Clinical Pharmacology and Therapeutics

DRUGS USED TO TREAT HYPERTENSION 187
Each of these classes of drug reduces clinical end-points such
as stroke, but in uncomplicated hypertension B drugs may be
less effective than other classes. Other antihypertensive drugs
useful in specific circumstances include α-adrenoceptor
antagonists, aldosterone antagonists and centrally acting antihypertensive
drugs.
Key points
Pathophysiology of hypertension
• Few patients with persistent systemic arterial
hypertension have a specific aetiology (e.g. renal
disease, endocrine disease, coarctation of aorta). Most
have essential hypertension (EH), which confers
increased risk of vascular disease (e.g. thrombotic or
haemorrhagic stroke, myocardial infarction). Reducing
blood pressure reduces the risk of such events.
• The cause(s) of EH is/are ill-defined. Polygenic
influences are important, as are environmental factors
including salt intake and obesity. The intrauterine
environment (determined by genetic/environmental
factors) may be important in determining blood
pressure in adult life.
• Increased cardiac output may occur before EH becomes
established.
• Established EH is characterized haemodynamically by
normal cardiac output but increased total systemic
vascular resistance. This involves both structural
(remodelling) and functional changes in resistance
vessels.
• EH is a strong independent risk factor for atheromatous
disease and interacts supra-additively with other such
risk factors.
GENERAL PRINCIPLES OF MANAGING
ESSENTIAL HYPERTENSION
• Consider blood pressure in the context of other risk
factors: use cardiovascular risk to make decisions about
whether to start drug treatment and what target to
aim for. (Guidance, together with risk tables, is available,
for example, at the back of the British National
Formulary).
• Use non-drug measures (e.g. salt restriction) in addition to
drugs.
• Explain goals of treatment and agree a plan the patient is
comfortable to live with (concordance).
• Review the possibility of co-existing disease (e.g. gout,
angina) that would influence the choice of drug.
• The ‘ABCD’ rule provides a useful basis for starting
drug treatment. A (and B) drugs inhibit the
renin–angiotensin–aldosterone axis and are effective
when this is active – as it usually is in young white or
Asian people. An A drug is preferred for these unless
there is some reason to avoid it (e.g. in a young woman
contemplating pregnancy) or some additional reason
(e.g. co-existing angina) to choose a B drug. Older people
and people of Afro-Caribbean ethnicity often have a low
plasma renin and in these patients a class C or D drug is
preferred.
• Use a low dose and, except in emergency situations, titrate
this upward gradually.
• Addition of a second drug is often needed. A drug of the
other group is added, i.e. an A drug is added to patients
started on a C or D drug, a C or D drug is added to a
patient started on an A drug. A third or fourth drug may
be needed. It is better to use such combinations than to
use very high doses of single drugs: this seldom works
and often causes adverse effects.
• Loss of control – if blood pressure control, having been
well established, is lost, there are several possibilities to be
considered:
• non-adherence;
• drug interaction – e.g. with non-steroidal antiinflammatory
drugs (NSAIDs) – see Chapter 26;
• intercurrent disease – e.g. renal impairment,
atheromatous renal artery stenosis.
DRUGS USED TO TREAT HYPERTENSION
A DRUGS
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
Use
Several angiotensin-converting enzyme inhibitors (ACEI) are in
clinical use (e.g. ramipril, trandolapril, enalapril, lisinopril,
captopril). These differ in their duration of action. Longer-acting
drugs (e.g. trandolapril, ramipril) are preferred. They are given
once daily and produce good 24-hour control. Their beneficial
effect in patients with heart failure (Chapter 31) or following
myocardial infarction (Chapter 29) makes them or a sartan
(below) particularly useful in hypertensive patients with these
complications. Similarly an ACEI or sartan is preferred over
other anti-hypertensives in diabetic patients because they slow
the progression of diabetic nephropathy.
Treatment is initiated using a small dose given last thing at
night, because of the possibility of first-dose hypotension.
If possible, diuretics should be withheld for one or two days
before the first dose for the same reason. The dose is subsequently
usually given in the morning and increased gradually
if necessary, while monitoring the blood-pressure response.
Mechanism of action
ACE catalyses the cleavage of a pair of amino acids from
short peptides, thereby ‘converting’ the inactive decapeptide
angiotensin I to the potent vasoconstrictor angiotensin II
(Figure 28.4). As well as activating the vasoconstrictor
angiotensin in this way, it also inactivates bradykinin – a
vasodilator peptide. ACEI lower blood pressure by reducing
angiotensin II and perhaps also by increasing vasodilator