Angiotensin Converting Enzyme (ACE) Inhibitors
ACE inhibitors produce vasodilation by inhibiting the formation of angiotensin II. This vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on circulating angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme.
ACE also breaks down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors. The increase in bradykinin is also believed to be responsible for a troublesome side effect of ACE inhibitors, namely, a dry cough.
Angiotensin II constricts arteries and veins by binding to AT1 receptors located on the smooth muscle, which are coupled to a Gq-protein and the the IP3 signal transduction pathway. Angiotensin II also facilitates the release of norepinephrine from sympathetic adrenergic nerves and inhibits norepinephrine reuptake by these nerves. This effect of angiotensin II augments sympathetic activity on the heart and blood vessels.
Cardiorenal Effects of ACE Inhibitors
- Vasodilation (arterial & venous)
- reduce arterial & venous pressure
- reduce ventricular afterload & preload
- Decrease blood volume
- Depress sympathetic activity
- Inhibit cardiac and vascular hypertrophy
ACE inhibitors have the following actions:
- Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload and afterload on the heart.
- Down regulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine.
- Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney and by blocking angiotensin II stimulation of aldosterone secretion. This reduces blood volume, venous pressure and arterial pressure.
- Inhibit cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction.
Elevated plasma renin is not required for the actions of ACE inhibitors, although ACE inhibitors are more efficacious when circulating levels of renin are elevated. We know that renin-angiotensin system is found in many tissues, including heart, brain, vascular and renal tissues. Therefore, ACE inhibitors may act at these sites in addition to blocking the conversion of angiotensin in the circulating plasma.
Therapeutic Use of
- Heart failure
- Post-myocardial infarction
ACE inhibitors are effective in the treatment of primary hypertension and hypertension caused by renal artery stenosis, which causes renin-dependent hypertension owing to the increased release of renin by the kidneys. Reducing angiotensin II formation leads to arterial and venous dilation, which reduces arterial and venous pressures. By reducing the effects of angiotensin II on the kidney, ACE inhibitors cause natriuresis and diuresis, which decreases blood volume and cardiac output, thereby lowering arterial pressure.
Some of the older literature indicated that ACE inhibitors (and angiotensin receptor blockers, ARBs) were less efficacious in African American hypertensive patients, which unfortunately led to lower utilization of these important, beneficial drugs in African Americans. While it is true that African Americans do not respond as well as other races to monotherapy with ACE inhibitors or ARBs, the differences are eliminated with adequate diuretic dosing. Therefore, current recommendations from the JNC 7 report are that ACE inhibitors and ARBs are appropriate for use in African Americans, with the recommendation of adequate diuretic dosing to achieve the target blood pressure.
ACE inhibitors have proven to be very effective in the treatment of heart failure caused by systolic dysfunction (e.g., dilated cardiomyopathy). Beneficial effects of ACE inhibition in heart failure include:
- Reduced afterload, which enhances ventricular stroke volume and improves ejection fraction.
- Reduced preload, which decreases pulmonary and systemic congestion and edema.
- Reduced sympathetic activation, which has been shown to be deleterious in heart failure.
- Improving the oxygen supply/demand ratio primarily by decreasing demand through the reductions in afterload and preload.
- Prevents angiotensin II from triggering deleterious cardiac remodeling.
Finally, ACE inhibitors have been shown to be effective in patients following myocardial infarction because they help to reduce deleterious remodeling that occurs post-infarction.
ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart failure.
The first ACE inhibitor marketed, captopril, is still in widespread use today. Although newer ACE inhibitors differ from captopril in terms of pharmacokinetics and metabolism, all the ACE inhibitors have similar overall effects on blocking the formation of angiotensin II. ACE inhibitors include the following specific drugs: (Go to www.rxlist.com for specific drug information)
Note that each of the ACE inhibitors named above end with "pril."
Side Effects and Contraindications
As a drug class, ACE inhibitors have a relatively low incidence of side effects and are well-tolerated. A common, annoying side effect of ACE inhibitors is a dry cough appearing in about 10% of patients. It appears to be related to the elevation in bradykinin. Hypotension can also be a problem, especially in heart failure patients. Angioedema (life-threatening airway swelling and obstruction; 0.1-0.2% of patients) and hyperkalemia (occurs because aldosterone formation is reduced) are also adverse effects of ACE inhibition. The incidence of angioedema is 2 to 4-times higher in African Americans compared to Caucasians. ACE inhibitors are contraindicated in pregnancy.
Patients with bilateral renal artery stenosis may experience renal failure if ACE inhibitors are administered. The reason is that the elevated circulating and intrarenal angiotensin II in this condition constricts the efferent arteriole more than the afferent arteriole within the kidney, which helps to maintain glomerular capillary pressure and filtration. Removing this constriction by blocking circulating and intrarenal angiotensin II formation can cause an abrupt fall in glomerular filtration rate. This is not generally a problem with unilateral renal artery stenosis because the unaffected kidney can usually maintain sufficient filtration after ACE inhibition; however, with bilateral renal artery stenosis it is especially important to ensure that renal function is not compromised.