Definition-Heart Failure (HF)

Key Concepts
• CO = SV x HR-becomes insufficient to
meet metabolic needs of body
• SV- determined by preload, afterload
and myocardial contractility
• EF< 40% (need to understand)
• *Classifications HF
– Systolic failure- dec. contractility
– Diastolic failure- dec. filling
– Mixed
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90/140= 64% EF- 55-65 (75) normal
Click for animated EF
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 Heart Failure
Etiology and Pathophysiology
• Systolic failure- most common cause
– Hallmark finding: Dec. in *left ventricular ejection fraction
(EF)
• Due to
– Impaired contractile function (e.g.,
MI)
– Increased afterload (e.g., hypertension)
– Cardiomyopathy
– Mechanical abnormalities (e.g., valve disease)

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 Heart Failure
Etiology and Pathophysiology
• Diastolic failure
– Impaired ability of ventricles to relax
and fill during diastole > dec. stroke volume
and CO
– Diagnosis based on presence of
pulmonary congestion, pulmonary hypertension
, ventricular hypertrophy

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 Heart Failure
Etiology and Pathophysiology

• Mixed systolic and diastolic failure

– Seen in disease states such as dilated
cardiomyopathy (DCM)
– Poor EFs (<35%)
– High pulmonary pressures
• Biventricular failure (both may be
dilated and have poor filling and emptying
ventricles
capacity)

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FACTORS EFFECTING HEART PUMP EFFECTIVENESS

Preload
• Volume of blood in ventricles at end diastole
• Depends on venous return
• Depends on compliance

Afterload
•Force needed to eject blood into circulation
•Arterial B/P, pulmonary artery pressure
•Valvular disease increases afterload
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Cardiomegaly/ventricular remodeling occurs as heart overworked> changes in size, shape, and
function of heart after injury to left ventricle. Injury due to acute myocardial infarction or due to causes
that
pre1sinc.
2s/u27re/20o1r8volume overload as in Heart PATKI 710
failure
 Right Heart Failure
• Signs and Symptoms
– fatigue, weakness,
lethargy
– wt. gain, inc. abd. girth,
anorexia, pain
– elevated neck veins
– Hepatomegaly
– may not see signs of
LVF
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 Heart Failure
Low output cardiac failure – CO is low and it is common HF where
metabolic demands of the body are within normal limits

High output cardiac failure occurs rarely – hyperthyroidism, severe

anaemia and A-V shunt where metabolic demands of the body are
excessive that even ↑ CO is insufficient to meet them – treatment
correct the underlying cause

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 Compensatory physiological responses in CHF
Increased sympathetic activity – initially ↑CO - ↑ preload and ↑
afterload finally ↓ CO

 Activation of Renin- Angiotension-Aldosterone system(RAAS) - ↑in

blood
volume ↑ preload and also ↑ afterload .
Atrial stretch releases ANP(atrial natriuretic peptide)

Ventricular Remodeling –↑end diastolic M. fibre length – initially

maintains cardiac performance – later ventricular wall tension ↑ -
ventricular dilatation and mechanical performance of heart ↓
Ventricular hypertrophy, myocardial cell apoptosis, fibrotic change in
myocardium

 With the compensatory mechanisms – adequate CO- HF said to be

compensated HF

 Adoptive mechanisms fails to maintain CO – decompensated HF 10

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Signs and symptoms of HF

a) Pulmonary and peripheral oedema

b) Dyspnoea and cyanosis
c) Hepatomegaly
d) Cardiomegaly
e) Reflex tachycardia
f) Decreased urine output
g) Muscle fatigue and ↓ exercise tolerance

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Various classes of drugs in different stages of heart failure

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 Treatment of CHF
The goals of treatment are
Relieve the symptoms of disease
Prevent disease progression
Prolong survival
Therapeutic strategies in CHF
Role of drugs
Vasodilators – which reduce excessive preload (volume of blood
that fills the ventricle during diastole (venous return) and afterload
(the pressure that must be overcome for the heart to pump blood
into the arterial system
 Diuretics – ↓volume load and improve ventricular efficiency
Remove peripheral edema and pulmonary congestion
 Positive inotropic agents - ↑ CO
 Drugs to be avoided – NSAID’s, verapamil , plasma expanders
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 Treatment of CHF
There are two distinct goals of drug therapy in CHF
a) Relief of congestive/low output symptoms and restoration of
cardiac performance
Inotropic drugs – digoxin, Dobutamine/dopamine,
amrinone / milrinone
Diuretics – Furosemide, thiazides
Vasodilators – ACE inhibitors / AT1 antagonists, hydralazine,
nitrate, nitroprusside
β blockers – metoprolol, bisoprolol, carvedilol
b) Arrest/reversal of disease progression and prolongation of survival
ACE inhibitors / AT1 antagonists (ARB’s)
β blockers
Aldosterone antagonist - Spironolactone
c) Salt restriction, rest and treatment of underlying cause of CHF

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 Treatment of CHF
High ceiling diuretics – Furosemide, bumetonide with Spironolactone
 ↓ preload and improve ventricular efficiency by reducing vol.
load

 Remove pulmonary congestion and peripheral edema

 don't influence the primary disease process in CHF

 chronic diuretic therapy –hypokalemia may ↑ digitalis toxicity

 They may cause activation of renin- angiotensin system

 diuretics should be combined ACEI/digoxin (improves LV

function)
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 Treatment of CHF
Vasodilators

Venodilators (primarily ↓preload)

GTN, Isosorbide dinitrate
 Arteriolar dilator s (primarily
↓afterload)
Hydralazine, Minoxidil, CCB-
Nifedipine, K chanel opener-
Nicorandil
 Mixed dilators ( ↓pre and after
load)
ACE Inhibitors, AT1 antagonists
(ARBs), Prazosin (α1 blocker),
Amrinone, Milrinone,
Nitroprusside
They have become the mainstay 17
ACE Inhibitors / ARBs
 Agent of choice in CHF and superior to other vasodilators
 ↓ circulating levels of Angiotensin II
 ↓ rate of bradykinin inactivation - ↑bradykinin – vasodilatation
 ↓ secretion of aldosterone - ↓ sodium and water retention
 ↓ preload and after load
 ↓ Ang II direct toxic effect (↓ risk of coronary ischemic events)
 Afford symptomatic / disease modifying benefits by retarding
ventricular hypertrophy, myocyte apoptosis.
 Spironolactone + ACEI – beneficial further reduces mortality
low dose 12.5 – 25mg/day (to avoid hyperkalemia)

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Uses
 All grades of CHF - if renal impairment – replace with
hydralazine
 Left ventricular enlargement
 CHF in asymptomatic patients with ejection fraction < 40%
 Immediately after MI
Dose
Start with small dose enalapril /ramipril-2.5mg, (max10/5mg) bid
ARBs – Losartan/ candesartan (block AT1 receptor on heart, vessel
and kidney)
Used in patients who can’t tolerate ACEI because
of dry
cough, angioedema, neutropenia

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β1 blockers - Metoprolol, bisoprolol
Β blocker – Carvedilol ISE
 Long term R improves symptoms, ↓ hospitalization, ↓ mortality
 Always given in combination with ACEI +diuretic/digitalis
 It antagonizes excess sympathetic activity in CHF that enhances
ventricular wall stress

Used (unless contraindicated) in mild to moderate cases of dilated

cardiomyopathy with systolic dysfunction
They are not indicated in –
Decompensated HF/ Acute HF after acute MI
HR-< 60/min, asthma, COPD

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Sympathomimetic inotropic drugs – Dobutamine, dopamine, amrinone, milrinone

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Dobutamine - acts on β1, β2 and α1 receptors
Selective β1 – Inotropic action ↑- CO
Little effect on BP / HR (counterbalance of β2 and α1)
Used for short term management of acute HF with MI - IV infusion (5-
15μg/kg/min)in acute HF with MI/cardiac surgery

Dopamine - in moderate dose (5-10 μg/kg/min)

β1 – Inotropic action ↑- CO
TPR – unchanged due to renal and splanchnic vasodilatation (D1)
Higher dose ↑ TPR and ↑ afterload
Used in acute HF with renal impairment

Due to development of tolerance - no role in the long term

management of CHF
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Amrinone – phosphodiesterase inhibitor

↑ myocardial cAMP and -↑transmembrane influx of Ca++

+ve inotropic and direct vasodilator action – INODILATOR
↑ LVEF and ↓ left ventricular end diastolic volume

Used for short term R of severe HF – administered IV

0.5mg/kg bolus followed by 5-10μg/kg/min IV infusion

A/E – nausea, diarrhoea, fever, hepatotoxicity, arrhythmias,

thrombocytopenia

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Cardiac Glycosides

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Cardiac Glycosides

Digitalis purpurea
(Fox glove)
aglycone
Seeds of strophanthus
gratus
Strophanthin-G &
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Ouabain
MOA of cardiac glycosides

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 MOA of cardiac glycosides

RYANODINE RECEPTOR
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 MOA of cardiac glycosides
↑ Na+ alters the driving force (↓ transmembrane gradient of Na+
which drives the extrusion of Ca2+) for Na-Ca exchange by the
exchanger (NCX) – so that less Ca2+ is removed from the cell

In ANS, inhibit sympathetic

outflow and ↑ vagal tone
At AV node prolong ERP
and slow CV
↑ serum K+ inhibits
digitalis binding
to Na/K ATPase
(Hypokalemia↑ risk
of digit toxicity)

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 Pharmacological actions of digitalis

1. Cardiac actions
2. Extra cardiac actions
Cardiac actions – (more prominent in failing heart)
Direct action on the heart (by inhibiting Na+ /K+ ATPase) and
Indirect actions on the heart by stimulating Vagus (vagomimetic)
Myocardial contractility → +ve Inotropic effect – “Cardiotonic”
↑ Force of contraction of the myocardium (more prominent in failing
heart)
Digitalized heart contracts more forcibly and completely
This causes complete emptying of the ventricles during systole and ↑ CO
This ↓ pulmonary congestion and systemic venous pressure
Diastolic size of the heart is reduced – size of the muscle fibre length also
reduced. – Reduced oxygen requirement of myocardium- digitalized
heart thus,can do more work for the same energy expenditure

12/27/2018 PATKI 35
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 Heart rate – causes bradycardia (more marked in CHF patients)
Reduces HR (-ve chronotropic effect) by direct and indirect action (small dose)
Extravagal – direct depressant action on SA and AV nodes

Electrophysiological properties – differs with the cardiac fibres

Action Potential – RMP progressively ↓
 Excitability ↑ at low doses
(↓ gap between RMP & TP)
but depressed at toxic
dose

 The slope of phase 4 depolzn ↑ in PFs

& ventricular muscle – ectopic
automcity. Results in ventricular extra
systoles, Coupled beats

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Conduction velocity
Conduction through AV node depressed
(by both action)

ECG
↑ PR interval
(slowing of AV conduction)

AV block at toxic doses

Shortening of QT interval
(reflecting shortening of systole)

Depression of ST segment
(at high doses due to
interference Ĉ repolarzn)

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Blood vessels – digitalis has mild direct vasoconstrictor action – not significant

Extra cardiac actions

Kidney – digitalis causes diuresis in CHF secondary to improvement in circulation
and renal perfusion (no diuresis in patients with edema due to other causes)

CNS- in high doses – CTZ activation – vomiting, central sympathetic stimulation,

confusion, disorientation, blurring of vision

GIT – Anorexia, nausea, vomiting (CTZ stimulation and direct action on the gut)

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Pharmacokinetics
Digoxin / Digitoxin
commonly used glycoside – administered by oral route
food delays the absorption, widely distributed,
concentrated in heart, liver, kidney and skeletal muscle
crosses BBB mainly excreted unchanged in urine
(digoxin- filtered at the glomeruli) (dose adjust-renal
fail)
Cardiac glycosides are cumulative drugs
Steady state levels and full therapeutic effect
with daily maintenance from the beginning
are attained after 6-7 days for digoxin and
4 weeks for digitoxin (after 4xt1/2 )
Preparations
Digoxin – 0.25mg tab, 0.5mg/2ml inj
0.05mg/ml paediatric elixir
Used for routine and in emergency
Digitoxin – 0.1mg tab
Used for maintenance (long t1/2)
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 Adverse effects
Toxicity of digitalis is high – margin of safety is low
(Therapeutic Index is 1.5 - 3)
Extra cardiac A/E
Anorexia, nausea, vomiting, fatigue, mental confusion, restlessness,
psychosis, visual disturbances, diarrhoea, skin rashes,
gynecomastia(rare)
Cardiac A/E
Bradycardia, partial/complete heart block, coupled beats (bigeminy),
ventricular extrasystoles/tachycardia/fibrillation, atrial extrasystoles,
AF

Factors affecting digitalis toxicity

Age, IV digitalization, hypokalemia, hypercalcaemia,
hypomagnesaemia, Hyper/hypothyroidism, renal failure, myocarditis
(predisposing factors)
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Management of digitalis toxicity

 Potassium supplementation – mild toxicity KCl 5gm daily oral

tid More serious arrhythmias - IV infusion KCl 20m.mol/hr
Stop digoxin and K depleting diuretics

 Supraventricular arrhythmias – treated with oral/IV propranolal

 Ventricular arrhythmias – Lignocaine IV (suppresses excessive

automaticity and doesn't accentuate AV block)

 AV block and bradycardia – Atropine 0.6 – 1.2mg im /cardiac

pacing

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Digoxin antibodies (Digibind)

 Used in serious digitalis toxicity

 It neutralizes circulating digitalis - given IV - rapidly reverses the

toxicity (40mg neutralises 0.6mg of digoxin stored in the body)

 But very expensive

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 Contraindications
a. Hypokalemia

b. Elderly, associated disease like renal/hepatic disease

c. MI except when HF with AF and rapid ventricular rate

d. Hyper / hypothyroidism (slow elimination)

e. Partial AV block

f. Myocarditis (more prone to arrhythmias)

g. Wolff-Parkinson-White syndrome – Digitalis may enhance

transmission through bypass tract and ↑ transmission of rapid
atrial impulses to ventricles - VF
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Drug interactions

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 Therapeutic Uses
1. Congestive Heart Failure
2. To control ventricular rate in AF/AFl
Low output failure especially when associated with AF.
It is ineffective in high output failure – severe anaemia, thyrotoxicosis
and A-V shunt
Subsides pulmonary congestion – provides relief from dyspnoea
↑ Urinary output- ↓ edematous fluid by ↑ing renal perfusion
Engorged tender liver regresses and engorgement of neck veins
disappear because of diminished systemic venous pressure
Mild to moderate cases – slow digitalization
Digoxin 0.125-0.25mg/day from the beginning (maintenance dose)
Relief of signs and symptoms like ↓HR, bradycardia(HR<60 stop drug)

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 Therapeutic Uses
Rapid oral digitalization – Digoxin 0.5mg – 1mg stat, followed by
0.25mg every 6 hrs till response occurs (6-24 hrs) – seldom practised

Emergent IV digitalization – Digoxin 0.25mg followed by 1mg hrly

slow IV injection with close monitoring till response occurs(2-6hrs)
(total dose 0.5mg-1mg) – rarely practised

Digitalis still most effective drug, especially in patients with dilated

heart and low ejection fraction (systolic dysfunction)

Mild to moderate cases can be managed without digitalis – with

diuretics , vasodilators (like ACE inhibitor) and β blockers.

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 Therapeutic Uses
Cardiac arrhythmias
Atrial Fibrillation (500 beats/min)
To control ventricular rate – protects the ventricles from the too rapid
atrial impulses by depressing AV conduction
Ventricular rate of 70-80 not achieved – verapamil /β blockers may
be added

Atrial flutter (AFl) (200-300 beats/min) regular and homogenous

AFl is often converted to AF and withdrawal of digoxin at this stage
may restore normal rhythm (since the cause of atrial inhomogeneity
is gone)

PSVT (150 – 200/min and 1:1 AV conduction)

PSVT with HF - ↑ vagal tone and terminates arrhythmia.
Verapamil, adenosine –more effective, act faster and less toxic.
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 Management of acute LVF with pulmonary edema

 Semi-upright posture

 Oxygen 6-8litres/min

 Furosemide 40-80mg IV– Repeated every 30 min

 Morphine IV 2-5mg IV
 Aminophylline IV slowly 250-500mg

 Sublingual 0.4mg rpt every 15 min if required /IV Nitroglycerine

 Digoxin IV 0.5mg – associated with AF/SVT

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Goals of Treatment-ADHF/Pulmonary Edema)
• MAD DOG
• Improve gas exchange
– Start O2/elevate HOB/intubate
– Morphine –dec anxiety/afterload
– A- (airway/head up/legs down) AMINOPHYLLIN E
– D- (Drugs) Dig not first now- but drugs as
• IV nitroglycerin; IV
– D- Diuretics
– O- oxygen /measure sats;
• Hemodynamics, careful observation
– G- blood gases

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