ANGINA

PECTORIS
&
VASODILATORS

Dr. Mariam Yousif

Pharmacology & Toxicology Dept
17/10/2006
 Objectives
1. Definition of angina pectoris.
2. Identify the 3 types of angina with their underlying
pathophysiology.
3. What is the aim/rationale of therapy?
4. What are the 3 main classes of antianginal drugs?
5. Identify the mechanism of action, main pharmacological
actions, major side effects and main drug examples for
each class.
6. What anti-thrombotic therapies are available for the
treatment of unstable angina.
7. What are the new emerging anti-anginal drugs?
 Definition
Angina pectoris is the clinical syndrome of
transient cardiac ischaemia resulting from
inadequate coronary blood flow.

It is characterized by severe retrosternal chest pain

or pressure that radiates to the left shoulder, left
arm or to the back.
 It occurs when the oxygen supply to the
myocardium is insufficient for its needs.

 Imbalance in myocardial oxygen

supply-demand relationship results from
spasm or obstruction of the coronary blood
vessels.
 Types of Angina

1- Stable (Classic / Typical / Angina of Effort)

2- Unstable Angina

3- Variant (Prinzmetal's Angina)

 1- Stable

 Characterized by predictable pain on exertion.

 Occurs due to a fixed narrowing of the coronary

arteries by atherosclerosis.
 2- Unstable Angina

 Characterized by pain that occurs with less

exertion, can occur at rest.

 Occurs due to disruption of an atherosclerotic

plaque with subsequent cascade of platelet

activation and aggregation, and thrombosis leading
to a decrease in coronary blood flow.
 3- Variant (Prinzmetal's Angina)

 Cardiac pain that occurs

exclusively at rest.

 Caused by coronary artery vasospasm

(vasospastic) which reduces coronary flow leading
to reduction of blood flow to the myocardium.
 Aim of Therapy
To improve the balance between myocardial oxygen
demand and supply.

Supply = Demand
Coronary Blood Flow
Systolic Wall Tension
Contractility
Heart rate
 How to achieve the aim?

A. Coronary vasodilators
Increase blood flow to the myocardium by dilating
the coronary arteries.

B. Drugs that ⇓ work load of the heart

Decrease oxygen demand by reducing cardiac work.

 Types of Therapy for Angina

# Prevention

# Medical Therapy Using Anti-Anginal Drugs

# Revascularization
PTCA: Percutaneous Transluminal Coronary Angioplasty
CABG: Coronary Artery Bypass Graft Surgery
 Prevention
 Quit smoking
 Lose weight
 Reduce cholesterol levels
 Exercise
 Better control of diabetes
 Better control of hypertension
 Medical Therapy

Anti-Anginal Drugs

# Beta-adrenoceptor blocking drugs

# Nitrates
# Calcium channel blockers

Can be used alone or in combination

 1. β -Adrenergic Blocking Agents

e. g. Propranolol, Atenolol, Metoprolol

# Predominant receptor subtype in the myocytes is

β 1-receptor, its blockade minimizes the influence of
endogenous catecholamines.
Molecular mechanism of action of beta1-adrenoceptor antagonists.
Stimulation of beta1-adrenoceptors by catecholamines leads to
activation of adenylyl cyclase and an elevation of cAMP. This
process is inhibited by beta1-adrenoceptor antagonists.
Beta-blockers
Negative chronotropic effect ( HR) and
negative inotropic effect ( contractility),
therefore reduce the oxygen demand by the
heart.

# Cardioselective β1-blockers may be used to

minimize bronchospasm in asthmatic patients.
# Contraindicated in variant angina.
2. Organic Nitrates and Nitrites

Esters of nitric and nitrous acid.

 Nitroglycerin (GTN) is the prototype
drug.
 Isosorbide dinitrate
 Amyl nitrite

-Nitrates are extremely important agents for the

treatment of angina.
Nitroglycerin concentrations are affected by the
route of administration
Preparations
Sublingual, Tablet forms, Topical.

Peak concentrations
Sublingual: 2-4 minutes
Oral route: 15-30 minutes
Transdermal route: 1-2 hours
-Nitroglycerin is rapidly inactivated by hepatic
metabolism. Given sublingually to avoid the
first pass effect and to achieve a therapeutic
blood level rapidly.

- Oral and transdermal products are acceptable

for the long-term prophylaxis.
 Mechanism of Action
Organic nitrates

nitric oxide (NO)

[activates guanylyl cyclase]

⇑ synthesis of cGMP

vascular smooth muscle relaxation

Molecular and cellular mechanisms of action of nitrate and nitrite
vasodilators. The product, phosphorylated protein kinase, leads to
de-phosphorylation of myosin light chain and causes vascular
smooth muscle relaxation.
PHARMACOLOGICAL ACTIONS

-Relax vascular smooth muscle and cause

vasodilation of vessels, both veins and arteries.

-The effect on veins is more pronounced than on

the arteries (starts at lower doses).
Pharmacological Actions
At low doses:
Venodilation
(pooling of blood in veins)

⇑ Venous capacitance

⇓ preload (⇓ venous return)

⇓ work on the heart

⇓ Oxygen consumption.
 At higher doses:

Nitroglycerin dilates arterioles

⇓ peripheral resistance

⇓ after-load

⇓ myocardial O2 demand
 ⇓ Blood pressure → reflex tachycardia → ⇑ HR →
⇑ O2 consumption (combination therapy with β blockers).
 # Nitroglycerin dilates the coronary arteries

Blood supply to the heart muscle

# Nitroglycerin diverts blood from

normal to ischaemic areas of the
myocardium through
dilatation of collateral vessels
(redistribution).
 Development of Tolerance
Continuous exposure to high doses of organic
nitrates ⇒ ⇓ most of their pharmacological
effects.

 Caused by depletion of tissue sulfhydryl groups,

can be partially reversed by sulfhydryl group
donors, e.g. N- acetylcysteine.
Organic Nitrates
Smooth muscle cell
Tissue
thiols Thiols
H+ R-SH
NO2- NO Nitrosothiols
R-SNO
+

Guanylate cyclase

GTP
cGMP
+
PKG
relaxation

Mode of action of nitrates

(L-Arg=L-arginine; GTP=guanosine 5’-triphosphate; cGMP=cyclic
guanosine 3’5’monophosphate; PKG=cGMP-dependent protein kinase
 The offset of tolerance is as rapid as its
onset. Therefore, one alternative dosing
strategy to minimize tolerance is to
provide a daily nitrate-free interval of 6-8
hours.
 Adverse Effects & Toxicity

 Postural hypotension

 Headache
 Reflex tachycardia
 3. Ca2+ Channel Blockers

Nifedipine (smooth muscle selective)

Verapamil (cardioselective)
Diltiazem (intermediate)

-Their main action is to interfere with the entry of

calcium into the myocytes and vascular smooth
muscle cells.
 Vasodilator effects (nifedipine) on resistance

vessels: ⇓ after-load.
 Coronary arterial dilation ⇒ ⇑ coronary blood

flow (variant angina).

 Effects on the heart: Calcium channel block in
myocardium ⇒ impaired AV conduction and
⇓ myocardial contractility (-ve inotropic effect).
Side Effects
Constipation, heart failure.
Other antianginal & Vasodilator drugs

3. Dipyridamole.
4. Molsidomine.
5. Hydralazine.
6. Sodium nitroprusside.
7. Nicorandil :K+ channel activator and
nitrovasodilator (NO donor) actions.
 Antithrombotic Therapy In Unstable Angina

-Platelet aggregation and thrombosis play a major

role in acute phase of unstable angina.
-Both aspirin and heparin are extremely effective.
-They reduce the occurrence of recurrent angina
and the occurrence of MI or death.
-Alternative antiplatelet agents available are
clopidogrel and ticlopidine.
Mechanism of action of Aspirin. Aspirin blocks the activity of cyclo-
oxygenase and reduces the formation of prostacyclin and
thromboxane A2. PGG2 and PGH2 are both prostaglandin cyclic
endoperoxides and are unstable intermediated.
The molecular mechanism of aspirin is a selective
inhibition of thromboxane synthesis.
This is achieved because platelets do not possess a
cell nucleus and are therefore unable to
resynthesize cyclo-oxygenase, whereas endothelial
cells can resynthesize cyclo-oxygenase within a few
hours.
Low dose aspirin (30 mg/day) is insufficient
to block the activity of cyclo-oxygenase
completely, so its use can achieve a
maintained suppression of thromboxane
synthesis, with only a transient inhibition of
prostacyclin synthesis, and an overall effect
of reduced platelet aggregation.
Emerging Drugs
Ranolazine: Acts on mitochondria to inhibit
fatty acid oxidation, stimulate glucose
oxidation and improve oxygen metabolism.

Dalteparin and enoxaparin: low molecular

weight heparin fragments, under
investigation for treatment of unstable
angina.
Dalteparin is already approved in many
countries.
 Revascularization

Coronary artery bypass and percutaneous

interventions such as angioplasty are
alternatives to pharmacological treatment in
some patients.

PTCA: Percutaneous Transluminal Coronary Angioplasty

CABG: Coronary Artery Bypass Graft Surgery
 Recommended reading from your text book (Integrated
Pharmacology by Page et al)

(Fig. 18.19 page: 378): Diseases that cause unstable

angina
(Fig. 18.20 page: 378): Clinical features of variant
angina pectoris.

THIS MATERIAL IS INCLUDED IN THE EXAM.

LIST OF ANTIANGINAL DRUGS
Nitroglycerin, Isosorbide dinitrate
Propranolol, Atenolol,
Verapamil, Nifedipine, Diltiazem
Aspirin, heparin, Clopidogrel, Ticlopidine