Therapeutic Use and Rationale
Therapeutic Uses of
- Heart failure (β-blockers only)
Cardioinhibitory drugs depress cardiac function by decreasing heart rate (chronotropy), myocardial contractility (inotropy), or both, which decreases cardiac output and arterial pressure. These cardiac changes reduce the work of the heart and therefore decrease myocardial oxygen consumption. The mechanisms of action of these drugs also lead to depressed electrical conduction (dromotropy) within the heart. Some of these drugs may also impair relaxation (lusitropy).
The mechanical and metabolic effects of these drugs make them very suitable for treating hypertension, angina caused by coronary artery disease, and myocardial infarction. Their effects on electrical activity make them good candidates for treating cardiac arrhythmias. Finally, some cardioinhibitory drugs, notably certain beta-blockers and ivabradine, are used in the treatment of heart failure.
Hypertension is defined as an arterial systolic pressure greater than 140 mmHg and/or a diastolic pressure greater than 90 mmHg. Hypertension can be caused by either an increase in cardiac output or by an increase in systemic vascular resistance. It is not uncommon for hypertension to be caused by elevations in both. Since cardiac output is the product of heart rate and stroke volume, cardioinhibitory drugs that reduce either or both will decrease cardiac output and decrease arterial pressure.
Angina and myocardial infarction
Cardioinhibitory drugs, by reducing heart rate, contractility, and arterial pressure, reduce the work of the heart and the oxygen demand of the heart. By reducing oxygen demand, the oxygen supply/demand ratio is improved, which can relieve a patient of anginal pain that is caused by a reduction in the oxygen supply/demand ratio because of coronary artery disease. Furthermore, cardioinhibitory drugs that block beta-adrenoceptors are used to treat myocardial infarction. Their benefit is derived not only from improving the oxygen supply/demand ratio, but also from their ability to inhibit subsequent cardiac remodeling.
Because cardioinhibitory drugs alter pacemaker activity and electrical conduction within the heart, they are useful for treating arrhythmias caused by both abnormal automaticity and abnormal conduction.
Although it seems counterintuitive that cardioinhibitory drugs would be used in heart failure, clinical studies have shown conclusively that beta-blockers improve cardiac function in certain types of heart failure. Furthermore, they have been shown to reduce deleterious cardiac remodeling that occurs in chronic heart failure. The benefit of beta-blockers may be derived from their blockade of excessive sympathetic stimulation of the heart, which is known to be harmful to the failing heart.
Another drug used in some heart failure patients is ivabradine. This relatively new drug blocks sinoatrial "funny" currents that are responsible for generating pacemaker currents controlling heart rate. By blocking these currents, ivabradine reduces heart rate and myocardial oxygen demand, which is beneficial in heart failure patients. Although beta-blockers also reduce heart rate, their actions on beta-adrenoceptors can also depress inotropy. Therefore, ivabradine acts as a "pure" heart rate reducing drug.
Drug Classes and General Mechanisms of Action
Three Classes of
- Calcium-channel blockers
- Centrally acting sympatholytics
Cardioinhibitory drugs can be divided into three mechanistic classes: beta-adrenoceptor antagonists (beta-blockers), calcium-channel blockers, and centrally acting sympatholytics.
Beta-blockers bind to beta-adrenoceptors in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both beta1 (β1) and beta2 (β2) adrenoceptors, although the predominant receptor type in number and function is β1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind to norepinephrine and epinephrine that circulate in the blood. Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the beta-adrenoceptor by competing for the binding site. Because there is some level of sympathetic tone acting on the heart, beta-blockers can reduce sympathetic influences that normally stimulate chronotropy, inotropy, dromotropy and lusitropy. These drugs have an even greater effect when there is elevated sympathetic activity. Beta-blockers that are used clinically are either non-selective (β1/β2) blockers, or relatively selective β1 blockers. Some beta-blockers have additional mechanisms of action besides beta-blockade. Beta-blockers are used for treating hypertension, angina, myocardial infarction, and arrhythmias.
Calcium-channel blockers (CCBs) bind to L-type calcium channels on cardiac myocytes and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels regulate the influx of calcium into cardiomyocytes, which stimulates cardiac myocyte contraction. In cardiac nodal tissue, L-type calcium channels play an important role in pacemaker currents and in phase 0 of the action potentials. Therefore, by blocking calcium entry into the cell, CCBs decrease myocardial force generation (negative inotropy), decrease heart rate (negative chronotropy), and decrease conduction velocity within the heart (negative dromotropy) particularly at the atrioventricular node. CCBs are used in treating hypertension, angina, and arrhythmias.
Centrally acting sympatholytics
Centrally acting sympatholytics block sympathetic activity by binding to and activating alpha2 (α2)-adrenoceptors on cardioregulatory cells within the medulla of the brain. This reduces sympathetic outflow to the heart, decreasing cardiac output by decreasing heart rate and contractility. These drugs are only used for treating hypertension.
Click below on a drug class for more details:
- Beta-adrenoceptor antagonists (beta-blockers)
- Calcium-channel blockers (CCBs)
- Centrally acting sympatholytics