Pharmacology Notes

Antiepileptic drugs decrease the excitability of neurones at spinal and brain levels. They work in neuropathic pain by stabilising excitable membranes and preventing repetitive neuronal discharges or by increasing the effectiveness of the major inhibitory network involving gamma-aminobutyric acid (GABA). Antiepileptic drugs have a major place in the treatment of neuropathic pain.

Sodium valproate is used for a number of indications, including:

Pharmacokinetics: Sodium valproate has almost complete bioavailability and its peak concentration occurs 1 to 4 hours after a dose from an immediate-release formulation or 3 to 7 hours after an enteric-coated tablet. It has a high degree of protein binding (90%) and its half-life is in the range 8 to 12 hours. Steady-state concentrations are achieved after about 4 days. Sodium valproate undergoes extensive hepatic metabolism, with little unchanged drug excreted in the urine.

Adverse effects and precautions: Tremor, hair changes, sedation, and appetite stimulation with weight gain are the commonest adverse effects. Gastrointestinal symptoms such as anorexia, nausea and vomiting can occur. Note that the 200 mg and 500 mg tablets are enteric coated, producing reduced gastrointestinal symptoms. Sodium valproate alters platelet function and may cause thrombocytopenia; platelet status should be ascertained before major surgery. Dose-related, reversible elevations in hepatic enzyme levels also occur. Of greater concern are sodium valproate–associated idiosyncratic hepatotoxicity and pancreatitis, which may be fatal. The risk of hepatotoxicity is significantly higher in infants. Infants (2 years or less) taking multiple antiepileptic drugs in addition to sodium valproate and with mental retardation or congenital metabolic disorders such as carnitine or ornithine carbamoyltransferase deficiency appear to be particularly at risk of developing fatal hepatic failure. An incidence of fatal hepatotoxicity of 1 in 500 to 1 in 800 has been estimated for the above high-risk group when on polytherapy, compared to 1 in 37 000 for those outside the high-risk group.

Several studies have implicated chronic valproate use in females as being associated with the polycystic ovary syndrome (ie polycystic ovaries, polycystic ovarian dysfunction and hyperandrogenism resulting in the clinical features of chronic anovulation, menstrual disorders, hypofertility, hirsutism, acne, obesity and hair loss). However, whether there is a causative association with valproate use is still controversial. Polycystic ovaries (as opposed to the polycystic ovary syndrome) are relatively common in the community (up to 20% of women), and the incidence increases with increased adiposity.

Monitoring: Assessment of haematological, renal, electrolyte and hepatic function before commencing sodium valproate could prove a useful baseline; however, there is no consensus on the value of subsequent routine haematological and biochemical monitoring. For further information on monitoring, see Monitoring antiepileptic drug therapy (Appendix 7.1). For information on monitoring in bipolar disorder, see above.

Interactions: The risk of skin reactions, including Stevens-Johnson syndrome, is increased with concomitant use of lamotrigine . For further information on drug interactions with sodium valproate, 

Pregabalin is an analogue of gamma-aminobutyric acid (GABA) and has anticonvulsant and analgesic properties. It is thought to act by binding to voltage-gated calcium channels in the central nervous system and possibly also by reducing release of neurotransmitters including glutamate, noradrenaline and substance P. It does not appear to interact with GABA receptors nor to interfere with GABA turnover.

Pregabalin is rapidly and well absorbed upon oral administration, with absorption being delayed but not reduced by food.

Excretion is almost completely urinary (about 98%) and dose reduction is recommended when glomerular filtration rate (GFR) is less than 60 mL/min. The dose in renal impairment should be reduced proportional to the reduction in GFR (see product information for details).

Metabolism in humans is negligible and pregabalin does not appear to have any significant drug interactions. In particular, no interaction has been observed with other anticonvulsants.

The main adverse effects observed are somnolence, dizziness, blurred vision, weight gain, peripheral oedema and elevations of creatine kinase.

Oxcarbazepine is chemically related to carbamazepine and, like carbamazepine, its primary mechanism of action is thought to be blockade of voltage-sensitive sodium channels. Although oxcarbazepine itself is active, most of its activity in humans comes from a 10-monohydroxy metabolite. The drug has a broad spectrum of action, with Australian marketing approval for treatment as monotherapy or adjunctive therapy of partial seizures and generalised tonic-clonic seizures.

Upon oral administration, the drug is completely absorbed and is unaffected by food. It is quickly and extensively metabolised to the 10-monohydroxy derivative and steady state is achieved after 2 to 3 days of twice-daily dosing. The monohydroxy derivative is excreted in urine both unchanged and as a glucuronide conjugate, accounting for about 80% of the total dose. Dose reduction is recommended in moderate to severe renal failure and the usual initial dose should be halved when the glomerular filtration rate (GFR) is less than 30 mL/min with the dose being subsequently titrated as needed. Dose reduction is not required for mild to moderate hepatic impairment.

Interactions: Oxcarbazepine has been found to inhibit CYP2C19 of the cytochrome P450 group of human oxidative liver enzymes and to induce both CYP3A4 and CYP3A5, giving rise to a number of clinically significant interactions with other drugs metabolised by these systems. Notably, components of oral contraceptives studied had average serum concentrations reduced by 32% to 52%. Female patients taking hormonal contraceptives should be warned to use additional nonhormonal contraception 

. For further information on drug interactions with oxcarbazepine, see Table 7.19.

Adverse effects: Common adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue. As with carbamazepine, asymptomatic hyponatraemia occurs in about 2.7% of patients. Because of this, monitoring may be required in patients on sodium-lowering drugs or in those who may be predisposed to fluid retention. More serious but rare adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, multi-organ hypersensitivity and hepatitis. With respect to the above immune-mediated reactions, it should be noted that there is a cross-reactivity with carbamazepine of about 30%. Oxcarbazepine is associated with the anticonvulsant hypersensitivity syndrome, with cross-reactivity with phenytoin having been reported. The absolute incidence of anticonvulsant hypersensitivity syndrome for oxcarbazepine is thought to be much less than for carbamazepine.

Gabapentin is structurally related to gamma-aminobutyric acid (GABA) and there is now evidence that it inhibits glutamate synthesis and elevates brain GABA levels. Its exact mechanism of action is unknown, but is thought to involve interaction with a subset of voltage-gated calcium channels. Gabapentin is also used in the management of neuropathic pain. It is known to interact with neuronal calcium channels in the spinal cord to reduce release of neurotransmitters, as well as increasing GABA synthesis and antagonising non-NMDA (N-methyl-D-aspartate) receptors. It has been shown to be efficacious in the treatment of diabetic neuropathy and postherpetic neuralgia, with around 30% of patients expecting to achieve more than 50% reduction in pain.

Gabapentin does not bind to plasma proteins or induce hepatic enzymes. It has a half-life of 5 to 7 hours, hence the need for 3 times daily dosing.

Gabapentin is absorbed by a saturable amino acid uptake system in the gastrointestinal tract, so that as the dose is increased, bioavailability decreases. Antacids bind with gabapentin and reduce its bioavailability by approximately 20%, so they should not be given together. Gabapentin has few other drug interactions. Gabapentin is excreted unchanged in the urine, therefore the dose must be reduced in renal impairment.

Common adverse effects are somnolence, dizziness and ataxia.

Carbamazepine is an anticonvulsant. It prevents rapid, repetitive, action potential firing, through voltage- and use-dependent blockade of sodium channels, thus limiting the propagation of seizure activity. It is also used in other neurological conditions—it has established efficacy in patients with trigeminal neuralgia, but clinical experience has been varied in other neuropathic pain states. It is also used in the treatment of bipolar disorder.

Precautions and interactions: Carbamazepine may cause worsening of absence and myoclonic seizures.

Carbamazepine has a marked ability to induce its own metabolism (autoinduction), which begins after 3 to 5 days of therapy and is usually complete after 3 to 4 weeks. Carbamazepine dosage must be titrated upwards slowly over a few weeks to avoid adverse effects. The eventual maintenance dose depends partly on the extent of autoinduction.

Carbamazepine can also accelerate the hepatic oxidation and conjugation of other lipid-soluble drugs (eg corticosteroids, cyclosporin, oral contraceptives, other antiepileptic drugs, warfarin). Carbamazepine undergoes hepatic metabolism by the cytochrome P450 isoform CYP3A4 and toxicity may result if drugs that inhibit CYP3A4 are also used (eg dextropropoxyphene, diltiazem, erythromycin, verapamil). For further information on drug interactions with carbamazepine, 

Adverse effects: Dose-related adverse effects include sedation, headache, ataxia, dizziness, nausea and visual symptoms such as diplopia. A mild elevation of gamma-glutamyltransferase, reflecting drug-induced enzyme induction, is common. A persistent rise in liver enzymes, however, should lead to cessation of carbamazepine because of the rare possibility of developing significant hepatic toxicity. Reversible mild leucopenia is common, but does not require discontinuation of therapy unless there is evidence of infection or the white cell count falls below 2000/mm3. At high plasma concentrations, carbamazepine has an antidiuretic hormone–like action, but the resulting hyponatraemia is usually mild and asymptomatic. If the plasma sodium concentration falls below 125 mmol/L, there may be confusion, peripheral oedema and decreasing control of seizures. Other idiosyncratic reactions include skin rash (usually mild erythematous, but may progress to Stevens-Johnson syndrome), diarrhoea and hepatitis. Carbamazepine is associated with the anticonvulsant hypersensitivity syndrome. 

Formulations: Controlled-release carbamazepine may give a lower maximal concentration than an equivalent dose of the regular preparation. When switching between regular and controlled-release carbamazepine, the same initial daily dose is used. This dose may require adjustment depending upon individual patient response. There may be some benefit in preferentially using controlled-release carbamazepine in terms of patient compliance and greater stability of blood levels.

Monitoring: Assessment of haematological, renal, electrolyte and hepatic function before commencing carbamazepine could prove a useful baseline; however, there is no consensus on the value of subsequent routine haematological and biochemical monitoring. For further information on monitoring, see Monitoring antiepileptic drug therapy (Appendix 7.1).

There is no evidence for the utility of designated therapeutic plasma concentrations when carbamazepine is used to treat bipolar disorder. Although antiepileptic plasma concentration ranges (20 to 50 micromol/L or 5 to 12 mg/L) are used as a guideline, dose increases should be titrated against the appearance of adverse effects and clinical response. In general terms, concentrations of at least the order of the published antiepileptic range are required to achieve efficacy in bipolar disorder. At concentrations above the antiepileptic range the risk of toxicity is high.