Pharmacology I

Dr. Doaa Elsherbiny

Department of Pharmacology and Toxicology
sherbini_doaa@hotmail.com
 Drugs Acting on the
Cardiovascular System
Antianginal Drugs
Angina pectoris
overview
Angina pectoris

translated as

"a strangling

feeling in the

chest"
Angina pectoris
Caused by coronary blood flow that is insufficient
to meet the oxygen demands of the myocardium
Angina pectoris

Angina pectoris has three overlapping patterns:

1) Stable angina
2) Unstable angina
3) Vasospastic angina
1) Stable angina
Stable angina = classic angina = typical angina
=effort-induced angina = angina of effort
=atherosclerotic angina

Caused by reduction of
coronary perfusion due
to a fixed obstruction
produced by coronary
atherosclerosis
1) Stable angina

• Precipitated by exertion

Physical activity, emotional blood supply cannot

stress or excitement, or any
other cause of increased
cardiac workload
BUT!! Fixed obstruction
increase  Ischemia
(blood flow, and thus oxygen,
is restricted or reduced);
heart muscle is starved
for oxygen &nutrients

• Rest or nitroglycerin  rapid relief of the pain

2) Unstable angina
Unstable angina = crescendo angina
• Chest pains occur with increased frequency,
duration, and intensity and can be precipitated by
progressively less effort
• Considered the immediate precursor of myocardial
infarction and is treated as a medical emergency
Heart attack = myocardial infarction (MI) = damage or death
of part of the heart muscle as a result of ischemia
• Symptoms are NOT relieved by rest or nitroglycerin
2) Unstable angina
2) Unstable angina
2) Unstable angina
3) Vasospastic angina
= rest angina = variant angina = Prinzmetal’s angina

spasm of the coronary artery 

decreased blood flow to the heart muscle
3) Vasospastic angina

• Occurs at rest (usually at night or early morning

hours) often without a predictable pattern.
• attacks are NOT related to physical activity, heart
rate, or blood pressure
• responds promptly to coronary vasodilators
 Angina pectoris
Imbalance
between
oxygen supplied oxygen demand
to the heart via of the heart
the coronary
vessels

reduce demand
By Reducing:
increase supply • heart rate &
By: contractility
dilating coronary • Preload
arteries • afterload
Preload

= load on the heart created by the volume of blood that

must be ejected upon contraction

= Venous return
= quantity of blood flowing
from the veins into the right
atrium

= amount of stretch to which the heart muscle is subjected,

at the end of diastole just before contraction
Afterload

= load against which the muscle exerts its contractile force

=load on the contracting ventricle created by the resistance
to the blood injected by the ventricle into the arterial system

It indicates how much effort

the ventricles must exert to
force blood into the systemic
circulation
Angina pectoris
Unstable angina
 reduce myocardial oxygen demand
 additional therapies are needed:
• drugs to reduce intracoronary
thrombosis
• Percutaneous Coronary
Interventions or coronary
bypass surgery to restore flow
by mechanical means
https://watchlearnlive.heart.org/?moduleS
elect=angiop
 Mechanism of vascular smooth muscle cell
contraction and relaxation

Vascular tone (degree of

contraction of vascular
smooth muscle) is an
important determinant of
myocardial oxygen
supply & demand
Mechanism of vascular smooth muscle cell
contraction and relaxation
Smooth muscle

Smooth muscles contain both actin and myosin filaments

(large polymerized protein molecules) responsible for the
muscle contraction
Smooth muscle

The lower part of the figure is an individual contractile unit

within a smooth muscle cell, showing large numbers of
actin filaments radiating from two dense bodies; the ends
of these filaments overlap a myosin filament located
midway between the dense bodies.
Smooth muscle

The myosin filament consists of several myosin molecules

The myosin molecule has a tail & 2 free heads at one end
• Each head contains 2 light polypeptide chains
• Tails of the myosin molecules form the body of the filament
Vascular smooth muscle cell contraction

Actin filaments are pulled inward among myosin filaments:

The head of the myosin filament binds with the actin filament.
The head then tilts toward the arm of the cross-bridge and drags
the actin filament along with it.
Vascular smooth muscle cell contraction

ATP energizes these movements

myosin kinase phosphorylates
myosin light chain
When light chain is phosphorylated
 head can bind with actin filament

Myosin LC Myosin LC
Kinase Kinase

myosin kinase activation:

Smooth muscle cells contain calmodulin
(Ca2+ -binding protein); When calcium ions
bind with calmodulin  calmodulin-calcium
complex joins with &activates myosin kinase
 Vascular smooth muscle cell contraction

Ca2+ entry through voltage-gated Ca2+

channels
 activates calmodulin (CaM)
 Ca2+-CaM complex activates myosin
light chain kinase (MLCK)
 phosphorylate myosin light chain
(myosin-LC)
phosphorylated myosin-LC interacts
with actin
vascular smooth muscle cell
contraction
 Vascular smooth muscle cell relaxation

Myosin LC Myosin LC Myosin LC

phosphatase phosphatase Kinase
Vascular smooth muscle cell relaxation

The endothelial cells synthesize a vasodilator substance

composed principally of nitric oxide (NO)
NO activates guanylyl cyclase
 Guanylyl cyclase catalyzes conversion of GTP to cGMP
 Elevated cGMP
 activation of myosin-LC phosphatase
 Myosin phosphatase splits phosphate from light chain
vascular smooth muscle relaxation
Mechanism of vascular smooth muscle cell
contraction and relaxation
Drugs Acting on the Cardiovascular System

Antianginal Drugs
Three classes of drugs (alone or in combination):

I. Organic nitrates
II. β-blockers
III. Calcium-channel blockers
Drugs Acting on the Cardiovascular System

Antianginal Drugs

I. Organic nitrates
Antianginal Drugs
I. Organic nitrates

Effective in stable angina, unstable angina & variant angina

Nitric & nitrous acid esters of glycerol

 solids at room temperature:

Isosorbide dinitrate
Isosorbide mononitrate

 moderately volatile: Nitroglycerin

Antianginal Drugs
I. Organic nitrates

Mechanism of action: Intracellularly:

nitrates convert to nitrite ions,
then to nitric oxide (NO)

NO activates guanylate cyclase

 increases cGMP
 Dephosphorylation of the myosin light chain
 vascular smooth muscle relaxation
Antianginal Drugs
I. Organic nitrates

Effects on the cardiovascular system

• relaxing veins
 dilation of large veins
 pooling of blood in veins
 decrease preload
 decrease myocardial work
 decreased myocardial oxygen consumption

Veins respond at the

venous dilation
lowest concentrations,
predominates at
Arteries at slightly
therapeutic doses
higher ones;
Antianginal Drugs
I. Organic nitrates

Effects on the cardiovascular system

• relaxing arteries
 decreased afterload
 decrease myocardial work
 decreased myocardial oxygen consumption

• relaxing coronary arteries:

decrease coronary vasoconstriction
increase myocardial blood supply
Antianginal Drugs
I. Organic nitrates

Pharmacokinetics
Nitroglycerin Isosorbide mononitrate

Onset: 1 minute Onset: > 1 hour

First-pass metabolism. Stable against hepatic

sublingually or transdermal patch breakdown
improved bioavailability &
long duration of action
Antianginal Drugs
I. Organic nitrates

Patients should be instructed to seek medical attention

immediately if three nitroglycerin sublingual tablets
taken over a 15-minute period do not relieve a sustained
attack because this situation may be indicative of
myocardial infarction
Antianginal Drugs
I. Organic nitrates

Adverse effects

Due to vasodilation:
Headache (vasodilation of cerebral arteries),

Facial flushing (vasodilation of cutaneous vascular beds)

Postural hypotension; high doses may reduce blood

pressure to such an extent that reflex tachycardia and
adrenergic enhancement of contractility
Antianginal Drugs
I. Organic nitrates

Tolerance
Develops rapidly

blood vessels become desensitized to vasodilation

Overcome by providing a daily nitrate-free interval‌to

restore sensitivity to the drug

This interval is typically 10 to 12 hours. Nitroglycerin

patches are worn for 12 hours then removed for 12 hours
Antianginal Drugs
I. Organic nitrates

Contraindications

Sildenafil (Viagra®) is a phosphodiesterase inhibitor that

potentiates the action of nitrates:
Sildenafil inhibits the enzyme that promotes degradation of
cGMP, which is: phosphodiesterase isoform 5
Antianginal Drugs
I. Organic nitrates

Contraindications

To prevent the dangerous hypotension that may occur

 this combination is contraindicated

In the event that patients develop significant hypotension

following combined administration:
fluids‌and‌α-adrenergic receptor agonists, if needed
Drugs Acting on the Cardiovascular System

Antianginal Drugs

II. β-blockers
Antianginal Drugs
II. β-blockers

• Selective β1 –blockers are preferred, such as:

Metoprolol or Atenolol
• Propranolol is the prototype for this class of compounds,
but it is not cardioselective
• Agents with intrinsic sympathomimetic activity, such as:
Acebutolol and Pindolol should be avoided
• All β-blockers are nonselective at high doses and can
inhibit β2 –receptors
Antianginal Drugs
II. β-blockers

Mechanism of action
Blocking β1 –receptors  inhibits the phosphorylion of
calcium channels in both types of cardiac cells:
 The mechanical component that pumps the blood
thus decreasing the force of contraction of the heart;
negative inotropic effect
 The electrical component that controls the rhythm of
the pump thus lowering the heart rate; negative
chronotropic effects
 reduction in the demand for oxygen
Antianginal Drugs
II. β-blockers

Uses

• Stable angina

• Myocardial infarction; shown to prolong

survival
Antianginal Drugs
II. β-blockers

Precautions and Contraindications

Contraindicated in variant angina; in which β-blockers

are ineffective and may actually worsen symptoms;
Due to unopposed vasoconstriction mediated by
epinephrine and norepinephrine on α-adrenoceptors
Antianginal Drugs
II. β-blockers

Precautions and Contraindications

• Severe bradycardia
• Asthma
• Chronic obstructive pulmonary disease
• Diabetes
• Peripheral vascular disease (e.g. Raynaud's disease)
Drugs Acting on the Cardiovascular System

Antianginal Drugs

III. Calcium-Channel blockers

Antianginal Drugs
III. Calcium-Channel blockers

• Dihydropyridine derivatives:
Nifedipine (prototype)
Amlodipine
Nicardipine
Felodipine

• Diphenylalkylamines: Verapamil

• Benzothiazepines: Diltiazem
Antianginal Drugs
III. Calcium-Channel blockers

Mechanism of action
Calcium-channel blockers inhibit L-type calcium channels:
• Cardiac effects: decrease
negative chronotropic effect myocardial
oxygen
negative inotropic effect demand

• Vascular effects: dilation of arteries

-systemic circulation: decrease in afterload
-coronary arteries increase oxygen supply
Antianginal Drugs
III. Calcium-Channel blockers

Effects on the cardiovascular system

Nifedipine mainly affects selectively dilates arterial

vascular blood vessels; if peripheral
smooth muscle vasodilation is marked 
reflex tachycardia

Verapamil action on the in comparison to nifedipine :

‌heart > vascular weaker vasodilator
‌smooth muscle direct negative chronotropic
& inotropic effects

Diltiazem intermediate in actions between verapamil & nifedipine

Antianginal Drugs
III. Calcium-Channel blockers

Pharmacokinetics:
• Nifedipine orally, usually as extended-release tablets
Short-acting  abrupt vasodilation with reflex sympathetic activation.

• Calcium-channel blockers are metabolized by the liver;

dose decreased in patients with liver dysfunction

Uses: stable and vasospastic angina

Antianginal Drugs
III. Calcium-Channel blockers

Adverse effects
Nifedipine:
• Vasodilation  flushing, headache, hypotension, peripheral
edema & reflex tachycardia
• Hypotension  Dizziness & fatigue
Verapamil and diltiazem
• should be avoided in heart failure or atrioventricular block
• increase digoxin levels
All calcium-channel blockers: Constipation due to excessive
smooth muscle relaxation in GIT
Antianginal Drugs
Combination therapy

Organic nitrates and β-blockers

β-blockers
block the reflex tachycardia & positive inotropic effects
that are sometimes associated with nitrates

Nitrates
alleviate the increase in coronary vascular resistance
associated with blockade of β-receptors
Antianginal Drugs
Combination therapy

Calcium-channel blockers and β-blockers

Nifedipine
blockade of β-receptors can be useful in blocking
the reflex tachycardia

Verapamil or diltiazem,
blockade of β-receptors may lead to excessive
bradycardia, heart block, or heart failure
Antianginal Drugs
Combination therapy

Calcium-channel blockers and Organic nitrates

• In severe angina, their combination additional relief

• But, excessive vasodilation & hypotension can occur

Organic nitrates, Calcium-channel blockers and

β-blockers

• incidence of side effects increases significantly

Thank you