CONGESTIVE HEART FAILURE

Heart failure

Heart failure, also known as congestive heart failure and congestive cardiac
failure, is when the heart is unable to pump sufficiently to maintain blood flow
to meet the body's needs. Signs and symptoms of heart failure commonly
include of breath, shortness excessive tiredness, and swelling. leg The shortness
of breath is usually worse with while exercise or laying down, and may wake the
person at night. A limited ability to exercise is also a common feature. Chest
pain, including angina, does not typically occur due to heart failure.

Common causes of heart failure-

-coronary artery diseases

-myocardial infarction (heart attack)
-high blood pressure
-fibrillation,
-atrial valvular heart disease,
-alcohol use
-excess infection

These cause heart failure by changing either the structure or the function of the
heart.

The two types of left ventricular heart failure

– heart failure with reduced ejection fraction

 - heart failure with preserve ejection fraction

These are based on whether the ability of the ventricle to contract, or to

relax, is affected. left The severity of the heart failure is graded by the severity of
symptoms with exercise.

Heart failure is not the same as heart attack (in which part of the heart muscle
dies) or cardiac arrest (in which blood flow stops altogether).

Other diseases that may have symptoms similar to heart failure include

-obesity
-failure
-liver problems
-kidney anemia

Diagnosis is based on symptoms, physical findings,and

echocardiography.Blood tests, thyroid electrocardiography, and chest
radiography may be useful to determine the underlying cause. Treatment
depends on the severity and cause of the disease.

In people with chronic stable mild heart failure, treatment commonly consists
of lifestyle modifications such as
-stopping smoking
-physical exercise
-dietary changes

In those with heart failure due to left ventricular dysfunction, angiotensin

converting enzyme inhibitors, blockers, or angiotensin receptor
valsartan/sacubitril along with beta blockers are recommended.

For those with severe disease, aldostron antagonists, or may be used.

hydralazine with a nitrate Diuretics are useful for preventing fluid retention and
the resulting shortness of breath. Sometimes, depending on the cause, an
implanted device such as a pacemaker or an implantable cardiac defibrillator
may be recommended. In some moderate or severe cases, therapy cardiac
resynchronization or cardiac contractility modulation may be of benefit.
 A ventricular assist device (for the left, right, or both ventricles), or
occasionally a heart transplant may be recommended in those with severe
disease that persists despite all other measures.

Heart failure is a common, costly, and potentially fatal condition. In 2015, it

affected about 40 million people globally. Overall around 2% of adults have heart
failure and in those over the age of 65, this increases to 6–10%. Rates are
predicted to increase. The risk of death is about 35% the first year after
diagnosis; while by the second year the risk of death is less than 10% for those
who remain alive.This degree of risk of death is similar to some cancers.In the
United Kingdom, the disease is the reason for 5% of emergency hospital
admissions. Heart failure has been known since ancient times, with the Ebers
papyrus commenting on it around 1550

*symptoms of Heart failure-

-Pain areas: in the chest

-Cough: can be dry or with phlegm

-Whole body: dizziness, fatigue, inability to exercise, or loss of appetite

-Respiratory: fast breathing, shortness of breath at night, shortness of breath on

exercise, or shortness of breath on lying down

-Gastrointestinal: bloating or water retention

-Also common: excess urination at night, palpitations, swollen feet, swollen

legs, or weight gain
 *Diagnosis of Heart failure-

No system of diagnostic criteria has been agreed on as the gold standard for
heart failure. The National Institute for Health and Care Excellence recommends
measuring brain natriuretic peptide followed by ultrasound of the heart if
positive. This is recommended in those with shortness of breath. In those with
worsening heart failure, both a BNP and a troponin are recommended to help
determine likely outcomes.

There are several terms which are closely related to heart failure and may be
the cause of heart failure, but should not be confused with it. Cardiac arrest and
asystole refer to situations in which there is no cardiac output at all. Without
urgent treatment, these result in sudden death. Myocardial infarction ("Heart
attack") refers to heart muscle damage due to insufficient blood supply, usually
as a result of a blocked coronary artery. Cardiomyopathy refers specifically to
problems within the heart muscle, and these problems can result in heart failure.
Ischemic cardiomyopathy implies that the cause of muscle damage is coronary
artery disease. Dilated cardiomyopathy implies that the muscle damage has
resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves
enlargement and thickening of the heart muscle.

-ultrasound
-Chest x ray
-Electrophysiology
-Angiography
-Blood test
-Algorithms
-Framingham criteria
-ESC algorithm

*Types-

1 left sided heart failure

•Systolic heart failure
•Diastolic heart failure
2 Right sided heart failure
3 congestive heart failure
*Stages of Heart failure-

In its 2001 guidelines the College of Cardiology/ American American Heart

Association working group introduced four stages of heart failure:

Stage A: People at high risk for developing HF in the future but no functional
or structural heart disorder.

Stage B: a structural heart disorder but no symptoms at any stage.

Stage C: previous or current symptoms of heart failure in the context of an

underlying structural heart problem, but managed with medical treatment.

Stage D:advanced disease requiring hospital-based support, a heart

transplant or palliative care.

*Treatment of Heart Failure:-

●Natural source:-

•Natural source Eg: [ fig - Natural source of CHF Treatment]

-Digitalis
-stropanthus
-ouabain
-Thevetia
-Indian squill
-Coleus
 •synthetic source-

CLASSIFICATION

Drugs for congestive Heart failure-

1) Diuretics-
a loop diuretics- furosemide, bumetanide
b Thiazide diuretic- metolazone,
c Aldosterone antagonist- spironlacton

2) Vasodialators-
a- Areterior & venodialator
•ACE inhibitor-enalapril, lisinopril
•AT Antagonist-losartan , condasartan
•Direct renin inhibitor-aliskiren
b- venodilators- Nitroglycerin
c- Anterior dilator- Minoxidil, Hydralazine

3) B adrenergic blocker- metoprolol

4) cardiac glycoside- Digoxin
5) phospodiesterase inhibitor- Inamirnon
6) sympathomimetic amine- Dopamine

(1)Diuretics-

The main diuretic drug classes are:

• Thiazides
• Loop diuretics
• Spironolactone.
Mechanism of action—

The antihypertensive action of diuretic drugs does not seem to correlate with
their diuretic activity:

loop diuretics are powerful diuretics but only moderate antihypertensives

while thiazides are moderate diuretics but powerful antihypertensives.

It has recently been suggested that the antihypertensive effects of diuretics

(especially the thiazides) are not necessarily due to their diuretic effect, but
rather may be due to activation of ATP-regulated potassium channels in
resistance arterioles, with a mechanism of action similar to that of nicorandil and
minoxidil.

This causes hyperpolarization, and thus inhibition of calcium entry into vascular
smooth muscle cells with consequent vasodilatation and reduced peripheral
vascular resistance

* Aldosterone antagonist:-
(Spironolactone, Eplerenone)

Over the past 2 decades it has been realized that rise in plasma aldosterone in
CHF, in addition to its well known Na+ and water retaining action, is an
important contributor to disease progression by direct and indirect effects:

(a) Expansion of e.c.f. volume → increased cardiac preload

.
(b) Fibroblast proliferation and fibrotic change in myocardium → worsening
systolic dysfunction and pathological remodeling.
 (c) Hypokalemia and hypomagnesemia → increased risk of ventricular
arrhythmias and sudden cardiac death.

(d) Enhancement of cardiotoxic and remodeling effect of sympathetic

overactivity.

The aldosterone antagonist spironolactone is a weak diuretic but can benefit

CHF by antagonizing the above effects of aldosterone.

In addition to several small studies, a large Randomised aldactone evaluation

study (RALES, 1999) conducted on 1663 NYHA class III and IV patients having left
ventricular ejection fraction < 35% has confirmed the additional survival benefit
(30%) of spironolactone when added to conventional therapy with ACE
inhibitors + other drugs. A subsequent trial (EPHESUS, 2003) using another
aldosterone antagonist eplerenone in post acute MI heart failure has further
substantiated the mortality and anti-remodeling benefit over and above that of
ACE inhibitors ± β blockers.

Though ACE inhibitors themselves lower aldosterone levels, this effect is

incomplete and short lasting. Current evidence suggests the following regarding
spironolactone/eplerenone therapy in CHF:

• It is indicated as add-on therapy to ACE inhibitors + other drugs in moderate-

to-severe CHF.
• It can retard disease progression, reduce episodes of decompensation and
death due to heart failure as well as sudden cardiac deaths, over and above the
protection afforded by ACE inhibitors/ARBs ± β blockers.
• Only low doses (12.5–25 mg/day) of spironolactone should be used to avoid
hyperkalaemia; particularly because of concurrent ACE inhibitor/ARB therapy.
• It may help restoration of diuretic response to furosemide when refractoriness
has developed.

◆ Adverse Reactions:

•The onset of benefit of aldosterone/antagonist in CHF is slow.

 •It is contraindicated in renal insufficiency because of risk of hyperkalemia—
requires serum K+ monitoring.

•Gynaecomastia occurs in a number of male patients treated with

spironolactone.

•This can be avoided by using eplerenone.

•Aldosterone antagonists are a significant additional therapeutic measure in

moderate-severe CHF with prognostic benefits.

(2) Vasodilators :

Vasodilators were first used i.v. to treat acute heart failure that occurs in
advanced cases or following MI, and serve to tide over crisis. Their use by oral
route has been extended to long-term therapy of chronic CHF, but vasodilators
other than ACE inhibitors/ARBs have only limited utility. Vasodilators with
differing profiles of arteriolar and venodilator action are available (see box).

(i) Preload reduction:

Nitrates cause pooling of blood in systemic capacitance vessels to reduce

ventricular end-diastolic pressure and volume. With reduction in size of
ventricles, effectiveness of myocardial fibre shortening in causing ejection of
blood during systole improves (Laplace relationship). Controlled i.v. infusion of
glyceryl trinitrate affords rapid relief in acute left ventricular failure, particularly
that due to myocardial ischaemia/infarction.
 It is indicated when the central venous pressure (CVP) is raised and in dilated
cardiomyopathy. However, lowering of preload (by vasodilators + strong
diuretics) beyond a limit may reduce output of a failing heart whose
performance is dependent upon elevated filling pressure. Occurrence of nitrate
tolerance limits their utility in routine treatment of CHF.

(ii) Afterload reduction

Hydralazine dilates resistance vessels and reduces aortic impedance so that

even weaker ventricular contraction is able to pump more blood; systolic wall
stress is reduced.

It is effective in forward failure when cardiac index (CI = min output/body

surface area) is low (< 2.5 L/min/m2) without a marked increase in CVP (< 18 mm
Hg). Marked tachycardia, worsening of myocardial ischaemia and fluid retention
limit long-term use of hydralazine monotherapy. Minoxidil is a more potent
arteriolar dilator, but has found little use in heart failure; so has nicorandil a
more specific pot. channel opener.
 Trials of the three prototype calcium channel blockers verapamil, diltiazem and
nifedipin in systolic dysfunction have been disappointing, even negative with
occasional worsening of symptoms and increase in mortality.

This may be due to reflex sympathetic activation (nifedipine) or negative

inotropic property (verapamil, diltiazem). Verapamil, however, is useful in
diastolic dysfunction due to hypertrophic cardiomyopathy. Trials with long-acting
and more vasoselective dihydropyridines (felodipine, amlodipine) have also not
been encouraging.

iii) Pre- and after load reduction

Sod. nitroprusside is a high efficacy i.v. dilator with equal action on the two
types of vessels. It acts by both the above mechanisms, i.e. reduces ventricular
filling pressure as well as systemic vascular resistance. Cardiac output and renal
blood flow are increased. The action is very fast and brief.

Titrated i.v. infusion of nitroprusside is employed in conjunction with a loop

diuretic + i.v. inotropic drug to tideover crisis in severely decompensated
patients. For symptomatic treatment of acute heart failure, choice of i.v.
vasodilator (glyceryl trinitrate or hydralazine or nitroprusside) depends on the
primary haemodynamic abnormality in individual patients.

In the long term oral therapy, survival benefit has been obtained only with a
combination of hydralazine + isosorbide dinitrate, but the ACE inhibitors and
ARBs are clearly superior in this regard. Hydralazine causes more marked renal
vasodilatation. Along with isosorbide dinitrate it may be selected for patients
with renal insufficiency, low renal blood flow or renal artery stenosis, who
cannot tolerate ACE inhibitors or ARBs.

Hydralazine alone or a nitrate alone have not proven useful in the treatment of
chronic heart failure. However, when combined they supplement each other and
nitrate tolerance is attenuated by hydralazine. Severe CHF patients already
receiving ACE inhibitors + digoxin + diuretic have obtained extra benefit from
addition of hydralazine with or without a nitrate. For reasons not known, the α1
blocker prazosin has not been able to afford prognostic benefit.
● Renin-angiotensin system (RAS) inhibitors:-

Since RAS activation is pivotal to development of symptoms and disease

progression in CHF, the ACE inhibitors and ARBs are the sheet anchor of drug
therapy in CHF. They afford symptomatic as well as disease modifying benefits in
CHF by causing vasodilatation, retarding/preventing ventricular hypertrophy,
myocardial cell apoptosis, fibrosis intercellular matrix changes and remodeling.

In addition to decreasing Ang II production, ACE inhibitors raise the level of

kinins which stimulate generation of cardioprotective NO and PGs. Symptomatic
and prognostic benefits of ACE inhibitors/ARBs have been established in mild to
severe (NYHA class I to IV) CHF as well as in subjects with asymptomatic systolic
dysfunction.

They are thus recommended for all grades of CHF, unless contraindicated, or if
renal function deteriorates by their use (mainly in those with decresed renal
blood flow/renal artery stenosis).

ACE inhibitor therapy is generally started at low doses which are gradually
increased to obtain maximum benefit or to near the highest recommended
doses.

(3) β-Adrenergic blockers:-

Extensive studies over the past 30 years have established the utility of β1
blockers (mainly metoprolol, bisoprolol, nebivolol) and the nonselective β +
selective α1 blocker carvedilol in mild to moderate CHF treated with ACE
inhibitor ± diuretic, digitalis.

A large number of randomized trials including Metoprolol in dilated

cardiomyopathy trial (1993), US carvedilol trial (1996), MERIT-HF trial (1999),
CIBIS-II trial (1999), CAPRICORN trial (2001), COPERNICUS trial (2002) have
demonstrated subjective, objective, prognostic and mortality benefits of the
above named β blockers over and above that afforded by ACE inhibitors +
diuretic ± digitalis.
Though the immediate hemodynamic action of β blockers is to depress
cardiac contractility and ejection fraction, these parameters gradually improve
over weeks. After a couple of months ejection fraction is generally higher than
baseline, and slow upward titration of dose further improves cardiac
performance. The hemodynamic benefit is maintained over long-term and
hospitalization/ mortality due to worsening cardiac failure, as well as all cause
mortality is reduced. The benefits appear to be due to antagonism of ventricular
wall stress enhancing, apoptosis promoting and pathological remodeling effects
of excess sympathetic activity (occurring reflexly) in CHF, as well as due to
prevention of sinister arrhythmias. Incidence of sudden cardiac death as well as
that due to worsening CHF is decreased. β blockers lower plasma markers of
activation of sympathetic, renin-angiotensin systems and endothelin-1.
However, β blocker therapy in CHF requires caution, proper patient selection
and observance of several guidelines:

• Greatest utility of β blockers has been shown in mild to moderate (NYHA class
II, III) cases of dilated cardiomyopathy with systolic dysfunction in which they are
now routinely coprescribed unless contraindicated.

• Encouraging results (upto 35% decrease in mortality) have been obtained in

class IV cases as well, but use in severe failure could be risky and needs constant
monitoring.

• There is no place for β blockers in decompensated patients. β blockers

should be stopped during an episode of acute heart failure and recommenced at
lower doses followed by uptitration after compensation is retored. Conventional
therapy should be continued along with them.

• Starting dose should be very low—then titrated upward as tolerated to the

target level (carvedilol 50 mg/day, bisoprolol 10 mg/day, metoprolol 200
mg/day) or near it, for maximum protection.

• In few patients any attempt to introduce a β blocker results in worsening of

heart failure. β blockers should not be used in such patients.

• A long-acting preparation (e.g. sustained release metoprolol) or 2–3 times

daily dosing to produce round-the-clock β blockade should be selected.

• There is no evidence of benefit in asymptomatic left ventricular dysfunction.

(4) Sympathomimetic inotropic drugs:-

Drugs with β adrenergic and dopaminergic D1 agonistic actions have positive

inotropic and (at low doses) vasodilator properties which may be utilized to
combat emergency pump failure.

*Dobutamine -

(2–8 μg/kg/min) a relatively selective β1 agonist with prominent inotropic

action is the preferred drug for i.v. infusion in acute heart failure accompanying
myocardial infarction (MI), cardiac surgery as well as to tide over crisis in
advanced decompensated CHF.

*Dopamine -

(3–10 μg/kg/min by i.v. infusion) has been used in cardiogenic shock due to MI
and other causes. While dobutamine does not raise (may lower) systemic
vascular resistance and is preferred in heart failure, dopamine tends to increase
afterload, especially at higher rates of infusion (>5 μg/kg/min) and has limited
utility in patients who are not in shock. Low rates of dopamine infusion (~2
μg/kg/min) cause selective renal vasodilatation (D1 agonistic action) which
improves renal perfusion and g.f.r. This can restore diuretic response to i.v.
furosemide in refractory CHF.

These drugs afford additional haemodynamic support over and above

vasodilators, digitalis and diuretics, but benefits are short-lasting. Due to
development of tolerance and cardiotoxic potential when used regularly, these
drugs have no role in the long-term management of CHF.

(5) Phosphodiesterase 3 inhibitors:-

Theophylline is a phosphodiesterase inhibitor that is nonselective for different

isoforms of this enzyme which degrades intracellular cAMP and cGMP.
Intravenous aminophylline had been used in past for acute left ventricular failure
with limited benefits, but unacceptable toxicity.
*Inamrinone (amrinone)-

It is chemically and pharmacologically distinct from digitalis and catecholamines.

This bipyridine derivative is a selective phosphodiesterase 3 (PDE3) inhibitor.
The PDE3 isoenzyme is specific for intracellular degradation of cAMP in heart,
blood vessels and bronchial smooth muscles. Amrinone increases myocardial
cAMP and transmembrane influx of Ca2+. It does not inhibit Na+K+ATPase, and
its action is independent of tissue catecholamines as well as adrenergic
receptors.

The two most important actions of amrinone are positive inotropy and direct
vasodilatation: has been called an ‘inodilator’. Both preload and afterload on the
heart is reduced. Compared to dobutamine, proportionately greater decrease in
systemic vascular resistance is noted.

In CHF patients i.v. amrinone action starts in 5 min and lasts 2–3 hours;
elimination t½ is 2–4 hours. It increases cardiac index, left ventricular ejection
fraction and decreases peripheral vascular resistance, CVP, left ventricular end
diastolic volume and pressure accompanied by mild tachycardia and slight fall in
BP.

Adverse effects-

-Thrombocytopenia is the most prominent and dose related side effect, but is
mostly transient and asymptomatic. -Nausea,
-diarrhoea,
-abdominal pain,
-liver damage,
-fever
-arrhythmias are the other adverse effects.

Use-

Though amrinone is active orally, its oral use in maintenance therapy of CHF has
been abandoned, because efficacy was lost and mortality was increased in
comparison to placebo. It is indicated only for short-term i.v. use in severe and
refractory CHF, as an additional drug to conventional therapy with digitalis,
diuretics and vasodilators. Dose: 0.5 mg/kg bolus injection followed by 5–10
µg/kg/ min i.v. infusion (max. 10 mg/kg in 24 hours).

*Milrinone

It is Related to inamrinone, it has similar action but is more selective for PDE3,
and is at least 10 times more potent. It is shorter-acting with a t½ of 40–80 min.

Thrombocytopenia is not significant. In long term prospective trials, increased

mortality has been reported with oral milrinone also. Milrinone is preferred over
amrinone and should be restricted to short-term use only. Dose: 50 µg/kg i.v.
bolus followed by 0.4–1.0 µg/kg/min infusion. PRIMACOR IV 10 mg/10 ml inj.

(6) CARDIAC GLYCOSIDES:-

These are glycosidic drugs having cardiac inotropic property. They increase
myocardial contractility and output in a hypodynamic heart without a
proportionate increase in O2 consumption. Thus, efficiency of failing heart is
increased. In contrast, ‘cardiac stimulants’ increase O2 consumption rather
disproportionately and tend to decrease myocardial efficiency.

William Withering, a Birmingham physician, learnt that a decoction containing

‘foxglove’ (Digitalis) with other herbals, prepared by an old lady, relieved dropsy.
He tried extract of foxglove alone and found it to be remarkably effective in
some cases. He published his classic monograph ‘An account of the Foxglove and
some of its medicinal uses: with practical remarks on dropsy and other diseases’
in 1785 and ascribed the beneficial effect to an action on the kidney. Cushney
and Mackenzie, in the beginning of 20th century, established its action on the
heart and its use in congestive heart failure (CHF).

Cardiac glycosides are found in several plants and in toad skin (Bufotoxin).
Digitalis lanata is the source of Digoxin, the only glycoside that is currently in
use. Others like Digitoxin (from Digitalis purpurea) and Ouabain (from
Strophan thus gratus), etc. are no longer clinically used or marketed.

By convention the term, ‘Digitalis’ has come to mean ‘a cardiac glycoside’.

*Chemistry-

The cardiac glycosides consist of an aglycone (genin) to which are attached

one or more sugar (glucose or digitoxose) moieties

The aglycone consists of a cyclopentanoperhydrophenanthrene (steroid) ring to

which is attached a 5 or 6 membered unsaturated lactone ring.

*PHARMACOLOGICAL ACTIONS-

All digitalis glycosides have qualitatively similar action. Digoxin is described as

prototype.

1. Heart

Digitalis has direct effects on myocardial contractility and electrophysiological

properties. In addition, it has vagomimetic action, reflex effects due to alteration
in haemodynamics and direct CNS effects altering sympathetic activity.

*Force of contraction:-

Digitalis causes a dose dependent increase in force of contraction of heart—a

positive inotropic action. This is especially seen in the failing heart which is
exquisitely sensitive. There is increased velocity of tension development and
higher peak tension can be generated. Systole is shortened, diastole is
prolonged. When a normal heart is subjected to increased impedance to
outflow, it generates increased tension so that stroke volume is maintained
upto considerably higher values of impedance, while the failing heart is not able
to do so and the stroke volume progressively decreases. The digitalized failing
heart regains some of its capacity to contract more forcefully when subjected to
increased resistance to ejection. There is more complete emptying of failing and
dilated ventricles—cardiac output is increased and end-diastolic volume is
reduced. However, therapeutic doses of digoxin do not increase resting tension
(tone) in myocardial fibers

Rate:-
Heart rate is decreased by digitalis. Bradycardia is more marked in CHF patients

because improved circulation (due to positive inotropic action) restores the

diminished vagal tone and abolishes sympathetic overactivity. In addition,
digitalis slows the heart by vagal and extravagal actions.

Vagal tone is increased reflexly by sensitization of baroreceptors, as well as by

stimulation of vagal centre.
 Extravagal A direct depressant action on SA and A-V nodes. This component of
bradycardia is not reversed by atropine.

* Electrophysiological properties:-

The electrophysiological effects of digitalis on different types of cardiac fibres

differ quantitatively and qualitatively. The Purkinje fibres, automatic and
conducting tissues are more sensitive. In addition to direct effects, the indirect
autonomic influences are important in the in situ heart.

(a) Action potential (AP ):-

• The resting membrane potential (RMP) is progressively decreased (to less

negative values) with increasing doses. Excitability is enhanced at low doses but
depressed at toxic doses because Na+ channels are inactivated.
• The rate of 0 phase depolarization is reduced resulting in slowing of
conduction. This action is most marked in A-V node and bundle of His.
• The slope of phase-4 depolarization is increased in the PFs—ectopic
automaticity is enhanced—

latent pacemakers become overt at high doses producing extrasystoles. High

doses of digitalis produce coupled beats by another mechanism: the RMP shows
oscillations during phase-4; when their magnitude is sufficient enough, delayed
after-depolarizations result.The SA and A-V node automaticity is reduced at
therapeutic concentrations by vagal action which hyperpolarizes these cells and
reduces their phase-4 slope. Toxic doses markedly reduce RMP of SA nodal cells
by direct action and stop impulse generation.
• The action potential duration (APD) is reduced (primarily at phase-2) and
amplitude of AP is diminished.

(b)Conduction:-
 A-V conduction is demonstrably slowed by therapeutic doses. At high doses,
intraventricular conduction in PFs is also depressed by uncoupling of gap
junctions.

(C) ECG :-

Therapeutic doses of digitalis produce changes in the ECG. These are

accentuated at high doses—may also produce arrhythmias.
• Decreased amplitude or inversion of T wave.
• Increased P-R interval (due to slowing of A-V conduction), A-V block at toxic
doses.
• Shortening of Q-T interval (reflecting shortening of systole).
• Depression of ST segment (at high doses— due to interference with
repolarization).

*Mechanism of action:-

Digitalis increases force of cardiac contraction by a direct action independent of

innervation. It selectively binds to extracellular face of the membrane associated
Na+K+ ATPase of myocardial fibres and inhibitis this enzyme. Inhibition of this
cation pump results in progressive accumulation of
Na+ intracellularly. This indirectly results in intracellular Ca2+ accumulation.
During depolarization Ca2+ ions enter the cell driven by the steep Ca2+
gradient (>1 mM extracellular to < 100 nM cytosolic during diastole) through
voltage sensitive L type Ca2+ channels. This triggers release of larger amount of
Ca2+ stored in sarcoplasmic reticulum (SR) through Ryanodine calcium channel 2
(RYR2) → cytosolic Ca2+ increases transiently to about 500 nM (calcium
transients) → triggers contraction by activating troponin C on myofibrils. The
sarcoplasmic-endoplasmic reticular Cal. ATPase 2 (SERCA2) is then activated
which pumps Ca2+ back into the SR. A fraction (equal to that which entered
from outside during depolarization) is extruded mainly by 3Na+/1Ca2+ exchange
transporter (NCX-antiporter) and to a lesser extent by sarcolemmal Ca2+ pump
(Ca2+ ATPase). During phase 3 of AP, membrane Na+K+ATPase moves 3
intracellular Na+ ions for 2 extracellular
K+ ions. The slight (1–1.5 mM) increase in cytosolic Na+ over normal (8–10
mM) due to partial inhibition of Na+K+ATPase by digitalis reduces
transmembrane gradient of Na+ which drives the extrusion of Ca2+. The excess
Ca2+ remaining in cytosol is taken up into SR which progressively get loaded with
more Ca2+ → subsequent calcium transients are augmented.

The relationship of cytosolic [Na+] and [Ca2+] is such that a small percentage
increase in Na+ concentration leads to a large percentage increase in Ca2+
concentration. Moreover, raised cytosolic Ca2+ induces greater entry of Ca2+
through voltage sensitive Ca2+ channels during the plateau phase. It has been
shown that 1 mM rise in cytosolic [Na+] results in 20–30% increase in the tension
developed by ventricular fibres.

Binding of glycoside to Na+K+ATPase is slow. Moreover, after Na+K+ATPase

inhibition, Ca2+ loading occurs gradually. As such, inotropic effect of digitalis
takes hours to develop, even after i.v. administration.

Inhibition of Na+K+ ATPase is clearly involved in the toxic actions of digitalis.

At high doses, there is depletion of intracellular K+; and digitalis toxicity is
partially reversed by infusing K+, because K+ decreases binding of glycoside to
Na+K+ ATPase. Excessive Ca2+ loading of SR results in spontaneous cycles of
Ca2+ release and uptake producing oscillatory after-depolarizations and after-
contractions. Since both therapeutic and toxic effects of digitalis are due to
myocardial Ca2+ loading, these are inseparable and therapeutic index is low.
 2. Blood vessels

Digitalis has mild direct vasoconstrictor action—peripheral resistance is

increased in normal individuals. However, in CHF patients this is more than
compensated by the indirect effect of improvement in circulation, i.e. reflex
sympathetic overactivity is withdrawn and a net decrease in peripheral
resistance occurs.

Digitalis has no prominent effect on BP: systolic BP may increase and diastolic
may fall in CHF patients—pulse pressure increases. Hypertension is no
contraindication to the use of digitalis. Therapeutic doses of digitalis have no
significant effect on coronary circulation coronary insufficiency is no
contraindication to its use.

3. Kidney

Diuresis occurs promptly in CHF patients, secondary to improvement in

circulation and renal perfusion. The retained salt and water is gradually
excreted. No diuresis occurs in normal individuals or in patients with edema due
to other causes.

4. CNS

Digitalis has little apparent CNS effect in therapeutic dose. Higher doses cause
CTZ activation → nausea and vomiting. Still higher doses produce hyperapnoea,
central sympathetic stimulation, mental confusion, disorientation and visual
disturbances.

*ADVERSE EFFECTS:-

Toxicity of digitalis is high, margin of safety is low. Higher cardiac mortality has
been reported among patients with steady-state plasma digoxin levels > 1.1
ng/ml but still within the therapeutic range during maintenance therapy. About
25% patients develop one or other toxic symptom. The manifestations are:
● Extracardiac:-

Anorexia, nausea, vomiting and abdominal pain are usually reported first: are
due to gastric irritation, mesenteric vasoconstriction and CTZ stimulation.
Fatigue, malaise, headache, mental confusion, restlessness, hyperapnoea,
disorientation, psychosis and visual disturbances are the other complaints. Skin
rashes and gynaecomastia are rare.

● Cardiac:-

Almost every type of arrhythmia can be produced by digitalis: pulsus bigeminus,

nodal and ventricular extrasystoles, ventricular tachycardia and terminally
ventricular fibrillation. Partial to complete A-V block may be the sole cardiac
toxicity, or it may accompany other arrhythmias. Severe bradycardia, atrial
extrasystoles, AF or AFl have also been noted. In about 2/3 patients showing
toxicity, extracardiac symptoms precede cardiac; in the rest serious cardiac
arrhythmias are the first manifestation.

● Treatment:-

Further doses of digoxins must be stopped at the earliest sign of toxicity;

nothing more needs to be done in many patients, especially if the manifestations
are only extracardiac.

(a) For tachyarrhythmias

When caused by chronic use of digitalis and diuretics (both induce K+ depletion)
—infuse KCl 20 m.mol/hour (max. 100 m. mol) i.v. or give orally in milder cases.
High extracellular K+ decreases binding of the glycosides to Na+K+ATPase by
favouring a conformation of the enzyme that has lower affinity for the glycoside,
and K+ tends to antagonize digitalis induced enhanced automaticity.

When toxicity is due to acute ingestion of large doses of digoxin, plasma K+

may be high; it should not be given from outside. In any case, it is desirable to
measure serum K+ to guide KCl therapy.

K+ is contraindicated if higher degree of A-V block is present, because

complete A-V block and ventricular asystole may be precipitated.

(b) For ventricular arrhythmias

Lidocaine i.v. repeated as required is the drug of choice. It suppresses the

excessive automaticity, but does not accentuate A-V block. Quinidine,
procainamide and propafenone are contraindicated.

(c) For supraventricular arrhythmias

Propranolol may be given i.v. or orally depending on the urgency.

(d) For A-V block and bradycardia

Atropine 0.6–1.2 mg i.m. may help; otherwise cardiac pacing is recommended.

Cardioversion by DC shock is contraindicated because severe conduction

defects may be unmasked in the digitalis intoxicated heart. Attempts to enhance
the elimination of digoxin by diuretics or haemodialysis are not very effective.

Digoxin antibody: Developed for measuring plasma concentration of digoxin by

radioimmunoassay, it has been found effective in treating toxicity as well.
Digoxin specific antibody crossreacts with digitoxin also. The Fab fragment has
been marketed in Europe as DIGIBIND (38 mg vial). It is nonimmunogenic
because it lacks the Fc fragment. Given by i.v. infusion it has markedly improved
the survival of seriously digitalis intoxicated patients. The digoxin-Fab complex is
rapidly excreted by kidney.

*PRECAUTIONS AND CONTRAINDICATIONS:-

(a) Hypokalemia: enhances digitalis toxicity.

(b) Elderly, renal or severe hepatic disease: patients are more susceptible to
digoxin toxicity.

(c) Myocardial ischaemia: severe arrhythmias are more likely.

(d) Thyrotoxicosis: patients are more prone to develop digitalis arrhythmias.

(e) Myxoedema: these patients eliminate digoxin more slowly; cumulative

toxicity can occur.

(f) Ventricular tachycardia: digitalis is contraindicated because it may precipitate

ventricular fibrillation.

(g) Partial A-V block: may be converted to complete A-V block by digoxin.

(h) Acute myocarditis: Diphtheria, acute rheumatic carditis, toxic carditis—

inotropic response to digitalis is poor, more prone to arrhythmias.

(i) Wolff-Parkinson-White syndrome: Digitalis is contraindicated because it

decreases the ERP of bypass tract in 1/3 patients. In them rapid atrial impulses
may be transmitted to ventricles → VF may occur. Digitalis can increase the
chances of reentry by slowing conduction in the normal A-V bundle and
accelerating it in the aberrant pathway.

● INTERACTIONS:-

1. Diuretics: cause hypokalemia which increases the risk of digitalis arrhythmias;

potassium supplements should be given prophylactically.

2. Calcium: synergises with digitalis → precipitates toxicity.

3. Quinidine: reduces binding of digoxin to tissue proteins as well as its renal and
biliary clearance by inhibiting efflux transporter P-glycoprotein → plasma
concentration of digoxin is doubled → toxicity can occur. Verapamil, diltiazem,
captopril, propafenone and amiodarone also increase plasma concentration of
digoxin to variable extents.

4. Adrenergic drugs: can induce arrhythmias in digitalized patients; both

increase ectopic automaticity.

5. Digoxin absorption may be reduced by metoclopramide, sucralfate, antacids,

neomycin, sulfasalazine. Absorption of digoxin is increased by atropinic drugs,
including tricyclic antidepressants.

6. Propranolol, verapamil, diltiazem and disopyramide: may additively depress

A-V conduction and oppose positive inotropic action.

7. Succinylcholine: can induce arrhythmias in digitalized patients.

● USES:

The two main indications of digitalis are CHF and control of ventricular rate in
atrial fibrillation/flutter.

◆ Management:-

Treatment focuses on improving the symptoms and preventing the progression

of the disease. Reversible causes of the heart failure also need to be addressed
(e.g. infection, thyrotoxicosis, alcohol ingestion, anemia, arrhythmia,
hypertension). Treatments include lifestyle and pharmacological modalities, and
occasionally various forms of device therapy and rarely cardiac transplantation.

● Acute decompensation:

In acute decompensated heart failure (ADHF), the immediate goal is to

reestablish adequate perfusion and oxygen delivery to end organs. This entails
ensuring that airway, breathing, and circulation are adequate. Immediate
treatments usually involve some combination of vasodilators such as
nitroglycerin, diuretics such as and possibly furosemide, noninvasive positive
pressure ventilation (NIPPV). Supplemental oxygen is indicated in those with
oxygen saturation levels below 90% but is not recommended in those with
normal oxygen levels on room air.

● Chronic management:

The goals of treatment for people with chronic heart failure are the prolongation
of life, the prevention of acute decompensation and the reduction of symptoms,
allowing for greater activity.

Heart failure can result from a variety of conditions. In considering therapeutic

options, it is important to first exclude reversible causes, including thyroid
disease, alcohol abuse, anemia, chronic tachycardia, hypertension and
dysfunction of one or more heart valves.

Treatment of the underlying cause is usually the first approach to treating heart
failure. However, in the majority of cases,either no primary cause is found or
treatment of the primary cause does not restore normal heart function. In these
cases, behavioral, medical and device treatment strategies exist which can
provide a significant improvement in outcomes, including the relief of
symptoms, exercise tolerance, and a decrease in the likelihood of hospitalization
or death. Breathlessness rehabilitation for chronic obstructive pulmonary
disease (COPD) and heart failure has been proposed with exercise training as a
core component.

Rehabilitation should also include other interventions to address shortness of

breath including psychological and education needs of people and needs of
carers.

◆ Prevention:-

A person's risk of developing heart failure is inversely related to their level of

physical activity.

Those who achieved at least 500 MET-minutes/week (the recommended

minimum by U.S. guidelines) had lower heart failure risk than individuals who did
not report exercising during their free time; the reduction in heart failure risk
was even greater in those who engaged in higher levels of physical activity than
the recommended minimum.
 Heart failure can also be prevented by lowering high blood pressure, high
blood cholesterol, and controlling diabetes. Also, remaining at the right weight
and reducing obesity can help. Lowering salt, alcohol, quitting smoking, and
lowering sugar intake may help.

◆ HEART FAILURE STATISTICS ◆

1.Age associate

Babies (0-2 years): rare

Toddlers (3-5 years): very rare

Children (6-13 years): very rare

Teenagers (14-18 years): very rare

Young adults (19-40 years): common

Adults (41-60 years): very common

Seniors (60+ years): very common

2.How many people dies in CHF per year?

•About 5.7 million adults in the United States have heart failure.
•One in 9 deaths in 2009 included heart failure as contributing cause.

•About half of people who develop heart failure die within 5 years of diagnosis

• Heart failurecosts the nation an estimated $30.7 billioneach year.

3.Most affected age of CHF

•Congestive heart failure affects people of all ages, from children and young
adults to the middle-aged and the elderly.

•Almost 1.4 million persons with CHF are under 60 years of age.

•CHF is present in 2 percent of persons age 40 to 59.

•More than 5 percent of persons age 60 to 69 have CHF.

4.The country with the highest & lowest rate of

Heart disease:
•Russia has the highest rate of heart disease, with 1,752 heart disease-related
deaths per 100,000 people

•For Males of Hong Kong have the lowest death rate for cardiovascular disease,
the Russian Federation rate being about six times greater.

•For females, the lowest death rates are found in France,

• Hong Kong and Japan. All of thesecountries have rates less than a quarter of
those in the Russian Federation.