Calcium channel blocking drugs (CCBs) bind to different calcium channel sites and have varying effects on cardiac and vascular tissue. Nifedipine is the most selective vasodilator while verapamil and diltiazem are more equipotent between cardiac tissue and vasculature. CCBs reduce afterload through peripheral vasodilation but have little effect on preload or contractility. Nifedipine is most likely to cause hypotension and reflex tachycardia due to its strong vasodilatory effects, while verapamil may worsen heart failure or cause heart block.

1. Calcium Channel Blocking Drugs

2. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

3. Three Classes of CCBs Chemical Type Chemical Names Brand Names Phenylalkylamines verapamil Calan, Calna SR, Isoptin SR, Verelan Benzothiazepines diltiazem Cardizem CD, Dilacor XR 1,4-Dihydropyridines Nifedipine nicardipine isradipine felodipine amlodipine Adalat CC, Procardia XL Cardene DynaCirc Plendil Norvasc

4. Angina pectoris Hypertension Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation - Paroxysmal SVT Widespread use of CCBs

5. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

6. The Three Classes of CCBs Bind to Different Sites 1,4- Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Ca 2+ pore - - - - + + -

7. Increase the time that Ca 2+ channels are closed Relaxation of the arterial smooth muscle but not much effect on venous smooth muscle Significant reduction in afterload but not preload CCBs – Mechanisms of Action

8. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

9. Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

10. N-type and P-type Ca 2+ channels mediate neurotransmitter release in neurons postsynaptic cell Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+

11. Skeletal muscle relies on intracellular Ca 2+ for contraction Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Tubules of SR Triad T SR

12. Cardiac cells rely on L-type Ca 2+ channels for contraction and for the upstroke of the AP in slow response cells Contractile Cells (atria, ventricle) L-Type Ca 2+ Ca 2+ Ca 2+ Slow Response Cells (SA node, AV node) L-Type Ca 2+ Ca 2+

13. Vascular smooth muscle relies on Ca 2+ influx through L-type Ca 2+ channels for contraction (graded, Ca 2+ dependent contraction) L-Type Ca 2+

14. CCBs Act Selectively on Cardiovascular Tissues Neurons rely on N-and P-type Ca 2+ channels Skeletal muscle relies primarily on [Ca] i Cardiac muscle requires Ca 2+ influx through L-type Ca 2+ channels - contraction (fast response cells) - upstroke of AP (slow response cells) Vascular smooth muscle requires Ca 2+ influx through L-type Ca 2+ channels for contraction

15. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

16. Differential effects of different CCBs on CV cells AV SN AV SN Potential reflex increase in HR, myocardial contractility and O 2 demand Coronary VD Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating Peripheral and coronary vasodilation Reduced inotropism Peripheral vasodilation

17. Hemodynamic Effects of CCBs Effect Verapamil Diltiazem Nifedipine Peripheral vasodilatation    Coronary vasodilatation    Preload 0 0 0/ Afterload    Contractility  0/   /  * Heart rate 0/    /0 AV conduction   0

18. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

19. CCBs: Pharmacokinetics Agent Oral Absorption (%) Bioavail- Ability (%) Protein Bound (%) Elimination Half-Life (h) Verapamil >90 10-35 83-92 2.8-6.3* Diltiazem >90 41-67 77-80 3.5-7 Nifedipine >90 45-86 92-98 1.9-5.8 Nicardipine -100 35 >95 2-4 Isradipine >90 15-24 >95 8-9 Felodipine -100 20 >99 11-16 Amlodipine >90 64-90 97-99 30-50

20. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

21. Comparative Adverse Effects Diltiazem Verapamil Dihydropyridines Overall 0-3% 10-14% 9-39% Hypotension ++ ++ +++ Headaches 0 + +++ Peripheral Edema ++ ++ +++ Constipation 0 ++ 0 CHF (Worsen) 0 + 0 AV block + ++ 0 Caution w/beta blockers + ++ 0

22. heart rate blood pressure anginal symptoms signs of CHF adverse effects CCBs - Monitoring

23. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

24. Contradications for CCBs Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV conduction defects ++ 0 ++ Severe cardiac failure ++ + +

25. Outline Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary

26. Which CCB is most likely to cause hypotension and reflex tachycardia? Diltiazem Nifedipine Verapamil

27. Contraindications for CCBs include (choose all appropriate): Supraventricular tachycardias Hypotension AV heart block Hypertension Congestive heart failure

28. CCBs may improve cardiac function by: Reducing cardiac afterload Increasing O 2 supply Decreasing cardiac preload Normalizing heart rate in patients with supraventricular tachycardias

29. Thank you!