Angina

Professor Peter Carroll

Sydney Medical School
University of Sydney
Northern Clinical School
Royal North Shore Hospital

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 Learning Objectives
•  Unfortunately there are people
in this world who will stop at
nothing in their pathological
pursuit of profit and personal
gain
•  These people have no moral
compass, and their greed
knows no limits
•  Never be like these people - as health care
professionals always put the interests and wellbeing
of patients first
•  Discuss angina and explain why it occurs
 Learning Objectives
•  Discuss the mechanism of action of the organic nitrates,
and explain their use in the treatment of angina
•  Understand that tolerance may develop with the use of
organic nitrates, discuss their adverse drug reactions
and describe why they should not be used with
phosphodiesterase type 5 inhibitors
•  Discuss the mechanism of action of the calcium channel
blockers, their adverse drug reactions, and their use in
the treatment of angina
•  Discuss the mechanism of action of beta blockers, their
adverse drug reactions, and their use in the treatment of
angina
 Angina
•  Angina occurs when the myocardial oxygen
demand exceeds supply - myocardial ischaemia
•  Angina includes
-  stable angina
-  variant (Printzmetal) angina (coronary spasm)
•  Acute coronary syndrome (ACS)
-  unstable angina
-  ST elevation myocardial infarction (STEMI)
-  non-ST elevation myocardial infarction (NSTEMI)
Rang and Dale’s Pharmacology, page 254, 8th Edition
Therapeutic Guidelines Cardiovascular (eTG June 2019 edition). Accessed 12/09/19
Kumar A and Cannon CP (2009) Mayo Clin Proc. 84(10), 917-938
https://twitter.com/nwamb_rod/status/841684429709987840
 Stable Angina
•  Occurs when the
myocardial oxygen
demand exceeds supply
•  Blood supply (oxygen)
is reduced because of
atherosclerotic changes
in the coronary arteries www. health.com

•  Treatment is aimed at reducing myocardial

oxygen demand, increasing oxygen delivery
and preventing plaque progression and
thrombotic complications
Rang and Dale’s Pharmacology, page 254, 8th Edition
Therapeutic Guidelines Cardiovascular (eTG June 2019 edition). Accessed 12/09/19
 Stable Angina
•  In stable angina the anginal pain is usually
transient and subsides with rest

•  It is precipitated by increased physical

activity or emotion

•  The pain is typically retrosternal and may

radiate to the jaw, neck or arm

•  Patients may experience band-like tightness

or discomfort
Rang and Dale’s Pharmacology, page 254, 8th Edition
Therapeutic Guidelines Cardiovascular (eTG June 2019 edition). Accessed 12/09/19
 Treatment of Stable Angina
•  Treatment and prevention
-  organic nitrates
-  calcium channel blocking agents
-  beta adrenoceptor blocking agents (beta blockers)

•  Treatment of underlying conditions

-  antiplatelet medication e.g. low dose aspirin
-  blood pressure control e.g. ACE inhibitor
-  lipid control e.g. HMG-CoA reductase inhibitors
(statins)
 Organic Nitrates
•  Examples include
-  glyceryl trinitrate
-  isosorbide mononitrate
-  isosorbide dinitrate
•  Are available as sublingual tablets,
sublingual sprays, tablets and
transdermal patches
•  Used in both the acute and prophylactic
treatment of stable angina
 Organic Nitrates
•  Organic nitrates
are metabolised
to nitric oxide
(NO), in a
reaction possibly
involving
sulfhydryl (SH)
groups
Rang and Dale’s Pharmacology, 8th Edition, PKG – protein kinase G
pages 260-262 Rang and Dale Flashcards, 7.02
 Organic Nitrates
•  Increase cyclic guanosine monophosphate
levels (cGMP) and activation of protein kinase G
•  Produce smooth muscle relaxation e.g. vascular
smooth muscle and smooth muscle in the
gastrointestinal tract and bronchi
•  Relaxation of vascular smooth muscle produces
vasodilation
•  Relax and dilate both arteries and veins
Relaxation of vascular
smooth muscle
Rang and Dale Flashcards, 7.02
 Organic Nitrates
•  Are effective in the treatment of angina
because they
-  cause venous dilation which reduces venous
return and preload, and reduces cardiac work
and oxygen demand
-  cause artery/arteriolar dilation which reduces
peripheral resistance and afterload, and
reduces cardiac work and oxygen demand
-  dilate coronary vessels and increase coronary
blood flow, particularly to ischaemic areas,
which increases myocardial oxygen supply
 Organic Nitrates
•  Too frequent or continuous use may lead to
the development of tolerance (reduced
therapeutic effect)
•  The reason why tolerance develops is not
fully understood. Possible mechanisms
include
-  reduced conversion of nitrate to nitric oxide
-  depletion of sulfhydryl (SH) groups
-  reduced vascular response
•  Nitrate free period restores activity e.g.
patch on at 8am and off at 8pm
 Organic Nitrates
•  May produce adverse drug reactions
including dizziness, postural hypotension
and headache

•  Drug interactions - note particularly

phosphodiesterase type 5 (PDE5)
inhibitors e.g. tadalafil and sildenafil
which are used in the treatment of
erectile dysfunction
 Organic Nitrates
•  Phosphodiesterase type 5 (PDE5) is responsible
for the degradation of cyclic guanosine
monophosphate (cGMP)
•  Phosphodiesterase type 5 (PDE5) inhibitors are
used in the treatment of erectile dysfunction e.g.
sildenafil and tadalafil - increase cGMP levels
•  Organic nitrates increase cGMP levels
•  Combination therapy with organic nitrates and
PDE5 inhibitors may result in severe hypotension
and cardiovascular collapse
•  Avoid combination eMIMS August 2019
 Organic Nitrates
•  Used in both the acute and prophylactic
treatment of stable angina
•  Treatment of an acute attack
-  glyceryl trinitrate
-  isosorbide dinitrate
•  Prophylactic treatment
-  glyceryl trinitrate
-  isosorbide mononitrate
-  isosorbide dinitrate
•  Can be used in the management of heart
failure (reduces preload and afterload) after MI
 Glyceryl Trinitrate
•  Used in the treatment of acute anginal attacks
•  Has a high first pass metabolism
•  Administration is sublingual (under the tongue) or
in the cheek which avoids first pass metabolism
•  Glyceryl trinitrate tablets are relatively unstable
and once the original bottle has been opened any
unused tablets should be discarded after three
months - keep lid tightly closed
•  Tablets should be stored in a cool place in the
original bottle, and not carried close to the body
•  Glyceryl trinitrate spray avoids these problems
Anginine Prescribing Information, eMIMS August 2019
 Calcium Channel Blocking
Agents
•  Calcium can enter cells in a number of ways
•  Voltage-gated calcium channels allow
calcium to enter the cell whenever the
membrane is depolarised
•  There are 5 different subtypes of voltage-
gated calcium channels, namely L,T,N,P
and R
•  L type channels are an important calcium
source for contraction of smooth and
cardiac muscle
 Calcium Channel Blocking
Agents
•  Bind to the alpha1 subunit of the voltage-
gated L type calcium channels and block the
entry of calcium into the cell
•  Block the entry, not the
intracellular actions of calcium
•  In blood vessels reduced calcium
levels result in vascular smooth
muscle relaxation (vasodilation), Rang and Dale’s Pharmacology
Flash Cards, 6.03

a reduction in peripheral vascular resistance

and a reduction in blood pressure
Rang and Dale Flash Cards, 7.01
 Calcium Channel Blocking
Agents
•  Are effective in the treatment of angina
because they
-  cause artery/arteriolar dilation which reduces
peripheral resistance and afterload, and
reduces cardiac work and oxygen demand
-  dilate coronary vessels and increase
coronary blood flow which increases the
oxygen supply to the heart muscle
-  do not affect veins or preload
 Calcium Channel Blocking
Agents
•  Those used in the treatment of angina
include
-  amlodipine, nifedipine, diltiazem and verapamil
•  Taken on a regular basis for the
prophylactic treatment of angina, not acute
attacks
•  If an acute attack occurs, the patient can
take a rapid acting nitrate e.g. glyceryl
trinitrate sublingual tablets or spray
 Calcium Channel Blocking
Agents
•  Hypotension, headache, flushes
•  Bradycardia e.g. diltiazem, verapamil
•  Peripheral oedema (ankle) - arteriole dilation
and increased permeability of post capillary
venules. Does not respond to diuretics
•  Constipation e.g. verapamil
•  Drug interactions
Beta Adrenoceptor Antagonists
(Beta Blockers)
•  Non-selective blockers (block both B1
and B2 receptors) e.g. propranolol
•  Cardio-selective blockers (selectivity for
B1 receptors) e.g. atenolol, metoprolol
•  Beta blockers are used to treat a
number of conditions including angina,
cardiac dysrhythmias (arrhythmias),
heart failure, hypertension, migraine
and tremor
Beta Adrenoceptor Antagonists
(Beta Blockers)
•  Are effective in the treatment of angina
because they
-  reduce the effects of the sympathetic nervous
system on the heart
-  reduce the increase in heart rate, contractility
and cardiac work following exercise or emotion
-  reduce cardiac work and oxygen demand
-  reduce afterload by reducing blood pressure
 Beta Adrenoceptor Antagonists
(Beta Blockers)
•  Those used in the treatment of angina
include
-  atenolol, metoprolol and propranolol
•  Taken on a regular basis for the
prophylactic treatment of angina, not acute
attacks
•  If an acute attack occurs, the patient can
take a rapid acting nitrate e.g. glyceryl
trinitrate sublingual tablets or spray
 Beta Adrenoceptor Antagonists
(Beta Blockers)
•  May precipitate wheezing and acute
asthmatic attacks in patients who have
asthma (includes cardio-selective B1
blockers)
•  Bradycardia, fatigue, reduced exercise
tolerance
•  Sleep disturbances, nightmares, impotence
•  Aggravation of Raynaud’s disease
 Beta Adrenoceptor Antagonists
(Beta Blockers)
•  Diabetes - may reduce some signs of
hypoglycaemia, and prolong hypoglycaemia
•  Abrupt withdrawal may be dangerous and
can result in severe angina, cardiac
arrhythmias, myocardial infarction and
rebound hypertension
•  Reduce dose gradually according to
guidelines
•  Drug interactions
Treatment of Stable Angina
•  Treatment of acute attacks
-  organic nitrates

•  Prevention (prophylaxis)
-  organic nitrates
-  calcium channel blocking agents
-  beta adrenoceptor blocking agents (beta blockers)

•  Treatment of underlying conditions

-  antiplatelet medication e.g. low dose aspirin
-  blood pressure control e.g. ACE inhibitor
-  lipid control e.g. HMG-CoA reductase inhibitors (statins)