American Family Physician - Using ACE inhibitors appropriately - Clinical Pharmacology
Cardiovascular disease affects one in four Americans. According to the American Heart Association, heart and related diseases are expected to cost Americans more than $329 billion in 2002. An estimated 10 million persons in this country are known to have diabetes and 3.6 million to have renal disease, incurring annual health care costs of $98 billion and $11 billion, respectively. Although angiotensin-converting enzyme (ACE) inhibitors have documented clinical benefits in a variety of clinical situations, the disparity between the evidence from clinical trials and bedside medicine is well documented.
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The National Registry of Myocardial Infarction 2 found that fewer than one half of patients surviving acute myocardial infarction who were candidates for therapy with ACE inhibitors received these life-saving drugs at discharge. (1) A recent review of patients with asymptomatic left ventricular dysfunction revealed an underuse of ACE inhibition (48 percent of eligible candidates) and a greater likelihood of being started on an ACE inhibitor if under the care of a cardiologist rather than a noncardiologist. (2) In 2000, Bahit and colleagues (3) reviewed actual versus ideal prescribing of drugs for secondary prevention after myocardial infarction and estimated that 30,600 lives would be saved annually by offering ACE inhibitors.
Renin-Angiotensin System
The renin-angiotensin system is systemically and locally driven. The systemic process is triggered by the kidney’s response to decreased effective blood volume and begins with the secretion of renin from the renal cortex. Once released, renin cleaves angiotensinogen to form angiotensin I. This product, in turn, is catalyzed by angiotensin-converting enzyme, formed primarily in the pulmonary vasculature, into angiotensin II. This potent vasoconstrictor affects tissues and systems throughout the body; research shows that these vasoconstrictor effects are attenuated by ACE inhibition (Table 1). (4,5)
Local renin-angiotensin systems exist in all vascular endothelium. Vascular cells maintain local vasomotor tone homeostasis primarily through the elaboration of angiotensin II and nitric oxide, a potent vasodilator. If this mechanism becomes impaired by oxidative stress, the endothelium can no longer maintain vasomotor tone in response to local needs. This phenomenon, termed endothelial dysfunction, precedes and contributes to atherosclerosis. (6) ACE inhibition attenuates endothelial dysfunction by decreasing the destruction of bradykinin, thereby enhancing production of nitric oxide. (5,7)
Clinical investigations support the benefits of ACE inhibition. The results of the Trial on Reversing ENdothelial Dysfunction (TREND) showed improved coronary blood flow with the administration of quinapril. (8) The Heart Outcomes Prevention Evaluation (HOPE) and the Microalbuminuria Cardiovascular and Renal Outcomes-HOPE (MICRO-HOPE) trials have provided evidence of reduced mortality rates, myocardial infarction, stroke, and overt nephropathy with the use of ramipril. (9,10)
Ace Inhibitors: Formulations
Ten ACE inhibitors presently approved for use in the United States work by competitive inhibition of angiotensin-converting enzymes. Captopril (Capoten) and enalapril (Vasotec) are off-patent, which makes them more economical. Enalapril is the only one available in intravenous form, which is called enalaprilat (Vasotec-IV). Drug formularies may dictate which ACE inhibitor a physician is able to prescribe because they are thought to be interchangeable. If a choice is possible, physicians should use those agents that have been proved by clinical trials to reduce morbidity and mortality for the condition being treated and work toward target dosages or clinical end points (Table 2). (11)
Initiating Treatment: Considerations
RENAL INSUFFICIENCY
In patients with renal insufficiency, no creatinine level is an absolute contraindication to ACE inhibitor therapy. ACE inhibitors are not nephrotoxic. Baseline serum creatinine levels of up to 3.0 mg per dL (27 [micro]mol per L) are generally considered safe. The manufacturers make recommendations for initiating treatment and suggest titrating the dosage slowly. An increase of 20 percent in the serum creatinine level is not uncommon and is not a cause for discontinuing the medication. For any higher increase, the family physician should consider a nephrologist. During the first four weeks of treatment, serum potassium and creatinine levels should be monitored closely.
HYPOTENSION
Hypotension can occur in patients with volume depletion or hyponatremia (sodium
