Heart failureit is the inability of the heart to meet the

metabolic requirements of the peripheral system.

In heart failure the compensatory mechanisms are
activated
1. Sympathetic nervous system pulse rate
2. Renin angiotensin aldosterone systemleg oedema
3. ADH secretion
Drugs used in the heart failure
A. Drugs with positive ionotropic action ( the force of
contraction)
i. Cardiac glycosides/digitalis
ii. -agonist
iii. Phosphodiesterase enzyme inhibitors
( i and ii Advised in heart failure but not used in case of
asthma)
B. Drugs without positive ionotropic action
i. Diuretics ( preload)
ii. Vasodilators ( after load)
iii. ACE inhibitorangiotensin converting enzyme ( both
preload and after load)
*** usually drugs of both groups are used in treatment.
*** in case abnormality of the ventricles, heart is unable to
adequately pump blood. So, tissue perfusion .
Types of heart failure
Right and left heart failure
Acute and chronic heart failure
Forward and backward heart failure
Factors
o Force of contraction
o Heart rate
o Preload
o After load

Cardiac Glycosides

Synthesized from the plant carbohydrate by hydrolysis. It has

sugar and non-sugar parts.
These are the glycosidic compounds with cardiotonic action.
They have
1. Steroid nucleus & Lactone ring (non-sugar part)
2. Sugar moiety
*** the steroid nucleus contains Cyclo-Pentano Phenanthrene
(CPP) ring
*** if the sugar part is glucose then it is called glycoside.
(fructosefructoside, pentosepentoside)
*** sugar part = glycone part, lactone ring +CPP ring =
Aglycone part.
Pharmacokinetic property depends upon sugar moiety
glycone part.
Pharmacodynamic property depends upon glycine moiety
/aglycone part.
Source of cardiac glycosides
Digitalis lanata (Digoxin)
Digitalis purpura (Digitoxin)
Stropanthus gratus (Stropanthin)
Stropanthus kombe (Ouabian)
Name of the Cardiac glycosides
1. Digoxin (most commonly used)
2. Digitoxin
3. Ouabian
*** DigitalisDigoxin and Digitoxin
Pharmacokinetics
Digitalis may be given as tablets or capsules
Therapeutic index is very low so, low safety margin
Wide distribution to various tissues because of lipid solubility
{Advantagereaches
the
target
site
very
quickly,
Disadvantagegoes to other tissues}

 Digoxin mainly eliminated by the kidney (may be given to

patients with liver diseases)
Digitoxin is mainly eliminated by hepatic metabolism (may
be given to patients with renal failure)
The presence of enzyme inducers or inhibitors can change
the extent of digitalis clearance
{so, digitalis and rifampicin is given together, acts as enzyme
inducer}
Indication of use of cardiac glycosides
1. CCF (congestive cardiac failure)
2. Atrial fibrillation
3. Atrial and nodal tachycardia
4. Ventricular tachycardia
Contraindication of use of cardiac glycosides
1. Heart block
2. Obstructive cardiomyopathy
Mechanical effects of Cardiac Glycosides
1. They inhibit Na+-K+-ATPase pump system on cardiac muscle
cell membrane.
2. There is increased intracellular Na+ concentration.
3. Less expulsion of calcium from the cells by the Na+Ca+ exchanger.
4. Also there is facilitation of Ca+ entry through the voltage
gated calcium channel.
5. There is increased release of calcium from intracellular
storage site (sarcoplasmic reticulum)
6. Net result is increased cardiac contractility, so the sign
symptom of cardiac failure is corrected.
Pharmacological effects / Mechanism
Digitalis (Digoxin and Digitoxin)

of

Action

of

On heartthe effects on the heart is of 2 types

a. Effects on contractilitycardiac contractility is increased
and heart rate is decreased. Both of these effects in failing
heart causes rise of cardiac output; thus symptoms are
relieved. This increased contractility is due to greater
availability of Ca++ within the myocardial cells. The increased

contractility of the heart causes greater evacuation of the

ventricles; thus causes reduction of venous congestion and
reduction of preload. Resulting in improvement of backward
failure.
Increased contractility also causes increased cardiac output,
leading to greater perfusion pressure, thus forward failure is
relieved.
b. Effects on rate and rhythmBradycardia; conductivity of A-V
node is delayed. Slowing of rate of origin of impulses from
the S-A node. In short heart rate becomes slow and threat of
A-V block appears. These effects are largely due to
parasympathetic stimulation.
On blood vesselsin presence of congestive heart failure,
where there is sympathetic over activity (compensatory).
Digitalis reduces the sympathetic over activity, so there is
HR and vasodilatation.
*** in normal person digitalis cause both atrial and venous
constriction.
On coronary circulation and myocardial O 2 supply
digitalis cause bradycardia, so cardiac metabolism is
decreased. So, there is reduction of O2 demand, it also reduces
the heart size.
All theses will cause less O2 demand by the failing heart.
Coronary blood supply also improves.
On ANSin congestive heart failure there is sympathetic over
activity (compensatory). Digitalis reduces the sympathetic over
activity and increases vagal activity.
In toxic dose digitalis causes sympathetic over activity by
stimulating VMC. In normal person it does the same thing in
normal dose.
On CNSin therapeutic dose the effects are minimal but
higher (toxic) doses cause stimulation of the chemoreceptor
trigger zone (CTZ) leading to nausea, vomiting, mental
confusion and visual disturbances.
Digitoxin is more prone to CNS symptoms than Digoxin.

On kidneysin congestive heart failure there is excessive

renin production, which causes vasospasm and hypervolumia.
Digitalis improves forward failure, Co and thus reduces renin
production and there is natriuresis and reduction of
hypervolumia. In congestive heart failure there is backward
failure, as a result there is congestion in the renal venous
circulation. And because there is less CO, less blood is
available in the renal arteriolar side. So there is sluggishness in
the renal circulation. All these cause stasis of circulation in the
kidney, so more Na+ and H2O is reabsorbed causing
hypervolumia, oedema, ascities etc.
Digitalis by increasing cardiac contractility improves CO thus
heart pumps more blood in the arterial side, as a result venous
congestion is relieved, renal circulation is improved and
diuresis starts in the kidney.
Influence of Glycosides on autonomic action
Glycosides influences both sympathetic and parasympathetic
effects on heart and it occurs throughout therapeutic and toxic
dose range.
Electrical effects of cardiac glycosides
On SA node and AV node and conducting tissuesdecreased
impulse discharge/generation from the SA node and decrease
impulse propagation through the AV node.
In toxic doses cardiac glycosides can increase the
sympathetic effect on heart.
*** cardiac glycosides also have pharmacological effects on
kidney, CNS and GIT
*** cardiac glycosides cause anorexia in the GIT
*** cardiac glycosides perfusion and filtration, so has
diuretic actions
*** digitalis are lipid soluble and therefore have effects in the
CNS and eliminated by the liver
Digitalizationit is a process of dosing with digitalis which
may be slow or rapid with the objective of attaining a steady
state of plasma concentration of drug in cardiac patient.
Loading doseit is the dose that is given to load the
concentration of drug in blood.

Maintenance doseit is the dose that is given to maintain

the concentration of drug in blood.
Digoxin
Digitoxin
Rapid digitalization 0.50.75mg every 8hrs for 30.20.4mg
every
doses
12hrs
Slow digitalization 0.1250.5mg
0.050.2mg

Toxicity
Cardiac effects
1. Severe bradycardiasome persons can have even sino-atrial
exit block. (these are all due to a combination of vagal
stimulation and withdrawal of sympathetic over-activity)
2. Paroxysmal or non-paroxysmal atrial tachycardiasupra
ventricular tachycardia. (due to increased automaticity or reentry phenomenon)
3. A-V nodal rhythm due to development of after depolarization
of AV node.
4. A-V block due to vagal over-activity.
5. Ventricular ectopicpremature beat. (due to re-entry
phenomenon in Hiss perkinjee system or after depolarization)
this may lead to bigeminus pulse.
6. Ventricular tachycardia or fibrillation.
Non-cardiac effects
1. Anorexia, nausea, vomiting (CNS effects)
2. Visual disturbance
3. Very rarely delirium or convulsion
Features of digitalis poisoning
GIT problemanorexia, nausea, vomiting
CVS problemarrhythmia, bradycardia
CNS problemvisual haloes, hallucination
Management of digitalis poisoning / Toxicity
1. Stop or correct the dose
2. Correct the electrolyte abnormality, that is hypokalemia
(K+ therapy can be given)
3. Use drug like atropine to the HR if Bradycardia is present
4. Administer digitalis antibody

5. To prevent arrhythmia Lidocaine or Phenytoin can be given

6. To insert temporary pacemaker
*** now a days Digitalis antibody (Digibine) is used IV.
Differences between Digitoxin and Digoxin
Digitoxin
Less polar and more lipid
soluble
Easily crosses BBB
Produces CNS symptom
life is 5 days
Heart : plasma ratio is 7:1
Mostly metabolized in the
liver, so its excretion is
independent
of
renal
function
Digitalization
requires
(4x5) 20 days

Digoxin
More polar and less lipid soluble
Does not cross BBB
Does not produce CNS symptom
life is 1 days
Heart : plasma ratio is 30:1
More than 80% excreted unchanged via
urine, rest is removed by non-renal
routes like biliary excretion and hepatic
metabolism
Digitalization requires (4x1) 20 days

Indication of Digoxin
1. Low output heart failure (where the rhythm is sinus rhythm)
2. Where CHF (congestive heart failure) is accompanied by
atrial fibrillation
3. It may be used in cardiac arrhythmias like atrial flatter, atrial
fibrillation, acute supraventricular tachycardia
Note:- when the heart failure is due to such cases like
thyrotoxicosis (high output failure), Beriberi, Cor pulmonate
digitalis are not of great help. (although the drug is not
contraindicated in such cases)
Contraindication of Digoxin
1. Wolff Parkinson white (WPW)
2. In diastolic failure
3. Heart block
4. Previous history of strokes Adams syndrome
5. Obstructive cardiac myopathy
Relative contraindication of Digoxin
1. Severe renal failure
2. Sinus bradycardia
3. After acute MI (myocardial infarction)

4. Cor pulmonate
Other drugs used in heart failure
1. Other positive ionotropic drugs
Dopamine / Dobutamine receptor stimulation. Used in
acute heart failure, on patient it is refractory to other
cardiac drugs (parenterally). They CO and force of
contraction.
2. Phosphodiesterase
inhibitorsdrugs
that
inhibit
phosphodiesterase and therefore intracellular cyclic-AMP.
So it increases cardiac contractility, force of contraction.
The newer phosphodiesterase inhibitors include Bipyridine.
They the intracellular influx of Ca++ into the heart cells
(Amrinone, Milrinone). But this drug does not inhibit Na +-K+ATPase pump and does not activate adrenoceptors.
In acute heart failure if Bipyridine is given they will CO and
pulmonary capillary pressure (lung congestion).
3. Drugs without positive ionotropic action
Reduction of the preload. Such as diuretics. This drug
preload (venous return) by increasing water and salt loss.
The nitrates dilate capacitans veins, thus reducing the
ventricular filling pressure and the heart wall stretch and
myocardial O2 demand. So can be used in acute left
ventricular failure.
*** Hydralazineit relaxes the arterioles, therefore
peripheral vascular resistance.
4. Reduction of both preload and after load
ACE inhibitors (angiotensinogen converting enzyme
inhibitors)here preload is decreased as reduced formation
of aldosterone thus reducing water and salt retention. It
decreases after load by preventing the conversion of
angiotensin-I to angiotensin-II thus decreases angiotensin-II
mediated vasoconstriction.