Angiotensinconverting Enzyme Inhibitors

The relative ease of administration and superior efficacy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARB) have largely relegated hydralazine and nitrate therapy to second-line therapies for CHF. The demonstration of the survival benefit conferred by vasodilator therapy resulted in a paradigm shift in the approach to CHF. It was recognized that the way to improve survival in heart failure was not by directly addressing the weakened heart pump but rather by reversing the inappropriate peripheral vasoconstriction that results from neurohumoral activation.

Captopril (Capoten) was the original prototype product, and it was administered three times a day. A once-a-day preparation was subsequently patented and marketed. Prospective multicenter double-blind placebo-controlled clinical trials have repeatedly demonstrated an early and persistent survival benefit with ACE inhibitors in CHF patients. ACE inhibitors were found superior to hydralazine and nitrates in a direct comparison. ACE inhibitors are now clearly the agents of first choice in the pharmacological management of CHF. There are also a number of additional reasons to use ACE inhibitors. The HOPE trial and other studies demonstrated additional survival and renal protective benefits of ACE inhibition in diabetic and/or hypertensive patients long before they develop CHF.

Our understanding of the mechanism of action of ACE inhibitors has evolved along with our growing appreciation of the physiological and pathophysiological role of angiotensin II. Initially, angiotensin II was shown to be elaborated in response to low blood flow to the kidney in animal models of hypertension. Low flow to the kidney occurs when damage to the heart results in a low cardiac output. The low EF criterion for CHF noted previously is a noninvasively determined surrogate marker for a low cardiac output. The low flow to the kidney is perceived as bleeding. The appropriate response by the kidney to low flow is to elaborate renin. Renin circulates to the liver. Renin in the liver converts an-giotensinogen to angiotensin I. Angiotensin I travels to the lung, where it is converted to angiotensin II by ACE.

Angiotensin II binds to its receptor and increases in-tracellular ionized free calcium. This increase in intra-cellular ionized free calcium causes vasoconstriction by vascular smooth muscle cells, aldosterone secretion by adrenal glomerulosa cells, increased central sympathetic outflow, and enhanced thirst. This system is activated as part of the normal host response to stressful injury, such as bleeding or trauma. The systemic an-giotensin II levels rise acutely to retain fluid and improve short-term survival following injury. Unfortunately, these short-term adaptive mechanisms are not designed to protect against the long-term consequences of chronic low blood flow from CHF. The extraordinary success of ACE inhibitors in CHF clearly demonstrates the harmful effects of chronic angiotensin II activation.

Further refinement of this basic understanding followed. First of all, ACE inhibitors not only block the conversion of angiotensin I to angiotensin II; they also block the breakdown of bradykinin. Kinins are vasodilators and serve as part of the yin-yang of the vas cular system (i.e., vasoconstrictors vs. vasodilators). The use of an ACE inhibitor results in the elaboration of more kinins and less angiotensin II. Thus, the benefits of ACE inhibitors may derive from their elaboration of more kinins in addition to their inhibition of an-giotensin II formation.

Efforts to elucidate the mechanisms responsible for the pharmacological efficacy of ACE inhibitors have been further complicated by the discovery of alternative pathways for forming angiotensin II independent of the conversion of angiotensin I to angiotensin II. Other cellular enzymes, such as chymases and trypsin, can also elaborate angiotensin II. And finally, at least two distinct angiotensin II receptors have been cloned and se-quenced; they are confusingly named the type 1 and type 2 angiotensin II (AT-1;AT-2) receptors.

Elaboration of angiotensin II can result in either of two effects on an individual cell, depending on the relative numbers of AT-1 and AT-2 receptors. Relatively selective AT-1 receptor blockers have been developed in an effort to achieve superior efficacy with enhanced selectivity. Thus far, clinical studies indicate that ARBs may be as effective as ACE inhibitors and have fewer side effects. The consensus in their use is to try an ACE inhibitor as the first-line therapy before using an ARB, such as valsartan or losartan. However, ACE inhibitors can induce a very troubling cough in susceptible individuals as a result of the increase in kinins. ARBs serve as a very good substitute for such patients.

p-ADRENOCEPTOR BLOCKING DRUGS

For many years the prevailing view was that p-blockers are contraindicated in CHF. The physiological rationale for not using p-blockers in heart failure was certainly well founded. Heart failure patients have a decrease in cardiac output. Since cardiac output is a function of stroke volume times heart rate (CO = SV XHR), an increased heart rate would be necessary to maintain an adequate cardiac output in the presence of the relatively fixed decrease in stroke volume observed in CHF. A rapid increase in heart rate does play an important role in the physiological response to acute hemorrhage. Thus, a decrease in heart rate, along with a depression in contractility produced by p-blockers, would be expected to precipitate catastrophic decompensation; and this certainly can happen in the acute setting.

Several subsequent studies have led to the incorporation of p-blocker therapy, using either carvedilol or metoprolol, into the standard of care for CHF. Patients already taking digitalis, furosemide, and an ACE inhibitor were prescribed a p-blocker in these studies. Surprisingly, the long-term use of p-blockers in CHF improved ventricular function and prolonged survival. The assumption that an increased heart rate is neces sary to maintain an adequate cardiac output in the face of a reduced stroke volume is clearly not true in CHF.

The benefits of the use of p-blockade appear to exceed by far the risks of bronchospasm in patients diagnosed with chronic obstructive pulmonary disease (COPD) and/or suppression of hypoglycemic responses in diabetics. COPD is very different from bronchospas-tic asthma. Young people with asthma have highly reactive airways and can die within hours of a broncho-spasm in response to an exposure to an external agent. This highly reversible dynamic condition contrasts sharply with the destruction of connective tissue in lung parenchyma and dead airway sacs that are not very reactive. This is a very different phenomenon.

p-Blockers are adrenoceptor antagonists that bind to the p-receptor at the same site as do endogenous p-adrenergic agonists, such as norepinephrine. Norepinephrine binds to the adrenergic receptor, which activates a G protein, which participates in the conversion of ATP to cAMP via adenylyl cyclase. cAMP activates protein kinase A (protein kinase A, or PKA) to phosphory-late proteins, such as the sarcolemmal L-type Ca++ channel, that subsequently increase calcium, increase heart rate, conduction, and contraction. p-Blockers bind to the same receptor as does norepinephrine but do not facilitate G protein coupling. Occupation of the binding site by the p-blocker prevents norepinephrine from binding to it and stimulating cAMP formation.

Circulating plasma norepinephrine levels correlate inversely with survival in CHF; that is, higher levels of norepinephrine are associated with a decrease in survival. It appears that norepinephrine levels are more than just markers of disease severity: norepinephrine is actually directly toxic to cardiac myocytes, at least in culture. The addition of either an a- or p-blocker confers partial protection from norepinephrine damage. Combined a- and p-blockade confers additive protection. These data from animal studies may be relevant to human heart failure, since they suggest that both a- and p- adrenoceptor blockade may be beneficial in the man-

agement of CHF. This rationale favors the use of the combined nonselective p- and a-blocker carvedilol over the relatively selective pj-antagonist metoprolol. In addition, in CHF the number of preceptors decreases while the number of p2-receptors increases, and the ratio of pj- to p2-receptors changes. Thus, the pi-selectivity of metoprolol may not confer any advantage over the less specific p-blocker carvedilol. It is clear from clinical trial data that p-adrenoceptor blockers are not all the same. Use of some has produced improvements in survival, and others have produced no improvements at all. The mechanisms responsible for these benefits are not yet established. Speculation includes up-regulation of p-adrenoceptors, improved G-protein coupling, altered regulation of nitric oxide, and so on.

cAMP-ELEVATING AGENTS

The immediate effect of increasing intracellular cAMP levels is an increase in contractility. This has been observed repeatedly in acutely ill patients in the intensive care unit with the intravenous infusion of either p-adrenergic agonists (e.g., dobutamine) or the phosphodiesterase inhibitors milrinone (Corotrope) and am-rinone (Inocor). Binding of dobutamine to cardiac myocyte adrenoceptors results in G-protein coupling, activation of adenylyl cyclase, and the conversion of ATP to cAMP.

Administration of either milrinone or amrinone increases cAMP levels by preventing its degradation by cardiac myocyte phosphodiesterases. Both classes of cAMP-elevating agents have been shown to be helpful for the acute short-term management of the decompen-sated patient. Unfortunately, the long-term continuous use of either of these classes of agents in the outpatient setting has been associated with an increase in mortality in CHF. However, the use of these drugs in appropriately selected patients is highly effective for symptomatic relief.

^Study Questions

1. A 40-year-old man goes to the emergency department because of an intractable cough for the past few days. No one else in his household has any cough, fever, upper respiratory infection, and so on. He was released from the hospital a week ago with the diagnosis of idiopathic dilated cardiomyopathy following an extensive evaluation that revealed normal coronary anatomy and a left ventricular EF of 38%. He was discharged with prescriptions for digitalis, furosemide, captopril, and carvedilol. He has been more active and has noted improvement in his dyspnea and fatigue that prompted his initial presentation j0 days ago. He appreciates all of the care that he received and apologizes for making a fuss over the cough. He states that his wife made him come in because she was concerned that it might be his heart. He states that the cough is different from the congested feeling he had j0 days ago. On examination, he was afebrile; his heart rate was 60 beats per minute; blood pressure, 100/60. Neck veins were flat; carotid upstrokes were normal. Chest and lungs were clear. Heart revealed a regular rate and rhythm without murmurs, gallops, or rubs. Abdomen was soft and not tender. Bowel sounds were present without organomegaly. Extremities revealed no cyanosis, clubbing, or edema. Chest radiograph and electrocardiogram revealed no acute changes and no active disease. The physician was satisfied that he was hemodynamically stable and the cough was not resulting from worsening heart failure. What is a reasonable next step?

(A) Admit to the hospital to exclude (rule out) a myocardial infarction

(B) Apply a PPD skin test to exclude tuberculosis

(C) Substitute an angiotensin II receptor blocker for the ACE inhibitor

(D) Provide reassurance and continue with current medications

(E) Immediately stop the p-adrenergic blocker, carvedilol

2. A 67 year old woman has had fatigue and shortness of breath over the past few months. She has diabetes and hypertension for which she has been treated for 25 years with appropriate medications. She is status post three myocardial infarctions (MI X3) and has known inoperable coronary artery disease and CHF. She has been very compliant with her complicated medical regimen, which includes digitalis, an ACE inhibitor (fosinopril), loop diuretic (furosemide), p-adrenergic receptor blocker (carvedilol) and aldosterone antagonist (spironolactone). On examination she was noted to be in acute respiratory distress with a respiratory rate of 24, a heart rate of 60, and blood pressure of 110/60. She was anxious and uncomfortable but polite and cooperative. Neck veins were elevated to 8 cm with the patient partially supine. Lungs revealed rales to the angles of the scapulae bilaterally. Heart revealed a third heart sound and a high pitched holosystolic murmur at the apex consistent with mitral regurgitation. Abdomen was protuberant with a fluid shift consistent with as-cites. Extremities revealed 2 to 3 + pretibial pitting edema bilaterally. What can the physician offer this woman?

(A) Intravenous (cAMP elevating) positive in-otropic agents

(B) Vasodilator therapy with hydralazine

(C) a-Adrenergic blockade with prazosin

(D) Stop the diuretic, furosemide

(E) Stop the ACE inhibitor, fosinopril

3. Digitalis functions to improve congestive heart failure by

(A) Induction of emesis

(B) Activation of a-adrenergic receptors

(C) Improving survival in patients of heart failure

(D) Binding to and inhibiting the Na-K ATPase enzyme in cardiac myocytes

(E) Deactivation of the angiotensin receptor

4. The combination of hydralazine and nitrates has been shown to improve survival in patients of heart failure. All of the following statements about this combination are true except:

(A) The combination serves to decrease both after-load and preload.

(B) Prazosin is as effective as the combination in treatment of congestive heart failure.

(C) The concept of afterload reduction is principally derived from patients of significant mitral regurgitation.

(D) The VA cooperative study was a landmark trial demonstrating the beneficial effect of hydralazine and nitrate combination in patients of heart failure.

5. p-Blockers have been effective in the treatment of heart failure. They primarily exert their effect by

(A) Binding to the receptor that binds norepineph-rine

(B) Inducing a prominent diuretic effect

(C) Increasing contractility

(D) Improving asthma control

(E) Increasing heart rate to meet the additional demands placed upon the heart in CHF

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