Cardiac Glycoside in heart

Cardiac glycosides are very useful and interesting elements in our nature chemically they contain Cardenolides and Bufadienolides 

both are steroidal structures, though, bufadienolides and their glycosides are toxic as they cause atrioventricular block, bradycardia, ventricular tachycardia and possible lethal heart attack. since both therapeutic and toxic effects of digitalis are due to myocardial calcium loading, these are inseperable  and therapeutic index is low. Besides,

Source	Glycosides
Digitalis purpurea(leaf)	Digitoxin                             Gitoxin                             Gitalin
Digitalis lanata	Digoxin                                Gitoxin
Stropanthus gratus(seed)	Stropanthus G (Ouabain)
Toad skin	Bufotoxin

Cardiac glycosides have certain characteristics for which it has been widely accepted as cardiac stimulant while others have few disadvantages, so, today I am going to discuss about various characteristics of cardiac glycosides. Anyway, major functions are:

·         It has inotropic property which means ability of modifying pace or speed of contraction of muscles,

·         It increases myocardial contractility in general, and,

·         It increases output in hypodynamic heart which marked by elevated end-diastolic pressure and slowly rising in ventriculare pressure without a proportionate increase in o₂ consumption, while other stimulants increase significant o₂ consumption and decrease heart efficiency. This could be major disadvantage for them.

Digoxin is currently in use while others aren't used in recent times at all, not only as cardiac stimulant but have great impacts in other cases, however, I am going to discuss the mechanism shortly.

Well, the mechanism mainly involves increasing force of cardiac contraction by a direct action independent of innervations. It selectively binds to extracellular face of the membrane associated Na⁺ K⁺ ATPase of myocardial fibres and inhibits the enzyme, resulting in progressive accumulation of Na⁺ intracellularly besides indirectly accumulate Ca²⁺. Now, during depolarization ca2+ enters the cell driven by the steep ca²⁺ gradient through voltage sensitive L type Ca²⁺ channels. This triggers release of larger amount of Ca²⁺ stored in sacroplasmic reticulum through Ryanodine calcium channel2 resulting in cytosolic Ca²⁺ increases transiently to about 500 nM further resulting in triggers contraction by activating troponin C on myofibrils. The sacroplasmic-endoplasmic reticular calcium ATPase 2 is then activated which pumps Ca²⁺ back into the SR. during phase 3 of AP, membrane Na⁺k⁺ATPase moves intracellular Na+ ions for 2 extracellular K⁺ ion. The slight increase in cytosolic Na⁺ over normal due to partial inhibition of Na⁺k⁺ATPase by digitalis reduces transmembrane gradient of Na+ which drives the extrusion of ca²⁺ .                                                                                                 

The excess Ca²⁺ remaining in cytosol is taken up into SR which progressively get loaded with more Ca²⁺ leading to subsequent calcium transients are augmented. Inotropic effect of digitalis takes hours to develop, even after i.v. administration, due to slow binding of glycoside to Na⁺K⁺ATPase. Toxic actions of digitalis inhibit Na⁺K⁺ATPase. Excessive Ca²⁺ loading of SR results in spontaneous cycles of Ca²⁺ release and uptake producing oscillatory after-depolarizations and after-contractions.

* At high doses, there is depletion of intracellular potassium ion , and digitalis toxicity is partially reversed by infusing potassium ion, because it decreases binding of  glycoside to the enzyme.