Phenytoin Cimetidine

Severe and life-threatening agranulocytosis in 2 patients and thrombocytopenia in 6 other patients " have been attributed to the concurrent use of phenytoin and cimetidine. Severe skin reactions have also been reported in 3 patients treated with phenytoin, cimetidine, and dexametha-sone after resection of brain tumours, which resolved on discontinuing phenytoin. See also Corticosteroids + Phenytoin , p.l059 for the effects of dexamethasone on phenytoin levels. 

Phenytoin interacts widi many different drugp. For example isoniazid, chloramphenicol, sulfonamides, benzodiazepines, succinimides, and cimetidine all increase phenytoin blood levels. The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin blood levels. When administering the hydantoins with meperidine, die analgesic effect of meperidine is decreased. 

The effects of buspirone are decreased when the drug is administered with fluoxetine Increased serum levels of buspirone occur if the drug is taken with erythromycin or itraconazole Should any of these combinations be required, the dosage of buspirone is decreased to 2.5 mg BID, and the patient is monitored closely. Venlafaxine blood levels increase with a risk of toxicity when administered witii MAOIs or cimetidine There is an increased risk of toxicity when trazodone is administered with the phenothiazines and decreased effectiveness of trazodone when it is administered with carbamazepine Increased serum digoxin levels have occurred when digoxin is administered with trazodone There is a risk for increased phenytoin levels when phenytoin is administered witii trazodone... 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

The answer is b. (Hardmanr p 906.) Cimetidine reversibly inhibits cytochrome P450. This is important in phase I bio transformation reactions and inhibits the metabolism of such drugs as warfarin, phenytoin, propranolol, metoprolol, quinidine, and theophylline. None of the other enzymes are significantly affected. 

The H2RAs are generally well tolerated. The most common adverse effects are headache, somnolence, fatigue, dizziness, and either constipation or diarrhea. Cimetidine may inhibit the metabolism of theophylline, warfarin, phenytoin, nifedipine, and propranolol, among other drugs. 

Caution is needed to avoid potential drug interactions. Tamsulosin decreases metabolism of cimetidine and diltiazem. Carbamazepine and phenytoin increase catabolism of a-adrenergic antagonists. 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Drugs that may interact include antacids, cimetidine, aspirin, digoxin, phenytoin, and theophylline. 

Drugs that may affect HMG-CoA reductase inhibitors include alcohol, amiodarone, antacids, azole antifungals, bile acid sequestrants, cimetidine, cyclosporine, diltiazem, erythromycin, gemfibrozil, isradipine, nefazodone, niacin, nicotinic acid, omeprazole, phenytoin, propranolol, protease inhibitors, ranitidine, rifampin, St. John s wort, and verapamil. 

Drugs that may affect valproic acid include carbamazepine, charcoal, chlorpromazine, cholestyramine, cimetidine, erythromycin, ethosuximide, felbamate, lamotrigine, phenytoin, rifampin, and salicylates. Drugs that may be affected by valproic acid include carbamazepine, clonazepam, diazepam, ethosuximide, lamotrigine, phenobarbital, phenytoin, tolbutamide, tricyclic antidepressants, warfarin, and zidovudine. 

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In particular, certain drugs may induce the metabolism of bupropion (eg, carbamazepine, phenobarbital, phenytoin) while other drugs may inhibit the metabolism of bupropion (eg, cimetidine, ritonavir). 

Drugs that affect voriconazole include the following barbiturates (long acting), cimetidine, nonnucleoside reverse transcriptase inhibitors (NNRIs), phenytoin, protease inhibitors, proton pump inhibitors, rifampin, rifabutin. 

Drugs that may affect fluconazole include cimetidine, hydrochlorothiazide, and rifampin. Drugs that may be affected by fluconazole include alfentanil, benzodiazepines, buspirone, carbamazepine, cisapride, oral contraceptives, corticosteroids, cyclosporine, haloperidol, HMG-CoA reductase inhibitors, losartan, nisoldipine, phenytoin, protease inhibitors, rifabutin, sirolimus, sulfonylureas, tacrolimus, theophylline, tolterodine, tricyclic antidepressants, vinca alkaloids, warfarin, zidovudine, and zolpidem. 

Drugs that may interact with zalcitabine include antacids, chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, vincristine, cimetidine, metoclopramide, amphotericin, aminoglycosides, foscarnet, antiretroviral nucleoside analogs, pentamidine, and probenecid. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

Diazepam (Valium, Diastat) [C-IVj [Anxiolytic, Skeletal Muscle Relaxant, Anticonvulsant, Sedative/Hypnotic/ Benzodiazepine] Uses Anxiety, EtOH withdrawal, muscle spasm, status epilepticus, panic disorders, amnesia, preprocedure sedation Action Benzodiazepine Dose Adults. Status epilepticus 5-10 mg IV/IM Anxiety 2-5 mg IM/IV Preprocedure 5-10 mg IV just prior to procedure Peds. Status epilepticus 0.5-2 mg IV/IM Sedation 0.2-0.5 mg/kg IV (onset w/in 5IV and 30 min IM duration about 1 h IV and IM) Caution [D, / -] Contra Coma, CNS depression, resp d es-sion, NAG, severe uncontrolled pain, PRG Disp Tabs 2, 5, 10 mg soln 1, 5 mg/mL inj 5 mg/mL rectal gel 2.5, 5, 10, 20 mg/mL SE Sedation, amnesia, bradycardia, i BP, rash, X resp rate Interactions T Effects W/ antihistamines, azole antifungals, BBs, CNS depressants, cimetidine, ciprofloxin, disulfiram, INH, OCP, omeprazole, phenytoin, valproic acid, verapamil, EtOH, kava kava, valman T effects OF digoxin, diuretics X effects w/ barbiturates, carbamazepine. 

Citalopram (Celexa) [Antidepressant/SSRI] WARNING Closely monitor for worsening depression or emergence of suicidality, particularly in pts <24 y Uses Depression Action SSRI Dose Initial 20 mg/d, may t to 40 mg/d X in elderly hqjatic/renal insuff Caution [C, +/-] Hx of mania, Szs pts at risk for suicide Contra MAOI or w/in 14 d of MAOI use Disp Tabs, cap, soln SE Somnolence, insomnia, anxiety, xerostomia, diaphoresis, sexual dysfxn Notes May cause X Na /SIADH Interactions t Effects W/ azole antifungals, cimetidine, Li, macrolides, EtOH t effects OF BBs, carbamazepine, CNS drugs, warfarin X effects W/ carbamaz ine X effects OF phenytoin may cause fatal Rxn W/ MAOIs EMS Use caution w/ CNS depressants, may need a reduced dose concurrent EtOH... 

Deravirdine (Rescnptor) [Antiretroviral/NNRTI] Uses HIV Infxn Action Nonnucleoside RT inhibitor Dose 400 mg PO tid Caution [C, ] CDC recommends HIV-infected mothers not to breast-feed (transmission risk) w/ renal/hepatic impair Contra Use w/ drugs dependent on CYP3A for clearance (Table VI-8) Disp Tabs SE Fat redistribution, immune reconstitution synd, HA, fatigue, rash, T transaminases, N/V/D Interactions T Effects W/ fluoxetine T effects OF benzodiazepines, cisapride, clarithromycin, dapsone, ergotamine, indinavir, lovastatin, midazolam, nifedipine, quinidine, ritonavir, simvastatin, terfena-dine, triazolam, warfarin effects W/ antacids, barbiturates, carbamazepine, cimetidine, famotidine, lansoprazole, nizatidine, phenobarbital, phenytoin, ranitidine, rifabutin, rifampin effects OF didanosine EMS Use of benzodiazepines and CCBs should be avoided may cause a widespread rash located on upper body and arms OD May cause an extension of nl SEs symptomatic and supportive Deferasirox (Exjade) [Iron Chelator] Uses Chronic iron overload d/t transfusion in pts >2 y Action Oral iron chelator Dose Initial 20 mg/kg... 

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