Calcium Channel  Blocking Drugs
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
Three Classes of CCBs Chemical Type Chemical Names Brand Names Phenylalkylamines verapamil Calan, Calna SR, Isoptin SR, Ve...
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 Nifedipin...
<ul><li>Angina pectoris </li></ul><ul><li>Hypertension </li></ul><ul><li>Treatment of supraventricular </li></ul><ul><li>a...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
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 ...
The expression and function of the   1C subunit  is modulated by other smaller subunits L-Type Ca 2+  Channel   NH 3 + NH...
The Three Classes of CCBs Bind to Different Sites   1,4- Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) Benzo...
<ul><li>Increase the time that Ca 2+  channels are closed </li></ul><ul><li>Relaxation of the arterial smooth muscle but n...
The different binding sites of CCBs result in differing  pharmacological effects Voltage-dependent binding (targets smooth...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
Why Do CCBs Act Selectively  on Cardiac and Vascular Muscle?
N-type and P-type Ca 2+  channels mediate  neurotransmitter release in neurons  postsynaptic cell Ca 2+ Ca 2+ Ca 2+ Ca 2+ ...
Skeletal muscle relies on intracellular Ca 2+  for contraction Myofibril Plasma   membrane Transverse  tubule Terminal  ci...
Cardiac cells rely on L-type Ca 2+  channels for contraction and for the upstroke of the AP in slow response cells Contrac...
Vascular smooth muscle relies on Ca 2+  influx through L-type Ca 2+  channels for contraction (graded, Ca 2+  dependent co...
CCBs Act Selectively on Cardiovascular Tissues <ul><li>Neurons rely on N-and P-type Ca 2+  channels </li></ul><ul><li>Skel...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
The different binding sites of CCBs result in differing  pharmacological effects Voltage-dependent binding (targets smooth...
Differential effects of different CCBs on CV cells AV SN AV SN Potential reflex increase in HR, myocardial contractility a...
Hemodynamic Effects of CCBs Effect Verapamil Diltiazem Nifedipine Peripheral vasodilatation    Coronary vasodilatation...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
CCBs: Pharmacokinetics Agent Oral Absorption (%) Bioavail- Ability (%) Protein Bound (%) Elimination  Half-Life (h) Verapa...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
Comparative Adverse Effects   Diltiazem Verapamil Dihydropyridines Overall 0-3% 10-14% 9-39% Hypotension ++ ++ +++ Headach...
<ul><li>heart rate </li></ul><ul><li>blood pressure </li></ul><ul><li>anginal symptoms </li></ul><ul><li>signs of CHF </li...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
Contradications for CCBs Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV con...
Outline <ul><li>Introduction </li></ul><ul><li>CCB binding sites </li></ul><ul><li>Heterogeneity of action </li></ul><ul><...
Which CCB is most likely to cause  hypotension and reflex tachycardia? <ul><li>Diltiazem </li></ul><ul><li>Nifedipine </li...
Contraindications for CCBs include (choose all  appropriate): <ul><li>Supraventricular tachycardias </li></ul><ul><li>Hypo...
CCBs may improve cardiac function by: <ul><li>Reducing cardiac afterload </li></ul><ul><li>Increasing O 2  supply </li></u...
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  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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