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Calcium Channel Blocking Drugs
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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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
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Three Classes of CCBs Verapamil Nifedipine Diltiazem H3C CH3 H3C CH3
CH3 CH CH3 H3C C CH2 CH2 CH2 N CH2 CH2 CH3 C N Verapamil NO2 CH3 S N CH2 CH2 N CH3 H3C C C CH3 C CH3 H3C CH3 N H CH3 Nifedipine Diltiazem
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Widespread use of CCBs Angina pectoris Hypertension
Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation - Paroxysmal SVT
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit
III IV II I 5 6 Out In I II III IV
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The expression and function of the 1C subunit
is modulated by other smaller subunits NH3+ COO- b a1C a2 I II III IV d L-Type Ca2+ Channel
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The Three Classes of CCBs Bind to Different Sites
1,4- Dihydropyridines (nifedipine) Phenylalkylamines (verapamil) Benzothiazepines (diltiazem) Ca2+ pore - +
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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
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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 -30 Nifedipine
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?
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N-type and P-type Ca2+ channels mediate
neurotransmitter release in neurons Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ postsynaptic cell
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Skeletal muscle relies on intracellular
Ca2+ for contraction Myofibril Plasma membrane Transverse tubule Terminal cisterna of SR Tubules of Triad T
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Cardiac cells rely on L-type Ca2+ channels for contraction
and for the upstroke of the AP in slow response cells Contractile Cells (atria, ventricle) L-Type Ca2+ Slow Response Cells (SA node, AV node)
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Vascular smooth muscle relies on Ca2+ influx
through L-type Ca2+ channels for contraction (graded, Ca2+ dependent contraction) L-Type Ca2+
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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
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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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 -30 Nifedipine
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Non -dihydropyridines: equipotent for cardiac tissue and vasculature
Differential effects of different CCBs on CV cells Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent for cardiac tissue and vasculature Peripheral vasodilation 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
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Hemodynamic Effects of CCBs
Verapamil Diltiazem Nifedipine Peripheral vasodilatation Coronary vasodilatation Preload 0/ Afterload Contractility 0/ / * Heart rate 0/ /0 AV conduction
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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CCBs: Pharmacokinetics
Agent Oral Absorption (%) Bioavail- Ability (%) Protein Bound (%) Elimination Half-Life (h) Verapamil >90 10-35 83-92 * Diltiazem >90 41-67 77-80 3.5-7 Nifedipine >90 45-86 92-98 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
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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Caution w/beta blockers
Comparative Adverse Effects Diltiazem Verapamil Dihydropyridines Overall 0-3% 10-14% 9-39% Hypotension ++ +++ Headaches + Peripheral Edema Constipation CHF (Worsen) AV block Caution w/beta blockers
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CCBs - Monitoring heart rate blood pressure anginal symptoms
signs of CHF adverse effects
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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Contradications for CCBs
Contraindication Verapamil Nifedipine Diltiazem Hypotension + ++ + Sinus bradycardia + + AV conduction defects ++ ++ Severe cardiac failure ++ + +
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Outline Introduction Pharmacokinetics CCB binding sites
Heterogeneity of action Cardiac & hemodynamic differentiation Pharmacokinetics Adverse effects Contraindications Summary
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Which CCB is most likely to cause
hypotension and reflex tachycardia? Diltiazem Nifedipine Verapamil
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Contraindications for CCBs include (choose all
appropriate): Supraventricular tachycardias Hypotension AV heart block Hypertension Congestive heart failure
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CCBs may improve cardiac function by:
Reducing cardiac afterload Increasing O2 supply Decreasing cardiac preload Normalizing heart rate in patients with supraventricular tachycardias
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Thank you!
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