic/ atonic seizures, absence seizures, myoclonic seizures).
• Epilepsy types: adjunctive (benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy), contraindicated (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy, Dravet syndrome, Lennox– Gastaut syndrome)
•  Psychiatry— treatment of anxiety disorders (unlicensed); treatment of alcohol withdrawal symptoms (unlicensed).
•  Neurology— treatment of neuropathic pain and restless leg syndrome (unlicensed) and prophylaxis of migraine (unlicensed).

Dose titration

Monotherapy or adjunctive therapy
300 mg od for day 1300 mg bd for day 2300 mg td for day 3 (or 300 mg td for day 1), then increased by 300 mg every 2– 3 days, divided into three doses; usual maintenance 900– 3600 mg daily, divided into three doses (max. 4800 mg daily) If gabapentin has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week, independent of the indication.

Cautions

• Patients with a history of psychotic illness.
• Patients with mixed seizures (including absences).
• Patients with diabetes mellitus.
• Elderly patients.

Interactions

With AEDs
Nil.

With other drugs

• Patients who require concomitant treatment with opioids should be carefully observed for signs of respiratory depression and/ or sedation, and the dose of gabapentin or opioid should be reduced appropriately
• Co-administration of gabapentin with antacids containing aluminium and magnesium, reduces gabapentin bioavailability up to 24%, and it is therefore recommended that gabapentin be taken at the earliest 2 hours following antacid administration

With alcohol/food
There are no known specific interactions between alcohol and gabapentin and there are no specific foods that must be excluded from diet when taking gabapentin.

Special populations

Renal impairment
Reduce maintenance dose according to degree of reduction in creatinine clearance.

Pregnancy

• The dose of gabapentin should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.
• No definite conclusion can be made as to whether gabapentin is associated with an increased risk of congenital malformations when taken during pregnancy. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.
• Gabapentin is excreted in human milk. Because the effect on the breastfed infant is unknown, gabapentin should be used in breastfeeding mothers with caution and only if the benefits clearly outweigh the risks.

Behavioural and cognitive effects in patients with epilepsy

Gabapentin has a relatively favourable behavioural profile, although paradoxical hyperactivity, irritability and aggression have been occasionally reported, especially in patients with severe intellectual disabilities. The cognitive profile of gabapentin is equally favourable, as this AED has been associated with only minor cognitive difficulties (mainly in the attention domain).

Psychiatric use

Although gabapentin has no approved indications in psychiatry, it has shown efficacy in the treatment of anxiety disorders, especially social phobia. Other offlabel uses include other anxiety disorders (panic disorder, post- traumatic stress disorder), alcohol dependence and withdrawal, behavioural and psychological symptoms of dementia, and aggression. Gabapentin has also been proposed to be useful in the maintenance treatment of bipolar disorder as adjunctive therapy.

Description

Gabapentin was introduced in 1993 in the UK and early 1994 in the USA as an adjunctive therapy in the treatment of refractory partial seizures and secondarily generalized tonic-clonic seizures. Although being a lipophilic analog of the neurotransmitter GABA, gabapentin appears to exert its anticonvulsive function by a GABA receptor independent mechanism, possibly involving the L-system amino acid transporter protein. Gabapentin easily crosses the blood brain barrier and exhibits a favorable pharmacokinetic profile with high tolerability. It does not interfere with the metabolism of other concomitant administered antiepileptic drugs, thus having a low potential for drug interactions. Studies are currently underway for the use of gabapentin as mono-therapy for the treatment of various seizures.

Description

γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter that functions by binding to the GABA receptors located in the spinal cord. Gabapentin is a γ-aminobutyric acid (GABA) analogue that acts as an anticonvulsant with proven analgesic effects in various neuropathic pain syndromes such as Complex Regional Pain Syndrome type one (CRPS 1). It is also prescribed to multiple sclerosis patients to control dysesthesias and may be useful in reducing neuropathic pain caused by cancer and HIV infection. It does not bind to GABA receptors, does not influence neural uptake of GABA, and does not inhibit the GABA-metabolizing enzyme, GABA transaminase. Unlike GABA, which does not pass through the blood-brain barrier, gabapentin penetrates into the central nervous system and binds to the α₂δ-type voltage-gated calcium channels. The mechanism for the analgesic and anticonvulsant effects of gabapentin are not known.

Chemical Properties

White Crystalline Solid

Originator

Warner-Lambert (U.S.A.)

Uses

antipsychotic, 5HT2A antagonist

Uses

For the treatment of adult Restless Legs Syndrome (RLS) and postherpetic neuralgia (PHN).

Uses

Gabapentin is an Amino acid structurally related to γ-Aminobutyric Acid (GABA), designed to cross the blood brain barrier. Used as an anticonvulsant.

Uses

selective H1-receptor antagonist

Indications

Gabapentin (Neurontin) significantly decreases pain scores and sleep interference associated with PHN. An initial dose of 300 mg/day is increased over 4 weeks (900, 1,800, 2,400, 3,600 mg/day divided t.i.d.) until efficacy is obtained or side effects become intolerable.

Definition

ChEBI: A gamma-amino acid that is cyclohexane substituted at position 1 by aminomethyl and carboxymethyl groups. Used for treatment of neuropathic pain and restless legs syndrome.

Manufacturing Process

32.8 g 1,1-cyclohexane-diacetic anhydride are mixed with 7 g anhydrous methanol and heated under reflux for 1 hour. After evaporation of the reaction mixture in a vacuum, was obtained 37.5 g monomethyl 1,1-cyclohexanediacetate in the form of a yellowish oil.
5.6 ml triethylamine in 16 ml anhydrous acetone are added dropwise at 0°C to a solution of 7.28 g monomethyl 1,1-cyclohexane-diacetate, then a solution of 3.6 ml ethyl chloroformate in 16 ml anhydrous acetone is added thereto. The reaction mixture is further stirred for 30 min at 0°C and and then a solution of 3.4 g sodium azide in 12 ml water added dropwise thereto. The reaction mixture is stirred for 1 hour at 0°C, then poured into ice water and extracted three times with 50 ml amounts of ice-cold toluene. The combined extracts are dried over anhydrous sodium sulphate at 0°C and subsequently introduced drop-wise into a flask pre-heated to 100°C. The mixture is then heated for a further hour under reflux and thereafter evaporated in a vacuum. The crude methyl 1-isocyanatomethyl-1-cyclohexane-acetate which remains behind is heated under reflux for 3 hours with 50 ml 20% hydrochloric acid. After cooling the solution, it is extracted three times with 100 ml amounts of chloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactam formed as a by-product product and the aqueous hydrochloric acid solution evaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acid crystallises as the hydrochloride; m.p. 117-118°C, after recrystallisation from acetone/methanol/ether. After recrystallization from methanol/ether the melting point of the product is 129-133°C.
By treatment with a basic ion exchanger and crystallisation from ethanol/ether, there is obtained pure 1-amino-methyl-1-cyclohexane-acetic acid; melting point 162-166°C.

brand name

Neurontin (ParkeDavis); Neurontin (Pfizer).

Therapeutic Function

Anticonvulsant

Biological Functions

Gabapentin (Neurotonin) was initially designed to be a rigid analogue of GABA. When it was discovered to have antiepileptic properties, it was assumed that this activity was related to a GABAergic mechanism. However, subsequent studies have failed to show any GABAergic activity of gabapentin. Although it has not yet been possible to ascribe any definite mechanism to its antiepileptic activity, there is recent evidence that it may function as an agonist at GABAB receptors in the brain.
Gabapentin is recommended as adjunctive therapy in the treatment of partial seizures in adults.When used with other drugs, it appears to be an effective AED; it is usually not effective when employed alone for patients with severe seizures.
Gabapentin is generally well tolerated, with somnolence, dizziness, and ataxia the most commonly reported adverse effects. A low incidence of potentially serious side effects and no significant allergic reactions have been reported.

General Description

Gabapentin and its closely related analog pregabalin,(S)-3-isobutyl-GABA, are broad-spectrum anticonvulsantswith multiple mechanisms of action.24,51 Inaddition to modulating calcium influx and stimulateGABA biosynthesis as discussed earlier, they also competefor the biosynthesis of L-glutamic acid because oftheir structural similarity to L-leucine.51 Gabapentin andpregabalin have very little liability for causing metabolicbaseddrug–drug interactions, particularly when used incombination with other AEDs because they are not metabolizedin humans. More than 95% of the drug is excretedunchanged through the kidneys. However, there are somedifferences in their bioavailability. Unlike gabapentin,which exhibits 60% bioavailability when given in lowdoses because of intestinal uptake by a saturable smallneutral L-amino acid transporter, the absorption of pregabalinis almost complete (98%) and exhibits an ideal linear pharmacokinetic profile.24 This high bioavailability of pregabalincan be attributed to its closer structure similarity tothe essential amino acid, L-leucine.

Biological Activity

Anticonvulsant with several possible mechanisms of action. Increases GABA in the brain and binds to a novel site associated with voltage-sensitive Ca 2+ channels. Prevents neuronal death and is antinociceptive and anxiolytic.

Biochem/physiol Actions

Primary Targetα2δ subunit of L-type voltage gated Ca2+ channels

Clinical Use

Antiepileptic:
Adjunctive treatment of partial seizures with or without secondary generalisation
Neuropathic pain
Migraine prophylaxis (unlicensed)

Side effects

Dose-limiting adverse effects include somnolence, dizziness, ataxia, peripheral edema, and infection (22).

Side effects

Long-Term Side Effects of Gabapentin:

• Mood changes.
• Behavioral changes.
• Depression.
• Anxiety.
• Memory loss.
• Weakened muscles.

Synthesis

In the original synthesis (Goedecke) cyclohexenone is reacted with ethyl cyanoacetate in the presence of ammonia to yield the Guareschi salt, which is hydrolyzed and decarboxylated to give 1,1-cyclohexanediacetic acid which is transformed by to the corresponding anhydride with acetic anhydride. This anhydride is treated with methanol to yield the half ester 2- acetic acid, which is subjected to a Curtius type rearrangement to give the isocyanate 2-acetic acid. The desired compound is obtained by hydrolysis of 2-acetic acid with HCl, followed by hydrochloric salt removal via anion exchange .

Veterinary Drugs and Treatments

Gabapentin may be useful as adjunctive therapy for refractory or complex partial seizures, or in the treatment of chronic pain in dogs or cats.

Drug interactions

Potentially hazardous interactions with other drugs
Antacids: reduce absorption.
Antidepressants: antagonism of anticonvulsive effect (convulsive threshold lowered); avoid with St John’s wort.
Antimalarials: anticonvulsant effect antagonised by mefloquine.
Antipsychotics: antagonism of anticonvulsive effect (convulsive threshold lowered).
Orlistat: possible increased risk of convulsions.

Metabolism

There is no evidence of gabapentin metabolism in humans. Gabapentin is eliminated unchanged solely by renal excretion.

References

1) Cheng et al. (2004), Does gabapentin act as an agonist at native GABA(B) receptors?; J. Biomed. Sci., 11 346 2) Lanneau et al. (2001), Gabapentin is not a GABAB receptor agonist; Neuropharmacology 41 965 3) Hendrich et al. (2008), Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin; Proc. Natl. Acad. Sci. USA, 105 3628

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