Tegretol Mechanism of Action

ATC code: N03AF01.
Pharmacology: Mechanism of action: The mechanism of action of carbamazepine, the active substance of Tegretol, has not yet been fully elucidated. Carbamazepine stabilizes hyperexcited nerve membranes, inhibits repetitive neuronal discharges and reduces synaptic propagation of excitatory impulses.
It is conceivable that inhibition of repetitive firing of sodium-dependent action potentials in depolarized neurons via use- and voltage-dependent blockade of sodium channels may be its main mechanism of action. Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the antiepileptic activity of carbamazepine, the inhibitory effect on dopamine and noradrenaline turnover might be responsible for its antimanic properties.
Pharmacodynamics: As an antiepileptic agent, Tegretol has a spectrum of activity that embraces: partial seizures (simple and complex) with or without secondary generalization, generalized tonic-clonic seizures, and combinations of these types of seizure.
In some, but not all, clinical studies involving administration of Tegretol as monotherapy to epileptic patients - particularly children and adolescents - the drug was reported to exert a psychotropic action, including a positive effect on attentiveness, cognitive behaviour and symptoms of anxiety and depression, as well as a reduction in irritability and aggressiveness.
As a neurotropic agent, Tegretol is clinically effective in a number of neurological disorders, e.g. it reduces paroxysmal attacks of pain in idiopathic and secondary trigeminal neuralgia. In addition, Tegretol has been observed to provide relief of neurogenic pain in a variety of conditions. In alcohol-withdrawal syndrome, Tegretol raises the lowered seizure threshold and has a beneficial effect on withdrawal symptoms (e.g. hyperexcitability, tremor, impaired gait).
As a psychotropic agent, Tegretol proved to be clinically effective in affective disorders, e.g. in the treatment of acute mania and in the maintenance treatment of manic-depressive bipolar disorders, when given either as monotherapy or in combination with other neuroleptics, antidepressants or lithium.
Pharmacokinetics: Absorption: Carbamazepine is absorbed almost completely from the tablets and relatively slowly depending on the dosage form: following a single dose, t_max is attained after 2 (oral suspension), 12 (tablets) or 24 hours (CR tablets).
Bioavailability: The bioavailability of carbamazepine is almost 100% following administration of tablets, and approximately 15% lower with CR tablets. Food intake has no effect on bioavailability.
At doses of up to 300 mg carbamazepine, approx. 75% of the total amount absorbed reaches the systemic circulation within 6 hours. The maximum recommended daily dose for this dosage form is therefore 250 mg four times daily.
Plasma concentrations: The C_max of carbamazepine following a single dose of 400 mg (tablets) is approx. 4.5 μg/ml.
With the CR tablets, there was a statistically significant reduction in fluctuation index and C_max- but no significant reduction in C_min- at steady state. Plasma concentrations in the therapeutic range at steady state are approx. 4-12 μg/ml, equivalent to 17-50 μmol/litre carbamazepine; concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite) are approx. 30% of carbamazepine concentrations.
Steady-state plasma concentrations of carbamazepine are reached within 1-2 weeks, depending individually on carbamazepine autoinduction and on heteroinduction by other enzyme-inducing drugs, as well as on pretreatment status, dosage and duration of treatment.
Distribution: Carbamazepine is 70-80% bound to serum proteins. Concentrations of unchanged substance in the CSF and saliva are equivalent to the non-protein-bound portion in the plasma (20-30%). The concentrations found in breast milk are equivalent to 25-60% of those in the plasma. Carbamazepine crosses the placental barrier.
The apparent distribution volume is 0.8-1.9 litres/kg.
Metabolism: Carbamazepine is metabolized in the liver, primarily via the epoxide-diol pathway. The first step involves oxidation to carbamazepine-10,11-epoxide, mainly via the cytochrome P450 3A4 isoenzyme. Human microsomal epoxide hydrolase is considered responsible for the formation of the pharmacologically active carbamazepine-10,11 epoxide, which is almost completely transformed into the 10,11-transdiol derivative and its glucuronides. About 30% of orally administered carbamazepine appears in the urine as the end-product of the epoxide pathway.
9-hydroxymethyl-10-carbamoyl acridan is a less important metabolite. Other important metabolic pathways lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.
Carbamazepine induces its own metabolism.
Elimination: Plasma elimination half-life following a single-dose: average of 36 hours; after repeated administration (autoinduction of the hepatic monooxygenase system): average of 16-24 hours; in patients receiving concomitant treatment with other liver-enzyme inducing drugs (e.g. phenytoin, phenobarbital): average of 9-10 hours.
Excretion: After a single 400 mg dose, 72% is excreted in the urine (2% unchanged, 1% epoxide, approx. 30% carbamazepine-10,11-transdiol and other inactive metabolites) and 28% in the faeces.
Pharmacokinetics in special patient populations: Note: The pharmacokinetics of carbamazepine are unaltered in the elderly. No data are available on patients with impaired hepatic or renal function.
Toxicology: Preclinical data: Base on conventional studies of single and repeated dose toxicity, preclinical data reveal no special risks for humans.
Mutagenic and tumorigenic potential: Standard in vitro tests and studies in animals provided no evidence that carbamazepine possesses any relevant mutagenic potential. However, some more recent studies using non-standard methods showed an increase in chromosomal aberrations and/or sister chromatid exchange in human lymphocytes. The relevance for humans is unclear.
In a 2-year carcinogenicity study with carbamazepine in rats, there was an increased incidence of hepatocellular tumours in female rats and benign testicular tumours in males. However, there is no evidence that these observations are of any relevance to therapeutic use in humans.
Developmental toxicity: Fertility studies in rats with oral carbamazepine, in some cases in the therapeutic dose range, showed inconsistent effects, ranging from a lack of findings, to impaired sperm quality, through to considerably reduced male fertility, with signs of reversibility.
In various developmental toxicity studies in rats and mice, reduced fetal weights and delayed ossification were found with carbamazepine, in some cases at doses in the therapeutic range. At higher carbamazepine doses (200-600 mg/kg/day), which led to reduced weight gain in the maternal animals, there was an increased incidence of abortions and visceral and skeletal malformations.
In a postnatal toxicity study, nursing offspring whose mothers were given 192 mg/kg/day carbamazepine showed delayed weight gain.
A risk to humans in terms of developmental toxicity cannot be ruled out.