This document discusses drugs used to treat congestive heart failure. It begins by defining CHF and describing its signs and symptoms. It then covers the classification, mechanisms of action, structures, and uses of several classes of drugs including cardiac glycosides like digoxin and digitoxin, vasodilators like nesiritide and tezosentan, and ACE inhibitors like besentan. Adverse drug reactions are also listed for each drug. In summary, the document provides an overview of the main drug classes used to treat CHF and highlights key details about individual drugs within each class.

1. 3rd UNIT
DRUGS USED IN
CONGESTIVE HEART FALIURE
Subject: Medicinal Chemistry-II
Year: B.Pharmacy 3rd Year
Semister: 1st Semister
1

2. Contents
2
⚫ Introduction.
⚫ Signs and Symptoms.
⚫ Types of CHF.
⚫ Classification .
⚫ Drugs used in CHF.
⚫ Mechanism of action.
⚫ Structure.
⚫ Adverse Drug Reactions and
⚫ Uses.
⚫ Reference

3. Introduction
⚫ Congestive heart failure (CHF) is defined as the inefficiency of the
heart to pump sufficient amounts of oxygenated blood to the organs
of the body to meet their normal metabolic demands.
3

4. Signs and Symptoms
4
fluid
Signs
⚫ Lateral displaced apex beats.
⚫ Gallop rhythm (additional heart sound)
⚫ Heart murmurs (Indicates the presence of valvular defect)
⚫ Aortic stenosis (abnormal narrowing of heart valves)
⚫ Pleural effusion (Increased volume of pleural cavity)
⚫ Pleural cyanosis (decrease absorption of oxygen due to
accumulation).

5. Symptoms
⚫ Paroxysmal nocturnal dyspnoea (night attacks of breathlessness).
⚫ Dysponea (shortness of breath)
⚫ Orthopnoea (increased breathlessness in lying posture)
⚫ Poor circulation results in dizziness, confusion, diaphoresis
(excessive sweating)
⚫ Tachycardia (increased heart rate)
⚫ Muscle fatigue
⚫ Pulmonary oedema (accumulation of blood or fluid in lungs)
⚫ Hepatomegaly (enlarged liver)
⚫ Cardiomegaly (enlarged heart)
5

6. Types of CHF
6
1. Based on the amount of cardiac output:
⚫ Low output cardiac failure
⚫ High output cardiac failure
2. Based on the side of heart effected:
⚫ Left sided cardiac failure
⚫ Right sided cardiac failure

7. Classification
7
Based on inotropic effects:
1. with positive inotropic effects:
Levoimendan,
a. Cardiac Glycosides: Digitoxin, Digoxin, Ouabain
b.Phosphodiesterase Inhibtors: Inamrinone,
Milrinone
c. β-adrenergic agonist: Dobutamine, Dopamine, Dopexamine

8. 2. without positive inotropic effects:
8
a. Angiotension converting enzyme (ACE)inhibitor: Captopril,
Enalapril, Ramipril, Lisinopril
b. β-adrenergic receptor antagonist: Bisoprolol, Carvedilol,
Metorolol
c. Diuretics: Acetazolamide, Bumetanide, Hydrochlorothiazine,
Metolazone, Spironolactone
d. Vasodilators: Hydralazine, Isosorbide dinitrate, sodium
nitropruside, Nesiritide

9. Cardiac Glycosides
9

10. Cardiac Glycosides
10
⚫ Cardiac Glycosides are naturally occurring drugs with positive
inotropic action.
⚫ They are also termed cardiotonics. Cardiac glycosides are obtained
from various sources.

11. Glycosides sources
Digitoxin, gitalin, gitoxin Leaves of Digitalis purpurea
(Fox leaves)
Digitoxin, lanatoide-C Leaves of Digitalis lanata
Strophanthin-G, Ouabain Seeds of Strophanthus gratus
Strophanthin-K Seeds of Strophanthus kmobe
Proscillaridin-A Urginea scilla
Thevetin Thevetia nerifolia
Bufotoxin Bufo vulgaris (Toad skin)
11

12. General Mechanism of Action
12
ionic movements occurring during the normal contraction of cardiac
muscle are as follows:
1. Initially calcium ions enter into the cardiac myocytes via the voltage
sensitive L-type calcium channel.
2. Such influx stimulates the release of large amounts of calcium ions
from the sarcoplasmic reticulum (SR) and mitochondria of the
myocytes. This results in contraction of cardiac muscles.

13. 3. The contractile process is followed by removal of calcium ions.
This is achieved by two ways reuptake of calcium ions by
sarcoplasmic reticulum and mitochondria as well as by sodium or
calcium ion exchange pump located in the cell walls of myocytes
which allows entry of 3 sodium ions for each effluxing calcium
ions.
4. sodium or calcium ion exchange pump may increase the
intracellular sodium ion channel, which each time effluxes 3 sodium
ions and influxes 2 potassium ions.
13

14. ⚫ Digitalis gets reversibly bound to the sodium or potassium ATPase
pump and inhibits its activity. This results in progressive
accumulation of intracellular sodium ions and loss of potassium
ions. Due to the deposition of intercellular sodium ions, sodium or
calcium exchange pump gets activated.
14

15. ⚫ Sodium or calcium exchanger extrudes sodium ions in exchange for
calcium ions. Intracellular calcium ions levels are further increased
due to increase in calcium permeability via voltage sensitive L-type
calcium channels. Increase in calcium levels by these two
mechanisms triggers the release of calcium ions from the
sarcoplasmic reticulum and mitochondria. Digitalis also inhibits the
reuptake of calcium ions by sarcoplasmic reticulum. All these
effects ultimately increases calcium levels in the cytosol which
eventually triggers contractile process in the failing heart.
15

16. ⚫Digoxin
Structure:
IUPAC: 4-[-3-{-5-{-5-{-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-4-
hydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-6-methyloxan-2-
yl]oxy}-12,14-dihydroxy-18,19-dimethyltetracycloheptadecan-17-
yl]-furan-2-one
Molecular Formula: C41H64O14
16

17. Properties:
⚫ Digoxin appears as clear to white crystals or white crystalline
powder, Odorless, Bitter taste, Practically insoluble in water, Very
soluble in ethanol, Freely soluble in pyridine; soluble in mixture
of chloroform and alcohol, More soluble in hot 80% alcohol
than gitoxin, Slightly soluble in dilute alcohol, chloroform.
Practically insoluble in ether, acetone, ethyl acetate, chloroform
17

18. Pharmacokinetics:
18
⚫ Oral, Intravenous, Intramuscular route of administration, about 13%
of a digoxin dose is found to be metabolized in healthy subjects.
Several urinary metabolites of digoxin exist,
including dihydrodigoxin and digoxigenin bisdigitoxoside.
⚫ Their glucuronidated and sulfated conjugates are thought to be
produced through the process of hydrolysis, oxidation, and
additionally, conjugation.
⚫ The cytochrome P-450 system does not play a major role in digoxin
metabolism, nor does this drug induce or inhibit the enzymes in this
system, excreted by kidneys in larger amounts i.e nearly 70% in an
unchanged form.

19. Adverse Drug Reactions:
⚫ Dizziness, Depression, Confusion,Anxiety
⚫ Nausea, Vomiting, Diarrhea
⚫ Head ache
⚫ Rashes, weakness
⚫ Irregular Heart rate
⚫ Blurred vision
Therapeutic Uses:
⚫ Used in the treatment of heart failure, used to relieve symptoms of
heart failure when the patient does not responding to ACE inhibitor
and diuretics.
⚫ It reduces the heart rate and increase the cardiac output.
19

20. ⚫Digitoxin
Structure:
IUPAC: 4-[-3-{-5-{-5-{-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-4-
hydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-6-methyloxan-2-
yl]oxy}-14-hydroxy-18,19-dimethyltetracycloheptadecan-17-yl]-
furan-2-one
Molecular Formula: C41H64O13
20

21. Properties:
⚫ White or pale buff microcrystalline powder, Odorless, Bitter taste,
slightly soluble in water, very soluble in ethanol, soluble in ethyl
ether, chloroform, methanol, pyridine
21
Pharmacokinetics:
⚫ Oral route of administration, absorption of digitoxin is decreased
by the presence of food in stomach.

22. Adverse Drug Reactions:
⚫ Dizziness,Anxiety
⚫ Nausea, Vomiting
⚫ Diarrhea
⚫ Head ache
⚫ Rashes, weakness
⚫ Irregular Heart rate
⚫ Visual problems
⚫ Low platelet count
Therapeutic Uses:
⚫ Used in the treatment of heart failure
⚫ Used to treat certain types of irregular heart beat can decrease the
risk for blood clots that may reduce the risk for heart attacks
22

23. Vasodilators
23

24. General Mechanism of Action
24
⚫ Vasodilators work on different substances in the body to help widen
(dilate) blood vessels. It is easier for the heart to pump blood if the
blood vessels are widened.
⚫ Vasodilators can improve heart failure symptoms by:
⚫ Dilating coronary arteries. This can help more blood reach your
heart muscle.
⚫ Dilating leg veins. This can lower the amount of blood returning to
the heart and limit the buildup of fluid in your lungs.
⚫ Dilating systemic arteries. Systemic arteries are blood vessels that
carry blood to the rest of the body (excluding the heart and lungs).
By dilating these arteries, vasodilators may relieve some of the
work your heart needs to do.
⚫ Dilating pulmonary arteries. Dilating the arteries of the lungs
(pulmonary arteries) also reduces the amount of work your heart
needs to do.

25. ⚫Nesiritide
Structure:
25

26. Properties:
⚫ White- to off-white lyophilized powder, Bitter taste, Practically
insoluble in water, Very soluble in ethanol
Pharmacokinetics:
⚫ Intravenous route of administration, Nesiritide undergoes
proteolytic cleavage of the peptide by endopeptidases, such as
neutral endopeptidase, which are present on the vascular lumenal
surface. Human BNP is cleared from the circulation via the
following three independent mechanisms, in order of decreasing
importance:
1)binding to cell surface clearance receptors with subsequent cellular
internalization and lysosomal proteolysis;
2) proteolytic cleavage of the peptide by endopeptidases, such as
neutral endopeptidase, which are present on the vascular lumenal
surface; and 3) renal filtration
26

27. Adverse Drug Reactions:
⚫ Head ache, Nausea, Vomiting
⚫ Rashes, Itching
⚫ Hypotension, Sweating
⚫ Anemia, Confusion
⚫ Cough
⚫ Increase creatinine
⚫ Injection side reactions
Therapeutic Uses:
⚫ It will relax and dilutes blood pressure, lowering blood pressure
improve the breathing in people with CHF.
27

28. ⚫Tezosentan
Structure:
IUPAC: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(4H-
1,2,3,4-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-(propan-2-
yl)pyridine-2-sulfonamide
Properties:
⚫ White solid, viscous, hygroscopic amino alcohol with an
ammoniacal odor, soluble in Water .
Molecular Formula: C27H27N9O6S
28

29. Pharmacokinetics:
⚫ Intravenous route of administration, metabolized in liver,
eliminated through urine
Adverse Drug Reactions:
⚫ Nausea
⚫ Head ache
⚫ Hypotension
Therapeutic Uses:
⚫ Used in the treatment of heart failure
⚫ Used to improve cardiac output
29

30. ⚫Besentan
Structure:
IUPAC: 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-
2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide
Molecular Formula: C27H29N5O6S
Properties:
⚫ white to yellowish powder, poorly soluble in water
30

31. metabolized in liver, eliminated
31
Pharmacokinetics:
⚫ Oral route of administration,
through urine .
Adverse Drug Reactions:
⚫ Dizziness
⚫ Allergic reaction
⚫ Swelling
Therapeutic Uses:
⚫ It is used treat high blood pressure, It acts as a vasodilator and was
designed as a therapy for patients with acute heart failure.

32. Reference books
32
⚫ Text book of Medicinal chemistry volume-1-3rd edition by
V.Alagarasamy.
⚫ Text book of Medicinal chemistry volume-2-3rd edition by
V.Alagarasamy.
⚫ Medicinal chemistry by Rama Rao Nadendla.
⚫ Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K
Kapoor.
⚫ Wilson and Gisvolid’s Textbook of Organic Medicinal and
Pharmaceutical chemistry-12th edition by John M. Beale, John. H.
Block.

33. THANK YOU
33