Page 220 - Basic _ Clinical Pharmacology ( PDFDrive )

206 SECTION III Cardiovascular-Renal Drugs

Special Coronary Vasodilators

Many vasodilators can be shown to increase coronary flow in the apadenoson) are investigational. Adenosine receptor ligands are
absence of atherosclerotic disease. These include dipyridamole also under investigation for anti-inflammatory and antinocicep-
and adenosine. In fact, dipyridamole is an extremely effec- tive and other neurological applications.
tive coronary dilator, but it is not effective in angina because Coronary steal is the term given to the action of nonselective
of coronary steal (see below). Adenosine, the naturally occur- coronary arteriolar dilators in patients with partial obstruction of
ring nucleoside, acts on specific membrane-bound receptors, a portion of the coronary vasculature. It results from the fact that
including at least four subtypes (A 1 , A 2A , A 2B , and A 3 ). Adenosine, in the absence of drugs, arterioles in ischemic areas of the myo-
acting on A 2A receptors, causes a very brief but marked dilation cardium are usually maximally dilated as a result of local control
of the coronary resistance vessels and has been used as a drug factors, whereas the resistance vessels in well-perfused regions
to measure maximum coronary flow (“fractional flow reserve,” are capable of further dilation in response to exercise. If a potent
FFR) in patients with coronary disease. The drug also markedly arteriolar dilator is administered, only the vessels in the well-
slows or blocks atrioventricular (AV) conduction in the heart perfused regions are capable of further dilation, so more flow
and is used to convert AV nodal tachycardias to normal sinus is diverted (“stolen”) from the ischemic region into the normal
rhythm (see Chapter 14). Regadenoson is a selective A 2A agonist region. Dipyridamole, which acts in part by inhibiting adenosine
and has been developed for use in stress testing in suspected uptake, typically produces this effect in patients with angina.
coronary artery disease and for imaging the coronary circulation. In patients with unstable angina, transient coronary steal may
It appears to have a better benefit-to-risk ratio than adenos- precipitate a myocardial infarction. Adenosine and regadenoson
ine in these applications. Similar A 2A agonists (binodenoson, are labeled with warnings of this effect.

Clinical Uses of Calcium Channel-Blocking level have also been demonstrated with diltiazem and nifedipine,
Drugs such interactions are less consistent than with verapamil.
In patients with unstable angina, immediate-release short-acting
In addition to angina, calcium channel blockers have well- calcium channel blockers can increase the risk of adverse cardiac
documented efficacy in hypertension (see Chapter 11) and events and therefore are contraindicated (see Toxicity, above). How-
supraventricular tachyarrhythmias (see Chapter 14). They also ever, in patients with non–Q-wave myocardial infarction, diltiazem
show moderate efficacy in a variety of other conditions, including can decrease the frequency of postinfarction angina and may be used.
hypertrophic cardiomyopathy, migraine, and Raynaud’s phenom-
enon. Nifedipine has some efficacy in preterm labor but is more BETA-BLOCKING DRUGS
toxic and not as effective as atosiban, an investigational oxytocin
antagonist (see Chapter 17). Although they are not vasodilators (with the exception of carvedilol
The pharmacokinetic properties of these drugs are set forth in and nebivolol), β-blocking drugs (see Chapter 10) are extremely
Table 12–5. The choice of a particular calcium channel-blocking useful in the management of effort angina and are considered
agent should be made with knowledge of its specific potential first-line drugs in chronic effort angina. The beneficial effects
adverse effects as well as its pharmacologic properties. Nifedipine of β-blocking agents are related to their hemodynamic effects—
does not decrease atrioventricular conduction and therefore can decreased heart rate, blood pressure, and contractility—which
be used more safely than verapamil or diltiazem in the presence of decrease myocardial oxygen requirements at rest and during exer-
atrioventricular conduction abnormalities. A combination of vera- cise. Lower heart rate is also associated with an increase in diastolic
pamil or diltiazem with β blockers may produce atrioventricular perfusion time that may increase coronary perfusion. However,
block and depression of ventricular function. In the presence of reduction of heart rate and blood pressure, and consequently
overt heart failure, all calcium channel blockers can cause further decreased myocardial oxygen consumption, appear to be the most
worsening of failure as a result of their negative inotropic effect. important mechanisms for relief of angina and improved exercise
Amlodipine, however, does not increase mortality in patients tolerance. Beta blockers may also be valuable in treating silent or
with heart failure due to nonischemic left ventricular systolic dys- ambulatory ischemia. Because this condition causes no pain, it is
function and can be used safely in these patients. usually detected by the appearance of typical electrocardiographic
In patients with relatively low blood pressure, dihydropyridines signs of ischemia. The total amount of “ischemic time” per day
can cause further deleterious lowering of pressure. Verapamil and is reduced by long-term therapy with a β blocker. Beta-blocking
diltiazem appear to produce less hypotension and may be better agents decrease mortality of patients with heart failure or recent
tolerated in these circumstances. In patients with a history of atrial myocardial infarction and improve survival and prevent stroke in
tachycardia, flutter, and fibrillation, verapamil and diltiazem pro- patients with hypertension. Randomized trials in patients with sta-
vide a distinct advantage because of their antiarrhythmic effects. ble angina have shown better outcome and symptomatic improve-
In the patient receiving digitalis, verapamil should be used with ment with β blockers compared with calcium channel blockers.
caution, because it may increase digoxin blood levels through a Undesirable effects of β-blocking agents in angina include an
pharmacokinetic interaction. Although increases in digoxin blood increase in end-diastolic volume and an increase in ejection time,