Cardiovascular agents:

Antihypertensives, anti-arrythmics, antianginal agents,

anticoagulants, antiplatelets and thrombolytics

Cardiovascular Agents
 Drugs Against Heart Failure
Heart failure, sometimes known as congestive heart
failure,
occurs when your heart muscle doesn't pump blood as
well as

Congestive Heart it should. Certain conditions, such as narrowed

Failure
arteries in your heart (coronary artery disease) or high
blood pressure, gradually leave your heart too weak
or stiff to fill and pump efficiently

[reduced contractibility of the cardiac muscles]

CO ; blood volume in heart   congested
Congestive heart failure (CHF) is a complex clinical syndrome
characterized by impaired ventricular performance (impaired
cardiac output), exercise intolerance, a high incidence of
ventricular
arrhythmias, and shortened life expectancy.
Drugs against heart failure
• Treatment of heart failure aims to relieve symptoms,
improve exercise tolerance, reduce incidence of
acute exacerbations, and reduce mortality.
• Cardiac glycosides, Phosphodiestrase inhibitors, β1
stimulants, ACEIs, Diuretics
• In addition, measures such as weight reduction,
moderate salt restriction, and appropriate exercise
should be introduced.
Cardiac glycosides
• The cardiac glycosides are an important class of
naturally occurring drugs which actions include
both beneficial and toxic effects on the heart, and
have played an outstanding role in the therapy of
congestive heart failures (CHF)
 Toxicity also results in changes to heart chronotropic activity,
resulting in multiple kinds of dysrhythmia and potentially fatal
ventricular tachycardia.
 • The terms ‘cardiac glycoside’ or ‘digitalis’ are used throughout to
refer to any of steroid or steroid glycoside compounds that
exert characteristic positively inotropic effect on the heart.
• The cardiac glycosides are composed of two structural features;
the
sugar (glycoside) and the non-sugar (aglycon) moieties.
MedChem,Alemu T.
Advanced
 O

CH3

CH3 H

H OH O
CH3 H
O
O
H OH
H CH3
CH3
O H
O
OH
CH3 H
CH3
O
O H OH
OH
CH3 H
O
OH O H
OH
CH3

Digitoxin (Digitoxinum) O
O

OH

CH3
MedChem,Alemu T.

O
O
OH
Digoxin (Digoxinum)
OH
Advanced

OH

• Digoxin and digitoxin are the two cardiac

glycosides most frequently used nowadays and
have obviously replaced digitalis in cardiac
therapy.
 O
O

H
CH3
HO
HO H
H
HO
H

H OH O
OH O O Nomenclature
O H OH
CH3
CH3
OH OH H
O
C H
Quabaine (Ouabainum)
O
H OH O
OH O
O OH
OH CH3
CH3
CH3 H
OH OH
H OH
CH3
MedChem,Alemu T.

Convallatoxin (Convallatoxinum) O
O
CH3
O
OH
CH3
O
Advanced

CH2OH OH
O
HO OCOCH3
OH
OH

Celanide (Celanidum) (digilanide or lanatoside C)

Structure Activity Relationship
 Cardiac glycosides and similar other glycosides are
composed of sugar and the non-sugar (aglycone)
moieties.
 The hydroxyl group at C-3 of the aglycone portion is
usually conjugated to a monosaccharide or a
polysaccharide with β- 1, 4-glucosidic linkages
 The number and identity of sugars vary from one
glycoside to another as detailed subsequently.
 The most commonly found sugars in the cardiac
glycosides are D-glucose, D- digitoxose, L-
rhamnose, and D- Cymarose.
• At a time, the aglycone portion may combine
with 1-4 molecule of sugar.
• The attached sugar through glycosidic linkage
may be mono-, di-, tri-, or tetra-saccharides.
• All aglycones represent similar set of
pharmacological action.
• It is the sugar moieties attached to the aglycone
play an important role in governing duration of
action, partition coefficient, absolute potency, and
protein binding properties of glycosides. It also
inhibits an enzyme induced metabolic change in the
aglycone configuration.
• Sugars predominately exist in the cardiac
glycosides in the β-conformation.
• Hydroxyl groups are located at C-3, the site of
the sugar attachment, and at C-14. The C-14
hydroxyl is normally unsubstituted and is crucial
for activity

Advanced
MedChem,Alemu T.
• However, additional hydroxyl groups may be found at
C-12 and C-16, the presence or absence of which
distinguishes the important genins: digitoxigenin,
digoxigenin, oubagenin and gitoxigenin
• The lactone ring is not essential for activity it only
used for receptor binding b/c side-chains instead of a
ring have even higher activity. The activity of a
compound depends to a great extent on the position
of the 23rd carbonyl oxygen, which is held quite rigidly
by ring D and the double bond
• Removal of the sugar portion allows epimerization of
the 3β- OH group, with a decrease in activity and an
increase in toxicity due to changes in polarity.

Advanced
MedChem,Alemu T.
 Phosphodiesterase inhibiters
• A phosphodiesterase inhibitor is a drug that
blocks one or more of the five subtypes of
the enzyme phosphodiesterase (PDE), thereby
preventing the inactivation of the intracellular second
messengers cyclic adenosine monophosphate (cAMP)
and cyclic guanosine monophosphate (cGMP) by the
respective PDE subtype(s).
• Drugs which inhibit the action of phosphodiesterase
(thus reducing the breakdown of cAMP) have a
therapeutic action on the heart, lung, and
vasculature as well as on platelet function and
inflammatory mechanisms.
• Nitrates or alpha-blockers are strongly
contraindicated in patients taking PDE5 inhibitors
because of the risk of life- threatening
Advanced
MedChem,Alemu T.
hypotension

Advanced
MedChem,Alemu T.
• The cyclic nucleotide phosphodiesterase's
constitute a group of enzymes that catalyze
the hydrolysis of various cyclic nucleotides
including cAMP and cGMP.
• Agents that interfere with the degradation of
the cyclic nucleotide have usefulness in
treating hypertension, erectile dysfunction,
etc.
• Phosphodiesterase type 5 (PDE5) is responsible
for the catalytic hydrolysis of cGMP in the
smooth muscle of the arteries in the penis and
lungs. Inhibitors of this particular
phosphodiesterase have been shown to relax
arteries in the penis, thus allowing the corpus
Advanced
MedChem,Alemu T.
cavernosum to fill with blood and aiding in an
erection

Advanced
MedChem,Alemu T.
 A) Nonselective phosphodiesterase inhibitors

Caffeine Theophylline
Theobromine

B) Selective phosphodiesterase inhibitors

Milrinone Vardenafil
Sildenafil
 1-andrenergic agonists: dobutamine

• Lot’s of 1 adrenergic receptors in myocardium

mechanism involves simulation of adenylate cyclase
and increased cAMP levels leading to increased Ca2+
levels/leading to increased CO.
OH

HO NH

HO

Dobutamine
(Dobutrex)
 Diuretics, vasodilators
• Goal of treatment is to eliminate clinical
evidence of fluid retention
1. Loop diuretics: These cause the kidneys to
produce more urine. This helps remove excess
fluid from your body. ex. Bumetanide,
Furosemide, Torsemide
2. Thiazide diuretics: These cause blood vessels to widen
and
help the body remove any extra fluid ex.
Hydrochlorothiazide
3. K+ sparing diuretics: These help get rid of fluids and
sodium while still retaining potassium. ex.
spironolactone, triamterene
SAR for Loop diuretics Furosemide
• SO2NH2 group at position 5 is prerequisite for activity, must be
free.
• The 2-or 3-amino group is required for good diuretic activity.
• Substitution at 1st position must be acidic for good diuretic
activity.
• The activating group at 4th position can be Cl or CF3 group
increases the activity.
Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted
at 4th
position decreases diuretic activity to some extent.
Advanced
MedChem,Alemu T.
• Furfuryl, benzyl and thienyl methyl group at 2-position
increases the activity.

Advanced
MedChem,Alemu T.
 SAR of Thiazides diuretics

electron withdrawing
group is necessary: saturation leads to 10x
CF3 > Cl >> H >>> CH3 increase in activity
or OCH3
lipophilic group at 3
increases potency and
duration: haloalkyl,
aralkyl, thioether
More lipid soluble leads
to longer
duration

The sulfamoyl group in leads to

the 7 position is little or no activity
essential …except for Quinethazone
replacement of sulfonamide [Hydromax]
Advanced
MedChem,Alemu T.
which has C=O substitution acidic proton: allows
with C2H5 at 3
formation of water-soluble
Na+ salt for IV delivery

Advanced
MedChem,Alemu T.
 ACE inhibitors and Angiotensin II Receptor
Antagonists

HS N
Excellent activity
but not orally
available… (poor
O
OH permeability or
O O limited residence
times)
N

N OH
H O
Captopril HO O

Enalaprilate

Excellent activity
and orally
available… Requires
N de-esterification
O hence may not be
N effective in hepatic
H O
C2H5O O
Advanced
MedChem,Alemu T.
 OH
compromised patients

Enalapril (Vasotec, Enacard)

Advanced
MedChem,Alemu T.
 Addition of this group
leads to better
bioavailability, hence
NH2
no need for
esterification

N
O
N OH
H O
O
HO

Lisinopril (Zestril, Prinivil)

Larger (hydrophobic) group is
tolerated here with similar
activity.

H
O OH O
C 2H 5O

N
O
N

HOOC
Ramapril
Advanced
(Altace)
 Other ACE
inhibitors are
similar:
Indolapril

HOO N
C N

HOOC
Ramapril
Advanced
(Altace)
 Structure Activity Relationship
• The N-ring must contain a carboxylic acid to mimic the C-
terminal carboxylate of ACE substrates.
• Large hydrophobic heterocyclic rings in the ~N-ring
increase potency and alter pharmacokinetic
parameters.
• The sulfhydryl group shows superior binding to zinc
(Phe in carboxylate and phosphinic acid side chain
compensates for sulfhydryl group).
• Sulfhydryl-containing compounds produce high
incidence of skin rash and taste disturbances
• Sulfhydryl-containing compounds can form disulfides,
which may shorten duration of action.
• Binding to zinc through either a carboxylate or phosphinate
mimics
the peptide hydrolysis transition state.
Advanced
MedChem,Alemu T.
• Esterification of the carboxylate or phosphinate produces
an orally bioavailable prodrug.

Advanced
MedChem,Alemu T.
 Antianginal Drugs

• The word ‘angina’ derived form the Greek verb

meaning to choke and associated with sudden,
sever chest pain and discomfort. Angina occurs
when the blood supply to the heart is not able
to meet the metabolic demands of the heart for
oxygen.
• Angina pectoris, or ischemic heart diseases, is
the name to the symptomatic oppressive pain
resulting from myocardial ischemia.
• This usually happens when there is imbalance
between the myocardial oxygen demand and
supply.
Advanced
MedChem,Alemu T.
Etiology
• A decreased oxygen supply from anemia,
hypotension, vasospasm, or arrhythmias or
• An increase in oxygen demand secondary to
exercise, emotional stress, CHF, hypertension,
tachycardia, sepsis, can lead to a worsening of
symptoms.
• Goal of Antianginal Drugs: to restore balance
Advanced
MedChem,Alemu T.
between Myocardial O2 Demand and Supply

Advanced
MedChem,Alemu T.
 Classification of Anti-anginal Drugs

• There are four classes of agents that relieve

anginal pain:
1. Organo Nitrates and nitrites
2. Calcium Channel Blockers
3. β-Adrenergic Antagonist
4. Coronary Vasodilators: e.g.
Dipyridamol, Cyclandelate,
Papaverine.

Advanced
MedChem,Alemu T.
 I. Organic Nitrates/nitrites
• results in decreased oxygen demand and better perfusion
of deeper layers of the myocardial tissue, reduce preload,
afterload, vasodilate coronary arteries, inhibit platelet
aggregation -
O O
N + +
N N -
O O O O O
O
O- O
+
N
Amyl nitrate (inhalent,
USP) O

O H
+ O O
Nitroglycerin (Nitro-bid, Deponit,
Nitro-
N
-
O dur, Nitrogar
O
-
d) O
-

+ + +
O N O N N O
O O-
O H O O
- -
Isosorbide dinitrate (Iso-bid, Sorbitrate, O O
Novosorbide, Isordil, Dilatrate) + O O
+
N
N
- -
O O O O
+ +
N
O
N
O Erythrityl tetranitrate (Cardilate)
O O

O O
O +
O
N +
N
-
O -
O Pentaerythritol tetranitrate (Duotrate,
Pentylan, Peritrate) Advanced MedChem,Alemu
T.
 II. Ca2+ channel blockers
• Four chemically distinct classes of calcium channel
blockers are currently used to treat angina
1. Phenylalkylamines: Verapamil (Calan)
2. Benzothiazipines: Diltiazem (Cardizem)
3. Dihydropyridines: Nifedipine (Procardia), nimodipine
(Nimotop),
nicardipine (Cardene)
4. Diarylaminopropylamine ethers: Bepridil (Vascor)
The desired therapeutic effects of CCBs in treating angina
are to:
– Reduce myocardial oxygen consumption by reducing
afterload ,reducing heart rate and contractility
(except for the dihydropyridines which have minimal
effects on contractility)
– Improve oxygen delivery to ischemic
myocardium by vasodilating coronary arteries
and by reducing heart rate (increased time spent
in diastole)

Advanced MedChem,Alemu T.
• Prevention of Ca2+ influx into myocardial cells may prevent angina.
• Clinically used as antianginal, antiarrhythmic and antihypertensive
agents

O
+
N
-
O
R1
O
O
O O
R2
O O N
O O
R3
N
H N
H

R1 = NO2 R2 = CH3 R3 = H Nifedipine

Nicardipine (Cardene)
R1 = Cl R2 = C2H5 R3 = O(CH2)2-NH2 Amlodipine

H N

S
H
O N
OH
N N
O
O O
N O

N Diltiazem (Cardizem)
 O

Bepridil
(Vascor) Verapamil Advanced
MedChem,Alemu T.
(Calan,
Isoptin)
Newer
agent
 3. β –blockers CH3
CH3

O N
O N H CH3
H OH
OH CH3

O NH

OH NH2 O
CH3
O
Metoprolol
Propranol Atenolol
ol
• Decreasing of power and frequency of heart contractions and
cardiac need in oxygen
• Decreasing of thrombocyte aggregation and prevention of
thrombus formation
• Increasing of
diastole duration – improvement of coronary vessels HO OH
saturation with blood – improvement of perfusion of ischemic areas N
of myocardium
N N

4. Other Antianginal Drugs (Coronary VDs)

OH N N
N
H3CO N
+ H HO OH
N N NO N Dipyridamol
O H3CO
2
H O
OCH3
Nicotinyl alcohol Nicorandil
Advanced Papaverine OCH3
MedChem,Alemu T.
 Anti-arrhythmic drugs

• Arrhythmia is a condition in which the heart beats

with an irregular or abnormal rhythm.
• The heart may beat too slowly (bradycardia),too
quickly
(tachycardia) or in an irregular way.
• Certain disease and the effect of some drugs are
usually responsible affecting the rhythm and the
normal heart rate.
• Antiarrhythmic drugs may be defined as drugs that
are capable of reverting any irregular cardiac
rhythm or rate to normal.
Advanced
MedChem,Alemu T.
• Antiarrhythmic agents are also termed as
antidysrhythmic drugs or antifibrillatory drugs.

Advanced
MedChem,Alemu T.
• Antiarrhthmia drugs are classified in to four
categories based on their effect on the cardiac
action potential
 Class I: (sodium channels blockers) local anesthetics
acting on nerve and myocardial membranes to slow
conduction. Decrease maximal rate of depolarization
without changing resting potential
 Class II: (-adrenergic receptor blocking agents)
block the role of the sympathetic nervous system
which will generate arrythmias. They work by
blocking the impulse that may cause an irregular
heart rhythm
 Class III: (potassium channels blockers): slow the
electrical impulses in the heart by blocking the
potassium channels
Advanced
MedChem,Alemu T.
 Class IV: (calcium channel blockers) selective
blockage of the slow inward current of Ca2+.
Effective for supraventricular arrythmias

Advanced
MedChem,Alemu T.
 Class-I Antiarrhythmic Drugs:

• They are called membrane stabilizing (depressant)

drugs, act on sodium channels and block the
depolarizing inward Na+ current.

• According to the rate of dissociation from the sodium

channels, (action potential) Class-I drugs could be
subdivided into:

– Class-IA (intermediate rate of dissociation), AP

MedChem,Alemu T.

duration
Advanced

– Class-IB (rapid rate of dissociation),decrease AP

duration
– Class-IC (slow rate of dissociation) no effect on AP
duration
 Class I (Sodium channels blockers)
Quinidine (cardioquin, cin-quin, duraquin, quinora)
• acute and long-term treatment of
ventricular and supraventricular
arrhythmias (supraventricular
tachycardia)
• found in Cinchona bark, close relative of quinine
(diastereomers)
• alkaline, hence always used in water-soluble salt
forms
• use of IV quinidine is rare (as gluconate salt)
• common contaminant, dihydroquinidine is more
potent and more toxic
HO
H N

O H
N Advanced MedChem,Alemu T.
 Procainamide (procan, promine, pronestyl,
rhythmin)
• noticed that procaine, a local anesthetic, when
given by IV gave pronounced, but short lived
antiarrhythmia effects. Problem, it is toxic (CNS)
and IV only
• similar activity to quinidine; may be effective in
patients unresponsive to quinidine
• isosteric replacement of ester with an amide: oral,
resistant to plasma esterases and chemical
hydrolysis
• acetylated metabolite is also active (~1/3 of
initial dose is converted to this form)
O

H2N

NH
 N

Advanced MedChem,Alemu T.
Disopyramide (norpace)
• orally active, used for treatment of certain
ventricular and atrial arrythmias (maintenance of
sinus rhythm in patients with atrial flutter or atrial
fibrulation, prevention of recurrent ventricular
fibrulation or ventricular
O
tachycardia)
NH2

N
Advanced MedChem,Alemu T.
 Lidocaine (baylocaine, LidoPen, xylocaine)
• similar to procaine in terms of local anesthetic
effects, way different in terms of cardiac…
• drug of choice for emergency room
treatment of ventricular arrythmias
• very rapid onset upon IV infusion (only
effective parenterally)
• Bind preferentially to the inactivated Na+ channel

N
HN

Advanced MedChem,Alemu T.
 Tocainide (tonocard)
 -methyl analogue structurally related to monoethylglycinexylide
•in contrast to lidocaine, is orally active
•used for ventricular arrhythmias
 -methyl slows metabolism
Mexiletine (Mexitil)
•good oral availability, similar to tocainide and lidocaine in activity
•Bind preferentially to the inactivated Na+ channel
Phenytoin (dilantin, diphenylhydantoin)
•used for many years as treatment for epileptic seizures
•used for atrial and ventricular arrhythmias resulting from
digitalis toxicity (although not officially approved for this use)

H H2N
MedChem,Alemu T.

2N O

O
NH
Advanced

HN O

N
H O
Tocainide Mexiletine Phenytoin
 Flecainide (Tambocor)
• relatively new, used for treatment of
ventricular arrhythmias
• orally available
• may be more effective than
quinidine or disopyramide
CF3

F 2C
O O
MedChem,Alemu T.

H
N
NH
Advanced

O
CF2
C

3
 Class II ( adrenergic blockers)
Propranolol (Inderal, Ipran, Betachron)
• andrenergic -receptor blocker
• supraventricular arrhythmias
• digitalis induced ventricular arrhythmias
• may be better in combination (quinidine) for
treatment of
atrial fibrulation
Sotalol (Betapace, OH

Sotacor) O
NH

S NH
O

Sotalol
OH H
O NH O
O O

OH
Propranolol
Esmolol
Advanced
MedChem,Alemu T.
 Class III (Potassium channels blockers)
Bretylium Tosylate (Bretytol)
• quaternary ammonium salt derivative, IV or IM
• limited antiarrhythmic use to emergency, life-
threatening, conditions where lidocaine,
procainamide have failed
• developed for use as antihypertensive
Amiodarone (Cordarone)
• antianginal agent (coronary vasodilator)
• approved by FDA for treatment of life-threatening
ventricular
arrhythmias refractory to other drugs
I
O
Br
O
+ -O
N S N
O I
 O O

Bretylium toxylate Amiodarone

Advanced
MedChem,Alemu T.
 Class IV (Calcium channel blockers)
• These are the cardio selective CCBs namely
Verapamil and Diltiazem they decrease the
conduction velocity and increase the refractory
period
Verapamil (Valan, Isoptin)
• supraventricular arrhythmias, coronary vasodilator
N OCH3

C
O N O
S
O C
CH3
O
O N
O
O

Advanced
Verapamil N
CH3 Diltiazem
H

Advanced
 Antihypertensives
• Hypertension or High Blood Pressure is the name of
a pathological condition in which blood pressure is
persistently elevated (i.e. it stays high for a long
period of time).
• The blood pressure is a measurement of the pressure
of the blood against the blood vessel walls. The
persistent high blood pressure puts undue stress on
the heart, blood vessels and other organs. In fact,
hypertension is a major public health problem of
largely unknown cause.
• The people suffering from this disorder are not only
at high risk of abnormally elevated blood pressure,
but also they gradually come under the
phenomena of secondary complications that may
produce other vital-organ diseases.
Advanced
• It is single contributing factor and responsible for
producing a number of Cardio-Vascular Diseases
(CVD), which causes morbidity and premature
deaths.

Advanced
• According to a study, it affects 25% of most adult
populations and is an important risk factor for
death from stroke, myocardial infraction (MI),
congestive heart failure (CHF) and renal failure.
• If, it is left untreated, hypertensive people may be
further sufferer of more heart problems, kidney
disease and stroke.
• Systolic Blood Pressure (SBP): When the heart
contracts to pump out blood, pressure is highest.
This measurement is called the systolic pressure.
• Diastolic Blood Pressure (DBP): After pumping,
the heart relaxes and pressure drops to its lowest
point just before new beat starts. This
measurement is called the diastolic pressure.
Advanced MedChem,Alemu T.
• According to WHO, the systolic and diastolic blood
pressure in normal adult is equal to or below 140 mm
Hg and 90 mm Hg.
• Hypertension: Systolic BP ≥ 140 mm Hg and/or diastolic
BP ≥
90 mm Hg
• Hypotension: Systolic BP < 90 mmHg and/or diastolic BP
< 60

Blood Pressure (mm-Hg)

Classification Systolic Diastolic

Normal <120 <80

Pre-hypertension 120-139 80-89

Advanced
Hypertension, 140-159 90-99
stage 1
Hypertension, ≥160 ≤100
stage 2

Advanced
1. Diuretics

Triamterene

Furosemide

Hydrochlorothiazide

Spironolactone
Amiloride
Advanced
2. Angiotensin-converting Enzyme (ACE) inhibitors

Ramipril
Captopril
Lisinopril

HOOC

COOC2H5 O
H H
CH2CH2CH N C C N

CH3

Enalapril Fosinopril
Advanced
3. Centrally acting α-2 agonists
OH Cl
Cl
NH2 O NH
H
N H2
HOOC C OH
N CH2CNHCNH2
CH3
N
H
Cl Cl

Methyldopa
Clonidine Guanfacine

4. Angiotensin (AT1) blockers

COOH
CH3
CH2OH CH
Cl C
N NH N CH3
H2 O
N NH C N N N
H2
N N Valsartan
CH2CH2CH2CH3

Losartan Advanced
CH2CH2CH2CH3

Losartan Advanced
5. ß-adrenergic blockers: CH3

O N CH3
HO
OH H
O NH
O NH
OH

H2N NH2
HO
O
Propranolol Labetolol
Atenolol
NHC(CH3)3

O
NHC(CH3)3
OH
O

N
O N HO OH

N S

Timolol HO Advanced
MedChem,Alemu T.
Nadolol
 6. α-1 adrenergic blockers

O
O

O
O N
N
O N N
O N N

N
N
O
O

NH2
NH2

Terazosin
Prazosin
O
MedChem,Alemu T.

O
N

O N N
O
Advanced

N
O

NH2

Doxazosin
7. Calcium Channel Blockers (CCB) N

H O N
S
R1
H O
O O
OH O
R2
N O O Verapamil
O
O
R3
N
H
N

Diltiazem R1 = NO2 R2 = CH3 R3 = H Nifedipine

(Cardizem) R1 = Cl R2 = C2H5 R3 = O(CH2)2-NH2 Amlodipine

8. Agents Depleting Neurotransmitter Stores

OCH3
O
N
C OCH3 NH
O
H3CO N
H OCH3 N CH2CH 2NHCNH 2

H3COOC OCH3

Advanced
Reserpine Guanethidine

Advanced
9. K+ Channel activators

Diazoxide
Minoxidil
10. Vasodilators

Na2[Fe(CN)5NO]

Sodium Nitroprusside
Hydralazine
Advanced
 Anticoagulants
• The blood circulatory system has to be self-
sealing, otherwise continued blood loss from
even the smallest injury would be life
threatening
• Anti-coagulants are molecules that
prevent blood from clotting.
• They are used in the treatment and
prophylaxis of thrombo-embolic occlusive
vascular diseases such as venous
thrombosis, pulmonary embolism and
cardiac infarction due to thrombosis of a
coronary artery.
• Heparin can cause haemorrhage as a
Advanced
consequence of its action this can be blocked
by using protamine sulfate/hydrochloride

Advanced
 • Heparin is a strongly acidic, high molecular
weight mucopolysaccharide that possesses rapid
anticoagulant effect.

• Warfarin Sodium is a white, odourless, crystalline

powder with a slightly bitter taste. it is slightly
soluble in chloroform and soluble in alcohol or
MedChem,Alemu T.

water.
O
Advanced

ONa
• Taking warfarin as a prototype a number of
derivatives of 4-hydroxycoumarin were
prepared 3 and 4’-positions have been
substituted by different substituents.
O

OH

NO2

O O

Phenprocoumon
Acenocoumarol
O

Anisindione Dicoumarol
Advanced MedChem,Alemu T.
 Anti-hyperlipidemic Agents
• The pharmacological agents which reduce the concentration
of plasma lipids are called hypocholesterolemic agents or
antihyperlipidemic agents or lipid lowering agents.
• An increase in plasma lipids, particularly cholesterol, is a
common feature of atherosclerosis, a condition involving
arterial damage, which may lead to ischemic heart diseases,
myocardial infarction and cerebral vascular accidents.
• These conditions are responsible for one third of all deaths
from disease in industrial nations.
• Lipids are insoluble in water, and they are transported in
the plasma as lipoproteins.
• An increase in the plasma concentration of these substances
is termed hyperlipidemia (or hyperlipoproteinaeinia).
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MedChem,Alemu T.
There are five main classes of lipoprotein, differing in the relative
proportion of the core lipids and in the type of apoprotein.
i. Chylomicrons: carry triglycerides (fat) from the intestine to
the liver, to skeletal muscle, and to adipose tissue
ii. High Density Lipoproteins (HDL): collects fat molecules
(phospholipids, cholestrole,triglycerides, etc) from the
body’s cells/tissues and take it back to the liver
iii. Very low density lipoproteins (VLDL): carry (newly
synthesized) triglycerides from the liver to adipose
tissue
iv. Intermediate density lipoproteins (IDL): are intermediate
between VLDL and LDL
v. Low Density Lipoproteins (LDL): carry fat molecules
(phospolipids, cholestrole, triglycerides, etc ) around the body.
They are reffered to as bad lipoproteins because
Advanced
MedChem,Alemu T.
concentrations, dose related, correlate with atherosclerosis
progression

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MedChem,Alemu T.
 Classification of antihyperlipidemic agents
1. HMG CoA-reductase Inhibitors:-A new class of
fungal derived compounds are potent inhibitors of
the enzyme β- Hydro-β-Methyl-Glutaryl-CoA
reductase (HMG-CoA reductase) and includes
compactin and mevinolin. This enzyme is the rate
determinig step in the endogenous synthesis of
cholesterol.
The lactone and bicyclic rings
as well as the ethylene bridge
between them responsible for
the activity

Lovastatin R1= CH3 R2= H

Simavastatin R1= CH3 R2=CH3
Advanced Fluvastatin
2. Fibric Acid Derivatives The isobutyric acid group is
essential for activity
Substitution at the para position
CH3 of the aromatic ring with a
chlorine or chlorine containing
ring increase half-lives
Cl O C COOC2H5
O_____________________ CH3
CH3 O C COOCH(CH3)2
C
Cl
Clorfibrate
CH3

3. Bile Acid Sequestrants Finofibrate

Are the example of bile-acid binding resigns

Colestipol
Cholestyramine
Advanced MedChem,Alemu T.
4. Inhibition of LDL oxidation

Probucol

5. Miscellaneous Agents
H3C
CH3

CH3
CH3

CH3

HO

Nicotinic acid

-Sitosterol D-Thyroxine

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