Antiepileptic Drug Interactions - Principles and Clinical Implications

INTRODUCTION

Neuroscience Basics: GABA Receptors and GABA Drugs, Animation

Dilantin and thorazine

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Pilestredet 50, N Oslo, Norway. Antiepileptic drugs AEDs are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction carbamazepine, phenobarbital, phenytoin, primidone or inhibition valproic acidresulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants.

Conversely, the serum dilantin and thorazine of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs as macrolides or isoniazid and decreased by other mechanisms dilantin and thorazine induction, reduced absorption or excretion as oral contraceptives, cimetidine, probenicid and antacides.

Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives.

Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should dilantin and thorazine implemented with caution, as it is dilantin and thorazine meant to oversimplify fact matters.

Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually dilantin and thorazine necessary.

Updated knowledge regarding drug interactions is important to predict the potential for harmful or lacking effects involving AEDs. Antiepileptic drugs AEDs are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to interactions. During the last years several new AEDs have been marketed.

Initially, all new AEDs are licensed for add-on therapy for epilepsy patients. Several AEDs as lamotrigine, valproic acid, oxcarbazepine, carbamazepine, pregabalin, gabapentin, and topiramate are also increasingly used in other indications as psychiatry, neuropathic pain and migraine [ 12 ]. Polytherapy and the potential for interactions with other dilantin and thorazine increase with increasing age, and the elderly is the largest group with newonset epilepsy having a considerable risk of interactions with commonly prescribed drugs [ dilantin and thorazine ], dilantin and thorazine.

The interactions with older AEDs are thoroughly described in earlier reviews [ 8 - 12 ]. The newer second- and third generation AEDs is less interacting than the older drugs, dilantin and thorazine, which results in less complicated therapeutic outcomes and complications for the patients [ 13 ]. But, however, since the newer AEDs also often are metabolized in the liver, many of them may cause drug interactions or their serum concentrations be increased or to a lesser extent decreased by the addition of comedication [ 13 - 16 ].

Clearly, the risk of clinically important drug-drug interactions is great in patients with epilepsy, with or without comorbid conditions. The purpose of the present review is to focus upon clinically relevant interactions between AEDs and AEDs in combination with other important therapeutic drug classes, with emphasis on pharmacokinetic interactions. The first part of the review deals with the principles for pharmacokinetic interactions, dilantin and thorazine, including cytochrome P CYP and uridine glucuronyl transferases UGT -mediated enzyme induction and inhibition.

In the following sections the implementation of the individual AED interactions in the clinical setting and the consequences of alterations in serum concentrations will be focused upon. This review comprises recent advances regarding drug interactions including new AEDs that have not been described in previous reviews.

The present review is based on published articles and searches in PubMed and Google Scholar from July to Mayin addition to references from the included articles. Peer-reviewed articles in English, from international journals, from the earliest relevant data, to were included.

Primary sources and review articles of importance for the field were used. Published abstracts were included when a complete published article was not available. Unpublished material, single case reports and preclinical studies were not included, but a few exceptions were made where clinical evidence was not available.

Negative findings were not included. The searches included combinations of the terms from group 1, 2 and CYP, enzyme induction, enzyme inhibition, interaction, metabolism, pharmacology, pharmacokinetics, dilantin and thorazine, pharmacodynamics and UGT.

Antiepileptic drugs, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, dilantin and thorazine, rufinamide, stiripentol, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide. In general, pharmacokinetic interactions may alter absorption, protein binding, dilantin and thorazine, metabolism, and excretion of any drug, and these have been investigated in detail for many drugs.

They are usually related to alterations in metabolism by enzyme inducers or inhibitors and are often well described in preclinical models, dilantin and thorazine. Most drug interactions in the past were discovered due to unexpected change in the clinical status of a patient after addition or withdrawal of a drug from existing medication.

Enzyme induction involves the synthesis of new enzyme, requires protein synthesis and may take many days before it is completed, resulting in increased metabolism, dilantin and thorazine, decreased serum concentrations and pharmacological effect if no active metabolites are present of the affected drug, dilantin and thorazine, and possibly loss of seizure control. The process is reversed when the inducer is withdrawn, resulting in increased serum concentrations and potential for toxic side effects of the affected drug.

Enzyme inhibition results from competition between drugs for the same active site on the enzyme and results in decreased metabolism of the affected drug. Circulating concentrations of the inhibited drug increase to a new steady-state about five half-lives after the interaction. Consequently, pharmacological potentiation will occur quickly if the drug has a short half-life and more slowly if it has a long half-life [ 12 ]. Conversely, if the inhibitor is withdrawn, drug concentrations will decrease with risk of seizures.

If the drug is a substrate, in vivo dilantin and thorazine in vitro inhibition is enzyme-specific and substrate-independent. All drugs that are metabolized to dilantin and thorazine significant degree by the same enzyme are inhibited by inhibitors of that enzyme and therefore exhibit the same spectrum of interactions.

For a given drug the knowledge of the isoform s that catalyze s its metabolism is important. If the drug is an inhibitor, the potential for any drug to inhibit the various CYPs can be assessed in vitro using a specific substrate for those isoforms. If a new drug inhibits one isoform at therapeutic concentrations, it can be predicted that it will interact with any substrate of that isoform [ 917 - 19 ]. There are a number of individual CYP isoenzymes, each of which is a specific gene product with characteristic substrate specificity.

The P enzyme system consists of a super family of hemoproteins. The nomenclature is based on similarities in amino acid sequences deduced from genes. Each isoform is identified by three terms representing families and subfamilies. An Arabic numeral designates the family f.

The third term, another Arabic numeral, designates a unique gene dilantin and thorazine with very similar amino acid sequences f, dilantin and thorazine. CYP2C9 [ 9 ]. Clinically important CYPs involve certain isoforms that appear to have therapeutic relevance. Knowledge of the isoenzymes involved in the metabolism of established AEDs allows a prediction of interactions with new drugs in development. Ultrarapid metabolizers also exist for this enzyme, as more than 20 gene copies may exist in a few percentage of patients [ 2122 ].

Phenotypically, in clinical practice, pharmacokinetic interactions involving enzyme induction and enzyme inhibition will mimic the genotypes of extensive and poor metabolizers, respectively.

Glucuronidation is the clearance mechanism of one of ten of the most prescribed drugs in the US [ 23 ]. The UGTs are in general less substrate specific, and even though many genetic polymorphisms have been identified, no clear polymodal distribution in genotypes has been identified as for the CYP families. During the last years details in genetics of the UGTs have become available [ 2425 ], dilantin and thorazine. Lamotrigine is metabolized through UGT1A4 [ 26 ].

Valproic acid seems to be a substrate for UGT2B7, dilantin and thorazine, and polymorphisms exist [ dilantin and thorazine27 ]. Probably, their role in the metabolism of AEDs will be closely investigated in the coming years.

Pharmacogenetic variability or genetic polymorphisms and variability in the capacity of drug metabolism is an issue that is under investigation [ 171828 ]. The treatment of epilepsy aims to prevent seizures, and since there is no direct measure to control the pharmacological effect, TDM is an important tool in pharmacovigilance [ 20 ].

When a patient is treated with more than one drug, there is often a risk of clinically important drug interactions that may result in altered therapeutic outcome, and interactions are a major contributor to pharmacological variation.

TDM may reveal interactions by the measurement of the serum concentrations of AEDs and appropriate dosage adjustments may be necessary [ 14dilantin and thorazine, 16 ]. It is important to be observant for loss of efficacy or clinical signs of intoxication and to monitor the drug concentrations closely 2- 4 dilantin and thorazine following addition or withdrawal of a drug.

Knowledge of the mechanism of an interaction may allow anticipation of the observed effect. Pharmacokinetic interations in the clinical setting may be divided in three levels depending on the magnitude of alterations dilantin and thorazine serum concentrations and clinical implications. Thus, the most important interactions may be easier to remember Level 1 and 2 interactions.

Since several of the older AEDs are well-known enzyme inducers carbamazepine, phenytoin, phenobarbital, and primidone or inhibitors valproic acidinteractions with AEDs are commonly occurring and often have potentially serious clinical implications Level 1 and 2 interactions. In various instances the knowledge of the possibility of a given interaction may help in better rationalizing the therapeutic approach in avoiding unnecessary risk to the patients. The clinical significance of some of the reported interactions with AEDs may, however, be questioned, if the alterations in serum concentrations are minor Level 3 interactions.

It should also be noted that enzyme-inducing AEDs affect endogenous biochemical pathways, as metabolism of sex hormones, vitamin D homeostasis and bone metabolism and cholesterol synthesis [ 2930 ]. The newer AEDs are less susceptible to cause pharmacokinetic interactions than the older drugs, but may often be affected by other AEDs or drug classes.

Recently, four new AEDs have been marketed eslicarbazepine acetate, lacosamide, rufinamide, and stiripentol. Lacosamide does not seem to be involved in pharmacokinetic interactions and will not be discussed further [ 3132 ].

Rufinamide seems to be involved dilantin and thorazine some interactions, and stiripentol has a greater interaction potential [ 33 - 35 ]. It should, be noted, dilantin and thorazine, however, that the use of rufinamide and stiripentol is limited to special pediatric populations.

The most commonly used AEDs are listed, dilantin and thorazine. Main routes of metabolism and affection of other enzymes are listed. Isoenzymes are given where they have been identified. Several sources are used, see text. The list is not all-including but relevant examples are given. Several references are used, see text for details and selected reviews, [ 7 - 13 ] and the spc of the various drugs.

The list is not all-including, but relevant examples are given. Several references are used, see text for details and selected reviews [ 7 - 13 ] and the spc of the various drugs. Several references are used, see text for details. Well-known interactions and newly established interactions of clinical importance will be highlighted.

Carbamazepine, phenytoin, phenobarbital, and primidone are the major enzyme-inducing AEDs that stimulate the rate of metabolism of most co-administered AEDs, including valproic acid, tiagabine, ethosuximide, lamotrigine, topiramate, oxcarbazepine and its monohydroxy-derivative, zonisamide, felbamate, many benzodiazepines and, to some extent, dilantin and thorazine, levetiracetam.

Carbamazepine undergoes autoinduction and also heteroinduction by phenytoin and barbiturates [ 1012 ]. The active 10,epoxide metabolite copywrite and bidding plans carbamazepine is metabolized by epoxide hydrolase. The clinical significance of these interactions is usually modest because the consequences of the reduction in serum concentration of the affected AED are compensated for by the pharmacological effect of the added comedication.

However, in some cases, seizure control may be adversely influenced Level 2 and 3 interactions. Particular caution is required when an enzyme-inducing drug is withdrawn from the therapeutic regimen of patients taking comedications, the metabolism of which has been increased by the inducing drug.

 

Dilantin and thorazine

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