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Calcium antagonists and coronary artery disease: an opportunity missed?
1Department of Pharmacology, King's College London, United Kingdom.
Insights
Calcium antagonists are not clinically used for myocardial protection due to vascular selectivity, despite animal studies showing potential. New drug development should focus on site-selective calcium antagonists for ischemic tissues.
Area of Science:
- Cardiovascular Pharmacology
- Myocardial Protection
- Drug Development
Background:
- Calcium antagonists show potential for myocardial protection in animal models.
- Clinical application is limited by vascular selectivity and insufficient myocardial effect at tested doses.
- A misconception exists that calcium antagonists lack protective effects in the myocardium.
Purpose of the Study:
- To investigate the reasons for the lack of clinical use of calcium antagonists in myocardial protection.
- To address the misconception regarding the efficacy of calcium antagonists in the myocardium.
- To propose a new direction for calcium antagonist drug development.
Main Methods:
- Review of existing animal experimental data on calcium antagonists and myocardial protection.
- Analysis of clinical trial data regarding vascular selectivity and myocardial effects.
- Critical evaluation of the scientific literature over the past 20 years.
Main Results:
- Calcium antagonists are vascular-selective, leading to insufficient inhibition of myocardial currents at clinical doses.
- This vascular selectivity has fostered a fallacious belief in their lack of cardioprotective activity.
- Animal studies consistently indicate cardioprotective actions of calcium antagonists.
Conclusions:
- The clinical underutilization of calcium antagonists for myocardial protection represents a missed opportunity in drug development.
- New calcium antagonist development should prioritize inbuilt site-selectivity for ischemic tissues.
- Targeted drug design can overcome current limitations and unlock cardioprotective potential.
Abstract:
Why are calcium antagonists not used clinically in myocardial protection to prevent sudden death despite evidence from animal experiments that such activity may exist? The reason is that calcium antagonists are relatively vascular-selective and, at the sub-vasodilatory doses which have been tested clinically, do not inhibit the slow inward current in the myocardium. As a result a belief has grown in the fallacious concept that calcium antagonist activity in the myocardium is not a protective mechanism. Animal studies suggest that the opposite is the case. In my view, in the 20 years since the cardioprotective actions of verapamil were first demonstrated, an opportunity for drug development has been wasted. To rectify this, new drug development should begin with the objective of designing calcium antagonists with inbuilt site-selectivity for ischaemic tissue.