Vasodilator s

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Vasodilators

Therapeutic Use and Rationale

As the name implies, vasodilator drugs relax the

smooth muscle in blood vessels, which causes thevessels to dilate. Dilation of arterial (resistance)

vessels leads to a reduction in systemic vascular

resistance, which leads to a fall in arterial bloodpressure. Dilation of venous (capacitance ) vessels

decreases venous blood pressure.

Vasodilators are used to treat hypertension, heart failureandangina; 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 becauseofreflex 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 aremixed (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 additionaltherapeutic benefit. For example, some calcium channel blockersnot 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 andpulmonaryhypertension, heart failureand angina. They reduce arterial pressure by decreasingsystemic

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 inventricularpreload 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 becauseventricular wall stressis 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 usingcardiac andsystemic vascular function curvesas shown to the right.

Selective arterial dilation decreases systemic vascular
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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 smallincrease 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 ventricleand 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 inresponse 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 onenhancing 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 intreating 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 theoxygen supply/demand ratio. Oxygendemand 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 filtrationand edema formation. Therefore, venous dilators aresometimes 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 asarteries, 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 bedepicted graphically usingcardiac and systemic vascular

function curvesas shown to the right. Venous dilation

increases venous complianceby relaxing the venous

smooth muscle. Increased compliance causes a parallelshift 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 fromA 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 andcardiac output by the Frank-Starling mechanism. Although not shown in this figure, reduced
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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 herefor more information).

Therefore, the cardiac and vascular responses to venous dilation are complex when both directeffects 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 preload2. 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 arehydralazine

(arterial dilator) and organic nitrate dilators(venous dilators).

The effects of mixed dilators oncardiac and systemicvascular function curvesare shown in the figure to the

right. The red line represents a systemic function curvegenerated when there is both venous dilation (increasedvenous 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 venousdilation, 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 decreasesystemic 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
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There are three potential drawbacks in the use of vasodilators:

1. Systemic vasodilation and arterial pressure reduction can lead to abaroreceptor-mediated

reflex stimulation of the heart (increased heart rate and inotropy). This increases oxygendemand, which is undesirable if the patient also has coronary artery disease.

2. Vasodilators can impair normal baroreceptor-mediated reflex vasoconstriction when aperson stands up, which can lead to orthostatic hypotension and syncope upon standing.

3. Vasodilators can lead torenal 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 bymechanism 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 dilatorproperties (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 drugclass 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
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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 alpha-

adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive

antagonists to the binding ofnorepinephrinethat is released bysympathetic nerves synapsing on

smooth muscle. Therefore, sometimes these drugs are referred to as sympatholytics becausethey 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 ason vascular smooth muscle. Smooth

muscle (postjunctional) 1 and 2-

adrenoceptors are linked to aGq-protein,

which activates smooth muscle

contraction through the IP3 signaltransduction pathway. Prejunctional 2-

adrenoceptors located on the sympatheticnerve 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 bysympathetic 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
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conditions of elevated sympathetic activity (e.g., during stress) or during pathologic increases in

circulating catecholaminescaused by an adrenal gland tumor (pheochromocytoma).

Therapeutic Uses

Alpha-blockers, especially 1-adrenoceptor antagonists, are useful in the treatment of primaryhypertension, 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 apheochromocytoma. 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 withbeta-blockadeto blunt the reflex tachycardia) until the tumorcan 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 arenon-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 sideeffects 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 thatcan be rectified by use of a diuretic in conjunction with the alpha-blocker. Alpha blockers have

not been shown to be beneficial inheart failure orangina, and should not be used in theseconditions.

Angiotensin Converting Enzyme (ACE) Inhibitors


ACE inhibitors produce

vasodilation by inhibitingthe formation of angiotensin

II. This vasoconstrictor isformed by the proteolytic

action of renin (released by

the kidneys) acting oncirculating angiotensinogen
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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, byblocking 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 beresponsible 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 smoothmuscle, which are coupled to aGq-proteinand 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 augmentssympathetic activity on the heart and blood vessels.

ACE inhibitors have the following actions:

Dilate arteries and veins by blockingangiotensin 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

aldosteronesecretion. This reducesblood 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 renin-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 ofprimary hypertension and hypertension caused by renal artery

stenosis, which causes renin-dependent hypertension owing to

the increased release of renin by the kidneys. Reducingangiotensin II formation leads to arterial and venous dilation,

which reduces arterial and venous pressures. By reducing the
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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 truethat 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 reportare 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 ofheart 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 ejectionfraction.

Reducedpreload, 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 followingmyocardial

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 heartfailure.

Specific Drugs

The first ACE inhibitor marketed, captopril, is still in widespread use today. Although newerACE 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.comfor specific drug

information)

benazepril

captopril

enalapril

fosinopril
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lisinopril

moexipril

quinapril

ramipril

Note that each of the ACE inhibitors named above end with "pril."


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 andobstruction; 0.1-0.2% of patients) and hyperkalemia (occurs becausealdosterone formation is

reduced) are also adverse effects of ACE inhibition. The incidence of angioedema is 2 to 4-timeshigher in African Americans compared to Caucasians. ACE inhibitors are contraindicated inpregnancy.

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 stenosisbecause the unaffected kidney can usually maintain sufficient filtration after ACE inhibition;

however, with bilateral renal artery stenosis it is especially important to ensure that renalfunction is not compromised.

Angiotensin Receptor Blockers (ARBs)


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). Theirmechanism of action, however, is very different from ACE inhibitors, which inhibit theformation 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).
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ARBs have the following actions, which are very similar to ACE inhibitors:

Dilate arteries and veins and thereby reduce arterial pressure andpreload 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

aldosteronesecretion.

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 inhibitorsfor 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."


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 andangioedema 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
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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 areblocked; however, with bilateral renal artery stenosis it is especially important to ensure that

renal function is not compromised.

Beta-Adrenoceptor Agonists (-agonists)


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 offsetsthe 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 andtherefore must be given by intravenous infusion.

Heart. Beta-agonists bind to beta-adrenoceptors located

in cardiac nodal tissue, theconducting system, and

contracting myocytes. The heart has both 1 and 2adrenoceptors, 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 norepinephrineand epinephrine that circulate in the blood.

Beta-adrenoceptors are coupled to aGs-proteins, which

activate adenylyl cyclase to formcAMP from ATP.
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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 inthe heart; these actions increase inotropy (contractility). Gs-protein activation also increases

heart rate by opening ion channels responsible forpacemaker currentsin the sinoatrial node. PK-

A phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calciumthrough 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 alsocontribute 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 bycirculating epinephrine. These receptors,like those in the heart, are coupled to a

Gs-protein, which stimulates the

formation ofcAMP. Although increased

cAMP enhances cardiac myocytecontraction (see above), in vascular

smooth muscle an increase in cAMP leads

to smooth muscle relaxation. The reasonfor 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 of2-adrenoceptors in the lungs causes bronchodilation. 2-

adrenoceptor 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 ofangiotensin II and the subsequent

release ofaldosterone by the adrenal cortex.

Specific Drugs and Therapeutic Uses

There are several different-agonists that are used clinically for the treatment ofheart 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 receptorselectivity is highly dose-dependent. (Go to www.rxlist.com for specific drug information).
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DrugReceptor

SelectivityClinical Use Comments

Epinephrine1 = 2 > 1*= 2*

Anaphylactic

shock;cardiogenic

shock; cardiac

arrest

Low doses produce cardiac stimulation

and vasodilation, which turns to

vasoconstriction at high doses. *Athigh plasma concentrations,

= selectivity.

Norepinephrine1 = 1 >

2 = 2

Severe

hypotension;

septic shock

Reflex bradycardia masks direct

stimulatory effects on sinoatrial node.

Dopamine 1 = 2 > 1*

Acute heartfailure,cardiogenic

shock and acute

renal failure

Biosynthetic precursor of

norepinephrine; stimulates

norepinephrine release. *At low doses,

it stimulates the heart and decreasessystemic vascular resistance; at high

doses, vasodilation becomes

vasoconstriction as lower affinity -

receptors bind to the dopamine; also

binds to D1 receptors in kidney,

producing vasodilation.

Dobutamine 1 > 2 > 1

Acute heartfailure;

cardiogenic

shock;refractory heartfailure

Net effect is cardiac stimulation with

modest vasodilation.

Isoproterenol 1 = 2

Bradycardiaand

atrioventricular

block

Net effect is cardiac stimulation and

vasodilation with little change in

pressure.


A major side effect of-agonists is cardiac arrhythmia. Because these drugs increase myocardial

oxygen demand, they can precipitate anginain patients with coronary artery disease. Headache

and tremor are also common.

Calcium-Channel Blockers (CCBs)
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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 responsiblefor regulating the influx of calcium into muscle cells,

which in turn stimulates smooth muscle contraction andcardiac myocyte contraction. In cardiac nodal tissue, L-

type calcium channels play an important role in

pacemaker currents and inphase 0 of the action

potentials. Therefore, by blocking calcium entry into thecell, 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 atrioventricularnode.

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 venouscapacitance vessels.

Angina. The anti-anginal effects of CCBs are derived from theirvasodilator and cardiodepressant actions. Systemic vasodilation reduces arterial pressure, which

reduces ventricularafterload(wall stress) thereby decreasing oxygen demand. The morecardioselective 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 inPrintzmetal'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 atrioventricularnode helps to blockreentry 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 mostsmooth muscle selective class of CCBs are the dihydropyridines. Because of their high vascular
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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 effectscan 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 towww.rxlist.com for specific druginformation)

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 themyocardium, 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 betweenverapamil 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.


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 beenshown 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 witha 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
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The sympathetic adrenergic nervous

system plays a major role in the regulationof arterial pressure. Activation of thesenerves to the heart increases the heart rate

(positive chronotropy), contractility

(positive inotropy) and velocity ofelectrical impulse conduction (positive

dromotropy). The norepinephrine-

releasing, sympathetic adrenergic nervesthat 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 sympatheticneurons 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 neuronalsystems 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-adrenoceptorandbeta-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 alpha 2(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 vascularresistance, which decreases arterial pressure.


Centrally acting 2-adrenoceptor agonists are used in the treatment ofhypertension. 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
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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 becausethey 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 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 assympathetic 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 isnecessary. Sudden discontinuation of clonidine can lead to rebound hypertension, which results

from excessive sympathetic activity.

Direct Acting Vasodilators


The one drug in this group, hydralazine, does not fit neatly into the other mechanistic classes, inpart, 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 musclehyperpolarization quite likely through the opening of K+-channels. It also may inhibit IP3-

induced release of calciumfrom the smooth muscle sarcoplasmic reticulum. This calcium

combines with calmodulin to activate myosin light chain kinase, which induces contraction.
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Finally, hydralazine stimulates the formation ofnitric oxide by the vascular endothelium, leading

to cGMP-mediated vasodilation.

The arterial vasodilator action of hydralazine reduces systemic vascular resistance and arterialpressure. Indirect cardiac stimulation (e.g., tachycardia) occurs with hydralazine administration

because of activation of thebaroreceptor 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 ofarterial hypertension. It is not first-line therapy for arterial hypertension. Its relatively short half-

life (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, andpulmonary hypertension. Itis often used in conjunction with abeta-blockeranddiureticto attenuate thebaroreceptor-

mediated reflex tachycardia and sodium retention, respectively.

Heart failure. Hydralazine has a role in the management of heart failure because of its ability toreduce 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.


Common side effects to hydralazine include headaches, flushing and tachycardia. Some patients

(~10%) experience a lupus-like syndrome. Reflex cardiac stimulation can precipitate angina inpatients with coronary artery disease.

Endothelin Receptor Antagonists


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 potentvasoconstrictor 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 andreceptor activation leads to the formation of

IP3, which causes the release of calcium by the
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sarcoplasmic reticulum (SR) and increased smooth muscle contraction and vasoconstriction.

There are also ETB receptors located on the endothelium that stimulate the formation ofnitric

oxide, which produces vasodilation in the absence of smooth muscle ETA and ETB receptoractivation. 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 IP 3 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.


Because of its powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1

has been implicated in the pathogenesis ofhypertension,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 cancontribute 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 ispulmonary hypertension.

Specific Drugs

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


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
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Sympathetic autonomic ganglia are

comprised of the paravertebral ganglia

(sympathetic chain ganglia) and theprevertebral ganglia. Preganglionic

sympathetic fibers that exit the spinal cord

synapse within these ganglia and releasethe neurotransmitteracetylcholine (ACh),

which binds to nicotinic receptors.

Activation of the nicotinic receptorsdepolarizes the cell body of the

postganglionic neuron and generates

action potentials that travel to the target

organ to elicit a response.

Parasympathetic autonomic gangliaare

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).


Sympatholytic drugs can block the sympathetic adrenergic system are three different levels.First, peripheral sympatholytic drugs such as alpha receptor antagonists andbeta 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 sympatheticganglia. 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 cellbodies 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. Reducedsympathetic 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.


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 antihypertensivedrugs that can be used. They are, however, occasionally used for hypertensive emergencies.
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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 of trimethaphan include prolonged neuromuscular blockade and potentiation of

neuromuscular blocking agents. It can produce excessive hypotension and impotence due to itssympatholytic effect, and constipation, urinary retention, dry mouth due to it parasympatholytic

effect. It also stimulates histamine release.

Nitrodilators


Nitric oxide (NO), a molecule produced by many cells in the body, and has several importantactions (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 NO-

stimulated 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 nitratesdo 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 toNO. Nitric oxide activates smooth muscle soluble

guanylyl cyclase (GC) to form cGMP. Increased

intracellular cGMP inhibits calcium entry into thecell, thereby decreasing intracellular calcium

concentrations and causing smooth muscle

relaxation (click here for details). NO alsoactivates K+ channels, which leads to

hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-

dependent protein kinase that activates myosin light chain phosphatase, the enzyme that

dephosphorylates myosin light chains, which leads to relaxation.
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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 itmay 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 whenthese drugs are given at normal therapeutic

doses. Venous dilation reduces venous pressure

and decreases ventricularpreload. This reducesventricular wall stressand 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 thelarge epicardial vessels, which diminishes the

likelihood ofcoronary vascular steal. Systemic

arterial dilation reduces afterload, which can enhance cardiac output while at the same timereducing ventricular wall stress and oxygen demand. At high concentrations, excessive systemic

vasodilation may lead to hypotension and abaroreceptor 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 forcoronary perfusion, most of which occurs during diastole (click here for more details).


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, aorticdissection, etc. Nitrodilators may also be used during surgery to to control arterial pressure

within desired limits.

Heart failure. Nitrodilators are used in acuteheart failure and in severe chronic heart failure.

Arterial dilation reduces afterload on the failing ventricle and leads to an increase in strokevolume 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
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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 anginaandmyocardial infarction. They are useful in Printzmetal's variant angina because they improve

coronary blood flow (i.e., increase oxygen supply) by reversing and inhibiting coronaryvasospasm. 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 ifdirect 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 towww.rxlist.com for specificdrug 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 administeredsublingually. 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 60minutes), but are effective for 12 to 24 hours. Intravenous nitroglycerin is used in the hospital

setting forunstable 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 short-acting 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, oraladministration of these compounds requires much higher doses than sublingual administration,

which is not subject to first-pass hepatic metabolism.
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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, andbecause of its short half-life, continuous infusion is required.


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 thereduction of cyanide by a sulfhydryl donor. There is clinical evidence that nitrodilators may

interact adversely with cGMP-dependent phosphodiesterase inhibitors that are used to treaterectile dysfunction (e.g., sildenafil [Viagra]). The reason for this adverse reaction is thatnitrodilators 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 ofsympathetic adrenergic to the heart releases the

neurotransmitter norepinephrine and increases

circulating catecholamines(epinephrine and

norepinephrine). These catecholamines bindprimarily tobeta1-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 otherintracellular messengers, increases contractility

(inotropy), heart rate (chronotropy) andconduction velocity (dromotropy). Cyclic-AMP is

broken down by an enzyme called cAMP-dependent 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
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