Influence of co-medication on the metabolism of valproate

Pisani, Francesco

doi:10.1007/bf01962698

Cited by 22 publications

(15 citation statements)

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“…Valproate is extensively metabolized in the liver and its plasma levels are reduced by enzyme-inducing drugs, including phenobarbitone, phenytoin and carbamazepine [18]. Conversely, drugs that inhibit the breakdown of valproate will increase its plasma levels.…”

Section: Drug Interactionsmentioning

confidence: 99%

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A review of valproate in psychiatric practice

Haddad

Das

Ashfaq

et al. 2009

Expert Opinion on Drug Metabolism & Toxicology

120

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Valproate (2-propylpentanoate) is available as valproic acid, sodium valproate and semisodium valproate. It has actions on dopamine, GABA and glutamate neurotransmission and intracellular signaling. Its main psychiatric use is to treat bipolar disorder. It has been used in other psychiatric disorders, including schizophrenia and borderline personality disorder, but data are insufficient to recommend this. In acute mania, valproate monotherapy has similar efficacy to antipsychotic drugs and lithium whereas the combination of valproate and an antipsychotic is more effective than either drug alone. In maintenance treatment of bipolar disorder, valproate monotherapy has comparable efficacy to olanzapine although placebo-controlled evidence is limited. Maintenance treatment with valproate and quetiapine or olanzapine is more efficacious than valproate alone when an acute episode responds to the combination. Common adverse effects of valproate include weight gain, gastrointestinal symptoms, sedation, tremor and mild elevation of hepatic enzymes. Serious hepatic toxicity is rare in adults. Many adverse effects are dose related and resolve with dose reduction. Valproate is teratogenic and specifically associated with neural tube defect. Preliminary evidence has linked in utero exposure to decreased verbal intelligence in the offspring. These effects, plus a probable increased risk of polycystic ovary syndrome, limit valproate's use in women of childbearing potential.

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Section: Drug Interactionsmentioning

confidence: 99%

“…Conversely, drugs that inhibit the breakdown of valproate will increase its plasma levels. Examples include fluoxetine, erythromycin and cimetidine [18].…”

Section: Drug Interactionsmentioning

confidence: 99%

A review of valproate in psychiatric practice

Haddad

Das

Ashfaq

et al. 2009

Expert Opinion on Drug Metabolism & Toxicology

120

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“…Teratogenic effects resulting from AED treatment occur in 5-6% of infants born to women with epilepsy, which is almost double the rate of the general population (46). Certain AED combinations are associated with enhanced risk (e.g., VPA), and an enzyme-inducing AED (e.g., PB, PHT, and CBZ) enhances the risk of malformations and hepatotoxicity and therefore alternative AEDs should perhaps be considered (47)(48)(49). Furthermore, there is evidence to suggest, from a study of a relatively small number of patients receiving polytherapy, that the incidence of malformations increases with increasing number of AEDs; exposure to two, three, or four AEDs is associated with an incidence rate of malformations of 5.5, 11, and 23%, respectively (50).…”

Section: Pregnancymentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

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Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

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“…However, there is evidence that increased hepatic elimination of valproate counterbalances this effect. Valporate and aspirin are highly bound to plasma proteins, such as albumin (Goulden, 1987;Abbott et al, 1986;Pisani, 1992). Thus when they are coadministered at sufficient doses, there is mutual displacement and a rise in the free fraction of each drug.…”

Section: Example Studiesmentioning

confidence: 99%

Drug interactions: A review with protein displacement drug-drug interaction

Kosanam¹

2018

Asian J Pharm Pharmacol

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IntroductionA drug interaction is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. This action can be synergistic (when the drug's effect is increased) or antagonistic (when the drug's effect is decreased) or a new effect can be produced that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances (National prescribing service, 2009).The risk of drug interactions is due to multiple drug therapy, multiple prescribers, poor patient compliance, patient risk factors such as predisposing factors, advancing illness.Drug interactions may include: drug-drug interactions, drugfood interactions, drug-laboratory interactions, drug-chemical interactions. Drug interactions may be the result of various processes. These processes may include alterations in the pharmacokinetics of the drug, such as alterations in the absorption, distribution, metabolism, and excretion (ADME) of a drug. Alternatively, drug interactions may be the result of the pharmacodynamic properties of the drug, e.g. the coadministration of a receptor antagonist and an agonist for the same receptor. Synergy and antagonismWhen the interaction causes an increase in the effects of one or both of the drugs the interaction is called a synergistic effect. An "additive synergy" occurs when the final effect is equal to the sum of the effects of the two drugs. When the final effect is much greater than the sum of the two effects this is called enhanced synergy (Zuzunaga, 2009). The opposite effect to synergy is termed antagonism. Two drugs are antagonistic when their interaction causes a decrease in the effects of one or both of the drugs. Both synergy and antagonism can both occur during different phases of the interaction of a drug with an organism, with each effect having a different name.For example, when the synergy occurs at a cellular receptor level this is termed agonise, and the substances involved are termed agonists. On the other hand, in the case of antagonism the substances involved are known as inverse agonists. The different responses of a receptor to the action of a drug has resulted in a number of classifications, which use terms such as"partial agonist", "competitive agonist" etc. These concepts have fundamental applications in the pharmacodynamics of these interactions (Díez and Pujol, 2002). Underlying factorsIt is possible to take advantage of positive drug interactions. AbstractDrug interactions are an important segment of drug related problems. Evaluation of Drug interactions is necessary along with patient management, especially in children and elderly patients who often receive multiple medications. Severity of drug-drug interactions is one of the problems which are poorly understood within the clinical medicine. It is increasingly necessary to become acquainted with the workings of protein bound metabolism and associated drug interaction which leads...

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Influence of co-medication on the metabolism of valproate

Cited by 22 publications

References 52 publications

A review of valproate in psychiatric practice

A review of valproate in psychiatric practice

The Importance of Drug Interactions in Epilepsy Therapy

Drug interactions: A review with protein displacement drug-drug interaction

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