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Can we use calcium antagonist better in antihypertensive therapy? Circadian consideration
1Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Insights
Calcium antagonists show limited benefits in reducing cardiac events, possibly due to sympathetic nervous system activation. A new chronotherapy approach may improve outcomes by timing medications to minimize risks.
Area of Science:
- Cardiology
- Pharmacology
- Chronobiology
Background:
- Theoretical models suggested calcium antagonists as superior antihypertensive agents.
- Large clinical trials and meta-analyses indicate limited benefits of dihydropyridine calcium antagonists in reducing cardiac mortality and morbidity.
- Reflex sympathetic nervous system (SNS) activation secondary to blood pressure reduction by calcium antagonists is a potential contributing factor.
Purpose of the Study:
- To investigate the multifactorial reasons behind the unexpected outcomes of calcium antagonists in cardiovascular disease.
- To explore the role of sympathetic nervous system (SNS) activation, particularly its circadian rhythm and interaction with calcium antagonist therapy.
- To propose a novel chronotherapy strategy for antihypertensive treatment to improve clinical outcomes.
Main Methods:
- Review of theoretical reasoning and large-scale clinical trial data on calcium antagonists.
- Meta-analysis of studies on dihydropyridine calcium antagonists and cardiac outcomes.
- Analysis of the circadian rhythm of the cardiovascular system and sympathetic nervous system activity.
- Theoretical proposal of a new chronotherapy combining different drug classes at specific times.
Main Results:
- Dihydropyridine calcium antagonists have shown smaller benefits than expected, failing to reduce cardiac mortality and morbidity.
- Reflex sympathetic nervous system (SNS) activation, potentially overlapping with the morning peak of cardiovascular events, may increase risks.
- The intrinsic circadian activation of SNS and extrinsic activation from calcium antagonists could synergistically elevate cardiovascular risks.
Conclusions:
- The efficacy of calcium antagonists may be limited by reflex sympathetic activation, especially during the morning hours when cardiovascular events are most frequent.
- Antihypertensive therapy with calcium antagonists could be improved by mitigating reflex SNS activation and inhibiting intrinsic SNS activation.
- A novel chronotherapy, utilizing two drug classes with different mechanisms administered at distinct times, is proposed to reduce adverse effects and risks during vulnerable periods.
Abstract:
On the basis of theoretical reasoning, it has been thought that calcium antagonists should be better than other classes of antihypertensive agents. However in several large scale clinical trials, the benefits have been smaller than expected. Meta-analysis has indicated that dihydropyridine calcium antagonists failed to reduce cardiac mortality and morbidity. The reason for this is probably multifactorial. Reflex activation of the sympathetic nervous system (SNS) secondary to the reduction of blood pressure by calcium antagonists may play a very important role. It has been documented that the cardiovascular system has circadian rhythm and that most of the cardiovascular events in the general population happen in the morning, when the SNS is at its most active. Thus intrinsic activation of SNS set by circadian rhythm and extrinsic activation secondary to direct vasodilatation induced by calcium antagonists may overlap, which could increase cardiovascular risks and therefore result in poor clinical outcome. Antihypertensive therapy with calcium antagonists could be improved if it were possible to avoid the reflex activation and inhibit the intrinsic activation of SNS. A new chronotherapy is suggested, of which the basic principle is: to choose two classes of drugs with different mechanisms of action and use them at different periods of time during the day. By appropriate choice of the drugs and their acting time, not only the adverse effects, but also the risk during the vulnerable period could be reduced. Clinical research is needed to test this hypothesis.