calcium channel blocking drugs. chemical typechemical namesbrand names...
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Calcium Channel Blocking Drugs
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
Prima generazione
Seconda generazione
Terza generazione
Phenylalkylamines
Vi appartengono formulazioni a lento rilascio dei CCBs di prima generazione
Altamente lipofile.
Benedipina lacidipina, lecarnidipina
Benzothiazepines
1,4-Dihydropyridines
nicardipineisradipinefelodipineamlodipine
Three Classes of CCBs
Canali del calcio:
•VOC (Voltage operated channels)
•ROC (Receptor operated channels
•SMOC (Second Messanger operated channels)
III IV
II IIVIII
56
56
Out
In
I II III IV
The 1C subunit of the L-type Ca2+ channel is the pore-forming subunit
D
NVN
DominiDomini
SegmentiSegmenti
Increase the time that Ca2+ channels are
closed/inactivated
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
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+
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+
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
Differential states of L-type calcium channel
restingactive
inactive
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
-80
mV 2
DiltiazemVerapamil
1
1
out
in
+20
-80
-30 2
1
Nifedipine
CellmembranemV
Angina pectoris
Hypertension
Treatment of supraventricular
arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT
Widespread use of CCBs
Calcium Channel BlockersCalcium Channel BlockersMechanisms of ActionMechanisms of Action
Calcium Channel BlockersCalcium Channel BlockersMechanisms of ActionMechanisms of Action
EffectVerapami
lDiltiazem Nifedipine
Peripheralvasodilatation
Coronaryvasodilatation
Preload 0 0 0/
Afterload
Contractility 0/ / *
Heart rate 0/ /0
AV conduction 0
Hemodynamic Effects of CCBs
Nimodipine and cerebral hemorrhage
Hemicranias (?)
Multi-drug resistance (MDR)
Additional use of CCBs
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 1.9-5.8
Nicardipine
-10035 >95 2-4
Isradipine >90
15-24 >95 8-9
Felodipine-100
20 >99 11-16
Amlodipine
>9064-90 97-99 30-50
CCBs: Pharmacokinetics
Diltiazem VerapamilDihydropyridin
es
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
Agent Drug MechanismPharmaco-
kinetics effect
Clinical effects
Verapamil Digoxin Clearance PC
Digoxin tox.
VerapamilTerfenedin
e CYP3A PC > QT
DiltiazemCyclospori
n CYP3A PC Renal tox.
Diltiazem Tacrolimus CYP3A
CYP3A
PC Renal tox.
Verapamil ß-blockers PC Toxicity
NifedipineRiphampic
in Clearance PC
< CCBs effect
Amlodipine
Teophilline Clearance PC Toxicity
CCBs: Pharmacokinetics interaction (CYP 3A andGlycoprotein-P inhibition
Contraindication
Verapamil Nifedipine Diltiazem
Hypotension + ++ +
Sinus bradycardia
+ 0 +
AV conduction defects
++ 0 ++
Severe cardiac failure
++ + +
Contradications for CCBs
Meccanismo d’azione dei nitroderivatiMeccanismo d’azione dei nitroderivati
Glutatione S-transferasiGlutatione S-transferasi
Glutatione nitrato Glutatione nitrato organico reduttasiorganico reduttasi
Polialcoli esterificati con Polialcoli esterificati con gli acidi nitrico e nitrosogli acidi nitrico e nitroso
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
Myofibril
Plasma membrane
Transverse tubule
Terminal cisterna ofSR
Tubules ofSR
TriadTSR
Skeletal muscle relies on intracellularCa2+ for contraction
Calcium Channel BlockersCalcium Channel BlockersSide EffectsSide Effects
PalpitationsPalpitations
HeadacheHeadache
Ankle edemaAnkle edema
Gingival hyperplasiaGingival hyperplasia
heart rate
blood pressure
anginal symptoms
signs of CHF
adverse effects
CCBs - Monitoring