1. Calcium Channel Blocking Drugs

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. Three Classes of CCBs N CH 2 CH 2 N 0 CH 3 0 C CH 3 0 CH 3 CH 3 Diltiazem C 0 CH 3 NO 2 CH 3 H 3 C C 0 H 3 C 0 0 Nifedipine C CH 2 CH 2 CH 2 CH 2 CH 2 N CH 3 CH 3 C N CH H 3 C 0 H 3 C 0 H 3 C 0 CH 3 0 CH 3 Verapamil N H S

7. The  1C subunit of the L-type Ca 2+ channel is the pore-forming subunit III IV II I IV III 5 6 5 6 Out In I II III IV

8. The expression and function of the  1C subunit is modulated by other smaller subunits L-Type Ca 2+ Channel NH 3 + NH 3 + COO - COO -   1C NH 3 + COO -  2 I II III IV COO - NH 3 + 

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

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

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

14. 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+

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

16. 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+

17. 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+

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

21. 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

22. 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

24. 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

26. 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

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

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