A Textbook of Clinical Pharmacology and Therapeutics

peptides, such as bradykinin. Angiotensin II causes aldos-
terone secretion from the zona glomerulosa of the adrenal cor-
tex and inhibition of this contributes to the antihypertensive
effect of ACE inhibitors.

Metabolic effects

ACEI cause a mild increase in plasma potassium which is usu-
ally 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 adminis-

tered 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;

captoprilis 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 aldos-

terone 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 hyper-

kalaemia, 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 clini-

cally 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

188 HYPERTENSION

Angiotensinogen

Angiotensin I

Angiotensin II

Renin

ACE

ACE inhibitor

AT 1 -receptor

Vasoconstriction Cell

growth

Sodium and

fluid

retention

Sympathetic

activation

Angiotensin receptor

blocker





Figure 28.4:Generation of angiotensin II, and mode of action of
ACE inhibitors and of angiotensin receptor blockers.