CLASSIFICATION

Dihydropyridines

amlodipine
isradipine niterendipine

felodipine

nifedipine

nicardipine nimodipine nisoldipine clevidipine(i/v only)

Benzothiazepines

deltiazem (Na+ also)

Phenylalkylamines verapamil (Na+ also)

Bepridil block Na+ Ca2+ & K+ channels produces delayed repolarization and prolonged Q-T interval.

CALCIUM CHANNELS TYPES

Receptor operated / Ligand gated e.g IP3 gated channel which causes release of Ca from ER Voltage Sensitive P cerebellar purkinje neurons N neuronal T low voltage, transient in opening, present in neurons and pacemaker cells L large in conductance, numbers in cardiac & smooth muscles Have 5 structural sub units 1 2 & 1 is the major sub unit, dihydropyridines bind only to this sub unit Only L type blocked by Ca2+ channel blockers

Although some neuronal cells harbor L-type calcium channels, their sensitivity to calcium channel blockers is lower because the channels in these cells spend less time in the open and inactivated states. dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects;

Why no action on skeletal muscles

Skeletal muscle

IN VASCULAR SMOOTH MUSCLE

Contraction of smooth muscle dependent on influx of Ca2+ Through voltage sensitive Ca 2+ channels depolarization Ca2+ influx

Calcium channel blockers act from the inner side of the membrane and bind more effectively to open channels and inactivated channels.
Binding of the drug reduces the frequency of opening in response to depolarization. The result is a marked decrease in transmembrane calcium current, which in turn results in smooth muscle with a long-lasting relaxation

IN CARDIAC CELL

Na & Ca influx in atrial & ventricular myocites & conducting tissue produces depolarization (Na+ fast) (Ca2+slow )
In SA & AV nodes depolarization largely dependent on Ca2+channels In myosites Ca2+binds troponin leading to a in its inhibitory effect contraction If Ca2+ channel blocked Ca2+ influx no Ca2+and troponin interaction so contraction inhibited

IN SINO-ATRIAL & ATRIOVENTRICULAR NODES

IN SINO-ATRIAL & ATRIOVENTRICULAR NODES

Activation of SA node and AV node exclusively depend upon calcium current Decrease in firing of SA node and delay AV nodal conduction. Hence decrease in sinus rate Effective refractory period is prolonged In M.I, ed Ca2+ influx in ischemic depolarized tissue es activity of ATP consuming enzymes leading to a decrease in arrhythmias & infarct size

Hemodynamic Effects

HEMODYNAMIC EFFECTS

Vary the route of administration

All Ca2+channel blockers coronary vascular resistance & coronary blood flow
Nifedipine Nicardipine & Nimodipine produce vasodilatation > Verapamil > Deltiazem

NIFEDIPINE: I/v selectively dilates arterial resistance vessels & causes in BP. sympathetic reflexes in H.R, + ve inotropy. (direct effect is ive inotropy large dose)
Thus BP is ed, contractility is ed, HR ,C.O . Oral: arterial dilatation peripheral blood flow venous tone= no change.*art resist & +inotropy produce an increase in cardiac output.

VERAPAMIL doses peripheral arterial dilatation but a more direct ive chronotropic inotropic & dromotropic effect. i/v - in vas resist in BP. Reflex in HR blunted by direct ive chronotropy in after load & reflex in adrenergic tone, antagonize partially the intrinsic ive inotropic effect of verapamil.

Thus patients without CCF ventricular work improves BUT in patients CCF i/v to a in contractility & Lt ventricular function
Oral- in PVR in BP & no change in HR.

DELTIAZEM: i/v PR & BP reflex in HR& C.O Later direct ive chronotropy in HR. Oral sustained fall in HR & mean arterial BP.

Other Effects

SUB ARACHNOID HEMORRHAGE: may lead to cerebral vasospasm & infarction and is treated with NIMODIPINE

Other Effects

SKELETAL MUSCLE not depressed Verapamil inhibits insulin release in humans Interferes platelet aggregation in vitro Prevent development of atheromatous lesions Verapamil blocks P170 Glycoprotein hence useful in treating cancer cell resistance to drugs

MECHANISM OF CLINICAL EFFECTS

myocardial contractile force O 2 requirement

arterial tone SVR arterial & intraventricular pressure ventricular wall stress O2 demand .
Verapamil & deltiazem depress S.A & A.V nodes in heart rate

Effective in the treatment of supraventricular tachycardia& in ing ventricular rate in atrial flutter & atrial fib
Non specific sympathetic antagonism most marked deltiazem, less verapamil least nifedipine So in BP reflex tachycardia nifedipine.

USES
1.

ANGINA

2.
3. 4.

HYPERTENSION (clevidipine and nicardipine are used i.v)

SUPRAVENTRICULAR TACHYARRHYTHMIAS SUBARACHNOID HEMORRHAGE

5.
6. 7. 8. 9.

ATHEROSCLEROSIS * * unlabelled indications

CONGESTIVE CARDIAC FAILURE * HYPERTROPHIC CARDIOMYOPATHY * MIGRAINE * RAYNAUDS PHENOMENON * (preferable to alpha blockers)

TOXICITY

MINOR: flushing, edema, dizziness, nausea, constipation.

MAJOR: Direct extension of therapeutic actions. *Serious cardiac depression Cardiac arrest Bradycardia AV block& CCF. *Prompt acting nifedipine myocardial infarction. *Bipridil prolongs cardiac action potential & in susceptible pts ( prolonged QT syndrome) produces dangerous arrhythmia (torsade de pointes). *Pts on blockers more sensitive to cardiodepressant effect .

CONTRAINDICATIONS

Pts AV conduction dont use verapamil. verapamil or deltiazem + blockers produce AV block. In CCF ive inotropy leads to worsening so dont use in vasodilator therapy of CCF.

Hypotensives have fall in BP nifedipine*.

Digitalized patients should use verapamil caution as digoxin levels ed (interaction).

In unstable angina immediate release, short acting nifedipine S/L adverse cardiac events.
Verapmil in patients with Ventricular tachycardia precipitate ventricular fibrillation

DRUG

INDICATIONS hypertension BP, raynauds, hypertension angina, BP, angina, BP, raynauds, migraine S. A. Hemorrhage, migraine BP, angina, raynauds, arrhythmias

Amlodipine Felodipine Isradipine Nicardipine Nifedipine Nimodipine Diltiazem

Verapamil

angina, BP, arrhythmias