C. E. Pippenger

Antiepileptic Drug Therapy in Pediatrics

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High‐dose monotherapy in treatment of intractable seizures

We evaluated the therapeutic efficacy and toxicity of high-dose monotherapy, using carbamazepine or phenytoin, in patients with previously uncontrolled seizures. Treatment with a single drug was equal to or better than polypharmacy, but only a few patients became free of seizures. Toxicity was mild and associated with higher total plasma levels after polypharmacy. Free fractions ranged from 0.14 to 0.30 for carbamazepine and from 0.60 to 0.13 for phenytoin. Toxicity was associated with free phenytoin levels above 3 μg/ml; there was no clear relationship between free carbamazepine level and toxicity.

Familial paroxysmal hypnogenic dystonia

We studied a family with dystonic spasms that occurred with non-REM sleep. This familial disorder may be related to the sporadic cases reported previously.

Treatment of a potentially lethal dose isoniazid ingestion

A seven-year-old boy ingested 3,000 mg (125 mg/kg) of isoniazid. Initial blood levels of isoniazid were 250 micrograms/mL approximately six hours after ingestion. Despite IV treatment in the emergency department with 3,000 mg pyridoxine and a repeat of the same antidote one hour later in the intensive care unit, the high isoniazid blood levels and persistent metabolic acidosis and coma prompted a decision to increase drug clearance by hemodialysis. Clearance data confirmed the effectiveness of hemodialysis in removing the poison, and the clinical response was dramatic.

Clinically Significant Carbamazepine Drug Interactions: An Overview

Summary: Knowledge of the principles of drug action and distribution contributes to an understanding of the occurrence of drug interactions. The pharmacologic action of most drugs is postulated to occur by the formation of a drug‐receptor complex at the site of action that is capable of altering the physiologic response of the target system. The therapeutic response observed depends on the sum of the numerous factors that can affect the disposition pattern of a drug. In an individual, the response to a given drug dose remains relatively constant, but in a large population, a fixed dose can produce a range of plasma concentrations and therefore varied clinical responses. For most drugs, there is a linear relationship between the total dose and the plasma concentration achieved at steady state. Saturation, or zero‐order, kinetics accounts for nonlinear increases in drug concentration with dosage increase. Drug‐drug interactions with carbamazepine include several types. (1) Autoinduction of carbamazepine metabolism increases the carbamazepine clearance rate, decreases the half‐life, and decreases serum concentrations; the clinician must reevaluate a patients serum levels at 4 to 6 weeks after initiation of therapy. (2) Carbamazepine induces the metabolism of other antiepileptic drugs, enhancing the clearance of phenytoin, primidone, valproic acid, clonazepam, and ethosuximide. (3) Other drugs added to the epileptic patients drug regimen may induce the metabolism of carbamazepine, causing increased serum concentrations. (4) Inhibition of carbamazepine metabolism by other drugs can also occur; symptoms of drug intoxication rapidly follow. Interactions occur between carbamazepine and macrolide antibiotics, cimetidine, propoxyphene, and isoniazid. Drug‐drug interactions are preventable. It is the responsibility of every physician to be alert to the potential for their occurrence whenever a change in the epileptic patients drug regimen is made.

Enhanced Gastrointestinal Excretion of Phenytoin in a Patient with Crohn's Disease

Summary: : A patient with Crohns disease and generalized seizures who lacked the distal small bowel and ascending colon required 600 mg of intravenous phenytoin daily (11 mg/kg/24 h) to maintain her plasma phenytoin levels in the 12–24 μg/ml range. She received no oral phenytoin. Stool volumes ranged from 1,125 to 1,875 ml/ 24 h, and stool fraction phenytoin levels from 15 to 41 μ.g/ml. Urinary 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin and phenytoin levels in three 24‐h samples were sufficient to account for 26, 46, and 57% of the administered drug, compared with the expected 70–90%. This was most likely due to an alteration of the normal cycle of absorption and reexcretion between the intestinal lumen and the blood resulting in net excretion of phenytoin into the bowel.

Choosing an antiepileptic drug. The case for individualized treatment.

The range of drugs available for seizure control is broad, but selection of the drug and the dosage most likely to be effective for an individual patient is complex. In general, drug choice is determined by type of seizures involved and total daily dosage is based on milligrams per kilogram, so that plasma levels for all patients can be easily interpreted. Optimal seizure control is often possible with use of a single drug; in fact, in most patients with epilepsy, single-drug therapy is more effective than multiple-drug therapy and more desirable.