Vasodilators

Therapeutic Use and Rationale

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 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. 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. 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 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 (xintercept). 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: 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. 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 ( 2-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

Alpha-Adrenoceptor Antagonists (Alpha-Blockers)

General Pharmacology
These drugs block the effect of sympathetic nerves on blood vessels by binding to alphaadrenoceptors 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 2adrenoceptors are linked to a Gq-protein, which activates smooth muscle contraction through the IP3 signal transduction pathway. Prejunctional 2adrenoceptors 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 2adrenoceptors 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 nonselective 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 non-selective antagonists (e.g., phentolamine, phenoxybenzamine). (Go to www.rxlist.com for specific drug information)

Side Effects and Contraindications

The most common side effects are related directly to alpha-adrenoceptor blockade. These side effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon standing), nasal congestion (due to dilation of nasal mucosal arterioles), headache, and reflex tachycardia (especially with non-selective alpha-blockers). Fluid retention is also a problem that can be rectified by use of a diuretic in conjunction with the alpha-blocker. Alpha blockers have not been shown to be beneficial in heart failure or angina, and should not be used in these conditions.

Angiotensin Converting Enzyme (ACE) Inhibitors

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:

Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload and afterload on the heart. Down regulate sympathetic adrenergic activity by blocking the facilitating 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. This reduces blood volume, venous pressure and arterial pressure. 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 reninangiotensin 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:

Reduced afterload, which enhances ventricular stroke volume and improves ejection fraction. Reduced preload, which decreases pulmonary and systemic congestion and edema. Reduced sympathetic activation, which has been shown to be deleterious in heart failure. Improving the oxygen supply/demand ratio primarily by decreasing demand through the reductions in afterload and preload. 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: (Go to www.rxlist.com for specific drug information)

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 welltolerated. A common, annoying side effect of ACE inhibitors is a dry cough appearing in 1030% 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.

Angiotensin Receptor Blockers (ARBs)

General Pharmacology
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: (Go to www.rxlist.com for specific drug information)

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.

Beta-Adrenoceptor Agonists ( -agonists)

General Pharmacology
Beta-adrenoceptor agonists (-agonists) bind to receptors on cardiac and smooth muscle tissues. They also have important actions in other tissues, especially bronchial smooth muscle (relaxation), the liver (stimulate glycogenolysis) and kidneys (stimulated renin release). Beta-adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and to circulating epinephrine. Therefore, agonists mimic the actions of sympathetic adrenergic stimulation acting through -adrenoceptors. Overall, the effect of -agonists is cardiac stimulation (increased heart rate, contractility, conduction velocity, relaxation) and systemic vasodilation. Arterial pressure may increase, but not necessarily because the fall in systemic vascular resistance offsets the increase in cardiac output. Therefore, the effect on arterial pressure depends on the relative influence on cardiac versus vascular -adrenoceptors. agonists cause -receptor down-regulation, which limits their therapeutic efficacy to short-term application. Beta-agonists, because they are catecholamines, have a low bioavailability and therefore must be given by intravenous infusion. Heart. Beta-agonists bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both 1 and 2 adrenoceptors, although the predominant receptor type in number and function is 1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood. Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP.

Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cells. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate by opening ion channels responsible for pacemaker currents in the sinoatrial node. PKA phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta-adrenoceptor stimulation. In summary, the cardiac effects of a -agonist are increased heart rate, contractility, conduction velocity, and relaxation rate. Blood vessels. Vascular smooth muscle has 2-adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by 2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation). Other tissues. ctivation of 2-adrenoceptors in the lungs causes bronchodilation. 2adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. 1-adrenoceptor stimulation in the kidneys causes the release of renin, which stimulates the production of angiotensin II and the subsequent release of aldosterone by the adrenal cortex.

Specific Drugs and Therapeutic Uses

There are several different -agonists that are used clinically for the treatment of heart failure or circulatory shock, all of which are either natural catecholamines or analogs. Nearly all of these -agonists, however, have some degree of -agonist activity. These drugs along with their agonist properties are given in the table below. Note that for some of the drugs the receptor selectivity is highly dose-dependent. (Go to www.rxlist.com for specific drug information).

Drug

Receptor Selectivity 1 = 2 > 1* = 2*

Clinical Use Anaphylactic shock; cardiogenic shock; cardiac arrest Severe hypotension; septic shock

Comments Low doses produce cardiac stimulation and vasodilation, which turns to vasoconstriction at high doses. *At high plasma concentrations, = selectivity. Reflex bradycardia masks direct stimulatory effects on sinoatrial node.

Epinephrine

1 = 1 > Norepinephrine 2 = 2

Dopamine

1 = 2 > 1*

Biosynthetic precursor of norepinephrine; stimulates Acute heart norepinephrine release. *At low doses, failure, it stimulates the heart and decreases cardiogenic systemic vascular resistance; at high shock and acute doses, vasodilation becomes renal failure vasoconstriction as lower affinity receptors bind to the dopamine; also binds to D1 receptors in kidney, producing vasodilation. Acute heart failure; cardiogenic Net effect is cardiac stimulation with shock; modest vasodilation. refractory heart failure Bradycardia Net effect is cardiac stimulation and and vasodilation with little change in atrioventricular pressure. block

Dobutamine

1 > 2 > 1

Isoproterenol

1 = 2

Side Effects and Contraindications

A major side effect of -agonists is cardiac arrhythmia. Because these drugs increase myocardial oxygen demand, they can precipitate angina in patients with coronary artery disease. Headache and tremor are also common.

Calcium-Channel Blockers (CCBs)

General Pharmacology
Currently approved CCBs bind to L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These channels are responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, Ltype 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 cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), and decreased conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular node.

Therapeutic Indications
CCBs are used to treat hypertension, angina and arrhythmias. Hypertension. By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance, which lowers arterial blood pressure. These drugs primarily affect arterial resistance vessels, with only minimal effects on venous capacitance vessels. Angina. The anti-anginal effects of CCBs are derived from their vasodilator and cardiodepressant actions. Systemic vasodilation reduces arterial pressure, which reduces ventricular afterload (wall stress) thereby decreasing oxygen demand. The more cardioselective CCBs (verapamil and diltiazem) decrease heart rate and contractility, which leads to a reduction in myocardial oxygen demand, which makes them excellent antianginal drugs. CCBs can also dilate coronary arteries and prevent or reverse coronary vasospasm (as occurs in Printzmetal's variant angina), thereby increasing oxygen supply to the myocardium. Arrhythmias. The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to their ability to decrease the firing rate of aberrant pacemaker sites within the heart, but more importantly are related to their ability to decrease conduction velocity and prolong repolarization, especially at the atrioventricular node. This latter action at the atrioventricular node helps to block reentry mechanisms, which can cause supraventricular tachycardia.

Different Classes of Calcium-Channel Blockers

There are three classes of CCBs. They differ not only in their basic chemical structure, but also in their relative selectivity toward cardiac versus vascular L-type calcium channels. The most smooth muscle selective class of CCBs are the dihydropyridines. Because of their high vascular

selectivity, these drugs are primarily used to reduce systemic vascular resistance and arterial pressure, and therefore are primarily used to treat hypertension. They are not, however, generally used to treat angina because their powerful systemic vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and increased inotropy), which can dramatically increase myocardial oxygen demand. Note that dihydropyridines are easy to recognize because the drug name ends in "pine." Dihydropyridines include the following specific drugs: (Go to www.rxlist.com for specific drug information)

amlodipine felodipine isradipine nicardipine nifedipine nimodipine nitrendipine

Non-dihydropyridines, of which there are only two currently used clinically, comprise the other two classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias. Diltiazem (benzothiazepine class) is intermediate between verapamil and dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.

Side Effects and Contraindications

Dihydropyridine CCBs can cause flushing, headache, excessive hypotension, edema and reflex tachycardia. The activation of sympathetic reflexes and lack of direct cardiac effects make dihydropyridines a less desirable choice for angina. Long-acting dihydropyridines have been shown to be safer anti-hypertensive drugs, in part, because of reduced reflex responses. The cardiac selective, non-dihydropyridine CCBs can cause excessive bradycardia, impaired electrical conduction (e.g., atrioventricular nodal block), and depressed contractility. Therefore, patients having preexistent bradycardia, conduction defects, or heart failure caused by systolic dysfunction should not be given CCBs, especially the cardiac selective, non-dihydropyridines. CCBs, especially non-dihydropyridines, should not be administered to patients being treated with a beta-blocker because beta-blockers also depress cardiac electrical and mechanical activity and therefore the addition of a CCB augments the effects of beta-blockade.

Centrally Acting Sympatholytics

General Pharmacology
The sympathetic adrenergic nervous system plays a major role in the regulation of arterial pressure. Activation of these nerves to the heart increases the heart rate (positive chronotropy), contractility (positive inotropy) and velocity of electrical impulse conduction (positive dromotropy). The norepinephrinereleasing, sympathetic adrenergic nerves that innervate the heart and blood vessels are postganglionic efferent nerves whose cell bodies originate in prevertebral and paraveterbral sympathetic ganglia. Preganglionic sympathetic fibers, which travel from the spinal cord to the ganglia, originate in the medulla of the brainstem. Within the medulla are located sympathetic excitatory neurons that have significant basal activity, which generates a level of sympathetic tone to the heart and vasculature even under basal conditions. The sympathetic neurons within the medulla receive input from other neurons within the medulla (e.g., vagal neurons), from the nucleus tractus solitarius (receives input from peripheral baroreceptors and chemoreceptors), and from neurons located in the hypothalamus. Together, these neuronal systems regulate sympathetic (and parasympathetic) outflow to the heart and vasculature. Sympatholytic drugs can block this sympathetic adrenergic system are three different levels. First, peripheral sympatholytic drugs such as alpha-adrenoceptor and beta-adrenoceptor antagonists block the influence of norepinephrine at the effector organ (heart or blood vessel). Second, there are ganglionic blockers that block impulse transmission at the sympathetic ganglia. Third, there are drugs that block sympathetic activity within the brain. These are called centrally acting sympatholytic drugs. Centrally acting sympatholytics block sympathetic activity by binding to and activating alpha2 (2)-adrenoceptors. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility. Reduced sympathetic output to the vasculature decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure.

Therapeutic Indications
Centrally acting 2-adrenoceptor agonists are used in the treatment of hypertension. However, they are not considered first-line therapy in large part because of side effects that are associated with their actions within the brain. They are usually administered in combination with a diuretic

to prevent fluid accumulation, which increases blood volume and compromises the blood pressure lowering effect of the drugs. Fluid accumulation can also lead to edema. Centrally acting 2-adrenoceptor agonists are effective in hypertensive patients with renal disease because they do not compromise renal function.

Specific Drugs
Several different centrally acting 2-adrenoceptor agonists are available for clinical use: (Go to www.rxlist.com for specific drug information)

clonidine guanabenz guanfacine -methyldopa

Clonidine, guanabenz and guanfacine are structurally related compounds and have similar antihypertensive profiles. -methyldopa is a structural analog of dopa and functions as a prodrug. After administration, -methyldopa is converted to -methynorepinephrine, which then serves as the 2-adrenoceptor agonist in the medulla to decrease sympathetic outflow.

Side Effects and Contraindications

Side effects of centrally acting 2-adrenoceptor agonists include sedation, dry mouth and nasal mucosa, bradycardia (because of increased vagal stimulation of the SA node as well as sympathetic withdrawal), orthostatic hypotension, and impotence. Constipation, nausea and gastric upset are also associated with the sympatholytic effects of these drugs. Fluid retention and edema is also a problem with chronic therapy; therefore, concurrent therapy with a diuretic is necessary. Sudden discontinuation of clonidine can lead to rebound hypertension, which results from excessive sympathetic activity.

Direct Acting Vasodilators

General Pharmacology
The one drug in this group, hydralazine, does not fit neatly into the other mechanistic classes, in part, because its mechanism of action is not entirely clear and it appears to have multiple, direct effects on the vascular smooth muscle. Hydralazine, which is highly specific for arterial vessels, may work by a couple of different mechanisms. First, hydralazine causes smooth muscle hyperpolarization quite likely through the opening of K+-channels. It also may inhibit IP3induced release of calcium from the smooth muscle sarcoplasmic reticulum. This calcium combines with calmodulin to activate myosin light chain kinase, which induces contraction.

Finally, hydralazine stimulates the formation of nitric oxide by the vascular endothelium, leading to cGMP-mediated vasodilation. The arterial vasodilator action of hydralazine reduces systemic vascular resistance and arterial pressure. Indirect cardiac stimulation (e.g., tachycardia) occurs with hydralazine administration because of activation of the baroreceptor reflex.

Specific Drugs and Therapeutic Indications

The direct acting vasodilator that is used clinically is hydralazine. This drug is used in the treatment of hypertension and heart failure. Hypertension. Hydralazine is used occasionally (although rarely alone) in the treatment of arterial hypertension. It is not first-line therapy for arterial hypertension. Its relatively short halflife (therefore requires frequent dosing) and precipitation of reflex tachycardia make it undesirable for treating chronic hypertension. However, it is used in treating acute hypertensive emergencies, secondary hypertension caused by preecclampsia, and pulmonary hypertension. It is often used in conjunction with a beta-blocker and diuretic to attenuate the baroreceptormediated reflex tachycardia and sodium retention, respectively. Heart failure. Hydralazine has a role in the management of heart failure because of its ability to reduce afterload and thereby enhance stroke volume and ejection fraction. When used in heart failure, it is given along with a diuretic and often with a nitrodilator.

Side Effects and Contraindications

Common side effects to hydralazine include headaches, flushing and tachycardia. Some patients (~10%) experience a lupus-like syndrome. Reflex cardiac stimulation can precipitate angina in patients with coronary artery disease.

Endothelin Receptor Antagonists

General Pharmacology
Endothelin-1 (ET-1) is a 21 amino acid peptide that is produced by the vascular endothelium (click here for details). It is a very potent vasoconstrictor that binds to smooth muscle endothelin receptors, of which there are two subtypes: ETA and ETB receptors. These receptors are coupled to a Gq-protein and receptor activation leads to the formation of IP3, which causes the release of calcium by the

sarcoplasmic reticulum (SR) and increased smooth muscle contraction and vasoconstriction. There are also ETB receptors located on the endothelium that stimulate the formation of nitric oxide, which produces vasodilation in the absence of smooth muscle ETA and ETB receptor activation. This receptor distribution helps to explain the phenomenon that ET-1 administration causes transient vasodilation (initial endothelial ETB activation) and hypotension, followed by prolong vasoconstriction (smooth muscle ETA and ETB activation) and hypertension. ET-1 receptors in the heart are also linked to the Gq-protein and IP3 signal transduction pathway (click here for details). Therefore, ET-1 in the heart causes SR release of calcium, which increases contractility. ET-1 also increases heart rate.

Therapeutic Indications
Because of its powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension, coronary vasospasm, and heart failure. A number of studies suggest a role for ET-1 in pulmonary hypertension, as well as in systemic hypertension. ET-1 has been shown to be released by the failing myocardium where it can contribute to cardiac calcium overload and hypertrophy. Endothelin receptor antagonists, by blocking the vasoconstrictor and cardiotonic effects of ET-1, produce vasodilation and cardiac inhibition. Endothelin receptor antagonists have been shown to decrease mortality and improve hemodynamics in experimental models of heart failure. At present, the one approved indication for endothelin antagonists is pulmonary hypertension.

Specific Drugs
One endothelin receptor antagonist has been approved. Bosentan, a non-selective ET-1 receptor antagonist (blocks for ETA and ETB receptors) is currently used in the treatment of pulmonary hypertension. (Go to www.rxlist.com for detailed information on bosentan)

Side Effects and Contraindications

Some of bosentan's side effects are common to most vasodilators; namely, headache, cutaneous flushing, and edema formation. Bosentan may cause birth defects and therefore is contraindicated in pregnancy. It also can cause liver injury.

Ganglionic Blockers
Autonomic Ganglia

Sympathetic autonomic ganglia are comprised of the paravertebral ganglia (sympathetic chain ganglia) and the prevertebral ganglia. Preganglionic sympathetic fibers that exit the spinal cord synapse within these ganglia and release the neurotransmitter acetylcholine (ACh), which binds to nicotinic receptors. Activation of the nicotinic receptors depolarizes the cell body of the postganglionic neuron and generates action potentials that travel to the target organ to elicit a response. Parasympathetic autonomic ganglia are found within the target organ. In the case of the vagal nerves that exit the brainstem, their long preganglionic fibers enter the target organ (e.g., heart) where they synapse with postganglionic neurons within small ganglia. Like the sympathetic ganglia, the neurotransmitter is ACh and it binds to nicotinic receptors to activate the short postganglionic fibers that lie near the target tissue (e.g., sinoatrial node).

General Pharmacology
Sympatholytic drugs can block the sympathetic adrenergic system are three different levels. First, peripheral sympatholytic drugs such as alpha receptor antagonists and beta receptor antagonists block the influence of norepinephrine at the effector organ (heart or blood vessel). Second, there are ganglionic blockers that block impulse transmission at the sympathetic ganglia. Third, there are drugs that block sympathetic activity within the brain. These are called centrally acting sympatholytic drugs. Neurotransmission within the sympathetic and parasympathetic ganglia involves the release of acetylcholine from preganglionic efferent nerves, which binds to nicotinic receptors on the cell bodies of postganglionic efferent nerves. Ganglionic blockers inhibit autonomic activity by interfering with neurotransmission within autonomic ganglia. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility. Reduced sympathetic output to the vasculature decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure. Parasympathetic outflow is also reduced by ganglionic blockers.

Therapeutic Indications
Ganglionic blockers are not used in the treatment of chronic hypertension in large part because of their side effects and because there are numerous, more effective, and safer antihypertensive drugs that can be used. They are, however, occasionally used for hypertensive emergencies.

Specific Drugs
Several different ganglionic blockers are available for clinical use; however, only one (trimethaphan camsylate) is very occasionally used in hypertensive emergencies or for producing controlled hypotension during surgery.

Side Effects and Contraindications

Side effects of trimethaphan include prolonged neuromuscular blockade and potentiation of neuromuscular blocking agents. It can produce excessive hypotension and impotence due to its sympatholytic effect, and constipation, urinary retention, dry mouth due to it parasympatholytic effect. It also stimulates histamine release.

Nitrodilators
General Pharmacology
Nitric oxide (NO), a molecule produced by many cells in the body, and has several important actions (click here for details). In the cardiovascular system, NO is primarily produced by vascular endothelial cells. This endothelial-derived NO has several important functions including relaxing vascular smooth muscle (vasodilation), inhibiting platelet aggregation (anti-thrombotic), and inhibiting leukocyte-endothelial interactions (anti-inflammatory). These actions involve NOstimulated formation of cGMP. Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues. These drugs act directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelial-independent vasodilators. There are two basic types of nitrodilators: those that release NO spontaneously (e.g., sodium nitroprusside) and organic nitrates that require an enzymatic process to form NO. Organic nitrates do not directly release NO, however, their nitrate groups interact with enzymes and intracellular sulfhydryl groups that reduce the nitrate groups to NO or to S-nitrosothiol, which then is reduced to NO. Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation (click here for details). NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMPdependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.

Tolerance to nitrodilators occurs with frequent dosing, which decreases their efficacy. The problem is partially circumvented by using the smallest effective dose of the compound coupled with infrequent or irregular dosing. The mechanism for tolerance is not fully understood, but it may involve depletion of tissue sulfhydryl groups, or scavenging of NO by superoxide anion and the subsequent production of peroxynitrite that may inhibit guanylyl cyclase. Although nitrodilators can dilate both arteries and veins, venous dilation predominates when these drugs are given at normal therapeutic doses. Venous dilation reduces venous pressure and decreases ventricular preload. This reduces ventricular wall stress and oxygen demand by the heart, thereby enhancing the oxygen supply/demand ratio. A reduction in preload (reduce diastolic wall stress) also helps to improve subendocardial blood flow, which is often compromised in coronary artery disease. Mild coronary dilation or reversal of coronary vasospasm will further enhance the oxygen supply/demand ratio and diminish the anginal pain. Coronary dilation occurs primarily in the large epicardial vessels, which diminishes the likelihood of coronary vascular steal. Systemic arterial dilation reduces afterload, which can enhance cardiac output while at the same time reducing ventricular wall stress and oxygen demand. At high concentrations, excessive systemic vasodilation may lead to hypotension and a baroreceptor reflex that produces tachycardia. When this occurs, the beneficial effects on the oxygen supply/demand ratio are partially offset. Furthermore, tachycardia, by reducing the duration of diastole, decreases the time available for coronary perfusion, most of which occurs during diastole (click here for more details).

Therapeutic Indications
The primary pharmacologic action of nitrodilators, arterial and venous dilation, make these compounds useful in the treatment of hypertension, heart failure, angina and myocardial infarction. Another beneficial action of nitrodilators is their ability to inhibit platelet aggregation. Hypertension. Nitrodilators are not used to treat chronic primary or secondary hypertension; however, sodium nitroprusside and nitroglycerine are used to lower blood pressure in acute hypertensive emergencies that may result from a pheochromocytoma, renal artery stenosis, aortic dissection, etc. Nitrodilators may also be used during surgery to to control arterial pressure within desired limits. Heart failure. Nitrodilators are used in acute heart failure and in severe chronic heart failure. Arterial dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection fraction. Furthermore, the venous dilation reduces venous pressure, which helps to reduce edema. Reducing both afterload and preload on the heart also helps to improve

the mechanical efficiency of dilated hearts and to reduce wall stress and the oxygen demands placed on the failing heart. Angina and myocardial infarction. Nitrodilators are used extensively to treat angina and myocardial infarction. They are useful in Printzmetal's variant angina because they improve coronary blood flow (i.e., increase oxygen supply) by reversing and inhibiting coronary vasospasm. They are important in other forms of angina because they reduce preload on the heart by producing venous dilation, which decreases myocardial oxygen demand. It is unclear if direct dilation of epicardial coronary arteries play a role in the antianginal effects of nitrodilators in chronic stable or unstable angina. These drugs also reduce systemic vascular resistance (depending on dose) and arterial pressure, which further reduces myocardial oxygen demand. Taken together, these two actions dramatically improve the oxygen supply/demand ratio and thereby reduce anginal pain.

Specific Drugs
Several different nitrodilators are available for clinical use: (Go to www.rxlist.com for specific drug information)

isosorbide dinitrate isosorbide mononitrate nitroglycerin erythrityl tetranitrate pentaerythritol tetranitrate sodium nitroprusside

The nitrodilators listed above differ in the route of administration, onset of action, and duration of action. Nitroglycerin, which has been used since the 19th century, is commonly used in the treatment of angina because it is very fast acting (within 2 to 5 minutes) when administered sublingually. Its effects usually wear off within 30 minutes. Therefore, nitroglycerin is particularly useful for preventing or terminating an acute anginal attack. Longer-acting preparations of nitroglycerin (e.g., transdermal patches) have a longer onset of action (30 to 60 minutes), but are effective for 12 to 24 hours. Intravenous nitroglycerin is used in the hospital setting for unstable angina and acute heart failure. Isosorbide dinitrate and mononitrate, and tetranitrate compounds have a longer onset of action and duration of action than nitroglycerin. This makes these compounds more useful than shortacting nitroglycerin for the long-term prophylaxis and management of coronary artery disease. Oral bioavailability of many organic nitrates is low because of first-pass metabolism by the liver. Isosorbide mononitrate, which has nearly 100% bioavailability, is the exception. Therefore, oral administration of these compounds requires much higher doses than sublingual administration, which is not subject to first-pass hepatic metabolism.

The metabolites of organic nitrates are biologically active and have a longer half-life than the parent compound. Therefore, the metabolites contribute significantly to the therapeutic activity of the compound. Sodium nitroprusside, which is used to treat severe hypertensive emergencies and severe heart failure, has a rapid onset of action. It is only available as an intravenous preparation, and because of its short half-life, continuous infusion is required.

Side Effects and Contraindications

The most common side effects of nitrodilators are headache (caused by cerebral vasodilation) and cutaneous flushing. Other side effects include postural hypotension and reflex tachycardia. Excessive hypotension and tachycardia can worsen the angina by increasing oxygen demand. Prolonged use of sodium nitroprusside carries the risk of thiocyanate toxicity because nitroprusside releases cyanide along with NO. The thiocyanate is formed in the liver from the reduction of cyanide by a sulfhydryl donor. There is clinical evidence that nitrodilators may interact adversely with cGMP-dependent phosphodiesterase inhibitors that are used to treat erectile dysfunction (e.g., sildenafil [Viagra]). The reason for this adverse reaction is that nitrodilators stimulate cGMP production and drugs like sildenafil inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary perfusion.

Phosphodiesterase Inhibitors
General Pharmacology of cAMP-Dependent Phosphodiesterase Inhibitors (PDE3)
Heart. Intracellular concentrations of cAMP play an important second messenger role in regulating cardiac muscle contraction. Activation of sympathetic adrenergic to the heart releases the neurotransmitter norepinephrine and increases circulating catecholamines (epinephrine and norepinephrine). These catecholamines bind primarily to beta1-adrenoceptors in the heart that are coupled to Gs-proteins. This activates adenylyl cyclase to form cAMP from ATP. Increased cAMP, through its coupling with other intracellular messengers, increases contractility (inotropy), heart rate (chronotropy) and conduction velocity (dromotropy). Cyclic-AMP is broken down by an enzyme called cAMPdependent phosphodiesterase (PDE). The isoform of this enzyme that is targeted by currently used clinical drugs is the type 3 form (PDE3). Inhibition of this enzyme prevents cAMP breakdown and thereby increases its

intracellular concentration. This increases cardiac inotropy, chronotropy and dromotropy. PDE3 inhibitors can be thought of as a backdoor approach to cardiac stimulation, whereas -agonists go through the front door to produce the same cardiac effects. Blood vessels. Cyclic-AMP also plays an important role in regulating the contraction of vascular smooth muscle. Beta2-adrenoceptor agonists such as epinephrine stimulate the Gs-protein and the formation of cAMP (click here for details). Unlike cardiac muscle, increased cAMP in smooth muscle causes relaxation. The reason for this is that cAMP normally inhibits myosin light chain kinase, the enzyme that is responsible for phosphorylating smooth muscle myosin and causing contraction. Like the heart, the cAMP is broken down by a cAMP-dependent PDE (PDE3). Therefore, inhibition of this enzyme increases intracellular cAMP, which further inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation). Overall cardiovascular effects. The cardiac and vascular effects of cAMP-dependent PDE inhibitors cause cardiac stimulation, which increases cardiac output, and reduced systemic vascular resistance, which tends to lower arterial pressure. Because cardiac output increases and systemic vascular resistance decreases, the change in arterial pressure depends on the relative effects of the PDE inhibitor on the heart versus the vasculature. At normal therapeutic doses, PDE3 inhibitors such as milrinone have a greater vascular than cardiac effect so that arterial pressure is lowered in the presence of augmented cardiac output. Because of the dual cardiac and vascular effects of these compounds, they are sometimes referred to as "inodilators."

General Pharmacology of cGMP-Dependent Phosphodiesterase Inhibitors (PDE5)

There is a second isoenyme form of PDE in vascular smooth muscle that is a cGMPdependent phosphodiesterase. The type 5 isoform of this enzyme (PDE5) is found in the corpus cavernosum of the penis and in vascular smooth muscle. This enzyme is responsible for breaking down cGMP that forms in response to increased nitric oxide (NO). Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation (click here for details). NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMPdependent protein kinase that activates myosin

light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation. Therefore, inhibitors cGMP-dependent phosphodiesterase, by increasing intracellular cGMP, enhance smooth muscle relaxation and vasodilation, and cause penile erection.

Therapeutic Indications
The cardiostimulatory and vasodilatory actions of PDE3 inhibitors make them suitable for the treatment of heart failure. Arterial dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection fraction, as well as increases organ perfusion. Reducing the afterload leads to a secondary decrease in preload on the heart that helps to improve the mechanical efficiency of dilated hearts and to reduce ventricular wall stress and the oxygen demands placed on the failing heart. The cardiostimulatory effects of these drugs increase inotropy, which further enhances stroke volume and ejection fraction. Tachycardia, however, also results, and this is not beneficial; therefore, doses are used that minimize the positive chronotropic actions of the drug. A baroreceptor reflex, which occurs in response to hypotension, may contribute to the tachycardia. Clinical trials have shown that long-term therapy with PDE3 inhibitors increases mortality in heart failure patients; therefore, these drugs are not used for long-term, chronic therapy. They are very useful, however, in treating acute, decompensated heart failure or temporary bouts of decompensated chronic failure. They are not used as a monotherapy. Instead, they are used in conjunction with other treatment modalities such as diuretics, ACE inhibitors, beta-blockers or digitalis. The somewhat selective vasodilatory actions of PDE5 inhibitors have made these compounds very useful in the treatment of male erectile dysfunction.

Specific Drugs
Several different PDE inhibitors are available for clinical use: (Go to www.rxlist.com for specific drug information)

PDE3 inhibitors - milrinone - amrinone PDE5 inhibitors - sildenafil - tadalafil

The PDE3 inhibitors are used for treating heart failure, whereas the PDE5 inhibitors are used for treating male erectile dysfunction. Note that the PDE3 inhibitors end in "one" and the PDE5 inhibitors end in "fil".

Side Effects and Contraindications

PDE3 inhibitors. The most common and severe side effect of PDE3 inhibitors is ventricular arrhythmias in about 12% of patients, some of which may be life-threatening. Headaches and

hypotension occur in about 3% of patients. These side effects are not uncommon for drugs that increase cAMP in cardiac and vascular tissues, other examples being -agonists. PDE5 inhibitors. The most common side effects for PDE5 inhibitors include headache and cutaneous flushing, both of which are related to vascular dilation caused by increased vascular cGMP. There is clinical evidence that nitrodilators may interact adversely with PDE5 inhibitors. The reason for this adverse reaction is that nitrodilators stimulate cGMP production while PDE5 inhibitors inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary perfusion.

Potassium-Channel Openers
General Pharmacology
Potassium-channel openers are drugs that activate (open) ATP-sensitive K+-channels in vascular smooth muscle. Opening these channels hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium. With less calcium available to combine with calmodulin, there is less activation of myosin light chain kinase and phosphorylation of myosin light chains (click here for details). This leads to relaxation and vasodilation. Because small arteries and arterioles normally have a high degree of smooth muscle tone, these drugs are particular effective in dilating these resistance vessels, decreasing systemic vascular resistance, and lowering arterial pressure. The fall in arterial pressure leads to reflex cardiac stimulation (baroreceptor-mediated tachycardia).

Therapeutic Indications
Being effective arterial dilators, potassium-channel openers are used in the treatment of hypertension. These drugs are not first-line therapy for hypertension because of their side effects, and therefore they are relegated to treating refractory, severe hypertension. They are generally used in conjunction with a beta-blocker and diuretic to attenuate the reflex tachycardia and retention of sodium and fluid, respectively.

Specific Drugs
Although several potassium-channel openers have been used in research for many years, only one, minoxidil, is approved for use in humans for treating hypertension. (Go to www.rxlist.com for detailed information on minoxidil)

Side Effects and Contraindications

Common side effects to minoxidil include headaches, flushing and reflex tachycardia. The potent vasodilator actions of minoxidil can lead to fluid retention and edema formation. Reflex cardiac stimulation can precipitate angina in patients with coronary artery disease. Minoxidil produces T

wave changes in a high percentage (~60%) of patients under chronic treatment. One of the most noted side effects of minoxidil is hypertrichosis, a thickening and enhanced pigmentation of body hair, and therefore this drug is more commonly used for treating baldness.

Renin Inhibitors
General Pharmacology
Renin inhibitors are one of three classes of compounds that affect the reninangiotensin-aldosterone system, the other two being angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Renin inhibitors produce vasodilation by inhibiting the activity of renin, which is responsible for stimulating angiotensin II formation. Renin is a proteolytic enzyme that is released by the kidneys in response to sympathetic activation, hypotension, and decreased sodium delivery to the distal renal tubule (click here for more details). Once released into the circulation, renin acts on circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme. Angiotensin II has a several important actions including vasoconstriction, stimulation of aldosterone, renal retention of sodium and water, enhancing sympathetic activity by increasing norepinephrine release by sympathetic nerves, and stimulating cardiac and vascular hypertrophy. Renin inhibitors have the following actions, which are similar to those produced by ACEIs and ARBs:

Dilate arteries and veins by blocking angiotensin II formation. This vasodilation reduces arterial pressure, preload and afterload on the heart. Down regulate sympathetic adrenergic activity by blocking the

facilitating 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. This reduces blood volume, venous pressure and arterial pressure. Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction.

Specific Drugs and Therapeutic Uses

Aliskiren is a renin inhibitor that was approved for the treatment of hypertension by the U.S. FDA in 2007. Aliskiren is an orally active nonpeptide drug with a half-life of about 24 hours, and is dosed once per day. Because of its relatively long half-life, it takes about 2 weeks of dosing to achieve a near maximal antihypertensive effect. It is metabolized by the liver and excreted by the kidneys. Normal therapeutic concentrations of aliskiren reduce plasma renin activity by 50-80%. It is effective as monotherapy. When used in conjunction with thiazide diuretics or ARBs, the antihypertensive effects are additive.

Side Effects and Contraindications

Aliskiren, like ACEIs and ARBs, has a relatively low incidence of side effects and is welltolerated. Aliskiren has dose-related gastrointestinal adverse effects in some patients; diarrhea is observed in less the 3% of patients. The incidence of cough is much lower in patients taking aliskiren than those taking ACEIs. Angioedema (life-threatening airway swelling and obstruction) can occur in patients taking aliskiren (as can occur with ACEI and ARB treatment), although fewer than 1% of patients develop this condition. When administered with an ACEI, aliskiren can produce hyperkalemia, especially in diabetic patients. As with ACEIs, aliskiren should not be administered anytime during pregnancy, particularly in second and third trimesters because of fetal and neonatal injury, and risk of birth defects.

OBAT VASODILATOR PERIFER

Obat vasodilator adalah golongan obat yang telah terbukti dapat menyebabkan peningkatan diameter vaskuler baik sistim arteri ataupun vena melalui mekanisme relaksasi otot polos vaskuler. Ada beberapa macam obat dari berbagai golongan sebagai obat vasodilator perifer maupun serebral. Diantaranya adalah : 1. Isoxsuprine adalah obat golongan vasodilator. Isoxsuprine membuat vena dan arteri relaksasi, sehingga saluran darah tersebut melebar dan membuat darah lebih mudah

mengalir. Aksi kerja tersebut dapat membantu pengobatan gejala seperti aliran darah ke otak lambat, arteriosklerosis (pengerasan dari arteri), fenomena Raynauld's dan kondisi lainnya yang berhubungan dengan tidak lancar aliran darah di vena dan arteri. Sumber : www.drugs.com 2. Flunarizine adalah obat dari golongan kalsium antagonis/ penghambat kalsium. Penghambat kalsium mempengaruhi pergerakan kalsium ke dalam sel dari jantung dan peredaran darah. Sehingga peredaran darah melemas dan meningkatkan suplai darah dan oksigen ke jantung akibatnya mengurangi kerja jantung. Flunarizine digunakan untuk mencegah sakit kepala migren. Sumber : www.drugs.com 3. Citicoline dalam pengembangan awalnya digunakan sebagai obat stroke, dan sekarang diselidiki untuk digunakan sebagai obat penyakit alzheimer. Dan dapat mencegah jaringan otak dari infark cerebral akibat stroke iskemik. Sumber : nootropics.com 4. Buflomedil bekerja secara langsung sebagai vasodilator, dan bisa digunakan untuk permasalahan selulit, peredaran darah, stretch marks, dan nyeri. Juga biasa digunakan untuk pengobatan impotensi. Sumber : www.prollenium.com 5. Nimodipin digunakan untuk pengobatan gejala yang disebabkan dari satu pecahnya saluran darah di otak (hemorrhage). Obat ini meningkatkan aliran darah ke jaringan otak yang terluka. Nimodipin berbentuk kapsul untuk diminum secara oral. Jika pasien tidak bisa menelan kapsul, dapat diberikan melalui pipa makanan yang dimasukan ke pencernaan. Biasanya diberikan 4 jam sekali selama 21 hari. Nimodipin diminum pada waktu perut kosong, baik 1 jam sebelum makan, atau 2 jam setelah makan. Pengobatan dengan obat ini dimulai 4 hari setelah hemorrhage otak. Sumber : www.nlm.nih.gov 6. Pentoxifylline digunakan untuk meningkatkan aliran darah pada pasien dengan masalah sirkulasi darah untuk mengurangi nyeri, kram dan lemah di bagian tangan atau kaki. Obat ini bekerja dengan cara mengurangi kekentalan (viskositas) darah. Dengan perubahan itu membuat darah mengalir lebih mudah, terutama pada saluran darah yang sempit pada kaki atau tangan. Sumber : www.pentoxifylline.com 7. Nicergolin adalah derivat ergot yang sekarang digunakan untuk mengatasi permasalahan kognitif, afektif dan kekacauan tingkah laku pada orang tua. Awalnya obat ini digunakan sebagai obat vasoaktif dan untuk pengobatan cerevascular disorder. Kini ditemukan kegunaan lain yang rasional sebagai obat pada pengobatan segala bentuk demensia, termasuk penyakit Alzheimers. Sumber : nootropics.com 8. Cinnarizin menghambat kontraksi vaskular pada sel otot polos dengan menghambat saluran kalsium. Cinnarizin meningkatkan deformabilitas eritrosit dan menurunkan

viskositas darah dalam penelitian. Cinnarizin mencegah stimulasi dari sistem vestibular. Digunakan untuk permasalahan vertigo, pusing, tinitus, nystagmus, mual dan muntah. Sumber : www.intekom.com 9. Naftidrofuryl oksalat bekerja dengan dua cara. Pertama, obat ini menyebabkan saluran darah membesar. Kedua, obat ini meningkatkan kemampuan sel untuk membuang sampah. Kedua kemampuan ini berguna dalam pengobatan dari kerusakan yang disebabkan oleh berkurangnya suplai darah pada beberapa bagian tubuh. Pada penyakit vaskular periferal, dimana saluran darah yang sangat sempit, darah dan suplai oksigen ke sel di tangan, tungkai atau kaki berkurang. Oksigen berguna bagi sel untuk membuang sampah dari sel, sehingga dengan keadaan tersebut sampah dapat menumpuk. Hal ini dapat menyebabkan kerusakan sel dan menjadi penyebab rasa nyeri, kram dan pendarahan. Terutama bila kerusakan aliran darah terjadi di otak akan merusak sel otak, sehingga menimbulkan gejala seperti bingung dan kemunduran mental. Naftidrofutyl memperbaiki gejala tersebut dengan meningkatkan suplai darah dan oksigen pada daerah yang bermasalah dan juga meningkatkan kemampuan sel untuk membuang sampah sel, walaupun dalam kondisi suplai oksigen rendah. Kegunaan ; kerusakan aliran darah di otak (cerebral insufficiency) Sumber : www.tiscali.co.uk 10. Co-dergocrine Mesylate dalam menangani permasalahan kemampuan mental dan panjang dari periode kerja mental yang intens dengan meningkatkan (dan juga menstabilkan) suplai oksigen ke otak. Juga obat ini mencegah otak dan jantung dari kerusakan yang disebabkan oleh radikal bebas dan dapat meningkatkan jumlah dan kemampuan koneksi dari dendrit, dimana berkaitan dengan peningkatan kemampuan intelektual. variasi dosisnya sangat tinggi, tetapi dengan dosis tinggi hanya memberikan efek samping yang kecil. Dosis biasanya antara 3 mg hingga 9 mg perhari, tingkatkan dosis secara perlahan untuk mencegah mual. Sumber : www.smart-drugs.net Untuk pemilihan Obat Vasodilator Perifer & Aktivator Serebral yang tepat ada baiknya anda harus periksakan diri dan konsultasi ke dokter. Di apotik online medicastore anda dapat mencari Obat Vasodilator Perifer & Aktivator Serebral dengan merk yang berbeda dengan isi yang sama secara mudah dengan mengetikkan di search engine medicastore. Sehingga anda dapat memilih dan beli obat sesuai dengan kebutuhan anda.