The document summarizes drugs used to treat congestive heart failure (CHF), including digitalis glycosides. CHF occurs when the heart cannot pump enough blood to meet the body's needs, causing peripheral and lung congestion. Digitalis increases myocardial contractility, improving cardiac output and reducing preload and afterload. Its mechanisms of action involve inhibiting sodium-potassium ATPase, increasing intracellular sodium and calcium levels, and positively inotropic effects. Digitalis administration relieves edema in CHF patients by improving circulation and reducing activation of the renin-angiotensin-aldosterone system.

1. Drugs used in Congestive Heart Failure
DIGITALIS GLYCOSIDES AND
OTHER POSITIVE INOTROPIC
AGENTS
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2. CONGESTIVE HEART FAILURE
(CHF)
Congestive heart failure (CHF) is a condition in which the heart
is unable to pump sufficient blood to meet the needs of body.
It increase the workload imposed on the heart.
Where heart muscle weakens and enlarges, leading to loss of
ability to pump blood through the heart & into the systemic
circulation leading to heart failure (or pump failure).
Peripheral & lung tissues become congested.
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3. • CHF is accompanied by abnormal increases in blood volume and
interstitial fluid- the heart, veins, and capillaries are therefore
generally dilated with blood.
• Hence the term Congestive heart failure since the symptoms include
pulmonary congestion with left heart failure,and peripheral edema
with right heart failure.
Common diseases contributing to CHF
 Cardiomyopathy
 Hypertension
 Myocardial ischemia & infarction
 Cardiac valve disease
 Coronary artery disease
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4. Clinical Features of CHF
 Reduced force of cardiac
contraction
 Reduced cardiac output
 Reduced tissue perfusion
 Oedema (congestion)
 Increased peripheral vascular
resistance
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5. • Afterload: pressure exerted on the left ventricle during systole
which is dependent on the peripheral vascular resistance.
• Preload : end-diastolic pressure when the ventricle has become
filled.(depend on venous return, venous pressure, and blood
volume)
• inotropic action ( myocardial contraction)
chronotropic action (HR)
dromotropic action(conduction velocity of the heart cells)
• Stroke volume-The amount of blood pumped by the left
ventricle of the heart in one contraction
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6. Baroreceptor Dysfunction
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Baroreceptor dysfunction
may account for increased
sympathetic & reduced
parasympathetic nervous
system activity in most
patients with congestive
heart failure

7. Congestive Heart Failure -Events
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8. Congestive Heart Failure -Events
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9. Congestive Heart Failure Events
• 99
The heart can’t
eject blood , so it
remains inside the
heart after systole
As compensation
mechanism the heart will
increase the incoming
volume of blood so the
heart can eject more
blood
Dilated heart 
ischemia of
cardiomyocytes 
↓contraction
↑ afterload
↑ preload
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10. Type of drugs we choose to treat this disease
β blockers to
decrease
sympathetic
activity.
Especially
HR to increase
diastolic time
To refill left
ventricle
ACEI or ARB to
inhibit the action
of anigiotensin
Diuretics to relieve
the edema
Positive inotropic
drugs to increase
contractility
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11. Drugs used
in HF
Inotropic
(cardiotonic)
dobutamine digoxin
Phosphodiesterase III
inhibitors
Non-
inotropic
ACEI
ARB
diuretics
β-
blockers
spironoloactone
Used in acute or decompensated HF
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12. TREATMENT OF CHF
Classification
1.Relief of congestion/low output symptoms and restoration of
cardiac performance
a) Positive inotropic drugs
• Cardiac glycosides- Digitalis
• β-adrenergic agonists (New dopamine receptor agonist)-
dobutamine/ Dopamine
• Phosphodiesterase inhibitors- Amrinone/Milrinone.
• Calcium sensitizers
b) Diuretics
• Furosemide, thiazide
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13. c) Vasodilators
• Nitrates
• Hydralazine
• Nitropruside
d) RAS inhibitors
• Antiotensin converting enzyme inhibitor
• ARBs
e) β-receptor blocker
• Metoprolol, Carvedilol, Nebivolol, Bisoprolol
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14. 2. Arrest/Reversal of disease progression and prolongation of
survival
a) ACE inhibitors
b) ARBs
c) β blockers
d) Aldosterone antagonist ,K-sparing diuretics
• Spironolactonee
• Eplerenone
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15. Cardiac Glycosides
• These are glycosidic drugs having cardiac inotropic
Property
• They increase myocardial contractility and output in a
hypodynamic heart
• They do not cause a proportionate increase in O2 consumption
• Thus, efficiency of failing heart is increased.
Cardiac Stimulants (Adr, theophylline)
• Increase O2 consumption rather disproportionately and tend to
decrease myocardial efficiency.
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16. Sources of Cardiac glycosides
• Bufadienolides - Bufo vulgaris, Toad skin (Bufotoxin) and Cardenolides -
Plants
• Digitalis lanata is the source of Digoxin, the only glycoside that is
currently in use.
• Digitoxin (from Digitalis purpurea) and Ouabain (from Strophanthus
gratus) are no longer clinically used
or marketed.
• Semi-synthetics-Acetyldigoxin, Acetyl strophanthidin, Desarcetyl
lanatoside
• Endogenous cardio tonic steroids (CTSs), also called digitalis-like factors,
have been on discussion for nearly half a century.
• There is evidence in mammals for the presence of an endogenous digitalis-
like factor closely similar to ouabain, a short-acting cardiac glycoside. Its
physiological significance is still uncertain
• By convention the term, ‗Digitalis‘ has come to mean ‗a cardiac glycoside‘.
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17. CARDIOTONIC DRUGS
Cardiac glycosides
O
OOH
CH3
CH3
H
O
C18 H31O9
12
C
B
17
D
3 A
Digitoxin
Digoxin
= H at 12 C
= OH at 12 C
Aglycones
steroid nucleus
Convey the
pharmacological
activity
Unsaturated lactone
Convey cardiotonic
activity
Sugars- 3 mols. of digitoxose
Modulate potency and
pharmacokinetic distribution
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18. • The basic chemical structure of glycosides consists of
three components:-
• A sugar moiety (e.g. glucose)
The sugar moiety consists of unusual 1-4 linked
monosaccharides.
• A steroid-cyclopentanoperhydrophenanthrene ring
• A lactone ring (5-member ring)
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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19. Cardiotonic drugs- Cardiac Glycosides
The principal beneficial effect of digitalis in CHF is the
increase in cardiac contractility (+ve inotropism) leading to
the following:
o increased cardiac output
o decreased cardiac size (via ↓EDV & ↓ ESV)
o decreased venous pressure and blood volume
o diuresis and relief of edema (due to ↑ CO & ↓capillary
permeability)
o Decrease O2 consumption.
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20. Physiology of contraction
First the cell depolarizes then
contraction occurs
In depolarization
Ca++ will enter the cell
Ca++ will trigger the release of Ca++ from the
sarcoplasmic reticulum
In repolarization
Ca++ will return to the sarcoplasmic reticulum
Intracellular Ca++ leaves by means
of Na+/Ca2+exchanger
Intracellular Na leaves
by means of Na+/ K+
ATPase
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21. continued
Na+/Ca2+ exchanger depends on Na electricgradient
Inside the cell outside
Na
Less Na More
Na
K
Na+/K +ATPase
Na
Ca
Na+/Ca2+exchanger
This exchanger operates bidirectionally
In depolarization
Ca++ in Na+
out
In repolarization
Ca++ out
Na+ in
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22. Molecular mechanism of the +ve inotropic effect
 Inhibition of the Na+-K+- pump (Na+-K+-ATPase) on the
cardiac myocyes sarcolemma
 A gradual increase in intracellular Na+ ([Na+]i) and a gradual
small fall in [K+]i
 An inhibitory effect on the non-enzymatic Na+- Ca2+-
exchanger, which exchanges extracellular Na+ for intracellular
Ca2+
 The net effect is the increase in intracellular Ca2+ [Ca2+]I
 The increased [Ca2+]I stimulates more Ca2+ ions to influx via
voltage gated Ca2+ channels and increase the storage of Ca2+
into sarcoplasmic reticulum available for release upon arrival
of an action potential
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23. Sodium pump inhibition by cardiac
glycosides
Digoxin
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24. The direction & magnitude of Na+ & Ca2+ transport
during depolarized myocyte (systole)
• The exchanger may
briefly run in reverse
during cell depolarization
when the electrical
gradient across the
plasma membrane is
transiently reversed
• The capacity of the
exchanger to extrude
Ca2+ from the cell
depends critically on the
intracellular Na+
concentrations
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25. Mechanism of action of cardiac glycosides
Cardiac
glycosides
Inhibit Na/K
ATPase
↑ intracellular
Na
Inhibition of
Na/Ca
exchanger
↑intracellular
Ca
↑contractility
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26. Digitalis MOA – contd.
1. Depolarization
2. Release Ca++
3. Contraction
4. NCX
5. Blocked
6. Na+ more
X Ca++
Ca++<<
Depleted K+
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27. Pharmacological Actions of Digitalis
 Inotropism. Digitalis exerts positive inotropic effect both
in the normal and failing heart via inhibition of Na+-K+-
ATPase at cardiac sarcolemma.
Cardiac output (CO)
 Digitalis increases the
stroke volume and hence
the CO
 No increase in oxygen
Consumption
 Decreased EDV & hence
the dilated cardiac muscle
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28. 28DR.R.Lavanya

29. Myocardial Automaticity/Conductivity
 SA nodal firing rate and AV conduction are slowed down by the direct and
indirect mechanisms
 Prolongation of the effective refractory period of the A-V node
 At high doses, automaticity is enhanced as result of the gradual loss of the
intracellular K+
Mechanism of
action
Direct -extravagal-
effect on the heart
(parasympathomimet
ic)
-slowing SA node
firing rate
-slowing AV
conduction and
prolongation of
refractory period of
AV node
Indirect –vagal-
effect through
↑ sensitivity of SA node to vagal stimulation
thus
decrease in firing rate
Stimulation of
vagal central nuceli
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30. Venous Pressure
• Venous pressure is increased in CHF
• Digitalis reduces venous pressure as a result of improved
circulation and tissue perfusion produced by the enhanced
myocardial contractility (decreased blood volume)
• This in turn relieves congestion
• Ventricular end-diastolic volume (VEDV) is reduced
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31. Pharmacological actions of Digitalis - HEART
Overall actions:
1.Direct Effects - Myocardial contractility and electrophysiology
2.Vagomimetic effect
3.Reflex action – alteration of hemodynamic
4.CNS effects – altering sympathetic activity
Force of Contraction:
Dose dependent increase in force of contraction in failing heart –
positive inotropic effect
Increased velocity of tension development and higher peak
tension
Systole is shortened and prolonged diastole
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32. Tone:
•is Maximum length of fibre in a given filling pressure (Resting tension)
•Not affected by digitalis
•Decreasing end diastolic size of failing ventricle
Rate: bradycardia is more marked with digitalis.
- Rate decreased because of improved circulation
-restores vagal tone and abolished sympathetic over activity. Additionally
decreases heart rate by vagal and extravagal action
--Reduce the rate of conduction through the atrioventricular (AV) node (by
increasing vagal outflow in the CNS)
--Slow the heart However they disturb cardiac rhythm through blockade of
AV conduction that could progress to AV block and increasing ectopic
pacemaker activity.
-Benefits: useful against rapid atrial fibrillation
-Disadvantages: large doses disturb cardiac rhythm
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33. Diuresis
• Digitalis causes relief of CHF-induced edema
• This depends on the improved CO that increases renal blood
flow & consequently glomerular filtration rate is increased
• This results in down-regulation of the renin-angiotensin-
aldosterone (RAA) system that is stimulated in CHF
• Hence, the edema (pulmonary and peripheral) is improved in
response to digitalis as a result of the inhibition of the RAA-
induced water and salt retention
digitalis ↑cardiac
output
↑renal
blood flow
and so GFR
↓renin
angiotensin
system
edema
relieved
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34. • Electrophysiological actions - AP
• Qualitative and quantitative difference on different fibers
• Action Potential:
– Excitability enhanced - RMP progressively decreased.
– AV and BoH: Rate of ―0 - phase‖ depolarization is reduced
– PF : Phase 4 slope is increased - latent pacemaking activity
(extrasystoles)
– SAN and AVN Automaticity – Reduced
– Higher doses: the RMP shows Oscillation at phase 4 – coupled beats.
– Amplitude of AP is diminished
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35. 35DR.R.Lavanya

36.  AP duration reduced.
 ERP: (Minimum interval between 2 propagated action potentials)-
shorten
 Conductivity: Slowed in AVN and BoH fibres
• - Depressed AV conduction.
 ECG:
 Increased PR interval
 Decreased QT (shortening of systole)
 A-V block at toxic doses
 Decreased/inversion of - T wave.
Depression of ST segment (at high doses—due to interference with
repolarization).
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37. Blood Vessels
• Mild vasoconstrictor and increased PR in Normal individuals
• In CHF – compensated by improvement of increased in cardiac output-
decrease in sympathetic overactivity – decrease in Peripheral
resistance occurs
• Improved venous tone in CHF
BP: No significant effect on BP in CHF.
Coronary vessels: No significant action on coronary vessels – not
contraindicated in patient with coronary artery disease
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38. Kidney:
 Diuresis due to the improvement of circulation in CHF patients
 No diuresis in Normal persons.
Other smooth muscles:
Inhibition of Na+/K+ ATPase – increased spontaneous activity
– anorexia, nausea, vomiting and diarrhoea.
CNS:
 No major visible action at therapeutic doses
 High doses – stimulation of CTZ - nausea and vomiting
 Toxic doses – central sympathetic stimulation, mental confusion,
disorientation and visual disturbance.
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39. Cardiac glycosides - Pharmacokinetics
 Absorption and Distribution:
 Digoxin is administered by mouth or, in urgent situations, intravenously.
 Vary in their ADME
 Presence of food in stomach delays absorption of Digoxin and Digitoxin
 Digitoxin is the most lipid soluble
 Vd of Cardiac glycosides are high (heart, skeletal muscle, kidney -
• concentrated) – 6-8 L/Kg (Digoxin).
 Metabolism:
 Digitoxin is metabolized in liver partly to Digoxin and excreted in bile
 Reabsorbed in gut wall - enterohepatic circulation – long half life
 No relation with renal impairment
 Digoxin is primarily excreted unchanged in urine and rate of excretion parallels creatinine clearance
 So, renal impairment and elderly – long half life (dose adjustment)
 All CGs are cumulative – steady state is attain after 4 half lives (1 wk for Digoxin and 4 weeks for
digitoxin)
Excretion:
 It is a polar molecule; elimination is mainly by renal excretion and involves P-glycoprotein 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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40. Pharmacokinetics features of Digoxin
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41. Digitalis –Adverse effects
• Toxicity of digitalis is high, margin of safety is low (therapeutic index 1.5–3).
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.
• Cardiac and Extracardiac:
• Extracardiac:
1. GIT: nausea, vomiting and anorexia etc.
2. CNS: CTZ stimulation, headache, blurring of vision (flashing light,
3. altered color vision), mental confusion etc.
4. Fatigue, no desire to walk.
5. Serum Electrolyte K+ : Digitalis competes for K+ binding at Na/K
ATPase.
• Hypokalemia: increase toxicity
• Hyperkalemia: decrease toxicity
• 5. Gynecomastia - rare Gynecomastia may occur in men either due to
peripheral esterogenic actions of cardiac glycosides or hypothalamic stimulation
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42. Adverse Effects of Digitalis Glycosides
• Cardiac: All Arrhythmias
 Tachyarrythmias: Heart rate abnormally increased due to prolong diuretic
and digitalis therapy (K depletion) – Potassium chloride 20 m.mol/hr i.v or
orally is given in case of toxicity
 Digitalis toxicity (acute ingestion of large doses)– K+ should not be
given
 Serum K+ estimation should be done
 Ventricular arrhythmia: Excessive ventricular automaticity: Lidocaine (i.v)
(or Phenytoin)
 PSVT: Propanolol (i.v) or Adenosine
 AV block: ↓conduction velocity Atropine - 0.6 to 1.2 mg IM
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43. Digitalis - contraindications
 Hypokalemia: enhances toxicity
 Myocardial Infarction or ischaemia: severe arrhythmias are more likely.
 WPW syndrome (wolff parkinson-white syndrome): VF may occur (due to
reduced ERP)
 Elderly, renal or severe hepatic disease: more susceptible to digitalis toxicity
 Ventricular tachyarrhythmias
 Thyrotoxicosis: more prone to develop digitalis arrhythmias.
 Myxoedema: these patients eliminate digoxin more slowly; cumulative toxicity
can occur
 Ventricular tachycardia: it may precipitate ventricular fibrillation
 Partial A-V block: may be converted to complete A-V block
 Acute myocarditis: Diphtheria, acute rheumatic carditis, toxic carditis—
inotropic response to digitalis is poor, more prone to arrhythmias.
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44. Digitalis – Common Drug interactions
• Diuretics: diuretic therapy with digoxin induce Hypokalaemia (risk of
digitalis arrhythmias) (K+ supplementation required)
• Calcium: synergizes with digitalis- precipitates toxicity
• Adrenergic drugs: arrhythmia, increases ectopic automaticity.
• Succinylcholine: induce arrhythmia
• Propranolol and Ca++ channel blockers: depress AV conduction and oppose
positive ionotropic effects
• Metoclopramide, sucralfate and antacids – reduces absorption while
increased by atropinic drugs, tricyclic antidepressants
• 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.
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45. Therapeutic Uses of Digitalis Glycosides
 Treatment of congestive heart failure which does not respond
optimally to diuretics or ACEI.
 Treatment of atrial fibrillation and flutter by slowing SA nodal
firing rate as well as AV conduction preventing the occurrence
of the life-threatening ventricular arrhythmias
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46. Treatment of Digitalis Toxicity
 Digitalis should be immediately withdrawn, toxicity symptoms may persist
for some time due to slow elimination
 K+ Supplementation, Digitalis treatment usually results in myocardial K+
loss
 Hence, intravenous administration of K+ salts usually produces immediate
relief, since K+ loss is the probable cause of dysrhythmias
 K+ supplementation would raise the extracellular K+ decreasing the slope
of phase-4 depolarization and diminishing increased automaticity
 However K+ supplementation may lead to complete A-V block in cases of
depresses automaticity or decreased conduction (contraindicated with
digitalis-induced second- and third-degree heart block)
 Lidocaine or phenytoin is effective against K+ digitalis- induced
dysryhthmias
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47. Digoxin-specific Fab fragments
• Digoxin-specific Fab fragments (cross reacts with digitoxin also)
DIGIBIND-38mg vial are used safely for the treatment of the life-
threatening cardiac glycosides-induced arrhythmias and heart block
 Digoxin-specific Fab fragments are produced by purification of
antibodies raised in sheep by immunization against digoxin
 The crude antiserum from sheep is fractionated to separate the IgG
fraction, which is cleaved into Fab and Fc fragments by papain digestion
 The Fab fragments are nonimmunogenic and with no complement
binding
 They are excreted fairly rapidly excreted by the kidney as a digoxin-
bound complex
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48. Treatment of Digitalis Toxicity
Immediate withdrawal of digitalis
I.V. K+ supplementaion to
compensate for ↓intracellular K.
This may lead to
Hyperkalemia  ↓slope of
phase 4  ↓ automaticity
Complete AV block
(contraindicated in
digitalis induced
heart block)
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49. continued
Lidocaine or phenytoin is effective against K+ digitalis-induced dysryhthmias
Use digoxin’s specific Fab fragments
If that doesn’t work
If that doesn’t work (severe case or resistance to drugs)
•They are antibodies against digoxin.
•Produced from sheep( digoxin given to the sheep and antibodies
produced against it is collected).
•separate the Fab portion from Fc portion by papain
•Fab portion is not antigenic thus, it doesn’t cause allergy (does not
produce anaphylactic shock).
•Antibody will bind to digoxin forming a complex which can be
excreted through the kidneys increasing renal blood flow
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50. 50
Other Drugs That Increase Myocardial Contraction
• 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
• Certain 1-adrenoceptor agonists, Dobutamine, (2–8 μg/kg/min ,iv) 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. It lowers systemic vascular resistance
• Dopamine (3–10 μg/kg/min by i.v. infusion) has been used in cardiogenic shock due
to MI and other causes. 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.
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51. Selective ß1- Adrenergic Agonists
β-receptor
β-A
β-A
51DR.R.Lavanya

52. Phosphodiesterase III (PDE-III) Inhibitors
• Inhibition of myocardial phosphodiesterase III (PDE-III), the enzyme responsible for cAMP
degradation, and transmembrane influx of Ca results in +ve inotropism via cAMP-PK
cascade in a similar way to the selective ß1- adrenergic agonists
• Amrinone
• Positive inotropy and direct vasodilatation, reduction of both preload and afterload on the
heart , greater decrease in systemic vascular resistance.
• i.v. amrinone action starts in 5 min and lasts 2–3 hours; elimination t½ is 2–4 hours
• Thrombocytopenia is the most prominent and dose related side effect.
• Nausea, diarrhoea, abdominal pain, liver damage, fever and arrhythmias are the other
adverse effects
• 0.5 mg/kg bolus injection followed by 5–10 μg/kg/min i.v. infusion (max. 10 mg/kg in 24
hours).
• Milrinone
• more selective for PDE3, and is at least 10 times more potent than amrinone. 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 .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.
• PD-III inhibitors are suitable only for acute CHF because they can induce life-threatening
arrhythmias on chronic use
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53. Phosphodiesterase III (PD-III)
Inhibitors
53DR.R.Lavanya

54. OTHER DRUGS OF USE IN CHF WITHOUT
INOTROPIC EFFECT
Diuretics
 Diuretics ↓cardiac preload by inhibiting sodium and water retention
and improve ventricular efficiency by reducing circulating volume.
 Remove peripheral edema and pulmonary congestion
 Cardiac pumping improves with the consequent reduction in venous
pressure relieving edema
 Thiazide ( hydrochlorthiazide) and loop diuretics (frusemide) are routinely
used in combination with digitalis
 Dose should be titrated to the lowest that will check fluid retention, but not
cause volume depletion to activate RAS
 Potassium-sparing diuretics can be concurrently used to correct
hypokalemia
 Spironolactone+Digitalis+ACEI  ↓mortality because spironolactone
antagonize aldosterone which cause myocardial and vascular fibrosis
54DR.R.Lavanya

55. Angiotensin Converting Enzyme Inhibitors
(ACEIs)
(Captopril)ACEIs
55DR.R.Lavanya

56. Angiotensin Converting Enzyme Inhibitors
(ACEIs)
ACEIs produces the following actions:
 Reduces sympathetic nervous system tone
 Increases vasodilator tone of vascular smooth muscle and hence total
vascular resistance falls promptly via:
• Decreased circulating AngII
• Increased bradykinin (which stimulate generation of cardioprotective NO and
PGs)
• Decreased catecholamines
 Reduces sodium and water retention as a result of the reduced AngII-induced
reduced aldosterone secretion
• Ultimately both preload and afterload are reduced
 retards/prevents ventricular hypertrophy,myocardial cell apoptosis, fibrosis
intercellular matrix changes and remodeling
• Started at low doses which are gradually increased to obtain maximum
benefit or to near the highest recommended doses.
• Clinical trials showed that the use of ACEIs in CHF has significantly reduced
morbidity and mortality
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57. AT-1 Receptor Blockers (ARBs)
• Agents include: losartan and valsartan
• They are recently approved for treatment of CHF
• They have the same beneficial effect of ACEIs
• They don‘t cause cough .They enhance AT-2 function
Action of AT 2
receptor:
1- release of NO so
vasodilatation.
2- prevent
hypertrophy.
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58. VASODILATORS
Vasodilators other than ACE inhibitors/ARBs have only limited utility
 Arteriolar dilator- reduce after load- Hydralazine
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.
 Venodilator – reduce preload - Organic nitrates- nitroglycerine
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
 Mixed dilators- reduce both pre load and afterload.-
ACEI, ARBs, sodium nitroprusside, α1 blocker (Prazosin),PDE 3 inhibitors.
Sodium nitroprusside I.V. infusion is used at a dose of 0.1- 0.2 µg/kg/min in
acute CHF to lower preload and afterload. 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.
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60. β-Adrenergic blockers
β1 blockers (mainly metoprolol, bisoprolol, nebivolol) and the nonselective β
+ selective α1 blocker carvedilol have been used in mild to moderate CHF treated
with ACE inhibitor ± diuretic, digitalis.
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
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
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
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61. Aldosterone antagonist
• Aldosterone antagonist- Spironolactone, Eplerenone
Aldosterone:
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 which benefits in
CHF by antagonizing the above effects of aldosterone
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62. Aldosterone antagonist
• 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.
• It is indicated as add-on therapy to ACE inhibitors + other drugs in
moderate-to-severe CHF.
• Only low doses (12.5–25 mg/day) of spironolactone should be used to
avoid hyperkalaemia; particularly because of concurrent ACE
inhibitor/ARB therapy
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63. Current status of digitalis
• Before the introduction of high ceiling diuretics and ACE inhibitors,
digitalis was considered an indispensible part of anti-CHF treatment.
Now the standard treatment
• ACEI/ARBs+ Diuretics+β-blockers
If patient not recovered with standard therapy shift to DIGITALIS treatment.
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64. References:
1.Essentials of Medical Pharmacology, Seventh Edition,KD Tripathi
2.Goodman & Gilman‘s The pharmacological basis of Therapeutics, 11th
Edition, Laurence L. Brunton
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65. Thank you
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