VASODILATOR DRUGS

     Vasodilator drugs play a central role in the treatment of heart failure and hypertension. As a result
of activating these pathways, two potent natural vasoconstrictors are released into the circulation: norepinephrine and angiotensin II (AII). These hormones bind to receptors in arterioles and veins, where they cause vascular smooth muscle contraction. Initially, such vasoconstriction is beneficial in heart failure because it maximizes left ventricular preload (increased venous tone enhances venous return) and helps to maintain systemic blood pressure (because of arterial constriction).
     However, venous constriction may ultimately cause excessive venous return to the heart, with a rise in the pulmonary capillary hydrostatic pressure and development of pulmonary congestion. In addition, excessive arteriolar constriction increases the resistance against which the left ventricle must contract and therefore ultimately impedes forward cardiac output. Vasodilator therapy is directed at modulating the excessive constriction of veins and arterioles, thus reducing pulmonary c ongestion and augmenting forward cardiac output.
     Vasodilators are also useful antihypertensive drugs. Recall from Chapter 13 that blood pressure is the product of cardiac output and total peripheral resistance (BP = CO X TPR). Vasodilator drugs decrease arteriolar resistance and therefore lower elevated blood pressure.
     Individual vasodilator drug classes act at specifi c vascular sites. Nitrates, for example, are primarily venodilators, whereas hydralazine is a pure arteriolar dilator. Some drugs, such as the ACE inhibitors, b -blockers, sodium nitroprusside, and nesiritide, are balanced vasodilators that act on both sides of the circulation.

Angiotensin-Converting Enzyme Inhibitors
     The renin–angiotensin system plays a critical role in cardiovascular homeostasis. The major effector of this pathway is AII, which is formed by the cleavage of angiotensin I by ACE. All the actions of AII known to affect blood pressure control are mediated by its binding to AII receptors of the angiotensin II type 1 (AT1) subtype. Interaction with this receptor generates a series of intracellular reactions that causes, among other effects, vasoconstriction and the adrenal release of aldosterone, which promotes Na reabsorption from the distal nephron. As a result of these actions on vascular tone and sodium homeostasis, AII plays a major role in blood pressure and blood volume regulation. By blocking the formation of AII, ACE inhibitors decrease the systemic arterial pressure, facilitate natriuresis (e.g., by decreasing aldosterone production and reducing Na reabsorption from the distal nephron), and reduce adverse ventricular remodeling.
     Another action of ACE inhibitors, which likely contributes to their hemodynamic effects, is related to bradykinin (BK) metabolism. The natural vasodilator BK is normally degraded to inactive metabolites by ACE. Because ACE inhibitors impede that degradation, BK accumulates and contributes to the antihypertensive effect, likely by stimulating the endothelial release of nitric oxide and biosynthesis of vasodilating prostaglandins.

Clinical Uses

Hypertension
     In hypertensive patients, ACE inhibitors lower blood pressure with little change in cardiac output
or heart rate. One might assume that because this class of drug interferes with the renin– angiotensin system, it would be effective only in patients with “high-renin” hypertension, but that is not the case. Rather, they are effective in most hypertensive patients, regardless of serum renin levels. The reason for this is not clear but may relate to the additional antihypertensive effects of BK and vasodilatory prostaglandins previously described. In addition, renin– angiotensin activity has been demonstrated within tissues outside the circulation, including the walls of the vasculature, where ACE inhibitors may exert a vasodilatory effect independent of the circulating renin concentration.
     ACE inhibitors increase renal blood fl ow,
usually without altering the glomerular filtration rate (GFR), because of dilation of both the afferent and efferent glomerular arterioles. Used alone, ACE inhibitors show similar antihypertensive efficacy as diuretics and -blockers, but unlike the latter drugs, they do not adversely affect serum glucose or lipid
concentrations. ACE inhibitors are often recommended therapy in diabetic hypertensive patients, because the drugs slow the development of diabetic nephropathy (a syndrome of progressive renal deterioration, proteinuria, and hypertension) through favorable effects on intraglomerular pressure.

Heart Failure
     In heart failure, ACE inhibitors reduce peripheral vascular resistance (decrease afterload), reduce cardiac fi lling pressures (decrease preload), and increase cardiac output. The rise in cardiac output usually matches the fall in peripheral resistance such that blood pressure tends not to fall (remember, BP = CO x TPR), except in patients with intravascular volume depletion as might result from overly vigorous diuretic therapy. The augmented cardiac output reduces the drive for compensatory  neurohormonal stimulation in CHF, such that elevated levels of norepinephrine fall. In addition, clinical trials have shown that ACE inhibitors signifi cantly improve survival in patients with chronic heart failure and following myocardial infarction. Some studies have shown that ACE inhibition also reduces
the risk of myocardial infarction and death in patients with chronic vascular disease, including coronary artery disease (CAD), even if left ventricular function is not impaired. The primary excretory pathway of most of these agents is through the kidney, so their dosages should generally be reduced in patients with renal dysfunction.

Adverse Effects

Hypotension
This is a rare side effect when ACE inhibitors are used to treat hypertension. It is more likely to occur in heart failure patients in whom intravascular volume depletion has resulted from vigorous diuretic use. Such patients have significant activation of the renin–angiotensin system; therefore, blood pressure is largely maintained by the vasoconstricting actions of circulating AII. The administration of an ACE inhibitor in that setting may result in hypotension because of the sudden reduction of AII levels. This side effect is avoided by temporarily reducing the diuretic regimen and starting the ACE inhibitor at a low dosage.

 Hyperkalemia
     Because ACE inhibitors indirectly reduce the serum aldosterone concentration, the serum potassium concentration may rise, but only rarely into the clinically important hyperkalemic range. Conditions that can further increase serum potassium levels and may result in dangerous hyperkalemia during ACE
inhibitor use include renal insuffi ciency, diabetes (owing to hyporeninemic hypoaldosteronism, a condition often present in elderly diabetics), and concomitant use of potassium-sparing diuretics.

 Renal Insufficiency
     Administration of an ACE inhibitor to patients with intravascular volume depletion may result
in hypotension, decreased renal perfusion, and azotemia. Correction of volume depletion, or reduction of the ACE inhibitor dosage, usually corrects this complication.
     ACE inhibitor therapy can also precipitate renal failure in patients with bilateral renal artery stenosis because such patients rely on high efferent glomerular arteriolar resistance (which is highly dependent on AII) to maintain intraglomerular pressure and filtration. Administering an ACE inhibitor abruptly decreases efferent arteriolar tone and glomerular hydrostatic pressure and may therefore worsen GFR in this setting.

 Cough
     Irritation of the upper airways resulting in a dry cough is reported in up to 20% of patients receiving ACE inhibitor therapy. Its mechanism has not been established but may relate to the
increased BK concentration provoked by ACE inhibitors. This side effect may last weeks after
the drug is discontinued.

Other Effects
     Very rare adverse reactions to ACE inhibitors include angioedema and agranulocytosis. ACE
inhibitors should not be used in pregnancy because they have been shown to cause fetal injury.

VASOPRESSORS

Sympathomimetic Amines
     Sympathomimetic amines are inotropic drugs that bind to cardiac B1-receptors. Stimulation of these receptors increases the activity of adenylate cyclase, causing increased formation of cyclic adenosine monophosphate (cAMP). Increased cAMP activates protein kinases, which promote intracellular calcium influx by phosphorylating L-type calcium channels. The increased calcium entry triggers a corresponding rise in Ca release from the sarcoplasmic reticulum, which enhances the force of contraction. Intravenous dopamine and dobutamine are commonly used sympathomimetic amines in the treatment of acute heart failure. Norepinephrine, epinephrine, and isoproterenol are prescribed in special circumstances, as described in the following paragraphs.

Sympathomimetic Drug Effects
                                                          Receptor Stimulation
Drug                   D1 ( ↑ Renal               Alfa                          Beta 1                       Beta 2
                          Perfusion)         (Vasoconstriction)        ( ↑ Contractility)           (Vasodilation)

Dopamine                  + (a)                  ++++ (b)                    ++++                           ++
Dobutamine              0                            +                            ++++                            +
Norepinephrine          0                        ++++                          ++++                            0
Epinephrine               0                        ++++ (b)                    ++++                           ++
Isoproterenol             0                           0                             ++++                         ++++




(a) : low dose
(b) : high dose

     Dopamine is an endogenous catecholamine and the precursor of norepinephrine. It possesses an unusual combination of actions that makes it attractive in the treatment of heart failure associated with hypotension and poor renal perfusion. There are various types of receptors with different affi nities for dopamine. At low dosages, < 2 mcg/kg/min, dopamine interacts primarily with dopaminergic receptors distributed in the renal and mesenteric vascular beds. Stimulation of these receptors causes local vasodilation and increases renal blood flow and glomerular filtration, facilitating diuresis.
     Medium dosages of dopamine, 2 to 10 mcg/kg/min, increase inotropy by stimulation of cardiac B1-receptors directly and indirectly by promoting release of norepinephrine from sympathetic nerve terminals. This action increases heart rate, cardiac contractility, and stroke volume, all of which augment cardiac output.
     At high dosages, > 10 mcg/kg/min, dopamine also stimulates systemic Alfa-receptors, thereby causing vasoconstriction and elevating systemic resistance. High-dose dopamine is indicated in hypotensive states such as shock. However, these doses are inappropriate in most patients with cardiac failure because the peripheral vasoconstriction increases the resistance against which the heart must contract (i.e., higher afterload), further impairing left ventricular output.
     The major toxicity of dopamine arises in patients who are treated with high-dose therapy. The most important side effects are acceleration of the heart rate and tachyarrhythmias.

     Dobutamine is a synthetic analog of dopamine that stimulates B 1-, B 2-, and Alfa -receptors. It increases cardiac contractility by virtue of the B 1 effect but does not increase peripheral resistance because of the balance between -mediated vasoconstriction and B 2-mediated vasodilation. Thus, it is useful in the treatment of heart failure not accompanied by hypotension. Unlike dopamine, dobutamine does not stimulate dopaminergic receptors (i.e., no renal vasodilating effect), nor does it facilitate the release of norepinephrine from peripheral nerve endings. Like dopamine, it is useful for short-term therapy ( <1 week), after which time it loses its effi cacy, presumably because of downregulation of adrenergic receptors. The major adverse effect is the provocation of tachyarrhythmias.

     Norepinephrine is an endogenous catecholamine synthesized from dopamine in adrenergic postganglionic nerves and in adrenal medullary cells (where it is both a final product and the precursor of epinephrine). Through its B 1 activity, norepinephrine has positive inotropic and chronotropic effects. Acting at peripheral Alfa -receptors, it is also a potent vasoconstrictor. The increase in total
peripheral resistance causes the mean arterial blood pressure to rise.
     With this combination of effects, norepinephrine is useful in patients suffering from “warm shock,” in which the combination of cardiac contractile dysfunction and peripheral vasodilation lowers blood pressure. However, the intense vasoconstriction elicited by this drug makes it less attractive than others in treating most other cases of shock. Norepinephrine’s side effects include precipitation
of myocardial ischemia (because of the augmented force of contraction and increased afterload) and tachyarrhythmias.

     Epinephrine, the predominant endogenous catecholamine produced in the adrenal medulla, is formed by the decarboxylation of norepinephrine. As indicated in Table 17.2, epinephrine is an agonist of Alfa-, B 1-, and B2- receptors. Administered as an intravenous infusion at low dosages, its stimulation of the B 1-receptor increases ventricular contractility and speeds impulse generation. As a result, stroke volume, heart rate, and cardiac output increase. However, at this dosage range, B2-mediated vasodilation may reduce total peripheral resistance and blood pressure.
     At higher dosages, epinephrine is a potent vasopressor because -mediated constriction dominates over B 2-mediated vasodilation. In this case, the effects of positive inotropy, positive chronotropy, and vasoconstriction act together to raise the arterial blood pressure.
     Epinephrine is therefore used most often when the combination of inotropic and chronotropic
stimulation is desired, such as in the setting of cardiac arrest. The Alfa-associated vasoconstriction may also help support blood pressure in that setting. The most common toxic effect is the precipitation of tachyarrhythmias. Epinephrine should be avoided in patients receiving B-blocker therapy, because unopposed Alfa-mediated vasoconstriction could produce signifi cant hypertension.

     Isoproterenol is a synthetic epinephrine analog. Unlike norepinephrine and epinephrine, it is a “pure” B-agonist, having activity almost exclusively at B 1- and B 2-receptors, with almost no -receptor effect. In the heart, isoproterenol has positive inotropic and chronotropic effects, thereby increasing cardiac output. In peripheral vessels, stimulation of B 2-receptors results in vasodilation and reduced peripheral resistance, which may cause blood pressure to fall.
     Isoproterenol is sometimes used in emergency circumstances to increase the heart rate in patients with bradycardia or heart block (e.g., as a temporizing measure before pacemaker implantation). It may also be useful in patients with systolic dysfunction and slow heart rates with high systemic vascular resistance (a situation sometimes encountered after cardiac surgery in patients who had previously been receiving B -blocker therapy). Isoproterenol should be avoided in patients with myocardial ischemia, in whom the increased heart rate and inotropic stimulation would further increase myocardial oxygen consumption.

Phosphodiesterase-3 Inhibitors
Milrinone is an example of a nondigitalis, noncatecholamine inotropic agent. It exerts its positive inotropic actions by inhibiting phosphodiesterase type 3 in cardiac myocytes. This inhibition reduces the breakdown of intracellular cAMP, the ultimate result of which is enhanced Ca ++ entry into the cell and increased force of contraction. Additionally, in vascular smooth muscle, phosphodiesterase-induced augmentation of cAMP results in beneficial vasodilation (in vascular tissue, cAMP inhibits myosin light chain kinase and crossbridge formation between myosin heads and
actin filaments).
     Milrinone is sometimes used in the treatment of acute heart failure when there has been insufficient improvement with conventional vasodilators, inotropic agents, and diuretics. It has the potential for serious adverse  effects, including provocation of ventricular arrhythmias, and chronic milrinone therapy is associated with increased mortality. Its use is therefore limited to hospitalized patients for short-term therapy.

Vasopressin
Vasopressin, the endogenous antidiuretic hormone secreted by the posterior pituitary, primarily functions to maintain water balance. It also acts as a potent nonadrenergic  vasoconstrictor when administered intravenously at higher-thannatural doses, by directly stimulating vascular smooth muscle V1 receptors. It has proved useful for maintaining blood pressure in patients with vasodilatory shock, as may occur in septic states. It may also be benefi cial during cardiac arrest advanced life support because it increases coronary perfusion pressure, augments blood flow to vital organs, and improves the likelihood of successful resuscitation in patients with ventricular fibrillation.

INOTROPIC DRUGS

Inotropic drugs are used to increase the force of ventricular contraction when myocardial systolic function is impaired. The pharmacologic agents in this category include the cardiac glycosides, sympathomimetic amines, and phosphodiesterase-3 inhibitors. Although they work through different mechanisms, they are all thought to enhance cardiac contraction by increasing the intracellular calcium concentration, thus augmenting actin and myosin interactions. The hemodynamic effect is to shift a depressed ventricular performance curve (Frank–Starling curve) in an upward direction, so that for a given ventricular filling pressure, stroke volume and cardiac output are increased.

Cardiac Glycosides (Digitalis).
The cardiac glycosides are called “digitalis” because the drugs of this class are based on extracts of the foxglove plant, Digitalis purpurea. The most commonly used member of this group is digoxin.

Mechanism of Action
The two desired effects of digoxin are (1) to improve contractility of the failing heart (mechanical
effect) and (2) to prolong the refractory period of the atrioventricular (AV) node in patients with supraventricular arrhythmias (electrical effect).

Mechanical Effect
The action by which digoxin improves contractility appears to be inhibition of the sarcolemmal Na+     K +-ATPase “pump,” normally responsible for maintaining transmembrane Na+ and K+ gradients. By binding to and inhibiting this pump, digitalis causes the intracellular [Na+ ] to rise. As shown in Figure 17.2, an increase in intracellular sodium content reduces Ca++ extrusion from the cell by the Na +   –Ca ++ exchanger. Consequently, more Ca++ is pumped into the sarcoplasmic reticulum, and when subsequent action potentials excite the cell, a greaterthan- normal amount of Ca++ is released to the myofi laments, thereby enhancing the force of contraction. The magnitude of the positive inotropic effect correlates with the degree of Na +K+ -ATPase inhibition.

Electrical Effect
     The major therapeutic electrical effect of digoxin occurs at the AV node, where it slows conduction velocity and increases refractoriness. Digoxin has modest direct effects on the electrical properties of cardiac tissue directly, but more importantly, it modifi es autonomic nervous system output by enhancing vagal tone and reducing sympathetic activity. As a result, digitalis decreases the frequency of transmission of atrial impulses through the AV node to the ventricles. This is benefi cial in reducing the rate of ventricular stimulation in patients with rapid supraventricular tachycardias such as
atrial fi brillation or atrial fl utter. In addition, by enhancing the refractoriness of the AV node, digoxin may convert supraventricular reentrant arrhythmias to normal rhythm. However, if digoxin  concentrations rise into the toxic range, further enhancement of vagal tone and more extreme inhibition of the Na+ K+ -ATPase pump can result in adverse electrophysiologic effects. For example, in atrial and ventricular Purkinje fi bers, a high digoxin concentration has three important actions that may lead to dangerous arrhythmias:
1. Less negative resting potential. Inhibition of the Na +K+ -ATPase causes the resting potential to become less negative. Since the Na +K+ -ATPase normally removes three Na+ ions from the cell in exchange for two inwardly moving K+ ions, inhibition of the pump results in a decrease of this outward current and a resulting depolarization of the cell. Consequently, there is a voltagedependent partial inactivation of the fast Na+ channels, which leads to a slower rise of phase 0 depolarization and reduction in conduction velocity. The slowed conduction, if present heterogeneously among neighboring cells, enhances the possibility of reentrant arrhythmias.

2. Decreased action potential duration. At high digitalis concentrations, the cardiac action potential shortens. This relates in part to the digitalis-induced elevated intracellular [Ca++ ], which increases the activity of a Ca ++-dependent K+ channel. The opening of this channel promotes K+ efflux and more rapid repolarization. In addition, high intracellular [Ca ++] inactivates the Ca++ channels, decreasing the inward depolarizing Ca++ current. The decrease in action potential duration and the associated shortened refractory period increase the time during which cardiac fi bers are responsive to external stimulation, allowing greater opportunity for propagation of arrhythmic impulses.

3. Enhanced automaticity. Digoxin enhances cellular automaticity and may generate ectopic rhythms by two mechanisms:
a. The less negative membrane resting potential may induce phase 4 gradual depolarization, even in nonpacemaker cells, and an action potential is triggered each time the threshold voltage is reached.
b. The digoxin-induced increase in intracellular [Ca ++] may trigger delayed afterdepolarizations. If an afterdepolarization reaches the threshold voltage, an action potential (ectopic beat) is generated. Ectopic beats may lead to additional afterdepolarizations and self-sustaining arrhythmias such as ventricular tachycardia.

In addition, the augmented direct and indirect vagal effects of toxic doses of digitalis slow conduction through the AV node, such that high degrees of AV block, including complete heart block, can occur. Thus, digoxin in toxic concentrations may lead to several types of rhythm disorders.

Electrophysiologic Effects of Digitalis

Region                           Mechanism of Action                        Effect 
Therapeutic effects
AV node                         Vagal effect                                     • ↓ Rate of transmission of atrial
                                    ↓ Conduction velocity                          impulses to the ventricles in
                                    ↑ Effective refractory period                supraventricular tachyarrhythmias
                                                                                          • ↓ Conduction velocity and ↑
                                                                                             refractory period may interrupt
                                                                                             reentrant circuits passing through
                                                                                             the AV node
Toxic effects
Sinoatrial node                ↑ Vagal effect and direct                   • Sinus bradycardia
                                        suppression                                 • Sinoatrial block (impulse not
                                                                                            transmitted from SA node to atrium)
                                      
Atrium                           Delayed afterdepolarizations             • Atrial premature beats
                                       (triggered activity), ↑ slope            • Nonreentrant SVT (ectopic rhythm)
                                       of phase 4 depolarization
                                       (↑ automaticity)
                                     Variable effects on conduction          • Reentrant PSVT
                                       velocity and ↑ refractory period
                                       (can fragment conduction
                                       and lead to reentry)

AV node                         Direct and vagal-mediated                • AV block (fi rst, second, or
                                       conduction block                              third degree)
                                    
AV junction                    Delayed afterdepolarizations             • Accelerated junctional rhythm
  (between AV node          (triggered activity), ↑ slope
    and His bundle)            of phase 4 depolarization
                                      (↑ automaticity)

Purkinje fibers and         Delayed afterdepolarizations              • Ventricular premature beats
ventricular muscle           (triggered activity), ↓ conduction
                                     velocity and ↑ refractory period
                                     (can lead to reentry)
                                   ↑ Slope of phase 4 depolarization        • Ventricular tachycardia
                                      (↑ automaticity)


Clinical Uses
     The most common use of digoxin historically has been as an inotropic agent to treat heart failure caused by decreased ventricular contractility. Digoxin increases the force of contraction and augments cardiac output, thereby improving left ventricular emptying, reducing left ventricular size, and decreasing the elevated ventricular filling pressures typical of patients with systolic dysfunction. It is not benefi cial in forms of heart failure associated with normal ventricular contractility (i.e., heart failure with preserved ejection fraction).
     Once the mainstay of therapy in congestive heart failure (CHF), the use of digitalis has waned in the face of newer. Nonetheless, digitalis continues to be useful in treating patients with CHF complicated by atrial fibrillation (it has the added benefit of slowing the ventricular heart rate), or when symptoms do not respond adequately to angiotensin-converting enzyme (ACE) inhibitors, B -blockers, and diuretics. Unlike ACE inhibitors and B-blockers, digoxin does not prolong the life expectancy of patients with chronic heart failure, though it may improve their quality of life.

     The second most common use of digoxin is as an antiarrhythmic agent in the treatment of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia (PSVT). In atrial fibrillation and flutter, digitalis reduces the number of impulses transmitted across the AV node, thereby slowing the ventricular rate. Digitalis may terminate reentrant supraventricular tachycardias, likely through enhancement of vagal tone, which slows impulse conduction, prolongs the effective refractory period,
and can therefore interrupt reentrant circuits that pass through the AV node.
     The use of digoxin as an antiarrhythmic has become less common because other agents such as B-blockers, calcium channel blockers (CCBs), and amiodarone are often more effective.

Pharmacokinetics and Toxicity
     Digoxin is excreted unchanged by the kidney. A series of loading doses is necessary to raise the drug’s concentration into the therapeutic range. If a loading dose is not given, the steady-state concentration is established in approximately 7 days. The maintenance dosage depends on the patient’s ability to excrete the drug (i.e., renal function).
     The potential for digitalis toxicity is significant because of a low toxic-to-therapeutic drug concentration ratio. Although many side effects are minor, life-threatening arrhythmias may result. Extracardiac signs of acute digitalis toxicity are often gastrointestinal (e.g., nausea, vomiting, anorexia), thought to be mediated by the action of digoxin on the area postrema of the brain stem. Cardiac toxicity includes several types of arrhythmias that may precede extracardiac warning symptoms. The most frequently encountered rhythm disturbance is the development of ventricular extrasystoles. As described above, various degrees of AV block may occur because of the
direct and vagal effects on AV nodal conduction. Digitalis toxicity is also a cause of nonreentrant
types of supraventricular tachycardia (i.e., those caused by enhanced automaticity or delayed afterdepolarizations).
     Many factors contribute to digitalis intoxication, the most common of which is hypokalemia, often caused by the concurrent administration of diuretics. Hypokalemia exacerbates digitalis toxicity because it further inhibits the Na+ K+ -ATPase pump. Other conditions that promote digitalis toxicity include hypomagnesemia and hypercalcemia. In addition, the concurrent administration of other
drugs (e.g., amiodarone) may raise the serum digoxin concentration by altering its clearance
or volume of distribution.
     The treatment of digitalis-induced tachyarrhythmias includes administration of potassium
(if hypokalemia is present) and often intravenous lidocaine (discussed later in the chapter). High-grade AV block may require temporary pacemaker therapy. In patients with severe intoxication, administration of digoxinspecific antibodies may be life saving.