Anticonvulsant drugs serum concentration

Drug-induced IgA deficiency has been found in 21 % of adults and 42% of children on anticonvulsants. The serum concentration in epileptic patients not taking anticonvulsants was normal (1 ). No particular clinical disturbance was found as a consequence. 

HYDANTOINS Fhenytoin is the most commonly prescribed anticonvulsant because of its effectiveness and relatively low toxicity. However, a genetically linked inability to metabolize phenytoin has been identified. For this reason, it is important to monitor serum concentrations of the drug on a regular basis to detect signs of toxicity Fhenytoin is administered orally and parenterally. If the drug is administered parenterally, the IV route is preferred over the intramuscular route because erratic absorption of phenytoin causes pain and muscle damage at the injection site... 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans. The development of blood level assays has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own. 

Immunoreactive parathyroid hormone concentrations may be increased by anticonvulsants, while bone mineral content is reduced. Hypocalcemia and osteopenia can occur, despite normal serum concentrations of active vitamin D metabolites, suggesting that they may be independent of drug effects on vitamin D metabolism. Bone biopsies have shown increased osteoid but normal calcification front formation, accelerated rate of mineralization, and reduced mineralization lag time, suggesting increased skeletal turnover rather than osteomalacia (96). The risk of age-related fractures in drug-treated epileptic patients is not greatly increased (97). 

Anticonvulsants (barbiturates and phenytoin) and other drugs that induce liver enzymes (such as rifampicin) can accelerate the hepatic catabolism of vitamin D and can lead to reduced serum concentrations of calcifediol and osteomalacia. Prophylactic vitamin D treatment of patients taking long-term enzyme inducers can be helpful and should be given at least in cases of anticonvulsant-drug-induced osteomalacia (74,75). 

Because of the long elimination half-hfe of phenobarbital, the blood concentration does not change rapidly. Therefore a serum specimen collected late in the dose interval (trough) is representative of the overall effect. Results from specimens collected 2 to 4 hours after the dose can be misleading, because they may be construed to be the peak concentration when in actuality they precede the peak. Table 33-1 summarizes pharmacokinetic data of the anticonvulsant drugs. 

Topiramate is routinely administered orally, absorbed rapidly, and metabolized minimally, but its disposition is affected by CyP 2C19. Serum concentrations of other anticonvulsant drugs are not significantly affected by the concurrent administration of topiramate, with the exception in individual patients on phenytoin who exhibit increased phenytoin plasma concentrations after addition of topiramate. Co-administration of phenytoin or carbamazepine decreases topiramate serum concentrations. Changes in cotherapy with phenytoin or carbamazepine (e.g., addition or withdrawal) for patients stabilized on topiramate therapy may require topiramate dose adjustment. As with other... 

Davis et al. found that folate was not the only B group vitamin which was reduced in patients receiving treatment with anticonvulsant drugs (D4). In a study of 68 patients suffering from severe epileptic seizures they found that 18 patients had a low folate, 10 a low serum pyridoxal, and in 15 both the folate and pyridoxal were reduced. Only two patients in this series had a reduced erythrocyte folate, and this is in accord with the infrequency with which a macrocytic anemia is seen in these patients. All the patients in this series had a normal hemoglobin concentration and a normal mean corpuscular volume. However, in a study of 75 epileptic children Maxwell (M3) found both the serum and erythrocyte folate levels to be reduced in 60% and similar observations have been made by other workers (M4, N2). 

Phenytoin has also been reported to cause peripheral neuropathy when used in high doses. Shorvon (S7) found that at a serum phenytoin concentration of 30 mg/liter there was a reduction in sural nerve conduction velocity in seven of nine patients and in median nerve sensory velocity in four of nine patients. It was not clear if the peripheral neuropathy was due to a toxic effect of the drug or, as seems more likely, to a folate deficiency associated wifli the anticonvulsant drug (H5). 

I. Pharmacology. The neuronal membrane-stabilizing actions of phenytoin make this a popular drug for sustained control of aoute and ohronic seizure disorders and a useful drug for certain cardiac arrhythmias. Because of the relatively slow onset of anticonvulsant action, phenytoin is usually administered after diazepam. At serum concentrations considered therapeutic for seizure control, phenytoin acts similarly to lidocaine to reduce ventricular premature depolarization and suppress ventricular tachycardia. After intravenous administration, peak therapeutic effects are attained within 1 hour. The therapeutic serum concentration for seizure control is 10-20 mg/L. Elimination is nonlinear, with an apparent half-life averaging 22 hours. Fosphenytoin, a prodrug of phenytoin for intravenous use, is converted to phenytoin after injection, with a conversion half-life of 8-32 minutes. 

Windorfer A, Sauer W, Gadeke R. Elevation of diphenylhydantoin and primidone serum concentration by additicn of dipropylacetate, a new anticonvulsant drug. Acta Paechatr Scand (1975)64,771-2. 

For example, in treating patients with epilepsy, physicians depend on laboratory tests to measure blood serum concentrations of anticonvulsant drugs. Low... 

Serum drug concentrations if previous anticonvulsant use is suspected or... 

Most anticonvulsants have linear elimination kinetics, which means that an increase in the dose of drug administered leads to a proportional increase in the blood concentration and pharmacological activity. However, diphenylhydantoin and valproate are exceptions the former does not follow linear kinetics so that the blood concentration is not directly related to the dose administered, while valproate is highly bound to serum proteins so that the total blood concentration may not directly reflect the quantity of drug available to the brain. 

After delivery, the maternal response to drug treatment and, if appropriate, serum drug concentrations should be monitored, because the disposition of anticonvulsants can change. The neonate should be monitored for potential residual effects of transplacentally acquired anticonvulsants and, in the case of barbiturates and benzodiazepines, withdrawal symptoms such as irritability and feeding difficulties. 

Similarly, drugs given for the treatment of associated disorders may inhibit the metabolism of anticonvulsants and precipitate signs of intoxication (Table 3). Examples include the increase in serum phenytoin concentrations by isoniazid and the increase in serum carbamazepine concentrations by verapamil, diltiazem, and most macrolide antibiotics (175-179). 

Tremor is seen in 15% of patients taking valproate (6), although its incidence can increase to over 60% at serum drug concentrations in a high range (80-150 pg/ml) (7) it is clinically reminiscent of essential tremor and responds to dosage reduction. Asterixis has been associated with intoxication by most anticonvulsants, but with valproate it can occur at therapeutic drug concentrations (SED-12,133) (8). 

Trepanier L A. van Schoick A, Schwark W S et al 1998 Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants 122 cases (1992-1996). Journal of the American Veterinary Medical Association 213 1449-1453... 

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