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CARDIAC GLYCOSIDES February, 2011

CARDIAC GLYCOSIDES February, 2011. Cardiac glycosides- 1. Introduction. Cardiac glycosides are substances from foxgloves ( Digitalis spp) and related plants. They exert their main pharmacological actions on the heart They increase myocardial contractility and output in a hypodynamic heart.

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CARDIAC GLYCOSIDES February, 2011

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  1. CARDIAC GLYCOSIDES February, 2011

  2. Cardiac glycosides-1. Introduction • Cardiac glycosides are substances from foxgloves (Digitalis spp) and related plants. • They exert their main pharmacological actions on the heart • They increase myocardial contractility and output in a hypodynamic heart

  3. 1. Introduction… • They do not cause a proportionate increase in O2 consumption

  4. Table 1: Sources of Cardiac glycosides in nature

  5. Table 1: Sources of Cardiac glycosides in nature

  6. Table 1: Sources of Cardiac glycosides in nature

  7. There is evidence of the presence of an endogenous digitalis-like factor closely similar to ouabain • Its physiological significance still uncertain

  8. 2. Chemistry of Cardiac Glycosides • Fox gloves contain several cardiac glycosides with similar actions (See table 1) • Three of these are digoxin, digitoxin and ouabain • Digoxin is the most important therapeutically (Table 1) • Ouabain is similar to Digoxin but shorter acting

  9. 2. Chemistry of Cardiac Glycosides … • The basic chemical structure of glycosides consists of three components:- • A sugar moiety (e.g. Glucose) • A steroid • A lactone (5-member ring)

  10. 2. Chemistry of Cardiac Glycosides… • The sugar moiety consists of unusual 1-4 linked monosaccharides. • The lactone ring is essential for activity • Substituted lactones can retain biological activity even when the steroid moiety is removed

  11. 3. Pharmacological Actions and Mechanisms of Action • The main actions of cardiac glycosides are on the heart • The main mechanisms of action of cardiac glycosides are increased vagal activity and inhibition of the Na+/K+ pump • Cardiac glycosides bind to a site on the extracellular aspect of the alpha-subunit of the Na+/K+ ATPase

  12. Effect on the Heart • Cardiac glycosides increase the force of contraction • The rate and rhythm of the heart: • Reduce the rate of conduction through the atrioventricular (AV) node • Slow the heart However they disturb cardiac rhythm through blockade of AV conduction and increasing ectopic pacemaker activity

  13. (i) Force of contraction • Force of contraction in a hypodynamic heart (Congestive Cardiac Failure) • Likely mechanism for the force of contraction positive inotropic action)

  14. K+ Na+ Ca++

  15. Mechanism of Action • There are two important ion transport mechanisms we need to know: • The Na+/K+ ATPase: is an energy dependent transporter. It removes 3Na+ from the cell in exchange for 2K+ from the extracellular space • Na+/Ca++ exchanger: Moves 1 Ca++ outward in exchange for 3 Na+ which move inward into the cell.

  16. Digitalis selectively binds to extracellular cell membrane of the cardiac muscle cell and binds to Na+/K+ ATPase (Na+/K+ pump enzyme) • The enzyme ATPase is inhibited by cardiac glycosides resulting in progressive accumulation of intracellular (Na+)

  17. The increase in intracellular Na+ indirectly causes accumulation of intracellular (Ca2+) by inhibiting Na+/Ca2+exchange 3)During depolarization Ca2+ ions enter the cell through Voltage sensitive Ca 2+ channels 4)This excess Ca2+ is actively taken up by Sarcoplasmic reticulum

  18. 5) The Ca2+ from Sarcoplasmic reticulum is also released during an action potential for Cardiac muscle Contraction

  19. (ii) On heart rate and rhythm • Cardiac glycosides slows AV conduction by increasing vagal activity via an action on the CNS • Benefits: useful against rapid atrial fibrillation • Disadvantages: large doses disturb cardiac rhythm • May slow AV conduction that could progress to AV block • May cause ectopic beats

  20. (4) Adverse Effects of Cardiac Glycosides • are dose-related. • Cardiac adverse effects • Cardiac slowing due to rate of conduction through AV node • force of contraction • Disturbance of cardiac rhythm

  21. (4) Adverse Effects of Cardiac Glycosides … B) Extracardiac adverse effects • Nausea • Vomiting • Diarrhoea • Confusion • Visual disturbances ( Photophobia, blurring of vision (colour visual disturbances)

  22. (5) A Summary of Pharmacokinetics profile of some clinically useful cardiac glycosides

  23. (5) A Summary of Pharmacokinetics profile of some clinically useful cardiac glycosides…

  24. (5) A Summary of Pharmacokinetics profile of some clinically useful cardiac glycosides…

  25. (6) Uses of Cardiac Glycosides • Treatment of Congestive Cardiac Failure (CCF) in patients who remain symptomatic despite optimal use of diuretics and angiotensin-converting enzyme inhibitors • To slow ventricular rate in rapid persistent atrial fibrillation i.e. (Anti-dysrrhythmic agents)

  26. H/W-Further Reading • Digoxin is the most widely used cardiac glycoside preparation. Discuss its:- • Chemistry • Characteristic features • Absorption, Distribution, Metabolism, Excretion • Actions & Mechanisms of Action • Adverse Effects • Uses • Digoxin toxicity • Treatment of Digoxin toxicity

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