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Calcium Channel Blocking Drugs. Outline. Pharmacokinetics Adverse effects Contraindications Summary. Introduction CCB binding sites Heterogeneity of action Cardiac & hemodynamic differentiation. Chemical Type. Chemical Names. Brand Names. Phenylalkylamines. verapamil.

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slide1

Calcium Channel

Blocking Drugs

slide2

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide3

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

Three Classes of CCBs

slide4

Three Classes of CCBs

H3C

CH3

CH3

H3C

0

0

CH3

CH

CH2

CH3

0

0

C

CH2

N

CH2

CH2

CH2

H3C

N

C

Verapamil

NO2

CH3

S

N

CH2

N

CH2

0

0

CH3

C

0

H3C

0

C

CH3

C

CH3

0

0

H3C

CH3

0

N

H

CH3

Diltiazem

Nifedipine

slide5

Widespread use of CCBs

  • Angina pectoris
  • Hypertension
  • Treatment of supraventricular

arrhythmias

- Atrial Flutter

- Atrial Fibrillation

  • - Paroxysmal SVT
slide6

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide7

I II III IV

Out

In

6

IV

III

5

5

IV

III

6

II

I

The 1C subunit of the L-type Ca2+ channel

is the pore-forming subunit

slide8

a2

a1C

NH3+

COO-

I II III IV

NH3+

COO-

d

COO-

NH3+

b

NH3+

COO-

The expression and function of the 1C subunit

is modulated by other smaller subunits

L-Type Ca2+ Channel

slide9

1,4-

Dihydropyridines

(nifedipine)

-

+

-

+

Ca2+

pore

-

-

Phenylalkylamines

(verapamil)

Benzothiazepines

(diltiazem)

-

The Three Classes of CCBs Bind to Different Sites

slide10

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
slide11

The different binding sites of CCBs result in differing

pharmacological effects

Use-dependent binding (targets cardiac cells)

out

+20

2

mV

1

Cell

membrane

1

-80

in

Diltiazem

Verapamil

Voltage-dependent binding (targets smooth muscle)

+20

out

-30

2

Cell

membrane

1

-80

1

mV

in

Nifedipine

slide12

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide13

Why Do CCBs Act Selectively

on Cardiac and Vascular Muscle?

slide14

N-type and P-type Ca2+ channels mediate

neurotransmitter release in neurons

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

postsynaptic cell

slide15

Myofibril

Plasma

membrane

Transverse

tubule

Terminal

cisterna of

SR

Triad

SR

T

Tubules of

SR

Skeletal muscle relies on intracellular

Ca2+ for contraction

slide16

Ca2+

Ca2+

L-Type

L-Type

Ca2+

Ca2+

Ca2+

Contractile Cells

(atria, ventricle)

Slow Response Cells

(SA node, AV node)

Cardiac cells rely on L-type Ca2+ channels for contraction

and for the upstroke of the AP in slow response cells

slide17

Ca2+

L-Type

(graded, Ca2+ dependent

contraction)

Vascular smooth muscle relies on Ca2+ influx

through L-type Ca2+ channels for contraction

slide18

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

slide19

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide20

The different binding sites of CCBs result in differing

pharmacological effects

Use-dependent binding (targets cardiac cells)

out

+20

2

mV

1

Cell

membrane

1

-80

in

Diltiazem

Verapamil

Voltage-dependent binding (targets smooth muscle)

+20

out

-30

2

Cell

membrane

1

-80

1

mV

in

Nifedipine

slide21

Peripheral

vasodilation

Differential effects of different CCBs on CV cells

Dihydropyridines: Selective vasodilators

Non -dihydropyridines: equipotent for

cardiac tissue and vasculature

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

slide22

Effect

Verapamil

Diltiazem

Nifedipine

Peripheral

vasodilatation



Coronary

vasodilatation







Preload

0

0

0/

Afterload







Contractility



0/

/*

Heart rate

0/

/0

AV conduction



0

Hemodynamic Effects of CCBs

slide23

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide24

Agent

Oral

Absorption

(%)

Protein

Bound

(%)

Elimination

Half-Life

(h)

Bioavail-

Ability

(%)

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

slide25

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide26

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

slide27

CCBs - Monitoring

  • heart rate
  • blood pressure
  • anginal symptoms
  • signs of CHF
  • adverse effects
slide28

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide29

Contraindication

Verapamil

Nifedipine

Diltiazem

Hypotension

+

++

+

Sinus bradycardia

+

0

+

AV conduction defects

++

0

++

Severe cardiac failure

++

+

+

Contradications for CCBs

slide30

Outline

  • Pharmacokinetics
  • Adverse effects
  • Contraindications
  • Summary
  • Introduction
  • CCB binding sites
  • Heterogeneity of action
  • Cardiac & hemodynamic

differentiation

slide31

Which CCB is most likely to cause

hypotension and reflex tachycardia?

  • Diltiazem
  • Nifedipine
  • Verapamil
slide32

Contraindications for CCBs include (choose all

appropriate):

  • Supraventricular tachycardias
  • Hypotension
  • AV heart block
  • Hypertension
  • Congestive heart failure
slide33

CCBs may improve cardiac function by:

  • Reducing cardiac afterload
  • Increasing O2 supply
  • Decreasing cardiac preload
  • Normalizing heart rate in patients with
  • supraventricular tachycardias