OBJECTIVE: To describe the primary types of antiepileptic drug (AED) interactions by using a mechanistic approach. DATA SOURCES: A literature search was performed using MEDLINE and bibliographies of recent review articles and published abstracts. DISCUSSION: AEDs are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition and protein-binding displacement. Hepatic induction by AEDs affects the metabolism of a limited number of drugs with low therapeutic indices. Anticipation of induction interactions and careful clinical monitoring may alleviate potential problems. Most commonly used AEDs are eliminated through hepatic metabolism catalyzed by the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Phenytoin, phenobarbital, and carbamazepine induce CYP and UGT enzymes. Lamotrigine is a weak inducer of UGT. Valproate is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and CYP2C enzymes. Felbamate induces CYP3A4, but inhibits CYP2C19 substrates. Topiramate inhibits only CYP2C19 substrates. Ethosuximide, gabapentin, tiagabine, and vigabatrin are neither inducers nor inhibitors of drug metabolism. Hepatic enzyme inhibition usually occurs because of competition at the enzyme site. Knowledge of the specific metabolic enzymes involved in the metabolism of AEDs allows clinicians to predict potential interactions. CONCLUSIONS: By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions

Summary: Generally, the efficacy of an anticonvulsant drug is a function of the intensity of the seizure process and the drug concentration in plasma and tissues. Because of the variability of the seizure process among individuals, a universally effective drug plasma level is not to be expected. Rather a 'desirable' plasma level range for each drug can be defined, the lower limits being those levels above which the majority of patients are well controlled, the upper limits being determined by the onset of drug intoxication. With the onset of administration of anticonvulsants in average doses, the maximum plasma levels and effect are reached only after several days or with some drugs, after several weeks of therapy. The lag time can be reduced with loading doses in the case of phenytoin or phenobarbitone (2 to 3 times the usual dose). For maintenance therapy phenytoin and phenobarbitone may be given in a single daily dose without marked fluctuations in the plasma levels. Some variations in the plasma levels relative to particular doses do occur, but in the majority of patients predictable ranges of plasma levels relative to doses can be defined. Marked deviations from these expected ranges are however, not infrequent. Low levels are most frequently caused by patients' failure to take the drug regularly. Rare causes for low plasma levels are malabsorption of the drug, or unusually rapid drug metabolism or elimination. High levels may be caused by ingestion of greater than the prescribed dose, by impaired drug metabolism or elimination (genetic or constitutional), or because of interactions with other drugs. Elevation of phenytoin plasma level to the toxic range has been caused by a number of drugs, most predictably with disulfiram, sulthiame and isoniazid. When the interfering drug cannot be discontinued, the phenytoin dosage must be reduced and a new dose titrated using the plasma level as the indicator. In the treatment of petit mal, the order of preference of drugs is based on efficacy and safety, with ethosuximide the drug of choice, followed in order by trimethadione, para-methadione, methsuximide and phensuximide. In grand mal and focal epilepsies, phenytoin and phenobarbitone are the best understood and successful drugs. Primidone is also very effective. Carbamazepine can be used as an alternative. A number of other agents are available for use in combination with the prime drugs in highly refractory cases, or alone when the major drugs are contra-indicated. ACTH, or if this fails, diazepam or nitrazepam, can be used to abolish seizures in infantile spasms. Diazepam is the drug of choice in status epilepticus; given intravenously in status grand mal, or intramuscularly or intravenously in status petit mal and status focal seizures. Adverse effects of anticonvulsants can be divided into three groups: those which are a result of intoxication and which are related to elevated plasma levels. These include nystagmus, sedation and unsteadiness, and are usually, but not inevitably, a consequence of overdosage. The second category includes the side-effects, which occur as by-products of the pharmacological action of the drugs when used in the usual doses and with plasma levels in the desirable range. They may be more severe with higher doses. Frequent among these are gum hypertrophy with phenytoin, photophobia with trimethadione and depression of folate with hydantoins and barbiturates. Idiosyncratic reactions comprise the third category of unwanted effects; these are unpredictable, are unrelated to dose or plasma level and presumably occur on an allergic basis. Most frequent are skin rashes, and most dangerous are blood dyscrasias. The dysmorphogenic effects, the effects on the pregnant mother and on the newborn are reviewed.

Acute hepatic necrosis is characteristically associated with single large overdoses of acetaminophen (paracetamol) ingested with suicidal intent. However, occasional reports have suggested that the continued administration of therapeutic doses may result in hepatic damage. We describe an additional case of hepatitis related to small doses of acetaminophen, the toxicity of which was apparently potentiated by the concomitant ingestion of phenobarbital.

A 13-year-old epileptic girl took an overdose of acetaminophen (Tylenol) and phenobarbital. Hepatic encephalopathy developed and the patient died eight days later. Necropsy revealed extensive centrilobular necrosis of the liver, degeneration of the renal distal tubules, and infarcted and demyelinated foci throughout the white matter of the cerebral cortex. Electron microscopy of intact hepatocytes showed a proliferation of both smooth and rough endoplasmic reticulum consistent with enzyme induction from phenobarbital. To our knowledge, this is the first reported death in a child in the United States as a result of acetaminophen and should alert physicians to an expected increase in acetaminophen toxicity as the drug becomes more widely available

Treatment nomograms are used in paracetamol poisoning for indicating when antidotes should be given to prevent hepatic or renal damage. We report a fatal case of paracetamol poisoning in an epileptic taking phenytoin, in whom no antidotal treatment was given because it was not indicated

1 The serum concentration profile of paracetamol has been determined after administration of single 1000 mg intravenous and oral doses in six normal subjects and six epileptic patients on chronic antiepileptic drug therapy. The urinary excretion of free and conjugated paracetamol has also been determined. 2 Following intravenous administration, serum paracetamol concentration declined with first-order kinetics. Both elimination rate and total body clearance were higher in the epileptic patients, although in neither case was the difference statistically significant. 3 The oral bioavailability (mean +/- s.e. mean) was significantly lower in the epileptic patients than in the normal subjects (0.77 +/- 0.03 and 0.89 +/- 0.02 respectively, P less than 0.01), whereas the urinary excretion total (free+conjugated) paracetamol was almost identical in the two groups. 4 It is suggested that the lower bioavailability of paracetamol in the epileptic patients results from enhancement of first-pass metabolism, secondary to enzyme induction

With the introduction of three new anti-epileptic drugs (AEDs) in the UK during the past 4 years as adjunctive add-on therapy, the possibility of AED pharmacokinetic interactions has become a relevant consideration. This review highlights the current status of AED interactions with particular emphasis on those interactions that are likely to be frequently experienced or whose outcome is potentially clinically significant