Objective: To evaluate the potential for drug interactions with therapies for pulmonary arterial hypertension (PAH). Treatments include calcium channel blockers, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, guanylate cyclase stimulators, prostacyclin analogues, and prostacyclin receptor agonists. Data Sources: A systemic literature search (January 1980-December 2021) was performed using PubMed and EBSCO to locate relevant articles. The mesh terms used included each specific medication available as well as "drug interactions." DAILYMED was used for product-specific drug interactions. Study Selection and Data Extraction: The search was conducted to identify drug interactions with PAH treatments. The search was limited to those articles studying human applications with PAH treatments and publications using the English language. Case reports, clinical trials, review articles, treatment guidelines, and package labeling were selected for inclusion. Data Synthesis: Primary literature and package labeling indicate that PAH treatments are subject to pharmacokinetic and pharmacodynamic interactions. The management of PAH is rapidly evolving. As more and more evidence becomes available for the use of combination therapy in PAH, the increasing use of combination therapy increases the risk of drug-drug interactions. Pulmonary arterial hypertension is also associated with other comorbidities that require concomitant pharmacotherapy. Conclusion: The available literature indicates that PAH therapies are associated with clinically significant drug interactions and the potential for subsequent adverse reactions. Clinicians in all practice settings should be mindful that increased awareness of drug interactions with PAH therapy will ensure optimal management and patient safety.

Stroke is a huge burden on our society and this is expected to grow in the future due to the aging population and the associated co-morbidities. The improvement of acute stroke care has increased the survival rate of stroke patients, and many patients are left with permanent disability, which makes stroke the main cause of adult disability. Unfortunately, many patients face other severe complications such as post-stroke seizures and epilepsy. Acute seizures (ASS) occur within 1 week after the stroke while later occurring unprovoked seizures are diagnosed as post-stroke epilepsy (PSE). Both are associated with a poor prognosis of a functional recovery. The underlying neurobiological mechanisms are complex and poorly understood. There are no universal guidelines on the management of PSE. There is increasing evidence for several risk factors for ASS/PSE, however, the impacts of recanalization, drugs used for secondary prevention of stroke, treatment of stroke co-morbidities and antiseizure medication are currently poorly understood. This review focuses on the common medications that stroke patients are prescribed and potential drug interactions possibly complicating the management of ASS/PSE.

Bipolar spectrum disorders carry a significant public health burden. Disproportionately high rates of suicide, incarceration, and comorbid medical conditions necessitate an extraordinary focus on understanding the intricacies of this disease. Elucidating granular, intracellular details seems to be a necessary preamble to advancing promising therapeutic opportunities. In this chapter, we review a wide range of intracellular mechanisms including mitochondrial energetics, calcium signaling, neuroinflammation, the microbiome, neurotransmitter metabolism, glycogen synthase kinase 3-beta (GSK3β), protein kinase C (PKC) and diacylglycerol (DAG), and neurotrophins (especially BDNF), as well as the glutamatergic, dopaminergic, purinergic, and neurohormonal systems. Owing to the relative lack of understanding and effective therapeutic options compared to the rest of the spectrum, special attention is paid in the chapter to the latest developments in bipolar depression. Likewise, from a therapeutic standpoint, special attention should be paid to the pervasive mechanistic actions of lithium as a means of amalgamating numerous, disparate cascades into a digestible cognitive topology.

Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy.

We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018.

Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives.

Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.

Drug-drug interactions (DDIs) are common and avoidable complications that are associated with poor patient outcomes. Neurocritical care patients may be at particular risk for DDIs due to alterations in pharmacokinetic profiles and exposure to medications with a high DDI risk. This review describes the principles of DDI pharmacology, common and severe DDIs in Neurocritical care, and recommendations to minimize adverse outcomes. A review of published literature was performed using PubMed by searching for 'Drug Interaction' and several high DDI risk and common neurocritical care medications. Key medication classes included anticoagulants, antimicrobials, antiepileptics, antihypertensives, sedatives, and selective serotonin reuptake inhibitors. Additional literature was also reviewed to determine the risk in neurocritical care and potential therapeutic alternatives. Clinicians should be aware of interactions in this setting, the long-term complications, and therapeutic alternatives.

The incidence of seizures in intensive care units ranges from 3.3% to 34%. It is therefore often necessary to initiate or continue anticonvulsant drugs in this setting. When a new anticonvulsant is initiated, drug factors, such as onset of action and side effects, and patient factors, such as age, renal, and hepatic function, should be taken into account. It is important to note that the altered physiology of critically ill patients as well as pharmacological and nonpharmacological interventions such as renal replacement therapy, extracorporeal membrane oxygenation, and target temperature management may lead to therapeutic failure or toxicity. This may be even more challenging with the availability of newer antiepileptics where the evidence for their use in critically ill patients is limited.

This article reviews the pharmacokinetics and pharmacodynamics of antiepileptics as well as application of these principles when dosing antiepileptics and monitoring serum levels in critically ill patients. The selection of the most appropriate anticonvulsant to treat seizure and status epileptics as well as the prophylactic use of these agents in this setting are also discussed. Drug-drug interactions and the effect of nonpharmacological interventions such as renal replacement therapy, plasma exchange, and extracorporeal membrane oxygenation on anticonvulsant removal are also included.

Optimal management of antiepileptic drugs in the intensive care unit is challenging given altered physiology, polypharmacy, and nonpharmacological interventions, and requires a multidisciplinary approach where appropriate and timely assessment, diagnosis, treatment, and monitoring plans are in place.

Resistance to antiepileptic drugs (AEDs) is a major clinical problem. The overexpression of P-glycoprotein (Pgp), one of the main transporters limiting the entry of xenobiotics into the brain, is among the factors contributing to the AED resistance. Presently, there is no consensus on the interaction of carbamazepine (CBZ) with the Pgp. This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid-induced epilepsy. Verapamil significantly increased the anticonvulsant effect of CBZ and reduced its effective dose by at least 30% (from 30 mg/kg to 20 mg/kg). Binding of carbamazepine to the poloxamer 188-coated PLGA nanoparticles enabled a 30-fold increase of its anticonvulsive effect, as compared to the free drug. The inhibition of Pgp did not influence the effectivity of carbamazepine encapsulated in nanoparticles.

Considering the potential of flavonoids in reversing the P-glycoprotein (P-gp)-mediated multidrug resistance, this work aimed to assess the combined effects of silymarin and (-)-epigallocatechin gallate (EPG) on the pharmacokinetics of the P-gp substrates oxcarbazepine (OXC) and licarbazepine (LIC). Rats were pre-treated intraperitoneally with silymarin (25 mg/kg), EPG (25 mg/kg), silymarin/EPG (12.5/12.5 mg/kg; 6.25/18.75 mg/kg; 18.75/6.25 mg/kg) or verapamil (25 mg/kg, reference P-gp inhibitor) before the intraperitoneal administration of OXC (50 mg/kg). Pre-treatment with dual silymarin/EPG combinations originated peak plasma concentrations of OXC and LIC (pharmacologically active metabolite of OXC) similar to those achieved in the presence of verapamil (positive control). Moreover, the effects promoted by silymarin/EPG combinations on the magnitude of systemic drug exposure to OXC and LIC were also reflected in the corresponding drug levels attained in the brain (biophase). These findings evidence the synergistic effect of silymarin and EPG in enhancing the degree of systemic exposure to OXC and LIC in rats, which occurred in a comparable extent to that observed with verapamil. Hence, our findings support the combination of flavonoid-type P-gp inhibitors and P-gp substrate antiepileptic drugs as a potential therapeutic strategy for the management of pharmacoresistant epilepsy.

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of 'brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Verapamil add-on treatment has been suggested as a novel therapeutic concept for overcoming transporter-mediated pharmacoresistance. Efficacy data have been limited so far to case reports in individual epileptic patients. Therefore, we aimed to thoroughly evaluate the efficacy and tolerability of verapamil add-on treatment.

In a prestudy in healthy Beagle dogs the tolerability of verapamil add-on treatment was investigated. The efficacy of verapamil was then evaluated in 11 dogs with phenobarbital-resistant epilepsy.

Verapamil add-on treatment (6.2-7.3 mg/kg) did not affect phenobarbital concentrations in plasma or cerebrospinal fluid. Side effects observed in healthy as well as in epileptic dogs comprised bradycardia and a decrease in blood pressure. Therefore, we had to limit the dosage to 1-1.5 mg/kg in the main study. In phenobarbital nonresponders, verapamil failed to improve seizure control. Verapamil treatment was discontinued prematurely in five animals due to worsening of seizure control or lack of an effect. In the remaining animals, seizure frequency tended to increase during the verapamil add-on phase, reaching a mean of two seizures per month compared to the pre-verapamil phase with phenobarbital monotherapy (mean of 1.4 seizures per month). In view of the detrimental effects in the majority of the dogs, the study had to be discontinued and no further animals were enrolled.

The failure of the maximum tolerated dosage to improve seizure control in dogs with phenobarbital-resistant epilepsy argues against the suitability of verapamil add-on treatment to overcome pharmacoresistance. Deterioration of seizure control in some individual animals suggests that verapamil might also exert unfavorable effects on seizure thresholds or its spread.

To identify clinically meaningful potential drug-drug interactions (PDIs) with antiepileptic drugs (AEDs), the AEDs and co-administered drugs commonly associated with AED-PDIs, and characteristics of patients with high likelihood of AED-PDI exposure.

Five-year retrospective cohort study of veterans with new-onset epilepsy.

National Veterans Affairs and Medicare databases.

Veterans aged 66 and older with a new diagnosis of epilepsy between October 1, 1999, and September 30, 2004 (N=9,682).

AED-PDI was restricted to clinically meaningful PDIs identified using prior literature review. AED-PDIs were identified using participants' date of initial AED prescription and overlapping concomitant medications. Logistic regression analysis identified factors associated with AED-PDI, including demographic characteristics, chronic disease states, and diagnostic setting.

AED-PDI exposure was found in 45.5% (4,406/9,682); phenytoin, a drug with many PDIs, was the most commonly prescribed AED. Cardiovascular drugs, lipid-lowering medications, and psychotropic agents were the most commonly co-administered AED-PDI medications. Individuals with AED-PDI exposure were more likely to have hypertension (odds ratio (OR)=1.46, 99% confidence interval (CI)=1.24-1.82) and hypercholesterolemia (OR=1.40, 99% CI=1.24-1.57) than those without and to be diagnosed in an emergency or primary care setting than a neurology setting (emergency: OR=1.30, 99% CI=1.08-1.58; primary care: OR=1.29 99% CI=1.12-1.49).

Exposure to AED-PDI was substantial but less common in patients with epilepsy diagnosed in a neurology setting. Because potential outcomes associated with AED-PDI include stroke and myocardial infarction in a population already at high risk, clinicians should closely monitor blood pressure, coagulation, and lipid measures to minimize adverse effects of AED-PDIs. Interventions to reduce AED-PDIs may improve patient outcomes.

Worldwide, the Brugada syndrome has been recognized as an important cause of sudden cardiac death in individuals at a relatively young age. Importantly, many drugs have been reported to induce the characteristic Brugada syndrome-linked ECG abnormalities and/or (fatal) ventricular tachyarrhythmias.

The purpose of this study was to review the literature on the use of drugs in Brugada syndrome patients, to make recommendations based on the literature and on expert opinion regarding drug safety, and to ensure worldwide online and up-to-date availability of this information to all physicians who treat Brugada syndrome patients.

We performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation to each drug, and initiated a website (www.brugadadrugs.org).

The literature search yielded 506 reports for consideration. Drugs were categorized into one of four categories: (1) drugs to be avoided (n = 18); (2) drugs preferably avoided (n = 23); (3) antiarrhythmic drugs (n = 4); and (4) diagnostic drugs (n = 4). Level of evidence for most associations was C (only consensus opinion of experts, case studies, or standard-of-care) as there are no randomized studies and few nonrandomized studies in Brugada syndrome patients.

Many drugs have been associated with adverse events in Brugada syndrome patients. We have initiated a website (www.brugadadrugs.org) to ensure worldwide availability of information on safe drug use in Brugada syndrome patients.

The issue of drug-drug interactions is particularly relevant for geriatric patients with epilepsy because they are often treated with multiple medications for concurrent diseases such as cardiovascular disease and psychiatric disorders (e.g., dementia and depression). The antidepressants with the least potential for altering antiepileptic drug (AED) metabolism are citalopram, escitalopram, venlafaxine, duloxetine, and mirtazapine. The use of established AEDs with enzyme-inducing properties, such as carbamazepine, phenytoin, and phenobarbital, may be associated with reductions in the levels of drugs such as donepezil, galantamine, and particularly warfarin. Carbamazepine, phenytoin, and phenobarbital have been reported to decrease prothrombin time in patients taking oral anticoagulants, although with phenytoin, an increase in prothrombin time has also been reported. Drugs associated with increased risk of bleeding in patients taking oral anticoagulants include selective serotonin reuptake inhibitors (especially fluoxetine), gemfibrozil, fluvastatin, and lovastatin. Other drugs affected by enzyme inducers include cytochrome P450 3A4 substrates, such as calcium channel blockers (e.g., nimodipine, nilvadipine, nisoldipine, and felodipine) and the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors atorvastatin, lovastatin, and simvastatin. Although there have been no reports of AEDs altering ticlopidine metabolism, ticlopidine coadministration can result in carbamazepine and phenytoin toxicity. Also, there is a significant risk of elevated levels of carbamazepine when diltiazem and verapamil are administered. In addition, there are case reports of phenytoin toxicity when administered with diltiazem. Drugs with a lower potential for metabolic drug interactions include (1) cholinesterase inhibitors (although the theoretical possibility of a reduction in donepezil and galantamine levels by enzyme-inducing AEDs should be considered) and the N-methyl-D-aspartate receptor antagonist memantine and (2) antihypertensives such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, hydrophilic beta-blockers, and thiazide diuretics. There is a moderate risk that enzyme-inducing AEDs will decrease levels of lipophilic beta-blockers. Newer AEDs have a lower potential for drug interactions. In particular, levetiracetam and gabapentin have not been reported to alter enzyme activity. In summary, there is a significant potential for drug interactions between AEDs and drugs commonly prescribed in geriatric patients with epilepsy.

In this article, epidemiological and clinical aspects related to the use of antiepileptic drugs (AEDs) in the elderly are highlighted. Studies have shown that people with epilepsy receiving AED treatment show important deficits in physical and social functioning compared with age-matched people without epilepsy. To what extent these deficits can be ascribed to epilepsy per se or to the consequences of AED treatment remains to be clarified. The importance of characterizing the effects of AEDs in an elderly population is highlighted by epidemiological surveys indicating that the prevalence of AED use is increased in elderly people, particularly in those living in nursing homes. Both the pharmacokinetics and the pharmacodynamics of AEDs may be altered in old age, which may contribute to the observation that AEDs are among the drug classes most commonly implicated as causing adverse drug reactions in an aged population. Age alone is one of several contributors to alterations in AED response in the elderly; other factors include physical frailty, co-morbidities, dietary influences, and drug interactions. Individualization of dosage, avoidance of unnecessary polypharmacy, and careful observation of clinical response are essential for an effective and safe utilization of AEDs in an elderly population.

The treatment of epilepsy extends far beyond seizure control. Many comorbidities have a significant impact on the medical management and quality of life of patients with epilepsy. In this review, we examine interactions between epilepsy and some common medical conditions. Psychiatric disorders with a high prevalence in epilepsy include mood disorders, anxiety disorders, and psychosis. Depression is common, psychosis occurs both in direct relation to seizures and interictally, and suicide rates are increased. Changes in sexual function and reduced fertility and marriage rates are described, including a discussion of polycystic ovary syndrome, which is increased in women with epilepsy. The effects of other chronic medical comorbid conditions are reviewed, including the effects of antiepileptic medications on bone health and the impact of renal insufficiency on pharmacological therapy of epilepsy.

Antiepileptic drugs (AEDs) are commonly prescribed for long periods, up to a lifetime, and many patients will require treatment with other agents for the management of concomitant or intercurrent conditions. When two or more drugs are prescribed together, clinically important interactions can occur. Among old-generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of hepatic enzymes, and decrease the plasma concentration of many psychotropic, immunosuppressant, antineoplastic, antimicrobial, and cardiovascular drugs, as well as oral contraceptive steroids. Most new generation AEDs do not have clinically important enzyme inducing effects. Other drugs can affect the pharmacokinetics of AEDs; examples include the stimulation of lamotrigine metabolism by oral contraceptive steroids and the inhibition of carbamazepine metabolism by certain macrolide antibiotics, antifungals, verapamil, diltiazem, and isoniazid. Careful monitoring of clinical response is recommended whenever a drug is added or removed from a patient's AED regimen.

To report a young man on phenytoin who developed acute neurologic symptoms after isradipine was introduced to his treatment regimen and discuss the possible causes of this drug interaction.

A 21-year-old white man, with propionic acidemia and seizures treated with phenytoin and carbamazepine, was started on isradipine for essential hypertension. Soon thereafter, he developed acute and severe lethargy, ataxia, dysarthria, and weakness that resolved once isradipine was withheld. Phenytoin concentrations were within normal limits or elevated, despite sequential reductions of phenytoin dosage, during concomitant isradipine administration.

Isradipine is a known inhibitor of the CYP450 isoenzyme family. Although the daily dose of phenytoin was decreased significantly, phenytoin blood concentrations remained high, suggesting a pharmacokinetic interaction. Previously, the patient had never had neurologic symptoms associated with increased phenytoin concentrations. This also indicates a likely pharmacodynamic interaction between phenytoin and the calcium-channel blocker. Both phenytoin and isradipine have been shown to bind to calcium channels and to inhibit calcium entry into the cells. Binding of isradipine to the brain has been described in humans and animals, and calcium-channel blockers have been shown to cause potentiation of anticonvulsant action of phenytoin.

Acute pharmacokinetic and pharmacodynamic interactions between phenytoin and isradipine were probably responsible for the lethargy, dysarthria, ataxia, and weakness our patient developed. The combination of phenytoin and calcium-channel blockers should be used with caution.

To review the epidemiology and pharmacologic management of epilepsy in elderly patients.

Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted.

Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures.

The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.

The drug-drug interactions discussed in this article have either documented or suspected clinical relevance for patients with cardiovascular disease and the clinician involved in the care of these patients. Oftentimes, drug-drug interactions are difficult, if not impossible, to predict because of the high degree of interpatient variability in drug disposition. Certain drug-drug interactions, however, may be avoided through knowledge and sound clinical judgment. Every clinician should maintain a working knowledge of reported drug-drug interactions and an understanding of basic pharmacokinetic and pharmacodynamic principles to help predict and minimize the incidence and severity of drug-drug interactions.

To describe the primary types of antiepileptic drug (AED) interactions by using a mechanistic approach.

A literature search was performed using MEDLINE and bibliographies of recent review articles and published abstracts.

AEDs are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition and protein-binding displacement. Hepatic induction by AEDs affects the metabolism of a limited number of drugs with low therapeutic indices. Anticipation of induction interactions and careful clinical monitoring may alleviate potential problems. Most commonly used AEDs are eliminated through hepatic metabolism catalyzed by the cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Phenytoin, phenobarbital, and carbamazepine induce CYP and UGT enzymes. Lamotrigine is a weak inducer of UGT. Valproate is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and CYP2C enzymes. Felbamate induces CYP3A4, but inhibits CYP2C19 substrates. Topiramate inhibits only CYP2C19 substrates. Ethosuximide, gabapentin, tiagabine, and vigabatrin are neither inducers nor inhibitors of drug metabolism. Hepatic enzyme inhibition usually occurs because of competition at the enzyme site. Knowledge of the specific metabolic enzymes involved in the metabolism of AEDs allows clinicians to predict potential interactions.

By understanding the mechanisms of drug interactions, the pharmacist can play a key role in patient care by anticipating and preventing AED drug interactions.

The interaction of calcium antagonists, including the dihydropyridine calcium antagonists (e.g. nifedipine), verapamil and diltiazem, with drugs from other classes has major clinical ramifications as the use of drug combinations increases in frequency. Combinations are used in the treatment of disorders ranging from hypertension to cardiac rhythm disturbances, angina pectoris and peripheral vasospastic disease. In this era of organ transplantation, drugs like cyclosporin are coming into potential conflict with an ever-growing list of drugs. Drug combinations used as part of long term therapies are also making their appearance in toxic drug reactions, including antituberculous and anticonvulsant agents. Bronchodilators and H2-blockers also fall into this category of potential culprits of combined drug toxicity, and the interactions of calcium antagonists with beta-blockers and antiarrhythmic agents are also becoming a matter of concern.

Nimodipine is indicated for a variety of conditions in elderly patients. Elderly patients often have multiple morbidity and receive treatment with a variety of drugs. Therefore, it is important to investigate the possible pharmacokinetic and pharmacodynamic interactions of nimodipine with various drugs commonly prescribed for elderly patients. There were no clinically relevant interactions of nimodipine with any of the following specific agents studied: the antiarrhythmics mexiletine, propafenone, disopyramide or quinidine, digoxin, the beta-adrenoceptor antagonists propranolol or atenolol, nifedipine, warfarin, diazepam, indomethacin, ranitidine or glibenclamide (glyburide). However, there were some notable interactions. In epileptic patients taking the anticonvulsants carbamazepine, phenobarbital (phenobarbitone) and/or phenytoin, there was a 7-fold decrease in the area under the plasma concentration versus time curve (AUC) and an 8- to 10-fold decrease in the maximum plasma concentration of nimodipine. These effects were to be expected, considering the hepatic enzyme-inducing properties of these anticonvulsant drugs. Therefore concomitant use of these agents with oral nimodipine is not recommended. In contrast, epileptic patients treated with nimodipine and valproic acid (sodium valproate) showed an increase in both the AUC (approximately 50%) and maximum plasma concentrations (approximately 30%) of nimodipine, which may be explained by valproic acid inhibiting the presystemic oxidative metabolism of nimodipine. Concomitant administration of cimetidine produced an approximate doubling of the bioavailability of nimodipine. This again was to be expected, considering the known inhibitory effect of cimetidine on cytochrome P450. However, no changes in haemodynamics, clinical or laboratory status or tolerability were observed, and dose adjustment did not appear to be clinically necessary.

In choosing an antiepileptic drug, not only efficacy but also potential adverse effects have to be considered. Adverse effects that have to be taken into account include acute and chronic systemic toxicity, cognitive side effects, and teratogenesis. Acute toxicity may be dose-related, allergic or an idiosyncratic reaction. Chronic toxicity may involve the nervous system or other organs. In determining the role of new antiepileptic drugs such as lamotrigine, vigabatrin, felbamate, and gabapentin a proper evaluation of both efficacy and adverse effects is required.

Approximately 20 to 30% of patients with active intractable epilepsy are commonly treated with polytherapy antiepileptic drug regimens, and these patients may experience complicated drug interactions. Furthermore, because of the long term nature of treatment, the possibility of drug interactions with drugs used for the treatment of concomitant disease is high. Classically, clinically significant drug interactions, both pharmacokinetic and pharmacodynamic, have been considered to be detrimental to the patient, necessitating dosage adjustment. However, this need not always be the case. With the introduction of new drugs (e.g. vigabatrin and lamotrigine) with known mechanisms of action, the possibility exists that these can be used synergistically. The most commonly observed clinically significant pharmacokinetic interactions can be attributed to interactions at the metabolic and serum protein binding levels. The best known examples relate to induction (e.g. phenobarbital, phenytoin, carbamazepine and primidone) or inhibition [e.g. valproic acid (sodium valproate)] of hepatic monoxygenase enzymes. The extent and direction of interactions between the different antiepileptic drugs are varied and unpredictable. Interactions in which the metabolism of phenobarbital, phenytoin or carbamazepine is inhibited are particularly important since these are commonly associated with toxicity. Some inhibitory drugs include macrolide antibiotics, chloramphenicol, cimetidine, isoniazid and numerous sulphonamides. A reduction in efficacy of antibiotic, cardiovascular, corticosteroid, oral anticoagulant and oral contraceptive drugs occurs during combination therapy with enzyme-inducing antiepileptic drugs. Discontinuation of the enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s) and may necessitate dosage readjustment.