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 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
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. 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.
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).
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. This type of classification scheme leads to the following drug classes:
• Alpha-adrenoceptor antagonists (alpha-blockers)
• Angiotensin converting enzyme (ACE) inhibitors
• Angiotensin receptor blockers (ARBs)
• Beta2-adrenoceptor agonists (b2-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 these drugs have other actions besides vasodilation, and therefore are classified additionally under other mechanistic classes.
These drugs block the effect of sympathetic nerves on blood vessels by binding to
alpha-adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as
competitive antagonists to the binding of norepinephrine that is released by sympathetic
nerves synapsing on smooth muscle. Therefore, sometimes these drugs are referred to as
sympatholytics because they antagonize sympathetic activity. Some alpha-blockers are
non-competitive (e.g., phenoxybenzamine), which greatly prolongs their action.
Vascular smooth muscle has two primary types of alpha-adrenoceptors: alpha1 (1) and
alpha2 (2). The 1-adrenoceptors are located on the vascular smooth muscle. In contrast,
2-adrenoceptors are located on the sympathetic nerve terminals as well as on vascular
smooth muscle. Smooth muscle (postjunctional) 1 and 2-adrenoceptors are linked to a
Gq-protein, which activates smooth muscle contraction through the IP3 signal transduction
pathway. Prejunctional 2-adrenoceptors located on the sympathetic nerve terminals serve
as a negative feedback mechanism for norepinephrine release.
1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine
to the smooth muscle receptors. Non-selective 1 and 2-adrenoceptor antagonists block
postjunctional 1 and 2-adrenoceptors, which causes vasodilation; however, the blocking of
prejunctional 2-adrenoceptors leads to increased release of norepinephrine, which
attenuates the effectiveness of the 1 and 2-postjunctional adrenoceptor blockade.
Furthermore, blocking 2-prejunctional adrenoceptors in the heart can lead to increases in
heart rate and contractility due to the enhanced release of norepinephrine that binds to beta1-adrenoceptors.
Alpha-blockers dilate both arteries and veins because both vessel types are innervated by
sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the
arterial resistance vessels. Because most blood vessels have some degree of sympathetic tone under basal conditions, these drugs are effective dilators. They are even more effective under conditions of elevated sympathetic activity (e.g., during stress) or during pathologic increases in circulating catecholamines caused by an adrenal gland tumor (pheochromocytoma). Therapeutic Uses
Alpha-blockers, especially 1-adrenoceptor antagonists, are useful in the treatment of
primary hypertension, although their use is not as widespread as other antihypertensive
drugs. The non-selective antagonists are usually reserve for use in hypertensive
emergencies caused by a pheochromocytoma. This hypertensive condition, which is most
commonly caused by an adrenal gland tumor that secretes large amounts of
catecholamines, can be managed by non-selective alpha-blockers (in conjunction with
beta-blockade to blunt the reflex tachycardia) until the tumor can be surgically removed.
Specific Drugs
Newer alpha-blockers used in treating hypertension are relatively selective 1-adrenoceptor
antagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs are
General Pharmacology
ACE inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme.
ACE also breaks down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors. The increase in bradykinin is also believed to be responsible for a troublesome side effect of ACE inhibitors, namely, a dry cough.
Angiotensin II constricts arteries and veins by binding to AT1 receptors located on the smooth muscle, which are coupled to a Gq-protein and the the IP3 signal transduction pathway. Angiotensin II also facilitates the release of norepinephrine from sympathetic adrenergic nerves and inhibits norepinephrine reuptake by these nerves. This effect of angiotensin II augments sympathetic activity on the heart and blood vessels. ACE inhibitors have the following actions:
• 1_Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload and afterload on the heart.
• 2_Down regulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine.
• 3_Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion. This reduces blood volume, venous pressure and arterial pressure.
• 4_Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction.
Elevated plasma renin is not required for the actions of ACE inhibitors, although ACE inhibitors are more efficacious when circulating levels of renin are elevated. We know that enin-angiotensin system is found in many tissues, including heart, brain, vascular and renal tissues. Therefore, ACE inhibitors may act at these sites in addition to blocking the conversion of angiotensin in the circulating plasma.
Therapeutic Uses
hypertension. ACE inhibitors are effective in the treatment of primary hypertension and hypertension caused by renal artery stenosis, which causes renin-dependent hypertension owing to the increased release of renin by the kidneys. Reducing angiotensin II formation leads to arterial and venous dilation, which reduces arterial and venous pressures. By reducing the effects of angiotensin II on the kidney, ACE inhibitors cause natriuresis and diuresis, which decreases blood volume and cardiac output, thereby lowering arterial pressure.
Some of the older literature indicated that ACE inhibitors (and angiotensin receptor blockers, ARBs) were less efficacious in African American hypertensive patients, which unfortunately led to lower utilization of these important, beneficial drugs in African Americans. While it is true that African Americans do not respond as well as other races to monotherapy with ACE inhibitors or ARBs, the differences are eliminated with adequate diuretic dosing. Therefore, current recommendations from the JNC 7 report are that ACE inhibitors and ARBs are appropriate for use in African Americans, with the recommendation of adequate diuretic dosing to achieve the target blood pressure. Heart Failure. ACE inhibitors have proven to be very effective in the treatment of heart failure caused by systolic dysfunction (e.g., dilated cardiomyopathy).
Beneficial effects of ACE inhibition in heart failure include:
• 1_Reduced afterload, which enhances ventricular stroke volume and improves ejection fraction.
• 2_Reduced preload, which decreases pulmonary and systemic congestion and edema.
• 3_Reduced sympathetic activation, which has been shown to be deleterious in heart failure.
• 4_Improving the oxygen supply/demand ratio primarily by decreasing demand through the reductions in afterload and preload.
• 5_Prevents angiotensin II from triggering deleterious cardiac remodeling.
Finally, ACE inhibitors have been shown to be effective in patients following myocardial infarction because they help to reduce deleterious remodeling that occurs post-infarction.
ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart failure.
Specific Drugs
The first ACE inhibitor marketed, captopril, is still in widespread use today. Although newer ACE inhibitors differ from captopril in terms of pharmacokinetics and metabolism, all the ACE inhibitors have similar overall effects on blocking the formation of angiotensin II. ACE inhibitors include the following specific drugs
• benazepril
• captopril
• enalapril
• fosinopril
• lisinopril
• moexipril
• quinapril
• ramipril
Note that each of the ACE inhibitors named above end with "pril."
Side Effects and Contraindications
As a drug class, ACE inhibitors have a relatively low incidence of side effects and are well-tolerated. A common, annoying side effect of ACE inhibitors is a dry cough appearing in 10-30% of patients. It appears to be related to the elevation in bradykinin. Hypotension can also be a problem, especially in heart failure patients. Angioedema (life-threatening airway swelling and obstruction; 0.1-0.2% of patients) and hyperkalemia (occurs because aldosterone formation is reduced) are also adverse effects of ACE inhibition. The incidence of angioedema is 2 to 4-times higher in African Americans compared to Caucasians. ACE inhibitors are contraindicated in pregnancy.
Patients with bilateral renal artery stenosis may experience renal failure if ACE inhibitors are administered. The reason is that the elevated circulating and intrarenal angiotensin II in this condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which helps to maintain glomerular capillary pressure and filtration. Removing this constriction by blocking circulating and intrarenal angiotensin II formation can cause an abrupt fall in glomerular filtration rate. This is not generally a problem with unilateral renal artery stenosis because the unaffected kidney can usually maintain sufficient filtration after ACE inhibition; however, with bilateral renal artery stenosis it is especially important to ensure that renal function is not compromised.
These drugs have very similar effects to angiotensin converting enzyme (ACE) inhibitors and are used for the same indications (hypertension, heart failure, post-myocardial infarction). Their mechanism of action, however, is very different from ACE inhibitors, which inhibit the formation of angiotensin II. ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on bloods vessels and other tissues such as the heart. These receptors are coupled to the Gq-protein and IP3 signal transduction pathway that stimulates vascular smooth muscle contraction. Because ARBs do not inhibit ACE, they do not cause an increase in bradykinin, which contributes to the vasodilation produced by ACE inhibitors and also some of the side effects of ACE inhibitors (cough and angioedema).
ARBs have the following actions, which are very similar to ACE inhibitors:
• Dilate arteries and veins and thereby reduce arterial pressure and preload and afterload on the heart.
• Down regulate sympathetic adrenergic activity by blocking the effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine.
• Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion.
• Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction.
Therapeutic Uses
ARBs are used in the treatment of hypertension and heart failure in a similar manner as ACE inhibitors (see ACE inhibitors for details). They are not yet approved for post-myocardial infarction, although this is under investigation. Specific Drugs
ARBs include the following drugs: • candesartan
• eprosartan
• irbesartan
• losartan
• olmesartan
• telmisartan
• valsartan
Note that each of the ARBs named above ends with "sartan."
Side Effects and Contraindications
As a drug class, ARBs have a relatively low incidence of side effects and are well-tolerated. Because they do not increase bradykinin levels like ACE inhibitors, the dry cough and angioedema that are associated with ACE inhibitors are not a problem. ARBs are contraindicated in pregnancy. Patients with bilateral renal artery stenosis may experience renal failure if ARBs are administered. The reason is that the elevated circulating and intrarenal angiotensin II in this condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which helps to maintain glomerular capillary pressure and filtration. Removing this constriction by blocking angiotensin II receptors on the efferent arteriole can cause an abrupt fall in glomerular filtration rate. This is not generally a problem with unilateral renal artery stenosis because the unaffected kidney can usually maintain sufficient filtration after AT1 receptors are blocked; however, with bilateral renal artery stenosis it is especially important to ensure that renal function is not compromised.
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