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
General Pharmacology
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."
Side Effects and Contraindications
As a drug class, ACE inhibitors have a relatively low incidence of side effects and are well-tolerated. A common, annoying side effect of ACE inhibitors is a dry cough appearing in 10-
30% of patients. It appears to be related to the elevation in bradykinin. Hypotension can also be a
problem, especially in heart failure patients. Angioedema (life-threatening airway swelling 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)
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). 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."
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 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)
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 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.
Side Effects and Contraindications
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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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 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.
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 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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General Pharmacology
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.
Therapeutic Indications
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 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 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
General Pharmacology
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.
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 inpatients 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 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.
Therapeutic Indications
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)
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
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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).
General Pharmacology
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.
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 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 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 itssympatholytic 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 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).
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, 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.
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 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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