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Calcium Channel Blocking Drugs Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation 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 Adalat CC, Procardia XL nicardipine isradipine felodipine amlodipine Cardene DynaCirc Plendil Norvasc Three Classes of CCBs H3C H3C 0 CH3 0 CH3 CH H3C 0 CH3 C CH2 C N CH2 CH2 N CH2 0 CH2 CH3 Verapamil NO2 CH3 S H3C 0 0 0 C C H3C N H CH3 N CH2 N CH3 0 CH3 0 C CH3 0 0 CH3 Nifedipine CH2 Diltiazem Widespread use of CCBs Angina pectoris Hypertension Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation - Paroxysmal SVT Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit I II III IV Out In III 5 6 5 6 IV III IV II I The expression and function of the 1C subunit is modulated by other smaller subunits 2 1C I II III IV NH3+ COONH3+ COONH3+ d b L-Type Ca2+ Channel NH3+ COO- COO- The Three Classes of CCBs Bind to Different Sites 1,4Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) - + - Ca2+ pore - + Benzothiazepines (diltiazem) 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 The different binding sites of CCBs result in differing pharmacological effects Use-dependent binding (targets cardiac cells) +20 mV -80 out Cell membrane in 1 1 2 d b Diltiazem Verapamil Voltage-dependent binding (targets smooth muscle) +20 -30 -80 mV out Cell membrane in 1 b 1 2 d Nifedipine Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation Why Do CCBs Act Selectively on Cardiac and Vascular Muscle? N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ postsynaptic cell Skeletal muscle relies on intracellular Ca2+ for contraction Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Tubules of SR SR T Triad Cardiac cells rely on L-type Ca2+ channels for contraction and for the upstroke of the AP in slow response cells Ca2+ Ca2+ L-Type Ca2+ L-Type Ca2+ Ca2+ Contractile Cells (atria, ventricle) Slow Response Cells (SA node, AV node) Vascular smooth muscle relies on Ca2+ influx through L-type Ca2+ channels for contraction Ca2+ L-Type (graded, Ca2+ dependent contraction) 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 Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation The different binding sites of CCBs result in differing pharmacological effects Use-dependent binding (targets cardiac cells) +20 mV -80 out Cell membrane in 1 1 2 d b Diltiazem Verapamil Voltage-dependent binding (targets smooth muscle) +20 -30 -80 mV out Cell membrane in 1 b 1 2 d Nifedipine Differential effects of different CCBs on CV cells Dihydropyridines: Selective vasodilators Peripheral vasodilation Non -dihydropyridines: equipotent for cardiac tissue and vasculature Heart rate moderating SN AV Potential reflex increase in HR, myocardial contractility and O2 demand SN AV Coronary VD Reduced inotropism Peripheral and coronary vasodilation Hemodynamic Effects of CCBs Verapamil Diltiazem Nifedipine Peripheral vasodilatation Coronary vasodilatation 0 0 0/ Afterload Contractility 0/ / * Heart rate 0/ /0 AV conduction 0 Effect Preload Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation CCBs: Pharmacokinetics Agent Oral Absorption (%) BioavailAbility (%) 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 35 >95 2-4 15-24 >95 8-9 20 >99 11-16 64-90 97-99 30-50 Nicardipine Isradipine Felodipine Amlodipine -100 >90 -100 >90 Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation 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 CCBs - Monitoring heart rate blood pressure anginal symptoms signs of CHF adverse effects Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation Contradications for CCBs Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + 0 + AV conduction defects ++ 0 ++ Severe cardiac failure ++ + + Outline Introduction Pharmacokinetics CCB binding sites Adverse effects Heterogeneity of action Contraindications Cardiac & hemodynamic Summary differentiation Which CCB is most likely to cause hypotension and reflex tachycardia? A. Diltiazem B. Nifedipine C. Verapamil Contraindications for CCBs include (choose all appropriate): A. Supraventricular tachycardias B. Hypotension C. AV heart block D. Hypertension E. Congestive heart failure CCBs may improve cardiac function by: A. Reducing cardiac afterload B. Increasing O2 supply C. Decreasing cardiac preload D. Normalizing heart rate in patients with supraventricular tachycardias Thank you!