Vasodilator Drugs

Therapeutic Use and Rationale

Therapeutic Uses of Vasodilators
 Systemic and pulmonary hypertension
 Heart failure
 Angina

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. Some vasodilators that act primarily on resistance
vessels (arterial dilators) are used for hypertension, and heart failure, and angina; however, reflex
cardiac stimulation makes some arterial dilators unsuitable for angina. 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 and therefore can have wide application in hypertension, heart failure and angina.
Some vasodilators, because of their mechanism of action, also have other important actions that can
in some cases enhance their therapeutic utility 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 dilators

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 when
aortic pressure is decreased. 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 curvesas 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 reduced relatively more causing arterial pressure to fall. 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.

Venous dilators

Drugs that dilate venous capacitance vessels serve two primary functions in treating cardiovascular
disorders:

1. 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.
2. 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 increasesvenous 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 P RA, 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:

1. Venous pressure and therefore cardiac preload

2. Cardiac output
3. Arterial pressure
4. Myocardial oxygen demand
5. 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:

1. 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.
2. Vasodilators can impair normal baroreceptor-mediated reflex vasoconstriction when a
person stands up, which can lead to orthostatic hypotension and syncope upon
standing.
3. 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. The figure to the right depicts important mechanistic classes of vasodilator drugs. These
classes of drugs, as well as other classes that produce vasodilation, are listed below. (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
 Nitrodilators
 Phosphodiesterase inhibitors
 Potassium-channel openers
 Renin inhibitors
Note that many of the drugs in the above mechanistic classes have actions other than vasodilation, and
therefore are classified additionally under other mechanistic classes. For example, dobutamine possesses
non-selective beta-adrenoceptor agonist properties and therefore produces both vasodilation and cardiac
stimulation. It also has alpha-adrenoceptor agonist properties that can cause vasoconstriction at high
plasma concentrations.