Ethosuximide toxicity

ETHOSUXIMIDE ANTIBIOTICS - ISONIAZID Case of t ethosuximide levels with toxicity Inhibition of metabolism Watch for early features of ethosuximide toxicity... 

A single report describes a patient who developed psychotic behaviour and signs of ethosuximide toxicity when given isoniazid. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

VPA is also a nonspecific but weak inhibitor of the CYP-450 enzyme system, causing serum levels of other hepatically metabolized drugs to be increased. For example, concomitant use of VPA with diazepam, ethosuximide, or phenobarbital can increase the levels of these latter drugs. VPA may also cause an elevation in serum levels of CBZ s epoxide metabolite, possibly inducing toxicity. Usually, however, these changes are not clinically significant ( 367). 

Phensuximide and methsuximide are phenylsuccinimides that were developed and marketed before ethosuximide. They are used primarily as antiabsence drugs. Methsuximide is generally considered more toxic, and phensuximide less effective, than ethosuximide. Unlike ethosuximide, these two compounds have some activity against maximal electroshock seizures, and methsuximide has been used for partial seizures by some investigators. 

Ethosuximide Reduces low threshold Ca2+ currents (T-type) Well absorbed orally, with peak levels in 3-7 h not protein-bound completely metabolized to inactive compounds tjy2 typically 40 h Absence seizures Toxicity Nausea, headache, dizziness, hyperactivity Interactions Valproate, phenobarbital, phenytoin, carbamazepine, rifampicin... 

Regarding the usefulness in measuring the serum concentrations of antiepileptic drugs, it is often of value to do so with those drugs that are liable to cause toxic side effects such as carbamazepine, ethosuximide, phenobarbitone and phenytoin. In general, there seems to be little advantage in determining the serum concentrations of the newer, and better tolerated, antiepileptics. 

Isonlazid Carbamazepine Diazepam Ethosuximide Phenobarbital Phenytoin Primidone Valproate High risk of toxicity, especially with carbamazepine and phenytoin Inhibition of metabolism of the object drugs... 

Ethosuximide, USE. Ethosuximide. 2-ethyl-2-methyl succinimide (Zarontin), conforms very well to the general structural pattern for antiabsence activity. The drug is more active and less toxic than trimelhadione. It is a calcium T channel-blocking drug. Toxicity primarily involves the. skin and blood. 

The consequences of trimethadione toxicity consist of hematologic side effects (neutropeifia, pancytopenia), hemeralopia (day blindness), photophobia, diplopia, dermatologic side effects (rash and erythema multiform), CNS side effects (drowsiness and tolerance), nephrotoxic syndrome (albuminuria), and teratogenic effects such as fetal trimethadione syndrome. From this it is apparent that trimethadione is only indicated for the control of absence seizures that are not responsive or have become refractory to treatment with less toxic substances such as ethosuximide or valproic acid. 

Ethosuximide is effective against absence seizures but not tonic-clonic seizures. An initial daily dose of250 mg in children (3-6 years old) and 500 mg in older children and adults is increased by 250-mg increments at weekly intervals until seizures are adequately controlled or toxicity intervenes. Divided dosage is required occasionally to diminish nausea or drowsiness. The usual maintenance dose is 20 mg/kg/day. Use caution if the daily dose exceeds 1500 mg in adults or 750—1000 mg in children. The use of ethosuximide is discussed further below. 

Ethosuximide Drug of choice for absence seizures. Mechanism unknown. Therapeutic levels are 40-100 pg/ml. Toxicity headache, nausea/dizziness/vomiting, fatigue, ataxia, convusion, blurred vision, rashes, hepatotoxicity, lupus-like syndrome (rare), blood dyscrasias (rare but serious). Metab Not protein bound. Metabolized by liver to inactive metabolites. 

Absence status epilepticus is a condition of impaired consciousness, perhaps including mild motor symptoms, that lasts from 30 minutes to 12 hours. It can be distinguished from ongoing seizures because of organic or toxic causes by the spike-and-wave EEC pattern that is characteristic of absence seizures. The usual pharmacological treatment of absence status employs diazepam or lorazepam, followed by ethosuximide. 

Because oxazolidinediones are toxic, an extensive search was undertaken to replace them with less toxic drugs. Substituting the ring O in the oxazolidinediones with a methylene group gave the antiseizure succinimides. The clinically used succinimides include ethosuximide, methsuximide, and phensuximide, which were introduced between 1951 and 1958 (Fig. 20.11) and widely accepted for the treatment of absence seizures. 

Although ethosuximide is thought to be the least toxic of the succinimides, it can cause gastrointestinal disturbances and dose-related CNS effects, such as drowsiness, dizziness, ataxia, sleep disturbances and depression. Idiosyncratic hypersensitivity reactions include severe rashes, leukopenia, agranulocytosis (some fatal), systemic lupus erythematosus, and parkinsonian-like symptoms. In addition to being less toxic than trimethadione, ethosuximide offers a wider range of protection against different kinds of absence seizures. 

Although methsuximide is less commonly used, it may be indicated for the control of absence seizures refractory to other drugs. Although it does not precipitate tonic-clonic convulsions, it often is combined with phenytoin or phenobarbital when absence seizures coexist with tonic-clonic symptoms. Much of the efficacy of methsuximide is attributed to its desmethyl metabolite. The half-life of methsuximide is between 2.6 and 4.0 hours, but the half-life for N-desmethylsuximide is 25 hours, causing it to accumulate substantially. Concentrations of greater than 40 g/mL may be associated with toxicity. Methsuximide is considered to be more toxic than ethosuximide. 

Ethosuximide is reported to have caused phen i oin toxicity in a few cases, and it appears that ethosuximide can reduce valproate serum levels. 

Three cases have occurred in which ethosuximide appeared to have been responsible for increasing phenytoin levels, " leading to the development of phenytoin toxicity in 2 patients. ... 

The concurrent use of antiepileptics is common and often advantageous. Information on these interactions is sparse and even contradictory and their clinical importance is uncertain. Nevertheless, good monitoring would clearly be appropriate if these drugs are used with ethosuximide to monitor for potential toxicity and to ensure adequate seizure control. 

Carbamazepine levels are increased by CYP3A4 inhibitors (cimetidine, macrolides, diltiazem, fluoxetine, ketoconazole, verapamil, valproate) levels are decreased by CYP3A4 inducers (cisplatin, doxorubicin, felbamate, phenobarbital, phenytoin, primidone, rifampin, theophylline). Carbamazepine may increase levels of clomipramine, phenytoin, and primidone and lithium toxicity may decrease levels of phenytoin, warfarin, oral contraceptives, doxycycline, theophylline, haloperidol, alprazolam, clozapine, ethosuximide, and valproate may interfere with other anticonvulsants. 

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