Phenytoin interaction with other drugs

The contraceptive efficacy of depot medroxyprogesterone acetate does not appear to be affected by interactions with other drugs some interactions are known (6), but the doses used for contraceptive purposes are sufficient to remain effective even if metabolism is increased, for example by aminoglutethimide or phenytoin. 

Drug interactions Cimetidine is a CYP450 inhibitor and can inhibit the metabolism of phenytoin, warfarin, and theophylline. Famotidine, nizatidine, and ranitidine are unlikely to cause clinically significant drug interactions. All antagonists have the potential to interact with other drugs that require gastric acid for absorption (e.g., ketoconazole, itraconazole). 

The manufacturers caution if enzyme-inducing anticonvulsants, particularly phenytoin, are used with modafiniL There is speculation, based on in vitro studies, about some possible interactions with other drugs, such as warfarin. Modafinil is an inducer of CYP3A4 and therefore may be expected to interact with substrates of this isoenzyme. 

Fosphenytoin is a prodrug of phenytoin, which is rapidly and completely hydrolysed to phenytoin in the body. It is predicted to interact with other drugs in the same way as phenytoin. No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. ... 

Carbamazepine, phenytoin, pheno-barbital, and other anticonvulsants (except for gabapentin) induce hepatic enzymes responsible for drug biotransformation. Combinations between anticonvulsants or with other drugs may result in clinically important interactions (plasma level monitoring ). 

Warfarin is heavily plasma protein-bound (> 97 percent). It therefore interacts with other protein-bound drugs (e.g., carbamazepine, phenytoin, and benzodiazepines) in that binding of warfarin to plasma proteins may displace bound drug that is administered as concurrent therapy. Thus, toxicity may result, due to elevated plasma levels, and the clearance rate of the drug may increase to compensate. 

In another variation of the RESS process, referred to as RESS-SC, a solid cosolvent such as menthol was used to modulate the solubility of the drug (phenytoin) in the polymer (Thakur and Gupta 2006). It was shown that when drug particles were mixed with solid cosolvent such as menthol, the presence of solid cosolvent inhibited particle-particle interactions between drug particles, thereby hindering the crystal growth. As illustrated in Eig. 19.2, phenytoin particles are surrounded by menthol, which reduced interparticulate interactions with other phenytoin particles. The cosolvent (menthol) is then removed by downstream processing such as sublimation or lyophilization. 

The pharmacokinetics, toxic effects and interactions of quinidine with other drugs have been reviewed (30 ). An important interaction has been reported between quinidine and concurrently administered pheno-barbitone or phenytoin which can lead to large changes in the plasma quinidine concentration (31 ). 

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

Since indinavir is a substrate as well as an inhibitor of CYP3 A4, numerous and complex drug interactions can occur as described above. Indinavir levels decrease with concurrent use of rifabutin, fluconazole, St. John s wort, and rifampin. Caution is advised with other 3 A4 inducers also, including phenobarbital, phenytoin, carbamezepine, and dexamethasone. Dose reduction of indinavir should be considered if coadministered with delavirdine, ketoconazole, or itraconazole, while an increase in the dose of indinavir is indicated if the drug is coadministered with efavirenz or rifabutin. 

The area of clinical pharmacology that first directed attention to the consequences of stereoisomerism on therapeutic and pharmacokinetics was that of drug interactions, particularly those of the anticoagulant warfarin. Not only may drug interactions be stereoselective, but there is a potential for one stereoisomer to alter the pharmacokinetics and pharmacodynamics of the other. A classical example is the interaction with achiral phenylbutazone, which inhibits the metabolism of active 5-warfarin but stimulates the metabolism of the less active R isomer. Other stereoselective drug interactions include the induced elimination of misoni-dazole by phenytoin. Phenytoin enhances the clearance of (4—)-misonidazole by 56%o, which is higher than the increase in clearance of 33%o noted for (—)-misonidazole. 

The overall safety record of the currently marketed agents, particularly cimetidine and ranitidine, which have had extensive worldwide use, is excellent, and in practice safety issues seldom affect drug choice (1), except perhaps when it is necessary to avoid interactions with phenytoin, theophylline, or warfarin. Surveillance studies, which have been going on for a quarter of a century (including 10-year studies in many patients, mainly involving cimetidine and ranitidine), have failed to detect any serious adverse effects other than those recognized by 1980, or any adverse effect on mortality (2). 

In a 30-year-old man stabilized on phenytoin, the addition of nelfinavir was associated with a fall in serum phenytoin concentration and seizure recurrence (75). However, other drugs were also added or withdrawn during the observation period and the role of nelfinavir in this possible interaction is speculative. 

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