A Textbook of Clinical Pharmacology and Therapeutics

(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 anti-
    inflammatory 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 subse-

quently 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

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 anti-
hypertensive drugs.

DRUGSUSED TOTREATHYPERTENSION 187

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