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 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.

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.

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 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, 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

chlorthalidonethiazide-like in action, not structure

hydrochlorothiazide

prototypical drug;

hydroflumethiazide

indapamidethiazide-like in action, not structure

methyclothiazide

metolazonethiazide-like in action, not structure

polythiazide

Loop bumetanide

ethacrynic acid

furosemide

torsemide

K+-sparing amiloridedistal tubule Na+-channel inhibitor

eplerenonealdosterone receptor antagonist; fewer side effects than spironolactone

spironolactonealdosterone receptor antagonist; side effect: gynecomastia

triamterenedistal tubule Na+-channel inhibitor

CA inhibitors

acetazolamideprototypical drug; not used in treating hypertension or heart failure

dichlorphenamidenot used in treating hypertension or heart failure

methazolamidenot 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

Thiazide hypokalemia

metabolic alkalosis

dehydration (hypovolemia), leading to hypotension

hyponatremia

hyperglycemia in diabetics

hypercholesterolemia; hypertriglyceridemia

increased low-density lipoproteins

hypokalemia potentiates digitalis toxicity

non-steroidal anti-inflammatory drugs: reduced diuretic efficacy

beta-blockers: potentiate hyperglycemia, hyperlipidemias

corticosteroids: enhance hypokalemia

hyperuricemia (at low doses)

azotemia (in renal disease patients)

Loop

hypokalemia

metabolic alkalosis

hypomagnesemia

hyperuricemia

dehydration (hypovolemia), leading to hypotension

dose-related hearing loss (ototoxicity)

hypokalemia potentiates digitalis toxicity

non-steroidal anti-inflammatory drugs: reduced diuretic efficacy

corticosteroids: enhance hypokalemia

aminoglycosides: enhance ototoxicity, nephrotoxicity

K+-sparing

hyperkalemia

metabolic acidosis

gynecomastia (aldosterone antagonists)

gastric problems including peptic ulcer

ACE inhibitors: potentiate hyperkalemia

non-steroidal anti-inflammatory drugs: reduced diuretic efficacy

Carbonic anhydrase inhibitors

hypokalemia

metabolic acidosis

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. 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.

General Pharmacology

These drugs block the effect of sympathetic nerves on blood

vessels by binding to alpha-adrenoceptors located on the

vascular smooth muscle. Most of these drugs act as

competitive antagonists to the binding of norepinephrine that is

released by sympathetic nerves synapsing on smooth muscle.

Therefore, sometimes these drugs are referred to

assympatholytics because they antagonize sympathetic

activity. Some alpha-blockers are non-competitive

(e.g.,phenoxybenzamine), which greatly prolongs their action,

whereas others are relatively selective for one type of alpha-

adrenoceptor.

Vascular smooth muscle has two types of alpha-

adrenoceptors: alpha1 (α1) and alpha2 (α2). The α1-

adrenoceptors are the predominant α-receptor located on

vascular smooth muscle. These receptors are linked to Gq-

proteins that activate smooth muscle contraction through

the IP3 signal transduction pathway. Depending on the tissue

and type of vessel, there are also α2-adrenoceptors found on

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 α2-adrenoceptors located on the sympathetic

nerve terminals that inhibit the release of norepinephrine and

therefore act as a feedback mechanism for modulating the

release of norepinephrine.

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.

General Pharmacology

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

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

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

Cardiorenal Effects of ACE Inhibitors

Vasodilation (arterial & venous)- reduce arterial & venous pressure- reduce ventricular afterload & preload

Decrease blood volume- natriuretic- diuretic

Depress sympathetic activity

Inhibit cardiac and vascular hypertrophy

ACE inhibitors have the following actions:

Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload and afterload on the heart.

Down regulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine.

Promote renal excretion of sodium and water (natriuretic anddiuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation ofaldosterone secretion. This reduces blood volume, venous pressure and arterial pressure.

Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction.

Elevated plasma renin is not required for the actions of ACE inhibitors, although ACE inhibitors are more efficacious when circulating levels of renin are elevated. We know that renin-angiotensin system is found in many tissues, including heart, brain, vascular and renal tissues. Therefore, ACE inhibitors may act at these sites in addition to blocking the conversion of angiotensin in the circulating plasma.

Therapeutic Uses

Therapeutic Use ofACE Inhibitors

Hypertension

Heart failure

Post-myocardial infarction

Hypertension

ACE inhibitors are effective in the treatment of primary hypertension and hypertension caused by renal artery stenosis, which causes renin-dependent hypertension owing to the increased release of renin by the kidneys. Reducing angiotensin II formation leads to arterial and venous dilation, which reduces arterial and venous pressures. By reducing the effects of angiotensin II on the kidney, ACE inhibitors cause natriuresis and diuresis, which decreases blood volume and cardiac output, thereby lowering arterial pressure.

Some of the older literature indicated that ACE inhibitors (and angiotensin receptor blockers, ARBs) were less efficacious in African American hypertensive patients, which unfortunately led to lower utilization of these important, beneficial drugs in African Americans. While it is true that African Americans do not respond as well as other races to monotherapy with ACE inhibitors or ARBs, the differences are eliminated with adequate diuretic dosing. Therefore, current recommendations from the JNC 7 report are that ACE inhibitors and ARBs are appropriate for use in African Americans, with the recommendation of adequate diuretic dosing to achieve the target blood pressure.

Heart Failure

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

Reduced afterload, which enhances ventricular stroke volume and improves ejection fraction.

Reduced preload, which decreases pulmonary and systemic congestion and edema.

Reduced sympathetic activation, which has been shown to be deleterious in heart failure.

Improving the oxygen supply/demand ratio primarily by decreasing demand through the reductions in afterload and preload.

Prevents angiotensin II from triggering deleterious cardiac remodeling.

Finally, ACE inhibitors have been shown to be effective in patients following myocardial infarction because they help to reduce deleterious remodeling that occurs post-infarction.

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

Specific Drugs

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

benazepril

captopril

enalapril

fosinopril

lisinopril

moexipril

quinapril

ramipril

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

Side Effects and Contraindications

As a drug class, ACE inhibitors have a relatively low incidence of side effects and are well-tolerated. A common, annoying side effect of ACE inhibitors is a dry cough appearing in about 10% of patients. It appears to be related to the elevation in bradykinin. Hypotension can also be a problem, especially in heart failure patients. Angioedema (life-threatening airway swelling and obstruction; 0.1-0.2% of patients) and hyperkalemia (occurs because 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) 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."

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.

General Pharmacology

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

Therapeutic Indications

CCBs are used to treat hypertension, angina and arrhythmias.

Hypertension

Therapeutic Use ofCalcium-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 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, 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.

General Pharmacology

The one drug in this group, hydralazine, does not fit neatly into the other mechanistic classes, in part, because its mechanism of action is not entirely clear and it appears to have multiple, direct effects on the vascular smooth muscle. First, hydralazine causes smooth

muscle hyperpolarization quite likely through the opening of K+-channels. It also may inhibit IP3-induced release of calcium from the smooth muscle sarcoplasmic reticulum. This calcium combines with calmodulin to activate myosin light chain kinase, which induces contraction. Finally, hydralazine stimulates the formation of nitric oxide by the vascular endothelium, leading to cGMP-mediated vasodilation.

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

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 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.

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 (anti-thrombotic), and inhibiting leukocyte-endothelial interactions (anti-inflammatory). These actions involve NO-stimulated formation of cGMP. Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues. These drugs act directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelial-independent vasodilators.

There are two basic types of nitrodilators: those that release NO spontaneously (e.g., sodium nitroprusside) and organic nitrates that

require an enzymatic process to form NO. Organic nitrates do not directly release NO, however, their nitrate groups interact with enzymes and intracellular sulfhydryl groups that reduce the nitrate groups to NO or to S-nitrosothiol, which then is reduced to NO. Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation (click here for details). NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.

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

Primary Cardiovascular Actionsof Nitrodilators

Systemic vasculature

vasodilation (venous dilation > arterial dilation)

decreased venous pressure

decreased arterial pressure (small effect)

Cardiac

reduced preload and afterload (decreased wall stress)

decreased oxygen demand

Coronary

prevents/reverses vasospasm

vasodilation (primarily epicardial vessels)

improves subendocardial perfusion

increased oxygen delivery

Although organic nitrates can dilate both arteries and veins, venous dilation predominates when these drugs are given at normal therapeutic doses. Venous dilation reduces venous pressure and decreases 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.

Specific Drugs

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

isosorbide dinitrate

isosorbide mononitrate

nitroglycerin

erythrityl tetranitrate

pentaerythritol tetranitrate

sodium nitroprusside

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

Isosorbide dinitrate and mononitrate, and tetranitrate compounds have a longer onset of action and duration of action than nitroglycerin. This makes these compounds more useful than short-acting nitroglycerin for the long-term prophylaxis and management of coronary artery disease. Oral bioavailability of many organic nitrates is low because of first-pass metabolism by the liver. Isosorbide mononitrate, which has nearly 100% bioavailability, is the exception. Therefore, oral administration of these compounds requires much higher doses than sublingual administration, which is not subject to first-pass hepatic metabolism.

The metabolites of organic nitrates are biologically active and have a longer half-life than the parent compound. Therefore, the metabolites contribute significantly to the therapeutic activity of the compound.

Sodium nitroprusside, unlike organic nitrates, dilates arterial resistance vessels more than venous vessels. Because of its rapid onset of action, it is used to treat severe hypertensive emergencies and severe heart failure. It is only available as an intravenous preparation, and because of its short half-life, continuous infusion is required.

Side Effects and Contraindications

The most common side effects of nitrodilators are headache (caused by cerebral vasodilation) and cutaneous flushing. Other side effects include postural hypotension and reflex tachycardia. Excessive hypotension and tachycardia can worsen the angina by increasing oxygen demand. Prolonged use of sodium nitroprusside carries the

risk of thiocyanate toxicity because nitroprusside releases cyanide along with NO. The thiocyanate is formed in the liver from the reduction of cyanide by a sulfhydryl donor. There is clinical evidence that nitrodilators may interact adversely with cGMP-dependent phosphodiesterase inhibitors that are used to treat erectile dysfunction (e.g., sildenafil [Viagra®]). The reason for this adverse reaction is that nitrodilators stimulate cGMP production and drugs like sildenafil inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary perfusion.

General Pharmacology

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

Therapeutic Indications

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

Specific Drugs

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

Side Effects and Contraindications

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

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.

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.

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.

Therapeutic Use and Rationale

Therapeutic Uses ofCardioinhibitory Drugs

Hypertension

Angina

Arrhythmias

Heart failure (β-blockers only)

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 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

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.

Arrhythmias

Because cardioinhibitors alter pacemaker activity and electrical conduction within the heart, they are useful for treatingarrhythmias caused by both abnormal automaticity andabnormal conduction.

Heart failure

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.

Drug Classes and General Mechanisms of Action

Three Classes ofCardioinhibitory 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 (β1) and beta2 (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 circulates in the blood. Beta-blockers 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 (β1/β2) blockers, or relatively selective β1 blockers. Some beta-blockers have additional mechanisms of action besides beta-blockade. Beta-blockers are used for treating hypertension, angina, myocardial infarction and arrhythmias.

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 (α2)-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 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 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 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 β1adrenoceptors. 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 the troponin-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.

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

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 ofBeta-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

Class/Drug HTN Angina Arrhy MI CHF Comments

Non-selective β1/β2

carteolol XISA; long acting; also used for glaucoma

carvedilol X X α-blocking activity

labetalol X XISA; α-blocking activity

nadolol X X X X long acting

penbutolol X X ISA

pindolol X X ISA; MSA

propranolol X X X XMSA; prototypical beta-blocker

sotalol Xseveral other significant mechanisms

timolol X X X Xprimarily used for glaucoma

β1-selective

acebutolol X X X ISA

atenolol X X X X

betaxolol X X X MSA

bisoprolol X X X

esmolol X Xultra short acting; intra or postoperative HTN

metoprolol X X X X X MSA

nebivolol X

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. 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-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

Decrease contractility(negative inotropy)

Decrease heart rate(negative chronotropy)

Decrease conduction velocity(negative dromotropy)

Vascular effects

Smooth muscle relaxation(vasodilation)

General Pharmacology

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

Therapeutic Indications

CCBs are used to treat hypertension, angina and arrhythmias.

Hypertension

Therapeutic Use ofCalcium-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 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, 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.

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 (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.

Therapeutic Indications

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 and Contraindications

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.