Calcium Channel Blockersand Digitalis

Dig

Ca ChannelBlockers

Mechanism of Ca+

+channel blocker action

•In cardiac muscle, Ca++ binding to troponin C relieves troponin inhibition of actin-myosin interactions.

•In smooth muscle, Ca++ binding to calmodulin activates myosin light chain kinase which in turn phosphorylates the P-light chain of myosin.

Mechanism of Ca+

+channel blocker action

• Channel blockers bind to the L-type channels ("slow channels"), which are abundant in cardiac and smooth muscle.

•This may partially explain their rather selective effects on the cardiovascular system.

Mechanism of Ca+

+channel blocker action

• Different classes of Ca++ channel blockers bind to different sites on the 1-subunit, which is the major channel-forming subunit (2,, , and subunits are also present).

Binding Sites for Selective Calcium Channel Blockers

Mechanism of Ca+

+channel blocker action

• Effects of Vascular Smooth Muscle

• Ca++ channel blockers inhibit L-type voltage-dependent Ca ++ channels in vascular smooth muscle

• Decreased intracellular Ca++ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure)

Mechanism of Ca+

+channel blocker action

•Effects on Cardiac Cells

•Inotropic effect (direct negative effect)

•Chronotropic/dromotropic effects (direct effects on pacemaker activity & conduction)

Mechanism of Ca+

+channel blocker action

• Nifedipine and related dihydropyridines do not have significant direct effects on atrioventricular conduction system or sinoatrial node.

•Therefore, they do not have direct effects on conduction or automaticity.

Mechanism of Ca+

+channel blocker action

• Verapamil (and to a lesser extent diltiazem) decrease the rate of recovery of the slow channel in AV conduction system and SA node, and therefore act directly to depress SA node pacemaker activity and to slow conduction.

Mechanism of Ca+

+channel blocker action

• Ca++-channel block by verapamil and diltiazem is frequency- and voltage-dependent, making them more effective in cells that are rapidly depolarizing (e.g.- tachycardias).

Mechanism of Ca+

+channel blocker action

• Verapamil Summary:–Slows conduction reducing HR and oxygen

demand

–Greater negative inotropic effect than nifedipine

– Weaker vasodilator than nifedipine

–Caution with Digoxin treated patients since it increases dig levels.

Mechanism of Ca+

+channel blocker action

• Diltiazem Summary:–Similar to Verapamil

–Reduces heart rate

–Decreases blood pressure

–Can relieve coronary spasm therefore good for variant angina

–Low incidence of adverse effects

Mechanism of Ca+

+channel blocker action

• Nifedipine Summary:–Mainly arteriolar vasodilator

–Minimal effects on conduction or heart rate

–Useful for variant angina

–Causes flushing, headache, hypotension

–May get reflex tachycardia

Risks with antihypertensive therapy

• Short-acting calcium channel blocker increase the incidence of MI especially in the hypertensive patient.

Selective Calcium Channel Blockersfor Hypertension

Digitalis

Calcium Homeostasis

Digitalis

•The first comprehensive description of digitalis glycosides in the treatment of congestive heart failure, as well as other ailments, was in William Withering's 1785 monograph on the therapeutic efficacy and toxicities of the leaves of the common foxglove plant, Digitalis purpurea

Digitalis

• Other clinically relevant glycosides are derived from the leaves of Digitalis lanata, from which digitoxin and digoxin are derived, and from the seeds of Strophanthus gratus, which contain ouabain.

• Although the terms digitalis glycoside and cardiac glycoside often are used interchangeably, cardiac glycoside is the more inclusive term; digitalis glycoside should be reserved for those agents derived from Digitalis species.

Digitalis

• Inhibition of Na+,K+-ATPase.

• All cardiac glycosides are potent and highly selective inhibitors of the active transport of Na+ and K+ across cell membranes, by binding to a specific site on the extra-cytoplasmic face of the a subunit of Na+,K+-ATPase, the enzymatic equivalent of the cellular "Na+ pump" .

Digitalis

• Importantly, the capacity of the exchanger to extrude Ca2+ from the cell depends on the intracellular Na+ concentration.

• Binding of cardiac glycosides to the sarcolemmal Na+,K+-ATPase and inhibition of cellular Na+ pump activity results in a reduction in the rate of active Na+ extrusion and a rise in cytosolic Na+.

Digitalis

• Positive Inotropic Effect. It has been known for over 70 years that cardiac glycosides increase the velocity of shortening of cardiac muscle, resulting in a shift upward and to the left of the ventricular function (i.e., Frank-Starling) curve, so that increased stroke work is generated for a given filling volume or pressure.

Digitalis• Other mechanisms may contribute to the

inotropic actions of cardiac glycosides.

• Increased cytosolic Ca2+ may act as a positive feedback signal to increase Ca2+ entry through sarcolemmal L-type voltage-sensitive Ca2+ channels.

• Also, cardiac glycosides have been demonstrated to enhance Ca2+-triggered Ca2+ release from cardiac (but not skeletal) muscle SR Ca2+-release channels in isolated SR vesicle preparations.

Digitalis

•Dig Effects:•positive inotropic •inhibition of Ca2+ currents in the AV

node •termination of reentrant

arrhythmias •controlling ventricular response

in patients with atrial fibrillation

Digitalis

• Adverse Effects. •Digitalis intoxication is a

common clinical problem. •Arrhythmias, nausea, and

disturbances of cognitive function are the usual manifestations.

Digitalis

• Adverse Effects.

• Elevated serum concentrations, hypoxia (e.g., due to chronic lung disease), and hypokalemia predispose patients to digitalis-induced arrhythmias

Digitalis

• Adverse Effects.

• Sinus bradycardia and AV block often respond to intravenous atropine, but the effect is transient.

•Mg2+ has been used successfully in some cases of digitalis-induced tachycardia.

Digitalis

• Adverse Effects.

• Any serious arrhythmia should be treated with antidigoxin Fab fragments, which are highly effective in binding digoxin and digitoxin, greatly enhancing the renal excretion of these drugs.

Digitalis

• Clinical Pharmacokinetics. •The most commonly used

preparation of digitalis glycosides in the United States is digoxin (LANOXIN), although digitoxin (CRYSTODIGIN) is also used for chronic oral therapy.

Digitalis

• Clinical Pharmacokinetics. • Quinidine elevates serum digoxin

concentrations by decreasing clearance and volume of distribution

• Other drugs that increase serum digoxin concentration, often through multiple mechanisms, include verapamil, diltiazem, amiodarone, flecainide, and spironolactone.

DigoxinVersusDigitoxin

Digoxin Versus Digitoxin