HF

Aetiology
Usually in old pts. Men > women in incidence but <
in prevalence (longer life expectancy).
Bad prognosis, 5- year mortality rate > 50% (40%
by sudden death). Also ↑morbidity (↑hospitalization
& eadmission).
1. CAD (70%). After acute MI → eccentric
(segmental) hypertrophy. Systolic dysfunction,
↓ejection fraction.
2. Hypertension → concentric (global) V
hypertrophy → diastolic dysfunction. In 60%
↓ejection fraction.a
3. Thyroid diseases, valvular diseases & dilated
cardiomyopathy.
Comorbidities: CAD, DM & renal dysfunction.

Drug – induced CHF

A-MYOCARDIAL DEPRESSION
- Antiarrhythmic drugs.
B-SALT & WATER RETENTION

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 Pathopysiology
In HF, there is increase of these mediators. Each
increase correlates with severity & mortality.
1. NE.
2. Angiotensin II.
3. Aldosterone
4. Endothelin.
5. Natriuretic peptides: VD & diuretics. ↑by
volume load.
ANP & BNP are stored & synthesized in
atrium & V respectively. >100 pg/ml.
6. Bradykinin: → VD & ↑PG.
7. Nitric oxide.
8. Cytokines.

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 CHF sequences & clinical features

Contraction

Backward Forward

↑Venous pressure ↓CO

a-Left: pulmonary
congestion&edema. a.↓systolic BP b.↓renal bl.flow c.pallor,fatigue,
↓ ↓ ischem.
b-Right: dyspepsia, liver
congestion &edema ↑ sympathetic ↑renin→
↑ang.II.
↓ ↓

↑contr. ↑HR VC VC aldosterone ↑contr.

&remodel. &remod.
↑ Diastolic BP Edema,↓K+,& Mg
. (↑afterload ) (→arrhythm.)&rem.

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 Cardiac remodeling
Chronic myocardial hypertrophy → ischemia,
proliferation of connective tissue cells and abnormal
myocytes → dilatation, stiff myocardium & changes
in ventricular geometry → diastolic dysfunction.
Remodeling is ↑ by:
1. Angiotensin II.
2. Aldosterone.
3. Catecholamines.
Accordingly, it is treated by:
1. ACEIs & ARBs.
2. Spironolactone.
3. β blockers.
These are the only drugs which ↓morbidity &
mortality in CHF.

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 Stages
A : ↑risk.
I(B): cardiac disease without limitation of
ordinary physical activity.
II(C): slight limitation of ordinary physical
activity.
III (C): symptoms by < ordinary physical
activity.
IV (D): symptoms by any physical activity.

Compensated HF:
Stable volume & symptoms.

Decompensated HF:
Volume overload & worsening of
manifestations.

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 Drug therapy of heart failure
The commonest cause of diastolic dysfunction is
hypertension. Its proportion increases with age.
The commonest cause of systolic dysfunction is
IHD.
Life style modification includes:
1. Decrease body weight.
2. Decrease Na+ and increase K+ in diet.
3. Mild, gradual, 30 minutes daily exercise.
4. Avoid physical and psychological effort.
5. No smoking. Smoking ↑mortality by 50%.
6. Influenza & pneumococcal vaccination.
Drug therapy
Beside ttt of cause & comorbidities.
1. ACEIs & ARBs.
2. Diuretics.
3. β blockers.
4. Digoxin.
1st line ttt of CHF are ACEIs, diuretics & β
blockers.
Generally, digoxin decreases symptoms but
does not increase survival. While reducing
progressive heart failure with subsequent
↓deaths, deaths are also ↑by ischemic &
arrhythmic effects. So it is used or added in pts.
remaining symptomatic by ACEIs combined
with diuretics or with AF.

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 Other drugs in HF
1. Vasodilators: hydralazine & minoxidil (orally) and
Na nitroprusside & diazoxide (IV). For short term
ttt because they ↑HR and → salt & water
retention.

2. CCBs: amlodipine for systolic HF. In uncontrolled

hypertension or angina if doses of other drugs are
maximized.

3. Nitrates: Nitric oxide in HF improves

inflammation, cardiac remodeling & oxidation
damage.
Various preparations for acute & chronic cases.
IV nitrates (nitroprusside or nitroglycerin) are
used mainly in acute or severe chronic cases,
specially with hypertension or myocardial
ischemia. They decrease dyspnea rather than
effects of cardiac output failure.

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 ACEIs & ARBs

In ttt & prophylaxis.

ACEIs are the 1st line for left ventricular systolic
dysfunction (ejection fraction <40%) in all cases &
stages, unless contraindication or intolerance,
usually with diuretics.
Start with low dose and after several weeks →
target doses, according to response & adverse
effects.
In HF, they ↑renal function by ↑CO & renal
perfusion.
↓intraglomerular pressure is renoprotective
chronically, but ↓renal blood flow decreases
filtration. Used in serum creatinine < 2.5 mg/dl.

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 Diuretics
Diuretics are the most effective for symptoms.
Mechanism: They are used in diastolic dysfunction.
a. ↓salt & water retention → ↓blood volume
→↓venous pressure → ↓edema specially in
lung→ better oxygenation.
b. ↓preload →↓heart size → ↑ pump efficiency.

1) Thiazides (oral) are used in mild & moderate

cases, mainly in hypertension & mild congestion.
Not in creatinine clearance <30 ml/min. (except
metolazone).
2) Frusemide (oral & IV) in severe & acute
cases and renal affection. Both diuretics (may be
also used in combination) cause hypokalemia
opposite to spironolactone (oral) which is used in
2ry hyperaldosteronism & in hepatic affection.
Bioavailability (oral absorption) is 50% by frusemide
& 90 - 100% by bumetanide & torsemide (used
orally instead of IV frusemide).
Torsemide (only) has longer t1/2 and is not affected
by food).
↑response by:
1. ↑dose.
2. ↑frequency (2 or 3 daily).
3. IV drip.
4. Loop + thiazides mainly metolazole (1/ day or
week).

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 3) Spironolactone (even alone) decreases
mortality and morbidity in CHF because it inhibits
remodeling and reduces edema.
Eplerenone decreases mortality and morbidity due
to ↓sudden cardiac death, so spironolactone is used
in stage III & IV and eplerenone in post- MI pts.
With left ventricular dysfunction.
Now are used in mild to moderate HF symptoms &
↓EF who are maximized on ACEIs or ARBs & β
blockers.
Not in serum creatinine >2.5 or creatinine clearance
<30 .

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 β blockers
Mechanism (chronically):
a. ↓ remodeling. ↓ventricular mass, ↓left
ventricular end - systolic & diastolic volume.
b. ↓ HR.
c. up regulation of β receptors.

Some β blockers are used in selected cases as

chronic, stable (in all stages), systolic & severe
types with diastolic dysfunction. Many β
antagonists (even in low dose for short period)
worsen CHF and may cause death. β antagonists
having α blocking or intrinsic sympathomimetic
activity are preferably used and in low doses e.g.
carvedilol, bisoprolol & metoprolol. They improve
EF and ↓mortality in systolic HF.
Start with low dose, when pt. is clinically stable &
euvolemic (volume overload worsen symptoms). If
symptoms of congestion, ↓dose of β receptor and
↑dose of diuretic. After weeks - months target dose.
Carvedilol (with α blocking action) is preferred in
uncontrolled hypertension. In symptomatic
hypotension as in advance left ventricular
dysfunction (LVEF <20%) metoprolol is used.
Contraindicated in acute HF.

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 Acute HF
a. Hypoperfusion: forward failure.↓cardiac index,
<2.2 L/min./m2.
Dry (euvolemic), cool.
b. Congestion (systemic & pulmonary): backward
failure, warm, hot.
A)Diuretics: in congestion, with SBP 120 - 160.
Loop diuretics. ↑dose in renal dysfuction.
If resistance, ↑oral dose or →IV or ↑ frequency
or add metolazone.
B)Vasodilators : in congestion, with SBP > 160.
C) +ve inotropic drugs: in manifestations of
hypoperfusion.

Vasodilators
1. Nitrates.
2. Nitroprusside.
3. Nesiritide is recombinant BNP.
It ↑ cGMP → VD of veins & arteries and
diuresis → ↓pulmonary capillary wedge
pressure. Short t1/2 (18 minutes).
In acute CHF. Improves dyspnea & fatigue.
By IV infusion for 1-3 days.
Adverse effects are hypotension & renal
damage.
Contraindicated in SBP< 90.

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 +ve inotropic drugs
They are used mainly in acute systolic dysfunction,
in patients with reduced ejection fraction (stroke
volume / end diastolic volume).
Long term use of +ve inotropic drugs may increase
cardiac remodeling, increasing morbidity and
mortality.
1- Cardiac glycosides : digoxin (oral & IV). Used
also in chronic CHF.
2- Dopamine & dobutamine by IV infusion.
3- Bipyridines (IV) as inamrinone
(more toxic) & milrinone:
Mechanism : inhibits phosphodiesterase →↑ c
AMP → ↑intracellular Ca++ → ↑ myocardial
contraction with minimal effect on HR. Also →VD
(↓afterload). So, inodilator.
Adverse.effects:
1-Thrombocytopenia.
2- Cardiac ischemia.
3- Liver and kidney damage.
Uses: short term refractory heart failure (acute or
exacerbation of chronic).

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 Drugs decreasing mainly afterload
1.ACEIs & ARBs.
2- Vasodilators.
3 - CCBs: amlodipine for systolic HF.
4- Prazosin (oral).

Drugs decreasing mainly preload

1- Diuretics.
2- Nitrates :

Vasodilators in CHF include drugs reducing

afterload and drugs decreasing preload.
Drug ↓after load are used if symptoms of low
cardiac output.
Drug ↓preload are used if symptoms of venous
congestion.

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 Cardiac glycosides

Pharmacokinetics
Digoxin ( commonest cardiac glycoside ) is partially
lipophilic and partially hydrophilic.
Oral bioavailability is 60%. 2/3 of dose is absorbed.
1/3 is inactivated by intestinal flora. So absorption is
↑by erythromycin.
It is given orally & IV.
Binding to plasma proteins is intermediate.
T1/2 is 30 hours → Css = 7 days.
It is mainly excreted unchanged by kidney , so can
be given in liver diseases.

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 Pharmacodynamics
1- The main direct action of cardiac glycosides is
+ve inotropic. They inhibit membrane bound
ATPase (Na+/K+ ATPase) by binding to its K+ site.
This prevents Na+ pump & causes ↑intracellular
Na+ influx. This is followed by ↑ Ca++ influx via
voltage dependent gates in channels in myocardial
cytoplasmic membrane. There is also release of
free Ca++ from sarcoplasmic reticulum. Excitation
contraction coupling produces interaction between
actin & myosin.
So, mechanical effect is ↑ contraction and electrical
effects are ↑ intracellular Na+ & Ca++ and ↑ K+
conductance (outflux).
2- Vagal by:
a. Sensitization of baroreceptors in carotid sinus
& aortic arch.
b. Sensitization of SAN to Ach.
c. Stimulation of vagus nucleus in big dose.
3- ↓sympathetic activity.

Recently, 2nd & 3rd mechanisms are more

beneficial.

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The 3 mechanisms →:
1. ↓ HR (↑vagal & ↓sympathetic).
2. ↓ AV conduction (vagal).
3. ↑ automaticity all over the heart. This is a
direct action. Also may → triggered activity
(late after depolarization).
4. Shortening of effective RP in atria & ventricle
directly (by ↑ K+ conductance) & by vagal
action.
ECG
a- Prolonged P-R interval by ↓ AV conduction.
b- Short QT interval (action potential duration) by
rapid ventricular repolarization.
c- Flattening or inversion of T wave & S-T segment
depression (by hypokalemia).

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 Effect of cardiac glycosides on heart failure
CHF is decompensated heart . Due to ↓ contraction
it produces forward failure (↓COP) & backward
failure (↑venous pressure).
Because cardiac glycosides are mainly + ve
inotropic, they reverse changes which follow
heart failure.
Accordingly , digoxin causes :
1. ↑Cardiac output due to increase myocardial
contraction.
2. ↓Heart size due to ↑COP→ complete emptying of
ventricle during systole →no stagnation of blood
during diastole.
3. ↓Venous pressure due to ↑contraction
→complete emptying of ventricle during systole
→no stagnation of blood in venous system
4. ↑Systolic blood pressure due to ↑COP.
5. ↓Diastolic BP by ↓sympathetic activity. So ↑pulse
pressure.
6. Diuretic by :
a. ↑ COP → ↑ glomerular filtration rate.
b. ↑COP → ↑renal blood flow →↓renin
release→↓aldosterone.
c. ↓ venous pressure.
d. Aldosterone antagonist (steroid).

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 Uses
1. CHF & acute pulmonary edema.
2. Paroxysmal supraventricular tachycardia with
CHF by :
a. Vagal action.
b. ↓Sympathetic activity.
3. Atrial flutter and permanent atrial fibrillation (AF)
with CHF by :
a. ↓AV conduction →protection of ventricle from
excessive atrial discharge.
b. ↑Myocardial contraction.

Dose
Digoxin is given as tablets (0.25 mg) & ampoules.
Initial dose 0.125 mg (in > 65 years age, creatinine
CL <60 & wt. <70 kg) or 0.25 mg.
Cardiac glycosides have narrow safety margin &
plasma level is measured to avoid toxicity (serum
digoxin should be < 1.2 ng /ml). Precautions also
include ECG and serum K+ estimation.
Children require relatively higher dose while old
patient need smaller dose.
They have biological lag & Css is delayed due to
long t1/2.

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 Adverse effects & toxicity
A-Cardiac:
1-↓HR (in small dose → effect on SAN) → sinus
bradycardia. 2-
Various degrees of heart block (↓AV conduction).
3-Atrial & ventricular extrasystole e.g. pulsus
bigeminy & trigeminy (means 70% of toxic
dose).
4- Atrial & ventricular tachycardia, flutter &
fibrillation.
The 3rd & 4th adverse effects are produced by large
dose → ectopic focus.
Cardiac glycosides cause all types of arrhythmias
(by ↑automaticity & shortening of effective RP).

B-Extracardiac:
1. Nausea & vomiting at start of treatment occurs
by local gastric irritation. After some period of
treatment it is due to central stimulation of CTZ
which indicates systemic toxicity (stop treatment).
2. Stimulation of visual centers, blurring of vision,
scotomata (defect in visual field) & abnormal
color perception as yellow vision.
3. Gynecomastia (steroid).
4. Psychic symptoms.

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 Contraindications
1- Atrial extrasystole.
2-Paroxysmal atrial fibrillation ( → permanent).
3-Ventricular arrhythmias.
1,2,3, because digoxin is arrhythmogenic.
4-Partial degrees of heart block(→ complete heart
block).
5-WPW due to shortening of refractory period in
accessory bundle of Kent increasing conduction
(opposite to its effect on normal bundle of His) .
Also verapamil.
6-Carotid sinus syndrome (high sensitivity of
baroreceptors). 7-Sick sinus
syndrome (weak SAN).
8-Recent myocardial infarction .
9-Acute rheumatic myocarditis.
In 8 & 9 digoxin ↑ contraction & → arrhythmias.
10-High COP failure due to hyperdynamic
circulation as anemia, fever & thyrotoxicosis.

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 Interactions
1- Hypokalemia e.g. by diuretics (as thiazides &
frusemide) and corticosteroids due to :
a. Digoxin competes with K+ for binding site in
ATPase.
b. ↑automaticity → cardiac arrhythmias (similar
to digoxin).
2- Hypercalcemia: Ca++ → stopping of heart at
systole.
3- Sympathomimetics: similar to digitalis they also
↑automaticity &→ shortening of RP→ cardiac
arrhythmias.
4- Drugs highly bound to plasma proteins as
NSAIDs, oral anticoagulants, oral hypoglycemics,
sulfonamides and T4. They potentiate digoxin.
5- Quinidine, verapamil & amiodarone potentiate
digoxin by:
a-Displace digoxin from plasma protein binding
sites increasing free level causing potentiation.
b- Decrease renal clearance of digoxin causing
cardiac arrhythmias.
6- Enzyme inducers → antagonism.
7- Cholestyramine binds digoxin.
8- Absorption is decreased by antacids &
metoclopramide & ↑by erythromycin &
anticholinergics.

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 Treatment of digitalis toxicity
In ICU with ECG monitoring.
1-Stop digitalis treatment.
2-Phenytoin stimulates Na+/K+ ATPase increasing
Na+ pump. It opposes digitalis. Also increases AV
conduction. It is first choice.
3-lidocaine: group Ib antiarrhythmic.
4-Potassium chloride orally: competes with digoxin
for Na+ /K+ ATPase.
5- β blockers as propranolol by antiarrhythmic
action (decrease automaticity & →prolongation of
effective RP). They are not used in heart block.
7- Atropine blocks vagal action specially in heart
block.
8- 7- Cholestyramine for binding.
9- Glycoside antibodies (fab fragments) forming
complex with digoxin or digitoxin (digibind) to be
excreted in urine.

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