calcium channel blocking drugs
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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Calcium Channel Blocking Drugs
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Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
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Chemical Type Chemical Names Brand Names
Phenylalkylamines
verapamil Calan,Calna SR,Isoptin SR,Verelan
Benzothiazepines diltiazem Cardizem CD,Dilacor XR
1,4-Dihydropyridines
Nifedipine nicardipineisradipinefelodipineamlodipine
Adalat CC,Procardia XL CardeneDynaCircPlendilNorvasc
Three Classes of CCBs
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Three Classes of CCBs
N CH2 CH2N
0
CH3
0 C CH3
0
CH3
CH3
Diltiazem
C 0 CH3
NO2
CH3H3C
C0H3C
0 0
Nifedipine
C CH2 CH2 CH2CH2 CH2N
CH3
CH3
C N
CH
H3C
0H3C
0H3C
0 CH3
0 CH3
Verapamil
NH
S
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Angina pectoris
Hypertension
Treatment of supraventricular
arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT
Widespread use of CCBs
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Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
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III IV
II IIVIII
56 5
6
Out
In
I II III IV
The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit
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NH3+
NH3+
COO-
COO-
1C
NH3+ COO-
2
I II III IV
COO-
NH3+
The expression and function of the 1C subunit is modulated by other smaller subunits
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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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
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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)
Cellmembrane
1
out
in
+20
-80mV 2
DiltiazemVerapamil
1
1
out
in
+20
-80-30 2
1
Nifedipine
CellmembranemV
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Outline
Introduction
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
postsynaptic cell
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
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MyofibrilPlasma membrane
Transverse tubule
Terminal cisterna ofSR
Tubules ofSR
TriadTSR
Skeletal muscle relies on intracellularCa2+ for contraction
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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+
Ca2+ Ca2+
Slow Response Cells(SA node, AV node)
L-Type
Ca2+
Ca2+
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Vascular smooth muscle relies on Ca2+ influxthrough L-type Ca2+ channels for contraction
(graded, Ca2+ dependentcontraction)
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
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)
Cellmembrane
1
out
in
+20
-80mV 2
DiltiazemVerapamil
1
1
out
in
+20
-80-30 2
1
Nifedipine
CellmembranemV
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Differential effects of different CCBs on CV cells
AV
SN
AV
SN
Potential reflexincrease inHR, myocardialcontractilityand O2 demand
CoronaryVD
Dihydropyridines: Selective vasodilators Non -dihydropyridines: equipotent forcardiac tissue and vasculature
Heart ratemoderating
Peripheraland coronaryvasodilation
Reducedinotropism
Peripheralvasodilation
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Effect Verapamil Diltiazem Nifedipine
Peripheralvasodilatation
Coronaryvasodilatation
Preload 0 0 0/
Afterload
Contractility 0/ / *
Heart rate 0/ /0
AV conduction 0
Hemodynamic Effects of CCBs
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Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
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AgentOral
Absorption(%)
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 1.9-5.8Nicardipin
e-100 35 >95 2-4
Isradipine >90 15-24 >95 8-9
Felodipine -100 20 >99 11-16Amlodipin
e>90 64-90 97-99 30-50
CCBs: Pharmacokinetics
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Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
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Diltiazem Verapamil Dihydropyridines
Overall 0-3% 10-14% 9-39%
Hypotension ++ ++ +++
Headaches 0 + +++Peripheral
Edema ++ ++ +++
Constipation 0 ++ 0
CHF (Worsen) 0 + 0
AV block + ++ 0Caution w/beta
blockers+ ++ 0
Comparative Adverse Effects
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heart rate
blood pressure
anginal symptoms
signs of CHF
adverse effects
CCBs - Monitoring
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Outline
Introduction
CCB binding sites
Heterogeneity of action
Cardiac & hemodynamic
differentiation
Pharmacokinetics
Adverse effects
Contraindications
Summary
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Contraindication Verapamil Nifedipine Diltiazem
Hypotension + ++ +
Sinus bradycardia + 0 +
AV conduction defects ++ 0 ++
Severe cardiac failure ++ + +
Contradications for CCBs
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Outline
Introduction
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?
A. Diltiazem
B. Nifedipine
C. Verapamil
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Contraindications for CCBs include (choose all appropriate):
A. Supraventricular tachycardias
B. Hypotension
C. AV heart block
D. Hypertension
E. Congestive heart failure
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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
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Thank you!