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