Lemmer B
Institute of Pharmacology and Toxicology, Ruprecht-Karls-University Heidelberg, Mannheim, Germany.
Semin Perinatol. 2000 Aug;24(4):280-90. doi: 10.1053/sper.2000.8595.
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 asthma attacks, coronary infarction, angina pectoris, stroke, and ventricular tachycardia are circadian-phase dependent. Asthma attacks predominantly occur around 4 o'clock 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, however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. Similar findings were obtained in children. This form of hypertension is accompanied by increased end organ damages. These observations call for a circadian time-specified drug treatment. In nocturnal asthma unequal dosing of antiasthmatic drugs with a higher/single evening dose is recommended. In secondary hypertension not only the elevated blood pressure must be reduced but the disturbed blood pressure profile should be normalized, too, possibly best achieved by evening dosing. Pharmacokinetics may also not be constant within 24 hours of a day as shown for cardiovascular active drugs, antiasthmatics, anticancer drugs, psychotropics, analgesics and local anesthetics, antibiotics to mention but a few. Far more drugs were shown to display significant daily variations in their effects even after chronic application or constant infusion. Because circadian rhythms undergo maturation with development, drug therapy in children can/may also be modified by circadian time of drug dosing as shown for anticancer drugs. 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.
身体的几乎所有功能，包括那些影响药代动力学参数的功能，如药物吸收与分布、药物代谢及肾脏排泄，均呈现出显著的每日变化。此外，诸如哮喘发作、冠状动脉梗死、心绞痛、中风及室性心动过速等疾病的发作和症状也依赖于昼夜节律相位。哮喘发作主要发生在夜间4点左右。血压正常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%的继发性高血压类型中，这种节律模式被消除甚至逆转，血压出现夜间峰值。儿童也有类似的发现。这种高血压形式伴有终末器官损害增加。这些观察结果表明需要进行昼夜定时药物治疗。对于夜间哮喘，建议使用不等剂量的抗哮喘药物，晚间剂量较高/单次给药。对于继发性高血压，不仅要降低升高的血压，还应使紊乱的血压曲线正常化，可能通过晚间给药效果最佳。药代动力学在一天24小时内也可能并非恒定不变，心血管活性药物、抗哮喘药物、抗癌药物、精神药物、镇痛药、局部麻醉药及抗生素等仅是其中一些例子。即使在长期应用或持续输注后，更多药物也显示出其效应存在显著的每日变化。由于昼夜节律会随着发育而成熟，儿童的药物治疗也可根据给药的昼夜时间进行调整，如抗癌药物所示。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/或其效应或副作用的一个重要变量加以考虑。
