Lemmer B
Institute of Pharmacology & Toxicology, Faculty of Clinical Medicine, Ruprecht-Karls-University Heidelberg, Germany.
Acta Physiol Pharmacol Bulg. 1999;24(3):71-80.
Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms are endogenous in nature, driven by oscillators or clocks, and persist under free-running (e.g. constant darkness) conditions. The genes expressing the biological clock have been identified in various species. The important feature of endogeneous biological rhythms is their anticipatory character. Rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 hours of a day as well as during changing seasons. Having this in mind it is easy to conceive that not only must the right amount of the right substance be at the right place, but also this must occur at the right time. Also in man nearly all functions of the body including those influencing pharmacokinetic parameters such as drug absorption and distribution, drug metabolism and renal elimination display significant daily variations. Also the onset and symptoms of diseases such as coronary infarction, angina pectoris, stroke, ventricular tachycardia are circadian phase dependent. Myocardial infarction and angina attacks as well as silent ischemias (ST-segment depression) in stable angina pectoris have an early morning peak between 8-12 h. In contrast, ECG abnormalities and angina attacks in variant angina mainly occur at night. Blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. In about 70% of forms of secondary hypertension (e.g. renal disease, hyperthyroidisms, hormonal diseases, gestational hypertension), however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. This form of hypertension is accompanied by increased end organ damages. Thus, different subtypes of a disease (angina pectoris, hypertension) can display different circadian patterns in symptoms. These observations are a challenge for basic and clinical research to get a better understanding on the underlying mechanisms of regulation. Moreover, they call for a circadian time-specified drug treatment. From above it is evident that pharmacokinetics may also not be constant within a day. Chronopharmacokinetics have been shown for several cardiovascular active drugs (propranolol, nifedipine, verapamil, enalapril, isosorbide-5-mononitrate, digoxin, etc.). Far more drugs were shown to display significant daily variations in their effects (chronopharmacodynamics, chronotoxicology) even after chronic application or constant infusion. In conclusion, there is clear evidence that the dose/concentration-response relationship of drugs can be significantly dependent on the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and/or its effects or side effects.
昼夜节律在真核生物组织的各个层面，从植物界到动物界都有记载。昼夜节律本质上是内源性的，由振荡器或生物钟驱动，并在自由运行（如持续黑暗）条件下持续存在。在各种物种中已鉴定出表达生物钟的基因。内源性生物节律的重要特征是其预期性。所有生命系统固有的节律性，使它们能够在一天24小时以及季节变化的环境条件变化下，更轻松地适应并更好地生存。考虑到这一点，很容易设想不仅必须在正确的位置有适量的正确物质，而且这必须在正确的时间发生。在人类中，身体的几乎所有功能，包括那些影响药代动力学参数（如药物吸收和分布、药物代谢和肾脏排泄）的功能，都表现出显著的每日变化。疾病如冠状动脉梗死、心绞痛、中风、室性心动过速的发作和症状也依赖于昼夜节律阶段。心肌梗死和心绞痛发作以及稳定型心绞痛中的无症状性缺血（ST段压低）在上午8点至12点之间有一个清晨高峰。相比之下，变异型心绞痛的心电图异常和心绞痛发作主要发生在夜间。正常血压者和原发性高血压患者的血压和心率在白天最高，随后夜间下降，清晨上升。然而，在约70%的继发性高血压（如肾病、甲状腺功能亢进、激素疾病、妊娠高血压）类型中，这种节律模式被消除甚至逆转, 血压出现夜间高峰。这种高血压形式伴随着终末器官损害的增加。因此，一种疾病（心绞痛、高血压）的不同亚型在症状上可以表现出不同的昼夜模式。这些观察结果对基础和临床研究来说是一个挑战，以便更好地理解潜在的调节机制。此外，它们要求进行昼夜定时药物治疗。从上述内容可以明显看出，药代动力学在一天内也可能不是恒定的。几种心血管活性药物（普萘洛尔、硝苯地平、维拉帕米、依那普利、5-单硝酸异山梨酯、地高辛等）已显示出时辰药代动力学特征。甚至在长期应用或持续输注后，更多药物被证明在其作用（时辰药效学、时辰毒理学）方面表现出显著的每日变化。总之，有明确证据表明药物的剂量/浓度-反应关系可能显著依赖于一天中的时间。因此，昼夜时间必须作为影响药物药代动力学和/或其作用或副作用的一个重要变量加以考虑。
