Non-Dihydropyridine Calcium Channel Blockers (CCBs)
The non-dihydropyridine calcium channel blockers (CCBs) are verapamil and diltiazem, which bind to different sites on the α1-subunit of the L-type calcium channel compared to dihydropyridine CCBs and have significant negative chronotropic, dromotropic, and inotropic effects on the heart. 1
Characteristics of Non-Dihydropyridine CCBs
Non-dihydropyridine CCBs include two main classes: phenylalkylamines (verapamil-like) and benzothiazepines (diltiazem-like) 1
They are less selective for vascular smooth muscle compared to dihydropyridine CCBs and have more pronounced effects on cardiac tissue 1
They have negative chronotropic (heart rate slowing) and dromotropic (conduction slowing) effects on sinoatrial and atrioventricular nodal conducting tissue 1, 2
They exert negative inotropic effects (decreased contractility) on cardiomyocytes 1, 3
Non-dihydropyridine CCBs have greater effects on the atrioventricular node than on the sinoatrial node 1
Clinical Applications
Both verapamil and diltiazem are indicated for the treatment of hypertension and angina pectoris 1
They are recommended for ischemic symptoms when beta blockers are not successful, contraindicated, or cause unacceptable side effects 1
In patients with NSTE-ACS (Non-ST-Elevation Acute Coronary Syndromes), non-dihydropyridine CCBs should be given as initial therapy when beta blockers are contraindicated, in the absence of significant LV dysfunction, increased risk for cardiogenic shock, PR interval >0.24 second, or high-degree AV block 1
They are particularly effective in treating angina due to coronary spasm (e.g., Prinzmetal's variant or cold-induced angina) 1
Pharmacological Properties
Verapamil and diltiazem inhibit voltage-dependent L-type calcium channels, leading to vascular smooth muscle relaxation and negative cardiac effects 4, 3
At low dose ranges, they primarily affect the L-type calcium receptors in the myocardium, while dihydropyridine CCBs primarily affect peripheral vasculature 2
The mean vascular/cardiac effect ratios of verapamil and diltiazem are approximately 3, which is lower than dihydropyridine CCBs like nifedipine (ratio of 10) 3
In overdose situations, non-dihydropyridine CCBs can cause severe bradycardia and negative inotropy 2
Clinical Considerations and Cautions
Non-dihydropyridine CCBs may predispose to high-degree atrioventricular block when administered to patients with preexisting atrioventricular nodal disease 1
They should be used cautiously when combined with other agents that depress the atrioventricular node, such as beta-blockers 1
Diltiazem or verapamil should not be used in patients with heart failure or left ventricular systolic dysfunction 1
Long-acting dihydropyridine agents are preferred over non-dihydropyridines when used in combination with beta-blockers to avoid excessive bradycardia or heart block 1
Non-dihydropyridine CCBs (diltiazem and verapamil) have important drug interactions with digoxin, cyclosporine, and certain statins 1, 5
Drug Interactions
Diltiazem and verapamil are moderate to weak inhibitors of CYP3A4 and can increase exposure to statins metabolized by this pathway (simvastatin, lovastatin, atorvastatin) 1
Combination therapy with atorvastatin and diltiazem results in a minor increase in statin exposure 1
Interactions between diltiazem and either lovastatin or simvastatin are associated with moderate increases in statin exposure 1
Rhabdomyolysis has been reported in patients on stable treatment with atorvastatin after diltiazem was added 1
By understanding the distinct properties of non-dihydropyridine CCBs compared to dihydropyridine CCBs, clinicians can make appropriate choices when selecting calcium channel blockers for specific clinical scenarios.