Congestive cardiac failure is a serious condition which - if not life threatening, can be managed well by Pharmacotherapy which has been briefly outlined in this presentation.

1. DRUGS ACTING
ON
Congestive CARDIAC Failure (CCF)
Dr. Prerana Kadam (JR-1)
Guide: Dr. Smita Tiwari

2. The heart failure syndrome clinically-
Low output (forward failure) –
fatigue, dizziness, muscle weakness, and shortness of breath, which is aggravated by
physical exercise.
Increased filling pressure (backward failure) -
leads to congestion of the organs upstream of the heart, clinically apparent as
peripheral or pulmonary edema, maldigestion, and ascites.
Heart failure is a state in which the heart is unable to pump blood at a
rate commensurate with the requirements of the body’s tissues or can do
so only at elevated filling pressure.
Dr, Prerana Manik Kadam 2

3. HEART FAILURE PATHOPHYSIOLOGY
↓ CO
↓FOC
↓ RENAL PERFUSION
↑ANP/BNP
↑Sympathetic
Discharge
VASOCONSTRICTION β 1 ACTIVATION
↑AFTERLOAD
↑FOC
↑HR
VENTRICULAR
DILALATION
↓ GFR
↑ RENIN RELEASE
↑ANG I
↑ANG II
PRELOAD
↑ ALDOSTERONE
↑NA+ &H2O RETENTION
Initially There is ↑ CO via
Compensation Later
Worsen HF Via
Decompensation OEDEMA
PULMONARY CONGESTION
DYSPNOEA
CYANOSIS
COUGH
B/L CREPTS
HEPATIC CONGESTION
ENLARGED LIVER
NAUSEA
VOMITING
ANOREXIA
PERIPHERAL CONGESTION
GENERAISED OEDEMA
TACHY CARDIA
ENGORGED NECK VEINS
↑PRELOAD
CARDIAC REMODELLING
Dr, Prerana Manik Kadam 3

4. NYHA STAGES OF CONGESTIVE CARDIAC FALIURE
 Congestive heart failure has four stages.
 It begins with stage I — sometimes called class I or pre-heart failure.
 It progresses over time to stage IV, sometimes called class IV or advanced heart failure.
Why is it important? Because treatment recommendations are different depending on
the stage.
STAGE SYMPTOMS TREATMENT AND MANAGEMENT
I
There are often no symptoms on routine work
Orthopnoea
Lifestyle modification ,
medication.
II Shortness of breath, palpitations and fatigue during activity and routine chores. Stage I + Monitoring.
III
Physical activity leads to more severe stage II symptoms.
Simple tasks like short walk cause extreme respiratory distress.
,Medication + Monitoring
IV
Advanced heart failure.
Physical activity is almost impossible
People may be confined to sitting on chairs and sleeping in upright beds.
,Medication + Monitoring
Treatment is focused on increasing a
patients comfort.
Dr, Prerana Manik Kadam 4

5. PATHOPHYSIOLOGIC MECHANISMS OF SYSTOLIC HEART FAILURE (HFREF)
AND THERAPEUTIC INTERVENTIONS.
Ref: Goodman and gilman’s 13th Edition
Dr, Prerana Manik Kadam 5

6. PATHOPHYSIOLOGICAL MECHANISMS OF DIASTOLIC HEART FAILURE (HFPEF)
AND POSSIBLE THERAPEUTIC INTERVENTIONS
Ref: Goodman and gilman’s 13th Edition
Dr, Prerana Manik Kadam 6

7. 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 – Hydralazine, nitrate, nitroprusside
ACE inhibitors / AT1 antagonists
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
Dr, Prerana Manik Kadam 7

8. RAAS
Myocyte apoptosis
Cardiac
remodeling
Preload &
Afterload
ACE Inhibitors / ARBs
Dr, Prerana Manik Kadam 8

9. • Status:
- All patients with heart
failure;
- NYHA I–IV
should receive an ACEI.
• Combination: Combined
with β blockers and/or
MRAs.
ACEI
↓ circulating levels of Angiotensin II ,
↓ rate of bradykinin inactivation - ↑bradykinin -
vasodilatation
↓ secretion of aldosterone - ↓ sodium and water retention
-- Indirect Diuretic --↓ Aldosterone dependant ENaC
↓ preload and after load
↓ Ang II decrease reabsorption of Na+ and HCO3- in PCT
Produces Sympatholytic effects
Retards cardiac remodelling of AngII induced ventricular
hypertrophy, myocyte apoptosis
ARBs
ARBs used in patients who can’t
tolerate ACEI because of dry cough and
angioedema
ACE INHIBITORS / ARBS
Dr, Prerana Manik Kadam 9

10. β BLOCKERS:
Sequelae of CCF are as follows:
 Increase HR (Positive chronotropic effect)
 Increase FOC (Positive inotropic effect)
 Increase rate of Force development
(Positive clinotrophy +dp/dt)
 Accelerate cardiac muscle relaxation
(Positive lucitrophic effect – dp/dt)
-aid ventricular filling
 Acceleration of AV conduction rate
(Positive dromotrophic effect)
-Increase heart rate
-Increase automaticity of cardiac fibres
 Decrease threshold for Arrythmia
(Positive bathmotropic effect)
-
CCF
Decreased perfusion
Activation of SNS
Nerve ending
Nor Epinephrine
Adrenal medulla
Epinephrine
Dr, Prerana Manik Kadam 10

11. Metoprolol, Bisoprolol, Carvedilol, Nebivolol
β blockers : Start low, go slow
1/8th of your target dose
doubling of dose every 4wks
Gives heart time to reset to a new equilibrium
at a low Adrenergic drive
 Reversal of Heart failure–specific gene program
Down-regulation of β adrenergic receptor density
Upregulation of inhibitory Gproteins
↓ expression of SR Ca2+-ATPase,
↓ the fast isoform of myosin heavy chain
↓ repolarizing K+ currents
β BLOCKERS
Dr, Prerana Manik Kadam 11

12. • Paradoxical increase in LVEF and ↓ rate of arrythmias (3-6 months of
therapy )
• Status:
- All patients with symptomatic heart failure NYHA II–IV
-All patients with left ventricular dysfunction NYHA I
- Post MI treated with a β blocker.
C/I : Asymptomatic and Decompensated HF
Acute HF after MI HR< 60/min, Asthma, COPD
• Combination: Combined with ACEI +Diuretic/Digitalis
β BLOCKERS
Dr, Prerana Manik Kadam 12

13. PRECAUTIONS
Heart rate lowering
Target heart rate : 60–70/min.
AV block
Beware of preexisting conduction disturbance / pacemaker implantation.
Bronchoconstriction.
Only β1-selective compounds used in patients with COPD.
Peripheral vasoconstriction (cold extremities)
Initial vasoconstriction turns into vasodilation under chronic therapy with β blockers.
Patients with peripheral artery disease or symptoms of claudication or Raynaud disease
should be carefully monitored and treated with Carvedilol if a β blocker is employed.
Dr, Prerana Manik Kadam 13

14. MINERALOCORTICOID RECEPTOR ANTAGONISTS
(MRAs)
Antagonists of nuclear receptors of Aldosterone
Aldosterone: RAAS activator, promotes Na+ and fluid retention, loss of K+
and Mg2+, sympathetic activation, parasympathetic inhibition, myocardial
and vascular fibrosis, baroreceptor dysfunction, and vascular damage, all
adverse effects in the setting of heart failure.
 MRAs inhibit all the effects of Aldosterone.
Dr, Prerana Manik Kadam 14

15. MINERALOCORTICOID RECEPTOR
ANTAGONISTS (MRAs)
Spironolactone and Eplerenone
 No gynaecomastia and dysmennorhoea with Eplerenone – Specific for MR
 Most important ADR of both MRAs : hyperkalemia.
• Status:
Low doses to All patients of NYHA Class II–IV (symptomatic HFrEF)
• Combination:
In low doses added to ACEIs, Diuretics,
and Digoxin
Dr, Prerana Manik Kadam 15

16. ANGIOTENSIN RECEPTOR AND NEPRILYSIN INHIBITORS
Sacubitril & ARB Valsartan
Neprilysin - peptidase mediating the enzymatic degradation and inactivation of
natriuretic peptides (ANP, BNP, CNP), bradykinin, and substance P.
Sacubitril inhibits Neprilysin, Cocrystallizing product of the the above two
drugs.
Thus, the drug combines
-inhibition of the RAAS
-inhibition of degradation of the natriuretic peptides
- Produces vasodilatation, natriuresis and diuresis.
Status: - Advanced cardiac failure , NYHA III and IV
- Decrease the incidence of death and acute decompensation
- Reduction in hospitalization and mortality
Dr, Prerana Manik Kadam 16

17. Furosemide, Bumetanide with Spironolactone
Inhibit the Na+-K+-2Cl symporter in the ascending limb of the loop of Henle,
where up to 15% of the primary filtrate (~150 L/d) is reabsorbed, explaining
their strong diuretic action.
↓ preload and improve ventricular efficiency by reducing volume overload
Remove pulmonary congestion and peripheral oedema
↓ cardiac size – improvement in pump efficiency
Don't influence the primary disease process in CHF
HIGH CEILING DIURETICS
Dr, Prerana Manik Kadam 17

18. Chronic diuretic therapy –hypokalemia may ↑ digitalis toxicity
They may cause activation of renin- angiotensin system
Diuretics improves LV function when combined with ACEI/digoxin
• Status: -Symptomatic cardiac failure NYHA II-IV
• Combination: Combined with ACEI/ARB + / - BETA blocker + / -
Digoxin + Spironolactone.
HIGH CEILING DIURETICS
Dr, Prerana Manik Kadam 18

19. VASODILATORS
Venodilators (primarily ↓preload)
-GTN, Isosorbide dinitrate
Arteriolar dilators (primarily ↓afterload)
-Hydralazine, Minoxidil, CCB-Nifedipine, K channel opener- Nicorandil
Mixed dilators ( ↓pre and after load)
-ACE Inhibitors, AT1 antagonists (ARBs), Prazosin (α1 blocker),
Amrinone, Milrinone, Nitroprusside
Dr, Prerana Manik Kadam 19

20. VASODILATORS
- They prevent cardiac remodelling & have become the mainstay of
anti-CHF measures
-Used IV in acute HF
• Status: -Acute cardiac failure
-NYHA III-IV
- AHA Stage B-D
-Orally for long term therapy for chronic CHF
• Combination: Combined with ACEI/ARB + / - BETA blocker
Dr, Prerana Manik Kadam 20

21. SYMPATHOMIMETIC INOTROPIC DRUGS
Dobutamine - β1, β2 and α1 receptors and Selective β1
- Inotropic action ↑ CO
- Little effect on BP / HR (counterbalance of β2 and α1)
- Short term management of acute HF with MI - IV infusion (5- 15μg/kg/min)in acute
HF with MI/cardiac surgery
Dopamine – β1 Inotropic action
-in moderate dose (5-10 μg/kg/min)
- ↑CO
- TPR – unchanged due to renal and splanchnic vasodilatation (D1)
- Higher dose ↑ TPR and ↑ afterload
- HF with renal impairment
- Due to development of tolerance - no role in the long term management of CHF
Dr, Prerana Manik Kadam 21

22.  Amrinone – Phosphodiesterase inhibitor
-↑ myocardial cAMP and
-↑transmembrane influx of Ca++ +ve inotropic and direct vasodilator action
-Used for short-term circulation support in advanced CHF.
 Milrinone - phosphodiesterase inhibitor
More potent than amrinone Shorter acting (t1/2 40-80 min)
–Used for short term treatment of severe HF
– administered IV 50 μg/kg bolus followed by 0.4-1.0μg/kg/min IV infusion
Dr, Prerana Manik Kadam 22

23. Levosimendan – Inodilators
- ↑ 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
•Status
No role in long term therapy
Useful in patients of HF with low BP
Acutely Decompensated severe HF NYHA
Dr, Prerana Manik Kadam 23

24. RECOMBINANT BRAIN NATRIURETIC PEPTIDE
Nesiritide
–↑ cGMP in vascular smooth muscle – reduces venous and arteriolar tone
–↓ pre & afterload,↑ salt and water excretion
Status: Acutely decompensated CCF a/w dyspnoea at rest
–2mg/kg bolus followed by 0.01-0.03μg/kg/min IV infusion
Dr, Prerana Manik Kadam 24

25. VASOPRESSIN RECEPTOR ANTAGONISTS
- Increased plasma osmolality, decreased arterial
pressure and reduced cardiac filing- release of
ADH.
- V1 : vasoconstriction V2 : antidiuretic action
Conivaptan
- Mixed V1 + V2 receptor antagonist
- Acute CF with hyponatremia
Tolvaptan
- V2 antagonist
• Status NYHA III & IV
Dr, Prerana Manik Kadam 25

26. HCN GATED CHANNEL BLOCKER
Ivabradine
• Works by slowing of the heart rate so that heart
can pump more blood through the body
• Acts selectively and specifically by inhibiting
cardiac pacemaker funny current- a mixed
sodium potassium inward current that controls
diastolic depolarization in SA node.
• Lowers RAAS activation – improved renal
function and vascular pressures – decrease in
cardiac wall stress
• Used when Beta blockers are c/I or ineffective.
Status:
-- Symptomatic chronic CCF , NYHA II to IV in
sinus rhythm with LVEF less than or equal to 35%
-- Reduce the risk of hospitalization for worsening
CF
Combination: ACEI, Diuretic, Aldosterone
antagonists. Dr, Prerana Manik Kadam 26

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28. CARDIAC GLYCOSIDES
Dr, Prerana Manik Kadam 28

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32. PHARMACOLOGICALACTIONS OF DIGITALIS
1. Cardiac
– (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)
–+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 ↓ oxygen requirement of myocardium
–The digitalized heart, thus, can do more work for the same energy
expenditure
Dr, Prerana Manik Kadam 32

33. Heart rate
– causes bradycardia (more marked in CHF patients) , -ve
chronotropic effect by direct and indirect action (small dose)
Electrophysiological properties
– direct depressant action on SA and AV nodes
– differs with the cardiac fibres Action Potential
– RMP progressively ↓
–The slope of phase 4 depolzn ↑ in PFs & ventricular muscle
– ectopic automaticity results in ventricular extra systoles, coupled
beats (due to delayed after depolarisation)
– ERP↑ at AV node & bundle of His
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34. Conduction velocity
Conduction through AV node depressed
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 with
repolarisation)
Dr, Prerana Manik Kadam 34

35. 2. Extra cardiac
• Blood vessels
– digitalis has mild direct vasoconstrictor action
–Blood vessels : not significant 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)
• CTZ activation
– in high doses vomiting, central sympathetic stimulation, confusion, disorientation,
blurring of vision
• GIT – Anorexia, nausea, vomiting (CTZ stimulation and direct action on the gut)
Dr, Prerana Manik Kadam 35

36. PHARMACOKINETICS
Digoxin is the commonly used glycoside
- 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 faiure)
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 )
•Status: Moderate to severe heart failure NYHA II-IV
Dr, Prerana Manik Kadam 36

37. 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,
headache, 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)
Dr, Prerana Manik Kadam 37

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39. DIGITALIS TOXICITY
• Stop Digoxin
• Infuse KCL at 20mmol/hr or oral supplements.
Reduces actions of digoxin.
• Ventricular arrhythmias: Lignocaine iv
• Supraventricular arrhythmias: Propranolol iv
• AV block i.m Atropine 1.2 mg
Dr, Prerana Manik Kadam 39

40. • Digoxin antibodies (Digibind)
- This is purified Fab fragments of antibody obtained from antidigoxin antisera
- Used in digitalis toxicity
- Digoxin antibody binds with circulating digoxin an this complex is excreted in
urine
- Given IV
- Rapidly reverses the toxicity (40mg neutralises 0.6mg of digoxin stored in the
body)
- Expensive
Dr, Prerana Manik Kadam 40

41. CONTRAINDICATIONS
a. Hypokalemia
b. Elderly, associated disease like renal/hepatic disease
c. MI
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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43. RECENT ADVANCES
Omecamtiv mecarbil activates cardiac myosin complex.
Also prolongs systole without increasing oxygen consumption of the heart
Istaroxime is an investigational steroid derivative that increase contractility by inhibiting Na + /K+
-ATPase (like digoxin)
Bosentan and tezosentan , orally activate competitive inhibitors of endothelin may have some
benefits in experimental animal models
Patiromer and zirconium cyclosilicate are attractive agents that are expected to prevent
hyperkalemia during renin-angiotensin-aldosterone system inhibition, and serelaxin (Recombinant
form of human hormone relaxin) and urodilatin (inhibits RAAS and causes vasodilation) are
promising drugs in the treatment of acute heart failure which are still in pipeline. (2015)
Cimaglermin, a neuregulin GGF2 protein has shown benefits in animal models
Dr, Prerana Manik Kadam 43

44. 15*
CONCLUSION
 Heart failure is a complex syndrome that can result from various reasons
 Focus should be to stop disease progression, correct the underlying
disease if any and relieve symptoms.
 Drugs should be prescribed by taking EF and symptoms into consideration
44
Dr, Prerana Manik Kadam

45. REFERENCES
Brunton LL, Hilal-Dandan R, Knollmann BC. As Bases Farmacológicas da Terapêutica de
Goodman e Gilman-13. Artmed Editora; 2018 Dec 19.
Tripathi KD. Essentials of medical pharmacology. JP Medical Ltd; 2013 Sep 30.
Sharma HL, Sharma KK. Principles of pharmacology. Paras medical publisher; 2007.
Barrett KE, Boitano S, Barman SM, Brooks HL. Ganong’s review of medical physiology
twenty.
Satoskar RS, Bhandarkar SD, Ainapure SS. Pharmacology and pharmacotherapeutics. Indian
Journal of Pharmacology. 1997 Sep 1;29(5):330
Kitai, T., & Tang, W. W. (2015). Recent advances in treatment of heart
Failure. F1000Research, 4, F1000 Faculty Rev-1475.
https://doi.org/10.12688/f1000research.7022.1
Dr, Prerana Manik Kadam 45

46. Live healthy, stay young at heart
Dr, Prerana Manik Kadam 46