Calcium Channel Blocker

PHRM 304

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

Stimulation Ca+2 Cell membrane Increase cytosolic concentration of Ca+2 Binding Ca+2 to a regulatory protein
Also released from sarcoplasmic reticulum Troponin C & Calmodulin

Uncovers myosin binding site on actin Myosin & actin interaction results muscle contraction

Ca2+ enters cell Triggers intracellular Ca2+ release

Ca2+ binds to Troponin C in cardiac and skeletal Calmodulin in vasculature

Ca2+ forms complex Allows actin & myosin to interact & contract

Types of calcium channel

4 types 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

Types of calcium channel

Among the Ca channels L-type calcium channel is the target for calcium channel blockers. L-type consists of 5 peptide subunit: 1, 2 ,, , 1 provide central pore of the channel Other subunits cover 1 and maintain lipophilicity of the cell membrane.

Fig: L-type channel

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

Calcium channel blockers

Calcium channel blockers are useful in the treatment of hypertension and ischemic heart disease. Hypertension: Slows heart rate & contraction Ischemic heart disease: Vasodilator

CCB: Classification
Three different chemical classes - Phenylalkylamines - 1,4-dihydropyridines - Benzothiazepines Second generation are more potent analogues than first generation

CCB: Classification

* 3rd Gen

SAR of 1,4-dihydropyridines
R1
6

H N1
2

CH3
3

R2 X

R3

General structure

SAR of 1,4-dihydropyridines
Ester group at C3 and C5 position

Isradipine (Blocker)

Activator

Amlodipine More selective & potent

Nifedipine Only symmetrical compound

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

Chemistry
Amlodipine is used therapeutically as a racemic mixture, composed of S- and Renantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; Ramlodipine has 1000-fold less activity than its S-enantiomer. The affinity of its levorotary (-)-enantiomer to the calcium channels is 1,000 times superior to that of its dextrorotary (+)-enantiomer.

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.

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.

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

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

Calcium channel blockers

Verapamil
Cardioselective
Slows heart rate & contraction Vasodilator Causes reflex tachycardia Same as verapamil but lesser extent

Dihydropyridines

Smooth muscle selective

Diltiazem

Intermediate