Many vasodilators can be shown to increase coronary flow in the absence of atherosclerotic disease. These include dipyridamole and adenosine. In fact, dipyridamole is an extremely effec-tive coronary dilator, but it is not effective in angina because of coronary steal (see below). Adenosine, the naturally occur-ring nucleoside, acts on specific membrane-bound receptors, including at least four subtypes (A1, A2A, A2B, and A3). Adenosine, acting on A2A receptors, causes a very brief but marked dilation of the coronary resistance vessels and has been used as a drug to measure maximum coronary flow (“fractional flow reserve,” FFR) in patients with coronary disease. The drug also markedly slows or blocks atrioventricular (AV) conduction in the heart and is used to convert AV nodal tachycardias to normal sinus rhythm (see Chapter 14). Regadenoson is a selective A2A agonist and has been developed for use in stress testing in suspected coronary artery disease and for imaging the coronary circulation. It appears to have a better benefit-to-risk ratio than adenos-ine in these applications. Similar A2A agonists (binodenoson, apadenoson) are investigational. Adenosine receptor ligands are also under investigation for anti-inflammatory and antinocicep-tive and other neurological applications. Coronary steal is the term given to the action of nonselective coronary arteriolar dilators in patients with partial obstruction of a portion of the coronary vasculature. It results from the fact that in the absence of drugs, arterioles in ischemic areas of the myo-cardium are usually maximally dilated as a result of local control factors, whereas the resistance vessels in well-perfused regions are capable of further dilation in response to exercise. If a potent arteriolar dilator is administered, only the vessels in the well-perfused regions are capable of further dilation, so more flow is diverted (“stolen”) from the ischemic region into the normal region. Dipyridamole, which acts in part by inhibiting adenosine uptake, typically produces this effect in patients with angina. In patients with unstable angina, transient coronary steal may precipitate a myocardial infarction. Adenosine and regadenoson are labeled with warnings of this effect.
Clinical Uses of Calcium Channel-Blocking Drugs
In addition to angina, calcium channel blockers have well-documented efficacy in hypertension (see Chapter 11) and supraventricular tachyarrhythmias (see Chapter 14). They also show moderate efficacy in a variety of other conditions, including hypertrophic cardiomyopathy, migraine, and Raynaud’s phenomenon. Nifedipine has some efficacy in preterm labor but is more toxic and not as effective as atosiban, an investigational oxytocin antagonist (see Chapter 17).
The pharmacokinetic properties of these drugs are set forth in Table 12–5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with β blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of failure as a result of their negative inotropic effect. Amlodipine, however, does not increase mortality in patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients.