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calcim

  1. 1. Calcium Channel Blocking Drugs
  2. 2. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li> Summary </li></ul>
  3. 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. 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
  5. 5. <ul><li>Angina pectoris </li></ul><ul><li>Hypertension </li></ul><ul><li>Treatment of supraventricular </li></ul><ul><li>arrhythmias </li></ul><ul><li> - Atrial Flutter </li></ul><ul><li>- Atrial Fibrillation </li></ul><ul><li>- Paroxysmal SVT </li></ul>Widespread use of CCBs
  6. 6. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  7. 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. 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. 9. The Three Classes of CCBs Bind to Different Sites 1,4- Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Ca 2+ pore - - - - + + -
  10. 10. <ul><li>Increase the time that Ca 2+ channels are closed </li></ul><ul><li>Relaxation of the arterial smooth muscle but not </li></ul><ul><li>much effect on venous smooth muscle </li></ul><ul><li>Significant reduction in afterload but not preload </li></ul>CCBs – Mechanisms of Action
  11. 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
  12. 12. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  13. 13. Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?
  14. 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. 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. 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. 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+
  18. 18. CCBs Act Selectively on Cardiovascular Tissues <ul><li>Neurons rely on N-and P-type Ca 2+ channels </li></ul><ul><li>Skeletal muscle relies primarily on [Ca] i </li></ul><ul><li>Cardiac muscle requires Ca 2+ influx through </li></ul><ul><li>L-type Ca 2+ channels </li></ul><ul><li>- contraction (fast response cells) </li></ul><ul><li>- upstroke of AP (slow response cells) </li></ul><ul><li>Vascular smooth muscle requires Ca 2+ influx </li></ul><ul><li>through L-type Ca 2+ channels for contraction </li></ul>
  19. 19. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  20. 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. 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. 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
  23. 23. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  24. 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
  25. 25. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  26. 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
  27. 27. <ul><li>heart rate </li></ul><ul><li>blood pressure </li></ul><ul><li>anginal symptoms </li></ul><ul><li>signs of CHF </li></ul><ul><li>adverse effects </li></ul>CCBs - Monitoring
  28. 28. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  29. 29. Contradications for CCBs Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV conduction defects ++ 0 ++ Severe cardiac failure ++ + +
  30. 30. Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><li>Cardiac & hemodynamic </li></ul><ul><li>differentiation </li></ul><ul><li>Pharmacokinetics </li></ul><ul><li>Adverse effects </li></ul><ul><li>Contraindications </li></ul><ul><li>Summary </li></ul>
  31. 31. Which CCB is most likely to cause hypotension and reflex tachycardia? <ul><li>Diltiazem </li></ul><ul><li>Nifedipine </li></ul><ul><li>Verapamil </li></ul>
  32. 32. Contraindications for CCBs include (choose all appropriate): <ul><li>Supraventricular tachycardias </li></ul><ul><li>Hypotension </li></ul><ul><li>AV heart block </li></ul><ul><li>Hypertension </li></ul><ul><li>Congestive heart failure </li></ul>
  33. 33. CCBs may improve cardiac function by: <ul><li>Reducing cardiac afterload </li></ul><ul><li>Increasing O 2 supply </li></ul><ul><li>Decreasing cardiac preload </li></ul><ul><li>Normalizing heart rate in patients with </li></ul><ul><li>supraventricular tachycardias </li></ul>
  34. 34. Thank you!

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