1. DRUGS THAT INCREASE MYOCARDIAL CONTRACTION
February 2017

2. Definitions
Myocardium: the middle and thickest layer of the heart wall, composed of cardiac muscle
Myocardial contraction: individual myocardial cells transmit motor impulses across cell boundaries and act as a syncytium

3. CARDIAC GLYCOSIDES

4. Cardiac Glycosides- 1. Introduction
Cardiac glycosides are substances from foxgloves (Digitalis spp) and related plants.
William Withering (1775) wrote on the use of the foxglove: ‘ it has a power over the motion of the heart to a degree yet unobserved in any other medicine….’

5. Foxglove plant

6. Cardiac Glycosides- 1. Introduction…
They exert their main pharmacological actions on the heart
They increase myocardial contractility and output in a hypodynamic heart
They do not cause a proportionate increase in O2 consumption 6

7. 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

8. 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

9. Table 1: Sources of Cardiac Glycosides in Nature…
9. Semi-synthetics
-Acetyl digoxin
-Acetyl strophanthidin
-Desarcetyl lanatoside

10. Endogenous cardio tonic steroids (CTSs), also called digitalis-like factors, have been mooted for nearly half a century.
There is evidence in mammals of the presence of an endogenous digitalis-like factor closely similar to ouabain, a short-acting cardiac glycoside.
Its physiological significance is still uncertain

11. 2. Chemistry of Cardiac Glycosides
Fox gloves contain several cardiac glycosides with similar actions (see table 1-slides No. 7-9)
Three of these are digoxin, digitoxin and ouabain
Digoxin is the most important therapeutically (Table 1)
Ouabain is similar to Digoxin but shorter acting

12. 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 ring (5-member ring)

13. 2. Chemistry of Cardiac Glycosides…
The sugar moiety consists of unusual 1-4 linked monosaccharides.
The lactone is essential for activity, the other parts of the molecule mainly determining potency and pharmacokinetic properties.
Substituted lactones can retain biological activity even when the steroid moiety is removed

14. 3. Pharmacological Actions and Mechanisms of Action
The main actions of cardiac glycosides are on the heart
The mechanism whereby cardiac glycosides increase the force of cardiac contraction (positive inotropic effect) is inhibition of the Na+ /K+ pump in the cardiac myocytes.

15. Cardiac glycosides bind to a site on the extracellular aspect of the  subunit of the
Na+ -K+ -ATPase (which is an ß heterodimer), and are useful experimental tools for studying this important transport system.
The molecular mechanism underlying increased vagal tone (negative chronotropic effect) is unknown, but could also be due to inhibition of the Na+ /K+ pump.

16. 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 (by increasing vagal outflow)
Slow the heart
However they disturb cardiac rhythm through blockade of AV conduction and increasing ectopic pacemaker activity

17. Effect on the Heart (i) Force of contraction
Increases
Force of contraction in a hypodynamic heart (Congestive Cardiac Failure)

18. Likely mechanism for the force of contraction (positive inotropic action)
K Na Ca++

19. 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+ /Ca2+ exchanger: Moves 1 Ca2+ outward in exchange for 3 Na+ which move inward into the cell.

20. Mechanism of Action…
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+ )

21. Mechanism of Action…
The increase in intracellular Na+ indirectly causes accumulation of intracellular (Ca2+) by inhibiting Na+ / Ca2+ exchange
During depolarization Ca2+ ions enter the cell through Voltage sensitive Ca 2+ channels
This excess Ca2+ is actively taken up by Sarcoplasmic reticulum
The Ca2+ from Sarcoplasmic reticulum is also released during an action potential for Cardiac muscle contraction

22. (ii) Effect 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

23. (4) Adverse Effects of Cardiac Glycosides
Adverse effects are common and can be severe.
One of the main drawbacks of glycosides in clinical use is the narrow margin between effectiveness and toxicity.

24. (4) Adverse Effects of Cardiac Glycosides….
are dose-related.
Cardiac adverse effects
Cardiac slowing and reduced rate of conduction through AV node
Increased force of contraction
Disturbances of cardiac rhythm especially block of AV conduction and increased ectopic pacemaker activity

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

26. (5a) Pharmacokinetics Aspects
Digoxin is administered by mouth or, in urgent situations, intravenously.
It is a polar molecule; elimination is mainly by renal excretion and involves P-glycoprotein (refer to drug ADME), leading to clinically significant interactions with other drugs used to treat heart failure, such as spironolactone, and with antidysrhythmic drugs such as verapamil and amiodarone.

27. (5a) Pharmacokinetics Aspects…
Elimination half-time is approx. 36h in patients with normal renal function, but considerably longer in elderly patients and those with overt renal failure, in whom reduced doses are indicated.
A loading dose is used in urgent situations.
The therapeutic range of plasma concentrations, below which digoxin is unlikely to be effective and above which the risk of toxicity increases substantially, is fairly well defined (1-2.6 nmol/l).
Determination of plasma digoxin concentration is useful when lack of efficacy or toxicity is suspected.

28. (5b) 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
36-40hrs
20hrs
3. Plasma protein binding
95%
25%
negligible

29. (5b) 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

30. (5b) 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

31. (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)

32. OTHER DRUGS THAT INCREASE MYOCARDIAL CONTRACTION

33. Other Drugs That Increase Myocardial Contraction
Certain 1-adrenoceptor agonists, for e.g. dobutamine, are used to treat acute but potentially reversible heart failure (e.g. following cardiac surgery or in some cases of cardiogenic or septic shock) on the basis of their positive inotropic action.
Dobutamine, for reasons not well understood, produces less tachycardia than other 1- agonists.
It is administered intravenously

34. Other Drugs That Increase Myocardial Contraction…
Glucagon also increases myocardial contractility by increasing synthesis of cAMP, and has been used in patients with acute cardiac dysfunction owing to overdosage of ß –adrenoceptor antagonists.

35. Other Drugs That Increase Myocardial Contraction….
Inhibitors of the heart-specific subtype (type III) of phosphodiasterase, the enzyme responsible for the intracellular degradation of cAMP, increase myocardial contractility.
Consequently, like ß-adrenoceptor agonists, they increase intracellular cAMP but cause dysrhythmias for the same reason.

36. Other Drugs That Increase Myocardial Contraction…
Compounds in this group include amrinone and milrinone.
They improve haemodynamic indices in patients with heart failure but paradoxically worsen survival, presumably because of dysrhythmias.
This dichotomy has had a sobering effect on clinicians and drug regulatory authorities.

37. Homework
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

38. H/W….
Describe the origin; chemistry; actions and adverse effects; mechanisms of action and the uses of cardiac glycosides.

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