Pharmacokinetic factors in the adverse cardiovascular effects of antipsychotic drugs

Antipsychotics may cause serious adverse cardiovascular effects, including prolonged QT interval and sudden death. This review considers antipsychotic-induced cardiovascular events from three perspectives: high-risk drugs, high-risk individuals and high-risk drug interactions. Pharmacokinetic drug interactions involving the cytochrome P450 (CYP) enzymatic pathway and pharmacodynamic interactions leading to direct cardiotoxic effects are discussed. Original reports on antipsychotic-induced drug interactions are reviewed, with consideration of management guidelines.The literature was reviewed from 1 January 1966 to 1 February 2002. The literature search revealed only 12 original articles published on antipsychotic drug interactions leading to cardiovascular adverse events. Only 4 of the 12 reports were prospective studies; the remainder were either retrospective or anecdotal.Although poor study designs preclude a definitive statement, it appears that pharmacokinetic interactions primarily involved the CYP2D6 and CYP3A4 enzymatic pathways. Those involving the CYP2D6 isozyme included interactions with tricyclic antidepressants, selective serotonergic reuptake inhibitors and beta-blockers. Among these drug interactions, tricyclic antidepressants were most likely to reach clinical significance because of their limited therapeutic index. Drug interactions related to the CYP3A4 pathway were generally less severe, and involved high-potency antipsychotics coadministered with inhibitors such as clarithromycin.Strategies are discussed for the management of adverse cardiovascular events related to antipsychotic drug interactions, including the use of an algorithm. Large, randomised, placebo-controlled studies with strict inclusion criteria are needed to determine the role that antipsychotics play in QT prolongation and sudden death.     

Antiplatelet drugs in cardiovascular prevention: take adverse effects and costs into account

(1) Several antiplatelet drugs have proven preventive efficacy, including aspirin, aspirin + dipyridamole, clopidogrel, ticlopidine and flurbiprofen. They differ mainly in their adverse effects and costs. (2) Aspirin has essentially gastrointestinal adverse effects, whose incidence can be limited by prescribing a daily dose below 350 mg. (3) The addition of dipyridamole to aspirin can cause headache and diarrhoea. (4) Ticlopidine should be avoided because of the risk of agranulocytosis. (5) Adverse effects are less frequent and less severe with clopidogrel than with ticlopidine. (6) Like other nonsteroidal antiinflammatory drugs, flurbiprofen has mainly gastrointestinal adverse effects. (7) Treatment is least costly with low-dose aspirin and most costly with clopidogrel.     

739例心血管类药物不良反应分析

目的:调查心血管类药物ADR的临床特点及产生原因。方法:从1998年～2001年4月公开发行的国内70余种医药学期刊中收集到心血管类药物不良反应个案776例,其中符合药物不良反应判定标准的739例,按照不良反应类别进行归纳、统计和分析。结果:心血管类药物的不良反应共涉及人体7个系统,其中呼吸系统所占的比例最大(29.8%);涉及相关药物六大类,以ACEI类药物较为常见(230例);重度不良反应46例,死亡15例,死亡占2.03％;51岁以上年龄组的不良反应(78.9％)高于其 他年龄组;口服给药(65.5％)较其他给药途径发生的比例高。结论:心血管类药物ADR的发生与药物的药理作用、给药途径、合并用药及患者的年龄、个体差异、饮食习惯等有关。     

Pharmacogenomics and drug response in cardiovascular disorders

There are a total of 17 families of drugs that are used for treating the heterogeneous group of cardiovascular diseases. We propose a comprehensive pharmacogenomic approach in the field of cardiovascular therapy that considers the five following sources of variability: the genetics of pharmacokinetics, the genetics of pharmacodynamics (drug targets), genetics linked to a defined pathology and its corresponding drug therapies, the genetics of physiologic regulation, and environmental-genetic interactions. Examples of the genetics of pharmacokinetics are presented for phase I (cytochromes P450) and phase II (conjugating enzymes) drug-metabolizing enzymes and for phase III drug transporters. The example used to explain the genetics of pharmacodynamics is glycoprotein IIIa and the response to antiplatelet effects of aspirin. Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome. The examples of cytochrome P450s, APOE and ADRB2 in relation to ethnicity, age and gender are presented to describe genetics of physiologic regulation. Finally, environmental-genetic interactions are exemplified by CYP7A1 and the effects of diet on plasma lipid levels, and by APOE and the effects of smoking in cardiovascular disease. We illustrate this five-tiered approach using examples of cardiovascular drugs in relation to genetic polymorphism.     

药物基因组学与高血压病的药物选择

药物基因组学是研究遗传学与药物反应的相互关系。本综述了药物基因组学的基本概念、高血压病和抗高血压药物反应异质性、与药物新陈代谢相关的基因、个体化治疗等方面的应用情况。对不同个体高血压相关基因、基因影响抗高血压药物治疗对血压作用的药物动力学等的研究，不仅为药物治疗的分子机制提供了新的思路，也可明确血压水平相关基因的个体差异及其在高血压发生中的重要作用。     

Pharmacogenomics and cardiovascular drugs: need for integrated biological system with phenotypes and proteomic markers

Personalized medicine is based on a better knowledge of biological variability, considering the important part due to genetics. When trying to identify involved genes and their products in differential cardiovascular drug responses, a five-step strategy is to be followed: 1) Pharmacokinetic-related genes and phenotypes (2) Pharmacodynamic targets, genes and products (3) Cardiovascular diseases and risks depending on specific or large metabolic cycles (4) Physiological variations of previously identified genes and proteins (5) Environment influences on them. After summarizing the most well-known genes involved in drug metabolism, we will take as example of drugs, the statins, considered as very important drugs from a Public-Health standpoint, but also for economical reasons. These drugs respond differently in human depending on multiple polymorphisms. We will give examples with common ApoE polymorphisms influencing the hypolipemic effects of statins. These drugs also have pleiotropic effects and decrease inflammatory markers. This illustrates the need to separate clinical diseases phenotypes in specific metabolic pathways, which could propose other classifications, of diseases and related genes. Hypertension is also a good example of clinical phenotype which should be followed after various therapeutic approaches by genes polymorphisms and proteins markers. Gene products are under clear environmental expression variations such as age, body mass index and obesity, alcohol, tobacco and dietary interventions which are the first therapeutical actions taken in cardiovascular diseases. But at each of the five steps, within a pharmacoproteomic strategy, we also need to use available information from peptides, proteins and metabolites, which usually are the gene products. A profiling approach, i.e., dealing with genomics, but now also with proteomics, is to be used. In conclusion, the profiling, as well as the large amount of data, will more than before render necessary an organized interpretation of DNA, RNA as well as proteins variations, both at individual and population level.     

Anti-Alzheimer drugs: life-threatening adverse effects

Cardiovascular disorders are the most frequently reported adverse effects of drugs used to treat Alzheimer's disease. They are potentially fatal.     

The adverse effects of antiepileptic drugs in children

Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.     

Behavioral adverse effects of antiepileptic drugs in epilepsy

Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs.     

The adverse effects of antiepileptic drugs in children

Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.     

Renal adverse effects of nonsteroidal anti-inflammatory drugs

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.     

喹诺酮类药物不良反应的分析

目的：探讨喹诺酮类药物不良反应发生的相关因素,为临床合理用药提供参考。方法：搜集2009年10月~2010年4月门诊149例患者服用喹诺酮类抗菌药物（左氧氟沙星、加替沙星、诺氟沙星、环丙沙星、莫西沙星、洛美沙星,依诺沙星）所导致不良反应的临床资料,进行回顾分析。结果：喹诺酮类抗菌药物不良反应主要表现在变态反应、神经、消化、呼吸、免疫、泌尿系统等,其中变态反应、消化及神经系统症状较多也更加突出。结论：合理选用喹诺酮类药物,防止药物滥用,减少毒性反应及不良反应,对提高临床疗效具有重要的意义。     

Cardiovascular adverse effects of antipsychotic drugs.

Minor cardiovascular adverse effects from antipsychotic drugs are extremely common. They include effects such as postural hypotension and tachycardia due to anticholinergic or alpha1-adrenoceptor blockade, and may occur in the majority of patients at therapeutic dosages. There are a number of pharmacological effects that are of uncertain clinical significance, such as blockade of calmodulin, sodium and calcium channels and alpha2-adrenoceptors in the central nervous system. The most serious consequences of treatment, arrhythmias and sudden death, are probably uncommon and are most likely to be caused primarily by blockade of cardiac potassium channels such as HERG. Incomplete evidence suggests that arrhythmias and sudden death are a particular problem with certain drugs (thioridazine and droperidol), high risk populations (elderly, pre-existing cardiovascular disease, inherited disorders of cardiac ion channels or of antipsychotic drug metabolism) or people taking interacting drugs (such as drugs that prolong the QT interval, e.g. tricyclic antidepressants, drugs that inhibit antipsychotic drug metabolism, or diuretics). Clozapine may be unique in also causing death from myocarditis and cardiomyopathy. Much further research is required to more clearly identify high risk drugs and the populations that are at risk of sudden death, as well as the mechanisms involved and the extent of the risk.     

普罗帕酮致严重心血管不良反应8例

本文报道普罗帕酮(propafenone)致严重心血管不良反应8例。静脉注射普罗帕酮7例中,显著血压下降者6例;窦房结功能抑制3例;急性左心衰竭2例;心房扑动患者静脉给药后,心房扑动变为1:1传导,心室率显著加快1例;另1例心房扑动患者,口服普罗帕酮600mg/d,9d后发生完全性房室传导阻滞,呈缓慢室性自搏性心律伴显著血压下降。作者推荐先用最低有效量,逐渐加量,特别对左室功能受损,窦房结功能不全和有传导障碍者,尤须谨慎。     

降血压药物的潜在不良反应及其预防

了解抗高血压药物的不良反应对高血压的长期治疗具有重要临床意义。本文回顾抗高血压药物的潜在不良反应如心脏抑制、肾损害及血钾异常等,其目的为有助于预防严重不良反应的发生和改善高血压患者的用药依从性。