Page 319 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 305

Drugs That Block Renin Release it has been proposed that increased bradykinin levels are more
important than decreased ANG II levels. Bradykinin is appar-
Drugs that block the sympathetic nervous system inhibit the release ently responsible for some adverse side effects, including cough
of renin. Examples are propranolol and other β-adrenoceptor- and angioedema. These drugs are contraindicated in pregnancy
blocking drugs, which act by blocking the renal β receptors because they cause fetal kidney damage.
involved in the sympathetic control of renin release.
Angiotensin Receptor Blockers
Renin Inhibitors
ANG II receptor blockers are now widely used. Losartan,
Cleavage of angiotensinogen by renin (Figures 17–1 and 17–3) valsartan, and several others are orally active, potent, and
is the rate-limiting step in the formation of ANG II and thus specific competitive antagonists at angiotensin AT receptors.
1
represents a logical target for inhibition of the renin-angiotensin The efficacy of these drugs in hypertension is similar to that of
system. Several nonpeptide, low-molecular-weight, orally active ACE inhibitors, but they are associated with a lower incidence
inhibitors are available. Aliskiren was the first nonpeptide renin of cough. Like ACE inhibitors, ARBs slow the progression of
inhibitor to be approved for the treatment of hypertension. In diabetic nephropathy and valsartan has been reported to decrease
healthy subjects, aliskiren produces dose-dependent reductions the incidence of diabetes in patients with impaired glucose toler-
in plasma renin activity and plasma ANG I, ANG II, and ance. The antagonists are also effective in the treatment of heart
aldosterone concentrations. In patients with hypertension, some failure and provide a useful alternative when ACE inhibitors are
of whom have elevated plasma renin levels, aliskiren suppresses not well tolerated. ARBs are generally well tolerated but should
plasma renin activity and causes dose-related reductions in blood not be used by patients with nondiabetic renal disease or in preg-
pressure similar to those produced by ACE inhibitors and ARBs nancy. In addition, some ARBs may cause a syndrome known as
(see below). The safety and tolerability of aliskiren are compa- sprue-like enteropathy.
rable to ARBs. Thus, renin inhibition has become an established Marfan’s syndrome is a connective tissue disorder associated
treatment for hypertension. Aliskiren is contraindicated in with aortic disease and other abnormalities involving increased
pregnancy. transforming growth factor-β (TGF-β) signaling. Since ANG II
Inhibition of the renin-angiotensin system with ACE inhibi- increases TGF-β levels, it was reasoned that blockade of the renin-
tors or ARBs may be incomplete because the drugs disrupt the angiotensin system might be beneficial in Marfan’s syndrome.
negative feedback action of ANG II on renin release and thereby Clinical studies indicate that the ARB losartan may be as effective
increase plasma renin activity. Other antihypertensive drugs, nota- as atenolol, the standard treatment for this syndrome.
bly hydrochlorothiazide and other diuretics, also increase plasma The currently available ARBs are selective for the AT receptor.
1
renin activity. Aliskiren not only decreases baseline plasma renin Since prolonged treatment with the drugs disinhibits renin release
activity in hypertensive subjects, but also eliminates the rise pro- and increases circulating ANG II levels, there may be increased
duced by ACE inhibitors, ARBs, and diuretics, thereby enhancing stimulation of AT receptors. This may be significant in view
2
their antihypertensive effects. For this reason, aliskiren has been of the evidence noted above that activation of the AT receptor
2
used in combination with an ACE inhibitor or ARB. However, causes vasodilation and other beneficial effects. Indeed, a selective,
such dual blockade may not produce significant clinical benefit orally active AT agonist, Compound 21 (C21), has been shown
and may be associated with adverse effects. 2
to produce several beneficial effects in animal models of cardio-
vascular disease. The drug is under clinical development and may
Angiotensin-Converting Enzyme represent the first of a new class of cardiovascular drugs.
Inhibitors The clinical benefits of ARBs are similar to those of renin and
ACE inhibitors, and it is not clear if any has significant advantages
Orally active ACE inhibitors are directed against the active site
of ACE and are now extensively used. Captopril and enalapril over the others.
are examples of the many ACE inhibitors that are available. Summary: Renin-Angiotensin System
These drugs differ in their structure and pharmacokinetics, but
they are interchangeable in clinical use. ACE inhibitors decrease The renin-angiotensin system is an important control system
systemic vascular resistance without increasing heart rate and involved in the regulation of blood pressure, fluid and electrolyte
promote natriuresis. As described in Chapters 11 and 13, they balance, and other functions. Overactivity of this system has
are effective in the treatment of hypertension, decrease morbid- been implicated in hypertension, heart failure, and other diseases.
ity and mortality in heart failure and left ventricular dysfunction Drugs that block the formation or actions of ANG II are used
after myocardial infarction, and delay the progression of diabetic extensively in the treatment of these diseases.
nephropathy. More recent observations suggest that the system is even more
ACE inhibitors not only block the conversion of ANG I to complex than originally envisioned. Specifically, there is evidence
ANG II but also inhibit the degradation of other substances, for roles of ANG 1-7, possibly acting via the Mas receptor, and the
including bradykinin, substance P, and enkephalins. The action (pro)renin receptor, which may act via angiotensin-independent
of ACE inhibitors to inhibit bradykinin metabolism contributes pathways. However, the significance of these findings remains to
significantly to their hypotensive action (see Figure 11–5); indeed, be defined.