Chronopharmacology and its impact on antihypertensive treatment.

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.