VASODILATORS:

Therapeutic Use and Rationale

Therapeutic Uses of Vasodilators
Systemic and pulmonary hypertension
Heart failure
Angina

As the name implies, vasodilator drugs relax the smooth muscle in blood vessels, which
causes the vessels to dilate. Dilation of arterial (resistance) vessels leads to a reduction
in systemic vascular resistance, which leads to a fall in arterial blood pressure. Dilation of
venous (capacitance ) vessels decreases venous blood pressure.

Vasodilators are used to treat hypertension, heart failure and angina; however, some
vasodilators are better suited than others for these indications. Some vasodilators that act
primarily on resistance vessels (arterial dilators) are used for hypertension, and heart failure,
and angina; however, reflex cardiac stimulation makes some arterial dilators unsuitable for
angina. Venous dilators are very effective for angina, and sometimes used for heart failure, but
are not used as primary therapy for hypertension. Most vasodilator drugs are mixed (or
balanced) vasodilators in that they dilate both arteries and veins and therefore can have wide
application in hypertension, heart failure and angina. Some vasodilators, because of their
mechanism of action, also have other important actions that can in some cases enhance their
therapeutic utility or provide some additional therapeutic benefit. For example, some calcium
channel blockers not only dilate blood vessels, but also depress cardiac mechanical and
electrical function, which can enhance their antihypertensive actions and confer additional
therapeutic benefit such as blocking arrhythmias.

Arterial dilators

Arterial dilator drugs are commonly used to treat systemic and pulmonary hypertension, heart
failure and angina. They reduce arterial pressure by decreasing systemic vascular resistance.
This benefits patients in heart failure by reducing the afterload on the left ventricle, which
enhances stroke volume and cardiac output and leads to secondary decreases in
ventricular preload and venous pressures. Anginal patients benefit from arterial dilators
because by reducing afterload on the heart, vasodilators decrease the oxygen demand of the
heart, and thereby improve the oxygen supply/demand ratio. Oxygen demand is reduced
because ventricular wall stress is reduced when aortic pressure is decreased. Some
vasodilators can also reverse or prevent arterial vasospasm (transient contraction of arteries),
which can precipitate anginal attacks.

Most drugs that dilate arteries also dilate veins; however, hydralazine, a direct acting
vasodilator, is highly selective for arterial resistance vessels.
The effects of arterial dilators on overall cardiovascular function can be depicted graphically
using cardiac and systemic vascular function curvesas shown to the right. Selective arterial
dilation decreases systemic vascular resistance, which increases the slope of the systemic
vascular function curve (red line) without appreciably changing the x-intercept (mean
circulatory filling pressure). This alone causes the operating point to shift from A to B,
resulting in an increase in cardiac output (CO) with a small increase in right atrial pressure
(PRA). The reason for the increase in PRA is that arterial dilation increases blood flow from the
arterial vasculature into the venous vasculature, thereby increasing venous volume and
pressure. However, arterial dilators also reduce afterload on the left ventricle and therefore
unload the heart, which enhances the pumping ability of the heart. This causes the cardiac
function curve to shift up and to the left (not shown in figure). Adding to this afterload effect
is the influence of enhanced sympathetic stimulation due to a baroreceptor reflex in response
to the fall in arterial pressure, which increases heart rate and inotropy. Because of these
compensatory cardiac responses, arterial dilators increase cardiac output with little or no
change in right atrial pressure (cardiac preload). Although cardiac output is increased,
systemic vascular resistance is reduced relatively more causing arterial pressure to fall. The
effect of reducing afterload on enhancing cardiac output is even greater in failing
hearts because stroke volume more sensitive to the influence of elevated afterload in hearts
with impaired contractility.

Venous dilators

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

1. Venous dilators reduce venous pressure, which reduces preload on the heart
thereby decreasing cardiac output. This is useful in angina because it decreases
the oxygen demand of the heart and thereby increases the oxygen
supply/demand ratio. Oxygen demand is reduced because decreasing preload
leads to a reduction in ventricular wall stress by decreasing the size of the heart.
2. Reducing venous pressure decreases proximal capillary hydrostatic pressure,
which reduces capillary fluid filtration and edema formation. Therefore, venous
dilators are sometimes used in the treatment of heart failure along with other
drugs because they help to reduce pulmonary and/or systemic edema that results
from the heart failure.
Although most vasodilator drugs dilate veins as well as arteries, some drugs, such as organic
nitrate dilators are relatively selective for veins.

The effects of selective venous dilators on overall cardiovascular function in normal subjects
can be depicted graphically using cardiac and systemic vascular function curves as shown to
the right. Venous dilation increasesvenous compliance by relaxing the venous smooth muscle.
Increased compliance causes a parallel shift to the left of the vascular function curve (red
line), which decreases the mean circulatory filling pressure (x-intercept). This causes the
operating point to shift from A to B, resulting in a decrease in cardiac output (CO) with a
small decrease in right atrial pressure (PRA). The reason for these changes is that venous
dilation, by reducing PRA, decreases right ventricular preload, which decreases stroke volume
and cardiac output by the Frank-Starling mechanism. Although not shown in this figure,
reduced cardiac output causes a fall in arterial pressure, which reduces afterload on the left
ventricle and leads to baroreceptor reflex responses, both of which can shift the cardiac
function curve up and to the left. Sympathetic activation can also lead to an increase in
systemic vascular resistance. The cardiac effects (decreased cardiac output) of venous dilation
are more pronounce in normal hearts than in failing hearts because of where the hearts are
operating on their Frank-Starling curves (cardiac function) curves (click here for more
information).

Therefore, the cardiac and vascular responses to venous dilation are complex when both direct
effects and indirect compensatory responses are taken into consideration. The most important
effects in terms of clinical utility for patients are summarized below.

Venous dilators reduce:

1. Venous pressure and therefore cardiac preload

2. Cardiac output
3. Arterial pressure
4. Myocardial oxygen demand
5. Capillary fluid filtration and tissue edema
Mixed or "balanced" dilators

As indicated above, most vasodilators act on both arteries and veins, and therefore are termed
mixed or balanced dilators. Notable exceptions are hydralazine (arterial dilator) and organic
nitrate dilators (venous dilators).
The effects of mixed dilators on cardiac and systemic vascular function curves are shown in
the figure to the right. The red line represents a systemic function curve generated when there
is both venous dilation (increased venous compliance) and arterial dilation (reduced systemic
vascular resistance) - the mean circulatory filling pressure (x-axis) is decreased and the slope
is increased. Point B represents the new operating point, although it is important to note that
where this point lies depends on the relative degree of venous and arterial dilation. If there is
more arterial dilation than venous dilation, then point B may be located slightly above point A
where the cardiac function curve intersects with the new vascular function curve.

To summarize the effects of mixed vasodilators, we can say that in general they decrease
systemic vascular resistance and arterial pressure with relatively little change in right atrial (or
central venous) pressure (i.e., little change in cardiac preload), and they have a relatively little
effect on cardiac output.

Side-Effects of Vasodilators

There are three potential drawbacks in the use of vasodilators:

1. Systemic vasodilation and arterial pressure reduction can lead to a baroreceptor-

mediated reflex stimulation of the heart (increased heart rate and inotropy). This
increases oxygen demand, which is undesirable if the patient also has coronary
artery disease.
2. Vasodilators can impair normal baroreceptor-mediated reflex vasoconstriction
when a person stands up, which can lead to orthostatic hypotension and syncope
upon standing.
3. Vasodilators can lead to renal retention of sodium and water, which increases
blood volume and cardiac output and thereby compensates for the reduced
systemic vascular resistance.
Drug Classes and General Mechanisms of Action

Vasodilator drugs can be classified based on their site of action (arterial versus venous) or by
mechanism of action. Some drugs primarily dilate resistance vessels (arterial dilators; e.g.,
hydralazine), while others primarily affect venous capacitance vessels (venous dilators; e.g.,
nitroglycerine). Most vasodilator drugs, however, have mixed arterial and venous dilator
properties (mixed dilators; e.g., alpha-adrenoceptor antagonists, angiotensin converting
enzyme inhibitors).
It is more common, however, to classify vasodilator drugs based on their primary mechanism
of action. The figure to the right depicts important mechanistic classes of vasodilator drugs.
These classes of drugs, as well as other classes that produce vasodilation, are listed
below. (Click on the drug class for more details)

Alpha-Adrenoceptor Antagonists (Alpha-Blockers)

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 act as competitive
antagonists to the binding of norepinephrine that is released by sympathetic nerves synapsing on
smooth muscle. Therefore, sometimes these drugs are referred to assympatholytics because
they antagonize sympathetic activity. Some alpha-blockers are non-competitive
(e.g.,phenoxybenzamine), which greatly prolongs their action, whereas others are relatively
selective for one type of alpha-adrenoceptor.
Vascular smooth muscle has two types of alpha-adrenoceptors: alpha 1 (1) and alpha2 (2). The
1-adrenoceptors are the predominant -receptor located on vascular smooth muscle. These
receptors are linked toGq-proteins that activate smooth muscle contraction through the IP3 signal
transduction pathway. Depending on the tissue and type of vessel, there are also 2-
adrenoceptors found on the smooth muscle. These receptors are linked to Gi-proteins, and
binding of an alpha-agonist to these receptors decreases intracellular cAMP, which causes
smooth muscle contraction. There are also 2-adrenoceptors located on the sympathetic nerve
terminals that inhibit the release of norepinephrine and therefore act as a feedback mechanism
for modulating the release of norepinephrine.

1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine to the

smooth muscle receptors. Non-selective 1 and 2-adrenoceptor antagonists block postjunctional
1 and 2-adrenoceptors, which causes vasodilation; however, the blocking of prejunctional 2-
adrenoceptors leads to increased release of norepinephrine, which attenuates the effectiveness
of the 1 and 2-postjunctional adrenoceptor blockade. Furthermore, blocking 2-prejunctional
adrenoceptors in the heart can lead to increases in heart rate and contractility due to the
enhanced release of norepinephrine that binds to beta1-adrenoceptors.

Alpha-blockers dilate both arteries and veins because both vessel types are innervated by
sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial
resistance vessels. Because most blood vessels have some degree of sympathetic tone under
basal conditions, these drugs are effective dilators. They are even more effective under
conditions of elevated sympathetic activity (e.g., during stress) or during pathologic increases
incirculating catecholamines caused by an adrenal gland tumor (pheochromocytoma).

Therapeutic Uses

Alpha-blockers, especially 1-adrenoceptor antagonists, are useful in the treatment of primary

hypertension, although their use is not as widespread as other antihypertensive drugs. The non-
selective antagonists are usually reserve for use in hypertensive emergencies caused by a
pheochromocytoma. This hypertensive condition, which is most commonly caused by an adrenal
gland tumor that secretes large amounts of catecholamines, can be managed by non-selective
alpha-blockers (in conjunction with beta-blockade to blunt the reflex tachycardia) until the tumor
can be surgically removed.

Specific Drugs
Newer alpha-blockers used in treating hypertension are relatively selective 1-adrenoceptor
antagonists (e.g.,prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs are
non-selective antagonists (e.g.,phentolamine, phenoxybenzamine). (Go to www.rxlist.com for
specific drug information)

Side Effects and Contraindications

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

Angiotensin Converting Enzyme (ACE) Inhibitors

General Pharmacology

ACE inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This
vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on
circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II
by angiotensin converting enzyme.

ACE also breaks down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by
blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the
vasodilator action of ACE inhibitors. The increase in bradykinin is also believed to be responsible
for a troublesome side effect of ACE inhibitors, namely, a dry cough.

Angiotensin II constricts arteries and veins by binding to AT1 receptors located on the smooth
muscle, which are coupled to a Gq-protein and the the IP3 signal transduction pathway.
Angiotensin II also facilitates the release of norepinephrine from sympathetic adrenergic nerves
and inhibits norepinephrine reuptake by these nerves. This effect of angiotensin II augments
sympathetic activity on the heart and blood vessels.

Cardiorenal Effects of ACE Inhibitors

Vasodilation (arterial & venous)

- reduce arterial & venous pressure
- reduce ventricular afterload & preload
Decrease blood volume
- natriuretic
- diuretic
Depress sympathetic activity
Inhibit cardiac and vascular hypertrophy
ACE inhibitors have the following actions:

Dilate arteries and veins by blocking angiotensin II formation and inhibiting

bradykinin metabolism. This vasodilation reduces arterial
pressure, preload and afterload on the heart.
Down regulate sympathetic adrenergic activity by blocking the facilitating effects of
angiotensin II on sympathetic nerve release and reuptake of norepinephrine.
Promote renal excretion of sodium and water (natriuretic anddiuretic effects) by
blocking the effects of angiotensin II in the kidney and by blocking angiotensin II
stimulation ofaldosterone secretion. This reduces blood volume, venous pressure
and arterial pressure.
Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart
failure, and myocardial infarction.
Elevated plasma renin is not required for the actions of ACE inhibitors, although ACE inhibitors
are more efficacious when circulating levels of renin are elevated. We know that 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

Therapeutic Use of
ACE Inhibitors

Hypertension
Heart failure
Post-myocardial infarction

Hypertension

ACE inhibitors are effective in the treatment of primary hypertension and hypertension caused by
renal artery stenosis, which causes renin-dependent hypertension owing to the increased release
of renin by the kidneys. Reducing angiotensin II formation leads to arterial and venous dilation,
which reduces arterial and venous pressures. By reducing the effects of angiotensin II on the
kidney, ACE inhibitors cause natriuresis and diuresis, which decreases blood volume and cardiac
output, thereby lowering arterial pressure.
Some of the older literature indicated that ACE inhibitors (and angiotensin receptor blockers,
ARBs) were less efficacious in African American hypertensive patients, which unfortunately led to
lower utilization of these important, beneficial drugs in African Americans. While it is true that
African Americans do not respond as well as other races to monotherapy with ACE inhibitors or
ARBs, the differences are eliminated with adequate diuretic dosing. Therefore, current
recommendations from the JNC 7 report are that ACE inhibitors and ARBs are appropriate for use
in African Americans, with the recommendation of adequate diuretic dosing to achieve the target
blood pressure.

Heart Failure

ACE inhibitors have proven to be very effective in the treatment of heart failure caused by systolic
dysfunction (e.g., dilated cardiomyopathy). Beneficial effects of ACE inhibition in heart failure
include:

Reduced afterload, which enhances ventricular stroke volume and improves

ejection fraction.
Reduced preload, which decreases pulmonary and systemic congestion
and edema.
Reduced sympathetic activation, which has been shown to be deleterious in heart
failure.
Improving the oxygen supply/demand ratio primarily by decreasing demand
through the reductions in afterload and preload.
Prevents angiotensin II from triggering deleterious cardiac remodeling.
Finally, ACE inhibitors have been shown to be effective in patients following myocardial
infarction because they help to reduce deleterious remodeling that occurs post-infarction.

ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart
failure.

Specific Drugs

The first ACE inhibitor marketed, captopril, is still in widespread use today. Although newer ACE
inhibitors differ from captopril in terms of pharmacokinetics and metabolism, all the ACE inhibitors
have similar overall effects on blocking the formation of angiotensin II. ACE inhibitors include the
following specific drugs: (Go to www.rxlist.com for specific drug information)

benazepril
captopril
enalapril
fosinopril
lisinopril
moexipril
quinapril
ramipril
Note that each of the ACE inhibitors named above end with "pril."

Side Effects and Contraindications

As a drug class, ACE inhibitors have a relatively low incidence of side effects and are well-
tolerated. A common, annoying side effect of ACE inhibitors is a dry cough appearing in about
10% of patients. It appears to be related to the elevation in bradykinin. Hypotension can also be a
problem, especially in heart failure patients. Angioedema (life-threatening airway swelling and
obstruction; 0.1-0.2% of patients) and hyperkalemia (occurs because aldosteroneformation is
reduced) are also adverse effects of ACE inhibition. The incidence of angioedema is 2 to 4-times
higher in African Americans compared to Caucasians. ACE inhibitors are contraindicated in
pregnancy.

Patients with bilateral renal artery stenosis may experience renal failure if ACE inhibitors are
administered. The reason is that the elevated circulating and intrarenal angiotensin II in this
condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which
helps to maintain glomerular capillary pressure and filtration. Removing this constriction by
blocking circulating and intrarenal angiotensin II formation can cause an abrupt fall in glomerular
filtration rate. This is not generally a problem with unilateral renal artery stenosis because the
unaffected kidney can usually maintain sufficient filtration after ACE inhibition; however, with
bilateral renal artery stenosis it is especially important to ensure that renal function is not
compromised

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 (stimulate renin release). Beta-
adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and
to circulating epinephrine. Therefore, -agonists mimic the actions of sympathetic adrenergic
stimulation acting through -adrenoceptors. Overall, the effect of -agonists is cardiac stimulation
(increased heart rate, contractility, conduction velocity, relaxation) and systemic vasodilation.
Arterial pressure may increase, but not necessarily because the fall in systemic vascular
resistance offsets the increase in cardiac output. Therefore, the effect on arterial pressure
depends on the relative influence on cardiac versus vascular -adrenoceptors. Long-term
exposure to -agonists can cause -receptor down-regulation, which limits their therapeutic
efficacy to short-term application. Beta-agonists, because they are catecholamines, have a low
bioavailability and therefore must be given by intravenous infusion.

Heart

Beta-agonists bind to beta-adrenoceptors located in cardiac nodal tissue, theconducting system,

and contracting myocytes.

Beta-Agonists
Cardiac effects

Increase contractility
(positive inotropy)
Increase relaxation rate
(positive lusitropy)
Increase heart rate
(positive chronotropy)
Increase conduction velocity
(positive dromotropy)

Vascular effects

Smooth muscle relaxation

(vasodilation)

Other actions

Bronchodilation
Hepatic glycogenolysis
Pancreatic release of glucagon
Renin release by kidneys
The heart has both 1 and 2 adrenoceptors, although the predominant receptor type in number
and function is 1. These receptors primarily bind norepinephrine that is released from
sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that
circulate in the blood.

Beta-adrenoceptors are coupled to Gs-proteins, which activate adenylyl cyclase to

form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that
phosphorylates L-type calcium channels, which causes increased calcium entry into the cells.
Increased calcium entry during action potentials leads to enhanced release of calcium by the
sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein
activation also increases heart rate by opening ion channels responsible for pacemaker
currents in the sinoatrial node. PK-A phosphorylates sites on the sarcoplasmic reticulum, which
enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-
release channels) associated with the sarcoplasmic reticulum. This provides more calcium for
binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light
chains, which may also contribute to the positive inotropic effect of beta-adrenoceptor stimulation.
In summary, the cardiac effects of a -agonist are increased heart rate, contractility, conduction
velocity, and relaxation rate.

Blood vessels

Vascular smooth muscle has 2-adrenoceptors that have a high binding affinity for circulating
epinephrine and a relatively lower affinity to norepinephrine released by sympathetic adrenergic
nerves.

These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the
formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see
above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The
reason for this is that cAMP inhibits myosin light chain kinase that is responsible for
phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by 2-
agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting
relaxation).

Other tissues

Activation of 2-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 of angiotensin II and the subsequent release of aldosterone by
the adrenal cortex.

Specific Drugs and Therapeutic Uses

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

Receptor
Drug Clinical Use Comments
Selectivity

Anaphylactic
Low doses produce cardiac stimulation and
shock;
1 = 2 > vasodilation, which turns to vasoconstriction at
Epinephrine cardiogenic
1* = 2* high doses. *At high plasma concentrations, =
shock; cardiac
selectivity.
arrest

Severe
1 = 1 > Reflex bradycardia masks direct stimulatory
Norepinephrine hypotension;
2 = 2 effects on sinoatrial node.
septic shock

Biosynthetic precursor of norepinephrine;

Acute heart stimulates norepinephrine release. *At low
failure, doses, it stimulates the heart and decreases
1 = 2 > cardiogenic systemic vascular resistance; at high doses,
Dopamine
1* shock and vasodilation becomes vasoconstriction as lower
acute renal affinity -receptors bind to the dopamine; also
failure binds to D1 receptors in kidney, producing
vasodilation.

Acute heart
failure;
cardiogenic Net effect is cardiac stimulation with modest
Dobutamine 1 > 2 > 1
shock; vasodilation.
refractory
heart failure

Bradycardia
and Net effect is cardiac stimulation and vasodilation
Isoproterenol 1 = 2
atrioventricular with little change in pressure.
block

Side Effects and Contraindications

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

Calcium-Channel Blockers (CCBs)

Calcium-Channel Blockers
Cardiac effects

Decrease contractility
(negative inotropy)
Decrease heart rate
(negative chronotropy)
Decrease conduction velocity
(negative dromotropy)

Vascular effects

Smooth muscle relaxation

(vasodilation)

General Pharmacology

Currently approved CCBs bind to L-type calcium channels located on the vascular smooth
muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). These
channels are responsible for regulating the influx of calcium into muscle cells, which in turn
stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue,
L-type calcium channels play an important role in pacemaker currents and in phase 0 of the
action potentials. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth
muscle relaxation (vasodilation), decreased myocardial force generation (negative inotropy),
decreased heart rate (negative chronotropy), and decreased conduction velocity within the heart
(negative dromotropy), particularly at the atrioventricular node.

Therapeutic Indications

CCBs are used to treat hypertension, angina and arrhythmias.

Hypertension

Therapeutic Use of
Calcium-Channel Blockers

Hypertension
(systemic & pulmonary)
Angina
Arrhythmias
By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance,
which lowers arterial blood pressure. These drugs primarily affect arterial resistance vessels, with
only minimal effects on venous capacitance vessels.

Angina

The anti-anginal effects of CCBs are derived from their vasodilator and cardiodepressant actions.
Systemic vasodilation reduces arterial pressure, which reduces ventricular afterload (wall stress)
thereby decreasing oxygen demand. The more cardioselective CCBs (verapamil and diltiazem)
decrease heart rate and contractility, which leads to a reduction in myocardial oxygen demand,
which makes them excellent antianginal drugs. CCBs can also dilate coronary arteries and
prevent or reverse coronary vasospasm (as occurs in Printzmetal's variant angina), thereby
increasing oxygen supply to the myocardium.

Arrhythmias

The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to their ability to
decrease the firing rate of aberrant pacemaker sites within the heart, but more importantly are
related to their ability to decrease conduction velocity and prolong repolarization, especially at the
atrioventricular node. This latter action at the atrioventricular node helps to
block reentrymechanisms, which can cause supraventricular tachycardia.

Different Classes of Calcium-Channel Blockers

There are three classes of CCBs. They differ not only in their basic chemical structure, but also in
their relative selectivity toward cardiac versus vascular L-type calcium channels. The most
smooth muscle selective class of CCBs are the dihydropyridines. Because of their high vascular
selectivity, these drugs are primarily used to reduce systemic vascular resistance and arterial
pressure, and therefore are used to treat hypertension. Extended release formulations or long-
acting compounds are used to treat angina and are particularly effecting for vasospastic angina;
however, their powerful systemic vasodilator and pressure lowering effects can lead to reflex
cardiac stimulation (tachycardia and increased inotropy), which can offset the beneficial effects of
afterload reduction on myocardial oxygen demand. Note that dihydropyridines are easy to
recognize because the drug name ends in "pine."

Dihydropyridines include the following specific drugs: (Go to www.rxlist.com for specific drug
information)

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

Side Effects and Contraindications

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

Direct Acting Vasodilators

General Pharmacology

The one drug in this group, hydralazine, does not fit neatly into the other mechanistic classes, in
part, because its mechanism of action is not entirely clear and it appears to have multiple, direct
effects on the vascular smooth muscle. First, hydralazine causes smooth muscle
hyperpolarization quite likely through the opening of K+-channels. It also may inhibit IP3-induced
release of calcium from the smooth muscle sarcoplasmic reticulum. This calcium combines with
calmodulin to activate myosin light chain kinase, which induces contraction. Finally, hydralazine
stimulates the formation of nitric oxide by the vascular endothelium, leading to cGMP-mediated
vasodilation.

Hydralazine, which is highly specific for arterial vessels, reduces systemic vascular resistance
and arterial pressure. Indirect cardiac stimulation (e.g., tachycardia) occurs with hydralazine
administration because of activation of the baroreceptor reflex.

Specific Drugs and Therapeutic Indications

The direct acting vasodilator that is used clinically is hydralazine. This drug is used in the
treatment of hypertension and heart failure.

Hypertension

Hydralazine is used occasionally (although rarely alone) in the treatment of arterial hypertension.
It is not first-line therapy for arterial hypertension. Its relatively short half-life, which necessitates
frequent dosing, and its precipitation of reflex tachycardia make it undesirable for treating chronic
hypertension. However, it is used in treating acute hypertensive emergencies, secondary
hypertension caused by preecclampsia, and pulmonary hypertension. It is often used in
conjunction with a beta-blocker anddiuretic to attenuate the baroreceptor-mediated reflex
tachycardia and renal sodium retention, respectively.

Heart failure

Hydralazine has a role in the management of heart failure because of its ability to
reduce afterload and thereby enhance stroke volume and ejection fraction. When used in heart
failure, it is given along with a diuretic and often with a nitrodilator.

Side Effects and Contraindications

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

Nitrodilators
General Pharmacology

Nitric oxide (NO), a molecule produced by many cells in the body, and has several important
actions (click here for details). In the cardiovascular system, NO is primarily produced by vascular
endothelial cells. This endothelial-derived NO has several important functions including relaxing
vascular smooth muscle (vasodilation), inhibiting platelet aggregation (anti-thrombotic), and
inhibiting leukocyte-endothelial interactions (anti-inflammatory). These actions involve 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 nitrates
do not directly release NO, however, their nitrate groups interact with enzymes and intracellular
sulfhydryl groups that reduce the nitrate groups to NO or to S-nitrosothiol, which then is reduced
to NO. Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP.
Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular
calcium concentrations and causing smooth muscle relaxation (click here for details). NO also
activates K+channels, which leads to hyperpolarization and relaxation. Finally, NO acting through
cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain
phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.

Tolerance to organic nitrates occurs with frequent dosing, which decreases their efficacy. The
problem is partially circumvented by using the smallest effective dose of the compound coupled
with infrequent or irregular dosing. The mechanism for tolerance is not fully understood, but it
may involve depletion of tissue sulfhydryl groups, or scavenging of NO by superoxide anion and
the subsequent production of peroxynitrite that may inhibit guanylyl cyclase.

Primary Cardiovascular Actions

of Nitrodilators
Systemic vasculature

vasodilation
(venous dilation > arterial dilation)
decreased venous pressure
decreased arterial pressure (small effect)

Cardiac

reduced preload and afterload

(decreased wall stress)
decreased oxygen demand

Coronary

prevents/reverses vasospasm
vasodilation (primarily epicardial vessels)
improves subendocardial perfusion
increased oxygen delivery
Although organic nitrates can dilate both arteries and veins, venous dilation predominates when
these drugs are given at normal therapeutic doses. Venous dilation reduces venous pressure and
decreases ventricularpreload. This reduces ventricular wall stress and oxygen demand by the
heart, thereby enhancing the oxygen supply/demand ratio. A reduction in preload (reduced
diastolic wall stress) also helps to improve subendocardial blood flow, which is often
compromised in coronary artery disease. Mild coronary dilation or reversal of coronary
vasospasm will further enhance the oxygen supply/demand ratio and diminish the anginal pain.
Coronary dilation occurs primarily in the large epicardial vessels, which diminishes the likelihood
of coronary vascular steal. Systemic arterial dilation reducesafterload, which can enhance cardiac
output while at the same time reducing ventricular wall stress and oxygen demand. At high
concentrations, excessive systemic vasodilation may lead to hypotension and 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 for coronary perfusion, most of which occurs during
diastole (click here for more details).

Therapeutic Indications

The primary pharmacologic action of nitrodilators, arterial and venous dilation, make these
compounds useful in the treatment of hypertension, heart failure, angina and myocardial
infarction. Another beneficial action of nitrodilators is their ability to inhibit platelet aggregation.

Hypertension

Nitrodilators are not used to treat chronic primary or secondary hypertension; however, sodium
nitroprusside and nitroglycerine are used to lower blood pressure in acute hypertensive
emergencies that may result from a pheochromocytoma, renal artery stenosis, aortic dissection,
etc. Nitrodilators may also be used during surgery to control arterial pressure within desired limits.

Heart failure
Nitrodilators are used in acute heart failure and in severe chronic heart failure. Arterial dilation
reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection
fraction. Furthermore, the venous dilation reduces venous pressure, which helps to reduce
edema. Reducing both afterload and preload on the heart also helps to improve the mechanical
efficiency of dilated hearts and to reduce wall stress and the oxygen demands placed on the
failing heart.

Angina and myocardial infarction

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

Specific Drugs

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

isosorbide dinitrate
isosorbide mononitrate
nitroglycerin
erythrityl tetranitrate
pentaerythritol tetranitrate
sodium nitroprusside
The nitrodilators listed above differ in the route of administration, onset of action, and duration of
action. Nitroglycerin, which has been used since the 19th century, is commonly used in the
treatment of angina because it is very fast acting (within 2 to 5 minutes) when administered
sublingually. Its effects usually wear off within 30 minutes. Therefore, nitroglycerin is particularly
useful for preventing or terminating an acute anginal attack. Longer-acting preparations of
nitroglycerin (e.g., transdermal patches) have a longer onset of action (30 to 60 minutes), but are
effective for 12 to 24 hours. Intravenous nitroglycerin is used in the hospital setting for unstable
angina and acute heart failure.

Isosorbide dinitrate and mononitrate, and tetranitrate compounds have a longer onset of
action and duration of action than nitroglycerin. This makes these compounds more useful than
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, oral administration of these compounds requires much higher doses than sublingual
administration, which is not subject to first-pass hepatic metabolism.

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

Side Effects and Contraindications

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

Potassium-Channel Openers
General Pharmacology

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

Therapeutic Indications

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

Specific Drugs

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

Side Effects and Contraindications

Common side effects to minoxidil include headaches, flushing and reflex tachycardia. The potent
vasodilator actions of minoxidil can lead to fluid retention and edema formation. Reflex cardiac
stimulation can precipitate angina in patients with coronary artery disease. Minoxidil produces T
wave changes in a high percentage (~60%) of patients under chronic treatment. One of the most
noted side effects of minoxidil is hypertrichosis, a thickening and enhanced pigmentation of body
hair, and therefore this drug is more commonly used for treating baldness.

DISCLAIMER: These materials are for educational purposes only, and

Renin Inhibitors

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

Renin inhibitors have the following actions, which are similar to those produced by ACEIs and
ARBs:

Cardiorenal Effects of Renin Inhibitors

Vasodilation (arterial & venous)

- reduce arterial & venous pressures
- reduce ventricular afterload & preload
 Decrease blood volume
- natriuretic
- diuretic
Depress sympathetic activity
Inhibit cardiac and vascular hypertrophy
Dilate arteries and veins by blocking angiotensin II formation. This vasodilation
reduces arterial pressure, preload andafterload 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 anddiuretic effects) by
blocking the effects of angiotensin II in the kidney and by blocking angiotensin II
stimulation of aldosteronesecretion. This reduces blood volume, venous pressure
and arterial pressure.
Inhibit cardiac and vascular remodeling associated with chronichypertension, heart
failure, and myocardial infarction.

Specific Drugs and Therapeutic Uses

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

Side Effects and Contraindications

Aliskiren alone, like ACEIs and ARBs, has a relatively low incidence of side effects and is well-
tolerated. Aliskiren has dose-related gastrointestinal adverse effects in some patients; diarrhea is
observed in less the 3% of patients. The incidence of coughis much lower in patients taking
aliskiren than those taking ACEIs. Angioedema (life-threatening airway swelling and obstruction)
can occur in patients taking aliskiren (as can occur with ACEI and ARB treatment), although fewer
than 1% of patients develop this condition. When administered with an ACEI, aliskiren can
produce hyperkalemia, especially in diabetic patients. Recent studies (ALTITUDE trial, 2011)
have noted increased adverse events (non-fatal stroke, renal complications, hyperkalemia,
hypotension) with no apparent additional benefits when added to treatment with an ACEI or ARB
in diabetic patients.

As with ACEIs, aliskiren should not be administered anytime during pregnancy, particularly in
second and third trimesters because of fetal and neonatal injury, and risk of birth defects.
 Vasoconstrictor Drugs
Therapeutic Use and Rationale

As the name implies, vasoconstrictor drugs contract the smooth muscle in blood vessels, which
causes the vessels to constrict. Constriction of arterial (resistance) vessels increases systemic
vascular resistance, which leads to an increase in arterial blood pressure because mean arterial
pressure is determined by the product of systemic vascular resistance and cardiac output..
Constriction of venous (capacitance) vessels increases venous blood pressure and increases
cardiac preload and cardiac output by the Frank-Starling mechanism, which increases arterial
pressure. Because vasoconstrictor drugs increase arterial pressure, they comprise a functional
group of drugs known as pressor drugs.

Hypotension, which is a systolic pressure of less than 90 mmHg or a diastolic pressure less than
60 mmHg, needs to be aggressively treated because blood flow to critical organs, particularly the
brain, heart and kidneys may become compromised to an extent that organ failure and death
occur. Although vasoconstrictors can elevate arterial pressure, there is a drawback to their use.
Unless cardiac output is increased at the same time systemic vascular resistance is increased,
blood flow to some organs may actually decrease. The reason for this is that if the vascular
resistance of an organ increases, for example, by 30% and mean arterial pressure increases by
30%, the organ blood flow will not change. If on the other hand, resistance is increased in some
organs by 50%, and in others by only 10%, yet the arterial pressure is increased by 30%, blood
flow will be increased to those organs that had the smaller increase in resistance because arterial
pressure increased more than their resistance. This is precisely how pressor drugs can have a
benefit in treating hypotension. Although blood flow may be reduced in some organs (e.g., to the
splanchnic and muscle circulations), blood flow to critical organs (e.g., brain, heart and kidneys)
may actually increase. Part of this benefit may be lost if systemic vascular resistance is increased
too much with a pressor drug, especially if the hypotension is caused by cardiogenic shock,
because the increase in ventricular afterload will reduce cardiac output. For a greater
understanding of the hemodynamics associated with regional vasoconstriction, the reader is
encouraged to read about the significance of the parallel arrangement of vascular beds in the
body.

Drug Classes, General Mechanisms of Action, and Contraindications

There are two general functional classes of vasoconstrictors based on their mechanism of action
that are used in the treatment of hypotension. The first class is sympathomimetic drugs that have
alpha-adrenoceptor agonist (-agonist) properties. Although many sympathomimetics possess
other mechanisms that contribute to their pressor effects (e.g., 1-adrenoceptor agonist activity), a
common property of several of these these drugs is that they bind to 1-adrenoceptors on
vascular smooth muscle thereby promoting smooth muscle contraction. A second class of
vasoconstrictor (non-sympathomimetic) that has been utilized increasingly in recent years is
vasopressin analogs. These drugs are a synthetic form of the naturally occurring hormone
(vasopressin or antidiuretic hormone) that is released by the posterior pituitary. These drugs
possess both both vasoconstrictor and antidiuretic properties, both of which contribute to
elevating arterial pressure.

Alpha1-agonists produce systemic vasoconstriction, which increases the work of the heart. If the
coronary circulation is impaired, as in patients with coronary artery disease, the resulting
decrease in myocardial oxygen supply/demand ratiocan precipitate angina. Likewise, AVP can
produce a powerful vasoconstrictor response, and therefore should be administered cautiously to
patients with coronary artery disease because it constricts coronary arteries (thereby
reducing oxygen delivery) and increases myocardial oxygen demand by increasing afterload on
the heart

Alpha-Adrenoceptor Agonists (-agonists)

General Pharmacology

Alpha-adrenoceptor agonists (-agonists) bind to -receptors on vascular smooth muscle and

induce smooth contraction and vasoconstriction, thus mimicking the effects of sympathetic
adrenergic nerve activation to the blood vessels.

Vascular smooth muscle has two types of alpha-adrenoceptors: alpha 1 (1) and alpha2 (2). The
1-adrenoceptors are the predominant -receptor located on vascular smooth muscle. These
receptors are linked toGq-proteins that activate smooth muscle contraction through the IP3 signal
transduction pathway. Depending on the tissue and type of vessel, there are also 2-
adrenoceptors found on the smooth muscle. These receptors are linked to Gi-proteins, and
binding of an alpha-agonist to these receptors decreases intracellular cAMP, which causes
smooth muscle contraction. There are also 2-adrenoceptors located on the sympathetic nerve
terminals that inhibit the release of norepinephrine and therefore act as a feedback mechanism
for modulating the release of norepinephrine.

Alpha-agonists constrict both arteries and veins; however, the vasoconstrictor effect is more
pronounced in the arterial resistance vessels. Constriction of the resistance vessels (small
arteries and arterioles) increases systemic vascular resistance, whereas constriction of the
venous capacitance vessels increases venous pressure.

Specific Drugs and Therapeutic Uses

Most -agonists used therapeutically are relatively selective for either 1 or 2-adrenoceptors. In
addition to the drugs listed below, there are other sympathomimetic drugs that have -agonist
properties in addition to their -adrenoceptor agonist properties. These drugs include the
naturally occurring catecholamines, dopamine, epinephrine and norepinephrine, as well as
catecholamine analogs such as dobutamine. (Go to www.rxlist.com for specific drug information).
1-adrenoceptor agonists (systemic vasoconstrictors)

methoxamine

phenylephrine
oxymetazoline
tetrahydrozoline
xylometazoline
Methoxamine and phenylephrine are used as pressor agents in treating hypotension and shock.
Oxymetazoline, tetrahydrozoline, xylometazoline and some preparations of phenylephrine are
used as nasal decongestants.

2-adrenoceptor agonists (centrally-acting vasodilators; Click here for details)

clonidine
guanabenz
guanfacine
-methyldopa
The 2-adrenoceptor agonists are used very occasionally as centrally-acting sympatholytic
vasodilators for the treatment of hypertension.

Side Effects and Contraindications

Alpha1-agonists can cause headache, reflex bradycardia, excitability, and restlessness. Because
alpha1-agonists produce systemic vasoconstriction, the work of the heart increases. If the
coronary circulation is impaired, as in patients with coronary artery disease, the decrease
in myocardial oxygen supply/demand ratio can precipitate angina. Preparations used as nasal
decongestants can cause a rebound effect (increased congestion) after a couple days of use.

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

Vasopressin Analogs
General Pharmacology

Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH) is a nonapeptide hormone

formed in the hypothalamus and released from the posterior pituitary. Its primary function in the
body is to regulate extracellular fluid volume by affecting renal handling of water; however, it also
is a potent vasoconstrictor.

There are several mechanisms regulating the release of AVP. Hypovolemia, as occurs during
hemorrhage, results in a decrease in atrial pressure. Specialized stretch receptors within the atrial
walls and large veins (cardiopulmonary baroreceptors) entering the atria decrease their firing rate
when there is a fall in atrial pressure. Afferent nerve fibers from these receptors synapse within
the nucleus tractus solitarius of the medulla, which sends fibers to the hypothalamus, a region of
the brain that controls AVP release by the pituitary. Atrial receptor firing normally inhibits the
release of AVP by the posterior pituitary. With hypovolemia or decreased central venous pressure,
the decreased firing of atrial stretch receptors leads to an increase in AVP release. Hypothalamic
osmoreceptors sense extracellular osmolarity and stimulate AVP release when osmolarity rises,
as occurs with dehydration. Finally, angiotensin II receptors located in a region of the
hypothalamus regulate AVP release an increase in angiotensin II simulates AVP release.

AVP has two principal sites of action: the kidney and blood vessels. The most important
physiological action of AVP is to increase water reabsorption in the kidneys by increasing water
permeability in the collecting duct, thereby permitting the formation of more concentrated urine.
This is the antidiuretic effect of AVP and it acts through vasopressin type 2 (V 2) receptors coupled
to adenylyl cyclase. AVP also constricts arterial blood vessels by binding to V 1 receptors, which
are coupled to the Gq-protein and the phospholipase C/IP3 signal transduction pathway. Normal
physiological concentrations of AVP are below its vasoactive range; however, in hypovolemic
shock when AVP release is very high, AVP does contribute to the compensatory increase
insystemic vascular resistance.

Specific Drugs

Arginine vasopressin (AVP) is being utilized in clinical studies involving the treatment of patients
in shock. Terlipressin (triglycyl lysine vasopressin) is a long-acting vasopressin analog that is also
under clinical investigation. In contrast to AVP, this analog has a relatively higher affinity for
vascular V1 receptors than for renal V2 receptors.

Therapeutic Uses

The main uses of AVP are for treating excessive water loss caused by diabetes insipidus and for
treating bleeding caused by esophageal varices. AVP infusion is being investigated for use in
treating septic shock, a condition that can be caused by a bacterial infection in the blood and the
release of bacterial endotoxins such as lipopolysaccharide. Infusion of AVP increases systemic
vascular resistance and thereby elevates arterial pressure. Some studies have shown that low-
dose infusions AVP (which are used in septic shock) also cause cerebral, pulmonary and renal
dilation (mediated by endothelial release of nitric oxide) while constricting other vascular beds.
AVP is also being investigated for use in other forms of shock, such as cardiogenic and
hypovolemic shock.

Side Effects and Contraindications

Side effects include headache, nausea, bronchoconstriction and abdominal cramps. Its
antidiuretic effects can lead to water intoxication and hyponatremia. Because of AVP's powerful
constrictor response, it should be administered cautiously to patients with coronary artery disease
because it constricts coronary arteries (thereby reducing oxygen delivery) and increases
myocardial oxygen demand by increasing afterload on the heart.

Thrombolytic (Fibrinolytic) Drugs

Thrombolytic drugs are used to dissolve (lyse) blood clots (thrombi). Blood clots can occur in any
vascular bed; however, when they occur in coronary, cerebral or pulmonary vessels, they can be
immediately life-threatening - coronary thrombi are the cause of myocardial infarctions,
cerebrovascular thrombi produce strokes, and pulmonary thromboemboli can lead to respiratory
and cardiac failure. Therefore, it is important to rapidly diagnose and treat blood clots.

Mechanisms of Thrombolysis

Thrombolytic drugs dissolve blood clots by activating plasminogen, which forms a cleaved
product called plasmin. Plasmin is a proteolytic enzyme that is capable of breaking cross-links
between fibrin molecules, which provide the structural integrity of blood clots. Because of these
actions, thrombolytic drugs are also called "plasminogen activators" and "fibrinolytic drugs."

There are three major classes of fibrinolytic drugs: tissue plasminogen activator
(tPA), streptokinase (SK), and urokinase (UK). While drugs in these three classes all have the
ability to effectively dissolve blood clots, they differ in their detailed mechanisms in ways that alter
their selectivity for fibrin clots.
The figure to the right illustrates the fibrinolytic mechanisms for tPA and SK. Derivatives of tPA are
the most commonly used thrombolytic drugs, especially for coronary and cerebral vascular clots,
because of their relative selectivity for activating fibrin-bound plasminogen. Tissue plasminogen
activator produces clot lysis through the following sequence:

1. tPA binds to fibrin on the surface of the clot

2. Activates fibrin-bound plasminogen
3. Plasmin is cleaved from the plasminogen associated with the fibrin
4. Fibrin molecules are broken apart by the plasmin and the clot dissolves
Plasmin is a protease that is capable of breaking apart fibrin molecules, thereby dissolving the
clot. However, it is important to note that plasmin also breaks down other circulating proteins,
including fibrinogen. But because of the relative fibrin specificity of tPA, clot dissolution occurs
with less breakdown of circulating fibrinogen than occurs with SK and UK. Although tPA is
relatively selective for clot-bound plasminogen, it still activates circulating plasminogen thereby
releasing plasmin, which can lead to the breakdown of circulating fibrinogen and cause an
unwanted systemic fibrinolytic state. Normally, circulating 2-antiplasmin inactivates plasmin, but
therapeutic doses of tPA (and SK) lead to sufficient plasmin formation to overwhelm the limited
circulating concentrations 2-antiplasmin. In summary, although tPA is relatively selective for clot-
associated fibrin, it can produce systemic lytic state and undesirable bleeding.

SK is not a protease and has no enzymatic activity; however, it forms a complex with
plasminogen that releases plasmin. Unlike tPA, it does not bind preferentially to clot-associated
fibrin and therefore binds equally to circulating and non-circulating plasminogen. Therefore, SK
produces significant fibrinogenolysis along with clot fibrinolysis. For this reason, tPA is generally
preferred as a thrombolytic agent over SK, especially when used for dissolving coronary and
cerebral vascular thrombi. Because SK is derived from streptococci, patients who have had
recent streptococci infections can require significantly higher doses of SK to produce
thrombolysis.

It is important to note that the efficacy of thrombolytic drugs depends on the age of the clot. Older
clots have more fibrin cross-linking and are more compacted; therefore, older clots are more
difficult to dissolve. For treating acute myocardial infarction, the thrombolytic drugs should ideally
be given within the first 2 hours. Beyond that time, the efficacy diminishes and higher doses are
generally required to achieve desired lysis.

Specific Thrombolytic Drugs

Tissue Plasminogen Activators

This family of thrombolytic drugs is used in acute myocardial infarction, cerebrovascular

thrombotic stroke and pulmonary embolism. For acute myocardial infarctions, tissue plasminogen
activators are generally preferred over streptokinase.

Alteplase (Activase; rtPA) is a recombinant form of human tPA. It has a short half-
life (~5 min) and therefore is usually administered as an intravenous bolus followed
by an infusion.
Retaplase (Retavase) is a genetically engineered, smaller derivative of
recombinant tPA that has increased potency and is faster acting than rtPA. It is
usually administered as IV bolus injections. It is used for acute myocardial
infarction and pulmonary embolism.
 Tenecteplase (TNK-tPA) has a longer half-life and greater binding affinity for fibrin
than rtPA. Because of its longer half-life, it can be administered by IV bolus. It is
only approved for use in acute myocardial infarction.

Streptokinase

Streptokinase and anistreplase are used in acute myocardial infarction, arterial and venous
thrombosis, and pulmonary embolism. These compounds are antigenic because they are derived
from streptococci bacteria.

Natural streptokinase (SK) is isolated and purified from streptococci bacteria. Its
lack of fibrin specificity makes it a less desirable thrombolytic drug than tPA
compounds because it produces more fibrinogenolysis.
Anistreplase (Eminase) is a complex of SK and plasminogen. It has more fibrin
specificity and has a longer activity than natural SK; however, it causes
considerable fibrinogenolysis.

Urokinase

Urokinase (Abbokinase; UK) is sometimes referred to as urinary-type plasminogen activator

(uPA) because it is formed by kidneys and is found in urine. It has limited clinical use because,
like SK, it produces considerable fibrinogenolysis; however, it is used for pulmonary embolism.
One benefit over SK is that UK is non-antigenic; however, this is offset by a much greater cost.

Adverse Effects and Contraindications

Common adverse effects of all the thrombolytic drugs is bleeding complications related to
systemic fibrinogenolysis and lysis of normal hemostatic plugs. The bleeding is often noted at a
catheterization site, although gastrointestinal and cerebral hemorrhages may occur. Therefore,
patients who have experienced trauma injury or who have a history of cerebral hemorrhagic
stroke are not usually administered thrombolytics. Re-thrombosis can occur following
thrombolysis, and therefore anticoagulants such as heparin are usually co-administered, and
continued after thrombolytic therapy for a period of time.