Cardiovascular Agents

Cardiac Disorders
• Heart diseases can be primarily grouped
into three major disorders:
– Cardiac failure,
– Ischemia and
– Cardiac arrhythmia.

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•  Cardiac failure (CHF)
– Inability of the heart to pump blood effectively
at a rate that meets the needs of the
metabolizing tissues.
– This occurs when the muscles that perform
contraction and force the blood out of heart are
performing weakly.
– Thus cardiac failures primarily arise from the reduced
contractility of heart muscles, especially the
ventricles.

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 – Reduced contraction of heart leads to reduced heart
output but new blood keeps coming in resulting in the
increase in heart blood volume.
– The heart feels congested. Hence the term
congestive heart failure.
• Congested heart leads to lowered blood
pressure and poor renal blood flow.
– This results in the development of edema in
the lower extremities and the lung (pulmonary
edema) as well as renal failure.
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• Cardiac Glycosides
– Increasing the force of contraction of the heart
(positive inotropic activity) is very important
for most heart failure patients.
• Cardiac steroids are perhaps the most useful
drugs that increase heart contractility.
• The cardiac glycosides are an important class of
naturally occurring drugs whose actions include
both beneficial and toxic effects on the heart.

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• Cardiac steroids are widely used in the modern
treatment of CHF and for treatment of atrial
fibrillation and flutter.
• Yet their toxicity remains a serious problem.
• Structure
– Cardiac glycosides are composed of two
structural features :
• The sugar (glycoside) moiety
• The non-sugar (aglycone - steroid) moieties.

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• The R group at the 17-position defines the
class of cardiac glycoside.
• Two classes have been observed in
Nature –
– The cardenolides and the bufadienolides.
– The cardenolides have an unsaturated
butyrolactone ring while the bufadienolides
have an a-pyrone ring. 

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•  The aglycone moiety:
– The steroid nucleus has a unique set of fused
ring system that makes the aglycone moiety
structurally distinct from the other more
common steroid ring systems.
– Rings A/B and C/D are cis fused while rings
B/C are trans fused.
– Such ring fusion gives the aglycone nucleus of
cardiac glycosides the characteristic 'U' shape.

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• The steroid nucleus has hydroxyls at 3- and
14- positions of which the sugar attachment
uses the 3-OH group.
• 14-OH is normally unsubstituted.
• Many genins have OH groups at 12- and
16- positions.
– These additional hydroxyl groups influence the
partitioning of the cardiac glycosides into the
aqueous media and greatly affect the DOA.
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• The lactone moiety at C-17 position is an
important structural feature.
• The size and degree of unsaturation varies
with the source of the glycoside.
• Normally plant sources provide a 5-
membered unsaturated lactone while
animal sources give a 6-membered
unsaturated lactone.
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• Sugar moiety:
• One to four sugars are found to be present in
most cardiac glycosides attached to the 3b-OH
group.
• The sugars most commonly used include:
– L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-
digginose, D-sarmentose, L-vallarose, and D-fructose.
• These sugars predominantly exist in the cardiac
glycosides in the β-conformation.

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• The presence of acetyl group on the sugar
affects
– Lipophilic character and the kinetics of the entire
glycoside. 
• Because the order of sugars appears to have
little to do with biological activity
– Nature has synthesized a repertoire of numerous
cardiac glycosides with differing sugar skeleton
but relatively few aglycone structures.

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• Structure - Activity Relationships
– The sugar moiety appears to be
important only for the partitioning and
kinetics of action
– It possesses no biological activity.
• For example, elimination of the aglycone
moiety eliminates the activity of alleviating
symptoms associated with cardiac failure.

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 – The "backbone" U shape of the steroid nucleus
appears to be very important.
– Structures with C/D trans fusion are inactive.
– Conversion to A/B trans system leads to a marked
drop in activity.
• Thus, although not mandatory A/B cis fusion is important.
–  The 14 β -OH groups are now believed to be
dispensable.
• A skeleton without 14 β -OH group but retaining the C/D cis
ring fusion was found to retain activity.

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 – Lactones alone, when not attached to the steroid
skeleton, are not active.
• Thus the activity rests in the steroid skeleton.
–  The unsaturated 17-lactone plays an important
role in receptor binding.
• Saturation of the lactone ring dramatically reduced the
biological activity.
–  The lactone ring is not absolutely required.
• For example, using α,β-unsaturated nitrile (C=C-CN
group), the lactone could be replaced with little or no
loss in biological activity.

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•  Biochemical Mechanism of Action
– The mechanism whereby cardiac glycosides
cause a positive inotropic effect and
electrophysiologic changes is still not
completely clear.
– Several mechanisms have been proposed,
but the most widely accepted involves
• The ability of cardiac glycosides to inhibit the
membrane bound Na+-K+-ATPase pump
responsible for Na+-K+ exchange.

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• The process of membrane depolarization /
repolarization is controlled by the movement
of three cations
– Na+, Ca+2, and K+, in and out of the cell.
• At the resting stage, the concentration of
Na+ is high on the outside.
• On membrane depolarization sodium fluxes-
in leading to an immediate elevation of the
action potential.
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• Elevated intracellular Na+ triggers the influx of free
Ca++ that occurs more slowly.
– The higher intracellular [Ca++] results in the efflux of K+.
• The re-establishment of the action potential
occurs later by the reverse of the Na+-K+
exchange. 
• The Na+ / K+ exchange requires energy
which is provided by an enzyme Na+-K+-
ATPase.
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• Cardiac glycosides are proposed to inhibit this
enzyme with a net result of reduced sodium
exchange with potassium that leaves increased
intracellular Na+.
– This results in increased intracellular [Ca++].
• Elevated intracellular calcium concentration
triggers a series of intracellular biochemical
events that ultimately result in an increase in the
force of the myocardial contraction or a positive
inotropic effect.
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 Antianginal agents &
vasodilators
• Angina pectoris: is the principle
symptom of ischemic heart disease
– Caused by an imbalance between myocardial
oxygen demand and oxygen supply by
coronary vessels.
– Such an imbalance can result from increased
myocardial oxygen demand caused by
exercise, decreased myocardial oxygen
delivery, or both.

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• Angina pectoris is always associated with
sudden, severe chest pain and
discomfort, although some individuals do
not experience pain with ischemia.
• Thus, angina occurs because the blood
supply to the myocardium through
coronary vessels is insufficient to meet
the metabolic needs of the heart muscle
for oxygen
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• Goal of Antianginal Drugs: to restore
balance between Myocardial O2 Demand
and Supply

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Classes and MOA of Anti-anginal Drugs

Heart
Coronary Blood Flow 2, 3
Rate

1, 2, 4

OO2 OO2
2 2 2, 3
Supply = Demand Cardiac
Supply Demand Contractility

Regional Flow Distribution Myocardial Wall Tension

1, 2, 3 1, 2, 4

1. Organic nitrates 2. Calcium channel blockers

3. Beta-blockers 4. Vasodilators

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 Organic nitrates
• Nitrovasodilators were used in prophylaxis
& treatment of angina
– Their importance reduced due to the
introduction of
• Calcium channel blockers
-blockers
• But are still of choice for acute anginal
episodes

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• Nitroglycerin
– One of the first & still important member of the
group
  O2NO ONO2

ONO2

Glyceryl trinitrate

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 O2N O
O

NO
O O
O NO2
Isopentyl Nitrite Isosorbid dinitrate

• Nitrovasodilators
– Cause relaxation of vascular smooth muscle
by generating NO in situ

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 MOA of nitrovasodilators

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 Calcium channel blockers
– Introduced into clinical medicine in 1960’s
– Calcium is vital to
• Generation of nerve impulses
• Heart muscle contraction
– Stimulation of heart cell causes ion channel
activation
• Ca enters cell stimulating further Ca release from
within the cell
– This in turn initiates contraction

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 – All Ca antagonists are vasodilators
• Basis for use in
– Angina
– Hypertension
– Inhibition of Ca influx into cardiac tissue
• Basis for their use as antiarrhythmic agents

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• Three classes of Calcium Channels
Blockers (CCBs)
– Phenylalkylamines
– Benzothiazepines
– Dihydropyridines

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 Phenylalkylamines
• Verapamil
– A coronary vasodilator with Ca channel
blocking activity
– (-) form more potent
– Rapidly absorbed after oral administration
– Quickly metabolized in liver
• Has low bioavailability
CH3
O
H3C CH3
CN
H3CO N OCH3 N
N

H3CO Verapamil OCH3 Bepridil

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 Dihydropyridines
• Nifedipine
– Most potent of the group as a vasodilator
• Used to treat hypertension as well as angina
– Members have greater vascular
selectivity
• Less cardiac depression, for a given degree
of vasodilation

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 Dihydropyridines…
Cl
NO2
MeOOC COOMe Cl Cl
MeOOC COOEt MeOOC COOEt
N O
H N NH2 N
H H

Nifedipine Amlodipine Felodipin

N
O NO2
N O
MeOOC O O
O
O
O O
N
H N
H

Isradipine Nimodipine

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 Benzothiazepines
• Diltiazem
– Vasodilating action is stereospecific for the d-
cis isomer

OCH3
N
O O

H3C N
Diltiazem
CH3
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 Antiarrhythmic drugs
• Cardiac arrhythmia is caused by
– Disorders of impulse formation
– Disturbance in conduction of nerve impulses
through myocardial tissue
• Cardiac impulses generated by special
tissues in the right atrium
– Sinoatrial node
• Or
– Pacemaker cells
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• Released impulse excites heart tissue in a
pattern related to
– Myocardial cell membrane potentials
– Na & K fluxes in and out of the cells
• Disorders in impulse conduction can arise
from
– Blocking of some fibers
• E.g. through localized myocardial disease (infracts)

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• Four classes of drugs are used in the
treatment of arrhythmia:
– Class-I: (sodium channels blockers).
– Class-II (β -adrenergic blockers)
– Class-III (potassium channels blockers)
– Class-IV (cardioselective CCBs)

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 Class-I Antiarrhythmic Drugs
• They are called membrane stabilizing
(depressant) drugs, act on sodium channels and
block the depolarizing inward Na+ current.
• They bind Na+ channels in the open or
inactivated state and dissociate from the
channels in the resting state.
• They affect arrhythmic hearts more than normal
hearts (use dependent channels blockade).

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• According to the rate of dissociation from
the sodium channels, Class-I drugs could
be subdivided into:
– Class-IA (intermediate rate of dissociation)
– Class-IB (rapid rate of dissociation)
– Class-IC (slow rate of dissociation)

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• Class-IA Drugs
H

H N O N
HO
N N
O N
Ph NH2
H
N H2N O

Quinidine procainamide Disopyramide

• Class-IB Drugs
O O
NH2 NH2
N O
N N
H H
Lidocaine Cocainize Mexiletine

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• Class-IC Drugs
O

N
H
O N

Encainide

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Class-II Antiarrhythmic Drugs
• They decrease inward calcium current by
blocking the β-adrenergic receptors and
inhibiting sympathetic activation of cardiac
automaticity and conduction.
• Propranolol, Acebutolol, Metoprolol and
Esmolol, OH H

CH3 O O O N

O N CH3
H
OH

Propranolol Esmolol

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Class-III Antiarrhythmic Drugs
• Drugs from this class share the ability to
block potassium channels; some members
are able to block other channels as well.
• Potassium channels are activated during
the repolarization (Phase 3) of the action
potential; thus, their blockade prolongs
action potential duration resulting in an
increase in effective refractory period

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 O OH H
I
N
O
N H3C
O O S
N
I O
H

Amiodarone Sotalol

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 Class-IV Antiarrhythmic Drugs
• These are the cardio-selective CCBs
namely Verapamil, Biperidil and Diltiazem
• They decrease the conduction velocity and
increase the refractory period
• Refer structures above

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 Antihypertensive agents
• Hypertension = high blood pressure
• Usually defined as
– Mild
– Moderate
– Severe
• Often referred to as the silent killer
– Because patients feel well & have no obvious
clinical symptoms

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 Hypertension …
• Hypertension
– Systolic BP 140 mm Hg or higher
– Diastolic BP 90 mm Hg or higher
• 95 % of all cases are primary (essential)
hypertension, the rest is either renal or due to
endocrine abnormalities
• Risk of stroke or heart attack rises sharply
when systolic pressure > 165mm Hg
(normal 110-140)
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 Hypertension …
• Remains major risk of stroke in patients
bellow 65
– Second only to diabetes as important cause
of renal failure
• Hypertension often divided into two
categories
– Essential or primary hypertension
– Secondary hypertension

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• Primary hypertension
• Most common form
– Causes are complex & not fully understood
» Enhanced adrenergic activity recognized as principal
contributor
– If not treated, result in increased risk of death from
» Stroke
» Heart attack
» Heart failure
» Kidney problems
» Diabetes

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• Secondary hypertension is a consequence
of other diseases
• That need their own treatments
– Various kidney diseases
– Hormonal disorders etc.

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 Arterial Blood Cardiac Peripheral
Arterial Blood Cardiac Peripheral
Pressure
Pressure = Output
Output X Resistance
Resistance

Blood Volume
Filling Heart Arteriolar
Pressure Rate Volume

Contractility
Venous Tone

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Classes of Antihypertensive Drugs
– Diuretics
– Sympatholytics
– Renin Angiotenin System (RAS) inhibitors
– Vasodilators

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Diuretics:
• First line single drug treatment for mild
hypertension
• Decrease BP by two mechanisms
– Decrease Blood Volume so decrease COP
– Decrease PVR by decreasing sodium content of the
smooth muscles so decrease contractility

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• Increase diuresis lowers blood volume
 lower blood pressure
– Thiazide diuretics (e.g. chlorothiazide) were
introduced in the late 1950’s
• Were the first major antihypertensive drugs
– Main criticism of diuretics
• Cause hypokalemia  & possibly fatal cardiac
arrhythmias

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• Sympatholytic:
– Adrenergic Receptor Blockers
– Ganglionic Blockers
– Agents depleting NE Stores
– Centrally Acting Drugs

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 -blockers
• Act on -adrenergic receptors
– Reduce the rate at which the heart works 
reduced blood output
– Relax smooth muscle in arteries  reduction
in peripheral resistance to blood flow

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• Common adverse effects of -blockers are
– Easy fatigue with exercise
– Frequent compliant of cold hands & feet
• Due to reduced cardiac output
• Combination therapy of diuretics & -
blockers is very effective
• Two drug types currently advised in the US for
initiation of treatment

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• Calcium antagonists & ACE inhibitors
– Act through vasodilation
• Enlargement of small blood vessels
• Reduce resistance & hence pressure
 

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 Renin-angiotensin-aldosterone system

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 Angiotensin converting enzyme
inhibitors (ACEI)
• Captopril
– First orally active ACE inhibitor
– ACE’s active site contains Zn where the SH of
captopril binds
– Many retain significant structural features of
captopril
• One example is alacepril
– However all lack specificity
• Cleave peptides other than angiotensin I
– Causing side effects

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 H
O O N
COOH
O O

HS COOH
N
H H3C S N
CH3
CH3 Alacepril
Captopril

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a. Ganglionic Blockers
Ph
N O

+
N Ph
S

Trimethaphan

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• Agents Depleting NE Stores
N
O N
H
H H
N NH2
H
O N
O O
O
O O
NH
O
O

Reserpine Guanethidine
NH
NH
O N NH2
N NH2
H
O
Guanadrel Debrisoquin

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 4,
• Centrally Acting Drugs:
OH
HO NH2 HO NH2
COOH
HO HO

α- methyl dopa (Aldomet®) α- methyl NE

H
Cl N Cl H H
Cl
N N NH2 O NH
N N
H NH N NH2
Cl Cl
Cl H
Clonidine Guanabenz Guanfacine

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