RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in

Éirinn

Antianginal Therapy
April 2025

Prof Niamh Moran (RCSI Dublin)

Learning outcomes

• Outline the nature of angina

• Outline the role of the endothelium in maintaining vascular tone
• Describe the synthesis and actions of nitric oxide
• Describe the role of organic Nitrates in treating angina
• Outline the benefits of other agents such as Beta adrenergic
antagonists, Calcium channel blockers, ACE inhibitors and Anti-
platelet agents in the treatment of angina

• Summarise the clinical aspects of anti-anginal therapy

• Describe the pharmacological management of angina with reference
to epidemiological physiology and clinical outcome
• Describe the side effects of the drugs used to treat angina
 A reminder that Atherosclerosis
underpins CAD
• Coronary artery disease (CAD) is almost
always due to atheromatous narrowing
and subsequent occlusion of the an
artery.
• In affluent societies, CAD causes severe
disability and more death than any other
disease, including cancer.
• It manifests as angina, silent ischaemia,
unstable angina, myocardial infarction,
arrhythmias, heart failure, and sudden
death.
• The prevalence of stable angina
increases with age and is higher in men
than women

https://watchlearnlive.heart.org/?moduleSelect=chlcad
 Pathogenesis of Atherosclerotic Plaques
Endothelial damage

Protective response results in production of

cellular adhesion molecules

Monocytes and T lymphocytes attached to

‘sticky’ surface of endothelial cells

Migrate through arterial wall to subendothelial space

Macrophages take up oxidised LDL cholesterol

Lipid-rich foam cells

Fatty streak and plaque

Silent CVD
Increased Stable Angina
Plaque rupture, thrombus formation, Occlusion
Unstable Angina
blockage of Artery Myocardial Infarct
 Angina symptoms

• Pathophysiology.
– Usually associated with the presence of significant obstructive
coronary disease (stable disease)
– unstable disease associated with plaque rupture

• Clinical presentation
– Retrosternal discomfort
– Pressure-like
– may radiate down arm or into neck
– occurs with exertion and relieved by rest,
 Angina (1)
Angina occurs when the oxygen supply to
the myocardium is insufficient for its needs.

• Cardiac myocytes rely on aerobic metabolism.

• If the supply of oxygen falls below a critical value,
a sequence of events leading to cell death
ensues,
• This is detected clinically by an elevation of
circulating troponin (a biochemical marker of
myocardial injury), as well as of cardiac enzymes
(e.g. the cardiac isoform of creatine kinase) and
changes in the surface ECG.

The pain has a characteristic distribution in the chest, arm

and neck, and is brought on by exertion, cold or
excitement.
 Angina (2)

• Three kinds of angina are recognised clinically:

1. Stable: - no change in symptoms over previous weeks
2. Unstable: - abrupt pattern change typically at rest
3. and Variant: - usually stress related, patients develop
coronary spasm

• The treatment goals of angina pectoris are:

• improvement in quality of life,
• by limiting the number and severity of attacks,
• protection against future lethal events, and
• measures to lower the burden of risk factors to slow disease progression.

• This requires lifestyle modification as well as medical treatment

 Stable angina

• Predictable chest pain on exertion.

• Caused by an increased demand on the heart
• usually caused by fixed narrowing(s) of the coronary arteries by
atheroma,
– ….although, narrowing of the aortic valve (‘aortic stenosis’) can also cause
angina by reducing coronary blood flow even in the absence of coronary
artery narrowing.

• Symptomatic therapy is directed at reducing cardiac work with

• organic nitrates,
• β-adrenoceptor antagonists
• and/or calcium antagonists,
– together with treatment of the underlying atheromatous disease,
usually including lipid-lowering drugs such as a Statin
– and prophylaxis against thrombosis with an antiplatelet drug, such
as aspirin
 Unstable angina

• This is characterised by pain that occurs with less and less

exertion, culminating in pain at rest.
– The pathology is similar to that involved in myocardial infarction,
namely platelet–fibrin thrombus associated with a ruptured
atheromatous plaque, but without complete occlusion of the vessel.
• Treatment is similar to that for myocardial infarction and
includes imaging and consideration of revascularisation
procedures.
– Antiplatelet drugs (aspirin and/or an ADP antagonist such
as clopidogrel or prasugrel) reduce the risk of myocardial infarction
in this setting,
– and anticoagulant drugs add to this benefit at the cost of increased
risk of haemorrhage.
– Organic nitrates (see later) are used to relieve ischaemic pain.
Variant angina

• Variant angina, also known as Prinzmetal angina or vasospastic

angina, is a rare type of chest pain that typically occurs at rest,
often during the night or early morning hours
• Unlike stable angina, which is usually triggered by physical exertion
or stress, variant angina is caused by a temporary spasm in the
coronary arteries, leading to reduced blood flow to the heart muscle
• This is relatively uncommon. It can occur at rest and is caused by
coronary artery spasm, often in association with atheromatous
disease.
• Therapy is with coronary artery vasodilators (e.g. organic nitrates,
calcium antagonists).
 Pharmacological vs Non-Pharmacological
Treatments to improve Angina Symptoms
• There are three classes of Non-Pharmacological
anti-ischemic drugs commonly treatment: stents, PCI
used in the management of
angina pectoris: Diet
– nitrates Exercise
Smoking Cessation
– beta blockers, Weight Management
– calcium channel Stress Management
blockers.
– Ranolazine (a sodium channel
blocker) is a newer addition.
• Often, a combination of these
agents is used for control of
symptoms.

Note: regardless of the acute treatment, long term preventative treatment

with cholesterol lowering drugs and antiplatelet agents is initiated in all
patients.
Intact Endothelium regulates coagulation:

Intact endothelial cells

• express Heparin &
Thrombomodulin on their
surface
• produce inhibitory reagents
NO & PGI2 that prevent • Heparin coordinates the Anti-
platelet activation Thrombin (aka Anti-Thrombin III; ATIII)
• Secrete tissue-Plasminogen pathway
Activator (tPA)
• Thrombomodulin coordinates the
Protein C pathway
 Factors that favor or inhibit thrombosis

Intrinsic
Intrisic Coagulation
Coagulation
sequence

Thrombin

Fibrinogen

Fibrin Polymer

Stasis allows the iniatiation

of the coagulation cascade
 The role of the Intact Endothelium in
Hemostasis/Thrombosis
• Synthesize & secretes NO, PGI2 to inhibit platelet
activation
• Synthesize & secrete vasoactive peptides eg
Endothelin
• Prevents exposure of platelets to sub-endothelial matrix
components such as collagen
• Produces heparin to inhibit the coagulation cascade
• Produce thrombomodulin which, when bound to
thrombin, can generate activated protein C which
degrades FVa and FVIIIa.
• Secretes tPA and urokinase to degrade formed clots.
Normal arterial wall
Tunica adventitia
Tunica media
Tunica intima
Endothelium

Subendothelial connective
tissue
Internal elastic membrane
Smooth muscle cell

Elastic/collagen fibres

External elastic membrane

 There are three classes of anti-
ischemic drugs commonly used in
the management of angina
pectoris:
nitrates
beta blockers,
calcium channel blockers.
Ranolazine (a sodium channel
blocker) is a newer addition.
NITRATES Note: regardless of the acute
treatment, long term preventative
treatment with cholesterol lowering
drugs and antiplatelet agents is
initiated in all patients.
 Synthesis and actions of nitric oxide in
Endothelial cells
• Nitric oxide (NO) is a soluble gas
continuously synthesized from the amino
acid L-arginine in endothelial cells by the
constitutive enzyme nitric oxide
synthase (NOS).

• NO has a wide range of biological

functions that contributes to the
regulation of vascular homeostasis
– modulation of vascular dilator tone,
– regulation of local cell growth,
– protection of the vessel from injurious
consequences of platelets activation.
– Inhibition of platelet activation
 Organic Nitrates for treatment of Angina

• Nitroglycerin (Glyceryl Trinitrate (GTN)) has been used

since 1867 in medicine as a potent vasodilator in the
treatment of angina pectoris and chronic heart failure,
and, in its extended release forms, it still remains first-
line drug therapy for many patients.
– It was previously known that these beneficial effects were due to
nitroglycerin being converted to nitric oxide NO. The enzyme for
this conversion was only discovered to be
mitochondrial aldehyde dehydrogenase (ALDH2) in 2002.
• Organic nitrates are metabolised with release of NO.
– NO activates soluble guanylyl cyclase, increasing formation of cGMP,
which activates protein kinase G and leads to a cascade of effects in
smooth muscle culminating in dephosphorylation of myosin light chains,
sequestration of intracellular Ca 2+ and consequent relaxation.
Arterial Endothelial Function: Role of Nitric Oxide
(NO)
• NO activates Guanylate Cyclase
• Guanylate Cyclase generates cGMP- a
local mediator
• cGMP enables smooth muscle
relaxation and vasodilation

• Hypertension, hypercholesterolemia,
smoking, diabetes mellitus and heart failure
are associated with diminished local
synthesis of nitric oxide

• Reduced NO leads to:

– Enhanced expression of chemo-attractants
– Enhanced expression of cell adhesion
proteins on Endothelial cells-enabling
monocyte adhesion
– Enhanced oxidation of LDL
– Enhanced Platelet activation
Methods of administration of nitrates as drugs
– Sublingual (tablets and spray)
• Nitroglycerin (GTN), metabolised in liver
• Peak concentration in 4 mins, half life of 40 mins
• Isosorbide dinitrate – 2-5 minutes
– Oral
• Isosorbide dinitrate, peak 6 minutes
• Half life 2-5 hrs. (mononitrate longer half life*)
– Cutaneous
• Transdermal patch (GTN)
– Intravenous

• Nitrates, usually in the form of a sublingual preparation, are the first-

line therapy for the treatment of acute anginal symptoms. Patients
should be instructed to use them at the onset of an episode of angina,
or for prophylaxis of anginal episodes.
 Nitrates in the management of acute coronary
syndrome
Commonly Used Nitrate Medical Uses of Side Effects of Nitrates
Preparations: Nitrates include

• Sublingual nitroglycerin
• Nitroglycerin spray • Prophylaxis and Headache and flushing are
• Isosorbide dinitrate
•
Management of acute common symptoms
Isosorbide
mononitrate -Extended- coronary syndrome Hypotension* can occur.
release (ACS), which includes ST-
• Transdermal elevation and non-ST *Contraindicated in patients
nitroglycerin patches elevation MI, taking sildenafil
• Stable angina (Viagra) or similar within 24
• Unstable angina hours (because of the risk of
• Chronic Coronary severe hypotension).
Syndrome

While they act as venodilators, coronary vasodilators, and modest arteriolar dilators, the primary
antiischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation
more than coronary vasodilation. This systemic vasodilation reduces left ventricular systolic wall stress.
 Side effects of Nitrates
• The main adverse effects of nitrates are a direct
consequence of their main pharmacological
actions, and include postural hypotension*
and a throbbing headache.
Sildenafil (Viagra)

• Transient episodes of hypotension - may be

exacerbated by alcohol

• Excessive use can also result in the formation

of methaemoglobin , an oxidation product of haemoglobin that
is ineffective as an oxygen carrier

• Danger of additive effect with PDE Inhibitors eg

sildenafil (Viagra)
 Nitrates vs Calcium Channel Blocker

• Most of the anti-ischemic efficacy of nitrates pertains to their ability to

decrease myocardial oxygen demand as a result of systemic vasodilatation
rather than any activity as a coronary vasodilator. Nitrates do not have a
direct effect on cardiac chronotropy or inotropy.
• Nitrates also have significant antiplatelet and antithrombotic properties
 Tolerance to Nitrates

• Repeated administration of nitrates to smooth muscle preparations

in vitro can result in tolerance
– This leads to a diminished vascular relaxation in response to each dose
• Tolerance to the anti-anginal effect of nitrates does not occur to a clinically
important extent with ordinary formulations of short-acting drugs (e.g.
glyceryl trinitrate)

• but Tolerance does occur with longer-acting drugs (e.g. isosorbide

mononitrate)
• or when glyceryl trinitrate is administered by prolonged intravenous infusion
or by frequent application of slow-release transdermal patches (see later).

• Hence, it is usual to require a nitrate free period of 10-12 hours in

each 24 hours
 There are three classes of anti-
ischemic drugs commonly used in
the management of angina
pectoris:
nitrates
beta blockers,
calcium channel blockers.
Ranolazine (a sodium channel
blocker) is a newer addition.
BETA BLOCKERS Note: regardless of the acute
treatment, long term preventative
treatment with cholesterol lowering
drugs and antiplatelet agents is
initiated in all patients.
 β-Adrenoceptor antagonists (β-Blockers)
• Sympathetic activity, acting through β1 adrenoceptors, increases
heart rate (+ Chronotropic effect), contractility(+Inotropic effect) and
automaticity,
– but reduces cardiac efficiency (in relation to oxygen consumption).
• The β1 adrenoceptors act by increasing cAMP formation, which
increases Ca 2+ currents.

• β-Adrenoceptor antagonists (beta blockers), slow the heart rate &

decrease the force of contraction.
• They therefore reduce the oxygen demand of the heart and reduce
the frequency of angina attacks.
 β-Adrenoceptor antagonists (β-Blockers)

• They reduce the myocardial oxygen demand by:

– Reducing the Heart Rate (Chronotropic effect)
– Decrease contractility (Inotropic effect)
– Decrease the blood pressure (afterload)
• Since beta blockers reduce the heart rate-blood pressure product during
exercise, the onset of angina or the ischemic threshold during exercise is
delayed or avoided.
• They reduce mortality and re-infarction in post-myocardial infarction
patients.

Current guidelines recommend beta blockers as first-line treatment in

patients with angina, either on their own or in combination with a calcium
channel blocker.
 Cardio-selective β-blockers

• These drugs act on the heart -where β1 adrenergic receptors predominate: not the
vasculature- or pulmonary bronchioles, where β2 adrenergic receptors predominate.
– Any effects on coronary vessel diameter are of minor importance,

• Cardioselectivity refers to selectivity at beta-1 receptors, and is “dose-dependent”. Most beta-

blockers in clinical use are “cardioselective”, offering the potential advantage of not interfering
with bronchodilatation or peripheral vasodilatation. The clinical applicability of this effect is uncertain
since cardioselectivity may be lost at the high doses needed to treat angina.

• Metoprolol 2.3-fold selectivity for β1 over β2 adrenergic receptors

• Atenolol 4.7-fold selectivity for β1 over β2
• Carvedilol is a nonselective beta blocker that has vasodilating properties as a result
of selective alpha-1 antagonism.
Fro
• Pindolol (β1 selective antagonist and partial agonist at β2 adrenoceptors) h y m an per
ten s t i-
• Nebivolol –Beta blocker (β1 selective) and releases NO (vasodilation) l e ct i
u re v e

• β-Adrenoceptor antagonists are avoided in variant angina because of the theoretical risk that
they will increase coronary spasm.
 β-blockers

All β-blockers share Medical Uses of Side Effects of β-

the common Suffix cardioselective β1- blockers include
‘olol’ or ‘ol’ blockers include
Bronchoconstriction: block
Metoprolol beta-2 mediated smooth muscle
• Angina- stable and relaxation in the bronchi. Thus,
Atenolol
unstable contra-indicated in e.g., asthma
Carvedilol • Myocardial infarction Bradycardia
• Heart Failure, Arrhythmias
arrhythmias Mask symptoms of
hypogylcaemia
Fatigue, Somnolence, Depression
Impotence

*
 There are three classes of anti-
ischemic drugs commonly used in
CALCIUM the management of angina
pectoris:
ANTAGONISTS / nitrates
CALCIUM CHANNEL beta blockers,
BLOCKERS calcium channel blockers.
Ranolazine (a sodium channel
blocker) is a newer addition.

Note: regardless of the acute

treatment, long term preventative
treatment with cholesterol lowering
drugs and antiplatelet agents is
initiated in all patients.
 Calcium Antagonists
• Calcium antagonists (CAs) reduce angina by inhibiting
inward calcium currents through the cell membrane in many
tissues, including the myocardium, cardiac conduction
tissues, and vascular smooth muscle cells in both coronary
arteries and peripheral vessels. They are also called Calcium
Channel Blockers (CCBs)

– Intracellular calcium deprivation relaxes smooth muscle cells,

causing vasodilation in the peripheral and coronary beds and
increased coronary blood flow.

• Therapeutically important calcium antagonists act on L-type

channels.
• L-type calcium antagonists comprise three chemically distinct
classes:
1. dihydropyridines (e.g. nifedipine, amlodipine)
2. phenylalkylamines (e.g. verapamil),
3. benzothiazepines (e.g. diltiazem).
 The subclasses of Calcium Antagonists

Type Properties Drugs

Amlodipine,
Nifedipine,
Peripheral and coronary
felodipine,
Dihydropyridines (DHPs) vasodilators, negative inotropic
isradipine,
action
nicardipine,
nisoldipine

Non-dihydropyridines (non-DHPs)

Additional negative chronotropic

Phenylalkylamine Verapamil
and inotropic actions

Additional negative chronotropic

Benzothiazepine Diltiazem
and inotropic actions
 Calcium Antagonists

• The main effects of calcium antagonists, as used therapeutically,

are on cardiac and smooth muscle.
1. most of the dihydropyridines (e.g. nifedipine) exert a greater
effect on vascular smooth muscle than on the heart.
2. whereas Verapamil preferentially affects the heart
3. Diltiazem is intermediate in its actions.

• In the heart: they cause a decrease in contractility

• They can favourably alter the ratio of supply and demand in chronic stable
angina
• Verapamil and Diltiazem, slow sinoatrial (SA) and atrioventricular (AV) nodal
conductions to reduce heart rate and depress contractility under
physiological conditions.

• In the periphery: they cause relaxation of vascular smooth muscle,

decreasing peripheral resistance and reducing arteriolar pressure (afterload).
 Calcium channel blockers

• These drugs lower the frequency of angina, lower the need for
nitrates, increase treadmill walking time, and improve ischaemic ST-
segment changes on exercise testing and electrocardiographic
monitoring.

• Calcium antagonists have been shown to be equally effective as

beta-blockers in the management of stable angina.

– ESC guidelines on stable coronary artery disease for the management of stable
angina consider either a beta-blocker or a CA as appropriate first-line treatment.

• The usual dose of calcium antagonists in common use for angina

and their common side effects are summarised in Table on next
slide
 Duration
Drug of action
Usual dose Common side effects

Dihydropyridines (DHPs)
Nifedipine, slow Long 30-180 mg/d Hypotension, oedema,
release dizziness, flushing, nausea,
constipation

Amlodipine Long 5-20 mg (daily) Headache, oedema

Isradipine, sustained Medium 2.5-10mg (twice a Headache, fatigue

day)
rel

Nicardipine Short 20-40mg (3 times Headache, oedema, dizziness,

a day) flushing

Non-dihydropyridines (non-DHPs)
Diltiazem, immediate Short 30-80mg (4 times Hypotension, dizziness,
release a day) flushing, bradycardia, oedema

Diltiazem, slow Long 120-320 (daily) Hypotension, dizziness,

release flushing, bradycardia, oedema

Verapamil, immediate Short 80-160mg (3 times a Hypotension, negative

release day) inotropism, HF, bradycardia,
oedema
 Calcium Antagonists-Calcium Channel blockers
(CCBs)
CCBs do not share a Medical Uses Side Effects include
common Suffix but are
usually remembered as include
“Very Nice Drugs” Headache
• Primary (essential) Dizziness
hypertension Flushing
• Angina- stable and Hypotension
Verapamil unstable Peripheral oedema /
Nifedipine • hypertrophic ankle swelling
Diltiazem cardiomyopathy, Bradycardia
• supraventricular Constipation
arrhythmias Precipitate heart failure

*
 Calcium Antagonists-Usage
Drugs Interactions:
• Calcium channel antagonists are
absorbed well orally, however many – Interaction with other negative
have low bioavailability due to hepatic chronotropic or inotropic agents
first-pass metabolism, primarily by to produce bradycardia, heart
CYP3A4. block, or HF has been reported.
• – CAs compete with other drugs for
Calcium blockers should be tried in
access to the CYP3A4 enzyme in
patients who cannot tolerate beta- the liver and, therefore, may raise
blockers. levels of statins and many other
drugs, something which may be
overlooked.
– Cimetidine and grapefruit juice
may raise the effective level of
CAs.
 Summary: Anti-Anginal Drugs

Angina is managed by using drugs that improve perfusion

of the myocardium or reduce its metabolic demand, or
both.
• The main anti-anginal drugs are vasodilators and
produce both these effects
– organic nitrates and
– calcium antagonists
– β-adrenoceptor antagonists: slow the heart and hence reduce
metabolic demand
– ± ACE Inhibitors
 Combination therapy for persistent
symptoms
• Combination therapy is commonly used in the treatment
of patients who have continued symptoms on
monotherapy.
• In general, any combination of a beta blocker, calcium
channel blocker, and long-acting nitrate can be
appropriate.
• However, some patients may not tolerate the
combination of a beta blocker and calcium channel
blocker due to hypotension or bradycardia.
• Ranolazine, a late sodium channel blocker can be added
as a third medication, if needed
 PREVENTING DISEASE PROGRESSION

• The optimal management of patients with stable angina requires more than
antianginal therapy.
• Therapies aimed at preventing cardiovascular events are central to long-
term care.
• All patients should receive education and counselling about issues such as
medication compliance, control of risk factors, and regular exercise
• In addition, there are several medical therapies which can reduce the
risk of cardiovascular events and disease progression:

• Antiplatelet therapy
– In the absence of a contraindication, all patients should be treated with low-dose
aspirin.
• Lipid-lowering therapy
– All patients with CCS be treated with evidence-based doses of a high-intensity
statin, regardless of the baseline low-density lipoprotein (LDL) cholesterol.
 Treating vascular stenosis with Drug-eluting
stents
a surgical, rather than a Pharmacological
solution
Drug-eluting stents
(DES), also known as
Coated stents, are a
type of stent used to
treat coronary artery
disease. These stents
are coated with
medication that is
slowly released to help
prevent the artery from
becoming blocked
again.
The stent is coated with
a drug that inhibits cell
proliferation, reducing
the risk of restenosis
 Surgical methods used in the treatment of
angina primarily aim to improve blood flow
to the heart.
1. Angioplasty with Stenting: A tiny balloon is inserted into the
narrowed artery and inflated to widen it. A stent (a small mesh
tube) is then placed to keep the artery open. This helps to restore
blood flow and relieve angina symptoms.
2. Coronary Artery Bypass Grafting (CABG): This is a type of
open-heart surgery where a vein or artery from another part of the
body is used to bypass a blocked or narrowed coronary artery. It
creates a new pathway for blood to flow to the heart muscle,
reducing angina and improving heart function.
3. Enhanced External Counterpulsation (EECP): This non-invasive
treatment involves wearing cuffs around the legs that inflate and
deflate in sync with the heartbeat to improve blood flow to the
heart. It can help reduce angina symptoms in patients who are not
candidates for other surgical procedures.
These procedures are typically considered when lifestyle changes and
medications are not sufficient to manage angina symptoms.
Stenosis in coronary artery
 Anti-Angina Therapy – Summary

• Understand the nature of angina

• Understand the role of the endothelium in maintaining vascular
tone,
– the role of NO
• Know the drugs commonly used for treating angina symptoms
• beta-adrenergic antagonists,
• calcium channel blockers,
• organic nitrates
• Be aware of non-pharmacological options (eg stenting)
• Be aware of the need to threat the underlying causes of angina
(cardiovascular disease CVD) with anti-platelet agents (eg
aspirin / clopidogrel) and lipid-lowering agents (eg statins)
in the long-term treatment of patients with Angina