Therapeutic Overview

For an overview of the disorders indicative of treatment with ACEIs and ARBs, see the respective chapters (Table 22-1).

Mechanism of Action

Two types of angiotensin receptors have been identified: AT₁ and AT₂. Most of the biologic effects of angiotensin II are mediated by the AT₁ receptor. AT₂ receptors may exert antiproliferative and vasodilatory effects. ACEIs block angiotensin-converting enzyme (ACE), which is responsible for the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and is a stimulus for aldosterone release from the adrenal glands (Figure 22-1). Reduction in aldosterone secretion results in less water absorption and sodium/potassium exchange in the distal renal tubule, causing a slight increase in serum potassium.

ACEIs inhibit the breakdown of bradykinin, a potent and naturally occurring vasodilator, by blocking the enzyme kininase II. This is thought to be the cause of the cough commonly experienced by patients who take this class of drugs.

ARBs block the effects of angiotensin II by blocking the binding of angiotensin II to its receptors. They do not affect bradykinin (Figure 22-2). Receptor affinity is highest by candesartan > irbesartan > eprosartan > telmisartan> valsartan > losartan.

ARBs differ from ACEIs in the following four respects:

Whether these differences translate to significant clinical outcomes is unknown.

The pharmacologic effects of ACE inhibition produce a reduction in systemic vascular resistance, with no effect or a moderate increase in cardiac output. Blood pressure is lowered through decreased systemic vascular resistance. Blood pressure reduction is not accompanied by changes in heart rate. Renal perfusion is increased and renal vascular resistance is decreased, but the glomerular filtration rate is usually unchanged. In patients with heart failure syndrome, ACEIs significantly decrease preload by reducing sodium and water retention (through reduction of aldosterone secretion) and reduce afterload through their effects on angiotensin II (decreasing systemic vascular resistance). This causes a modest increase in ejection fraction and a decrease in ventricular end-diastolic pressure and volume. These in turn improve myocardial energy metabolism. ACEIs also act on the renal vasculature to reduce arteriolar resistance, which improves renal hemodynamics. This may improve the course of patients with diabetic nephropathy and other renal diseases with glomerular hypertension. The ACE escape phenomenon may be seen in some patients when alternate enzyme pathways are used for formation of angiotensin II, thus increasing the benefit of ARBs.

Treatment Principles

For information on standardized treatment guidelines, for evidence supporting these guidelines, and for information on nonpharmacologic treatment for patients with hypertension, MI, chronic heart failure, and diabetic nephropathy, see the related chapters: Chapters 17, 18, 19, and 53. In this chapter, only pharmacologic treatment with ACEIs and ARBs is discussed.

ACEIs have similar therapeutic and adverse reactions. They differ basically in terms of pharmacokinetics (Table 22-2). Some are provided as prodrugs that must be metabolized by the liver to the active drug. The duration of hypotensive effects is critical. Many products claim that they provide 24-hour protection, but their effects may wear off within 24 hours. Blood pressure (BP) should be checked shortly before the time of administration to ensure 24-hour BP control. These agents differ in terms of tissue distribution, and this may result in differences in the renin-angiotensin systems affected. Except for fosinopril, these agents are cleared predominantly by the kidney. ACEIs generally are considered safe and effective in patients with mild to moderate renal impairment; however, dosage reduction is required in patients whose renal clearance is diminished. Fosinopril, lisinopril, and ramipril are eliminated by both hepatic and renal mechanisms, and they have the ability to compensate for renal dysfunction by shifting to hepatic elimination. Dehydration and renal insufficiency increase the risk of elevated K when an ACEI is started.

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