DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Combination Therapy and New Anti-Anginal Drugs.
Because the different categories of anti-anginal agents
have different mechanisms of action, it has been suggested
that combinations of these agents would allow
the use of lower doses, increasing effectiveness and
reducing the incidence of side effects. However, despite
the predicted advantages, combination therapy rarely
achieves this potential and may be accompanied by serious
side effects. The new anti-anginal agent ranolazine
elicits its therapeutic effects by different and incompletely
understood mechanisms that distinguish this new
drug from the “classical” classes of anti-anginal drugs
(organic nitrates, β adrenergic blockers and Ca 2+
channel blockers). Some studies have suggested that
ranolazine may have additional efficacy in combination
with other anti-anginal agents (Chaitman et al., 2004),
and the effects of ranolazine on cardiac arrhythmias and
glucose metabolism may identify indications for this
drug independent of its role as an anti-anginal agent
(Morrow et al., 2009). Indeed, most of the anti-anginal
drugs have broader indications in cardiovascular therapeutics,
including (among others): β blockers for treatment
of hypertension, arrhythmias, and heart failure;
dihydropyridine calcium channel blockers in treatment
of hypertension and heart failure; and diltiazem and verapamil
to treat cardiac arrhythmias and hypertension.
Table 27–3 shows some of the important indications and
contraindications for use of anti-anginal agents in the
context of other disease states.
Nitrates and β Adrenergic Receptor Antagonists. The concurrent
use of organic nitrates and β adrenergic receptor
antagonists can be very effective in the treatment of
typical exertional angina. The additive efficacy primarily
is a result of the blockade by one drug of a reflex
effect elicited by the other. β Adrenergic receptor antagonists
can block the baroreceptor-mediated reflex
tachycardia and positive inotropic effects that are sometimes
associated with nitrates, whereas nitrates, by
increasing venous capacitance, can attenuate the
increase in left ventricular end-diastolic volume associated
with β receptor blockade. Concurrent administration
of nitrates also can alleviate the increase in
coronary vascular resistance associated with blockade
of β adrenergic receptors.
Ca 2+ Channel Blockers and β Receptor Antagonists. Because
there is a proven mortality benefit from the use of β
adrenergic receptor antagonists in patients with heart disease,
this class of drugs represents the first line of therapy.
However, when angina is not controlled adequately by a
β receptor antagonist plus nitrates, additional improvement
sometimes can be achieved by the addition of a Ca 2+
channel blocker, especially if there is a component of
coronary vasospasm. The differences among the chemical
classes of Ca 2+ channel blockers can lead to important
adverse or salutary drug interactions with β receptor
antagonists. If the patient already is being treated with
maximal doses of verapamil or diltiazem, it is difficult to
demonstrate any additional benefit of β receptor blockade,
and excessive bradycardia, heart block, or heart failure
may ensue. However, in patients treated with a
dihydropyridine such as nifedipine or with nitrates, substantial
reflex tachycardia often limits the effectiveness
of these agents. A β receptor antagonist may be a helpful
addition in this situation, resulting in a lower heart rate
and blood pressure with exercise. The efficacy of
amlodipine is improved by combination with a β adrenergic
receptor antagonist. However, in the Total Ischaemic
Burden European Trial (TIBET), which compared the
effects of atenolol, a sustained-release form of nifedipine,
and their combination on exercise parameters and ambulatory
ischemia in patients with mild angina, there were
no differences between the agents, either singly or in combination,
on any of the measured ischemic parameters
(Fox et al., 1996). On the other hand, in studies of patients
with more severe but still stable angina, atenolol and propranolol
were shown to be superior to nifedipine, and the
combination of propranolol and nifedipine was more
effective than a β receptor antagonist alone.
Relative contraindications to the use of β receptor antagonists
for treatment of angina—bronchospasm, Raynaud’s syndrome,
or Prinzmetal angina—may lead to a choice to initiate therapy with
a Ca 2+ channel blocker. Fluctuations in coronary tone are important
determinants of variant angina. It is likely that episodes of increased
tone, such as those precipitated by cold and by emotion, superimposed
on fixed disease have a role in the variable anginal threshold
seen in some patients with otherwise chronic stable angina. Increased
coronary tone also may be important in the anginal episodes occurring
early after MI and after coronary angioplasty, and it probably
accounts for those patients with unstable angina who respond to dihydropyridines.
Atherosclerotic arteries have abnormal vasomotor
responses to a number of stimuli (Dudzinski et al., 2006), including
exercise, other forms of sympathetic activation, and cholinergic agonists;
in such vessels, stenotic segments actually may become more
severely stenosed during exertion. This implies that the normal exercise-induced
increase in coronary flow is lost in atherosclerosis.
Similar exaggerated vascular contractile responses are seen in hyperlipidemia,
even before anatomical evidence of atherosclerosis develops.
Because of this, coronary vasodilators (nitrates and/or Ca 2+
channel blockers) are an important part of the therapeutic program
in the majority of patients with ischemic heart disease.
Ca 2+ Channel Blockers and Nitrates. In severe exertional
or vasospastic angina, the combination of a nitrate and
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION