1. CARDIAC GLYCOSIDES February, 2011
REMEMBER MECHANISM OF ACTION OF CARDIAC GLYCOSIDES

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
1.Digitalis purpurea –purple foxglove (leaf)
Digitoxin Gitoxin
2. Digitalis lanata- white foxglove (leaf)
Digitoxin Digoxin
3. Strophanthus kombe (seed)
Strophanthin-K
4. Strophanthus gratus (seed)
Strophanthin-G

5. Table 1: Sources of Cardiac glycosides in nature
5. Urginea maritima (bulb)
Proscillaridin-A
6. Thevetia neriifolia (nut)
Thevetin
7. Convallaria majalis
Convallotoxin
8. Bufo vulgaris (toad skin)
Bufotoxin

6. Table 1: Sources of Cardiac glycosides in nature
9. Semi-synthetics
-Acetyl digoxin
-Acetyl strophanthidin
-Desarcetyl lanatoside

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
Characteristics
Digitoxin
Digoxin
Ouabain
1. Oral absorption
Very good
Good
Virtually poor
erratic
2. Plasma t1/2
5-7 days
40hrs
20hrs
3. Plasma protein binding
95%
25%
negligible

23. (5) A Summary of Pharmacokinetics profile of some clinically useful cardiac glycosides…
Characteristics
Digitoxin
Digoxin
Ouabain
4. Onset of action
½ hours
15-30 minutes
10-15 minutes
5. Duration of action
2-3 weeks
2-6 days
1-2 days
6. Potency
Least
Intermediate
Highest
7. Route of administration
Oral
Oral/I.V
I/V

24. (5) A Summary of Pharmacokinetics profile of some clinically useful cardiac glycosides…
Characteristics
Digitoxin
Digoxin
Ouabain
8. Route of elimination
Hepatic
Unchanged via kidney
Renal Excretion
9. Uses
Maintainer
Emergency

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