Angiotensin-converting enzyme inhibitors
Pharmacology and mechanisms of action
The renin–angiotensin system plays a major role in the regulation of blood pressure and extracellular fluid volume. Angiotensin-converting enzyme (Angiotensin-converting enzyme) inhibitors are a major group of drugs available to inhibit this system. Table Angiotensin Converting Enzyme Inhibitors lists some currently available Angiotensin-converting enzyme inhibitors. Although pharmacologic differences among these drugs are often emphasized, the clinical relevance of these distinctions is not obvious.
A number of actions of Angiotensin-converting enzyme inhibitors potentially contribute to their antihypertensive effects. The enzyme Angiotensin-converting enzyme is a kininase responsible for the conversion of angiotensin I to angiotensin II, a potent endogenous octapeptide that causes arterial smooth muscle contraction. As a consequence, inhibition of this conversion may lead to vasodilation. Angiotensin II stimulates the secretion of aldosterone from the adrenal cortex, leading to increased sodium retention and potassium excretion by the kidney. Inhibition of this action may lead to a decrease in plasma volume. Inhibiting aldosterone secretion by an Angiotensin-converting enzyme inhibitor may enhance the action and antagonize fluid retention that may occur with other classes of vasodilating drugs. In addition, angiotensin II may facilitate the release of norepinephrine from sympathetic nerve endings; Angiotensin-converting enzyme inhibitors may attenuate the contribution of the sympathetic nervous system to increased peripheral resistance.
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Angiotensin-converting enzyme is also the enzyme responsible for metabolizing and inactivating the vasodilator bradykinin and related kinins. As a consequence, Angiotensin-converting enzyme inhibitors tend to enhance accumulation of vasodilating substances that may contribute to their antihypertensive actions. Different mechanisms of the Angiotensin-converting enzyme inhibitors effects may contribute to efficacy at different times over the course of therapy with this class of drugs. For example, the degree of blood pressure reduction may or may not correlate well with the degree of inhibition of plasma Angiotensin-converting enzyme. As with the β-adrenergic antagonists, labeling of a drug class by mechanism does not necessarily define all its important pharmacologic actions.
Angiotensin II has the capacity to activate a variety of biochemical pathways that enhance cell growth. This is potentially particularly important for the cardiac hypertrophy and vascular remodeling that occur in many patients with hypertension. Angiotensin-converting enzyme inhibitors can prevent or reverse cardiac hypertrophic changes in hypertensive animals and humans, although most other antihypertensive drugs have efficacy in reducing hypertrophy as well.
Captopril, a sulfhydryl-containing compound, was the first Angiotensin-converting enzyme inhibitor approved for treating hypertension. Other Angiotensin-converting enzyme inhibitors lacking the sulfhydryl group became available several years later. Enalapril is an inactive pro-drug that must be converted by the liver to enalaprilat, the active Angiotensin-converting enzyme inhibitor. Lisinopril is an active lysine derivative of enalaprilat. Many additional Angiotensin-converting enzyme inhibitors have subsequently became available.
Angiotensin-converting enzyme inhibitors are typically well absorbed after oral administration. Food decreases the absorption of captopril by 30% but has no effect on absorption of enalapril. Captopril begins its antihypertensive effects within 30 minutes, and the effects of lisinopril begin within 90 minutes of ingestion. The required conversion of enalapril to enalaprilat in the liver results in its slow accumulation and a delayed peak effect. Elimination of Angiotensin-converting enzyme inhibitors is prolonged in patients with advanced renal failure. Although many Angiotensin-converting enzyme inhibitors are labeled for use once daily, for a substantial number of patients, especially patients receiving relatively low doses, the antihypertensive effects may not last 24 hours. For these patients, the chosen Angiotensin-converting enzyme inhibitor should probably be administered twice daily.
Clinical use and adverse effects of Angiotensin-converting enzyme inhibitors
As with most other within-class comparisons, Angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, lisinopril) have similar capacities to decrease elevated blood pressure, in the order of 10–15/5–12 mm Hg. These agents, like a number of antihypertensives — particularly diuretics — have relatively steep dose–response curves at low doses, with plateauing of the dose–response curve at higher doses.
Principles
For drugs with easily measured effects (e.g., blood pressure), the physician may adjust dose based on the patient’s actual response to the drug, rather than relying solely on the drug’s labeling.
The Angiotensin-converting enzyme inhibitors used as monotherapy have efficacy similar to many other classes of antihypertensives used as monotherapy. Addition of a diuretic to an Angiotensin-converting enzyme inhibitor appears to have synergistic effects in lowering blood pressure. This attractive interaction may be due in part to the capacity of Angiotensin-converting enzyme inhibitors to antagonize the effects of activation of the renin-angiotensin system typically found in patients receiving a diuretic alone. In addition, hypokalemia caused by diuretics is opposed by combination of the diuretic with an Angiotensin-converting enzyme inhibitor because of inhibition of aldosterone secretion.
Angiotensin-converting enzyme inhibitors are effective as antihypertensive agents in about 60–70% of patients. The magnitude of the decrease in blood pressure is proportional to the pretreatment values. Clinical trials have shown that the antihypertensive effects are secondary to a decrease in peripheral vascular resistance with little change in cardiac output and no reflex tachycardia. Angiotensin-converting enzyme inhibitors reduce overall renal vascular resistance and can increase renal blood flow. Indeed, the capacity of Angiotensin-converting enzyme inhibitors to lower glomerular pressure, possibly owing to preferentially dilating glomerular efferent arterioles, has suggested that these drugs may be especially efficacious in preserving renal function in hypertensive patients with nephropathy, especially type I diabetics. Patients with renovascular hypertension may respond very well to Angiotensin-converting enzyme inhibitors, but there are caveats in these patients. These agents are useful in treating severe hypertension, for example, as a vasodilator third-drug therapy added to a regimen of β-adrenergic antagonists and diuretics.
Excessive declines in blood pressure even leading to severe orthostatic hypotension can occur, especially when patients are volume-depleted or taking diuretics. In these settings, angiotensin II may be playing a particularly large role in maintaining blood pressure. In patients at risk, Angiotensin-converting enzyme inhibition should be initiated cautiously and with particularly low starting doses (e.g., 2.5 mg lisinopril, 6.25 mg captopril). Skin rashes, disturbance of taste, and mucosal lesions are more common with captopril than with other Angiotensin-converting enzyme inhibitors; these adverse effects may be related to its sulfhydryl moiety or to the rather large doses used in early trials. Probably the most common adverse effect of Angiotensin-converting enzyme inhibitors is dry cough that occurs in about 10% of patients and is severe in 1–3% of patients. The mechanism is unclear but may relate to the accumulation of peptide mediators that can enhance the cough reflex. Cough may be dose-dependent and is fully reversible with discontinuation of the drug. On the other hand, cough is an unusual adverse effect in patients receiving angiotensin II receptor antagonists.
Early reports of neutropenia and proteinuria with captopril appeared when patients were taking very high doses and had other diseases such as renal failure and connective tissue disease (with associated cytotoxic drug treatments) that may have predisposed them to the toxic effects. These adverse effects are rare. Angioneurotic edema, which can occur with all Angiotensin-converting enzyme inhibitors, can be life-threatening and is observed in less than 0.1% of patients. The risk of angioneurotic edema probably is higher in patients in whom drug administration is continued despite the development of mouth ulcers or skin rash.
Because Angiotensin-converting enzyme inhibitors decrease aldosterone concentrations, hyperkalemia may result, but it is rarely encountered in patients with normal renal function. Caution should be exercised in administrating Angiotensin-converting enzyme inhibitors to patients with renal impairment, type 4 renal tubular acidosis (hyporeninemic hypoaldosteronism) as is seen in diabetic patients, and in combination with potassium-sparing diuretics or potassium supplementation. Angiotensin-converting enzyme inhibitors should not be used during pregnancy because of the high risk of renal developmental anomalies.
The Angiotensin-converting enzyme inhibitors can exacerbate renal insufficiency in patients with renal vascular stenosis. This complication deserves scrutiny. With decreased renal blood flow during renal artery narrowing, preferential vasodilatation of the glomerular afferent arteriole occurs in order to reduce resistance to blood flow, while tending to preserve glomerular pressure. This adaptation is associated with angiotensin II–induced vasoconstriction of the efferent arteriole. Although this increases postglomerular resistance to blood flow, it increases hydrostatic pressure in the glomerulus and favors glomerular filtration at any perfusion pressure. In this setting of decreased renal blood flow, the filtration fraction is increased, tending to preserve glomerular filtration. Interruption of this compensatory mechanism with an Angiotensin-converting enzyme inhibitor can lead to a decrease in glomerular filtration rate in the underperfused kidney. In fact, this phenomenon has been exploited with the use of captopril during isotopic renography.
The drug exaggerates a difference between the normal (non-angiotensin II–dependent) and renal arterial stenotic (angiotensin II–dependent) kidney. The normal kidney in a patient with unilateral renovascular hypertension can compensate for the effects of Angiotensin-converting enzyme inhibition by increasing glomerular filtration rate and keeping serum creatinine concentrations constant. However, when both kidneys are underperfused or when there is a solitary kidney with a stenotic artery, loss of this compensating mechanism leads to rapid reversible rises in serum creatinine concentration. Administration of an Angiotensin-converting enzyme inhibitor in any clinical setting of decreased renal perfusion has the potential for worsening the insufficiency.
On the other hand, as indicated above, the effect of Angiotensin-converting enzyme inhibitors on postglomerular resistance has a potential long-term advantage in patients with diabetic glomerulopathy. Inhibition of postglomerular tone reduces the transglomerular capillary hydraulic pressure gradient that is thought to play a role in development of glomerular basement membrane damage and subsequent diabetic glomerulosclerosis.
Principles
Understanding the pharmacology of new drugs may lead to new diagnostic or therapeutic hypotheses and uses. The actual value and place of these new, potential indications must be established in clinical studies.
Recommendations
Angiotensin-converting enzyme inhibitors are valuable as effective and reasonably safe antihypertensive agents. Their adverse effects are generally predictable, avoidable, or reversible. Angiotensin-converting enzyme inhibitors may be considered as first-line therapy, especially for patients in whom diuretics and/or β-adrenergic antagonists are contraindicated. They are especially useful when combined with diuretics. Of course, using Angiotensin-converting enzyme inhibitors to treat patients with heart failure and hypertension exploits the two-for-one principle. Because of their additive effects with other agents, they are also useful in treating severe hypertension and as third-drug vasodilator in combined regimens.
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