A Textbook of Clinical Pharmacology and Therapeutics

Key points
Drugs used in essential hypertension
• Diuretics: thiazides (in low dose) are preferred to loop
diuretics unless there is renal impairment. They may
precipitate gout and worsen glucose tolerance or
dyslipidaemia, but they reduce the risk of stroke and
other vascular events. Adverse effects include
hypokalaemia, which is seldom problematic, and
impotence. They are suitable first-line drugs, especially
in black patients, who often have low circulating renin
levels and respond well to salt restriction and diuretics.
• Beta-blockers reduce the risk of vascular events, but are
contraindicated in patients with obstructive pulmonary
disease. Adverse events (dose-related) include fatigue
and cold extremities. Heart failure, heart block or
claudication can be exacerbated in predisposed
patients. They are particularly useful in patients with
another indication for them (e.g. angina, postmyocardial
infarction). Patients of African descent tend
to respond poorly to them as single agents.
• ACE inhibitors are particularly useful as an addition to a
thiazide in moderately severe disease. The main
adverse effect on chronic use is cough; losartan, an
angiotensin-II receptor antagonist, lacks this effect but
is otherwise similar to ACE inhibitors.
• Calcium-channel antagonists are useful, especially in
moderately severe disease. Long-acting
drugs/preparations are preferred. The main adverse
effect in chronic use is ankle swelling.
• α 1-Blockers are useful additional agents in patients who
are poorly controlled on one or two drugs. Long-acting
drugs (e.g. doxazosin) are preferred. Effects on vascular
event rates are unknown. Unlike other
antihypertensives, they improve the lipid profile.
• α-Methyldopa is useful in patients with hypertension
during pregnancy.
• Other drugs that are useful in occasional patients with
severe disease include minoxidil, hydralazine and
nitroprusside.
OTHER ANTIHYPERTENSIVE DRUGS
Other important drugs (aldosterone antagonists, other
vasodilators and centrally acting drugs) are summarized in
Table 28.3.
ALDOSTERONE ANTAGONISTS
Neither spironolactone nor the more selective (and much more
expensive) eplerenone is licensed for treating essential hypertension.
They are used to treat Conn’s syndrome, but are also
effective in essential hypertension (especially low renin essential
hypertension) and are recommended as add-on treatment
for resistant hypertension by the British Hypertension Society
(BHS) guidelines. The main adverse effects are hyperkalaemia
(especially in patients with renal impairment) and, with
spironolactone, oestrogen-like effects of gynaecomastia, breast
tenderness and menstrual disturbance.
OTHER VASODILATORS
OTHER ANTIHYPERTENSIVE DRUGS 193
α-ADRENOCEPTOR ANTAGONISTS
There are two main types of α-adrenoceptor, α1- and α2. α1- Adrenoceptor antagonists lower blood pressure.
Use
Phenoxybenzamine irreversibly alkylates α-receptors. It is
uniquely valuable in preparing patients with phaeochromocytoma
for surgery, but has no place in the management of
essential hypertension. Prazosin is a selective α1-blocker, but
its use is limited by severe postural hypotension, especially
following the first dose. It has a short elimination half-life.
Doxazosin is closely related to prazosin, but is longer lasting,
permitting once daily use and causing fewer problems with
first-dose hypotension. It did not compare well with diuretic,
Ca2� antagonist or ACEI as first-line agent in ALLHAT, but is
useful as add-on treatment in patients with resistant hypertension.
It is given last thing at night.
Doxazosin improves symptoms of bladder outflow tract
obstruction (Chapter 36), and is useful in men with mild
symptoms from benign prostatic hypertrophy.
Mechanism of action
Noradrenaline activates α1-receptors on vascular smooth
muscle, causing tonic vasoconstriction. α1-Antagonists cause
vasodilatation by blocking this tonic action of noradrenaline.
Adverse effects
• First-dose hypotension and postural hypotension are
adverse effects.
• Nasal stuffiness, headache, dry mouth and pruritus have
been reported, but are relatively infrequent.
• α-Blockers can cause urinary incontinence, especially in
women with pre-existing pelvic pathology.
Metabolic effects
α1-Adrenoceptor antagonists have a mild favourable effect on
plasma lipids, with an increase in HDL and a reduction in
LDL cholesterol.
Pharmacokinetics
Doxazosin has an elimination half-life of approximately 10–12
hours and provides acceptably smooth 24-hour control if used
once daily.