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

DRUGS USED TO TREAT HYPERTENSION 189
AT 1 receptor) produce good 24-hour control. Their beneficial
effect in patients with heart failure (Chapter 31) or following
myocardial infarction (Chapter 29) makes them or an ACEI
(above) useful in hypertensive patients with these complications.
Similarly, an ACEI or a sartan is preferred over other
anti-hypertensive drugs in diabetic patients where they slow
the progression of nephropathy. Head to head comparison of
losartan versus atenolol in hypertension (the LIFE study)
favoured the sartan. Their excellent tolerability makes them
first choice ‘A’ drugs for many physicians, but they are more
expensive than ACEI.
First-dose hypotension can occur and it is sensible to apply
similar precautions as when starting an ACEI (first dose at
night, avoid starting if volume contracted).
Change in flow (%)
20
0
20
40
60
80
Placebo
Enalapril
Losartan
Mechanism of action
Most of the effects of angiotensin II, including vasoconstriction
and aldosterone release, are mediated by the angiotensin
II subtype 1 (AT 1 ) receptor. The pharmacology of sartans differs
predictably from that of ACEI, since they do not inhibit
the degradation of bradykinin (Figure 28.5). This difference
probably explains the lack of cough with sartans.
Adverse effects
Adverse effects on renal function in patients with bilateral renal
artery stenosis are similar to an ACEI, as is hyperkalaemia and
fetal renal toxicity. Angio-oedema is much less common than
with ACEI, but can occur.
(a)
Change in flow (%)
600
400
200
10 1 10 2
Angiotensin II (pmol/min)
10 3
Placebo
Enalapril
Losartan
Pharmacokinetics
Sartans are well absorbed after oral administration. Losartan
has an active metabolite. Half-lives of most marketed ARB are
long enough to permit once daily dosing.
Drug interactions
There is a rationale for combining a sartan with an ACEI (not
all angiotensin II is ACE-derived, and some useful effects of
ACEI could be kinin-mediated); clinical experience suggests
that this has little additional effect in hypertensive patients,
however. Clinical trial data on this combination in heart failure
are discussed in Chapter 31.
B DRUGS
-ADRENOCEPTOR ANTAGONISTS
Use
See Chapter 32 for use of β-adrenoceptor antagonists in cardiac
dysrhythmias.
Examples of β-adrenoceptor antagonists currently in clinical
use are shown in Table 28.1. Beta-blockers lower blood
pressure and reduce the risk of stroke in patients with mild
essential hypertension, but in several randomized controlled
(b)
0
10 1 Bradykinin (pmol/min)
trials (particularly of atenolol) have performed less well than
comparator drugs. The explanation is uncertain, but one possibility
is that they have less effect on central (i.e. aortic) blood
pressure than on brachial artery pressure. ‘B’ drugs are
no longer preferred over ‘A’ drugs as first line in situations
where an A or B would previously have been selected, as
explained above.
They are, however, useful in hypertensive patients with an
additional complication such as ischaemic heart disease
(Chapter 29) or heart failure (Chapter 31). The negative
inotropic effect of beta-blocking drugs is particularly useful
for stabilizing patients with dissecting aneurysms of the
thoracic aorta, in whom it is desirable not only to lower the
10 3
Figure 28.5: Differential effects of angiotensin converting
enzyme inhibition (enalapril) and of angiotensin receptor
blockade (losartan) on angiotensin II and bradykinin vasomotor
actions in the human forearm vasculature. (Redrawn with
permission from Cockcroft JR et al. Journal of Cardiovascular
Pharmacology 1993; 22: 579–84.)