Rationale for Pharmacologic Treatment of Hypertension

Patients with primary hypertension are generally

treated with drugs that 1) reduce blood volume (which
reduces central venous pressure and cardiac output),
2) reduce systemic vascular resistance, or 3) reduce
cardiac output by depressing heart rate and stroke
volume. Patients with secondary hypertension are best
treated by controlling or removing the underlying
disease or pathology, although they may still require
antihypertensive drugs.

decreasing heart rate and contractility. Some calciumchannel blockers (most notably the dihydropyridines)
are more selective for the systemic vasculature and
therefore reduce systemic vascular resistance.
General Pharmacology

Rationale for Reducing

Arterial Pressure
Reduce Cardiac Output
Reduce blood volume
Reduce heart rate
Reduce stroke volume
Reduce Systemic Vascular Resistance
Dilate systemic vasculature

Renal handling of sodium and water

Arterial pressure can be reduced by decreasing cardiac

output, systemic vascular resistance, or central venous
pressure. An effective and inexpensive way of reducing
venous pressure and cardiac output is by using drugs
that reduce blood volume. These drugs (diuretics) act
on the kidney to enhance sodium and water excretion.
Reducing blood volume not only reduces central
venous pressure, but even more importantly, reduces
cardiac output by the Frank-Starling mechanism due to
the reduction in ventricular preload. An added benefit
of these drugs is that they reduce systemic vascular
resistance with long-term use.

To understand the action of diuretics, it is first

necessary to review how the kidney filters fluid and
forms urine. The following discussion and
accompanying illustration provide a simple overview of
how the kidney handles water and electrolytes. For
more detailed explanation, particularly related to ion
and fluid movement across the renal tubular cells, the
reader should consult a physiology textbook.

Many antihypertensive drugs have their primary action

on systemic vascular resistance. Some of these drugs
produce vasodilation by interfering with sympathetic
adrenergic vascular tone (sympatholytics) or by
blocking the formation of angiotensin II or its vascular
receptors. Other drugs are direct arterial dilators, and
some are mixed arterial and venous dilators. Although
less commonly used because of a high incidence of
side effects, there are drugs that act on regions in the
brain that control sympathetic autonomic outflow. By
reducing sympathetic efferent activity, centrally acting
drugs decrease arterial pressure by decreasing
systemic vascular resistance and cardiac output.
Some antihypertensive drugs, most notably betablockers, depress heart rate and contractility (this
decreases stroke volume) by blocking the influence of
sympathetic nerves on the heart. Calcium-channel
blockers, especially those that are more
cardioselective, also reduce cardiac output by

As blood flows through the kidney, it passes into

glomerular capillaries located within the cortex (outer
zone of the kidney). These glomerular capillaries are
highly permeable to water and electrolytes. Glomerular
capillary hydrostatic pressure drives (filters) water and
electrolytes into Bowman's space and into the proximal
convoluting tubule (PCT). About 20% of the plasma
that enters the glomerular capillaries is filtered (termed
filtration fraction). The PCT, which lies within the cortex
, is the site of sodium, water and bicarbonate transport
from the filtrate (urine), across the tubule wall, and into
the interstitium of the cortex. About 65-70% of the
filtered sodium is removed from the urine found within
the PCT (this is termed sodium reabsorption). This
sodium is reabsorbed isosmotically, meaning that
every molecule of sodium that is reabsorbed is
accompanied by a molecule of water. As the tubule
dives into the medulla, or middle zone of the kidney,
the tubule becomes narrower and forms a loop (Loop of
Henle) that reenters the cortex as the thick ascending
limb (TAL) that travels back to near the glomerulus.
Because the interstitium of the medulla is very
hyperosmotic and the Loop of Henle is permeable to
water, water is reabsorbed from the Loop of Henle and

into the medullary interstitium. This loss of water

concentrates the urine within the Loop of Henle.
The TAL, which is impermeable to water, has a
cotransport system that reabsorbs sodium, potassium
and chloride at a ratio of 1:1:2. Approximately 25% of
the sodium load of the original filtrate is reabsorbed at
the TAL. From the TAL, the urine flows into the distal
convoluting tubule (DCT), which is another site of
sodium transport (~5% via a sodium-chloride
cotransporter) into the cortical interstitium (the DCT is
also impermeable to water). Finally, the tubule dives
back into the medulla as the collecting duct and then
into the renal pelvis where it joins with other collecting
ducts to exit the kidney as the ureter. The distal
segment of the DCT and the upper collecting duct has
a transporter that reabsorbs sodium (about 1-2% of
filtered load) in exchange for potassium and hydrogen
ion, which are excreted into the urine. It is important to
note two things about this transporter. First, its activity
is dependent on the tubular concentration of sodium,
so that when sodium is high, more sodium is
reabsorbed and more potassium and hydrogen ion are
excreted. Second, this transporter is regulated by
aldosterone, which is a mineralocorticoid hormone
secreted by the adrenal cortex. Increased aldosterone
stimulates the reabsorption of sodium, which also
increases the loss of potassium and hydrogen ion to
the urine. Finally, water is reabsorbed in the collected
duct through special pores that are regulated
by antidiuretic hormone, which is released by the
posterior pituitary. ADH increases the permeability of
the collecting duct to water, which leads to increased
water reabsorption, a more concentrated urine and
reduced urine outflow (antidiuresis). Nearly all of the
sodium originally filtered is reabsorbed by the kidney,
so that less than 1% of originally filtered sodium
remains in the final urine.
Mechanisms of diuretic drugs
Diuretic drugs increase urine output by the kidney (i.e.,
promote diuresis). This is accomplished by altering how
the kidney handles sodium. If the kidney excretes more
sodium, then water excretion will also increase. Most
diuretics produce diuresis by inhibiting the
reabsorption of sodium at different segments of the
renal tubular system. Sometimes a combination of two
diuretics is given because this can be significantly
more effective than either compound alone (synergistic
effect). The reason for this is that one nephron
segment can compensate for altered sodium
reabsorption at another nephron segment; therefore,
blocking multiple nephron sites significantly enhances
efficacy.
Loop diuretics inhibit the sodium-potassium-chloride
cotransporter in the thick ascending limb (see above
figure). This transporter normally reabsorbs about 25%
of the sodium load; therefore, inhibition of this pump

can lead to a significant increase in the distal tubular

concentration of sodium, reduced hypertonicity of the
surrounding interstitium, and less water reabsorption in
the collecting duct. This altered handling of sodium and
water leads to both diuresis (increased water loss) and
natriuresis (increased sodium loss). By acting on the
thick ascending limb, which handles a significant
fraction of sodium reabsorption, loop diuretics are very
powerful diuretics. These drugs also induce renal
synthesis of prostaglandins, which contributes to their
renal action including the increase in renal blood flow
and redistribution of renal cortical blood flow.
Thiazide diuretics, which are the most commonly
used diuretic, inhibit the sodium-chloride transporter in
the distal tubule. Because this transporter normally
only reabsorbs about 5% of filtered sodium, these
diuretics are less efficacious than loop diuretics in
producing diuresis and natriuresis. Nevertheless, they
are sufficiently powerful to satisfy most therapeutic
needs requiring a diuretic. Their mechanism depends
on renal prostaglandin production.
Because loop and thiazide diuretics increase sodium
delivery to the distal segment of the distal tubule, this
increases potassium loss (potentially
causing hypokalemia) because the increase in distal
tubular sodium concentration stimulates the
aldosterone-sensitive sodium pump to increase sodium
reabsorption in exchange for potassium and hydrogen
ion, which are lost to the urine. The increased
hydrogen ion loss can lead to metabolic alkalosis. Part
of the loss of potassium and hydrogen ion by loop and
thiazide diuretics results from activation of the reninangiotensin-aldosterone system that occurs because of
reduced blood volume and arterial pressure. Increased
aldosterone stimulates sodium reabsorption and
increases potassium and hydrogen ion excretion into
the urine.
There is a third class of diuretic that is referred to
as potassium-sparing diuretics. Unlike loop and
thiazide diuretics, some of these drugs do not act
directly on sodium transport. Some drugs in this class
antagonize the actions of aldosterone (aldosterone
receptor antagonists) at the distal segment of the
distal tubule. This causes more sodium (and water) to
pass into the collecting duct and be excreted in the
urine. They are called K+-sparing diuretics because
they do not produce hypokalemia like the loop and
thiazide diuretics. The reason for this is that by
inhibiting aldosterone-sensitive sodium reabsorption,
less potassium and hydrogen ion are exchanged for
sodium by this transporter and therefore less
potassium and hydrogen are lost to the urine. Other
potassium-sparing diuretics directly inhibit sodium
channels associated with the aldosterone-sensitive
sodium pump, and therefore have similar effects on
potassium and hydrogen ion as the aldosterone
antagonists. Their mechanism depends on renal

prostaglandin production. Because this class of diuretic

has relatively weak effects on overall sodium balance,
they are often used in conjunction with thiazide or loop
diuretics to help prevent hypokalemia.
Carbonic anhydrase inhibitors inhibit the transport
of bicarbonate out of the proximal convoluted tubule
into the interstitium, which leads to less sodium
reabsorption at this site and therefore greater sodium,
bicarbonate and water loss in the urine. These are the
weakest of the diuretics and seldom used in
cardiovascular disease. Their main use is in the
treatment of glaucoma.

to reduce pulmonary and/or systemic congestion and

edema, and associated clinical symptoms (e.g.,
shortness of breath - dyspnea). Long-term treatment
with diuretics may also reduce the afterload on the
heart by promoting systemic vasodilation, which can
lead to improved ventricular ejection.

Cardiovascular effects of diuretics

Through their effects on sodium and water balance,
diuretics decrease blood volume and venous pressure.
This decreases cardiac filling (preload) and, by
the Frank-Starling mechanism, decreases
ventricular stroke volume andcardiac output, which
leads to a fall in arterial pressure. The decrease in
venous pressure reduces capillary hydrostatic pressure,
which decreases capillary fluid filtration and promotes
capillary fluid reabsorption, thereby reducing edema if
present. There is some evidence that loop diuretics
cause venodilation, which can contribute to the
lowering of venous pressure. Long-term use of diuretics
results in a fall in systemic vascular resistance (by
unknown mechanisms) that helps to sustain the
reduction in arterial pressure.
Therapeutic Uses
Hypertension
Most patients with hypertension, of which 90-95% have
hypertension of unknown origin (primary or essential
hypertension), are effectively treated with diuretics.
Antihypertensive therapy with diuretics is particularly
effective when coupled with reduced dietary sodium
intake. The efficacy of these drugs is derived from their
ability to reduce blood volume, cardiac output, and
with long-term therapy, systemic vascular resistance.
The vast majority of hypertensive patients are treated
with thiazide diuretics. Potassium-sparing, aldosteroneblocking diuretics (e.g., spironolactone) are used in
secondary hypertension caused by
hyperaldosteronism, and sometimes as an adjunct to
thiazide treatment in primary hypertension to prevent
hypokalemia.

When treating heart failure with diuretics, care must be

taken to not unload too much volume because this can
depress cardiac output. For example, if pulmonary
capillary wedge pressure is 25 mmHg (point A in figure)
and pulmonary congestion is present, a diuretic can
safely reduce that elevated pressure to a level (e.g., 14
mmHg; point B in figure) that will reduce pulmonary
pressures without compromising ventricular stroke
volume. The reason for this is that heart failure caused
by systolic dysfunction is associated with a depressed,
flattened Frank-Starling curve. However, if the volume
is reduced too much, stroke volume will fall because
the heart will now be operating on the ascending limb
of the Frank-Starling relationship. If the heart failure is
caused by diastolic dysfunction, diuretics must be used
very carefully so as to not impair ventricular filling. In
diastolic dysfunction, ventricular filling requires
elevated filling pressures because of the
reduced ventricular compliance.
Most patients in heart failure are prescribed a loop
diuretic because they are more effective in unloading
sodium and water than thiazide diuretics. In mild heart
failure, a thiazide diuretic may be used. Potassiumsparing, aldosterone-blocking diuretics (e.g.,
spironolactone) are being used increasingly in heart
failure.
Pulmonary and systemic edema

Heart failure
Heart failure leads to activation of the reninangiotensin-aldosterone system, which causes
increased sodium and water retention by the kidneys.
This in turn increases blood volume and contributes to
the elevated venous pressures associated with heart
failure, which can lead to pulmonary and systemic
edema. The primary use for diuretics in heart failure is

Capillary hydrostatic pressure and therefore capillary

fluid filtration is strongly influenced by venous pressure
(click herefor more details). Therefore, diuretics, by
reducing blood volume and venous pressure, lower
capillary hydrostatic pressure, which reduces net
capillary fluid filtration and tissue edema.
Specific Drugs

Specific drugs comprising the five class of diuretics are

listed in the following table. See www.rxlist.com for
more details on individual diuretics.
Class

Specific
Drugs

Thiazid
e

chlorothiazide

chlorthalidone

not used in treating

dichlorphenami
hypertension or heart
de
failure

Comments

not used in treating

methazolamide hypertension or heart
failure
thiazide-like in action, not
structure

hydrochlorothia
prototypical drug;
zide
hydroflumethia
zide
indapamide

failure

thiazide-like in action, not

structure

Adverse Side Effects and Contraindications

The most important and frequent problem with thiazide
and loop diuretics is hypokalemia. This sometimes
requires treatment with potassium supplements or with
a potassium-sparing diuretic. A potentially serious side
effect of potassium-sparing diuretics is hyperkalemia.
Other side effects and drug interactions are list below:
Class

methyclothiazid
e
metolazone

thiazide-like in action, not

structure

Adverse Side Effects

hypokalemia

metabolic
alkalosis

dehydration
(hypovolemia),
leading to
hypotension

polythiazide
Loop

bumetanide
ethacrynic acid
Thiazi
de

furosemide

hyponatremia

hyperglycemia
in diabetics

hypercholester
olemia;
hypertriglycerid
emia

torsemide
K+amiloride
sparing

distal tubule Na+-channel

inhibitor

eplerenone

aldosterone receptor
antagonist; fewer side
effects than
spironolactone

increased lowdensity
lipoproteins

hyperuricemia
(at low doses)

spironolactone

aldosterone receptor
antagonist; side effect:
gynecomastia

azotemia (in
renal disease
patients)

hypokalemia

triamterene

distal tubule Na+-channel

inhibitor

metabolic
alkalosis

hypomagnese

CA
acetazolamide
inhibito
rs

prototypical drug; not

used in treating
hypertension or heart

Loop

Drug Interactions

hypokalemi
a
potentiates
digitalis
toxicity

nonsteroidal
antiinflammator
y drugs:
reduced
diuretic
efficacy

betablockers:
potentiate
hyperglyce
mia,
hyperlipide
mias

corticosteroi
ds: enhance
hypokalemi
a

hypokalemi
a
potentiates
digitalis
toxicity

non-

steroidal
antiinflammator
y drugs:
reduced
diuretic
efficacy

mia

K+sparin
g

Carbo
nic
anhyd
rase
inhibi
tors

hyperuricemia

dehydration
(hypovolemia),
leading to
hypotension

dose-related
hearing loss
(ototoxicity)

hyperkalemia

metabolic
acidosis

gynecomastia
(aldosterone
antagonists)

gastric
problems
including peptic
ulcer

hypokalemia

metabolic
acidosis

corticosteroi
ds: enhance
hypokalemi
a

aminoglycos
ides:
enhance
ototoxicity,
nephrotoxici
ty

ACE
inhibitors:
potentiate
hyperkalemi
a

nonsteroidal
antiinflammator
y drugs:
reduced
diuretic
efficacy

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.
Vasodilators that act primarily on resistance vessels
(arterial dilators) are used for hypertension and heart
failure, but not for angina because of reflex cardiac
stimulation. Venous dilators are very effective for
angina, and sometimes used for heart failure, but are
not used as primary therapy for hypertension. Most
vasodilator drugs are mixed (or balanced) vasodilators
in that they dilate both arteries and veins; however,
there are some very useful drugs that are highly
selective for arterial or venous vasculature. Some
vasodilators, because of their mechanism of action,
also have other important actions that can in some
cases enhance their therapeutic utility as vasodilators
or provide some additional therapeutic benefit. For
example, some calcium channel blockers not only
dilate blood vessels, but also depress cardiac
mechanical and electrical function, which can enhance
their antihypertensive actions and confer additional
therapeutic benefit such as blocking arrhythmias.
Arterial dilators
Arterial dilator drugs are commonly used to
treat systemic and pulmonary hypertension, heart
failure and angina. They reduce arterial pressure by
decreasing systemic vascular resistance. This benefits
patients in heart failure by reducing the afterload on
the left ventricle, which enhances stroke volume and
cardiac output and leads to secondary decreases in
ventricular preload and venous pressures. Anginal
patients benefit from arterial dilators because by
reducing afterload on the heart, vasodilators decrease
the oxygen demand of the heart, and thereby improve
the oxygen supply/demand ratio. Oxygen demand is
reduced because ventricular wall stress is reduced by
arterial dilators. Some vasodilators can also reverse or
prevent arterial vasospasm (transient contraction of
arteries), which can precipitate anginal attacks.
Most drugs that dilate arteries also dilate veins;
however, hydralazine, a direct acting vasodilator, is
highly selective for arterial resistance vessels.

The effects of arterial dilators on overall cardiovascular

function can be depicted graphically using cardiac and
systemic vascular function curves as shown to the

right. Selective arterial dilation decreases systemic

vascular resistance, which increases the slope of the
systemic vascular function curve (red line) without
appreciably changing the x-intercept (mean circulatory
filling pressure). This alone causes the operating point
to shift from A to B, resulting in an increase in cardiac
output (CO) with a small increase in right atrial
pressure (PRA). The reason for the increase in PRA is that
arterial dilation increases blood flow from the arterial
vasculature into the venous vasculature, thereby
increasing venous volume and pressure. However,
arterial dilators also reduce afterload on the left
ventricle and therefore unload the heart, which
enhances the pumping ability of the heart. This causes
the cardiac function curve to shift up and to the left
(not shown in figure). Adding to this afterload effect is
the influence of enhanced sympathetic stimulation due
to a baroreceptor reflex in response to the fall in
arterial pressure, which increases heart rate and
inotropy. Because of these compensatory cardiac
responses, arterial dilators increase cardiac output with
little or no change in right atrial pressure (cardiac
preload). Although cardiac output is increased,
systemic vascular resistance is reduce relatively more
so arterial pressure falls. The effect of reducing
afterload on enhancing cardiac output is even greater
in failing heartsbecause 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.

2.

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.
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).

compensates for the reduced systemic

vascular resistance.
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,

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.

2.

3.

whereas others are relatively selective for one type of alphaadrenoceptor.

Vascular smooth muscle has two types of alphaadrenoceptors: alpha1 (1) and alpha2 (2). The 1adrenoceptors are the predominant -receptor located on
vascular smooth muscle. These receptors are linked to Gqproteins that activate smooth muscle contraction through
the IP3 signal transduction pathway. Depending on the tissue

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.

and type of vessel, there are also 2-adrenoceptors found on

Vasodilators can impair normal baroreceptormediated reflex vasoconstriction when a

person stands up, which can lead to orthostatic
hypotension and syncope upon standing.

therefore act as a feedback mechanism for modulating the

Vasodilators can lead to renal retention of

sodium and water, which increases blood
volume and cardiac output and thereby

the smooth muscle. These receptors are linked toGi-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
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,

been shown to be beneficial in heart failure or angina, and

which attenuates the effectiveness of the 1 and 2-

should not be used in these conditions.

postjunctional adrenoceptor blockade. Furthermore, blocking

2-prejunctional adrenoceptors in the heart can lead to

General Pharmacology

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 alphablockers (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

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

The most common side effects are related directly to alphaadrenoceptor blockade. These side effects include dizziness,

Vasodilation (arterial & venous)

- reduce arterial & venous pressure
- reduce ventricular afterload & preload

Decrease blood volume

- natriuretic
- diuretic

Depress sympathetic activity

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

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.

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.

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 renindependent 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.

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

receptors on bloods vessels and other tissues such

as the heart. These receptors are coupled to
theGq-protein and IP3 signal transduction
pathway that stimulates vascular smooth muscle
contraction. Because ARBs do not inhibit ACE, they
do not cause an increase in bradykinin, which
contributes to the vasodilation produced by ACE
inhibitors and also some of the side effects of ACE
inhibitors (cough and angioedema).
ARBs have the following actions, which are very
similar to ACE inhibitors:

Dilate arteries and veins and thereby reduce

arterial pressure and preload and afterload on
the heart.

Down regulate sympathetic adrenergic activity

by blocking the effects of angiotensin II on
sympathetic nerve release and reuptake of
norepinephrine.

Promote renal excretion of sodium and water

(natriuretic and diuretic effects) by blocking the
effects of angiotensin II in the kidney and by
blocking angiotensin II stimulation
of aldosterone secretion.

Inhibit cardiac and vascular remodeling

associated with chronic hypertension, heart
failure, and myocardial infarction.

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 aldosterone formation is reduced) are also
adverse effects of ACE inhibition. The incidence of
angioedema is 2 to 4-times higher in African
Americans compared to Caucasians. ACE inhibitors
are contraindicated in pregnancy.
Patients with bilateral renal artery stenosis may
experience renal failure if ACE inhibitors are
administered. The reason is that the elevated
circulating and intrarenal angiotensin II in this
condition constricts the efferent arteriole more
than the afferent arteriole within the kidney, which
helps to maintain glomerular capillary pressure and
filtration. Removing this constriction by blocking
circulating and intrarenal angiotensin II formation
can cause an abrupt fall in glomerular filtration
rate. This is not generally a problem with unilateral
renal artery stenosis because the unaffected
kidney can usually maintain sufficient filtration
after ACE inhibition; however, with bilateral renal
artery stenosis it is especially important to ensure
that renal function is not compromised.
General Pharmacology
These drugs have very similar effects
to angiotensin converting enzyme (ACE)
inhibitors and are used for the same indications
(hypertension, heart failure, post- myocardial
infarction). Their mechanism of action, however, is
very different from ACE inhibitors, which inhibit the
formation of angiotensin II. ARBs are receptor
antagonists that block type 1 angiotensin II (AT1)

Therapeutic Uses
ARBs are used in the treatment of hypertension
and heart failure in a similar manner as ACE
inhibitors (see ACE inhibitors for details). They are
not yet approved for post-myocardial infarction,
although this is under investigation.
Specific Drugs
ARBs include the following drugs: (Go
to www.rxlist.com for specific drug information)

candesartan

eprosartan

irbesartan

losartan

olmesartan

telmisartan

valsartan

Note that each of the ARBs named above ends with

"sartan."

Side Effects and Contraindications

As a drug class, ARBs have a relatively low

incidence of side effects and are well-tolerated.
Because they do not increase bradykinin levels like
ACE inhibitors, the dry cough and angioedema that
are associated with ACE inhibitors are not a
problem. ARBs are contraindicated in pregnancy.
Patients with bilateral renal artery stenosis may
experience renal failure if ARBs are administered.
The reason is that the elevated circulating and
intrarenal angiotensin II in this condition constricts
the efferent arteriole more than the afferent
arteriole within the kidney, which helps to maintain
glomerular capillary pressure and filtration.
Removing this constriction by blocking angiotensin
II receptors on the efferent arteriole can cause an
abrupt fall in glomerular filtration rate. This is not
generally a problem with unilateral renal artery
stenosis because the unaffected kidney can usually
maintain sufficient filtration after AT1 receptors are
blocked; however, with bilateral renal artery
stenosis it is especially important to ensure that
renal function is not compromised.

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.

General Pharmacology

Arrhythmias

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.

The antiarrhythmic properties (Class IV

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

Therapeutic Indications
CCBs are used to treat hypertension, angina and
arrhythmias.
Hypertension
Therapeutic Use of
Calcium-Channel Blockers

Hypertension
(systemic & pulmonary)

Angina

Arrhythmias

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.

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

amlodipine

felodipine

isradipine

nicardipine

nifedipine

nimodipine

nitrendipine

Non-dihydropyridines, of which there are only

two currently used clinically, comprise the other
two classes of CCBs.Verapamil (phenylalkylamine
class), is relatively selective for the myocardium,
and is less effective as a systemic vasodilator drug.
This drug has a very important role in treating
angina (by reducing myocardial oxygen demand
and reversing coronary vasospasm) and
arrhythmias. Diltiazem (benzothiazepine class) is
intermediate between verapamil and
dihydropyridines in its selectivity for vascular
calcium channels. By having both cardiac
depressant and vasodilator actions, diltiazem is
able to reduce arterial pressure without producing
the same degree of reflex cardiac stimulation
caused by dihydropyridines.
Side Effects and Contraindications
Dihydropyridine CCBs can cause flushing,
headache, excessive hypotension, edema and
reflex tachycardia. The activation of sympathetic
reflexes and lack of direct cardiac effects make
dihydropyridines a less desirable choice for angina.
Long-acting dihydropyridines have been shown to
be safer anti-hypertensive drugs, in part, because
of reduced reflex responses. The cardiac selective,
non-dihydropyridine CCBs can cause excessive
bradycardia, impaired electrical conduction (e.g.,
atrioventricular nodal block), and depressed
contractility. Therefore, patients having preexistent
bradycardia, conduction defects, or heart failure
caused by systolic dysfunction should not be given
CCBs, especially the cardiac selective, nondihydropyridines. CCBs, especially nondihydropyridines, 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.

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 IP3induced release of calcium from the smooth muscle
sarcoplasmic reticulum. This calcium combines with
calmodulin to activate myosin light chain kinase, which
induces contraction. Finally, hydralazine stimulates the
formation of nitric oxide by the vascular endothelium,
leading to cGMP-mediated vasodilation.
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 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 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 and diuretic 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 anitrodilator.
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.
Autonomic Ganglia

General Pharmacology
The one drug in this group, hydralazine, does not fit
neatly into the other mechanistic classes, in part,

inhibit autonomic activity by interfering with

neurotransmission within autonomic ganglia. This
reduces sympathetic outflow to the heart thereby
decreasing cardiac output by decreasing heart rate and
contractility. Reduced sympathetic output to the
vasculature decreases sympathetic vascular tone,
which causes vasodilation and reduced systemic
vascular resistance, which decreases arterial pressure.
Parasympathetic outflow is also reduced by ganglionic
blockers.
Therapeutic Indications
Ganglionic blockers are not used in the treatment of
chronic hypertension in large part because of their side
effects and because there are numerous, more
effective, and safer antihypertensive drugs that can be
used. They are, however, occasionally used for
hypertensive emergencies.
Sympathetic autonomic ganglia are comprised of the
paravertebral ganglia (sympathetic chain ganglia) and
the prevertebral ganglia. Preganglionic sympathetic
fibers that exit the spinal cord synapse within these
ganglia and release the
neurotransmitter acetylcholine (ACh), which binds to
nicotinic receptors. Activation of the nicotinic
receptors depolarizes the cell body of the
postganglionic neuron and generates action potentials
that travel to the target organ to elicit a response.
Parasympathetic autonomic ganglia are found within
the target organ. In the case of the vagal nerves that
exit the brainstem, their long preganglionic fibers enter
the target organ (e.g., heart) where they synapse with
postganglionic neurons within small ganglia. Like the
sympathetic ganglia, the neurotransmitter is ACh and it
binds to nicotinic receptors to activate the short
postganglionic fibers that lie near the target tissue
(e.g., sinoatrial node).
General Pharmacology
Sympatholytic drugs can block the sympathetic
adrenergic system are three different levels.
First, peripheral sympatholytic drugs such as alpha
receptor antagonists and beta receptor
antagonists block the influence of norepinephrine at
the effector organ (heart or blood vessel). Second,
there are ganglionic blockers that block impulse
transmission at the sympathetic ganglia. Third, there
are drugs that block sympathetic activity within the
brain. These are called centrally acting sympatholytic
drugs.
Neurotransmission within the sympathetic and
parasympathetic ganglia involves the release of
acetylcholine from preganglionic efferent nerves, which
binds to nicotinic receptors on the cell bodies of
postganglionic efferent nerves. Ganglionic blockers

Specific Drugs
Several different ganglionic blockers are available for
clinical use; however, only one (trimethaphan
camsylate) is very occasionally used in hypertensive
emergencies or for producing controlled hypotension
during surgery.
Side Effects and Contraindications
Side effects of trimethaphan include prolonged
neuromuscular blockade and potentiation of
neuromuscular blocking agents. It can produce
excessive hypotension and impotence due to its
sympatholytic effect, and constipation, urinary
retention, dry mouth due to it parasympatholytic
effect. It also stimulates histamine release.
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 (antithrombotic), 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 endothelialindependent vasodilators.

decreased oxygen demand

Coronary

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)

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
ventricular preload. This reduces ventricular wall
stressand 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 reduces afterload, which can
enhance cardiac output while at the same time
reducing ventricular wall stress and oxygen demand. At
high concentrations, excessive systemic vasodilation
may lead to hypotension and a baroreceptor reflex that
produces tachycardia. When this occurs, the beneficial
effects on the oxygen supply/demand ratio are partially
offset. Furthermore, tachycardia, by reducing
the duration of diastole, decreases the time available
for coronary perfusion, most of which occurs during
diastole (click here for more details).
Therapeutic Indications
The primary pharmacologic action of nitrodilators,
arterial and venous dilation, make these compounds
useful in the treatment of hypertension, heart failure,
angina and myocardial infarction. Another beneficial
action of nitrodilators is their ability to inhibit platelet
aggregation.
Hypertension
Nitrodilators are not used to treat chronic primary or
secondary hypertension; however, sodium
nitroprusside and nitroglycerine are used to lower
blood pressure in acute hypertensive emergencies that
may result from a pheochromocytoma, renal artery
stenosis, aortic dissection, etc. Nitrodilators may also
be used during surgery to 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 angina because they improve
coronary blood flow (i.e., increase oxygen supply) by
reversing and inhibiting coronary vasospasm. They are
important in other forms of angina because they
reduce preload on the heart by producing venous
dilation, which decreases myocardial oxygen demand.
It is unclear if direct dilation of epicardial coronary
arteries play a role in the antianginal effects of
nitrodilators in chronic stable or unstable angina. These
drugs also reduce systemic vascular resistance
(depending on dose) and arterial pressure, which
further reduces myocardial oxygen demand. Taken
together, these two actions dramatically improve the
oxygen supply/demand ratio and thereby reduce
anginal pain.

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 firstpass 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.

Specific Drugs

Side Effects and Contraindications

Several different nitrodilators are available for clinical

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

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.

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.

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).

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 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

(natriureticand diuretic 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.

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 betablocker and diuretic to attenuate the reflex tachycardia
and retention of sodium and fluid, respectively.
Specific Drugs
Although several potassium-channel openers have
been used in research for many years, only
one, minoxidil, is approved for use in humans for
treating hypertension. (Go to www.rxlist.com for
detailed information on minoxidil)
Side Effects and Contraindications
Common side effects to minoxidil include headaches,
flushing and reflex tachycardia. The potent vasodilator
actions of minoxidil can lead to fluid retention and
edema formation. Reflex cardiac stimulation can
precipitate angina in patients with coronary artery
disease. Minoxidil produces T wave changes in a high
percentage (~60%) of patients under chronic
treatment. One of the most noted side effects of
minoxidil is hypertrichosis, a thickening and enhanced
pigmentation of body hair, and therefore this drug is
more commonly used for treating baldness.
Renin inhibitors 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

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 halflife 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 cough is much
lower in patients taking aliskiren than those taking
ACEIs. Angioedema (life-threatening airway swelling
and obstruction) can occur in patients taking aliskiren
(as can occur with ACEI and ARB treatment), although
fewer than 1% of patients develop this condition. When
administered with an ACEI, aliskiren can produce
hyperkalemia, especially in diabetic patients. 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.

in systemic vascular resistance. It is not uncommon for

hypertension to be caused by elevations in both. Since
cardiac output is the product of heart rate and stroke
volume, cardioinhibitory drugs that reduce either or
both will decrease cardiac output and thereby decrease
arterial pressure.
Angina and myocardial infarction

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.

Cardioinhibitors, by reducing heart rate, contractility,

and arterial pressure, reduce the work of the heart and
the oxygen demand of the heart. By reducing oxygen
demand, the oxygen supply/demand ratio is improved,
which can relieve a patient ofanginal pain that is
caused by a reduction in the oxygen supply/demand
ratio due to coronary artery disease. Furthermore,
cardioinhibitors that block beta-adrenoceptors have
been found to be very important in the treatment of
myocardial infarction. Their benefit is derived not only
from improving the oxygen supply/demand ratio, but
also from their ability to inhibit subsequent cardiac
remodeling.

Therapeutic Use and Rationale

Arrhythmias

Therapeutic Uses of
Cardioinhibitory Drugs

Hypertension

Because cardioinhibitors alter pacemaker activity and

electrical conduction within the heart, they are useful
for treatingarrhythmias caused by both abnormal
automaticity andabnormal conduction.

Angina

Heart failure

Arrhythmias

Heart failure (-blockers only)

Although it seems counterintuitive that cardioinhibitors

would be used in heart failure that occurs because of a
functionally depressed myocardium, clinical studies
have shown very conclusively that some
cardioinhibitors (i.e., specific beta-blockers)
significantly improve cardiac function in certain types
of heart failure. Furthermore, they have been shown to
reduce deleterious cardiac remodeling that occurs in
chronic heart failure. Their benefit may be derived from
their blockade of excessive sympathetic influences on
the heart, which are known to be harmful to the failing
heart.

Cardioinhibitory drugs depress cardiac function by

decreasing heart rate (chronotropy) and myocardial
contractility (inotropy), which decreases cardiac
output and arterial pressure. These cardiac changes
reduce the work of the heart and myocardial oxygen
consumption. The mechanisms of action of these drugs
also lead to depressed electrical
conduction (dromotropy) within the heart. Some of
these drugs may also impair relaxation (lusitropy).
The mechanical and metabolic effects of these drugs
make them very suitable for treating hypertension,
angina caused by coronary artery disease, and
myocardial infarction. Furthermore, their effects on
electrical activity make them good candidates for the
treatment of cardiac arrhythmias. Finally, some
cardioinhibitors, notably certain beta-blockers, are
used in the treatment of heart failure.
Hypertension
Hypertension is defined as an arterial systolic pressure
greater than 140 mmHg and/or a diastolic pressure
greater than 90 mmHg. Hypertension can be caused by
either an increase in cardiac output or by an increase

Drug Classes and General Mechanisms of Action

Three Classes of
Cardioinhibitory Drugs

Beta-blockers

Calcium-channel blockers

Centrally-acting sympatholytics

Cardioinhibitors used in clinical practice can be divided

into three mechanistic classes: beta-adrenoceptor
antagonists (beta-blockers), calcium-channel blockers,
and centrally-acting sympatholytics.

Beta-blockers
Beta-blockers bind to beta-adrenoceptors located in
cardiac nodal tissue, the conducting system, and
contracting myocytes. The heart has both beta1 (1)
and beta2 (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 circulates in the blood. Betablockers prevent the normal ligand (norepinephrine or
epinephrine) from binding to the beta-adrenoceptor by
competing for the binding site. Because there is
generally some level of sympathetic tone on the heart,
beta-blockers are able to reduce sympathetic
influences that normally stimulate chronotropy,
inotropy, dromotropy and lusitropy. These drugs have
an even greater effect when there is elevated
sympathetic activity. Beta-blockers that are used
clinically are either non-selective (1/2) blockers, or
relatively selective 1 blockers. Some beta-blockers
have additional mechanisms of action besides betablockade. Beta-blockers are used for treating
hypertension, angina, myocardial infarction and
arrhythmias.

of norepinephrine and epinephrine to these receptors.

This inhibits normal sympathetic effects that act
through these receptors. Therefore, beta-blockers are
sympatholytic drugs. Some beta-blockers, when they
bind to the beta-adrenoceptor, partially activate the
receptor while preventing norepinephrine from binding
to the receptor. These partial agonists therefore
provide some "background" of sympathetic activity
while preventing normal and enhanced sympathetic
activity. These particular beta-blockers (partial
agonists) are said to possess intrinsic
sympathomimetic activity (ISA). Some beta-blockers
also possess what is referred to as membrane
stabilizing activity (MSA). This effect is similar to the
membrane stabilizing activity ofsodium-channels
blockers that represent Class I antiarrhythmics.
The first generation of beta-blockers were nonselective, meaning that they blocked both beta-1 (1)
and beta-1 (2) adrenoceptors. Second generation
beta-blockers are more cardioselective in that they
are relatively selective for 1adrenoceptors. Note that
this relative selectivity can be lost at higher drug
doses. Finally, the third generation beta-blockers are
drugs that also possess vasodilator actions through
blockade of vascular alpha-adrenoceptors.

Calcium-channel blockers
Calcium-channel blockers (CCBs) bind to L-type calcium
channels located on cardiac myocytes and cardiac
nodal tissue (sinoatrial and atrioventricular nodes).
These channels are responsible for regulating the influx
of calcium into cardiomyocytes, which in turn
stimulates 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 decrease myocardial force
generation (negative inotropy), decreased heart rate
(negative chronotropy), and decrease conduction
velocity within the heart (negative dromotropy
particularly at the atrioventricular node). CCBs are
used in treating hypertension, angina and arrhythmias.
Centrally acting sympatholytics
Centrally acting sympatholytics block sympathetic
activity by binding to and activating alpha2 (2)adrenoceptors located on cardioregulatory cells within
the medulla of the brain. This reduces sympathetic
outflow to the heart, thereby decreasing cardiac output
by decreasing heart rate and contractility. These drugs
are only used for treating hypertension.
Click below on a drug class for more details:
General Pharmacology
Beta-blockers are drugs that bind to betaadrenoceptors and thereby block the binding

Heart
Beta-blockers bind to beta-adrenoceptors located in
cardiac nodal tissue, the conducting system, and
contracting myocytes. The heart has both 1 and
2 adrenoceptors, although the predominant receptor
type in number and function is 1. These receptors
primarily bind norepinephrine that is released from
sympathetic adrenergic nerves. Additionally, they bind

norepinephrine and epinephrine that circulate in the

blood. Beta-blockers prevent the normal ligand
(norepinephrine or epinephrine) from binding to the
beta-adrenoceptor by competing for the binding site.
Beta-adrenoceptors are coupled to a Gs-proteins, which
activate adenylyl cyclase to form cAMP from ATP.
Increased cAMP activates a cAMP-dependent protein
kinase (PK-A) that phosphorylates L-type calcium
channels, which causes increased calcium entry into
the cell. 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 (chronotropy). PK-A also
phosphorylates sites on the sarcoplasmic reticulum,
which lead to enhanced release of calcium through the
ryanodine receptors (ryanodine-sensitive, calciumrelease 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
contribute to the positive inotropic effect of betaadrenoceptor stimulation.
Because there is generally some level of sympathetic
tone on the heart, beta-blockers are able to reduce
sympathetic influences that normally stimulate
chronotropy (heart rate), inotropy (contractility),
dromotropy (electrical conduction) and lusitropy
(relaxation). Therefore, beta-blockers cause decreases
in heart rate, contractility, conduction velocity, and
relaxation rate. These drugs have an even greater
effect when there is elevated sympathetic activity.

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).
Compared to their effects in the heart, beta-blockers
have relatively little vascular effect because 2adrenoceptors have only a small modulatory role on
basal vascular tone. Nevertheless, blockade of 2adrenoceptors is associated with a small degree of
vasoconstriction in many vascular beds. This occurs
because beta-blockers remove a small 2-adrenoceptor
vasodilator influence that is normally opposing the
more dominant alpha-adrenoceptor mediated
vasoconstrictor influence.
Therapeutic Indications
Beta-Blockers
Cardiac Effects

Decrease contractility
(negative intropy)

Decrease relaxation rate

(negative lusitropy)

Decrease heart rate

(negative chronotropy)

Decrease conduction velocity

(negative dromotropy)

Vascular Effects

Smooth muscle contraction

(mild vasoconstriction)

Beta-blockers are used for treating hypertension,

angina, myocardial infarction, arrhythmias and heart
failure.
Hypertension

Blood vessels
Vascular smooth muscle has 2-adrenoceptors that are
normally activated by norepinephrine released by
sympathetic adrenergic nerves or by circulating
epinephrine. These receptors, like those in the heart,
are coupled to a Gs-protein, which stimulates the
formation ofcAMP. Although increased cAMP enhances

Beta-blockers decrease arterial blood pressure by

reducing cardiac output. Many forms of hypertension
are associated with an increase in blood volume and
cardiac output. Therefore, reducing cardiac output by
beta-blockade can be an effective treatment for
hypertension, especially when used in conjunction with
adiuretic. Acute treatment with a beta-blocker is not
very effective in reducing arterial pressure because of
a compensatory increase in systemic vascular
resistance. This may occur because of baroreceptor
reflexes working in conjunction with the removal of
2 vasodilatory influences that normally offset, to a

small degree, alpha-adrenergic mediated vascular

tone. Chronic treatment with beta-blockers lowers
arterial pressure more than acute treatment possibly
because of reduced renin release and effects of betablockade on central and peripheral nervous systems.
Beta-blockers have an additional benefit as a
treatment for hypertension in that they inhibit the
release of renin by the kidneys (the release of which is
partly regulated by 1-adrenoceptors in the kidney).
Decreasing circulating plasma renin leads to a
decrease in angiotensin II and aldosterone, which
enhances renal loss of sodium and water and further
diminishes arterial pressure.
Hypertension in some patients is caused by emotional
stress, which causes enhanced sympathetic activity.
Beta-blockers can be very effective in these patients.
Beta-blockers are used in the preoperative
management of hypertension caused by a
pheochromocytoma, which results in elevated
circulating catecholamines. When used for this
condition, the blood pressure is first controlled using an
alpha-blocker such as phenoxybenzamine, and then a
beta-blocker can be carefully administered to reduce
the excessive cardiac stimulation by the
catecholamines. It is important that a beta-blocker is
administered only after adequate blockade of vascular
alpha-adrenoceptors so that a hypertensive crisis does
not occur as a result of unopposed alpha-adrenoceptor
stimulation.
Angina and myocardial infarction
Theraputic Use of
Beta-Blockers

Hypertension

Angina

Myocardial infarction

Arrhythmias

Heart failure

The antianginal effects of beta-blockers are attributed

to their cardiodepressant and hypotensive actions. By
reducing heart rate, contractility, and arterial pressure,
beta-blockers reduce the work of the heart and
the oxygen demand of the heart. Reducing oxygen
demand improves the oxygen supply/demand ratio,
which can relieve a patient of anginal pain that is
caused by a reduction in the oxygen supply/demand
ratio due to coronary artery disease. Furthermore,
beta-blockers have been found to be very important in
the treatment of myocardial infarction in that they
have been shown to decrease mortality. Their benefit is
derived not only from improving the oxygen

supply/demand ratio and reducing arrhythmias, but

also from their ability to inhibit subsequent cardiac
remodeling.
Arrhythmias
The antiarrhythmic properties beta-blockers (Class II
antiarrhythmic) are related to their ability to inhibit
sympathetic influences on cardiac electrical activity.
Sympathetic nerves increase sinoatrial node
automaticity by increasing the pacemaker currents,
which increases sinus rate. Sympathetic activation
also increases conduction velocity (particularly at the
atrioventricular node), and stimulates aberrant
pacemaker activity (ectopic foci). These sympathetic
influences are mediated primarily through 1adrenoceptors. Therefore, beta-blockers can attenuate
these sympathetic effects and thereby decrease sinus
rate, decrease conduction velocity (which can
block reentry mechanisms), and inhibit aberrant
pacemaker activity. Beta-blockers also affect nonpacemaker action potentials by increasing action
potential duration and the effective refractory period.
This effect can play a major role in blocking
arrhythmias caused by reentry.
Heart failure
The majority of patients in heart failure have a form
that is called systolic dysfunction, which means that
the contractile function of the heart is depressed (loss
of inotropy). Although it seems counterintuitive
that cardioinhibitory drugs such as beta-blockers would
be used in cases of systolic dysfunction, clinical studies
have shown quite conclusively that some specific betablockers actually improve cardiac function and reduce
mortality. Furthermore, they have been shown to
reduce deleterious cardiac remodeling that occurs in
chronic heart failure. Although the exact mechanism by
which beta-blockers confer their benefit to heart failure
patients is poorly understood, it may be related to
blockade of excessive, chronic sympathetic influences
on the heart, which are known to be harmful to the
failing heart.
Different Classes of Beta-Blockers and Specific
Drugs
Beta-blockers that are used clinically can be divided
into two classes: 1) non-selective blockers (block
both 1and 2receptors), or 2) relatively selective
1 blockers ("cardioselective" beta-blockers). Some
beta-blockers have additional mechanisms besides
beta-blockade that contribute to their unique
pharmacologic profile. The two classes of beta-blockers
along with specific compounds are listed in the
following table. Additional details for each drug may be
found atwww.rxlist.com. The clinical uses indicated in
the table represent both on and off-label uses of betablockers. For example, a given beta-blocker may only

be approved by the FDA for treatment of hypertension;

however, physicians sometimes elect to prescribe the
drug for angina because of the class-action benefit that
beta-blockers have for angina.
Clinical Uses
Class/Dr
ug

HT
N

Angi
na

Arr
hy

M CH
Comments
I
F

Nonselective
1/2

metoprol
X
ol

nebivolol X

ISA; long
acting; also
used for
glaucoma

carteolol X

carvedilo
X
l

-blocking
activity
ISA; -blocking
activity

labetalol

nadolol

penbutol
X
ol

ISA

pindolol

ISA; MSA

proprano
X
lol

sotalol

timolol

esmolol

ultra short
acting; intra or
postoperative
HTN

acebutol
ol

atenolol

betaxolol X

MSA;
prototypical
beta-blocker
several other
significant
mechanisms

long acting

primarily used
for glaucoma

1selective

bisoprolo
X
l

ISA
X
MSA

relatively
selective in
most patients;
vasodilating
(NO release)

Abbreviations: HTN, hypertension; Arrhy, arrhythmias;

MI, myocardial infarction; CHF, congestive heart failure;
ISA, intrinsic sympathomimetic activity.
Side Effects and Contraindications
Cardiovascular side effects
Many of the side effects of beta-blockers are related to
their cardiac mechanisms and include bradycardia,
reduced exercise capacity, heart failure, hypotension,
and atrioventicular (AV) nodal conduction block. Betablockers are therefore contraindicated in patients with
sinus bradycardia and partial AV block. The side effects
listed above result from excessive blockade of normal
sympathetic influences on the heart. Considerable care
needs to be exercised if a beta-blocker is given in
conjunction with cardiac selective calcium-channel
blockers (e.g., verapamil) because of their additive
effects in producing electrical and mechanical
depression. Although this may change with future
clinical trials on safety and efficacy of beta-blockers in
heart failure, at present only carvedilol and metoprolol
have been approved by the FDA for this indication.
Other side effects
Bronchoconstriction can occur, especially when nonselective beta-blockers are administered to asthmatic
patients. Therefore, non-selective beta-blockers are
contraindicated in patients with asthma or chronic
obstructive pulmonary disease. Bronchoconstriction
occurs because sympathetic nerves innervating the
bronchioles normally activate 2-adrenoceptors that
promote bronchodilation. Beta-blockers can also mask
the tachycardia that serves as a warning sign for
insulin-induced hypoglycemia in diabetic patients;
therefore, beta-blockers should be used cautiously in
diabetics.
Calcium-Channel Blockers
Cardiac effects

MSA

Decrease contractility
(negative inotropy)

Decrease heart rate

(negative chronotropy)

Decrease conduction velocity

(negative dromotropy)

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.

Vascular effects

Arrhythmias
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.

The antiarrhythmic properties (Class IV

antiarrhythmics) of CCBs are related to their ability to
decrease the firing rate of aberrant pacemaker sites
within the heart, but more importantly are related to
their ability to decrease conduction velocity and
prolong repolarization, especially at the atrioventricular
node. This latter action at the atrioventricular node
helps to block reentry mechanisms, which can cause
supraventricular tachycardia.
Different Classes of Calcium-Channel Blockers

Hypertension

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 thedihydropyridines. Because of
their high vascular selectivity, these drugs are
primarily used to reduce systemic vascular resistance
and arterial pressure, and therefore are primarily used
to treat hypertension. They are not, however, generally
used to treat angina because their powerful systemic
vasodilator and pressure lowering effects can lead to
reflex cardiac stimulation (tachycardia and increased
inotropy), which can dramatically increase myocardial
oxygen demand. Note that dihydropyridines are easy
to recognize because the drug name ends in "pine."

Therapeutic Use of
Calcium-Channel Blockers

Dihydropyridines include the following specific drugs:

(Go towww.rxlist.com for specific drug information)

Therapeutic Indications
CCBs are used to treat hypertension, angina and
arrhythmias.

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

amlodipine

felodipine

isradipine

nicardipine

nifedipine

nimodipine

nitrendipine

Non-dihydropyridines, of which there are only two

currently used clinically, comprise the other two
classes of CCBs.Verapamil (phenylalkylamine class), is
relatively selective for the myocardium, and is less
effective as a systemic vasodilator drug. This drug has
a very important role in treating angina (by reducing
myocardial oxygen demand and reversing coronary

vasospasm) and
arrhythmias. Diltiazem (benzothiazepine class) is
intermediate between verapamil and dihydropyridines
in its selectivity for vascular calcium channels. By
having both cardiac depressant and vasodilator
actions, diltiazem is able to reduce arterial pressure
without producing the same degree of reflex cardiac
stimulation caused by dihydropyridines.
Side Effects and Contraindications
Dihydropyridine CCBs can cause flushing, headache,
excessive hypotension, edema and reflex tachycardia.
The activation of sympathetic reflexes and lack of
direct cardiac effects make dihydropyridines a less
desirable choice for angina. Long-acting
dihydropyridines have been shown to be safer antihypertensive 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, nondihydropyridines. CCBs, especially nondihydropyridines, 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.

General Pharmacology
The sympathetic adrenergic nervous system plays a
major role in the regulation of arterial pressure.
Activation of these nerves to the heart increases the
heart rate (positive chronotropy), contractility (positive
inotropy) and velocity of electrical impulse conduction
(positive dromotropy). The norepinephrine-releasing,
sympathetic adrenergic nerves that innervate the heart
and blood vessels are postganglionic efferent nerves
whose cell bodies originate in prevertebral and
paraveterbral sympathetic ganglia. Preganglionic
sympathetic fibers, which travel from the spinal cord to
the ganglia, originate in the medulla of the brainstem.
Within the medulla are located sympathetic excitatory
neurons that have significant basal activity, which
generates a level of sympathetic tone to the heart and
vasculature even under basal conditions. The
sympathetic neurons within the medulla receive input
from other neurons within the medulla (e.g., vagal
neurons), from the nucleus tractus solitarius (receives
input from peripheral baroreceptors and
chemoreceptors), and from neurons located in the
hypothalamus. Together, these neuronal systems
regulate sympathetic (and parasympathetic) outflow to
the heart and vasculature.

Sympatholytic drugs can block this sympathetic

adrenergic system are three different levels.
First, peripheral sympatholytic drugs such
as alpha-adrenoceptor and beta-adrenoceptor
antagonists block the influence of norepinephrine at
the effector organ (heart or blood vessel). Second,
there are ganglionic blockers that block impulse
transmission at the sympathetic ganglia. Third, there
are drugs that block sympathetic activity within the
brain. These are called centrally acting
sympatholytic drugs.
Centrally acting sympatholytics block sympathetic
activity by binding to and activating alpha2 (2)adrenoceptors. This reduces sympathetic outflow to the
heart thereby decreasing cardiac output by decreasing
heart rate and contractility. Reduced sympathetic
output to the vasculature decreases sympathetic
vascular tone, which causes vasodilation and reduced
systemic vascular resistance, which decreases arterial
pressure.
Therapeutic Indications
Centrally acting 2-adrenoceptor agonists are used in
the treatment of hypertension. However, they are not
considered first-line therapy in large part because of
side effects that are associated with their actions
within the brain. They are usually administered in
combination with a diuretic to prevent fluid
accumulation, which increases blood volume and
compromises the blood pressure lowering effect of the
drugs. Fluid accumulation can also lead to edema.
Centrally acting 2-adrenoceptor agonists are effective
in hypertensive patients with renal disease because
they do not compromise renal function.
Specific Drugs
Several different centrally acting 2-adrenoceptor
agonists are available for clinical use: (Go
to www.rxlist.com for specific drug information)

clonidine

guanabenz

guanfacine

-methyldopa

Clonidine, guanabenz and guanfacine are structurally

related compounds and have similar antihypertensive
profiles. -methyldopa is a structural analog of dopa
and functions as a prodrug. After administration, methyldopa is converted to -methynorepinephrine,
which then serves as the 2-adrenoceptor agonist in
the medulla to decrease sympathetic outflow.
Side Effects and Contraindications
Side effects of centrally acting 2-adrenoceptor
agonists include sedation, dry mouth and nasal

mucosa, bradycardia (because of increased vagal

stimulation of the SA node as well as sympathetic
withdrawal), orthostatic hypotension, and impotence.
Constipation, nausea and gastric upset are also
associated with the sympatholytic effects of these
drugs. Fluid retention and edema is also a problem
with chronic therapy; therefore, concurrent therapy
with a diuretic is necessary. Sudden discontinuation of
clonidine can lead to rebound hypertension, which
results from excessive sympathetic activity.