DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

cardiac index increase, as do indices of stroke work and
stroke volume. In systolic dysfunction, AngII decreases
arterial compliance, and this is reversed by ACE inhibition
(Lage et al., 2002). Heart rate generally is reduced.
Systemic blood pressure falls, sometimes steeply at the
outset, but tends to return toward initial levels.
Renovascular resistance falls sharply, and renal blood
flow increases. Natriuresis occurs as a result of the
improved renal hemodynamics, the reduced stimulus to
the secretion of aldosterone by AngII, and the diminished
direct effects of AngII on the kidney. The excess
volume of body fluids contracts, which reduces venous
return to the right side of the heart. A further reduction
results from venodilation and an increased capacity of
the venous bed.
Although AngII has little acute venoconstrictor activity, longterm
infusion of AngII increases venous tone, perhaps by central or
peripheral interactions with the sympathetic nervous system. The
response to ACE inhibitors also involves reductions of pulmonary
arterial pressure, pulmonary capillary wedge pressure, and left atrial
and left ventricular filling volumes and pressures. Consequently, preload
and diastolic wall stress are diminished. The better hemodynamic
performance results in increased exercise tolerance and
suppression of the sympathetic nervous system. Cerebral and coronary
blood flows usually are well maintained, even when systemic
blood pressure is reduced.
In heart failure, ACE inhibitors reduce ventricular dilation
and tend to restore the heart to its normal elliptical shape. ACE
inhibitors may reverse ventricular remodeling via changes in
preload/afterload, by preventing the growth effects of AngII on
myocytes, and by attenuating cardiac fibrosis induced by AngII and
aldosterone.
ACE Inhibitors in Acute Myocardial Infarction. The beneficial
effects of ACE inhibitors in acute myocardial
infarction are particularly large in hypertensive (Borghi
et al., 1999) and diabetic (Zuanetti et al., 1997) patients
(Chapter 27). Unless contraindicated (e.g., cardiogenic
shock or severe hypotension), ACE inhibitors should be
started immediately during the acute phase of myocardial
infarction and can be administered along with
thrombolytics, aspirin, and β adrenergic receptor antagonists
(ACE Inhibitor Myocardial Infarction
Collaborative Group, 1998). In high- risk patients (e.g.,
large infarct, systolic ventricular dysfunction), ACE
inhibition should be continued long term.
ACE Inhibitors in Patients Who Are at High Risk of
Cardiovascular Events. The HOPE study demonstrated
that patients at high risk of cardiovascular events benefited
considerably from treatment with ACE inhibitors
(Heart Outcomes Prevention Study Investigators,
2000). ACE inhibition significantly decreased the rate
of myocardial infarction, stroke, and death in patients
who did not have left ventricular dysfunction but had
evidence of vascular disease or diabetes and one other
risk factor for cardiovascular disease. The EUROPA
trial demonstrated that in patients with coronary artery
disease but without heart failure, ACE inhibition
reduced cardiovascular disease death and myocardial
infarction (European Trial, 2003).
ACE Inhibitors in Diabetes Mellitus and Renal Failure.
Diabetes mellitus is the leading cause of renal disease.
In patients with type 1 diabetes mellitus and diabetic
nephropathy, captopril prevents or delays the progression
of renal disease. Renoprotection in type 1 diabetes,
as defined by changes in albumin excretion, also is
observed with lisinopril. The renoprotective effects of
ACE inhibitors in type 1 diabetes are in part independent
of blood pressure reduction. In addition, ACE
inhibitors may decrease retinopathy progression in type
1 diabetics and attenuate the progression of renal insufficiency
in patients with a variety of nondiabetic
nephropathies (Ruggenenti et al., 2010).
Several mechanisms participate in the renal protection
afforded by ACE inhibitors. Increased glomerular capillary pressure
induces glomerular injury, and ACE inhibitors reduce this parameter
both by decreasing arterial blood pressure and by dilating renal efferent
arterioles. ACE inhibitors increase the permeability selectivity
of the filtering membrane, thereby diminishing exposure of the
mesangium to proteinaceous factors that may stimulate mesangial
cell proliferation and matrix production, two processes that contribute
to expansion of the mesangium in diabetic nephropathy.
Because AngII is a growth factor, reductions in the intrarenal levels
of AngII may further attenuate mesangial cell growth and matrix
production.
ACE Inhibitors in Scleroderma Renal Crisis. The use of ACE inhibitors
considerably improves survival of patients with scleroderma renal
crisis (Steen and Medsger, 1990).
Adverse Effects of ACE Inhibitors. In general, ACE
inhibitors are well tolerated. Metabolic side effects are
rare during long- term therapy with ACE inhibitors. The
drugs do not alter plasma concentrations of uric acid or
Ca 2+ and may improve insulin sensitivity in patients
with insulin resistance and decrease cholesterol and
lipoprotein (a) levels in proteinuric renal disease.
Hypotension. A steep fall in blood pressure may occur following the
first dose of an ACE inhibitor in patients with elevated PRA. Care
should be exercised in patients who are salt depleted, are on multiple
antihypertensive drugs, or who have congestive heart failure.
Cough. In 5-20% of patients, ACE inhibitors induce a bothersome,
dry cough mediated by the accumulation in the lungs of bradykinin,
substance P, and/or prostaglandins. Thromboxane antagonism,
aspirin, and iron supplementation reduce cough induced by ACE
inhibitors. ACE dose reduction or switching to an ARB is sometimes
735
CHAPTER 26
RENIN AND ANGIOTENSIN