Download - Calcium channel blockers (1)
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
Nifedipine nicardipineisradipinefelodipineamlodipine
Adalat CC,Procardia XL CardeneDynaCircPlendilNorvasc
Three Classes of CCBs
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
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
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
NH3+
NH3+
COO-
COO-
b
1C
NH3+ COO-
2
I II III IV
COO-
NH3+
d
The expression and function of the 1C subunit is modulated by other smaller subunits
L-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
out
in b
+20
-80mV 2
d
DiltiazemVerapamil
1
b
1
out
in
+20
-80-30 2
d1
Nifedipine
CellmembranemV
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 membrane
Transverse tubule
Terminal cisterna ofSR
Tubules ofSR
TriadTSR
Skeletal 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-Type
Ca2+
Ca2+ Ca2+
Slow Response Cells(SA node, AV node)
L-Type
Ca2+
Ca2+
Vascular smooth muscle relies on Ca2+ influxthrough L-type Ca2+ channels for contraction
(graded, Ca2+ dependentcontraction)
L-Type
Ca2+
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
out
in b
+20
-80mV 2
d
DiltiazemVerapamil
1
b
1
out
in
+20
-80-30 2
d1
Nifedipine
CellmembranemV
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
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
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
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 + ++ 0Caution w/beta
blockers+ ++ 0
Comparative Adverse Effects
heart rate
blood pressure
anginal symptoms
signs of CHF
adverse effects
CCBs - 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?
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!
