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Calcium Channel Blocker

PHRM 304

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Stimulation Ca+2

Cell membrane

Increase cytosolic concentration of Ca+2 Also released fromsarcoplasmic

reticulum

Binding Ca+2 to a

regulatory proteinTroponin C &

Calmodulin

Uncovers myosin binding site on actin

Myosin & actin interaction results

muscle contraction

Role of Ca+2 & Ca+2 channels in muscle contraction:

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Ca2+ enters cell

Triggers

intracellularCa2+ release

Ca2+ binds to

Troponin C in

cardiac andskeletal

Calmodulin

in

vasculature

Ca2+ forms

complex

Allows actin

& myosin tointeract &

contract

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Types of calcium channel

4types of calcium channel

L type: located in skeletal, cardiac and smooch

muscles T type: found in pacemaker cells

N type: found in neurons

P type: located in purkinje cells

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Types of calcium channel

Among the Ca channels L-type calcium

channel is the target for calcium channel

blockers.

L-type consists of5 peptide subunit: 1, 2 ,,

,

1 provide central pore of the channel

Other subunits cover 1 and maintain

lipophilicity of the cell membrane.

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Fig: L-type channel

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Calcium channel blockers

Inhibition of Ca+2 flow through the channels

results in: vasodilatation and decrease cellular

response to contractile stimuli.

Sensitivity to vasodilatation action:

Coronary and

cerebral artery

Arterial

Venous

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Calcium channel blockers

Calcium channel blockers are useful in the

treatment ofhypertension and ischemic heart

disease.

Hypertension: Slows heart rate & contraction

Ischemic heart disease: Vasodilator

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CCB: Classification

Three different chemical classes

- Phenylalkylamines

- 1,4-dihydropyridines- Benzothiazepines

Second generation are more potent analogues

than first generation

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CCB: Classification

* 3rd Gen

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SAR of 1,4-dihydropyridines

N

X

HCH

3R1

R2

R3

1

2

34

5

6

General structure

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SAR of 1,4-dihydropyridines

Ester group at C3 and C5 position

Isradipine (Blocker) Activator

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Amlodipine

More

selective &

potent

Nifedipine

Only symmetrical

compound

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Chemistry

Diltiazem and verapamil are both chiral,

possessing asymmetric centers.

In each case, the dextro-rotatory ( i.e. , the

(+)-enantiomer) is approximately one order of

magnitude (10 times) more potent as a

calcium channel blocker than the levo-

rotatory (i.e., ()-enantiomer ).

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Chemistry

Amlodipine is used therapeutically as a

racemic mixture, composed of S- and R-

enantiomers, but its calcium channel-blocking

effect is confined to S-amlodipine; R-

amlodipine has 1000-fold less activity than its

S-enantiomer.

The affinity of its levorotary (-)-enantiomer tothe calcium channels is 1,000 times superior

to that of its dextrorotary (+)-enantiomer.

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Mechanism of action

Do not simply plug the hole and physically

block the channel.

Bind to a specific receptor site at 1

subunit of

L-type channel: thus inhibit Ca inflow.

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Mechanism of action

Contraction of the myocardial cells are

mediated, in part, by calcium influx.

The calcium channel blockers produce a

negative inotropic effect by interrupting the

contractile response.

The calcium channel blockers inhibit vascular

smooth muscle contraction by depriving the

cell from the calcium ions.

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Mechanism of action

Verapamil and diltiazem: ionic at physiological

pH: enter into the binding site when channel

is open.

Nifedipine (Dihydropyridines): neutral at

physiological pH-interact with Ca channel

when it is open or closed: due to its lipophillic

nature.

Verapamil

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Drug specificity

Verapamil and Diltiazem affect both the heart

and the arteriolar bed

The dihydropyridines have much less effect on

the cardiac tissues and higher specificity for

the arteriolar vascular bed.

Diltiazem

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Calcium channel blockers

Verapamil CardioselectiveSlows heart

rate &

contraction

DihydropyridinesSmooth

muscle

selective

Vasodilator

Causes reflex

tachycardia

Diltiazem IntermediateSame as

verapamil but

lesser extent

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