Therapeutic Use and Rationale
Therapeutic Uses of Vasodilators
- Systemic and pulmonary hypertension
- Heart failure
As the name implies, vasodilator drugs relax the smooth muscle in blood vessels, which causes the vessels to dilate. Dilation of arterial (resistance) vessels leads to a reduction in systemic vascular resistance, which leads to a fall in arterial blood pressure. Dilation of venous (capacitance ) vessels decreases venous blood pressure.
Vasodilators are used to treat hypertension, heart failure and angina; however, some vasodilators are better suited than others for these indications. Vasodilators that act primarily on resistance vessels (arterial dilators) are used for hypertension and heart failure, but not for angina because of reflex cardiac stimulation. Venous dilators are very effective for angina, and sometimes used for heart failure, but are not used as primary therapy for hypertension. Most vasodilator drugs are mixed (or balanced) vasodilators in that they dilate both arteries and veins; however, there are some very useful drugs that are highly selective for arterial or venous vasculature. Some vasodilators, because of their mechanism of action, also have other important actions that can in some cases enhance their therapeutic utility as vasodilators or provide some additional therapeutic benefit. For example, some calcium channel blockers not only dilate blood vessels, but also depress cardiac mechanical and electrical function, which can enhance their antihypertensive actions and confer additional therapeutic benefit such as blocking arrhythmias.
Arterial dilator drugs are commonly used to treat systemic and pulmonary hypertension, heart failure and angina. They reduce arterial pressure by decreasing systemic vascular resistance. This benefits patients in heart failure by reducing the afterload on the left ventricle, which enhances stroke volume and cardiac output and leads to secondary decreases in ventricular preload and venous pressures. Anginal patients benefit from arterial dilators because by reducing afterload on the heart, vasodilators decrease the oxygen demand of the heart, and thereby improve the oxygen supply/demand ratio. Oxygen demand is reduced because ventricular wall stress is reduced by arterial dilators. Some vasodilators can also reverse or prevent arterial vasospasm (transient contraction of arteries), which can precipitate anginal attacks.
Most drugs that dilate arteries also dilate veins; however, hydralazine, a direct acting vasodilator, is highly selective for arterial resistance vessels.
The effects of arterial dilators on overall cardiovascular function can be depicted graphically using cardiac and systemic vascular function curves as shown to the right. Selective arterial dilation decreases systemic vascular resistance, which increases the slope of the systemic vascular function curve (red line) without appreciably changing the x-intercept (mean circulatory filling pressure). This alone causes the operating point to shift from A to B, resulting in an increase in cardiac output (CO) with a small increase in right atrial pressure (PRA). The reason for the increase in PRA is that arterial dilation increases blood flow from the arterial vasculature into the venous vasculature, thereby increasing venous volume and pressure. However, arterial dilators also reduce afterload on the left ventricle and therefore unload the heart, which enhances the pumping ability of the heart. This causes the cardiac function curve to shift up and to the left (not shown in figure). Adding to this afterload effect is the influence of enhanced sympathetic stimulation due to a baroreceptor reflex in response to the fall in arterial pressure, which increases heart rate and inotropy. Because of these compensatory cardiac responses, arterial dilators increase cardiac output with little or no change in right atrial pressure (cardiac preload). Although cardiac output is increased, systemic vascular resistance is reduce relatively more so arterial pressure falls. The effect of reducing afterload on enhancing cardiac output is even greater in failing hearts because stroke volume more sensitive to the influence of elevated afterload in hearts with impaired contractility.
Drugs that dilate venous capacitance vessels serve two primary functions in treating cardiovascular disorders:
- Venous dilators reduce venous pressure, which reduces preload on the heart thereby decreasing cardiac output. This is useful in angina because it decreases the oxygen demand of the heart and thereby increases the oxygen supply/demand ratio. Oxygen demand is reduced because decreasing preload leads to a reduction in ventricular wall stress by decreasing the size of the heart.
- Reducing venous pressure decreases proximal capillary hydrostatic pressure, which reduces capillary fluid filtration and edema formation. Therefore, venous dilators are sometimes used in the treatment of heart failure along with other drugs because they help to reduce pulmonary and/or systemic edema that results from the heart failure.
Although most vasodilator drugs dilate veins as well as arteries, some drugs, such as organic nitrate dilators are relatively selective for veins.
The effects of selective venous dilators on overall cardiovascular function in normal subjects can be depicted graphically using cardiac and systemic vascular function curves as shown to the right. Venous dilation increases venous compliance by relaxing the venous smooth muscle. Increased compliance causes a parallel shift to the left of the vascular function curve (red line), which decreases the mean circulatory filling pressure (x-intercept). This causes the operating point to shift from A to B, resulting in a decrease in cardiac output (CO) with a small decrease in right atrial pressure (PRA). The reason for these changes is that venous dilation, by reducing PRA, decreases right ventricular preload, which decreases stroke volume and cardiac output by the Frank-Starling mechanism. Although not shown in this figure, reduced cardiac output causes a fall in arterial pressure, which reduces afterload on the left ventricle and leads to baroreceptor reflex responses, both of which can shift the cardiac function curve up and to the left. Sympathetic activation can also lead to an increase in systemic vascular resistance. The cardiac effects (decreased cardiac output) of venous dilation are more pronounce in normal hearts than in failing hearts because of where the hearts are operating on their Frank-Starling curves (cardiac function) curves (click here for more information).
Therefore, the cardiac and vascular responses to venous dilation are complex when both direct effects and indirect compensatory responses are taken into consideration. The most important effects in terms of clinical utility for patients are summarized below.
Venous dilators reduce:
- Venous pressure and therefore cardiac preload
- Cardiac output
- Arterial pressure
- Myocardial oxygen demand
- Capillary fluid filtration and tissue edema
Mixed or "balanced" dilators
As indicated above, most vasodilators act on both arteries and veins, and therefore are termed mixed or balanced dilators. Notable exceptions are hydralazine (arterial dilator) and organic nitrate dilators (venous dilators).
The effects of mixed dilators on cardiac and systemic vascular function curves are shown in the figure to the right. The red line represents a systemic function curve generated when there is both venous dilation (increased venous compliance) and arterial dilation (reduced systemic vascular resistance) - the mean circulatory filling pressure (x-axis) is decreased and the slope is increased. Point B represents the new operating point, although it is important to note that where this point lies depends on the relative degree of venous and arterial dilation. If there is more arterial dilation than venous dilation, then point B may be located slightly above point A where the cardiac function curve intersects with the new vascular function curve.
To summarize the effects of mixed vasodilators, we can say that in general they decrease systemic vascular resistance and arterial pressure with relatively little change in right atrial (or central venous) pressure (i.e., little change in cardiac preload), and they have a relatively little effect on cardiac output.
Side-Effects of Vasodilators
There are three potential drawbacks in the use of vasodilators:
- Systemic vasodilation and arterial pressure reduction can lead to a baroreceptor-mediated reflex stimulation of the heart (increased heart rate and inotropy). This increases oxygen demand, which is undesirable if the patient also has coronary artery disease.
- Vasodilators can impair normal baroreceptor-mediated reflex vasoconstriction when a person stands up, which can lead to orthostatic hypotension and syncope upon standing.
- Vasodilators can lead to renal retention of sodium and water, which increases blood volume and cardiac output and thereby compensates for the reduced systemic vascular resistance.
Drug Classes and General Mechanisms of Action
Vasodilator drugs can be classified based on their site of action (arterial versus venous) or by mechanism of action. Some drugs primarily dilate resistance vessels (arterial dilators; e.g., hydralazine), while others primarily affect venous capacitance vessels (venous dilators; e.g., nitroglycerine). Most vasodilator drugs, however, have mixed arterial and venous dilator properties (mixed dilators; e.g., alpha-adrenoceptor antagonists, angiotensin converting enzyme inhibitors).
It is more common, however, to classify vasodilator drugs based on their primary mechanism of action. This type of classification scheme leads to the following drug classes: (Click on the drug class for more details)
- Alpha-adrenoceptor antagonists (alpha-blockers)
- Angiotensin converting enzyme (ACE) inhibitors
- Angiotensin receptor blockers (ARBs)
- Beta2-adrenoceptor agonists (β2-agonists)
- Calcium-channel blockers (CCBs)
- Centrally acting sympatholytics
- Direct acting vasodilators
- Endothelin receptor antagonists
- Ganglionic blockers
- Phosphodiesterase inhibitors
- Potassium-channel openers
- Renin inhibitors
Note that many of these drugs have other actions besides vasodilation, and therefore are classified additionally under other mechanistic classes.