These pharmacokinetic properties result in high intraindividual and interindividual variability, necessitating dosage adjustment. These drugs should be used with caution when combined with cyclosporine, carbamaz- epine, lithium carbonate, amiodarone, or digoxin (ie, 50% to 70% increase in digoxin concentrations in first week of therapy). Combining verapamil or diltiazem with beta block- ers generally should be avoided because of potentially pro- found adverse effects on AV nodal conduction, heart rate, or cardiac contractility. Overall, calcium channel blockers, particularly diltiazem, are well tolerated. The major adverse effects of dihydropyr- idines are related to vasodilation and systemic hypotension, including headache, dizziness, palpitations, and flushing. Many patients experience peripheral edema because of ex- cessive arterial vasodilation unmatched to venous dilation. Verapamil can cause constipation that can be severe, partic- ularly in the elderly. 4.4.3.1.3. Nitrates. Nitrates are effective in the treatment of all forms of angina. They relax vascular smooth muscle in the systemic arteries, inclusive of the coronary arteries, and veins (predominant effect at lower doses) in patients with SIHD. Short-term continuous nitroglycerin delivery by the intrave- nous or transdermal route for only 2 to 4 hours protects the endothelium from experimental ischemia in healthy volun- teers and reduces ischemia during coronary angioplasty and physical exercise in IHD patients.863 865 Oxygen free radical release seems to be associated with these protective out- comes. 