DRUGS THAT INCREASE

MYOCARDIAL CONTRACTION

February 2017

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 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

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CARDIAC GLYCOSIDES

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 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….’

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Foxglove plant

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 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

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 Table 1: Sources of Cardiac
Glycosides in Nature
Source Glycoside

1.Digitalis purpurea –purple Digitoxin Gitoxin

foxglove (leaf)
2. Digitalis lanata- white Digitoxin Digoxin
foxglove (leaf)
3. Strophanthus kombe Strophanthin-K
(seed)
4. Strophanthus gratus Strophanthin-G
(seed) 7
 Table 1: Sources of Cardiac
Glycosides in Nature…
Source Glycoside

5. Urginea maritima (bulb) Proscillaridin-A

6. Thevetia neriifolia (nut) Thevetin

7. Convallaria majalis Convallotoxin

8. Bufo vulgaris (toad skin) Bufotoxin

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 Table 1: Sources of Cardiac
Glycosides in Nature…
Source Glycoside

9. Semi-synthetics -Acetyl digoxin

-Acetyl strophanthidin
-Desarcetyl lanatoside

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• 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

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

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 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
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 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.

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• 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.

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 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
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ectopic pacemaker activity
 Effect on the Heart
(i) Force of contraction
• Increases
Force of contraction in a hypodynamic
heart (Congestive Cardiac Failure)

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 Likely mechanism for the force of
contraction (positive inotropic action)

• K+ Na+ Ca++

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 Mechanism of Action
• There are two important ion transport
mechanisms we need to know:
1) The Na+ /K+ ATPase: is an energy
dependent transporter. It removes 3Na+
from the cell in exchange for 2K+ from
the extracellular space
2) Na+ /Ca2+ exchanger: Moves 1 Ca2+
outward in exchange for 3 Na+ which
move inward into the cell.
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 Mechanism of Action…
1) Digitalis selectively binds to extracellular cell
membrane of the cardiac muscle cell and
binds to Na+ /K+ ATPase (Na+ /K+ pump
enzyme)
2) The enzyme ATPase is inhibited by cardiac
glycosides resulting in progressive
accumulation of intracellular (Na+ )

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 Mechanism of Action…
• 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
5) The Ca2+ from Sarcoplasmic reticulum is also
released during an action potential for Cardiac
muscle contraction
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 (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

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 (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.

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 (4) Adverse Effects of Cardiac
Glycosides….
• are dose-related.
A) Cardiac adverse effects
i) Cardiac slowing and reduced rate of
conduction through AV node
ii) Increased force of contraction
iii) Disturbances of cardiac rhythm
especially block of AV conduction and
increased ectopic pacemaker activity
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 (4) Adverse Effects of Cardiac
Glycosides …
B) Extracardiac adverse effects
i. Nausea
i) Vomiting
ii) Diarrhoea
iii) Confusion
iv) Visual disturbances ( Photophobia,
blurring of vision (colour visual
disturbances)
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 (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.
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(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.
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 (5b) A Summary of Pharmacokinetics
Profile of Some Clinically Useful Cardiac
Glycosides
Characteri Digitoxin Digoxin Ouabain
stics
1. Oral Very good Good Virtually
absorption poor
erratic
2. Plasma 5-7 days 36-40hrs 20hrs
t1/2
3. Plasma 95% 25% negligible
protein
binding 28
 (5b) A Summary of Pharmacokinetics
Profile of Some Clinically Useful Cardiac
Glycosides…
Characteri Digitoxin Digoxin Ouabain
stics
4. Onset of ½ hours 15-30 10-15
action minutes minutes
5. Duration 2-3 weeks 2-6 days 1-2 days
of action
6. Potency Least Intermediat Highest
e
7. Route of Oral Oral/I.V I/V
administrati
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on
 (5b) A Summary of Pharmacokinetics
Profile of Some Clinically Useful Cardiac
Glycosides…
Characteri Digitoxin Digoxin Ouabain
stics

8. Route of Hepatic Unchanged Renal

elimination via kidney Excretion

9. Uses Maintainer Emergency

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 (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)

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 OTHER DRUGS THAT
INCREASE MYOCARDIAL
CONTRACTION

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 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
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 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.

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 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.

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 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.
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 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

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

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