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 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

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

-80mV 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

Effect Verapamil Diltiazem 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 1.9-5.8Nicardipin

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

  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

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

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

MyofibrilPlasma membrane

Transverse tubule

Terminal cisterna ofSR

Tubules ofSR

TriadTSR

Skeletal muscle relies on intracellularCa2+ for contraction

Calcium Channel BlockersCalcium Channel BlockersSide EffectsSide Effects

PalpitationsPalpitationsHeadacheHeadacheAnkle edemaAnkle edemaGingival hyperplasiaGingival hyperplasia

heart rate

blood pressure

anginal symptoms

signs of CHF

adverse effects

CCBs - Monitoring