A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

188 HYPERTENSION
Angiotensin receptor
blocker
Vasoconstriction
Angiotensinogen
Cell
growth
Angiotensin I
Angiotensin II
AT 1 -receptor
Sodium and
fluid
retention
Renin
ACE
ACE inhibitor
Sympathetic
activation
Figure 28.4: Generation of angiotensin II, and mode of action of
ACE inhibitors and of angiotensin receptor blockers.
peptides, such as bradykinin. Angiotensin II causes aldosterone
secretion from the zona glomerulosa of the adrenal cortex
and inhibition of this contributes to the antihypertensive
effect of ACE inhibitors.
Metabolic effects
ACEI cause a mild increase in plasma potassium which is usually
unimportant, but may sometimes be either desirable or
problematic depending on renal function and concomitant
drug therapy (see Adverse effects and Drug interactions
below).
Adverse effects
ACE inhibitors are generally well tolerated. Adverse effects
include:
• First-dose hypotension.
• Dry cough – this is the most frequent symptom (5–30% of
cases) during chronic dosing. It is often mild, but can be
troublesome. The cause is unknown, but it may be due to
kinin accumulation stimulating cough afferents. Sartans
(see below) do not inhibit the metabolism of bradykinin
and do not cause cough.
• Functional renal failure – this occurs predictably in
patients with haemodynamically significant bilateral renal
artery stenosis, and in patients with renal artery stenosis
in the vessel supplying a single functional kidney. Plasma
creatinine and potassium concentrations should be
monitored and the possibility of renal artery stenosis
considered in patients in whom there is a marked rise in
creatinine. Provided that the drug is stopped promptly,
such renal impairment is reversible. The explanation of
acute reduction in renal function in this setting is that
glomerular filtration in these patients is critically
dependent on angiotensin-II-mediated efferent arteriolar
vasoconstriction, and when angiotensin II synthesis is
inhibited, glomerular capillary pressure falls and
glomerular filtration ceases. This should be borne in
mind particularly in ageing patients with atheromatous
disease.
• Hyperkalaemia is potentially hazardous in patients with
renal impairment and great caution must be exercised in
this setting. This is even more important when such
patients are also prescribed potassium supplements
and/or potassium-sparing diuretics.
• Fetal injury – ACEI cause renal agenesis/failure in the
fetus, resulting in oligohydramnios. ACEI are therefore
contraindicated in pregnancy and other drugs are usually
preferred in women who may want to start a family.
• Urticaria and angio-oedema – increased kinin
concentration may explain the urticarial reactions and
angioneurotic oedema sometimes caused by ACEI.
• Sulphhydryl group-related effects – high-dose captopril
causes heavy proteinuria, neutropenia, rash and taste
disturbance, attributable to its sulphhydryl group.
Pharmacokinetics
Currently available ACE inhibitors are all active when administered
orally, but are highly polar and are eliminated in the urine.
A number of these drugs (e.g. captopril, lisinopril) are active
per se, while others (e.g. enalapril) are prodrugs and require
metabolic conversion to active metabolites (e.g. enalaprilat). In
practice, this is of little or no importance. None of the currently
available ACEI penetrate the central nervous system. Many of
these agents have long half-lives permitting once daily dosing;
captopril is an exception.
Drug interactions
The useful interaction with diuretics has already been alluded
to above. Diuretic treatment increases plasma renin activity
and the consequent activation of angiotensin II and aldosterone
limits their efficacy. ACE inhibition interrupts this loop
and thus enhances the hypotensive efficacy of diuretics, as well
as reducing thiazide-induced hypokalaemia. Conversely, ACEI
have a potentially adverse interaction with potassium-sparing
diuretics and potassium supplements, leading to hyperkalaemia,
especially in patients with renal impairment, as
mentioned above. As with other antihypertensive drugs,
NSAIDs increase blood pressure in patients treated with ACE
inhibitors.
ANGIOTENSIN RECEPTOR BLOCKERS
Several angiotensin receptor blockers (ARB or ‘sartans’) are in
clinical use (e.g. losartan, candesartan, irbesartan, valsartan).
Use
Sartans are pharmacologically distinct from ACEI, but clinically
similar in hypotensive efficacy. However, they lack the
common ACEI adverse effect of dry cough. Long-acting drugs
(e.g. candesartan, which forms a stable complex with the