A Textbook of Clinical Pharmacology and Therapeutics

OTHER ANTIHYPERTENSIVE DRUGS

Other important drugs (aldosterone antagonists, other
vasodilators and centrally acting drugs) are summarized in
Table 28.3.

ALDOSTERONE ANTAGONISTS

Neitherspironolactonenor the more selective (and much more
expensive)eplerenoneis licensed for treating essential hyper-
tension. They are used to treat Conn’s syndrome, but are also
effective in essential hypertension (especially low renin essen-
tial 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

α-ADRENOCEPTOR ANTAGONISTS

There are two main types of α-adrenoceptor, α 1 - and α 2 .α 1 -

Adrenoceptor antagonists lower blood pressure.

Use

Phenoxybenzamineirreversibly alkylates α-receptors. It is

uniquely valuable in preparing patients with phaeochromocy-

toma for surgery, but has no place in the management of

essential hypertension. Prazosinis a selective α 1 -blocker, but

its use is limited by severe postural hypotension, especially

following the first dose. It has a short elimination half-life.

Doxazosinis 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,

Ca^2 antagonist or ACEI as first-line agent in ALLHAT, but is

useful as add-on treatment in patients with resistant hyperten-

sion. It is given last thing at night.

Doxazosinimproves symptoms of bladder outflow tract

obstruction (Chapter 36), and is useful in men with mild

symptoms from benign prostatic hypertrophy.

Mechanism of action

Noradrenaline activatesα 1 -receptors on vascular smooth

muscle, causing tonic vasoconstriction. α 1 -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

α 1 -Adrenoceptor antagonists have a mild favourable effect on

plasma lipids, with an increase in HDL and a reduction in

LDL cholesterol.

Pharmacokinetics

Doxazosinhas an elimination half-life of approximately 10–12

hours and provides acceptably smooth 24-hour control if used

once daily.

OTHERANTIHYPERTENSIVEDRUGS 193

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-blockersreduce 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, post-
  myocardial infarction). Patients of African descent tend
  to respond poorly to them as single agents.


• ACE inhibitorsare 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 antagonistsare 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-Methyldopais useful in patients with hypertension
  during pregnancy.


• Other drugs that are useful in occasional patients with
  severe disease include minoxidil,hydralazineand
  nitroprusside.