Calcium Channel Blocking Drugs

1. Calcium Channel Blocking Drugs

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

3. 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 Three Classes of CCBs

4. Three Classes of CCBs H3C CH3 CH3 H3C 0 0 CH3 CH CH2 CH3 0 0 C CH2 N CH2 CH2 CH2 H3C N C Verapamil NO2 CH3 S N CH2 N CH2 0 0 CH3 C 0 H3C 0 C CH3 C CH3 0 0 H3C CH3 0 N H CH3 Diltiazem Nifedipine

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

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

7. I II III IV Out In 6 IV III 5 5 IV III 6 II I The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit

8. a2 a1C NH3+ COO- I II III IV NH3+ COO- d COO- NH3+ b NH3+ COO- The expression and function of the 1C subunit is modulated by other smaller subunits L-Type Ca2+ Channel

9. 1,4- Dihydropyridines (nifedipine) - + - + Ca2+ pore - - Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) - The Three Classes of CCBs Bind to Different Sites

10. CCBs – Mechanisms of Action • Increase the time that Ca2+ channels are closed • Relaxation of the arterial smooth muscle but not much effect on venous smooth muscle • Significant reduction in afterload but not preload

11. The different binding sites of CCBs result in differing pharmacological effects Use-dependent binding (targets cardiac cells) out +20  2 mV 1 Cell membrane 1  -80 in  Diltiazem Verapamil Voltage-dependent binding (targets smooth muscle) +20 out  -30 2 Cell membrane 1 -80 1  mV in  Nifedipine

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

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

14. N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ postsynaptic cell

15. Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Triad SR T Tubules of SR Skeletal muscle relies on intracellular Ca2+ for contraction

16. Ca2+ Ca2+ L-Type L-Type Ca2+ Ca2+ Ca2+ Contractile Cells (atria, ventricle) Slow Response Cells (SA node, AV node) Cardiac cells rely on L-type Ca2+ channels for contraction and for the upstroke of the AP in slow response cells

17. Ca2+ L-Type (graded, Ca2+ dependent contraction) Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction

18. CCBs Act Selectively on Cardiovascular Tissues • Neurons rely on N-and P-type Ca2+ channels • Skeletal muscle relies primarily on [Ca]i • Cardiac muscle requires Ca2+ influx through L-type Ca2+ channels - contraction (fast response cells) - upstroke of AP (slow response cells) • Vascular smooth muscle requires Ca2+ influx through L-type Ca2+ channels for contraction

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

20. The different binding sites of CCBs result in differing pharmacological effects Use-dependent binding (targets cardiac cells) out +20  2 mV 1 Cell membrane 1  -80 in  Diltiazem Verapamil Voltage-dependent binding (targets smooth muscle) +20 out  -30 2 Cell membrane 1 -80 1  mV in  Nifedipine

21. Peripheral vasodilation Differential effects of different CCBs on CV cells Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating Peripheral and coronary vasodilation SN AV Potential reflex increase in HR, myocardial contractility and O2 demand Coronary VD SN AV Reduced inotropism

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

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

24. Agent Oral Absorption (%) Protein Bound (%) Elimination Half-Life (h) Bioavail- Ability (%) 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 CCBs: Pharmacokinetics

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

26. 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 Comparative Adverse Effects

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

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

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

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

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

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

33. CCBs may improve cardiac function by: • Reducing cardiac afterload • Increasing O2 supply • Decreasing cardiac preload • Normalizing heart rate in patients with • supraventricular tachycardias

34. Thank you!