A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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DRUGS USED TO TREAT HYPERTENSION 187<br />
Each <strong>of</strong> these classes <strong>of</strong> drug reduces clinical end-points such<br />
as stroke, but in uncomplicated hypertension B drugs may be<br />
less effective than other classes. Other antihypertensive drugs<br />
useful in specific circumstances include α-adrenoceptor<br />
antagonists, aldosterone antagonists <strong>and</strong> centrally acting antihypertensive<br />
drugs.<br />
Key points<br />
Pathophysiology <strong>of</strong> hypertension<br />
• Few patients with persistent systemic arterial<br />
hypertension have a specific aetiology (e.g. renal<br />
disease, endocrine disease, coarctation <strong>of</strong> aorta). Most<br />
have essential hypertension (EH), which confers<br />
increased risk <strong>of</strong> vascular disease (e.g. thrombotic or<br />
haemorrhagic stroke, myocardial infarction). Reducing<br />
blood pressure reduces the risk <strong>of</strong> such events.<br />
• The cause(s) <strong>of</strong> EH is/are ill-defined. Polygenic<br />
influences are important, as are environmental factors<br />
including salt intake <strong>and</strong> obesity. The intrauterine<br />
environment (determined by genetic/environmental<br />
factors) may be important in determining blood<br />
pressure in adult life.<br />
• Increased cardiac output may occur before EH becomes<br />
established.<br />
• Established EH is characterized haemodynamically by<br />
normal cardiac output but increased total systemic<br />
vascular resistance. This involves both structural<br />
(remodelling) <strong>and</strong> functional changes in resistance<br />
vessels.<br />
• EH is a strong independent risk factor for atheromatous<br />
disease <strong>and</strong> interacts supra-additively with other such<br />
risk factors.<br />
GENERAL PRINCIPLES OF MANAGING<br />
ESSENTIAL HYPERTENSION<br />
• Consider blood pressure in the context <strong>of</strong> other risk<br />
factors: use cardiovascular risk to make decisions about<br />
whether to start drug treatment <strong>and</strong> what target to<br />
aim for. (Guidance, together with risk tables, is available,<br />
for example, at the back <strong>of</strong> the British National<br />
Formulary).<br />
• Use non-drug measures (e.g. salt restriction) in addition to<br />
drugs.<br />
• Explain goals <strong>of</strong> treatment <strong>and</strong> agree a plan the patient is<br />
comfortable to live with (concordance).<br />
• Review the possibility <strong>of</strong> co-existing disease (e.g. gout,<br />
angina) that would influence the choice <strong>of</strong> drug.<br />
• The ‘ABCD’ rule provides a useful basis for starting<br />
drug treatment. A (<strong>and</strong> B) drugs inhibit the<br />
renin–angiotensin–aldosterone axis <strong>and</strong> are effective<br />
when this is active – as it usually is in young white or<br />
Asian people. An A drug is preferred for these unless<br />
there is some reason to avoid it (e.g. in a young woman<br />
contemplating pregnancy) or some additional reason<br />
(e.g. co-existing angina) to choose a B drug. Older people<br />
<strong>and</strong> people <strong>of</strong> Afro-Caribbean ethnicity <strong>of</strong>ten have a low<br />
plasma renin <strong>and</strong> in these patients a class C or D drug is<br />
preferred.<br />
• Use a low dose <strong>and</strong>, except in emergency situations, titrate<br />
this upward gradually.<br />
• Addition <strong>of</strong> a second drug is <strong>of</strong>ten needed. A drug <strong>of</strong> the<br />
other group is added, i.e. an A drug is added to patients<br />
started on a C or D drug, a C or D drug is added to a<br />
patient started on an A drug. A third or fourth drug may<br />
be needed. It is better to use such combinations than to<br />
use very high doses <strong>of</strong> single drugs: this seldom works<br />
<strong>and</strong> <strong>of</strong>ten causes adverse effects.<br />
• Loss <strong>of</strong> control – if blood pressure control, having been<br />
well established, is lost, there are several possibilities to be<br />
considered:<br />
• non-adherence;<br />
• drug interaction – e.g. with non-steroidal antiinflammatory<br />
drugs (NSAIDs) – see Chapter 26;<br />
• intercurrent disease – e.g. renal impairment,<br />
atheromatous renal artery stenosis.<br />
DRUGS USED TO TREAT HYPERTENSION<br />
A DRUGS<br />
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS<br />
Use<br />
Several angiotensin-converting enzyme inhibitors (ACEI) are in<br />
clinical use (e.g. ramipril, tr<strong>and</strong>olapril, enalapril, lisinopril,<br />
captopril). These differ in their duration <strong>of</strong> action. Longer-acting<br />
drugs (e.g. tr<strong>and</strong>olapril, ramipril) are preferred. They are given<br />
once daily <strong>and</strong> produce good 24-hour control. Their beneficial<br />
effect in patients with heart failure (Chapter 31) or following<br />
myocardial infarction (Chapter 29) makes them or a sartan<br />
(below) particularly useful in hypertensive patients with these<br />
complications. Similarly an ACEI or sartan is preferred over<br />
other anti-hypertensives in diabetic patients because they slow<br />
the progression <strong>of</strong> diabetic nephropathy.<br />
Treatment is initiated using a small dose given last thing at<br />
night, because <strong>of</strong> the possibility <strong>of</strong> first-dose hypotension.<br />
If possible, diuretics should be withheld for one or two days<br />
before the first dose for the same reason. The dose is subsequently<br />
usually given in the morning <strong>and</strong> increased gradually<br />
if necessary, while monitoring the blood-pressure response.<br />
Mechanism <strong>of</strong> action<br />
ACE catalyses the cleavage <strong>of</strong> a pair <strong>of</strong> amino acids from<br />
short peptides, thereby ‘converting’ the inactive decapeptide<br />
angiotensin I to the potent vasoconstrictor angiotensin II<br />
(Figure 28.4). As well as activating the vasoconstrictor<br />
angiotensin in this way, it also inactivates bradykinin – a<br />
vasodilator peptide. ACEI lower blood pressure by reducing<br />
angiotensin II <strong>and</strong> perhaps also by increasing vasodilator