Renin-angiotensin-aldosterone system inhibitors

Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol 2010 5(3) 531. ... 

Renin-Angiotensin-Aldosterone System ACE Inhibitors Nuclear Factor-icB... 

Renin-Angiotensin-Aldosterone System Epithelial Na+ Channels ACE Inhibitors... 

Aliskiren blocks the renin-angiotensin-aldosterone system at its point of a activation, which results in reduced plasma renin activity and BP. It provides BP reductions comparable to an ACE inhibitor, ARB, or CCB. It also has additive antihypertensive effects when used in combination with thiazides, ACE inhibitors, ARBs, or CCBs. It is approved for monotherapy or in combination with other agents. 

Renal function impairment In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe CHF), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and with acute renal failure or death (rarely). No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted. AIIRAs are not dialyzable. 

Mechanism of Action An ACE inhibitor that suppresses the renin-angiotensin-aldosterone system. Decreases plasma angiotensin II, increases plasma renin activity, and decreases aldosterone secretion. Therapeutic Effect Reduces peripheral arterial resistance and BP. 

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11-1) arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of hormones from vascular endothelium may also be involved in the regulation of vascular resistance. For example, nitric oxide (see Chapter 19 Nitric Oxide, Donors, Inhibitors) dilates and endothelin-1 (see Chapter 17 Vasoactive Peptides) constricts blood vessels. 

Bristow MR, Port JD, Kelly RA. Inhibitors of the renin-angiotensin-aldosterone system. In Braunwald E, Libby P Zipes DD, Zipes DP eds. Heart Disease A Textbook of Cardiovascular Medicine. Philadelphia WB Saunders, 2001 582-583. 

A test dose should be given to patients who are in cardiac failure (or who are already taking a diuretic for another reason, e.g. hypertension). Maintenance of blood pressure in such individuals may depend greatly on an activated renin-angiotensin-aldosterone system and a standard dose of an ACE inhibitor can cause a catastrophic fall in blood pressure. Except for captopril, most ACE inhibitors (including enalapril) are prodrugs, which are inactive for several hours after dosing. This has favoured the use of captopril... 

The results of SPICE (The Study of Patients Intolerant of Converting Enzyme Inhibitors) and of the previously published RESOLVD led to the design of the current CHARM trial, which is investigating the effect of candesartan in 6600 patients with heart failure in three different ways versus an ACE inhibitor in patients with preserved left ventricular function versus placebo in patients intolerant of ACE inhibitors and in addition to ACE inhibitors in all other patients. While waiting for the results of this trial it is advisable to continue to use ACE inhibitors as the initial therapy for heart failure. In patients with documented intolerance of ACE inhibitors (which may represent 10-20% of patients with heart failure) angiotensin receptor antagonists may be useful as a substitute to block the renin-angiotensin-aldosterone system. 

The beneficial effects of other contemporary therapies such as aspirin, beta-blockers, and inhibitors of the renin-angiotensin-aldosterone system as well as an aggressive approach to revascularization following STEMI may override any small differences in myocardial perfusion related to the acute reperfusion therapy administered. 

Captopril, l-[(2S)-3-mercapto-2-methyl-propionyl]-L-proline, the first orally active inhibitor of the angiotensin-converting enzyme (ACE) on the market. The positive effects of captopril and other ACE inhibitors like enalapril in hypertension and heart failure result primarily from suppression of the renin-angiotensin-aldosterone system. Captopril causes a fall in blood pressure in hypertensive patients [M. A. Ondetti et al.. Science 1977,196,441 ... 

Case DB, Atlas SA, Laragh JH, Sealey JE, Sullivan PA, McKinstry DN. Clinical experience with blockade of die renin-angiotensin-aldosterone system by an oral convertii -en me inhibitor (SQ14,225, captopril) in hypertensive patients. Prog CarSovasc Dis (1978) 21,195-206. 

Palmer BF, Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system, NEnglJMed 2m) 351, 585-92... 

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