Prehospital Pharmacology: ACE Inhibitors

Vasotec (enalapril), Altace (ramipril), Capoten (captopril) and Cozaar (losartan potassium) are commonly prescribed medications. The first three belong to a class of drugs called ACE inhibitors. ACE stands for angiotensin-converting enzyme. Cozaar belongs to a relatively new class of drugs known as angiotensin 2 receptor blockers, or ARBs. Together, ACE inhibitors and angiotensin receptor blockers (ARB) are known as a renin-angiotensin system (RAS). Their use has been hailed as one of the most successful therapeutic interventions in medicine.1 Therapy using these drugs results in reduced blood pressure and left ventricular hypertrophy, and reduces protein in the urine, often associated with kidney failure.2-4 Use of these drugs results in decreased death among CHF patients and in patients after myocardial infarction.5,6 These drugs also prevent the progression of renal insufficiency in patients with both type I and type II diabetes.7 Interestingly, a high dose of an ACE inhibitor in the evening reduces the overall risk of death, cardiovascular events and stroke in a high-risk population.8 With such impressive credentials, EMS providers should develop a closer understanding of these drugs, their usage and effects.

How Ace Inhibitors Work
     As blood flows through the body, it flows through the kidney. One part of the kidney is called the macula densa. Within the macula densa is a structure called the juxtaglomerular apparatus, or JGA. The JGA senses the pressure of the blood coming through it. If it senses the pressure is too low, it takes measures to correct this perceived hypotension. Blood pressure needs to be maintained in the kidneys to filter out toxins and ions. Without adequate blood pressure, the kidneys cannot filter the blood, the kidneys "fail" and toxins back up.

     When the JGA senses low blood pressure, it causes the secretion of a substance called renin. Renin circulates in the blood and combines with another substance called angiotensinogen. Angiotensinogen is always circulating in the blood and is benign in the absence of renin. Renin turns angiotensinogen into its active form, angiotensin 1. Angiotensin 1 has no known effects on the body until it circulates through the lungs' vascular supply. There, it meets ACE (angiotensin-converting enzyme). ACE is chiefly secreted by lung tissue. ACE converts angiotensin 1 into angiotensin 2. Angiotensin 2 has a multitude of effects that increase blood pressure (see Figure 1).

     Remember, this is the body's protective mechanism to save your life, as your body thinks you are bleeding to death.

     Angiotensin 2 stimulates the secretion of aldosterone. This hormone causes the kidney to hold as much sodium as possible in the bloodstream. Where salt goes, water follows. This increase in vascular water helps to increase blood pressure. Angiotensin 2 stimulates the secretion of the antidiuretic hormone (ADH), which reduces the amount of fluid passed from the blood into urine. Angiotensin 2 also stimulates the brain's thirst center, and causes dilation of the left ventricle.

     All of these processes work quite well to increase your blood pressure. One problem-you are not bleeding to death and you do not have low blood pressure! The JGA has mistakenly sensed low blood pressure, and caused the secretion of renin and the entire cascade of reactions that followed. ACE inhibitors prevent the secretion of ACE, thereby preventing angiotensin 1 from becoming angiotensin 2. Since the bad effects are only caused by angiotensin 2, this step succinctly prevents the hypertensive effects of A-2.

     Cozaar (losartan potassium) and Diovan (valsartan) are examples of angiotensin 2 receptor blockers, or ARBs. These drugs have roughly the same effects as ACE inhibitors, but by a different mechanism. Instead of inhibiting the enzyme ACE, these ARBs act on the cells that are sensitive to angiotensin 2 and block the effects after angiotensin 2 has already been created. A common side effect of ACE inhibitors is a dry cough.9 ARBs do not produce this side effect and may be used to replace ACE inhibitors in patients complaining of a cough.

     A recent study in the New England Journal of Medicine identified ARBs as preventing people with prehypertension from developing hypertension.10 People who have blood pressures higher than normal but less than what is considered hypertension have prehypertension. Prehypertension is defined as systolic blood pressure in the range of 120 to 139 mm Hg and diastolic blood pressure of 80-89 mm Hg. Some 70 million Americans have the condition. Like people with hypertension, people with prehypertension are at an elevated risk for heart disease. They will also typically go on to develop hypertension. All participants in the study had prehypertension.

     RAS blockers are an important weapon in the arsenal used against hypertension and cardiovascular disease. One can only predict that their usage will become as common as aspirin, furosemide and beta-blockers.

References

1. Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists.Circulation 109(21):2492-9, 2004.
2. Neal B, MacMahon S, Chapman N. Blood pressure lowering treatment trialists' collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Lancet 356(9246):1955-64, 2000.
3. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients. A metaanalysis of 109 treatment studies. Am J Hypertens (2):95-110, 1992.
4. Marre M, Chatellier G, Leblanc H, et al. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ 297(6656):1092-5, 1988.
5. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: A systematic overview of data from individual patients. Lancet 355(9215):1575-81, 2000.
6. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomised trial. Lancet 360(9335):752-60, 2002.
7. Agodoa LY, et al. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. JAMA. 285(21):2719-28, 2001.
8. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342(3):145-53, 2000.
9. Nishizawa A. Angiotensin-Converting Enzyme Inhibitor Induced Cough Among Asians. www.med.ucla.edu/modules/wfsection/article.php?articleid=135.
10. Gardner A. Blood Pressure Drugs Keep Hypertension in Check. www.healthscout.com/news/1/531542_3/main.html.

Rob Curran has been an EMT in New York City for more than 12 years. He is also a Doctor of Chiropractic, specializing in sports rehabilitation, with an office in Brooklyn, NY. He can be contacted through www.healingtouchnyc.com.