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

778 normal renal function. However, substantial retention of
K + can occur in some patients with renal insufficiency.
Furthermore, the potential for developing hyperkalemia
should be considered when ACE inhibitors are used with
other drugs that can cause K + retention, including the
K + -sparing diuretics (amiloride, triamterene, and
spironolactone), NSAIDs, K + supplements, and β receptor
antagonists. Some patients with diabetic nephropathy
may be at greater risk of hyperkalemia.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
There are several cautions in the use of ACE inhibitors in
patients with hypertension. Angioedema is a rare but serious and
potentially fatal adverse effect of the ACE inhibitors. Patients starting
treatment with these drugs should be explicitly warned to discontinue
their use with the advent of any signs of angioedema. Due
to the risk of severe fetal adverse effects, ACE inhibitors are contraindicated
during pregnancy, a fact that should be communicated
to women of childbearing age.
In most patients, there is no appreciable change in glomerular
filtration rate following the administration of ACE inhibitors. However,
in renovascular hypertension, the glomerular filtration rate is generally
maintained as the result of increased resistance in the postglomerular
arteriole caused by AngII. Accordingly, in patients with bilateral renal
artery stenosis or stenosis in a sole kidney, the administration of an
ACE inhibitor will reduce the filtration fraction and cause a substantial
reduction in glomerular filtration rate. In some patients with preexisting
renal disease, the glomerular filtration may decrease with an ACE
inhibitor. More information is needed on how to balance the potential
risk of reversible drug-induced impairment of glomerular filtration rate
versus inhibition of the progression of kidney disease.
ACE inhibitors lower the blood pressure to some extent in
most patients with hypertension. Following the initial dose of an
ACE inhibitor, there may be a considerable fall in blood pressure in
some patients; this response to the initial dose is a function of
plasma renin activity prior to treatment. The potential for a large
initial drop in blood pressure is the reason for using a low dose to
initiate therapy, especially in patients who may have a very active
RAS supporting blood pressure, such as patients with diureticinduced
volume contraction or congestive heart failure. With continuing
treatment, there usually is a progressive fall in blood
pressure that in most patients does not reach a maximum for several
weeks. The blood pressure seen during chronic treatment is not
strongly correlated with the pretreatment plasma renin activity.
Young and middle-aged Caucasian patients have a higher probability
of responding to ACE inhibitors; elderly African-American
patients as a group are more resistant to the hypotensive effect of
these drugs. While most ACE inhibitors are approved for once-daily
dosing for hypertension, a significant fraction of patients has a
response that lasts <24 hours and may require twice-daily dosing
for adequate control of blood pressure.
AT 1
RECEPTOR ANTAGONISTS
The importance of AngII in regulating cardiovascular
function has led to the development of nonpeptide antagonists
of the AT 1
AngII receptor for clinical use. Losartan,
candesartan, irbesartan, valsartan, telmisartan, olmesartan,
and eprosartan have been approved for the treatment
of hypertension. The pharmacology of AT 1
receptor
antagonists is presented in detail in Chapter 26. By antagonizing
the effects of AngII, these agents relax smooth
muscle and thereby promote vasodilation, increase renal
salt and water excretion, reduce plasma volume, and
decrease cellular hypertrophy. AngII-receptor antagonists
also theoretically overcome some of the disadvantages of
ACE inhibitors, which not only prevent conversion of
angiotensin I (AngI) to AngII but also prevent ACEmediated
degradation of bradykinin and substance P.
There are two distinct subtypes of AngII receptors,
AT 1
and AT 2
. The AT 1
receptor subtype is located predominantly
in vascular and myocardial tissue and also in
brain, kidney, and adrenal glomerulosa cells, which
secrete aldosterone (see Chapter 26). The AT 2
subtype
is found in the adrenal medulla, kidney, and CNS and
may play a role in vascular development (Horiuchi et al.,
1999). Because the AT 1
receptor mediates feedback inhibition
of renin release, renin and AngII concentrations
are increased during AT 1
receptor antagonism. The clinical
consequences of increased AngII effects on an uninhibited
AT 2
receptor are unknown; however, emerging
data suggest that the AT 2
receptor may elicit anti-growth
and anti-proliferative responses.
Adverse Effects and Precautions. The adverse effects of
AT 1
receptor antagonists may be considered in the context
of those known to be associated with the ACE
inhibitors. ACE inhibitors cause problems of two major
types, those related to diminished concentrations of
AngII and those due to molecular actions independent
of abrogating the function of AngII.
Adverse effects of ACE inhibitors that result from inhibiting
AngII-related functions (see above and Chapter 26) also occur with AT 1
receptor antagonists. These include hypotension, hyperkalemia, and
reduced renal function, including that associated with bilateral renal
artery stenosis and stenosis in the artery of a solitary kidney.
Hypotension is most likely to occur in patients in whom the blood pressure
is highly dependent on AngII, including those with volume depletion
(e.g., with diuretics), renovascular hypertension, cardiac failure, and
cirrhosis; in such patients, initiation of treatment with low doses and
attention to blood volume are essential. Hyperkalemia may occur in conjunction
with other factors that alter K + homeostasis, such as renal insufficiency,
ingestion of excess K + , and the use of drugs that promote K +
retention. Cough, an adverse effect of ACE inhibitors, is less frequent
with AT 1
receptor antagonists. Angioedema occurs very rarely.
ACE inhibitors and AT 1
receptor antagonists should not be
administered during pregnancy and should be discontinued as soon
as pregnancy is detected.
Therapeutic Uses. When given in adequate doses, the
AT 1
receptor antagonists appear to be as effective as