Cardiovascular Drugs

By Frehiwot Beyene
1
 Introduction
Cardiovascular diseases (CVD) are conditions that include
diseased vessels, structural problems and blood clots.
These include:-
1. Coronary heart disease (CAD)
2. High blood pressure (hypertension)
3. Cardiac arrest
4. Heart failure
5. Arrhythmia
6. Stroke
7. Congenital heart disease 2
 Cardiovascular Drugs

 Cardiovascular drugs generally exert their action on the

heart or blood vessels in a direct or indirect manner
thereby affecting the distribution of blood to certain
specified portions of the circulatory system.

 The following class of drugs are used in the treatment of

angina, hypertension, heart failure, cardiac arrhythmias,
hyperlipidemia and disorders of blood coagulation

3
Cardiovascular Drugs…..

1) Antianginal agents and vasodilators

2) Anti-hypertensive agents
3) Drugs in treatment of congestive heart failure
4) Antiarrhythmic drugs
5) Antihyperlipidemic drugs
6) Coagulants & anticoagulants

4
 A. Antianginal agents and
vasodilators

What is angina?
Angina literally means “chocking pain”.
 Angina pectoris means chest pain or discomfort caused
when the heart muscle doesn't get enough oxygen-rich
blood.
 It is due to obstruction of the coronary arteries (the heart's
blood vessels).
 So there is imbalance between oxygen supply and utilization
 The patients may feel pressure or squeezing in the chest.
The discomfort radiate your shoulders, arms, neck, jaw, or
back.
 if the ischemia is not treated it cause myocardial infarction
& death. 5
 Major cause of angina are:
Coronary artery disease (CAD)
Coronary artery spasm (CAS)
 Coronary artery disease develops when one or
more of the coronary arteries that supply blood
to the heart become narrowed that is due to
build up of cholesterol & other substance in the
wall of artery affecting the blood flow to the
heart.

6
 Types of angina

1. Stable angina

Result from a fixed obstruction of blood flow to the
heart
Angina attack occur when the heart doing much
work, during physical exercise , emotion or eating
When there is no enough supply of blood for fast
pumping heart 7
 Types of angina….
2. Unstable Angina
 Occurs due to sudden interruption of blood flow to the heart
 Because of partial or complete blockade of the arteries
 Result from rupture of plaque which triggers thrombus
formation
 Can occur when a person is at resting, sleep or under physical
exertion
 It’s very dangerous as it may quickly progress into myocardial
infarction (MI)
 MI-is the death of heart muscle tissue resulting from
obstruction of the blood supply to the heart muscle
8
 Types of angina….
3. Variant angina pectoris (vasospatic angina)

 Caused by Coronary artery spasm (CAS), which restricts

blood flow to myocardium.

 In contrast to classic angina (stable angina) whose

symptoms occur at a time of exertion, variant angina
can cause pain at any time, even during rest and sleep

 Oxygen delivery decrease as a result of reversible

coronary vasospasm 9
Coronary artery disease Vs Coronary artery spasm

10
Antianginal agents and vasodilators….
 Antianginal drugs may relieve attacks of acute myocardial
ischemia by
Increasing myocardial oxygen supply or
Decreasing myocardial oxygen demand or both

 The main goals of Rx in angina pectoris are to

relieve the symptoms
Slow the progression of disease, and
Reduce the possibility of future events, especially MI and
premature death 11
 Antianginal agents and vasodilators….

 Three groups of pharmacological agents:

A. Organic nitrates
B. Adrenoceptor antagonists and
C. Calcium channel blockers (CCBs)
 Organic nitrates & CCBs are indicated in spasmatic and
chronic stable angina, while β-adrenergic antagonists
are primarily for exertion-induced angina
 Anti-anginal agents mainly alleviate the pain
by reducing the oxygen requirements of the heart 12
 A. Organic nitrates
Organic nitrates are esters of simple organic
alcohols or polyols with nitric acid
Organic nitrates are also called nitrovasodilators
-
O O
+ +
N N
-
O O O O
-
O O
+
N

13
 The prototype of Organic nitrates is nitroglycerin
 These agents are solid at room temperature
 All organic nitrates are very lipid soluble
MoA of Organic nitrates
 They act by the formation of free radical nitric oxide (NO), which
interact with and activate guanylate cyclase, an enzyme that
produces cGMP
 Increase in the concentration of cGMP, in turn, activates protein kinases
that phosphorylate MLCK (myosin light chain kinase)
 Thus, preventing the phosphorylation of myosin and resulting in muscle
relaxation
 Muscle relaxation, or vasodilation, results in reduced workload for the
heart, thus easing anginal pain
14
 MOA
Administered Nitrates (NO3-)

Nitrites (NO2-)

Nitric oxide (No)

GTP cGMP
cGMP cause dephosphorylation of myocin light kinases,
which resulting in vascular smooth muscle relaxation

Vasodilatation in coronary artery increased blood supply

15
B. Beta-Adrenergic blocking agents
• Their use as antiaginal agent is limited to the treatment of
exertion-induced angina. Propranolol is a prototype drug in
this class.

• MoA: reduces the heart rate and decreases myocardial

contractibility and decrease the oxygen demands of the
myocardium.

16
 C. calcium channel blockers (CCBs)
Three classes of CCBs are approved for use in the
prophylactic treatment of angina
1) The dihydropyridines
E.g. Nifedipine, nimodipine, and amlodipine
2) The benzothiazepine derivatives
E.g. Diltiazem
3) Aryl alkyl amine derivatives
E.g. Verapamil

17
 C. calcium channel blockers (CCBs) …
The desired therapeutic effects of CCBs in treating angina are to:

– Reduce myocardial oxygen consumption by reducing afterload ,reducing

heart rate and contractility

– Improve oxygen delivery to ischemic myocardium by vasodilating

coronary arteries and by reducing heart rate

 MoA: Prevention of Ca2+ influx into myocardial cells

may prevent angina.

18
A. 1, 4- dihydropyridines (DHPs)
 act on the coronary arteries and vasodilators.

19
 B. Non-dihydropyridines (benzothiazepine & aryl
alkyl amine)
 have negative inotropic effect on the heart
muscle.
H N

S
H
O N

OH
N
O O
O

O
N

Diltiazem Verapamil 20
B. Antihypertensives
Hypertension is a pathological condition in which
blood pressure is persistently elevated.
Blood Pressure is 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
Nowadays, hypertension is a major public health
problem of largely unknown cause 21
• 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.
22
• 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

Hypertension, stage 1 140-159 90-99

Hypertension, stage 2 ≥160 ≤100

23
 Classification of Antihypertensive agents

Antihypertensives are those agents which are

used to reduce high blood pressure
• They are classified as:
1) Diuretics
2) Agents Acting on Renin-angiotensin system
3) vasodilators
4) Adrenoceptor Blocking Agents

24
1. Diuretics

Triamterene

Furosemide

Hydrochlorothiazide

Spironolactone
Amiloride 25
2. Agents Acting on Renin-angiotensin-aldosterone
system (RAAS)

A. Angiotensin converting enzyme inhibitors (ACEI) Angiotensin

converting enzyme (ACE) is a member of a group of enzymes
called the zinc metallopeptidases

• It catalyses the hydrolysis of a dipeptide fragment from the

end of angiotensin I to give angiotensin II

• Angiotensin II is an important hormone that causes blood

vessels to constrict, resulting in a rise in blood pressure
26
27
ACE Inhibitors, based on the Zn2+ binding groups
1. Sulphydral containing inhibitors: Captopril
2. Dicarboxylate containing inhibitors:
Enalapril, Lisinopril, Ramipril, Quinapril,
Perindropril
3. Phosphate containing inhibitors: Fosinpril

Abera D.D. 28
• Captopril is the first to be discovered as ACEI drug.
• It is Sulfhydryl-containing antihypertensive agent.
• -SH group enhance binding to Zn2+ In the ACE
• Sulfhydryl Produce high incidence of skin rash and
taste disturbances

29
 SAR of ACEI
O
CH2 Zn2+ C
n N ring
X

Zn2+ Binding groups are

CHOOH OH
HS-CH2- P
-CH NH2
O
Thiol Carboxylate Phosphate

A B C

 The N-ring should be large hydrophobic rings b/s it increase

the potency by altering pharmacokinetic parameters
The N-ring must contain carboxylic acid
30
 SAR of ACEI…….

The A, B, C( thiol, COOH, PO4-3 )groups can serve as Zn+2

binding sites
This binding is important for activity
The thiol group shows superior binding to Zn2+ among
the carboxylate and phosphate.
Estrification of carboxylate (B) and phosphate (C)
produces orally active products
 The X should be –CH3
The n usually 2 (ethyl) for activity
31
2. Angiotensin-converting Enzyme (ACE) inhibitors…..
O
COOH
H H
CH2 C N C C N
2 H C4H8NN2
HOOC
Lisinopril

O
COOC2H5
H H
CH2 N
2
C C C N
Fosinopril
H CH3
HOOC
Enalapril

O
COOC2H5
H H
CH2 C N C C N
2 H CH3
HOOC
Quinapril Ramipril

32
B. Angiotensin Receptor Blockers (ARBs):

Mechanism of action :
Block AT1 receptors.

But But
CH3
Aldoserone production N O

N Cl N CH CH3
Na reabsorption
CH2OH COOH
Blood volume
N NH N NH
Cardiac output N
N
N
N

BP

Losartan Valsartan
33
 ARBs…
• Advantages over ACEI :
 They have no effect on bradykinin system: No cough,
– wheezing or angioedema.
 Complete inhibition of angiotensin action compared
with ACEI
– Side Effects: are similar to ACEIs but with no cough
and
– Angioedema.

34
 3) vasodilators
A) calcium channel Blockers
B) potassium channel openers
C) Sodium Nitroprusside

35
 A. Ca2+ channel blockers
1,4- dihydropyrimidines (DHPs)
Amlodipine
Nifedipine
Felodipine
Nicardipine
Benzothiazepines
Diltiazem
Phenylalkylamines
Verapamil

36
 B. Potassium Channel Openers

i) Minoxidil

ii) Diazoxide

37
 MOA
Potassium Channel Activators combines with ATP
modulated Potassium Channel (Smooth Muscle)

Opening of Potassium Channel

Efflux of Potassium

Hyperpolarization of Smooth Muscle

Vasodilatation

Decrease PVR Decrease BP 38

A. Minoxidil: Arterial Vasodilator
B. Diazoxide: Employed exclusively for
emergency reduction of BP
Minoxidil

Diazoxide

39
 C. Sodium Nitroprusside
It is a short-acting hypotensive agent.
It is mostly employed as a vasodilator in the
emergency treatment of hypertensive crises
that normally do not respond to other
antihypertensive measures.
CN
CN

NC Fe 2Na+
ON CN
CN

40
 4) Adrenoceptor Blocking Agents
A. Centrally acting α-2 agonists
B. ß-adrenergic blockers
C. α-1 adrenergic blockers

41
A. Centrally acting α-2 agonists
OH Cl
Cl NH2 O NH
H H2
N HOOC C OH
CH2CNHCNH2
N
CH3
N
H
Cl Cl
Methyldopa
Guanfacine
Clonidine

42
B. 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

HO
Timolol
Nadolol
43
C. 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

O
N

O N N
O

N
O

NH2

Doxazosin 44
 C. Drugs Used for Treatment of Congestive Heart
Failure (CHF)
Congested cardiac failure is inability of the heart
to pump blood effectively at a rate that meets the
needs of metabolizing tissues.
This is a direct result of a reduced contractility of
the cardiac muscles, especially those of the
ventricles which causes a decrease in cardiac output
1. Cardiac glycosides
• They are an important class of naturally occurring
drugs available to treat CHF
45
 MoA of Cardiac glycosides
 Cardiac glycosides (digitalis) exert positive inotropic
effect on heart
At the cellular level, digitalis inhibits membrane
bound Na+/K+-activated adenosine triphosphatase
 This inhibition increases intracellular Na+
 This Na+ in turn exchanges with extracellular Ca++, thus
increasing intracellular Ca2+ levels
Inhibition of the enzyme also decreases outward pumping of
Na+
The net effect is an increase in the Ca++ pool available for
excitation-contraction coupling
46
Chemistry of the cardiac Glycosides
 Cardiac glycosides and similar other glycosides are composed of two
portions (sugar and aglycone)
 The aglycone portion of the cardiac glycosides is a steroid nucleus
with a unique set of fused rings, which makes these agents easily
distinguished from the other steroids

47
 Rings A–B and C-D are cis fused, while rings B-C have a trans
configuration
Such ring fusion gives the aglycone nucleus of cardiac glycosides the
characteristics “U shape”
 The steroid nucleus also carries, two methyl groups at C-10 and C–13
 Hydroxyl groups are located at C-3, the site of sugar attachment, and at C-14
 The C-14 hydroxyl is normally unsubstituted

48
 However additional hydroxyl groups are located at C–12
and C-16, the presence or absence of which distinguishes
the important genins:– Digitoxigenin, digoxigenin and
gitoxigenin
 The lactone ring at C–17 is another major structural feature
of the cardiac aglycones

49
 Sugars
 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
 The most commonly found sugars in the cardiac glycosides
are
D-glucose, D-digitoxose, D-rhamnose, and D-cymarose
 These sugars predominantly exist in cardiac glycosides in
the β-conformation

50
 The cardiac glycosides are composed of two
structural features; the sugar (glycoside) and the
non-sugar (aglycon) moieties.

51
 O

CH3

CH3 H

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

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

O
Digitoxin (Digitoxinum) O
OH

CH3
O
O OH
Digoxin (Digoxinum)
OH

OH

 Digoxin and digitoxin are the two cardiac glycosides most frequently
used nowadays.

52
 SAR of Cardiac Glycoside
The importance of steroid nucleolus
 The 14- β-hydroxyl and 17- unsaturated lactone are important
for activity
The 17-lactone ring is important for drug– receptor
interaction

53
2.  1-andrenergic agonists: dobutamine
•Lot’s of 1 andrenergic receptors in myocardium mechanism
involves simulation of adenylate cyclase and increased cAMP
levels leading to increased Ca2+ levels
OH

HO NH

HO

Dobutamine

54
 3. diuretics, vasodilators
Diuretics reduce the edema (extracellular fluid volume) and
ventricular filling pressures (“preload”) without reducing CO
1. loop diuretics: inhibit a specific Na+-K+-Cl—symporter (advanced
heart failure)
2. thiazide diuretics (in mild heart failure)
3. K+ sparing diuretics (not useful as single diuretic agent) prevent
renal K+ and Mg2+ wasting.

Furosemide Torsemide Bumetanide

(Lasix) Abera D.D.
(Demadex) (Bumex) 55
 4. ACE inhibitors
ACEIs have a very good cardioprotective capacity and reduce the progression of
cardiomegaly

HS N Enalaprilate has excellent

N activity but not orally
O O
OH
available…
OH N
O H O (poor permeability or limited
HO O
residence times)
Captopril Enalaprilate

Enalapril has excellent activity and orally available…

Requires de-esterification hence may not be effective in
hepatic compromised patients
N
O
N OH
H O
C2H5O O

Enalapril 56
D. 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.
• Antiarrhythmic agents are also termed as antidysrhythmic
drugs or antifibrillatory drugs.
57
• 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

58
 Class III: (potassium channels blockers): slow the
electrical impulses in the heart by blocking the
potassium channels

 Class IV: (calcium channel blockers) selective

blockage of the slow inward current of Ca2+.
Effective for supraventricular arrythmias

59
 Class I (Sodium channels blockers)
Quinidine
• acute and long-term treatment of ventricular and
supraventricular arrhythmias (supraventricular tachycardia)
• found in Cinchona bark, close relative of quinine
(diastereomers)

HO
H N

O H

60
Procainamide
• 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

H2N

NH

61
Disopyramide

• 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 tachycardia)

62
Lidocaine
• 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

63
 Class II ( adrenergic blockers)
Propranolol
• andrenergic -receptor blocker
• supraventricular arrhythmias
• digitalis induced ventricular arrhythmias
• may be better in combination (quinidine) for treatment of atrial
fibrulation
OH
Sotalol
NH
O
S NH
O

Sotalol
OH H
O NH O
O O

OH

Propranolol Esmolol 64
 Class III (Potassium channels blockers)
Amiodarone
• antianginal agent (coronary vasodilator)
• approved by FDA for treatment of life-threatening ventricular
arrhythmias refractory to other drugs

I
O

I
O

Amiodarone

65
 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.

OCH3
N

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

N
Verapamil CH3 Diltiazem
H
66
E. 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.

67
• Heparin is a strongly acidic, high molecular weight
mucopolysaccharide that possesses rapid anticoagulant effect.

• Warfarin Sodium is the an other anticoagulant agent which used to

treat blood clotting.

ONa

O O 68
 F. 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.

69
 F. Anti-hyperlipidemic Agents...

• 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).

70
 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). 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
Pravastatin R1= OH R2=H 71
3. Bile Acid Sequestrants
 Are the example of bile-acid binding resins which used to bind
certain components of bile in the gastrointestinal tract.
 The Sequestrants prevent the reabsorption of the bile from the
gut.

Colestipol
Cholestyramine 72
4. Increase of LDL catabolism

Probucol

5. Miscellaneous Agents
H3C
CH3

CH3
CH3

CH3

HO

Nicotinic acid

-Sitosterol D-Thyroxine

73