Renin tolerance

In an attempt to conserve sodium, the kidney secretes renin increased plasma renin activity increases the release of aldosterone, which regulates the absorption of potassium and leads to kafluresis and hypokalemia. Hypokalemia is responsible in part for decreased glucose intolerance (82). Hyponatremia, postural hypotension, and pre-renal azotemia are considered of tittle consequence. Hypemricemia and hypercalcemia are not unusual, but are not considered harmful. However, hypokalemia, progressive decreased glucose tolerance, and increased semm cholesterol [57-88-5] levels are considered... 

Kurz, S., Hink, U., Nickenig, G., Borthayre, A. B., Harrison, D. G., Munzel, T., Evidence for a causal role for the renin-angiotensin system in nitrate tolerance. Circulation 99 (1999), p. 3181-3187... 

Kurz S et al. Evidence for a causal role of the renin-angiotensin system in nitrate tolerance. Circulation 1999 99 3181-3187. 

The reduction in plasma volume produced by p-blockers contrasts with the increased volume seen with other types of antihypertensives. Tolerance to the antihypertensive actions of p-blockers therefore is less of a problem than with the vasodilating drugs. An additional difference from the vasodilators is that plasma renin activity is reduced, rather than increased, by propranolol (Inderal). Orthostatic hypotension does not occur with p-blockers. 

Mechanism of Action AnACE inhibitor that suppresses the renin-angiotensin-aldos-terone system and prevents conversion of angiotensin I to angiotensin 11, a potent vasoconstrictor may also inhibit angiotensin II at local vascular and renal sites. Decreases plasma angiotensin II, increases plasma renin activity, and decreases aldosterone secretion. Therapeutic Effect Reduces peripheral arterial resistance, pulmonary capillary wedge pressure improves cardiac output and exercise tolerance. Pharmacokinetics ... 

Aliskiren is the most advanced of these and the first to be approved for the treatment of hypertension. In healthy subjects, aliskiren produces a dose-dependent reduction in plasma renin activity and Ang I and II and aldosterone concentrations. In patients with hypertension, many of whom have elevated plasma renin levels, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by ACE inhibitors (Figure 17-3). The safety and tolerability of aliskiren appear to be comparable to angiotensin antagonists and placebo. 

In view of his cardiovascular status and proteinuria, WD should be on anti-ACE therapy of some kind. If he is unable to tolerate an ACE inhibitor, an alternative might be to try an ARB. This has the advantage of blocking the renin-angiotensin system, thereby achieving the required therapeutic effect, but since ACE itself is not affected, the patient should not develop a cough. 

Heart failure is due to defects in cardiac contractility (the vigor of heart muscle), leading to inadequate cardiac output. Signs and symptoms include decreased exercise tolerance and muscle fatigue, coupled with the results of compensatory responses (neural and humoral) evoked by decreases in mean BP. Increased SANS activity leads to tachycardia, increased arteriolar tone T afterload, 4- output, 4 renal perfusion), and increased venous tone (T preload, T fiber stretch). Activation of the renin-angiotensin system results in edema, dyspnea, and pulmonary congestion. Intrinsic compensation results in myocardial hypertrophy. These effects are summarized in Figure IH-4-1. 

Plasma concentrations of norepinephrine fall in association with the rednction in arterial pressnre, and this reflects the decrease in sympathetic tone. Renin secretion also is reduced by methyldopa, but this is not a major effect of the drng and is not necessary for its hypotensive effects. Salt and water often are gradnally retained with prolonged use of methyldopa, and this tends to blnnt the antihypertensive effect. This has been termed psendo-tolerance, and can be overcome with concnrrent nse of a diuretic. 

This active metaboiite of methyidopa decreases total peripheral resistance, with little change in cardiac output and heart rate, through its stimulation of central inhibitory a2-adrenoceptors. A reduction of plasma renin activity also may contribute to the hypotensive action of methyidopa. Postural hypotension and sodium and water retention also are effects related to a reduction in blood pressure. If a diuretic is not administered concurrently with methyidopa, tolerance to the antihypertensive effect of the methyidopa during prolonged therapy can result. 

White WB, Bresaher R, Kaplan AP, Palmer BF, Riddell RH, Lesogor A, Chang W, Keefe DL. Safety and tolerability of the direct renin inhibitor ahskiren a pooled analysis of clinical experience in more than 12,000 patients with hypertension. J Clin Hypertens (Greenwich) 2010 12(10) 765-75. 

Rashid H. Direct renin inhibition an evaluation of the safety and tolerability of aliskiren. Curr Med Res Opin 2008 24(9) 2627-37. 

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