Download - Calcium Channel Blocking Drugs
![Page 1: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/1.jpg)
Calcium Channel Blocking Drugs
![Page 2: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/2.jpg)
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
![Page 3: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/3.jpg)
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
![Page 4: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/4.jpg)
Canali del calcio:
•VOC (Voltage operated channels)
•ROC (Receptor operated channels
•SMOC (Second Messanger operated channels)
![Page 5: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/5.jpg)
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
D
N VN
DominiDomini
SegmentiSegmenti
![Page 6: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/6.jpg)
![Page 7: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/7.jpg)
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
![Page 8: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/8.jpg)
Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?
![Page 9: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/9.jpg)
N-type and P-type Ca2+ channels mediate neurotransmitter release in neurons
postsynaptic cell
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
![Page 10: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/10.jpg)
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+
![Page 11: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/11.jpg)
Vascular smooth muscle relies on Ca2+ influxthrough L-type Ca2+ channels for contraction
(graded, Ca2+ dependentcontraction)
L-Type
Ca2+
![Page 12: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/12.jpg)
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
![Page 13: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/13.jpg)
Differential states of L-type calcium channel
restingactive
inactive
![Page 14: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/14.jpg)
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
![Page 15: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/15.jpg)
Angina pectoris
Hypertension
Treatment of supraventricular
arrhythmias
- Atrial Flutter
- Atrial Fibrillation
- Paroxysmal SVT
Widespread use of CCBs
![Page 16: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/16.jpg)
![Page 17: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/17.jpg)
![Page 18: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/18.jpg)
Calcium Channel BlockersCalcium Channel BlockersMechanisms of ActionMechanisms of Action
![Page 19: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/19.jpg)
Calcium Channel BlockersCalcium Channel BlockersMechanisms of ActionMechanisms of Action
![Page 20: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/20.jpg)
Effect Verapamil Diltiazem Nifedipine
Peripheralvasodilatation
Coronaryvasodilatation
Preload 0 0 0/
Afterload
Contractility 0/ / *
Heart rate 0/ /0
AV conduction 0
Hemodynamic Effects of CCBs
![Page 21: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/21.jpg)
Nimodipine and cerebral hemorrhage
Hemicranias (?)
Multi-drug resistance (MDR)
Additional use of CCBs
![Page 22: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/22.jpg)
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
![Page 23: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/23.jpg)
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
![Page 24: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/24.jpg)
Agent Drug MechanismPharmaco-
kinetics effect
Clinical effects
Verapamil Digoxin Clearance PC Digoxin
tox.Verapamil Terfenedin
e CYP3A PC > QT
Diltiazem Cyclosporin CYP3A PC Renal tox.
Diltiazem Tacrolimus CYP3A
CYP3A
PC Renal tox.
Verapamil ß-blockers PC Toxicity
Nifedipine Riphampicin Clearance PC < CCBs
effectAmlodipin
e Teophilline Clearance PC Toxicity
CCBs: Pharmacokinetics interaction (CYP 3A andGlycoprotein-P inhibition
![Page 25: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/25.jpg)
Contraindication Verapamil Nifedipine Diltiazem
Hypotension + ++ +
Sinus bradycardia + 0 +
AV conduction defects ++ 0 ++
Severe cardiac failure ++ + +
Contradications for CCBs
![Page 26: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/26.jpg)
![Page 27: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/27.jpg)
![Page 28: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/28.jpg)
![Page 29: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/29.jpg)
![Page 30: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/30.jpg)
![Page 31: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/31.jpg)
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
![Page 32: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/32.jpg)
![Page 33: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/33.jpg)
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
![Page 34: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/34.jpg)
MyofibrilPlasma membrane
Transverse tubule
Terminal cisterna ofSR
Tubules ofSR
TriadTSR
Skeletal muscle relies on intracellularCa2+ for contraction
![Page 35: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/35.jpg)
Calcium Channel BlockersCalcium Channel BlockersSide EffectsSide Effects
PalpitationsPalpitationsHeadacheHeadacheAnkle edemaAnkle edemaGingival hyperplasiaGingival hyperplasia
![Page 36: Calcium Channel Blocking Drugs](https://reader031.vdocument.in/reader031/viewer/2022012319/56813988550346895da11a6b/html5/thumbnails/36.jpg)
heart rate
blood pressure
anginal symptoms
signs of CHF
adverse effects
CCBs - Monitoring