The role of CYP450 system on metabolism of psychotropic drugs The role of the CYP450 enzyme system and glucuronosyltransferases in clinical psychopharmacology is being increasingly recognized. Among antidepressants, Tricyclic antidepressant drugs, such as amitriptyline, clomipramine and imipramine, are extensively metabolized by CYP1A2,2D6 and 3A4 (Table CYP enzymes involved in psychotropic drug metabolism). Nortriptyline and desipramine are, respectively, the active metabolites of amitriptyline and imipramine and are metabolized mainly by CYP2D6. Moclobemide is primarily metabolized by CYP2C subfamily, of which it is …
[ Continue Reading... ]Category: Drugs
Anticonvulsants and antidepressants Antidepressants have been extensively evaluated in relation to the general problem of their proconvulsant activity. But the definition of pharmacodynamic interaction implies that the typical pharmacologic properties of a drug are modified by another drug, without any change in the drug concentration. This definition comprises also side effects such as sedation, confusion, psychomotor impairment and others. The risk of antidepressant-induced seizures is well known, particularly in people with epilepsy. Most of the data arise from studies using in vitro technique, animal studies and clinical observations. Among selective serotonin re-uptake inhibitors, fluoxetine is the most studied drug. It is interesting to note …
[ Continue Reading... ]Background In 1972 Kenyon sent a letter to the British Medical Journal describing a patient with epilepsy treated with phenytoin (combination of phenytoin) who became pregnant despite taking usual amounts of oral contraceptive pills. She astutely attributed the contraceptive failure to an inductive effect of the combination of phenytoin on the metabolism of the sex steroid hormones. This observation was soon confirmed by others and the underlying mechanisms were further elucidated. All the older antiepileptic drugs, carbamazepine, phenobarbital, combination …
[ Continue Reading... ]Most pharmacokinetic studies have suggested the estrogens and progestins in the oral contraceptive pill were cleared approximately twice as rapidly in women patients receiving enzyme-inducing antiepileptic drugs compared to normal controls. The primary mechanism of action of the contraceptive sex hormones is thought to be due to inhibition of release of luteinizing hormone by the progestin and prevention of ovulation. The critical concentration of hormones needed to have this effect is not predictable, but the evidence that doubling of hormone clearance has been associated with contraceptive failure indicates a concentration below which failure is possible or likely. The concentration of contraceptive sex hormones in the blood and brain is determined by …
[ Continue Reading... ]Among the older antiepileptic drugs, carbamazepine, phenobarbital, primidone and combination of phenytoin have specifically been found to increase clearance of the oral contraceptive sufficiently to reduce sex hormone levels by approximately 50% whereas valproate had no such effect. Among the new antiepileptic drugs introduced since the 1990s Gabapentin, lamotrigine, levetiracetam, tiagabine and vigabatrin have been studied and found to have no significant effect on clearance of the oral contraceptives. In addition progesterone levels did not rise during the luteal phase in the studies of lamotrigine, levetiracetam or tiagabine, a finding that confirmed the prevention of ovulation. Felbamate administration had modest effect on clearance of ethinylestradiol but lowered the area under the …
[ Continue Reading... ]Epilepsy in the mentally retarded differs from epilepsy in the mentally normal patient in relation to etiology, seizure types, epilepsy syndromes, choice of anti-epileptic drugs, identification of their side effects and treatment outcome. Consequently, a successful antiepileptic drug therapy is a demanding task in terms of choice of drug therapy, combinations of drugs and side effects in mentally retarded patients compared with mentally normal people. Adverse effects and interactions between different antiepileptic drugs are a potential risk in the presence of many and difficult-to-treat seizure types, leading to frequent polytherapy. …
[ Continue Reading... ]Epilepsy occurs in approximately 15% of patients with mild mental retardation (IQ 50-69) and 30% of those with severe mental retardation (IQ < 50). In institutionalized patients with mostly severe or profound mental retardation, the prevalence of epilepsy ranges from 35% to 60%. The age at the onset of the epilepsy does not differ from that in the general population. However, children with severe mental retardation were found to have a significantly earlier seizure onset than those with a mild mental retardation. Table Occurrence of epilepsy in certain syndromes with MR shows several lesional, developmental, chromosomal and metabolic conditions in which epilepsy is associated in up to 100% of the cases. …
[ Continue Reading... ]Most of the untoward effects are not as readily recognized in mentally retarded as in mentally normal patients. These patients may also be at higher risk for certain adverse effects of antiepileptic therapy, such as reduced bone density. Pharmacokinetics of antiepileptic drugs maybe affected in many ways. Administration of the drugs maybe complicated by the reluctance of the patient to take the pills, or decreased absorption due to slow bowel movements and constipation. Elimination of drugs metabolized by the liver may also be altered due to changes in genetic capacity, especially in inborn errors of neurometabolism involving the liver. Table Intractability of epilepsy in the mentally retarded Physician related Incorrect diagnosis …
[ Continue Reading... ]Scope of the problem Women with epilepsy require chronic antiepilepsy drugs to prevent seizures, maintain their function and health. Unlike most young women they are unable to discontinue their medications if they become pregnant, for to do so increases their risk of seizures, personal injury, miscarriage and developmental …
[ Continue Reading... ]A discussion of pregnancy needs to be preceded by reviewing the problems of contraception. Oral contraceptives have not been associated with exacerbation of epilepsy. The effectiveness of hormonal contraceptives can, however, be reduced by enzyme-inducing antiepileptic drug (carbamazepine, phenytoin, phenobarbital, felbamate, topiramate). Hormonal contraceptives come in three formulations: • oral (estrogen-progesterone combinations or progesterone only); • subcutaneous (levonorgestrel) or intrauterine (progestasert) implants; • injectable (depoprovera). All three forms can be adversely impacted by enzyme-inducing antiepileptic drug. Antiepileptic drugs may lower concentrations of estrogens by 40-50%. They also increase sex hormone-binding globulin, which increases the binding of progesterone and reduces the unbound fraction. The result is that hormonal contraception is less reliable …
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