Anti Hypertensive Drugs

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.
Rationale for Reducing

Arterial Pressure
Reduce Cardiac Output
• Reduce blood volume
• Reduce heart rate
• Reduce stroke volume
Reduce Systemic Vascular Resistance
• Dilate systemic vasculature
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 mechanismdue to
the reduction in ventricular preload. An added benefit of these drugs is that they reduce systemic
vascular resistance with long-term use.
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 beta-blockers, 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
decreasing heart rate and contractility. Some calcium-channel blockers (most notably the
dihydropyridines) are more selective for the systemic vasculature and therefore reduce systemic
vascular resistance.
Drugs Used to Treat Hypertension
Classes of drugs used in the treatment of hypertension are listed below. Clicking on the drug class
will link you to the page describing the pharmacology of that drug class.
• Diuretics
- thiazide diuretics
- loop diuretics
- potassium-sparing diuretics
• Vasodilators
- alpha-adrenoceptor antagonists (alpha-blockers)
- angiotensin converting enzyme inhibitors (ACE inhibitors)
- angiotensin receptor blockers (ARBs)
- calcium-channel blockers
- direct acting arterial dilators
- ganglionic blockers
- nitrodilators
- potassium-channel openers
- renin inhibitors
• Cardioinhibitory drugs
- beta-blockers
- calcium-channel blockers
• Centrally acting sympatholytics
General Pharmacology
Renal handling of sodium and water
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.
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 renin-angiotensin-
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.
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 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 result 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, aldosterone-blocking 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.
Heart failure
Heart failure leads to activation of the renin-angiotensin-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 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.
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. Potassium-sparing, aldosterone-blocking diuretics (e.g., spironolactone) are being used
increasingly in heart failure.
Pulmonary and systemic edema
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 Comments

Thiazide chlorothiazide
chlorthalidone thiazide-like in action, not structure
hydrochlorothiazide prototypical drug;
hydroflumethiazide
indapamide thiazide-like in action, not structure
methyclothiazide
metolazone thiazide-like in action, not structure
polythiazide
Loop bumetanide
ethacrynic acid
furosemide
torsemide
K+-sparing amioloride distal tubule Na+-channel inhibitor
aldosterone receptor antagonist; fewer side effects than
eplerenone
spironolactone
spironolactone aldosterone receptor antagonist; side effect: gynecomastia
triamterene distal tubule Na+-channel inhibitor
CA prototypical drug; not used in treating hypertension or heart
acetazolamide
inhibitors failure
dichlorphenamide not used in treating hypertension or heart failure
methazolamide not used in treating hypertension or heart failure
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 Adverse Side Effects Drug Interactions

• hypokalemia
• metabolic alkalosis
• dehydration • hypokalemia
(hypovolemia), leading to potentiates digitalis
hypotension toxicity
• hyponatremia • non-steroidal anti-
• hyperglycemia in diabetics inflammatory drugs:
Thiazide • hypercholesterolemia; reduced diuretic efficacy
hypertriglyceridemia • beta-blockers:
• increased low-density potentiate hyperglycemia,
lipoproteins hyperlipidemias
• hyperuricemia (at low • corticosteroids:
doses) enhance hypokalemia
• azotemia (in renal disease
patients)
Loop • hypokalemia • hypokalemia
• metabolic alkalosis potentiates digitalis
• hypomagnesemia toxicity
• hyperuricemia • non-steroidal anti-
• dehydration inflammatory drugs:
(hypovolemia), leading to reduced diuretic efficacy
hypotension • corticosteroids:
• dose-related hearing loss enhance hypokalemia
• aminoglycosides:
(ototoxicity) enhance ototoxicity,
nephrotoxicity
• hyperkalemia
• ACE inhibitors:
• metabolic acidosis
potentiate hyperkalemia
• gynecomastia (aldosterone
K+-sparing • non-steroidal anti-
antagonists)
inflammatory drugs:
• gastric problems including
reduced diuretic efficacy
peptic ulcer
Carbonic
• hypokalemia
anhydrase
• metabolic acidosis
inhibitors
VASODILATOR DRUGS
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 andpulmonary 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. Venous dilators reduce venous pressure, which reduces preload on the

heart thereby decreasing cardiac output. This is useful in angina because it
decreases the oxygen demand of the heart and thereby increases the oxygen
supply/demand ratio. Oxygen demand is reduced because decreasing preload
leads to a reduction in ventricular wall stress by decreasing the size of the
heart.
2. Reducing venous pressure decreases proximal capillary hydrostatic
pressure, which reduces capillary fluid filtration and edema formation.
Therefore, venous dilators are sometimes used in the treatment of heart
failure along with other drugs because they help to reduce pulmonary and/or
systemic edema that results from the heart failure.
Although most vasodilator drugs dilate veins as well as arteries, some drugs, such
as organic nitrate dilators are relatively selective for veins.
The effects of selective venous dilators on overall cardiovascular function in normal subjects
can be depicted graphically using cardiac and systemic vascular function curves as shown
to the right. Venous dilation increasesvenous compliance by relaxing the venous smooth
muscle. Increased compliance causes a parallel shift to the left of the vascular function
curve (red line), which decreases the mean circulatory filling pressure (x-intercept). This
causes the operating point to shift from A to B, resulting in a decrease in cardiac output
(CO) with a small decrease in right atrial pressure (PRA). The reason for these changes is
that venous dilation, by reducing PRA, decreases right ventricular preload, which decreases
stroke volume and cardiac output by the Frank-Starling mechanism. Although not shown in
this figure, reduced cardiac output causes a fall in arterial pressure, which reduces afterload
on the left ventricle and leads to baroreceptor reflex responses, both of which can shift the
cardiac function curve up and to the left. Sympathetic activation can also lead to an
increase in systemic vascular resistance. The cardiac effects (decreased cardiac output) of
venous dilation are more pronounce in normal hearts than in failing hearts because of
where the hearts are operating on their Frank-Starling curves (cardiac function) curves
(click here for more information).
Therefore, the cardiac and vascular responses to venous dilation are complex when both
direct effects and indirect compensatory responses are taken into consideration. The most
important effects in terms of clinical utility for patients are summarized below.
Venous dilators reduce:
1. Venous pressure and therefore cardiac preload

2. Cardiac output
3. Arterial pressure
4. Myocardial oxygen demand
5. Capillary fluid filtration and tissue edema
Mixed or "balanced" dilators
As indicated above, most vasodilators act on both arteries and veins, and therefore are
termed mixed or balanced dilators. Notable exceptions are hydralazine (arterial dilator)
and organic nitrate dilators (venous dilators).
The effects of mixed dilators on cardiac and systemic vascular function curves are shown in
the figure to the right. The red line represents a systemic function curve generated when
there is both venous dilation (increased venous compliance) and arterial dilation (reduced
systemic vascular resistance) - the mean circulatory filling pressure (x-axis) is decreased
and the slope is increased. Point B represents the new operating point, although it is
important to note that where this point lies depends on the relative degree of venous and
arterial dilation. If there is more arterial dilation than venous dilation, then point B may be
located slightly above point A where the cardiac function curve intersects with the new
vascular function curve.
To summarize the effects of mixed vasodilators, we can say that in general they decrease
systemic vascular resistance and arterial pressure with relatively little change in right atrial
(or central venous) pressure (i.e., little change in cardiac preload), and they have a
relatively little effect on cardiac output.
Side-Effects of Vasodilators
There are three potential drawbacks in the use of vasodilators:
1. Systemic vasodilation and arterial pressure reduction can lead to

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

Vasodilator drugs can be classified based on their site of action (arterial versus venous) or
by mechanism of action. Some drugs primarily dilate resistance vessels (arterial dilators;
e.g., hydralazine), while others primarily affect venous capacitance vessels (venous dilators;
e.g., nitroglycerine). Most vasodilator drugs, however, have mixed arterial and venous
dilator properties (mixed dilators; e.g., alpha-adrenoceptor antagonists, angiotensin
converting enzyme inhibitors).
It is more common, however, to classify vasodilator drugs based on their primary

mechanism of action. This type of classification scheme leads to the following drug classes:
(Click on the drug class for more details)
• Alpha-adrenoceptor antagonists (alpha-blockers)

• Angiotensin converting enzyme (ACE) inhibitors
• Angiotensin receptor blockers (ARBs)
• Beta2-adrenoceptor agonists (β2-agonists)
• Calcium-channel blockers (CCBs)
• Centrally acting sympatholytics
• Direct acting vasodilators
• Endothelin receptor antagonists
• Ganglionic blockers
• Nitrodilators
• Phosphodiesterase inhibitors
• Potassium-channel openers
• Renin inhibitors
Alpha-Adrenoceptor Antagonists (Alpha-Blockers)

These drugs block the effect of sympathetic nerves on blood vessels by binding to alpha-
adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive
antagonists to the binding 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.
Vascular smooth muscle has two primary types of alpha-adrenoceptors: alpha1 (α1) and alpha2 (α2).
The α1-adrenoceptors are located on the vascular smooth muscle. In contrast, α2-adrenoceptors are
located on the sympathetic nerve terminals as well as on vascular smooth muscle. Smooth muscle
(postjunctional) α1 and α2-adrenoceptors are linked to a Gq-protein, which activates smooth muscle
contraction through the IP3 signal transduction pathway. Prejunctional α2-adrenoceptors located on
the sympathetic nerve terminals serve as a negative feedback mechanism for norepinephrine
release.
α1-adrenoceptor antagonists cause vasodilation by blocking the binding of norepinephrine to the
smooth muscle receptors. Non-selective α1 and α2-adrenoceptor antagonists block postjunctional
α1 and α2-adrenoceptors, which causes vasodilation; however, the blocking of prejunctional α2-
adrenoceptors leads to increased release of norepinephrine, which attenuates the effectiveness of
the α1 and α2-postjunctional adrenoceptor blockade. Furthermore, blocking α2-prejunctional
adrenoceptors in the heart can lead to increases in heart rate and contractility due to the enhanced
release of norepinephrine that binds to beta1-adrenoceptors.
Alpha-blockers dilate both arteries and veins because both vessel types are innervated by
sympathetic adrenergic nerves; however, the vasodilator effect is more pronounced in the arterial
resistance vessels. Because most blood vessels have some degree of sympathetic tone under basal
conditions, these drugs are effective dilators. They are even more effective under conditions of
elevated sympathetic activity (e.g., during stress) or during pathologic increases incirculating
catecholamines caused by an adrenal gland tumor (pheochromocytoma).
Therapeutic Uses
Alpha-blockers, especially α1-adrenoceptor antagonists, are useful in the treatment of primary

hypertension, although their use is not as widespread as other antihypertensive drugs. The non-
selective antagonists are usually reserve for use in hypertensive emergencies caused by a
pheochromocytoma. This hypertensive condition, which is most commonly caused by an adrenal
gland tumor that secretes large amounts of catecholamines, can be managed by non-selective
alpha-blockers (in conjunction with beta-blockade to blunt the reflex tachycardia) until the tumor can
be surgically removed.
Specific Drugs
Newer alpha-blockers used in treating hypertension are relatively selective α1-adrenoceptor

antagonists (e.g., prazosin, terazosin, doxazosin, trimazosin), whereas some older drugs are
non-selective antagonists (e.g., phentolamine,phenoxybenzamine). (Go to www.rxlist.com for
specific drug information)
Side Effects and Contraindications
The most common side effects are related directly to alpha-adrenoceptor blockade. These side
effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction upon
standing), nasal congestion (due to dilation of nasal mucosal arterioles), headache, and reflex
tachycardia (especially with non-selective alpha-blockers). Fluid retention is also a problem that can
be rectified by use of a diuretic in conjunction with the alpha-blocker. Alpha blockers have not been
shown to be beneficial in heart failure or angina, and should not be used in these conditions.
ACE
ACE inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This vasoconstrictor
is formed by the proteolytic action of renin (released by the kidneys) acting on circulating
angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by
angiotensin converting enzyme.
ACE also breaks down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking
the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator
action of ACE inhibitors. The increase in bradykinin is also believed to be responsible for a
troublesome side effect of ACE inhibitors, namely, a dry cough.
Angiotensin II constricts arteries and veins by binding to AT1 receptors located on the smooth
muscle, which are coupled to a Gq-protein and the the IP3 signal transduction pathway. Angiotensin
II also facilitates the release of norepinephrine from sympathetic adrenergic nerves and inhibits
norepinephrine reuptake by these nerves. This effect of angiotensin II augments sympathetic activity
on the heart and blood vessels.
Cardiorenal Effects of ACE Inhibitors

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

• Dilate arteries and veins by blocking angiotensin II formation and inhibiting
bradykinin metabolism. This vasodilation reduces arterial
pressure, preload and afterload on the heart.
• Down regulate sympathetic adrenergic activity by blocking the facilitating effects of
angiotensin II on sympathetic nerve release and reuptake of norepinephrine.
• Promote renal excretion of sodium and water (natriuretic anddiuretic effects) by
blocking the effects of angiotensin II in the kidney and by blocking angiotensin II
stimulation ofaldosterone secretion. This reduces blood volume, venous pressure and
arterial pressure.
• Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart
failure, and myocardial infarction.
Elevated plasma renin is not required for the actions of ACE inhibitors, although ACE inhibitors are
more efficacious when circulating levels of renin are elevated. We know that renin-angiotensin
system is found in many tissues, including heart, brain, vascular and renal tissues. Therefore, ACE
inhibitors may act at these sites in addition to blocking the conversion of angiotensin in the
circulating plasma.
Therapeutic Uses
Therapeutic Use of
ACE Inhibitors
• Hypertension
• Heart failure
• Post-myocardial infarction
Hypertension
ACE inhibitors are effective in the treatment of primary hypertension and hypertension caused by
renal artery stenosis, which causes renin-dependent hypertension owing to the increased release of
renin by the kidneys. Reducing angiotensin II formation leads to arterial and venous dilation, which
reduces arterial and venous pressures. By reducing the effects of angiotensin II on the kidney, ACE
inhibitors cause natriuresis and diuresis, which decreases blood volume and cardiac output, thereby
lowering arterial pressure.
Some of the older literature indicated that ACE inhibitors (and angiotensin receptor blockers, ARBs)
were less efficacious in African American hypertensive patients, which unfortunately led to lower
utilization of these important, beneficial drugs in African Americans. While it is true that African
Americans do not respond as well as other races to monotherapy with ACE inhibitors or ARBs, the
differences are eliminated with adequate diuretic dosing. Therefore, current recommendations from
the JNC 7 report are that ACE inhibitors and ARBs are appropriate for use in African Americans,
with the recommendation of adequate diuretic dosing to achieve the target blood pressure.
Heart Failure
ACE inhibitors have proven to be very effective in the treatment ofheart failure caused by systolic
dysfunction (e.g., dilated cardiomyopathy). Beneficial effects of ACE inhibition in heart failure
include:
• Reduced afterload, which enhances ventricular stroke volume and improves
ejection fraction.
• Reduced preload, which decreases pulmonary and systemic congestion
and edema.
• Reduced sympathetic activation, which has been shown to be deleterious in heart
failure.
• Improving the oxygen supply/demand ratio primarily by decreasing demand through
the reductions in afterload and preload.
• Prevents angiotensin II from triggering deleterious cardiac remodeling.
Finally, ACE inhibitors have been shown to be effective in patients following myocardial
infarction because they help to reduce deleterious remodeling that occurs post-infarction.
ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart failure.
Specific Drugs
The first ACE inhibitor marketed, captopril, is still in widespread use today. Although newer ACE
inhibitors differ from captopril in terms of pharmacokinetics and metabolism, all the ACE inhibitors
have similar overall effects on blocking the formation of angiotensin II. ACE inhibitors include the
following specific drugs: (Go to www.rxlist.com for specific drug information)
• benazepril
• captopril
• enalapril
• fosinopril
• lisinopril
• moexipril
• quinapril
• ramipril
Note that each of the ACE inhibitors named above end with "pril."
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
Angiotensin Receptor Blockers (ARBs)

These drugs have very similar effects to angiotensin converting enzyme (ACE)
inhibitors and are used for the same indications (hypertension, heart failure,
post- myocardial infarction). Their mechanism of action, however, is very different from ACE
inhibitors, which inhibit the formation of angiotensin II. ARBs are receptor antagonists that
block type 1 angiotensin II (AT1) receptors on bloods vessels and other tissues such as the
heart. These receptors are coupled to 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.
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."

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
Calcium-Channel Blockers (CCBs)

Calcium-Channel Blockers
Cardiac effects
• Decrease contractility
(negative inotropy)
• Decrease heart rate
(negative chronotropy)
• Decrease conduction velocity
(negative dromotropy)
Vascular effects
• Smooth muscle relaxation
(vasodilation)
Currently approved CCBs bind to L-type calcium channels located on the vascular smooth
muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes).
These channels are responsible for regulating the influx of calcium into muscle cells, which
in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac
nodal tissue, L-type calcium channels play an important role in pacemaker currents and
in phase 0 of the action potentials. Therefore, by blocking calcium entry into the cell, CCBs
cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force
generation (negative inotropy), decreased heart rate (negative chronotropy), and decreased
conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular
node.
Therapeutic Indications
CCBs are used to treat hypertension, angina and arrhythmias.
Hypertension
Therapeutic Use of
Calcium-Channel Blockers
• Hypertension
(systemic & pulmonary)
• Angina
• Arrhythmias
By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular

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

There are three classes of CCBs. They differ not only in their basic chemical structure, but
also in their relative selectivity toward cardiac versus vascular L-type calcium channels. The
most smooth muscle selective class of CCBs are the dihydropyridines. Because of their
high vascular selectivity, these drugs are primarily used to reduce systemic vascular
resistance and arterial pressure, and therefore are primarily used to treat hypertension.
They are not, however, generally used to treat angina because their powerful systemic
vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia
and increased inotropy), which can dramatically increase myocardial oxygen demand. Note
that dihydropyridines are easy to recognize because the drug name ends in "pine."
Dihydropyridines include the following specific drugs: (Go 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.

Dihydropyridine CCBs can cause flushing, headache, excessive hypotension, edema and
reflex tachycardia. The activation of sympathetic reflexes and lack of direct cardiac effects
make dihydropyridines a less desirable choice for angina. Long-acting dihydropyridines
have been shown to be safer anti-hypertensive drugs, in part, because of reduced reflex
responses. The cardiac selective, non-dihydropyridine CCBs can cause excessive
bradycardia, impaired electrical conduction (e.g., atrioventricular nodal block), and
depressed contractility. Therefore, patients having preexistent bradycardia, conduction
defects, or heart failure caused by systolic dysfunction should not be given CCBs,
especially the cardiac selective, non-dihydropyridines. CCBs, especially non-
dihydropyridines, should not be administered to patients being treated with a beta-blocker
because beta-blockers also depress cardiac electrical and mechanical activity and therefore
the addition of a CCB augments the effects of beta-blockade
Nitrodilators
Nitric oxide (NO), a molecule produced by many cells in the body, and has several
important actions (click here for details). In the cardiovascular system, NO is primarily
produced by vascular endothelial cells. This endothelial-derived NO has several important
functions including relaxing vascular smooth muscle (vasodilation), inhibiting platelet
aggregation (anti-thrombotic), and inhibiting leukocyte-endothelial interactions (anti-
inflammatory). These actions involve NO-stimulated formation of cGMP. Nitrodilators are
drugs that mimic the actions of endogenous NO by releasing NO or forming NO within
tissues. These drugs act directly on the vascular smooth muscle to cause relaxation and
therefore serve as endothelial-independent vasodilators.
There are two basic types of nitrodilators: those that release NO spontaneously (e.g.,
sodium nitroprusside) and organic nitrates that require an enzymatic process to form NO.
Organic nitrates do not directly release NO, however, their nitrate groups interact with
enzymes and intracellular sulfhydryl groups that reduce the nitrate groups to NO or to S-
nitrosothiol, which then is reduced to NO. Nitric oxide activates smooth muscle soluble
guanylyl cyclase (GC) to form cGMP. Increased intracellular cGMP inhibits calcium entry
into the cell, thereby decreasing intracellular calcium concentrations and causing smooth
muscle relaxation (click here for details). NO also activates K+ channels, which leads to
hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-
dependent protein kinase that activates myosin light chain phosphatase, the enzyme that
dephosphorylates myosin light chains, which leads to relaxation.
Tolerance to nitrodilators occurs with frequent dosing, which decreases their efficacy. The
problem is partially circumvented by using the smallest effective dose of the compound
coupled with infrequent or irregular dosing. The mechanism for tolerance is not fully
understood, but it may involve depletion of tissue sulfhydryl groups, or scavenging of NO by
superoxide anion and the subsequent production of peroxynitrite that may inhibit guanylyl
cyclase.
Primary Cardiovascular Actions

of Nitrodilators
Systemic vasculature
• vasodilation
(venous dilation > arterial dilation)
• decreased venous pressure
• decreased arterial pressure (small effect)
Cardiac
• reduced preload and afterload
(decreased wall stress)
• decreased oxygen demand
Coronary
• prevents/reverses vasospasm
• vasodilation (primarily epicardial vessels)
• improves subendocardial perfusion
• increased oxygen delivery
Although nitrodilators can dilate both arteries and veins, venous dilation predominates when
these drugs are given at normal therapeutic doses. Venous dilation reduces venous
pressure and decreases ventricular preload. This reduces ventricular wall 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 theduration of diastole, decreases the time
available for coronary perfusion, most of which occurs during diastole (click here for more
details).
The primary pharmacologic action of nitrodilators, arterial and venous dilation, make these
compounds useful in the treatment of hypertension, heart failure, angina and myocardial
infarction. Another beneficial action of nitrodilators is their ability to inhibit platelet
aggregation.
Hypertension
Nitrodilators are not used to treat chronic primary or secondary hypertension; however,
sodium nitroprusside and nitroglycerine are used to lower blood pressure in acute
hypertensive emergencies that may result from a pheochromocytoma, renal artery stenosis,
aortic dissection, etc. Nitrodilators may also be used during surgery to to control arterial
pressure within desired limits.
Heart failure
Nitrodilators are used in acute heart failure and in severe chronic heart failure. Arterial
dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume
and ejection fraction. Furthermore, the venous dilation reduces venous pressure, which
helps to reduce edema. Reducing both afterload and preload on the heart also helps to
improve the mechanical efficiency of dilated hearts and to reduce wall stress and the
oxygen demands placed on the failing heart.
Angina and myocardial infarction
Nitrodilators are used extensively to treat angina and myocardial infarction. They are useful
in Printzmetal's variant anginabecause they improve coronary blood flow (i.e., increase
oxygen supply) by reversing and inhibiting coronary vasospasm. They are important
in other forms of angina because they reduce preload on the heart by producing venous
dilation, which decreases myocardial oxygen demand. It is unclear if direct dilation of
epicardial coronary arteries play a role in the antianginal effects of nitrodilators in chronic
stable or unstable angina. These drugs also reduce systemic vascular resistance
(depending on dose) and arterial pressure, which further reduces myocardial oxygen
demand. Taken together, these two actions dramatically improve the oxygen
supply/demand ratio and thereby reduce anginal pain.
Specific Drugs
Several different nitrodilators are available for clinical use: (Go to www.rxlist.com for
specific drug information)
• isosorbide dinitrate
• isosorbide mononitrate
• nitroglycerin
• erythrityl tetranitrate
• pentaerythritol tetranitrate
• sodium nitroprusside
The nitrodilators listed above differ in the route of administration, onset of action, and
duration of action. Nitroglycerin, which has been used since the 19th century, is commonly
used in the treatment of angina because it is very fast acting (within 2 to 5 minutes) when
administered sublingually. Its effects usually wear off within 30 minutes. Therefore,
nitroglycerin is particularly useful for preventing or terminating an acute anginal attack.
Longer-acting preparations of nitroglycerin (e.g., transdermal patches) have a longer onset
of action (30 to 60 minutes), but are effective for 12 to 24 hours. Intravenous nitroglycerin is
used in the hospital setting for unstable angina and acute heart failure.
Isosorbide dinitrate and mononitrate, and tetranitrate compounds have a longer onset of
action and duration of action than nitroglycerin. This makes these compounds more useful
than short-acting nitroglycerin for the long-term prophylaxis and management of coronary
artery disease. Oral bioavailability of many organic nitrates is low because of first-pass
metabolism by the liver. Isosorbide mononitrate, which has nearly 100% bioavailability, is
the exception. Therefore, oral administration of these compounds requires much higher
doses than sublingual administration, which is not subject to first-pass hepatic metabolism.
The metabolites of organic nitrates are biologically active and have a longer half-life than
the parent compound. Therefore, the metabolites contribute significantly to the therapeutic
activity of the compound.
Sodium nitroprusside, which is used to treat severe hypertensive emergencies and

severe heart failure, has a rapid onset of action. It is only available as an intravenous
preparation, and because of its short half-life, continuous infusion is required.

The most common side effects of nitrodilators are headache (caused by cerebral
vasodilation) and cutaneous flushing. Other side effects include postural hypotension
and reflex tachycardia. Excessive hypotension and tachycardia can worsen the angina by
increasing oxygen demand. Prolonged use of sodium nitroprusside carries the risk of
thiocyanate toxicity because nitroprusside releases cyanide along with NO. The thiocyanate
is formed in the liver from the reduction of cyanide by a sulfhydryl donor. There is clinical
evidence that nitrodilators may interact adversely with cGMP-dependent
phosphodiesterase inhibitors that are used to treat erectile dysfunction
(e.g., sildenafil [Viagra®]). The reason for this adverse reaction is that nitrodilators stimulate
cGMP production and drugs like sildenafil inhibit cGMP degradation. When combined, these
two drug classes greatly potentiate cGMP levels, which can lead to hypotension and
impaired coronary perfusion.
Potassium-Channel Openers
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).
Being effective arterial dilators, potassium-channel openers are used in the treatment
of hypertension. These drugs are not first-line therapy for hypertension because of their
side effects, and therefore they are relegated to treating refractory, severe hypertension.
They are generally used in conjunction with a beta-blocker and diuretic to attenuate the
reflex tachycardia and retention of sodium and fluid, respectively.
Specific Drugs
Although several potassium-channel openers have been used in research for many years,
only one, minoxidil, is approved for use in humans for treating hypertension. (Go
to www.rxlist.com for detailed information on minoxidil)

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

• Vasodilation (arterial & venous)
- reduce arterial & venous pressures
- reduce ventricular afterload & preload
• Decrease blood volume
- natriuretic
- diuretic
• Depress sympathetic activity
• Inhibit cardiac and vascular hypertrophy
• Dilate arteries and veins by blocking angiotensin II formation. This
vasodilation reduces arterial pressure,preload 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.
Specific Drugs and Therapeutic Uses

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

Aliskiren, 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 ofcough is much lower in
patients taking aliskiren than those taking ACEIs. Angioedema (life-threatening airway
swelling and obstruction) can occur in patients taking aliskiren (as can occur with ACEI and
ARB treatment), although fewer than 1% of patients develop this condition. When
administered with an ACEI, aliskiren can produce hyperkalemia, especially in diabetic
patients.
As with ACEIs, aliskiren should not be administered anytime during pregnancy, particularly
in second and third trimesters because of fetal and neonatal injury, and risk of birth defects
Beta-Adrenoceptor Antagonists (Beta-Blockers)
Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding
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 asmembrane stabilizing activity
(MSA). This effect is similar to the membrane stabilizing activity of sodium-channels blockers that
represent Class I antiarrhythmics.
The first generation of beta-blockers were non-selective, meaning that they blocked both beta-1 (β1)
and beta-1 (β2) adrenoceptors. Second generation beta-blockers are more cardioselective in that
they are relatively selective for β1 adrenoceptors. 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.
Heart
Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system,
and contracting myocytes. The heart has both β1 and β2 adrenoceptors, although the predominant
receptor type in number and function is β1. 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, calcium-release channels) associated with the sarcoplasmic reticulum. This
provides more calcium for binding thetroponin-C, which enhances inotropy. Finally, PK-A can
phosphorylate myosin light chains, which may contribute to the positive inotropic effect of beta-
adrenoceptor 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.
Blood vessels
Vascular smooth muscle has β2-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 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 β2-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 β2-
adrenoceptors have only a small modulatory role on basal vascular tone. Nevertheless, blockade of
β2-adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This
occurs because beta-blockers remove a small β2-adrenoceptor vasodilator influence that is normally
opposing the more dominant alpha-adrenoceptor mediated vasoconstrictor influence.
Beta-Blockers
Cardiac Effects
• Decrease contractility
(negative intropy)
• Decrease relaxation rate
(negative lusitropy)
• Decrease heart reat
(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
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
β2 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 beta-blockade 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 β1-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 β1-adrenoceptors. 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 non-pacemaker 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 beta-blockers 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 β1and β2receptors), or 2) relatively selective β1 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
beta-blockers. 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
HT Angin Arrh CH
Class/Drug MI Comments
N a y F
Non-selective
β1/β2
carteolol X ISA; long acting; also used for glaucoma
carvedilol X X α-blocking activity
labetalol X X ISA; α-blocking activity
nadolol X X X X long acting
penbutolol X X ISA
pindolol X X ISA; MSA
propranolol X X X X MSA; prototypical beta-blocker
sotalol X several other significant mechanisms
timolol X X X X primarily used for glaucoma
β1-selective
acebutolol X X X ISA
atenolol X X X X
betaxolol X X X MSA
bisoprolol X X X
ultra short acting; intra or postoperative

esmolol X X
HTN
metoprolol X X X X X MSA
relatively selective in most patients;

nebivolol X
vasodilating (NO release)
Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial infarction; CHF, congestive
heart failure; ISA, intrinsic sympathomimetic activity.

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. Beta-blockers 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 non-selective 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 β2-receptors that promote bronchodilation.
Blockade of these receptors can lead to bronchoconstriction. Hypoglycemia can occur with beta-
blockade because β2-adrenoceptors normally stimulate hepatic glycogen breakdown
(glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma
glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer
metabolic side effects in diabetic patients; however, the tachycardia which serves as a warning sign
for insulin-induced hypoglycemia may be masked. Therefore, beta-blockers are to be used
cautiously in diabetics.
Centrally Acting Sympatholytics
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 (α2)-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.
Centrally acting α2-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 α2-adrenoceptor agonists are effective in hypertensive
patients with renal disease because they do not compromise renal function.
Specific Drugs
Several different centrally acting α2-adrenoceptor agonists are available for clinical use: (Go
to www.rxlist.com for specific drug information)
• clonidine
• guanabenz
• guanfacine
• α-methyldopa
Clonidine, guanabenz and guanfacine are structurally related compounds and have similar
antihypertensive profiles. α-methyldopa is a structural analog of dopa and functions as a
prodrug. After administration, α-methyldopa is converted to α-methynorepinephrine, which
then serves as the α2-adrenoceptor agonist in the medulla to decrease sympathetic outflow.

Side effects of centrally acting α2-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
Table 1. Classification of drugs used in the management of hypertension

Mechanism of action Examples Relevance to anaesthesia
Hydrochlorothiazide May produce hypokalaemia resulting in
Diuretics
Frusemide dysrhythmias
Hydralazine Tachycardia
Vasodilators
Diazoxide (unpredictable when given IV)
Clonidine
Central sympathetic Rebound hypertension if withdrawn.
Methyldopa
depression Slow acting.
reserpine
Adrenergic neurone Sensitive to vasopressors.
Guanethidine
blockers Postural hypotension.
Propranolol Avoid in asthmatics and patients with heart failure.
Beta blockers Atenolol Cause bradycardias which usually respond to
Labetalol (alpha also) atropine.
Phenoxybenzamine
Alpha blockers Tachycardia.
Phentolamine
Vasodilator.
Calcium channel Nifedipine
Cardiac depressant - avoid combining with beta
blockers Verapamil
blockers as extreme hypotension can occur.
Renin - angiotensin
Captopril Potentiate hypotensive action of anaesthetic drugs.
inhibitors

Anti Hypertensive Drugs

Hochgeladen von

Dokumentinformationen

Originalbeschreibung:

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Anti Hypertensive Drugs

Hochgeladen von

Copyright:

Verfügbare Formate

Rationale for Pharmacologic Treatment of Hypertension

Rationale for Reducing

Arterial pressure can be reduced by decreasing cardiac output,systemic vascular resistance,

Drugs Used to Treat Hypertension

• Centrally acting sympatholytics

Renal handling of sodium and water

Mechanisms of diuretic drugs

Heart failure leads to activation of the renin-angiotensin-aldosterone system, which causes

Pulmonary and systemic edema

Class Specific Drugs Comments

Adverse Side Effects and Contraindications

Class Adverse Side Effects Drug Interactions

Therapeutic Use and Rationale

1. Venous dilators reduce venous pressure, which reduces preload on the

Venous dilators reduce:

1. Venous pressure and therefore cardiac preload

1. Systemic vasodilation and arterial pressure reduction can lead to

Drug Classes and General Mechanisms of Action

It is more common, however, to classify vasodilator drugs based on their primary

• Alpha-adrenoceptor antagonists (alpha-blockers)

Alpha-Adrenoceptor Antagonists (Alpha-Blockers)

Alpha-blockers, especially α1-adrenoceptor antagonists, are useful in the treatment of primary

Newer alpha-blockers used in treating hypertension are relatively selective α1-adrenoceptor

Side Effects and Contraindications

Cardiorenal Effects of ACE Inhibitors

ACE inhibitors have the following actions:

Side Effects and Contraindications

Angiotensin Receptor Blockers (ARBs)

• Dilate arteries and veins and thereby reduce arterial pressure

Side Effects and Contraindications

Calcium-Channel Blockers (CCBs)

By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular

Different Classes of Calcium-Channel Blockers

Side Effects and Contraindications

Primary Cardiovascular Actions

Angina and myocardial infarction

Sodium nitroprusside, which is used to treat severe hypertensive emergencies and

Side Effects and Contraindications

Side Effects and Contraindications

Cardiorenal Effects of Renin Inhibitors

Specific Drugs and Therapeutic Uses

Side Effects and Contraindications

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

Beta-blockers are used in the preoperative management of hypertension caused by a

Angina and myocardial infarction

Different Classes of Beta-Blockers and Specific Drugs

carteolol X ISA; long acting; also used for glaucoma

carvedilol X X α-blocking activity

labetalol X X ISA; α-blocking activity

nadolol X X X X long acting

pindolol X X ISA; MSA

propranolol X X X X MSA; prototypical beta-blocker

sotalol X several other significant mechanisms

timolol X X X X primarily used for glaucoma

ultra short acting; intra or postoperative

relatively selective in most patients;

Side Effects and Contraindications

Other side effects

Bronchoconstriction can occur, especially when non-selective beta-blockers are administered to

Side Effects and Contraindications

Table 1. Classification of drugs used in the management of hypertension

Das könnte Ihnen auch gefallen