Anticonvulsants toxicity

In addition to sinus tachycardia and tremor, vomiting is common after overdose. Hypotension, tachycardia, hypokalemia, and hyperglycemia may occur, probably due to -adrenergic activation. The cause of this activation is not fully understood, but the effects can be ameliorated by the use of B-blockers (see below). Cardiac arrhythmias include atrial tachycardias, premature ventricular contractions, and ventricular tachycardia. In severe poisoning (eg, acute overdose with serum level > 100 mg/L), seizures often occur and are usually resistant to common anticonvulsants. Toxicity may be delayed in onset for many hours after ingestion of sustained-release tablet formulations. 

Phenytoin. Phenytoin sodium is sodium diphenylhydantoin [630-93-3] which is stmcturally related to the barbiturates. It was originally introduced as an anticonvulsant (18) (see Hypnotics, sedatives, and anticonvulsants) and later found to have antiarrhythmic properties (19), although not approved by the PDA for any arrhythmic indications. Phenytoin is effective in the treatment of ventricular arrhythmias associated with acute MI and with digitalis toxicity (20). It is not very effective in treatment of supraventricular arrhythmias (20). 

Methanol, l-isoquinolyl(phenyl)-confonnation, 2, 110 Methanol, pyrimidinyl-synthesis, 3, 113 Methanol, tetrahydropyran-2-yl-microwave spectra, 3, 625 Methantheline as neurotransmitter, 1, 175 therapeutic properties, 3, 882 Methaphenilene biological activity, 4, 911 Methapyrilene biological activity, 4, 911 toxicity, 4, 912 Methaqualone, 3, 150 as anticonvulsant, 1, 166 pyrido[2,3-d]pyrimidine analogues metabolism, 3, 205 as sedative, 1, 166 Metharbitone as anticonvulsant, 1, 166 Methazolamide... 

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... 

Leucovorin decreases the effectiveness of the anticonvulsants. There is an increased risk of 5-fluorouracil toxicity when the drug is administered with leucovorin. 

Review of the literature regarding toxic effects of mirex and chlordecone did not reveal any human populations that are known to be unusually sensitive to mirex or chlordecone. However, based on knowledge of the toxicities of mirex and chlordecone, some populations can be identified that may demonstrate unusual sensitivity to these chemicals. Those with potentially high sensitivity to mirex include the very young. Those with potentially high sensitivity to chlordecone include juvenile and elderly person and persons being treated with some antidepressants or the anticonvulsant, diphenylhydantoin. 

Anticonvulsants. Scattered case reports suggest that carbamazepine (Tegretol) and valproic acid (Depakote, Depakene) may be helpful in the treatment of panic disorder. This has yet to be verified in systematic studies. Furthermore, because these anticonvulsants are hindered by toxicity and side effect concerns (cf. Chapter 3), they should only be considered if other better studied and more tolerable treatment options have failed. 

Epoxide metabolites can be generated from a variety of aromatic systems. Anticonvulsants are a class of drug whose side-effects, such as hepatic necrosis and aplastic anaemia, are thought to be mediated by chemically reactive epoxide metabolites formed by cytochrome P450 oxidation. For instance phenytoin (Figure 8.6) toxicity is correlated with oxidation and the inhibition of epoxide hydrolase [8]. 

Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-... 

Valproic acid (VPA) is gaining increasing acceptance as a first-line drug it is less sedating than other anticonvulsants. Tremor, gastrointestinal upset, and weight gain are frequently observed reversible hair loss is a rarer occurrence. Hepatotoxicity may be due to a toxic catabolite (4-en VPA). 

Schaffarzick RW, Brown BJ The anticonvulsant activity and toxicity of methyl parafynol (Vormison) and some other alcohols. Science 116 663-665, 1952... 

Obtain cultures Obtain cultures and determine susceptibility before treatment. Determine blood levels Determine blood levels weekly for patients having reduced renal function, for individuals receiving more than 500 mg/day, and for those with symptoms of toxicity. Adjust dosage to maintain blood level less than 30 mcg/mL. Anticonvulsant drugs or sedatives Anticonvulsant drugs or sedatives may be effective in controlling symptoms of CNS toxicity, such as convulsions, anxiety, and tremor. Closely observe patients receiving more than 500 mg/day for such symptoms. Pyridoxine may prevent CNS toxicity, but its efficacy has not been proven. 

If we apply this concept of samration to drug elimination we get a similar picture. The anticonvulsant phenytoin depends critically for its elimination on one enzyme reaction (to produce the p-hydroxy-phenyl metabolite) and this, like the turnstile, can exceed its capacity to metabolize the drug. Phenytoin is then eliminated at a constant amount (not a constant proportion) per unit time. If input then exceeds this elimination capacity (and volume of distribution does not change), plasma concentration will rise rapidly into the toxic range. 

Head trauma, meningitis, childhood fevers, brain tumors, and degenerative diseases of the cerebral circulation are conditions often associated with the appearance of recurrent seizures that may require treatment with anticonvulsant drugs. Seizures also may be a toxic manifestation of the action of central nervous system (CNS) stimulants and certain other drugs. Seizures often occur in hyperthermia (febrile seizures are very common in infants) sometimes in eclampsia, uremia, hypoglycemia, or pyridoxine deficiency and frequently as a part of the abstinence syn-... 

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. 

HT2, and receptors and possesses very little extrapyramidal toxicity but significant sedative and autonomic side effects. Flumazenil is a benzodiazepine antagonist, and carbamazepine is an anticonvulsant neither possesses significant antipsychotic properties. 

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