A Textbook of Clinical Pharmacology and Therapeutics

DRUGSUSED INISCHAEMICHEARTDISEASE 201

Mechanism of action

GTNworks by relaxing vascular smooth muscle. It is metabo-
lized by smooth-muscle cells with generation of nitric oxide
(NO). This combines with a haem group in the soluble isoform
of guanylyl cyclase, activating this enzyme and thereby
increasing the cytoplasmic concentration of the second mes-
senger cGMP. cGMP causes sequestration of Ca^2 within the
sarcoplasmic reticulum, thus relaxing smooth muscle. NO is
also synthesized from endogenous substrate (L-arginine)
under physiological conditions by a constitutive enzyme in
vascular endothelial cells and is Furchgott’s ‘endothelium-
derived relaxing factor’. This endogenous NO is responsible
for the resting vasodilator tone present in human resistance
arterioles under basal conditions. Nitrovasodilator drugs pro-
vide NO in an endothelium-independent manner, and are
therefore effective even if endothelial function is severely
impaired, as in many patients with coronary artery disease.

Haemodynamic and related effects

GTNis relatively selective for venous rather than arteriolar
smooth muscle. Venodilatation reduces cardiac preload.
Reduced venous return reduces ventricular filling and hence
reduces ventricular diameter. Ventricular wall tension is
directly proportional to chamber diameter (the Laplace rela-
tionship), so ventricular wall tension is reduced by GTN. This
reduces cardiac work and oxygen demand. Coronary blood
flow (which occurs during diastole) improves due to the
decreased left ventricular end-diastolic pressure. Spasm is
opposed by NO-mediated coronary artery relaxation.
Reduced arterial tone reduces diastolic blood pressure and
arterial wave reflection hence reducing cardiac afterload and
myocardial oxygen demand. Nitrates relax some non-vascular
smooth muscles and therefore sometimes relieve the pain of
oesophageal spasm and biliary or renal colic, causing poten-
tial diagnostic confusion.

Adverse effects

Organic nitrates are generally very safe, although they can
cause hypotension in patients with diminished cardiac
reserve. Headache is common and GTNpatches have not
fared well when evaluated by ‘quality of life’ questionnaires
for this reason. Tolerance is another problem. This can be min-
imized by omitting the evening dose of isosorbide mono-
nitrate (or by removing a patch at night).

β-ADRENOCEPTOR ANTAGONISTS

For more information, see also Chapters 28, 31 and 32.

Use in ischaemic heart disease

The main uses of beta-blockers in patients with ischaemic
heart disease are:

• prophylaxis of angina;


• reduction of the risk of sudden death or reinfarction
  following myocardial infarction (‘secondary prevention’);


• treatment of heart failure (Chapter 31).

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

(ACEI) AND ANGIOTENSIN RECEPTOR BLOCKERS

Use in ischaemic heart disease

As well as their well established uses in hypertension (see

Chapter 28) and in heart failure, including chronic heart fail-

ure caused by ischaemic heart disease (see Chapter 31), there

is also substantial evidence to support the use of ACEI and

angiotensin antagonists in the early stages of myocardial

infarction (see above). The evidence suggests that any benefit

is very small (or non-existent) in patients with completely nor-

mal ventricular function, but that with increasing ventricular

dysfunction there is increasing benefit. Treatment should be

started with small doses with dose titration up to doses that

have been demonstrated to improve survival.

CALCIUM ANTAGONISTS

Use in ischaemic heart disease

Apart from their use in hypertension (Chapter 28) and in the

treatment of cardiac dysrhythmias (see Chapter 32), the main

use of calcium-channel antagonists in patients with ischaemic

heart disease is for the prophylaxis of angina. They are partic-

ularly useful in patients in whom beta-blockers are con-

traindicated. Disappointingly, despite having quite different

pharmacological actions to beta-blockers, these classes of

drugs do not appear to act synergistically in angina and

should not be routinely co-administered as prophylaxis to

such patients. They may be particularly useful in the rare

patients in whom spasm is particularly prominent (spasm can

be worsened by β-blockers). Short-acting dihydropyridines

should be avoided because they cause reflex tachycardia.

Diltiazemor a long-acting dihydropyridine (e.g. amlodipine

or a controlled-release preparation of nifedipine) are often

used in this setting. Unlike β-adrenoceptorantagonists and

ACEI, Ca^2 antagonists have not been found to prolong sur-

vival when administered early in the course of myocardial

infarction.

DRUGS THAT INFLUENCE THROMBOSIS

ASPIRIN AND CLOPIDOGREL

The use of aspirinas a mild analgesic is described in Chapter 25,

and the antiplatelet uses of aspirinandclopidogrelare dis-

cussed in Chapter 30. There is no evidence that the efficacy of

aspirinvaries with dose over the range 75–320 mg/day dur-

ing chronic use, but there is evidence that the adverse effect of

peptic ulceration and major upper gastro-intestinal haemor-

rhage is dose related over this range. Accordingly, the lower

dose should be used routinely for chronic prophylaxis. At the

onset of ACS it is appropriate to use a higher dose (e.g.

300 mg) to obtain rapid and complete inhibition of platelet

cyclo-oxygenase (COX). There has been considerable interest

in the possibility that very low doses of aspirin(40 mg/day or

less) may provide the highest degree of selectivity for inhibi-

tion of platelet TXA 2 biosynthesis as opposed to endothelial

prostacyclin (PGI 2 ) biosynthesis in blood vessels, thereby