Carbamazepine, interaction with

Carbamazepine, interaction with lithium, 36 66 Carbanion mechanism, 36 277-282 Carbenes... 

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24-4). It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. 

There is little evidence to suggest that carbamazepine interacts with digoxin, and topiramate causes only a small reduction in digoxin serum levels. Levetiracetam and tiagabine do not appear to interact with digoxin. 

Although this appears to be the only study, the effects of concurrent use are consistent with both the way carbamazepine interacts with many other CYP3A4 substrates and the way simvastatin interacts with other CYP3A4... 

Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations ofthe 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant. 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Carbamazepine is more widely used for treating chronically agitated dementia patients. Its onset of action is delayed by several days to a couple of weeks therefore, other tranquilizing medications such as antipsychotics may need to be used when first starting carbamazepine. Carbamazepine doses have problematic side effects that require blood monitoring, and it also interacts with many medications. 

Changes in the activity of adenosine receptors have been implicated in the stimulant effects of drugs like caffeine. Carbamazepine exhibits a partial agonist effect on adenosine receptors, and experimental evidence suggests that the reduced reuptake and release of noradrenaline caused by the drug are due to its interaction with these receptors. The precise relevance of these findings to its anticonvulsant and psychotropic effects is presently unclear. 

Drugs that may interact with halopehdol include anticholinergic agents, azole antifungal agents, carbamazepine, lithium, rifamycins, and fluoxetine. 

Drugs that may interact with isoniazid include acetaminophen, carbamazepine, chlorzoxazone, disulfiram, enflurane, hydantoins, ketoconazole, rifampin, and theophylline. 

Propoxyphene interacts with several drugs. The use of sedatives in combination with propoxyphene can be fatal. In addition, the metabolism of the drug is increased in smokers due to induction of liver enzymes. Thus, smokers may require a higher dose of the drug for pain relief. Propoxyphene enhances the effects of both warfarin and carbamazepine and may increase the toxicity associated with both drugs, such as bleeding and sedation, respectively. 

Most of the drug interactions with carbamazepine are related to its effects on microsomal drug metabolism. Carbamazepine can induce its own metabolism (autoinduction) after prolonged administration, decreasing its clearance rate, half-life, and serum concentrations. The possibility of autoinduction requires the clinician to reevaluate the patient s blood levels after a month of carbamazepine therapy. The autoinduction phenomenon is over in about a month. 

Itraconazole has significant interactions with a number of commonly prescribed drugs, such as rifampin, phenytoin, and carbamazepine. Itraconazole raises serum digoxin and cyclosporine levels and may affect the metabolism of oral hypoglycemic agents and coumadin. Absorption of itraconazole is impaired by antacids, Hj blockers, proton pump inhibitors, and drugs that contain buffers, such as the antiretroviral agent didanosine. 

Beta-blockers interact with a large number of other medications. The combination of beta-blockers with calcium antagonists should be avoided, given the risk for hypotension and cardiac arrhythmias. Cimetidine, hydralazine, and alcohol all increase blood levels of beta-blockers, whereas rifampicin decreases their concentrations. Beta-blockers may increase blood levels of phenothiazines and other neuroleptics, clonidine, phen-ytoin, anesthetics, lidocaine, epinephrine, monoamine oxidase inhibitors and other antidepressants, benzodiazepines, and thyroxine. Beta-blockers decrease the effects of insulin and oral hypoglycemic agents. Smoking, oral contraceptives, carbamazepine, and nonsteroidal anti-inflammatory analgesics decrease the effects of beta-blockers (Coffey, 1990). 

Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinei 1996 31 198-214. 

Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s wort, and certain anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone)... 

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. 

Incompatibilities of metoclopramide depend on drug concentration, pH, and temperature. It is incompatible with cephalosporins, chloramphenicol, sodium bicarbonate, doxorubicin, cisplatin, and cyclophosphamide. Caution should be exercised with simultaneous administration of metoclopramide with lithium, sym-pathomimetics, antidepressants, bromocriptine, and carbamazepine. Omperazole interacts with tolbutamide, clarithromycin, and phenytoin. Coadministration of rantidine and cisapride increases the plasma concentration of rantidine. Abuse of senna laxative has been reported and may cause hepatitis.176-178... 

Mebendazole Accidental mebendazole poisoning in infants is associated with convulsions, respiratory arrest, and tachyarrhythmia.181 If administered concomitantly, mebendazole interacts with phenytoin, carbamazepine, and cimetidine. 

Clonazepam Clonazepam interacts with carbamazepine, benzodiazepine, alcohol, and phenytoin. 

Ethosuximide Ethosuximide interacts with isoniazid, phenytoin, phenobarbi-tone, carbamazepine, valproic acid, antipsychotics, and antidepressants.193... 

Corticosteroids interact with barbiturates, carbamazepine, phenytoin, primidone, frusemide, thiazide, NSAIDs, antidiabetics, and antihypertensive drugs. Benzquinamide hydrochloride is incompatible with chlordiazepoxide, diazepam, and some barbiturates. Care should be exercised when handling bisacodyl to avoid contact with skin and mucosal membranes. 

E. Spina, et al., Clinically significant pharmocokinetic drug interactions with carbamazepine An update. Clin. Pharmacokinet. 31 198-214, 1996. 

Metabolism Erythromycin is extensively metabolized and is known to inhibit the oxidation of a number of drugs through its interaction with the cytochrome P-450 system (see p. 14). Clarithromycin is oxidized to the 14-hydroxy derivative, which retains antibiotic activity interference with the metabolism of drugs such as theophylline and carbamazepine has been reported. Azithromycin does not undergo metabolism. 

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

Rifampicin is an enzyme inducer and can increase the incidence and severity of isoniazid-induced hepatitis. Carbamazepine is an enzyme induction agent and interacts with isoniazid, increasing its hepatotoxicity. Isoniazid toxicity is associated with fast acetylator genotype. Although his phenotype was unknown, the interaction with carbamazepine increases risk of this toxicity. 

Khan A, Shad MU, Preskorn SH. Lack of sertraline efficacy probably due to an interaction with carbamazepine. J Clin Psychiatry 2000 61(7) 526-7. 

Alfaro CL, Nicolson R, Lenane M, Rapoport JL. Carbamazepine and/or fluvoxamine drug interaction with... 

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