Phenytoin toxicity

Which of the following adverse reactions, if observed in a patient prescribed phenytoin, would indicate that the patient may be developing phenytoin toxicity ... 

There is an increased risk for bone marrow suppression when levamisole or hydroxyurea are administered witii other antineoplastic dni. Use of levamisole witii phenytoin increases die risk of phenytoin toxicity. Pegaspargase may alter drug response of the anticoagulants. When procarbazine is administered with other central nervous system (CNS) depressants, such as alcohol, antidepressants, antihistamines, opiates, or the sedatives, an additive CNS effect may be seen. Procarbazine may potentiate hypoglycemia when administered witii insulin or oral antidiabetic dru . ... 

Phenytoin Increased plasma concentrations of phenytoin symptoms of phenytoin toxicity... 

Omeprazole is classified as a proton pump inhibitor, as it acts by blocking the hydrogen-potassium adenosine triphosphate enzyme system of the gastric parietal cells. Omeprazole therefore inhibits gastric acid release. Common side-effects associated with omeprazole include diarrhoea, headache, nausea and vomiting. Concurrent administration of omeprazole and phenytoin results in enhanced effects of phenytoin, which may lead to phenytoin toxicity. 

L E. Quinidine. These are the classic signs of cinchon-ism and are adverse effects of quinidine and quinine, constituents of the cinchona tree. Some of these effects could be seen as toxic effects of phenytoin. However, auditory acuity is associated with cinchonism and not with phenytoin toxicity. Nausea but not the other effects could be associated with ciprofloxacin. Excessive drowsiness would be expected if diazepam were involved. These effects would not be expected with the estrogen replacement therapy. 

Oral anticoagulants also may potentiate hypoglycemia caused by oral hypoglycemic agents, and may enhance phenytoin toxicity. 

High isoniazid plasma levels inhibit phenytoin metabolism and potentiate phenytoin toxicity when the two drugs are coadministered. The serum concentrations of phenytoin should be monitored, and the dose should be adjusted if necessary. 

Be alert for signs of IV phenytoin toxicity, such as cardiovascular collapse and CNS depression... 

Isoniazid Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls Bactericidal activity against susceptible strains of M tuberculosis First-line agent for tuberculosis treatment of latent infection less active against other mycobacteria Oral, IV hepatic clearance (half-life 1 h) reduces levels of phenytoin Toxicity Flepatotoxic, peripheral neuropathy (give pyridoxine to prevent)... 

An interesting example of racial differences in drug conversion is seen in the metabolism of the antitubercular, isoniazid. It is inactivated by an acetylation reaction. Slow acetylation leads to toxicity (lupus, drowsiness, nausea, cyanosis). Free isoniazid also inhibits the action of phenytoin (an anticonvulsive) and results in phenytoin toxicity. Normal acetylation has a half-life of 45-80 minutes while a "slow acetylator" shows a 140-200 min half-life. The U.S. population shows a 50/50 distribution of "slow" versus "fast" acetylators. 44-55% of American Causasians and blacks are "slow". 

Tricyclic antidepressants + phenytoin —> reduction in phenytoin metabolism can increase phenytoin toxicity. 

Barbiturates + phenytoin —> decreased anticonvulsant effect due to hepatic enzyme induction enhanced phenytoin toxicity on abruptly stopping barbiturate. 

Bruni J. Phenytoin toxicity. In Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. 4th ed. New York Raven Press, 1995 345-350. 

Phenytoin - increased serum phenytoin levels may occur leading to phenytoin toxicity. Serum phenytoin levels should be monitored. 

Chlorpromazine, and in some cases other phenothiazines, has been reported to increase plasma phenytoin concentrations (656-659), to reduce plasma phenytoin concentrations (657-661), or to have no effect (658). In one case co-administration of thioridazine caused phenytoin toxicity (662). 

Neurological abnormalities have been attributed to phenytoin toxicity caused by an interaction with diazepam (53). 

TCAs PHENYTOIN 1. t plasma concentrations of phenytoin and risk of phenytoin toxicity 2.1 plasma concentrations of mianserin 1.1 metabolism of phenytoin 2. t metabolism of mianserin 1. Caution with co-administration. Consider an alternative antidepressant in patients on phenytoin 2. Be aware and watch for signs of 1 antidepressant effect of mianserin... 

BARBITURATES PHENYTOIN Variable effect on phenytoin levels, t phenobarbital levels Phenobarbital induces metabolism of phenytoin but at high levels may competitively inhibit it. Uncertain why t phenobarbital level occurs Be aware and monitor levels. Watch for early features of phenytoin toxicity... 

VALPROATE PHENYTOIN Variable effect on phenytoin levels Uncertain Be aware and monitor levels. Watch for early features of phenytoin toxicity... 

CARBAMAZEPINE H2 RECEPTOR BLOCKERS -CIMETIDINE, FAMOTIDINE, RANITIDINE t plasma concentrations of phenytoin and risk of adverse effects including phenytoin toxicity, bone marrow depression and skin reactions Inhibition of metabolism via CYP2C9 and CYP2C19 Use alternative acid suppression (e.g. ranitidine) or warn patients that effects last about 1 week. Consider monitoring carbamazepine levels, and adjust dose as necessaiy... 

METHOTREXATE ANTIEPILEPTICS -PHENYTOIN t plasma concentrations of phenytoin may occur and t risk of toxic effects of phenytoin High doses of methotrexate 1 elimination of phenytoin Monitor phenytoin levels and clinically watch for signs and symptoms of phenytoin toxicity, e.g. nausea, vomiting, insomnia, tremor, acne, hirsutism... 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

Slow acetylator Isoniazid Hydralazine, procainamide Phenelzine, sulfasalazine Increased incidence of peripheral neuropathy SLE-like syndrome and more prone to phenytoin toxicity Increased incidence of SLE-like syndrome More prone to side effects... 

Monitor for phenytoin toxicity reduce dose as needed... 

Azapropazone Phenytoin Risk of phenytoin toxicity altered relation between total phenytoin concentration and effect Displacement from plasma proteins and inhibition of phenytoin metabolism... 

Tegafur uracil Antimicrobiai drugs Phenytoin Risk of phenytoin toxicity Unknown... 

Fluconazole Phenytoin Risk of phenytoin toxicity Inhibition of phenytoin metabolism... 

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