Enzyme inhibition phenytoin

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Phenytoin, a liver enzyme inducer, decreases serum levels of TCAs (especially desipramine and clomipramine). An increase in serum levels of nortriptyline and trazodone has also been reported. In these cases, the net effect of enzyme induction (by phenytoin) and enzyme inhibition (by TCAs) seem to be in favor of the inhibitory effects. Carbamazepine also induces liver enzymes, with a consequent reduction in serum levels of TCAs (amitriptyline, desipramine, doxepin, and nortriptyline). These effects of carbamazepine have not been observed with clomipramine, but have been reported with selective serotonin reuptake inhibitors (SSRIs). 

Enzyme-inhibiting drugs such as valproate increase the plasma concentration of lamotrigine, while enzyme-inducing drugs such as carbamazepine, phenobarbital, and phenytoin may decrease it. Lamotrigine may increase the serum concentration of the epoxide metabolite of carbamazepine. Lamotrigine enhances the metabolism of valproate. 

Due to the enzyme inhibiting potential of modafinil, the manufacturers say that care should be taken if phenytoin is also given. There is in vitro evidence to indicate that mod nil may possibly inhibit the metabolism of phenytoin by the cytochrome P450 isoenzymes CYP2C9 and CYKCW, and so there is some reason for monitoring concurrent use for evidence of increased phenytoin effects and toxicity... 

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

This is not really a treatment but there is a view that glial cells can protect against seizures since the enzyme systems they possess (e.g. Na-K+ATPase and carbonic anhydrase) facilitate the regulation of ion movements and reduce the spread of seizures. Certainly ageing, a fatty diet, and phenytoin itself increase glial cell count while decreasing seizure susceptibility. In fact inhibition of carbonic anhydrase and the production of bicarbonate was one of the first treatments for epilepsy and a recent discovery that under certain circumstances intracellular bicarbonate can depolarise neurons has created a fresh interest in it. 

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. 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

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. 

Isoniazid inhibits cytochrome P450 enzyme function and thus can interact with drugs that are subject to cytochrome P450 mediated metabolism like warfarin and the antiepileptic agents phenytoin and car-bamazepine. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Omeprazole can inhibit the metabolism of drugs metabolised mainly by the cytochrome P-450 enzyme subfamily 2C (diazepam, phenytoin), but not of those metabolished by subfamilies lA (caffeine, theophylline), 2D (metoprolol, propranolol), and 3A (ciclosporin, lidocaine (lignocaine), quinidine). Since relatively few drugs are metabolised mainly by 2C compared with 2D and 3A, the potential for omeprazole to interfere with the metabolism of other drugs appears to be limited, but the half lives of diazepam and phenytoin are prolonged as much as by cimetidine. 

Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides. 

Delavirdine is extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 enzymes. However, it also inhibits CYP3 A and thus inhibits its own metabolism. In addition to its interactions with other antiretroviral agents (see Table 49 1), delavirdine will result in increased levels of numerous agents (Table 49-3). Dose reduction of indinavir and saquinavir should be considered if they are administered concurrently with delavirdine. Delavirdine plasma concentrations are reduced in the presence of antacids, phenytoin, phenobarbital, carbamazepine, rifabutin, and rifampin concentrations are increased during coadministration with clarithromycin, fluoxetine, dexamethasone, and ketoconazole. 

Fluvoxamine inhibits CYP2C9 and CYP2C19, the enzymes responsible for the metabolism of phenytoin. 

AMIODARONE ANTIEPILEPTICS-PHENYTOIN Phenytoin levels may be t by amiodarone conversely, amiodarone levels may be 1 by phenytoin Uncertain amiodarone inhibits CYP2C9, which plays a role in phenytoin metabolism while phenytoin is a known hepatic enzyme inducer. Also, amiodarone inhibits intestinal P-gp, which may T the bioavailability of phenytoin 1 phenytoin dose by 25-30% and monitor levels watch for amiodarone toxicity. Note that phenytoin and amiodarone share similar features of toxicity, such as arrhythmias and ataxia... 

Interactions. Drugs that lower gastric acidity, e.g. antacids, histamine H2 receptor antagonists, impair the absorption of ketoconazole from the gastrointestinal tract. Like all imidazoles, ketoconazole binds strongly to several cytochrome P450 isoenzymes and thus inhibits the metabolism (and increases effects of) oral anticoagulants, phenytoin and cyclosporin, and increases the risk of cardiac arrhythmias with terfenadine. A disulfiram-like reaction occurs with alcohol. Concurrent use of rifampicin, by enzyme induction of CYP 3A, markedly reduces the plasma concentration of ketoconazole. 

Interactions. Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, cyclosporine, tacrolimus, midazolam, triazolam, cisapride and terfenidine (see above), increasing their intensity and/or duration of effect. 

---