calcium channel blockers (1)

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Calcium Channel Blocking Drugs

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

Chemical Type

Chemical Names

Brand Names

Phenylalkylamines

verapamil

Calan,Calna SR,Isoptin SR,Verelan

Benzothiazepines

diltiazem

Cardizem CD,Dilacor XR

1,4-Dihydropyridines

Nifedipinenicardipineisradipinefelodipineamlodipine

Adalat CC,Procardia XLCardeneDynaCircPlendilNorvasc

Three Classes of CCBs

Three Classes of CCBs

NCH2CH2N

0CH30

CCH30CH3CH3

Diltiazem

C0CH3

NO2CH3

H3CC0

H3C00

Nifedipine

CCH2CH2CH2CH2CH2

N

CH3CH3CNCH

H3C0H3C0H3C0CH3

0CH3

Verapamil

NH

S

Angina pectoris Hypertension Treatment of supraventricular arrhythmias - Atrial Flutter - Atrial Fibrillation - Paroxysmal SVT

Widespread use of CCBs

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

IIIIVIIIIVIII

5656

OutIn I II III IVThe 1C subunit of the L-type Ca2+ channel is the pore-forming subunit

NH3+NH3+COO-COO-b a1CNH3+ COO-a2

I II III IVCOO- NH3+d

The expression and function of the 1C subunit is modulated by other smaller subunitsL-Type Ca2+ Channel

The Three Classes of CCBs Bind to Different Sites

1,4-Dihydropyridines(nifedipine)Phenylalkylamines(verapamil)

Benzothiazepines(diltiazem)

Ca2+pore

----++

-

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

CCBs Mechanisms of Action

The different binding sites of CCBs result in differing pharmacological effects

Voltage-dependent binding (targets smooth muscle)Use-dependent binding (targets cardiac cells)

Cellmembrane

1

outin

+20-80mV

2

DiltiazemVerapamil

1

1out

in

+20-80-30

2

1

Nifedipine Cellmembrane

mV

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons

postsynaptic cell

Ca2+Ca2+Ca2+Ca2+Ca2+

MyofibrilPlasma membraneTransverse tubuleTerminal cisterna ofSRTubules ofSR

Triad

T

SRSkeletal muscle relies on intracellularCa2+ for contraction

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-TypeCa2+Ca2+Ca2+

Slow Response Cells(SA node, AV node)L-TypeCa2+

Ca2+

Vascular smooth muscle relies on Ca2+ influxthrough L-type Ca2+ channels for contraction

(graded, Ca2+ dependentcontraction)L-TypeCa2+

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 CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

The different binding sites of CCBs result in differing pharmacological effects

Voltage-dependent binding (targets smooth muscle)Use-dependent binding (targets cardiac cells)

Cellmembrane

1

outin

+20-80mV

2

DiltiazemVerapamil

1

1out

in

+20-80-30

2

1

Nifedipine Cellmembrane

mV

Differential effects of different CCBs on CV cells

AV

SN

AVSN

Potential reflexincrease inHR, myocardialcontractilityand O2 demandCoronaryVDDihydropyridines: Selective vasodilatorsNon -dihydropyridines: equipotent forcardiac tissue and vasculature

Heart ratemoderatingPeripheraland coronaryvasodilationReducedinotropism

Peripheralvasodilation

Effect

Verapamil

Diltiazem

Nifedipine

Peripheralvasodilatation

Coronaryvasodilatation

Preload

0

0

0/

Afterload

Contractility

0/

/ *

Heart rate

0/

/0

AV conduction

0

Hemodynamic Effects of CCBs

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

Agent

OralAbsorption(%)

Bioavail-Ability(%)

ProteinBound(%)

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

CCBs: Pharmacokinetics

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

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

Comparative Adverse Effects

heart rate blood pressure anginal symptoms signs of CHF adverse effectsCCBs - Monitoring

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

Contraindication

Verapamil

Nifedipine

Diltiazem

Hypotension

+

++

+

Sinus bradycardia

+

0

+

AV conduction defects

++

0

++

Severe cardiac failure

++

+

+

Contradications for CCBs

Outline

Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation

Pharmacokinetics Adverse effects Contraindications Summary

Which CCB is most likely to cause hypotension and reflex tachycardia? Diltiazem Nifedipine Verapamil

Contraindications for CCBs include (choose all appropriate): Supraventricular tachycardias Hypotension AV heart block Hypertension Congestive heart failure

CCBs may improve cardiac function by: Reducing cardiac afterload Increasing O2 supply Decreasing cardiac preload Normalizing heart rate in patients with supraventricular tachycardias

Thank you!

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