Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 45 Calcium Channel Blockers

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Calcium Channel Blockers  Drugs that prevent calcium ions from entering cells  Greatest impact on heart and blood vessels  Used to treat hypertension, angina pectoris, and cardiac dysrhythmias  Controversy: safety for patients with hypertension and diabetes  Also known as calcium antagonists and slow channel blockers

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Calcium Channel Blockers  Calcium channels: physiologic functions and consequences of blockade  Calcium channel blockers: classification and sites of action  Verapamil and diltiazem: agents that act on vascular smooth muscle and the heart  Dihydropyridines: agents that act mainly on vascular smooth muscle

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Physiologic Functions and Consequences of Blockade  Vascular smooth muscle  Calcium channels open = Contractile process  Calcium channels blocked = Vasoconstriction  Therapeutic doses  Selectively on peripheral arterioles and arteries and arterioles of the heart  No significant effect on veins

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Physiologic Functions and Consequences of Blockade  Heart  Myocardium  Sinoatrial (SA) node  Atrioventricular (AV) node  Coupling of cardiac calcium channels to beta 1 - adrenergic receptors

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 45–1. Coupling of cardiac calcium channels with beta 1 -adrenergic receptors.

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Classification and Sites of Action  Classification  Dihydropyridines—nifedipine  Phenylalanine—verapamil  Benzothiazepine—diltiazem  Sites of action  Dihydropyridines act primarily on arterioles  Verapamil and diltiazem act on arterioles and on the heart

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil and Diltiazem  Agents that act on vascular smooth muscle and the heart  Hemodynamic effects  Direct effects on the heart and blood vessels  Indirect (reflex) effects  Net effects

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil and Diltiazem: Hemodynamic Effects  Five direct hemodynamic effects  Blockade at peripheral arterioles Reduces arterial pressure Reduces arterial pressure  Blockade at arteries and arterioles of heart Increases coronary perfusion Increases coronary perfusion  Blockade at SA node Reduces heart rate Reduces heart rate  Blockade at AV node (most important) Decreases AV nodal conduction Decreases AV nodal conduction  Blockade in the myocardium Decreases force of contraction Decreases force of contraction

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil and Diltiazem: Hemodynamic Effects  Indirect (reflex) hemodynamic effects  Baroreceptor reflex  Net effects  Little or no net effect on cardiac performance  Vasodilation accompanied by reduced arterial pressure and increased coronary perfusion

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil (Calan, Covera-HS, Isoptin, Verelan)  Therapeutic uses  Angina pectoris Vasospastic angina and angina of effort Vasospastic angina and angina of effort  Essential hypertension First-line agent First-line agent  Cardiac dysrhythmias Atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia Atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia  Migraine

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil (Calan, Covera-HS, Isoptin, Verelan)  Adverse effects  Constipation Most common complaint Most common complaint Results from blockade of calcium channels in smooth muscle of the intestine Results from blockade of calcium channels in smooth muscle of the intestine Especially severe for the elderly Especially severe for the elderly Can be decreased by increasing dietary fiber and fluids Can be decreased by increasing dietary fiber and fluids

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil (Calan, Covera-HS, Isoptin, Verelan)  Adverse effects (cont’d)  Dizziness  Facial flushing  Headache  Edema of ankles and feet  Gingival hyperplasia  Heart block

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil (Calan, Covera-HS, Isoptin, Verelan)  Drug interactions  Digoxin  Beta-adrenergic blocking agents  Toxicity  Severe hypotension  Bradycardia and AV block  Ventricular tachydysrhythmias

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Verapamil (Calan, Covera-HS, Isoptin, Verelan)  IV verapamil for dysrhythmias can cause severe cardiovascular effects.  Blood pressure and ECG should be monitored with resuscitation equipment immediately available.

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diltiazem (Cardizem, Dilacor-XR, Tiazac, Others)  Actions and uses  Blocks calcium channels in the heart and blood vessels (similar to verapamil)  Lowers blood pressure Arteriolar dilation Arteriolar dilation Direct suppressant/reflex cardiac stimulation = Little net effect on heart Direct suppressant/reflex cardiac stimulation = Little net effect on heart

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diltiazem (Cardizem, Dilacor-XR, Tiazac, Others)  Therapeutic uses  Angina pectoris  Hypertension  Cardiac dysrhythmias Atrial flutter, atrial fibrillation, paroxysmal tachycardia Atrial flutter, atrial fibrillation, paroxysmal tachycardia

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diltiazem (Cardizem, Dilacor-XR, Tiazac, Others)  Adverse effects  Similar to verapamil, except for less constipation  Dizziness  Flushing  Headache  Edema of ankles and feet  Exacerbates bradycardia, sick sinus syndrome, heart failure, second- or third-degree heart block

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Diltiazem (Cardizem, Dilacor-XR, Tiazac, Others)  Drug interactions  Digoxin  Beta-adrenergic blocking agents

20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Dihydropyridines  Agents that act mainly on vascular smooth muscle  Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Significant blockade of calcium channels in blood vessels  Minimal blockade of calcium channels in the heart  Similar to verapamil in some respects and quite different in others

21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Vasodilation by blocking calcium channels  Blocks in vascular smooth muscle  Very little blockade of heart Ca channels  Cannot be used to treat dysrhythmias  Less likely than verapamil to exacerbate pre- existing cardiac disorders

22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Direct effects  Limited to blockade of Ca channels in vascular smooth muscle (VSM) No direct suppressant effects on: No direct suppressant effects on:  Automaticity, AV conduction, or contractile force  Indirect effects  Lowered blood pressure (BP) activates baroreceptor reflex  Primarily with fast-acting vs. sustained-release

23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Vasodilation by blocking calcium channels  Net effect Lowered blood pressure Lowered blood pressure Increased heart rate Increased heart rate Increased contractile force Increased contractile force

24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Therapeutic uses  Angina pectoris  Hypertension  Investigational basis to relieve migraine headache and to suppress preterm labor

25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Adverse effects  Flushing  Dizziness  Headache  Peripheral edema  Gingival hyperplasia  Chronic eczematous rash in older patients

26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Adverse effects (cont’d)  Reflex tachycardia  Increases cardiac oxygen demand  Can increase pain for anginal patients  Can be combined with a beta blocker for prevention of reflex tachycardia Note: Beta blockers decrease the adverse cardiac effects of nifedipine, but can intensify the adverse cardiac effects of verapamil and diltiazem Note: Beta blockers decrease the adverse cardiac effects of nifedipine, but can intensify the adverse cardiac effects of verapamil and diltiazem

27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nifedipine (Adalat, Nifedical, Nifediac, Procardia)  Adverse effects (cont’d)  Rapid-acting nifedipine (not sustained) Has been associated with increased mortality in patients with MI and unstable angina Has been associated with increased mortality in patients with MI and unstable angina Other rapid-acting calcium channel blockers also associated Other rapid-acting calcium channel blockers also associated No cause-and-effect relationship established No cause-and-effect relationship established National Heart, Lung, and Blood Institute (NHLBI) recommends these be used with great caution National Heart, Lung, and Blood Institute (NHLBI) recommends these be used with great caution

28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Dihydropyridines  Seven other dihydropyridines available  All similar to nifedipine  Produce greater blockade of Ca channels in the VSM than in the heart  Nicardipine, amlodipine, isradipine, felodipine, nimodipine, nisoldipine, and clevidipine