Inhibitors of the Renin Angiotensin System ACE Inhibitors and ATj Receptor Antagonists

RENIN-ANGIOTENSIN SYSTEM ANTAGONISTS The renin-angiotensin system (Figure 33-1; see Chapter 30) plays a central role in the pathophysiology of heart failure. Angiotensinogen is cleaved by renin to form the decapeptide angiotensin I (AngI); ACE converts AngI to the octapeptide AngII. AngII is a potent arterial vasoconstrictor and an important mediator of Na+ and water retention through its effects on glomerular filtration pressure and aldosterone secretion. In addition, AngII potentiates neural catecholamine release, stimulates catecholamine release from the adrenal medulla, is arrhythmogenic, promotes vascular hyperplasia and pathologic myocardial hypertrophy, and stimulates myocyte death. Consequently, the antagonism of AngII is a cornerstone of heart failure management.

ACE inhibitors suppress AngII and aldosterone production, decrease sympathetic nervous system activity, and potentiate the effects of diuretics in heart failure. However, AngII levels frequently return to baseline values following chronic treatment with ACE inhibitors, due in part to production of AngII through ACE-independent enzymes such as chymase, a tissue protease. The sustained clinical effectiveness of ACE inhibitors despite AngII "escape" suggests that there are alternate mechanisms that contribute to the clinical effects of ACE inhibitors in heart failure. ACE also degrades bradykinin and other kinins that stimulate production of NO, cyclic GMP, and vasoactive eicosanoids; these vasodilator substances seem to oppose the effects of AngII on growth of vascular smooth muscle and cardiac fibroblasts and on extracellular matrix production. Thus, increased levels of bradykinin resulting from ACE inhibition may play a role in the hemodynamic and anti-remodeling effects of ACE inhibitors.

ACE inhibitors are more potent arterial than venous dilators. In response to ACE inhibition, mean arterial pressure (MAP) may decrease or be unchanged; the change in MAP will be determined by the stroke volume response to afterload reduction. Heart rate typically is unchanged, even when there is a decrease in systemic arterial pressure, a response that likely reflects a decrease in sympathetic tone in response to ACE inhibition. The decrease in left ventricular afterload results in increased stroke volume and cardiac output. Venodilation results in decreases in right and left heart filling pressures and end-diastolic volumes.

An alternative means of attenuating the hemodynamic and vascular impact of the renin-angiotensin system is through inhibition of angiotensin receptors. Most of the known clinical actions of AngII, including its deleterious effects in heart failure, are mediated through the AT1 angiotensin receptor. AT2 angiotensin receptors, also present throughout the cardiovascular system, seem to mediate responses that counterbalance the biological effects of AT1 receptor stimulation. Due to their more distal site of action, AT1 receptor antagonists may provide more potent reduction of the effects of AngII than do ACE inhibitors. Furthermore, AT1 receptor blockade may result in greater AT2 receptor activation, as AngII levels rise as a consequence of AT1 receptor blockade. Note that blockade of AT1 receptors does not alter bradykinin metabolism, which ACE inhibitors reduce.

Angiotensin-Converting Enzyme Inhibitors Six ACE inhibitors-captopril (capoten), enalapril (Vasotec), ramipril (altace), lisinopril (prinivil, zestril), quinapril (accupril), andfos-inopril (monopril)—are currently FDA-approved for the treatment of heart failure. Data from numerous clinical trials support the use of ACE inhibitors for the treatment of patients with heart failure of any severity, including patients with asymptomatic left ventricular dysfunction.

ACE-inhibitor therapy should be initiated at a low dose (e.g., 6.25 mg of captopril or 5 mg of lisinopril), as some patients may experience an abrupt drop in blood pressure, particularly in the setting of volume contraction. It is therefore reasonable to consider initiation of these drugs while congestive symptoms are present. ACE-inhibitor doses are customarily increased over several days in hospitalized patients or a few weeks in ambulatory patients, with careful observation of blood pressure, serum electrolytes, and serum creatinine.

There is no precisely defined relationship between dose and long-term clinical effectiveness of these drugs, but it is reasonable to use doses comparable to those used in studies that established efficacy in patients with heart failure. On this basis, target doses of these drugs would be 50 mg three times/day for captopril; 10 mg twice daily for enalapril; 10 mg once daily for lisinopril; or 5 mg twice daily for ramipril. In patients who have not achieved an adequate clinical response at these doses, further increases, as tolerated, may be of value; high-dose lisinopril (32.5 or 35 mg) reduced the combined endpoint of mortality and hospitalization when compared to lower doses of this agent.

In patients with heart failure and reduced renal blood flow, ACE inhibitors limit the kidney's ability to autoregulate glomerular perfusion pressure due to their selective effects on efferent arteriolar tone. If this occurs, the dose of ACE inhibitor should be reduced or another class of vasodilator added or substituted. Rarely, renal function deteriorates following initiation of therapy with an ACE inhibitor, often in patients with bilateral renal artery stenosis. Preferably, the renal artery stenosis should be treated; if this is not feasible, another class of vasodilator should be substituted. Angioedema secondary to ACE inhibition mandates immediate cessation of therapy. A small rise in serum K+ occurs frequently with ACE inhibitors; this rise can be substantial in patients with renal impairment or in diabetic patients with type IV renal tubular acidosis (hyporeninemic hypoaldosteronism). Mild hyperkalemia is best managed by institution of a low-potassium diet but may require dosage adjustment. A troublesome cough may occur that is likely related to the effects of bradykinin. Substitution of an AT l receptor antagonist often alleviates this problem. The inability to use ACE inhibitors as a consequence of cardiorenal side effects (e.g., excessive hypotension, progressive renal insufficiency, or hyperkalemia) is itself a marker of poor prognosis in CHF patients.

Myocardial infarction is the leading cause of heart failure due to systolic dysfunction in industrialized countries. ACE inhibitors prevent the development of clinically significant ventricular dysfunction and mortality following acute infarction, likely by preventing adverse ventricular remodeling. ACE inhibitors are proven effective in specific patient subgroups, including women, African Americans, and the elderly.

ATj Receptor Antagonists Activation of the ATj receptor mediates most of the deleterious effects of AngII. The receptor blockade provided by ATj antagonists provides a pharmacologic means by which to reduce the AngII "escape" that occurs with ACE inhibitors. ATj receptor antagonism might also be expected to avoid the bradykinin-mediated side effects of ACE inhibition, principally cough. This side effect, which occurs in >10% of patients, represents an important limitation to the use of ACE inhibitors in clinical practice. Angioedema has been reported with ATJ receptor antagonists; caution is therefore warranted when prescribing these agents to patients with a history of ACE inhibitor-associated angioedema. AT1 receptor antagonists provide an alternative to ACE inhibitors in the treatment of heart failure and provide comparable mortality benefits.

The combined use of ACE inhibitors and ARBs in the treatment of heart failure offers the intriguing possibility of additive therapeutic benefit by virtue of distinctive modes of angiotensin antagonism. Some experts suggest that the addition of an ATl blocker to a heart failure regimen that includes an ACE inhibitor can be considered in an effort to reduce hospitalizations. ATl antagonists also appear to reduce hospitalization in patients with diastolic heart failure.

NITROVASODILATORS Nitrovasodilators have long been used to treat heart failure and remain among the most widely used vasoactive medications. These drugs relax vascular smooth muscle by supplying NO and thereby activating soluble guanylyl cyclase. Thus, they mimic the actions of endogenous NO, an intracellular and paracrine autocoid synthesized from arginine by NO synthases in endothelial and smooth muscle cells throughout the vasculature.

Organic Nitrates Organic nitrates are available in a number of formulations that include rapid-acting nitroglycerin tablets or spray for sublingual administration, short-acting oral agents such as isosorbide dinitrate (isordil, sorbitrate, others), long-acting oral agents such as isosorbide mononitrate (imdur), topical preparations such as nitroglycerin ointment and transdermal patches, and intravenous nitroglycerin. The nitrates are relatively safe and effective agents whose principal action in the treatment of congestive heart failure is reduction of left ventricular filling pressures. This preload reduction is due to an increase in peripheral venous capacitance. Nitrates will cause a decline in pulmonary and systemic vascular resistance, particularly at higher doses, although this response is less marked and less predictable than with nitroprusside. These drugs have a selective vasodilator effect on the epicardial coronary vasculature and may enhance both systolic and dias-tolic ventricular function by increasing coronary flow.

Isosorbide dinitrate when administered to patients with CHF is more effective than placebo in improving exercise capacity and reducing symptoms. However, the limited effects of these agents on the systemic vascular resistance and the development of tolerance limit the utility of organic nitrates as monotherapy in the treatment of CHF. An isosorbide dinitrate—hydralazine combination was proven effective in reducing overall mortality in patients with mild-to-moderate heart failure concurrently treated with digoxin and diuretics. The mononitrate formulation has not been studied in chronic heart failure; the transdermal formulations are infrequently used in the treatment of CHF, reflecting concerns related to perfusion-dependent drug absorption in such patients.

Tolerance can limit the long-term effectiveness of nitrates in the treatment of CHF. Blood levels of these drugs should be permitted to fall to negligible levels for at least 6-8 hours each day, which can be adjusted to the patient's symptoms. Patients with recurrent orthopnea or paroxysmal nocturnal dyspnea, for example, would likely benefit most by using nitrates at night. N-acetylcysteine (mucomyst) may diminish tolerance to the hemodynamic effects of nitrates in heart failure. Likewise, hydralazine may decrease nitrate tolerance by an antioxidant effect that attenuates superoxide formation, thereby increasing NO bioavailability.

HYDRALAZINE Hydralazine (apresoline) is an effective antihypertensive drug (see Chapter 32), particularly when combined with agents that blunt compensatory increases in sympathetic tone and salt and water retention. In heart failure, hydralazine reduces right and left ventricular afterload by reducing pulmonary and systemic vascular resistance. This augments forward stroke volume and reduces ventricular systolic wall stress. Hydralazine also appears to have moderate "direct" positive inotropic activity in cardiac muscle unrelated to afterload reduction. Hydralazine is effective in reducing renal vascular resistance and in increasing renal blood flow to a greater degree than are most other vasodilators, with the exception of ACE inhibitors. Reflecting these aggregate effects, hydralazine may be useful in heart-failure patients with renal dysfunction who cannot tolerate an ACE inhibitor. Hydralazine has minimal effects on venous capacitance and therefore is most effective when combined with agents with venodilating activity (e.g., organic nitrates).

The combination of hydralazine (300 mg/day) and isosorbide dinitrate increased survival when compared to placebo or the a1 adrenergic antagonist prazosin. Hydralazine, with or without nitrates, may provide additional hemodynamic improvement for patients with advanced heart failure who already are being treated with conventional doses of an ACE inhibitor, digoxin, and diuretics. A combination of isosorbide dinitrate—hydralazine (bidil) was most recently investigated in African Americans; when added to standard therapy that included neurohumoral blockade in patients with NYHA Class III or IV heart failure there was a significant reduction in all-cause mortality compared to placebo. This combination preparation is FDA-approved as adjunct to standard therapy for use in CHF patients self-identified as African American. It is the first race-based drug approved by the FDA.

Several important limitations constrain the use of hydralazine in the treatment of CHF. Although hydralazine therapy was associated with a greater increase in ejection fraction and exercise duration when compared to the ACE inhibitor enalapril, the latter was superior with respect to reduction of mortality. Side effects that may necessitate dose adjustment or withdrawal of hydralazine are common. The lupus-like side effects associated with hydralazine are relatively uncommon and may be more likely to occur in patients with the "slow-acetylator" phenotype (see Chapter 3). Finally, compliance with the multidosing regimen may be difficult in CHF patients who often are taking multiple concurrent medications.

The oral bioavailability and pharmacokinetics of hydralazine are not altered significantly by heart failure unless there is severe hepatic congestion or hypoperfusion. Intravenous hydralazine provides little practical advantage over oral formulations except for urgent use during pregnancy, a state in which relative or absolute contraindications exist for most other vasodilators.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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