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Recent Trends in the Pharmacotherapy of Angina Pectoris

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IOSR Journal Of Pharmacy
(e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219
Volume 10, Issue 5 Series. I (May 2020), PP. 01-13 www.iosrphr.org

Recent Trends in the Pharmacotherapy of Angina Pectoris

Godswill J. Udom,1, 2Daniel E. Effiong,3*Nkechi J. Onyeukwu,1 Daniel N.
Obot,4Mfonobong Alozie,3 and Omoniyi K. Yemitan,5
1
Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Uyo, PMB 1017 Uyo,
Nigeria
2
Gimmex Health Consult, Suites B6 Real Towers Complex, 26 Ekukinam Street, Utako District, Abuja, Nigeria
3
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Uyo, PMB
1017 Uyo, Nigeria
4
Department of Clinical Pharmacology and Therapeutics, Faculty of Clinical Sciences, University of Uyo, PMB
1017 Uyo, Nigeria
4
Department of Pharmacology, Therapeutics and Toxicology, Lagos State University College of Medicine,
Lagos, Nigeria
*corresponding author:Godswill J. Udom,
Received 28 May 2020; Accepted 16-June 2020

Abstract
Background and Objectives: Angina pectoris,a pain from the heart felt in the pectoral regionsof the upper
chest,is a predominant symptom of ischemicheart disease caused by transient episodes ofmyocardial ischemia.
The traditional medications for the treatment were discovered about 60years ago. The current presentations and
complications associated with angina are hardly well catered for by such medicines and present daymanagement
keeps evolving. The need for bringing health practitioners and researchers up to speed with recent advances in
drug management of angina pectoris becomes essential.
Methods: This review examines published literature of the last 3 decades on the recent pharmacotherapeutic
approaches to angina pectoris management.Online search of published literature from reputable sources of
pubmed, researchgate and google scholar were used as well as offline search from the pharmacy library resource
centre of the Faculty of Pharmacy, University of Uyo, Nigeria.
Results: This work reveals that currently, while the beta blockers, calciumchannel blockers and nitrates are
conventional first-line drug of choice, their limitation in being transitory is significant. Newer techniques are
more effective in refractory angina cases and are typically a combination of more than just pharmacotherapeutic
agents.
Conclusion: Poorly controlled angina still poses serious concern in a number of patients with ischemic heart
disease and current strategies is a combination therapy that targets cellular processes, altering lipid metabolism
or promoting angiogenesis, thus resulting in sustainable benefit that can improve not just the clinical outcome
of the diseasebut also add to patients quality of life.
Keywords:Pharmacotherapy, angiogenesis, angina, lipoprotein apheresis

I. INTRODUCTION
In humans, the heart is a muscular structure that serves as two separate pumps i.e. the right heartthat
pumps blood through the lungs, and the left heartthat pumps blood through the peripheral organs. Descriptively,
both the right and left hearts function distinctly asa pulsatile two-chamberpump composed of an atrium and a
ventricle.Eachatrium is a weak primer pump for the ventricle, and aids blood movement into the ventricle. The
ventricles then supply the mainpumping force that propels the blood either (1) through the pulmonary
circulationby the right ventricle or (2) through the peripheral circulation by the leftventricle.The very essence of
these muscular pumps is to ensure adequate tissue perfusion (supply of oxygen and nutrients) and removal of
waste materials. Since tissue perfusion is necessary for optimal cellular health, the heart which is an aggregate
of tissues must be perfused and this is done by the coronary arteries.
The narrowing or eventual blocking of the coronary arteries due to plaque formation otherwise known
as coronary artery diseases (CAD) predisposes an individual to many cardiovascular disorders including
ischemic heart disease, coronary heart disease (CHD), myocardial infarction, congestive heart failure (CHF)
amongst others. Angina pectorisis the primary symptom of ischemicheart disease and is caused by transient
episodes ofmyocardial ischemia (Michel and Hoffman, 2011).
Worldwide, angina is a highly prevalent condition. In the United States alone, it is estimated that more
than 8.2 million patients suffer from angina(Rosamond et al.,2008; Mozaffarian et al., 2016).Most certainly, the

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

condition is a major cause of poor quality of life, disability, and high heath care cost. Treatment for angina is
challenging, especially in the face of recalcitrant cases, thus priority has been to evolve newer and improved
strategies on the management of the condition (Ballaet al., 2018). This work is thus aimed at examining
medicines of choice in the management of angina and brings readers up to speed with the current advanced
pharmacotherapeutic options. This will help practitioners to choose effective, evidenced-based current options
for positive clinical outcomes as well as improved quality of life of patients.

II. MATERIAL AND METHODS

Published articles on the pharmacotherapeutic approaches to the management of angina pectoris,in the
last 20 years were sourced for in this review.Online search of published literature from pubmed, researchgate
and google scholar were used as well as offline search from the pharmacy library resource centre of the Faculty
of Pharmacy, University of Uyo, Nigeria. Search terms used were ‗angina pectoris‘, ‗management of angina‘,
‗medicine use in angina‘, ‗type of angina and medicine use in them‘ and these revealed altogether more than
1270 articles. Similar search words were checked in indexes and appendices of hard copies of books on
pharmacology and therapeutics consulted. Some of the articles in one search engine were duplicated in the other
hence the duplicates excluded. Other exclusion criteria were articles older than 30 years containing
recommendations for drug therapy of angina, articles on surgical approaches to angina management as well as
those on alternative methods to orthodox management of angina.

Aetiology of Angina Pectoris

Angina pectoris is a consequence of an imbalance in themyocardial oxygen supply-demand
relationship. Thisimbalance may be caused by an increase in myocardial oxygen demand or by a decrease in
myocardial oxygen supply or sometimes by both (Figure 1). Myocardial oxygen demand is determined by the
heart rate, contraction of the ventricles, and tension on the walls of the ventricles while coronary blood flow is
the primary determinant of myocardial oxygen supply. However, this supply may be occasionallymodified by
the oxygen-carrying capacity of the blood.Oxygenated blood is delivered to the myocardium via epicardial
coronary arteries that branch into arterioles, and the latter further branches into a network of capillaries.
Physiologically, the epicardial coronary arteries are a low resistance system and changes in the tone of the
arterioles is responsible for the auto regulation of blood flow. Also, circulation of blood through the coronary
arteries is chiefly determined by cross sectional stenosis. Once developed, the arterioles dilate to maintain
myocardial blood flow. When there is increase in myocardial oxygen demand, arterioles dilate in response to
nitric oxide, prostaglandins, carbon dioxide, hydrogen ion, adenosine, and other nucleotides (Duncker and
Bache, 2008). Through this mechanism, blood flow to normal myocardium can be augmented four to five-fold.
This is the coronary flow reserve or myocardial perfusion reserve. Plaques resulting from atherosclerosis,
narrow the lumen and increase the resistance of the epicardial coronary arteries. Despite its physiological
usefulness, persistent epicardial coronary stenosis (>70%), might result in inadequate blood supply to the
myocardium even at rest, culminating in ischemia and primary angina (Epsteinet al., 1985; Talbert,2014).
Myocardial oxygen supply also depends on some other factors such as collateral blood flow, left-
ventricular end diastolic pressure (known to reduce the perfusion pressure from epicardium to endocardium
capillaries), and diastolic-perfusion time (which is related to the heart rate and aortic diastolic pressure-product).
This is so especially as myocardial perfusion mostly occurs during diastole. Oxygen is the critical substrate for
energy production as adenosine triphosphate (ATP) in cardiac muscle cell. Myocardial oxygen requirement
depends on myocardial wall stress, myocardial contractility, systolic blood pressure, and the heart rate. In
addition, myocardial energy need depends on the systolic wall stress and left-ventricular mass. For example, the
myocardial energy need may increase up to four-fold in aortic stenosis and three-fold in essential hypertension
(Strauer, 1979).

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

Figure 1. Myocardial oxygen supply-demand relationship showing the hemodynamic sites for therapeutic
agents.
(Source: Bruntonet al.,2011)

Angina pectoris refers to the pain from the heart felt in the pectoral regionsof the upper chest (Guyton
and Hall, 2006). This pain usually radiates intothe left neck area and down the left arm (Figure 2). Put simply,
this is a visceral pain whose specific underlying mechanisms for pain generation are not entirely understood.
Myocardial ischemia leads to acidosis and loss of normal ATP sodium-potassium pump and membrane integrity
(Jain et al., 2017). Release of substances such as adenosine, lactate, serotonin, bradykinin, histamine, and
reactive oxygen species stimulate chemo-sensitive receptors (Figure 2). Stimulation of afferent sympathetic
fibres in the upper thoracic spinothalamic tract leads to chest and arm pain symptoms,while the stimulation of
vagal afferent fibres leads to excitation of cervical spinothalamic tracts which may result in neck and/or jaw pain
symptoms.

Figure 2. Schematic presentation of mechanisms and pathways involved in cardiac chest pain:Ischemic
myocardium releases nociceptive mediators that stimulate excitatory spinal and vagal afferent fibres.
Somatic fibres also converge on upper thoracic and cervical spinal segments as shown, leading to referred
pain. NTS = Nucleus TractusSolitarius.
(Source: Jain et al., 2017).

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

The biophysics of circulation suggests an inversely proportional relationship of blood flow to the fourth
powerof the artery‘s luminal radius, thus the progressive decreasein the radius or diameter of the coronary
arteries due to atheroma impairs coronary blood flow and lead to symptomsof angina when myocardial oxygen
demand increases,as with exertion, cold or excitement (Michel and Hoffman, 2011; Rang et al., 2012).In most
cases, there is a weak relationship between pain severity and degree of oxygen supply. In other words, there can
be severe pain but minimal disruption of oxygen supply or no pain, yet severe cases. As reported by Fisher
(2015), the traditional risk factors for coronary artery disease include the following:

 High levels of LDL cholesterol

 Low levels of HDL cholesterol
 Smoking
 High blood pressure
 Family history
 Obesity and
 Age (men above 45 years and post-menopausal women)

Historical background of Angina Pectoris and its Pharmacotherapy

Medical history points to the first mention of angina pectoris in 1772 by William Heberden during his
paper presentation entitled ―Some account of the disorders of the breast‖ at the Royal College of Physicians in
London (Zhou et al., 2005). He wrote ―There is a disorder of the breast…the seat of it, and sense of strangling
and anxiety, with which is attended, may make it not improperly be called angina pectoris. Those, who are
afflicted with it, are ceased [sic] while they are walking and most particularly when they walk soon after eating,
with a painful and most disagreeable sensation in the breast, which seems as it would take their breathe away, if
it were to increase or to continue; the moment they stand still, all this uneasiness vanishes‖.
Despite his first attempt at describing this heart condition, Heberden, obviously did not fully
comprehend the pathogenesis and pathophysiology of angina pectoris. In fact, he had inaccurately
describedoccurrence of angina pectoris as a strong cramp, an ulcer, or both.
According to Jain et al. (2017), for some 3,500 years ago, pain felt within the chest area and arm, in
relation to heart disease were experienced by the ancient Egyptian mummies. Furthermore, Liang et al. (2012)
reported that these mummies had atherosclerosis as was revealed by computed tomography.Of interest to us is
the fact that this finding was observed in renowned and highly placed Egyptian mummies. Though it is difficult
to pinpoint exactly when the civil society first became aware of heartconditions associated with ischemia,
however, as reported by Liu et al. (2007), Leonardo da Vinci (1452–1519)investigated the coronary arteries;
William Harvey (1578– 1657) described the blood circulation, while Friedrich Hoffman (1660–1742) observed
a ―reduced passage of blood within the coronary arteries,‖ though none of these investigations closed the link
with the condition now known as angina pectoris.
Angina was first linked with cardiovascular disease (CAD) by Edward Jenner, and he described the
coronary arteries with these words: ―a fleshy tube with a considerable quantity of ossific material dispersed
irregularly through it‖ (Liu et al., 2007). Lauder Bruntonimplicated the spasm of coronary vessels in the
aetiogenesis of angina, while other theories linked the condition to irritation of the nervous elements of the
cardiac plexus (Liu et al., 2007).
The varying ideas as regards the aetiology of angina pectoris potentiated diverse treatment options.
Heberdenoffered a ―quiet, warmth, and spirituous liquors‖ as well as opium, administered in the evenings as
prophylaxis. According to him, opium prevents nocturnal anginal crises.In 1867, Thomas Brunton suggested
amyl nitrite to cause symptomatic relief of angina pectoris, and this was the first treatment option with scientific
credence (Liu et al., 2007). In 1879, W.M. Morrell had reportedthat nitroglycerineadministered in alcohol could
relieve the symptoms of angina pectoris (Gauthieret al., 1996). James Black correctly associated episodes of
angina with emotions, exercise or physical exertion and strongly proposed the usefulness of beta blockers in the
management of angina pectoris, thus, in 1965 propanolol became the first clinically available beta-receptor
blocker (Elgendyet al., 2014). Albert Fleckenstein and colleagues, while investigating the properties of
prenylamine and verapamil (coronary dilators), observed that besides the expected coronary vasodilation, the
drugs provoked a negative inotropic effect on the heart, which was obliterated by calcium. Following their
conclusion that the observed negative inotropic action was due to the ability of prenylamine and verapamil to
block excitation-induced calcium influx, drugs tagged as calcium channel blockers or calcium antagonists were
introduced (Lertoraet al., 1975). Subsequently, these 3 classes of drugs (nitrates, beta blockers and calcium
channel blockers) are currently labelled by the guidelines as―first-choice‖ in the management of angina pectoris.

Types of Angina Pectoris

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

Basically, there are four types of angina pectoris, namely: Stable angina, unstable angina, microvascular angina
and prinzmetal‘s angina.
i. Stable Angina: This is otherwise known as typical, classic or effort-induced angina, and refers to a
predictable chest pain on exertion. It is produced by an increased demand on the heart and is caused by a
fixed narrowing of the coronary vessels, almost always by atheroma.Classic angina is the most common
form of angina and, therefore, is also called typical angina pectoris. It is usually characterized by a short-
lasting burning, heavy, or squeezing feeling in the chest. Some ischemic episodes may present
―atypically‖—with extreme fatigue, nausea, or diaphoresis—while others may not be associated with any
symptoms (silent angina). Atypical presentations are more commonin women, diabetic patients, and the
elderly.Classic angina is caused by the reduction of coronary perfusion due to a fixed obstruction of a
coronary artery produced by atherosclerosis. Due to the fixed obstruction, the blood supply cannot increase,
and the heart becomes vulnerable to ischemia whenever there is increased demand, such as that produced by
physical activity, emotional stress or excitement, or any other cause of increased cardiac workload.
ii. Unstable Angina: Unstable angina is classified between stable angina and myocardial infarction. In
unstable angina, chest pain occurs with increased frequency, duration, and intensity and can be precipitated
by progressively less effort. Manifestations of unstable angina could be expressed in the following ways:
Any episode of rest angina longer than 20 min, any new-onset angina, any increasing (crescendo) angina, or
even sudden development of shortness of breath. The symptoms are not relieved by rest or nitroglycerine.
Unstable angina is a form of acute coronary syndrome and requires hospital admission and more aggressive
therapy to prevent progression to MI and death. 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.
iii. Microvascular Angina:Acute coronary syndrome is an emergency that commonly results from rupture of
an atherosclerotic plaque and partial or complete thrombosis of a coronary artery. Most cases occur from
disruption of an atherosclerotic lesion, followed by platelet activation of the coagulation cascade and
vasoconstriction. This process culminates in intraluminal thrombosis and vascular occlusion. If the
thrombus occludes most of the blood vessel, and, if the occlusion is untreated, necrosis of the cardiac
muscle may ensue. MI (necrosis) is typified by increases in the serum levels of biomarkers such as
troponins and creatine kinase. The acute coronary syndrome may present as ST-segment elevation
myocardial infarction, non–ST-segment elevation myocardial infarction, or as unstable angina. (Note: In
unstable angina, no increases of biomarkers of myocardial necrosis are present).
iv. Prinzmetal’s Angina: Prinzmetal angina is an uncommon pattern of episodic angina that occurs at rest and
is due to coronary artery spasm. Symptoms are caused by decreased blood flow to the heart muscle from the
spasm of the coronary artery. Although individuals with this form of angina may have significant coronary
atherosclerosis, the angina attacks are unrelated to physical activity, heart rate, or blood pressure.
Prinzmetal‘s angina generally responds promptly to coronary vasodilators, such as nitroglycerineand
calcium channel blockers. This is uncommon. It occurs at rest and is caused by coronary artery spasm,
again usually in association with atheromatous disease.

Strategic Management of Angina Pectoris

Generally, the goal of therapy is to reduce myocardial oxygen demand, which is achieved via reduction
in the heart‘s firing rate (HR), and to increase coronary blood flow via vascular smooth muscle relaxation. Since
atherosclerotic plaque is implicated in the pathogenesis of angina, management of risk factors for progression of
atherosclerosis becomes essential. Therefore, lifestyle modification and prevention of progression of underlying
atherosclerosis isthe mainstay of management.

First-line Pharmacotherapy Options

The 3 classes of drugs currently labelled by the guidelines (Figure 3) as―first-choice‖or ―traditional drugs‖ in
treatment of angina pectoris are:

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

Figure 3. Algorithm for the management of stable angina pectoris

Source: Whalenet al., (2015).

iBeta-adrenergic Blockers
These drugs are known to modulate and/or inhibit the endogenous ligand binding to the beta adrenergic
receptors. There are three types of beta receptors. B 1 receptors, found primarily in the heart, and their activation
leads to increased contractility and heart rate (HR). B2 receptors are primarily located in the bronchial and
peripheral smooth muscle. Their activation results in vasodilation and bronchodilation. B 3 receptors are mainly
found in adipose tissue but also in the heart, and their activation helps with thermoregulation and decrease
myocardial contractility (Elgendyet al., 2014; 2016). Beta adrenergic inhibitors decrease myocardial oxygen
demand by slowing down the heart rate, reducing myocardial contractility, and blood pressure. They also
increase the time for coronary perfusion by decreasing HR and increasing diastolic time, thus favourably
altering the determinants of collateral perfusion.
The beta blocking drugs can be classified according to the adrenergic receptors that they block. Drugs
that principally block B1 receptors, preferentially to B2 or B3, are commonly referred to as ―relatively‖ cardio-
selective. The qualifier ―relatively‖ is fitting because at higher doses the selectivity may become partially or
completely lost (Lertoraet al., 1975; Jain et al., 2017). The non-selective beta blocker propranolol was first
introduced for clinical use and was shown to reduce angina episodes by more than 50% when compared with
placebo (Warren et al., 1976). Carvedilolis another commonly used drug. Althoughnot approved for the
management of angina pectoris, it is a non-selective beta blocker with α-1 receptor blocking properties. Non-
selective beta antagonists should be avoided in patients with asthma because of their ability to cause
bronchospasms. As reported by previous studies (Yonget al.,2015; Furberget al., 1978; Jackson et al., 1978),
cardio-selective agents such as atenolol and metoprolol were effective in improving exercise tolerance and
decreasing angina, with minimal and tolerable side effects compared to other non-selective agents like
propranolol. These cardio-selective agents (i.e.,metoprolol and atenolol) are considered the first line therapy for
angina. Nebivolol is another newer agentwith selective antagonism for B 1and a vasodilating effect made possible
by the stimulation and release of nitric oxide (Kobusiak-Prokopowiczet al., 2008).Though not approved as an
antianginal drug, nebivololis being investigated for microvascular angina relief in women in an on-going trial
[NCT01665508]. Beta blockers are recommended as first-line therapy for patients with angina chiefly because
they improve angina, reduce the risk of re-infarction, sudden cardiac death as well as all-cause mortality in post-
myocardial infarction and systolic heart failure patients (Packer et al., 1996). Because of fair tolerance profile,
beta blockers (cardio-selective) are widely used. Generally, the pharmacologically action of the beta blockers
and its attendant effect on angina pectoris are thought to be dose-dependent (Alderman et al., 1975; Jackson et
al., 1980).Common adverse effects of this class of drugs include:
 Depression,
 Fatigue,
 Male sexual dysfunction,
 Enhancement of hypoglycaemia and
 Increase weight gain.

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

ii Calcium Channel Blockers

Calcium is essential for muscular contraction. Influx of calcium ion into the cardiomyocytes triggers
intracellular release of calcium, potentiating myocardial contractility. During ischemia, the amount of calcium
entering the myocardium increases, primarily due to the membrane depolarization produced by tissue hypoxia.
This in turn, worsens the ischemia due depletion in energy stores brought about by enhanced activities of several
ATP-consumingenzymes (Mulqueen, 2015). Calcium channel blockers inhibit the entry of calcium into the
cardiac and smooth muscle cells of the coronary and systemic arterial beds. The overall effect of this is seen as a
reduction in the heart‘s firing rate, decreased myocardial contractility, vasodilation anddecreased blood pressure.
All calcium channel blockers are, therefore, tagged ―arteriolarvasodilators that cause a decrease in smooth
muscle tone and vascularresistance‖(Mulqueen, 2015). Calcium channel blockers exert their effects primarily by
decreasing vascular resistance, thereby decreasing afterload leading to a reduction in myocardial oxygen
consumption.Therefore, they are efficacious in the treatment of effort-induced angina. Their efficacy in
vasospastic angina is due to relaxation of the coronaryarteries.
Traditionally, calcium channel blockers are classified based on their chemical composition either as:
i. Dihydropyridines (e.g.,nifedipine, amlodipine, and nicardipine) or
ii. Non-dihydropyridines (e.g., verapamil and diltiazem).

Dihydropyridinesexert greater effect on the vascular smooth muscle than the cardiac musculature. As a
result, they cause vasodilation of the peripheral vasculature including the coronary arteries. However, these
agents elicit reflex adrenergic stimulation of the heart; hence they do not significantly affect contraction of the
cardiac muscles and the heart rate.On the other hand, non-dihydropyridinespreferably act on the calcium
channels in the myocardium, provoking a relatively more coronary vasodilation, against myocardial contractility
and heart rate. Though a non-dihydropyridine, diltiazemisintermediary in its actions (Mulqueen, 2015; Jain et
al., 2017).
As reported by earlier researchers, calcium channel blockers are more effective in relieving angina and
increasing exercise tolerance (Krikler, 1987; Taylor 1994).When combined, beta blockers and calcium channels
antagonists exert synergistic but not additive effects compared to monotherapy(Strauss andParisi,1985; Leon et
al., 1985; Dunselmanet al., 1997). It is worthy of note that though the combination of non-dihydropyridines with
beta adrenergic antagonists proves to be more effective, it is with higher risk of adverse effects like heart
palpitations,bradycardia, syncope as well as GIT intolerance (Strauss andParisi,1985;Knight and Fox,1998). In
patients who cannot tolerate the beta antagonists, then non-dihydropyridines are considered as safe alternatives.
Also, inpatients with vasospastic angina, the calcium antagonists are considered as the ‗choicest drugs‘(Harris et
al., 2016). Due to their negative inotropic effects, non-dihydropyridines worsens heart failure, and must be
avoided in patients with congestive heart failure.

iiiNitrates
Organic nitrates (Isosorbide-5-mononitrate, Nitroglycerine and Isosorbide dinitrate) are among the
first line therapy for angina pectoris because of their relaxation effects on the vascular smooth muscle. On
entering the smooth muscle cells, they are usually converted to nitrites and finally to nitric oxide. The nitric
oxide activates the enzyme guanylate cyclase and increases cyclic guanosine monophosphate(cGMP) production
in the smooth muscle cells. This provokes dephosphorylationof the myosin light chain, culminating in vascular
smooth muscle relaxation. According to Abrams (1985; 1992), at very low, low to moderate and high doses,
cGMP causes venodilatation, arterial dilatation, and arteriolar dilatation respectively. For example,
nitroglycerindilates larger veins, reducing the venous return to the heart (preload), and this ultimately reduces
myocardial contraction or the work load of the heart (Mulqueen, 2015). Nitrates also reduces myocardial oxygen
demand by dilating the coronary vasculature, thus blood supplyto the heart muscle is greatly increased.
Mostly, headache is the common adverse effect of nitrates reported (Weiet al., 2011). However, at
doses high than normal, postural hypotension, facial flushing, andtachycardia may occur. These adverse events
are potentiated by the 5-phosphodiesterase inhibitors (e.g.,sildenafil), and thus such combination is
contraindicated.Nitrate tolerance (i.e. the desensitization of the blood vessels to vasodilation), is a major
problem with long-term use of this class of drug. This can be alleviated by ensuring a daily ―nitrate-free interval
(10 – 12 hours)‖ to restore sensitivity of the blood vessels to thedrug. However, the drug-free interval poses the
theoretical risk of a rebound angina. As reported by Giuseppe et al. (2015), chronic or long-term use of organic
nitrates is implicated to induce oxidative stressand endothelial dysfunction (due to increase sympathetic
stimulation).Takahashi et al. (2015) associated the combination of long acting nitrates with calcium channel
blockers patients with increased risk of adverse cardiovascular events in patients with vasospastic angina. Figure
4 summaries the drugs commonly used in therapy in patients with concomitant or other underlying disease
conditions.

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

Figure 4. Therapy for angina in patients with comorbidities

(Source: Whalenet al.,2015).

Second-line Pharmacotherapy Options

The following drugs are considered internationally as second line for the therapy of angina pectoris:

iSodium Channel Antagonists

Ranolazineis a sodium channel blocker used in the treatment of angina pectoris. It inhibits the late
phase of the sodium current (INa), reducing myocardial intracellular sodium and calcium overload, balancing the
myocardial oxygen supply and demand equation, and ultimately improving diastolicfunction (Chaitman, 2006;
Mulqueen, 2015; Saadet al., 2016). The drug is indicated for the treatment of chronic angina and may be usedas
a monotherapy or in combination with other traditional therapies. However, the drug is oftenused in patients that
failed to respond to the first-line therapies. Ranolazineis extensively metabolized in the liver, mainly by the
CYP3A family andalso by CYP2D6. It use necessitate caution especially in polypharmacy involving QT
interval prolonging medications. This is so because ranolazine itself prolongs the QT interval.

a Direct Sinus Node Inhibitor

Elevated heart rate is often associated with heightened risk of cardiovascular crises in patients with
stable ischemic heart disease. This class of drug is believed to inhibit the activities of the pacemaker of the heart
or the sinoatrial node, thereby reducing the heart rate. The sinus node has some channels tagged as ―funny‖
channels (f-channels), and these channels are the target site for drug action. The only drug in this class that has
been approved for this purpose is Ivabradine®.

b Metabolic Modulation
Agents known to inhibit fatty acid metabolism have been exploited in the treatment of ischemic heart
disease. One of such drug is Trimetazidine®which is recommended in the European guidelines as a second-line
antiaginal drug (Montalescotet al., 2013). The drug inhibits fatty acid metabolism while stimulating glucose
metabolism (secondary action) thereby increasing cellular tolerance to ischemia.As reported by Szwedet al.,
(2001), the addition of trimetazidine to metoprolol in a randomized controlled trial demonstrated 46% reduction
in nitroglycerin consumption, 47%reduction in frequency of anginal crises as well as 15% increase in exercise
tolerance. Furthermore, Ciapponiet al., (2005) reported that a meta-analysis of 23 studies demonstrated
trimetazidine to be a potent antianginal agent; based on its ability to reduce the frequency of the attacks and
reduction in the use of organic nitrates regardless of whether or not it is administered alone or in combination
with other anginal medications.

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 Recent Trends in the Pharmacotherapy of Angina Pectoris

iiPotassium Channel Stimulants

A typical example of this class of drug is nicorandil. It is a potent vasodilator and causes vasodilation
by stimulating the potassium channels. The drug is recommended inthe European guidelinesas a second-choice
drug for the treatment of angina pectoris.In a randomized angina trial, nicorandilsignificantly reduced the risk of
the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction, or unplanned hospital
admission for chest pain. This was primarily due to a reduction in the risk of angina requiring hospital admission
(Jain et al., 2017).

Miscellaneous Agents
The following are other agents seldom used in the treatment of angina:
i. Allopurinol/Febuxostat: Allopurinol decreases the amount of uric acid produced either directly or
indirectly. By inhibiting the enzyme xanthine oxidase, the production of uric acid is directly reduced. Whereas
the decrease in purine synthesis by feedback inhibition of amidophosphoribosyltransferase, is the indirect
approach. The exact mechanism of this anti-ischemic effect of allopurinol is unclear, but xanthine oxidase
inhibition can reduce oxidative stress. Rajendraet al., (2011) reported that in patients with stable coronary artery
disease, 600 mg/day of allopurinol significantly improved vasodilation of the coronary vesselland completely
abolished oxidative stress related with the condition. Febuxostatis also a potent xanthine oxidase inhibitor.
Specifically, it is a non-purine selective inhibitor of this enzyme, which is actively involved in uric acid
production. Thus, by potently and selectively inhibiting it, Febuxostatreduces formation of uric acid and its
effect is comparatively greater to that of allopurinol. The agent significantly reduces and/or improved oxidative
stress (seen in virtually all disease conditions, including angina). However, there is paucity of evidence from
clinical trials to validate its use in the therapy of angina pectoris. Perhaps, on its completion, the on-going
double-blind randomized trial on the therapeutic usefulness of febuxostat in CAD patients
(https://clinicaltrials.gov/ct2/show/NCT01763996) may provide more details on its possible use in the therapy of
angina pectoris.
ii. Testosterone: Evidence suggests that hormones may be good candidates for angina therapy. For
example, Chou et al. (1996) reported testosterone to cause significant coronary artery dilatation and a
corresponding increase in coronary blood flow in man. The mechanism of this action very likely relates to the
physiology of ionic channels on vascular smooth muscles. According to Rosanoet al., (1999), testosterone
improves endothelial dysfunction and may be an effective candidate for angina pectoris. Earlier studies revealed
the anti-ischemic benefits of testosterone delivered transdermally (English et al., 2000), intramuscularly (Jaffe,
1977), and orally (Wu and Weng, 1993). Webb et al., (1999) demonstrated increased coronary artery diameter
and coronary blood flow in male patients with coronary artery disease with intracoronary infusion of
testosterone, confirming its coronary vasodilation effect. Till date, the therapeutic value of testosterone
replacement for angina pectoris remains an important lacuna.

Novel Therapies for Angina Pectoris

i. Therapeutic Angiogenesis: this is a novel promising approach (still under investigation) for the
management of refractory angina. It is focused on the regeneration of the dysfunctional or damaged
coronary microvasculature. Despite advances in medical and revascularization management of angina,
some patients remain refractory to therapy, and thus, are not suitable candidates for revascularization
(Mukherjee et al., 2001). In corroboration with the findings of Carmelietet al., (2000), by enhancing
neovascularization, therapeutic angiogenesis, may potentially raise the threshold for ischemia and
hence improve angina. Admittedly, use of angiogenic genes therapy, proteins and stem cell therapy are
options with promising outcomes. However, the associated challenges includes: (1) isolation of key
genes and cells, (2) identifying the relevant intracellular signalling processes, (3) development of
compounds that alter genetic expression, (4) autologous extraction and isolation of effective progenitor
cells (Jain et al., 2017), (5) identifying the optimal route and timing for delivery of active
compounds/cells, (6) the presence of co-morbid conditions (diabetes, atherosclerosis, amongst others)
that can inhibit angiogenic signalling (Simons, 2009) as well as (7) advanced patient age (Tirziu and
Simons, 2005). Aberrant vascular proliferation in adjacent and/or distant non-targeted tissues,
triggering the growth of coexisting neoplasms or the development of de novo tumours; hazards
associated with viral vectors; and hazards associated with direct myocardial delivery of angiogenic
factorsare the several potential complications associated with therapeutic angiogenesis.As earlier noted
by Jain et al. (2017), there are multiple clinical trials with different agents and varied results. Some
angiogenic factors that have been extensively investigated and being tried include the
Vascularendothelial growth factors (VEGF), fibroblast growth factor(FGF), platelet-derived growth

9
 Recent Trends in the Pharmacotherapy of Angina Pectoris

factors, PDGF and the angiopeitin-1. Therefore, despite the numerous potential complications, only
few significant complications have been observed in angiogenesis trials to date.
ii. Lipoprotein Apheresis: This process of removal of lipoprotein from the blood circulation either by
filtration, adsorption or precipitation is a modern effective method for angina therapy, particularly those related
to resistant hypercholesterolemia.This procedure is made possible using pharmacotherapeutic agents. This is so
whether it is used before (Alirocumab, Evolocumab), with the LA methods (using heparin and citrates)or post
apheresis procedure to reduce concomitant LA(Lomitapide, a microsomal transfer protein inhibitor) (Ulrich
2018). As reported by Khan (2016), lipoprotein apheresis resulted in significant improvements compared to
sham therapy in patients with refractory angina who had elevated lipoprotein Lp(a). The author reported a study
of randomized 20 patients with refractory angina and Lp(a) levels >500mg/L to weekly lipoprotein apheresis or
sham treatments over a 3-month period with a 1-month washout period, and reported a significant increase in
myocardial perfusion reserve, improved carotid wall volume and dispensability after apheresis, improved
exercise capacity, angina as well as improved quality of life (Khan, 2016).This is the first evidence that shows a
link between the reduction of lipoproteins and improved circumstances in patients with refractory angina.
iii. Other Novel Therapies: other novel therapies for angina still under investigation include coronary
sinus reduction (Banaiet al., 2007), external counter-pulsation - ECP (Arora et al., 1999; Soranet al.,
2006),spinal cord stimulation – SCS(Mannheimeret al., 1996) and trans-myocardial laser revascularization –
TMLR (Frazier et al., 1999).

III. CONCLUSION
The goal of pharmacotherapy for angina is to correctthe mismatch between perfusion and workload.
Till date, the beta-adrenergic receptor blockersare the most studied as well as the only antianginal drugs with
clear evidence for reduction in mortality. However, this is limited to those with recent myocardial infarction or
severe systolic left-ventricular dysfunction. Like the beta blockers, the calcium channel inhibitors and nitrates
are also mostlystudied and reliable for therapy of angina. They provide symptomatic relief and are better
tolerated than the beta blocking drugs. The issue with these classes of drugs is that they often times do not seem
to reduce frequency of mortality. Despite the applauded advances in medical therapy and revascularization
techniques, poorly controlled angina still poses serious concern in a greater number of patients with ischemic
heart disease. Most recent strategies target cellular processes to alter metabolism or promote angiogenesis, and
thus result in a sustainable benefit that can improve not just the clinical manifestations of the disease, but also
the patient‘s quality of life and reduction in mortality. The on-going researches in this field are promising with
keen anticipation for tremendous breakthroughs.

REFERENCES
[1]. Abrams, J. (1985). Hemodynamic effects of nitroglycerin and long-acting nitrates. American Heart
Journal, 110(1 Pt 2):216– 224.
[2]. Abrams, J. (1992). Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia.
American Journal of Cardiology, 70(8):30b–42b.
[3]. Alderman, E. L., Davies, R. O., Crowley, J. J. et al., (1975). Dose response effectiveness of propranolol
for the treatment of angina pectoris. Circulation, 51(6):964– 975.
[4]. Anonymous (No date). The influence of febuxostat on coronary artery endothelial dysfunction in
participants with chronic stable angina. Https://clinicaltrials.gov/ct2/show/NCT01763996 (Retrieved on
30th January 2020).
[5]. Arora, R. R., Chou, T. M., Jain, D. et al., (1999). The multicenter study of enhanced external counter-
pulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
Journal of American College Cardiology, 33(7):1833–40.
[6]. Banai, S., Ben,Muvhar, S., Parikh, K. H. et al., (2007). Coronary sinus reducer stent for the treatment of
chronic refractory angina pectoris: a prospective, open-label, multicenter, safety feasibility first-in-man
study. Journal of American College Cardiology, 49(17):1783– 1789.
[7]. Basaria, S., Coviello, A. D.,Travison, T. G. et al., (2010). Adverse events associated with testosterone
administration. New England Journal of Medicine, 363(2):109– 122.
[8]. Brunton, L.L., Chabner, B. A.and Knollmann, B. C. (2011). Goodman & Gilman’s The Pharmacological
Basis of Therapeutics. 12th Edition. The McGraw-Hill Companies, New York, 746p.
[9]. Carmeliet, P. (2000). Mechanisms of angiogenesis and arteriogenesis. Natures Medicine, 6(4):389– 395.
[10]. Chaitman, B. R. (2006). Ranolazine for the treatment of chronic angina and potential use in other
cardiovascular conditions. Circulation, 113(20):2462– 2472.
[11]. Chou, T. M., Sudhir, K., Hutchison, S. J. et al.,(1996). Testosterone induces dilation of canine coronary
conductance and resistance arteries in vivo. Circulation, 94(10):2614– 2619.

10
 Recent Trends in the Pharmacotherapy of Angina Pectoris

[12]. Ciapponi, A., Pizarro, R., Harrison, J. et al., (2005).Trimetazidine for stable angina. Cochrane Database
System Reviews, (4):Cd003614.
[13]. Duncker, D. J. and Bache, R. J. (2008). Regulation of coronary blood flow during exercise. Physiology
Reviews, 88(3):1009– 1086.
[14]. Dunselman, P., Liem, A. H., Verdel, G. et al., (1997). Addition of felodipine to metoprolol vs
replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade.
Results of the Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Working Group on
Cardiovascular Research, the Netherlands (WCN). European Heart Journal, 18(11):1755– 1764.
[15]. Elgendy, I. Y., Bavry, A. A., Gong, Y. et al., (2016). Long-term mortality in hypertensive patients with
coronary artery disease: results from the US Cohort of the International Verapamil (SR)/Trandolapril
Study. Hypertension, 68(5):1110– 1114.
[16]. Elgendy, I. Y., Mahmoud, A., Conti, C. R. et al., (2014). Beta-blockers in the management of coronary
artery disease: are we on the verge of a new paradigm shift? Recent Pat Cardiovasc Drug Discov.
9(1):11–21.
[17]. English, K. M, Steeds, R. P., Jones, T. H. et al., (2000). Low-dose transdermal testosterone therapy
improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-
controlled study. Circulation, 102(16):1906–1911.
[18]. Epstein, S. E., Cannon, R. O.III., Talbot, T. L. et al., (1985). Hemodynamic principles in the control of
coronary blood flow. American Journal of Cardiology, 56(9): 4–10.
[19]. Fisher, E. A. (2015). Coronary artery disease – coronary heart disease. http://www.heart.org/en/health-
topics/consumer-healthcare/what-is-cardiovascular-disease/coronary-artery-disease (Retrieved on 2nd
January 2020).
[20]. Frazier, O. H., March, R. J.,Horvath, K. A. et al., (1999). Trans-myocardial revascularization with a
carbon dioxide laser in patients with end-stage coronary artery disease. New England Journal of
Medicine, 341(14):1021– 1028.
[21]. Furberg, B., Dahlqvist, A.,Raak, A.et al., (1978). Comparison of the new beta-adrenoceptor antagonist,
nadolol, and propranolol in the treatment of angina pectoris. Current Medical Research Opinion,
5(5):388– 393.
[22]. Gauthier, C., Tavernier, G.,Charpentier, F. et al., (1996). Functional beta3-adrenoceptor in the human
heart. Journal of Clinical Investigation, 98(2):556– 562.
[23]. Giuseppe, C., Paul, J., Hans-Ulrich, I. et al. (2015). Use of nitrates in ischemic heart disease. Expert
Opinion in Pharmacotherapy, 16(11):1567– 1572.
[24]. Guyton, A. C. and Hall J. E. (2006). Textbook of Medical Physiology. 11th Edition.Elsevier Saunders
Inc.Philadelphia, pp 291 – 293.
[25]. Harris, J. R., Hale, G. M.,Dasari, T. W.et al., (2016). Pharmacotherapy of vasospastic angina. Journal of
Cardiovascular Pharmacology and Therapeutics, 21(5):439– 451.
[26]. Jackson, G., Harry, J. D., Robinson, C. et al., (1978). Comparison of atenolol with propranolol in the
treatment of angina pectoris with special reference to once daily administration of atenolol. British Heart
Journal,40(9):998–1004.
[27]. Jackson, G., Schwartz, J., Kates, R. E.et al., (1980). Atenolol: once-daily cardio-selective beta blockade
for angina pectoris. Circulation, 61(3):555– 560.
[28]. Jaffe, M. D. (1977). Effect of testosterone cypionate on post-exercise ST segment depression. British
Heart Journal, 39(11):1217– 1222.
[29]. Jain, A.,Elgendy, I. Y., Al-Ani, M., Agarwal, N. and Pepine, C. J. (2017). Advancements in
pharmacotherapy for angina. Expert Opinion in Pharmacotherapy, 18(5): 457–469.
doi:10.1080/14656566.2017.1303483.
[30]. Khan, T. (2016). Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a
randomised controlled trial. European Society of Cardiology Congress, Rome, 27 – 31 August 2016,
Abstract 3170.
[31]. Knight, C. J. and Fox, K. M. (1998). Amlodipine versus diltiazem as additional antianginal treatment to
atenolol. Centralised European Studies in Angina Research (CESAR) Investigators. American Journal of
Cardiology, 81(2):133– 136.
[32]. Krikler, D. M. (1987). Calcium antagonists for chronic stable angina pectoris. American Journal of
Cardiology, 59(3):95b–100b.
[33]. Kobusiak-Prokopowicz, M., Jolda-Mydlowska, B.,Zubkiewicz, A. et al., (2008). Impact of nebivolol on
levels of serum nitric oxide, plasma von Willebrand factor and exercise stress testing parameters in
hypertensive and ischemic heart disease patients. Cardiology Journal, 15(2):162– 168.

11
 Recent Trends in the Pharmacotherapy of Angina Pectoris

[34]. Leon, M. B., Rosing, D. R., Bonow, R. O. et al., (1985). Combination therapy with calcium-channel
blockers and beta blockers for chronic stable angina pectoris. American Journal of Cardiology,
55(3):69b–80b.
[35]. Lertora, J. J., Mark, A. L., Johannsen, J. et al., (1975). Selective beta-1 receptor blockade with oral
practolol in man. A dose-related phenomenon. Journal of Clinical Investigation, 56(3):719– 724.
[36]. Liang, Z., Liu, L. F., Yao, T. M. et al., (2012). Cardio-protective effects of Guanxinshutong (GXST)
against myocardial ischemia/ reperfusion injury in rats. Journal of Geriatrics and Cardiology, 9(2):130–
136.

[37]. Liu, C. L., Xie, L. X., Li, M. et al., (2007). Salvianolic acid B inhibits hydrogen peroxide-induced
endothelial cell apoptosis through regulating PI3K/Aktsignalling. PloS One, 2(12):1321.
[38]. Mannheimer, C., Eliasson, T.,Augustinsson, L. E. et al., (1998). Electrical stimulation versus coronary
artery bypass surgery in severe angina pectoris: the ESBY study. Circulation, 97(12):1157– 1163.
[39]. Michel, T. andHoffman, B. B. (2011). Treatment of myocardialischemia and hypertension. In: L.L.
Brunton, B. A. Chabner and B. C. Knollmann (Editors) Goodman & Gilman’s The Pharmacological
Basis of Therapeutics. 12th Edition. The McGraw-Hill Companies, New York, pp 745 - 748.
[40]. Montalescot, G., Sechtem, U., Achenbach, S. et al., (2013). European Society of Cardiology guidelines
on the management of stable coronary artery disease: the Task Force on the management of stable
coronary artery disease of the European Society of Cardiology. European Heart Journal, 34(38):2949–
3003.
[41]. Mozaffarian, D., Benjamin, E. J., Go, A. S. et al., (2016). Heart disease and stroke statistics, 2016 update:
recent statistics on cardiovascular disease in America; a report from the American Heart Association.
Circulation, 133(4):38– 60.
[42]. Mulqueen, K. (2015). Antiaginal drugs. In: K. Whalen, R. Finkel andT. A. Panavelil (Editors) Lippincott
Illustrated Reviews: Pharmacology. 6th Edition.Wolters Kluwer, Philadelphia, pp 281 – 287.
[43]. Mukherjee, D., Comella, K., Bhatt, D. L. et al., (2001). Clinical outcome of a cohort of patients eligible
for therapeutic angiogenesis or trans-myocardial revascularization. American Heart Journal, 142(1):72–
74.
[44]. Packer, M., Bristow, M. R., Cohn, J. N. et al., (1996). The effect of carvedilol on morbidity and mortality
in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. *Landmark trial
showing reduction of mortality and re-hospitalization with carvedilol use in heart failure patients with
reduced ejection fraction.New England Journal of Medicine, 334(21):1349– 1355.
[45]. Rajendra, N. S., Ireland, S., George, J. et al., (2011). Mechanistic insights into the therapeutic use of
high-dose allopurinol in angina pectoris. Journal of American College of Cardiology,58(8):820– 828.
[46]. Rang, H. P., Dale, M. M., Ritter, J. M., Flower R. J. and Henderson, G. (2012). Rang and
Dale’sPharmacology. 7th Edition. Elsevier Inc., Philadelphia, pp 257 – 260.
[47]. Rosamond, W., Flegal, K., Furie, K. et al., (2008).Heart disease and stroke statistics 2008 update: a report
from the American HeartAssociation Statistics Committee and Stroke StatisticsSubcommittee.
Circulation, 117:25–146.
[48]. Rosano, G. M., Leonardo, F.,Pagnotta, P. et al., (1999). Acute anti-ischemic effect of testosterone in men
with coronary artery disease. Circulation, 99(13):1666– 1670.
[49]. Saad, M., Mahmoud, A.Elgendy, I. Y. et al., (2016). Ranolazine in cardiac arrhythmia. Clinical
Cardiology, 39(3):170– 178.
[50]. Simons, M. (2009). Diabetic monocyte and vascular endothelial growth factor signalling impairment.
Circulation, 120(2):104– 105.
[51]. Soran, O., Kennard, E. D.,Kfoury, A. G. et al., (2006). Two-year clinical outcomes after enhanced
external counter-pulsation (EECP) therapy in patients with refractory angina pectoris and left ventricular
dysfunction (report from The International EECP Patient Registry). American Journal of Cardiology,
97(1):17–20.
[52]. Strauer, B. E. (1979). Myocardial oxygen consumption in chronic heart disease: role of wall stress,
hypertrophy and coronary reserve. American Journal of Cardiology, 44(4):730– 740.
[53]. Strauss, W. E. andParisi, A. F. (1985). Superiority of combined diltiazem and propranolol therapy for
angina pectoris. Circulation, 71(5):951– 957.
[54]. Szwed, H., Sadowski, Z.,Elikowski, W. et al., (2001). Combination treatment in stable effort angina
using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL
II). TRIMetazidine in POLand. European Heart Journal,22(24):2267– 2274.
[55]. Takahashi, J., Nihei, T., Takagi, Y. et al., (2015). Prognostic impact of chronic nitrate therapy in patients
with vasospastic angina: multicentre registry study of the Japanese coronary spasm association. European
Heart Journal, 36(4):228– 237.

12
 Recent Trends in the Pharmacotherapy of Angina Pectoris

[56]. Talbert, R. L. (2014). Ischemic heart disease. In: DiPiro, J. T., Talbert, R. L., Yee, GC., Matzke, G. R.,
Wells, B. G. and Posey, L. M.(Editors)Pharmacotherapy: A Pathophysiologic Approach. 9th Edition.The
McGraw-Hill Companies, New York.
[57]. Taylor, S. H. (1994). Usefulness of amlodipine for angina pectoris. American Journal of Cardiology,
73(3):28a–33a.
[58]. Tirziu, D, and Simons, M. (2005). Angiogenesis in the human heart: gene and cell therapy.
Angiogenesis,8(3):241– 251.
[59]. Ulrich J. (2018) Current role of Lipoprotein Apheresis in the management high-risk patients. Journal of
Cardiovascular Development and Disease, 5(2):27

[60]. Warren, S. G., Brewer, D. L.,Orgain, E. S. et al., (1976). Long-term propranolol therapy for angina
pectoris.*First study showing benefit of BBs in management of angina pectoris.American Journal of
Cardiology, 37(3):420– 426.
[61]. Webb, C. M., McNeill, J. G., Hayward, C. S. et al., (1999). Effects of testosterone on coronary vasomotor
regulation in men with coronary heart disease. Circulation, 100(16):1690– 1696.
[62]. Wei, J., Wu, T. and Yang, Q. (2011). Nitrates for stable angina: a systematic review and meta-analysis of
randomized clinical trials. International Journal of Cardiology, 146(1):4–12.
[63]. Whalen,K., Finkel, R. andPanavelil, T. A. (2015). Lippincott Illustrated Reviews: Pharmacology. 6th
Edition.Wolters Kluwer, Philadelphia, pp 283 - 284.
[64]. Wu, S. Z. andWeng, X. Z. (1993). Therapeutic effects of an androgenic preparation on myocardial
ischemia and cardiac function in 62 elderly male coronary heart disease patients. Chin Med J (Engl).
106(6):415– 418.
[65]. Yong Wee, Kylie Burns, Nicholas Bett (2015) Medical management of chronic stable
anginaAustralianPrescriber, 38(4): 131–136.Published online 2015 Aug 3.
doi:10.18773/austprescr.2015.042 PMCID: PMC4653970
[66]. Zhou, L., Zuo, Z. Chow, M. S. et al., (2005).Danshen: an overview of its chemistry, pharmacology,
pharmacokinetics, and clinical use. Journal of Clinical Pharmacology, 45(12):1345– 1359.

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