Clinical Pharmacology and Therapeutics

202 ISCHAEMIC HEART DISEASE
maximizing its cardiovascular benefits. Aspirin acetylates
platelet COX as platelets circulate through portal venous
blood (where the acetylsalicylic acid concentration is high
during absorption of aspirin from the gastro-intestinal tract),
whereas systemic endothelial cells are exposed to much lower
concentrations because at low doses hepatic esterases result in
little or no aspirin entering systemic blood. This has been
demonstrated experimentally, but the strategy has yet to be
shown to result in increased antithrombotic efficacy of very
low doses. In practice, even much higher doses given once
daily or every other day achieve considerable selectivity for
platelet vs. endothelial COX, because platelets (being anucleate)
do not synthesize new COX after their existing supply has
been irreversibly inhibited by covalent acetylation by aspirin,
whereas endothelial cells regenerate new enzyme rapidly
(within six hours in healthy human subjects). Consequently,
there is selective inhibition of platelet COX for most of the
dose interval if a regular dose of aspirin is administered every
24 or 48 hours.
FIBRINOLYTIC DRUGS
Several fibrinolytic drugs are used in acute myocardial
infarction, including streptokinase, alteplase, reteplase and
tenecteplase. Streptokinase works indirectly, combining with
plasminogen to form an activator complex that converts the
remaining free plasminogen to plasmin which dissolves fibrin
clots. Alteplase, reteplase and tenecteplase are direct-acting
plasminogen activators. Fibrinolytic therapy is indicated,
when angioplasty is not available, for STEMI patients with STsegment
elevation or bundle-branch block on the ECG. The
maximum benefit is obtained if treatment is given within 90
minutes of the onset of pain. Treatment using streptokinase
with aspirin is effective, safe and relatively inexpensive.
Alteplase, reteplase and tenecteplase, which do not produce
a generalized fibrinolytic state, but selectively dissolve
recently formed clot, are also safe and effective; reteplase and
tenecteplase can be given by bolus injection (two injections
intravenously separated by 30 minutes for reteplase, one single
intravenous injection for tenecteplase), whereas alteplase
has to be given by intravenous infusion. Despite their higher
cost than streptokinase, such drugs have been used increasingly
over streptokinase in recent years, because of the
occurrence of immune reactions and of hypotension with
streptokinase. Being a streptococcal protein, individuals who
have been exposed to it synthesize antibodies that can cause
allergic reactions or (much more commonly) loss of efficacy
due to binding to and neutralization of the drug. Individuals
who have previously received streptokinase (more than a few
days ago) should not be retreated with this drug if they
reinfarct. The situation regarding previous streptococcal infection
is less certain. Such infections (usually in the form of sore
throats) are quite common and often go undiagnosed; the
impact that such infections (along with more severe streptococcal
infections, such as cellullitis or septicaemia) have on the
efficacy of streptokinase treatment is uncertain, but likely to
be significant. Hypotension may occur during infusion of
streptokinase, partly as a result of activation of kinins and
other vasodilator peptides. The important thing is tissue perfusion
rather than the blood pressure per se, and as long as the
patient is warm and well perfused, the occurrence of hypotension
is not an absolute contraindication to the use of fibrinolytic
therapy, although it does indicate the need for particularly
careful monitoring and perhaps for changing to an alternative
(non-streptokinase) fibrinolytic agent.
Key points
Ischaemic heart disease: pathophysiology and
management
• Ischaemic heart disease is caused by atheroma in
coronary arteries. Primary and secondary prevention
involves strict attention to dyslipidaemia, hypertension
and other modifiable risk factors (smoking, obesity,
diabetes).
• Stable angina is caused by narrowing of a coronary
artery leading to inadequate myocardial perfusion
during exercise. Symptoms may be relieved or
prevented (prophylaxis) by drugs that alter the balance
between myocardial oxygen supply and demand by
influencing haemodynamics. Organic nitrates,
nicorandil and Ca 2 -antagonists do this by relaxing
vascular smooth muscle, whereas β-adrenoceptor
antagonists slow the heart.
• In most cases, the part played by coronary spasm is
uncertain. Organic nitrates and Ca 2 -antagonists
oppose such spasm.
• Unstable angina and NSTEMI are caused by fissuring of
an atheromatous plaque leading to thrombosis, in the
latter case causing some degree of myocardial necrosis.
They are treated with aspirin, clopidogrel and heparin
(usually low-molecular-weight heparin nowadays),
which improve outcome, and with intravenous glyceryl
trinitrate if necessary for relief of anginal pain; most
cases should undergo coronary angiography at some
stage to delineate the extent/degree of disease and
suitability for PCI or CABG, and this should be done
early in patients who fail to settle on medical therapy.
• STEMI is caused by complete occlusion of a coronary
artery by thrombus arising from an atheromatous
plaque, and is more extensive and/or involves a greater
thickness of the myocardium than NSTEMI. It is treated
by early (primary) angioplasty where this is available;
where not available, fibrinolytic drugs (with or without
heparin/low-molecular-weight heparin) should be
given. Important adjunctive therapy includes aspirin
and clopidogrel, inhaled oxygen and opoids.
Angiotensin-converting enzyme inhibition, angiotensin
receptor blockade and aldosterone antagonism (with
eplerenone) each improve outcome in patients with
ventricular dysfunction; whether the use of all three of
these treatment modalities in combination confers
additional benefit over maximal dosage with one of
these agents remains a matter of debate.
• After recovery from myocardial infarction, secondary
prophylaxis is directed against atheroma, thrombosis
(aspirin) and dysrhythmia (β-adrenoceptor antagonists,
which also prevent re-infarction) and in some patients
is used to improve haemodynamics (angiotensinconverting
enzyme inhibitors, angiotensin receptor
blockers and/or eplerenone).