Anti-anginal drugs–individualized approach to

pharmacotherapy.
Azza Baraka
Professor of Clinical Pharmacology
 Human heart miracle
100,000 beats, 9,000 L of blood/ day

July 18, 2018 2

Determinants of myocardial oxygen supply & demand
• Myocardial oxygen demand: heart rate, myocardial contractility, blood pressure
or afterload, myocardial wall tension, cardiac hypertrophy,
• Myocardial oxygen delivery (coronary blood flow): depends on the pressure
gradient across the coronary circuit and the integrity of the coronary arteries, as
well as on the oxygen-carrying capacity of the blood and the haemoglobin level.

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 Recent insights in angina pathogenesis
In angina there is alteration in balance between cardiac oxygen supply and
demand. Reduction in coronary blood flow might be a result of epicardial
vasospasm or coronary microvascular dysfunction.
It has become clear there are different mechanisms responsible for ischaemia
some of which may predominate more in one patient than another.

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July 18, 2018 5
 Angina on top of normal coronaries
“Microvascular angina, Prinzmetal’s angina”

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 Microvascular angina
• Stable angina caused by coronary microvascular dysfunction and was named
cardiac syndrome X, often pertains to women with symptoms of chronic stable
angina, normal or near-normal coronary arteries, and evidence of ischaemia
during stress testing.

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 Vasospastic angina
This condition occurs in a minority of patients, and is caused by an abnormal
reactivity of the smooth muscles of the coronary arteries (which, therefore,
cannot be considered functionally normal).
This form of angina presents with specific characteristics — pain is not triggered
by exercise, but occurs at rest. Vasospasm can be evoked by different triggers and
needs specific diagnostic tests and therapies.

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July 18, 2018 9
 Antianginal drugs according to recent guidelines
Current guidelines recommend pharmacological therapy with drugs classified as
being first line (beta blockers, calcium channel blockers, short acting nitrates)
or second line (long-acting nitrates, ivabradine, nicorandil, ranolazine, and
trimetazidine).
Second line drugs are indicated for patients who have contraindications to first
line agents, do not tolerate them or remain symptomatic.

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 Goals of pharmacotherapy
Pharmacological therapy has two main goals:
1. Alleviate symptoms, increase angina-free walking time, and improve
quality of life;
2. Prevent cardiovascular events, mainly myocardial infarction and death.
• Unfortunately, evidence-based studies indicate that these two goals cannot be
achieved with the same class of drugs
• Pharmacological therapy to prevent cardiovascular events (aspirin, statins,
and angiotensin-converting-enzyme inhibitors) does not alleviate symptoms
and, similarly, symptomatic therapy does not improve prognosis

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Factors affecting choice of
antianginals
 Factors affecting choice of antianginals
1. Mechanism of drug action: for example BB effectively reduces myocardial
oxygen demand but at the expense (in certain instances) of an increase in
coronary vascular resistance; consequently, patients with coronary spasm may
actually deteriorate by treatment with a beta blocker but benefit from treatment
with a vasodilator such as CCBs.
2. Common comorbidities such as hypertension, MR, AF, autonomic dysfunction.
In patients with HF a beta blocker and/or Ivabradine should be preferred,
patients with diabetes may do better with a calcium antagonist. Co-morbidities
that are CIs to use a particular class of drugs will clearly define the appropriate
treatments. Anti-anginal drugs without hemodynamic effects might be preferred
in patients with low heart rate or low blood pressure
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 Restore balance between cardiac supply & demand
Decreasing cardiac demands can be achieved by several mechanisms including:
1. lowering heart rate
2. decreasing myocardial contractility
3. decreasing afterload
4. decreasing preload.
Increasing coronary blood supply:
1. Coronary VD
2. Increasing diastolic filling time

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 Nitrates
• Nitrates are organic products that, in the vessel wall, undergo enzymatic
denitrification by mitochondrial aldehyde dehydrogenase, producing vasoactive
nitric oxide, which causes vasodilatation.
• At low doses, nitrates are predominantly venodilators and thus reduce preload
and venous return to the heart with reductions in ventricular volume and
myocardial wall tension, leading to a decrease in myocardial oxygen demand.
• At higher doses, nitrates also dilate coronary arteries, improve collateral blood
flow, improve subendocardial blood flow to the ischaemic areas & decrease
afterload.

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 Nitrates
• The effects of nitrates on preload and afterload are often partly offset by an
increase in heart rate and myocardial contractility owing to reflex sympathetic
activity. Combining nitrates with β-blockers can be useful to block tachycardia,
leading to a synergetic anti-ischaemic effect.

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 Nitrates ADRs
• The most important adverse effects of nitrates are headache, flushing,
palpitations, and hypotension. Tolerance is prevented by drug holidays.
• Rare cases of syncope might occur in the elderly owing to profound
hypotension.
• All these adverse effects are dose-dependent. Consequently, nitrates should be
titrated to control chronic stable angina at the lowest possible dose.

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 Nitrates Contraindications
Nitrates are contraindicated in patients with hypertrophic obstructive
cardiomyopathy, severe aortic or mitral stenosis, or constrictive pericarditis,
because they reduce venous return, increase outflow gradient, and reduce cardiac
output.
Nitrates are also contraindicated in patients with closed-angle glaucoma.
Concomitant administration of phosphodiesterase-5 inhibitors (used for the
treatment of erectile dysfunction or pulmonary hypertension) greatly potentiates
the vasodilator effect of nitrate

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 Key points for nitrates
• The vasodilatory effects of nitrates are independent from the integrity of the
endothelium as they undergo bioconversion into nitric oxide, by a mechanism
that is endothelium-independent. This finding could be relevant in patients with
micro vascular angina, which is characterized by dysfunction of the endothelium.
• Small arterioles are nitrate-resistant, which explains why nitrates have less action
on peripheral arterioles and evoke less reflex tachycardia than nitroprusside, a
direct nitric oxide donor.

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 β-Blockers
• In patients with chronic stable angina, β-blockade reduces ischaemic burden by
lowering heart rate and myocardial contractility, especially during exercise.
These changes result in a reduction in oxygen demand at rest and during
exercise.
• Slowing heart rate leads to increased diastolic time and coronary perfusion, thus
improving oxygen supply.
.

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 β-Blockers
• Several subtypes of β-blockers exist: nonselective, without intrinsic
sympathomimetic activity (such as propanolol, sotalol, timolol); nonselective,
with intrinsic sympathomimetic activity (oxyprenolol, pindolol); β1-selective
(atenolol, bisoprolol, metoprolol); β1-selective with α-blocking activity
(carvedilol, labetalol); and β1-selective with nitric oxide-mediated vasodilatory
properties (nebivolol).
• β-blockers share a range of adverse effects, including bradycardia, hypotension,
bronchospasms, and blunting of the tachycardia response to hypoglycaemia.

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 β-Blockers
• Other adverse effects are depression, lethargy, constipation, and impotence. β-
Blocker treatment should not be abruptly discontinued because upregulation of
β-adrenoceptors could lead to severe tachycardia and vasoconstriction, with
precipitation of ACS.
• β-blockers should not be prescribed to patients with vasospastic angina because
they can precipitate α-mediated vasospasm.

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 Key points for β-blockers
• In clinical practice, β-blockers are often combined with dihydropyridine
calcium-channel blockers and other vasodilating antianginal agents to enhance
their anti-ischaemic effect.
• β-Blockers should not be combined with verapamil, and only with caution with
diltiazem, because of the risk of bradycardia or atrioventricular block and
hypotension, but can be combined with ivabradine to reduce heart rate further
and to improve exercise duration.

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 Key points for β-blockers
• β-Blockers should be the preferred treatment in patients with:
1. reduced left ventricular ejection fraction (<40%) or with post-infarct angina,
or heart failure where there is improvement in angina associated with a
reduction in cardiovascular mortality and sudden death.
2. Patients with chronic stable angina and high blood pressure and heart rate,
history of SVT including AF, or hypertrophic cardiomyopathy.
• Nonselective, and also to some extent selective, β-blockers can result in
coronary constriction. β-Blockers are contraindicated in vasospastic angina,
and not useful in microvascular angina.

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 Calcium-channel blockers
• CCBs are classified according to their structure as being dihydropyridines
(amlodipine, nifedipine,..) or nondihydropyridines (diltiazem and verapamil).
All these drugs inhibit calcium influx through the L-type calcium channel,
located in the smooth muscle of the arterial wall and on the myocardium,
leading to smooth muscle relaxation and reduction of myocardial contractility.
• The different agents have different selectivity for L-type calcium channels in the
vasculature and myocardium. Dihydropyridines have high selectivity for L-type
channels of the vasculature and produce a decrease in coronary and systemic
vascular resistance. They exert an antianginal action by reducing oxygen
demand and improving coronary dilatation. Reflex tachycardia is not
uncommon, especially with short-acting dihydropyridines.
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 Calcium-channel blockers
• Diltiazem and verapamil are less selective for the vasculature than the
dihydropyridines, and have more pronounced effects on myocardial
contractility as well as cardiac pacemaker and AV conduction, leading to
negative inotropic and chronotropic effects. Their antianginal action is
owing to a reduction in oxygen demand because of reductions in afterload,
heart rate, and myocardial contractility.
• The major adverse effects, particularly for dihydropyridines, are systemic
hypotension, headache, dizziness, flushing, palpitations, and leg oedema,
diltiazem and verapamil might also reduce left ventricular contractility.
Verapamil decreases intestinal motility leading to constipation.

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 Key points for calcium-channel blockers
• The antianginal efficacy of all calcium-channel blockers is similar to that of the
other antianginal drugs. All calcium-channel blockers are effective alone or in
combination with nitrates in the treatment of vasospastic angina.
• CCBs do not improve survival of patients with chronic stable angina with or
without myocardial infarction or left ventricular dysfunction and, when used in
patients with heart failure, they might have deleterious effects on outcome.
• All calcium-channel blockers are metabolized in the liver by cytochrome P45-
3A4, the same enzyme that metabolizes ivabradine. Diltiazem and verapamil
should, therefore, not be used in combination with ivabradine owing to the risk of
severe bradycardia.

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 Ranolazine (Ranexa)
• Ranolazine works by a different mechanism than traditional antianginals. Instead
of acting on the oxygen supply-demand balance, ranolazine is a selective late-
sodium current inhibitor.
• By blocking the late sodium current during ischemia, the drug inhibits the
calcium overload within the myocyte that is normally a hallmark of an ischemic
cell. In untreated ischemic cells, calcium overload leads to diastolic activation of
contractile proteins and subsequent tonic contraction and increased energy
consumption in an already energy-depleted myocyte. Thus ranolazine decreases
diastolic tension during ischemia.

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 Ranolazine
• Since ranolazine has no major effect on heart rate or blood pressure, it can be
used safely in clinical scenarios where low heart rate or blood pressure limits the
use of other antianginal agents.
• Ranolazine is contraindicated in patients with cirrhosis and in patients who are
taking strong inhibitors (Azoles, clarithromycin, etc.) or inducers (rifampin,
phenytoin, etc.) of CYP3A.
• Ranolazine causes a very minor dose-related prolongation of the QTc interval.

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 Ivabradine (procoralan)
 Ivabradine acts on the If (or so-called “funny current”), which is highly
expressed in the SAN. If is a mixed Na+-K+ inward current activated by
hyperpolarization and modulated by the autonomic nervous system. It regulates
the pacemaker activity in the sinoatrial node. Ivabradine inhibits If in a dose-
dependent manner, thus causing greater heart rate reductions at higher doses.
The If inhibition is „use- dependent‟, and the heart-rate reduction with ivabradine
is greater when initial heart rate is high, and lower when the initial heart rate is
low.

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 Ivabradine
• Ivabradine has no negative inotropic or lusitropic effect. The ivabradine-
induced reduction in heart rate is similar to that with β-blockers, but with
maintenance of coronary dilatation during exercise.

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 Ivabradine
• Ivabradine is indicated for the treatment of chronic stable angina for patients in
sinus rhythm who cannot take beta-blockers or for patients with chronic stable
angina who have inadequate heart rate control (>60 beats/min) while on beta-
blockers.
• Ivabradine is contraindicated in patients with sick sinus syndrome and in patients
taking inhibitors of CYP3A4.
• Ivabradine is associated with significant bradycardia slightly more commonly
than with beta-blockers. Approximately 15% of patients also experience
“luminous phenomena” or “phosphenes” described by patients most often as
sensations of enhanced brightness.

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 Ivabradine
• Adverse effects of ivabradine are bradycardia and phosphenes.
• The visual symptoms induced by ivabradine are caused by the presence of If
channels in the retina that closely resemble the If channels of the sinus node. The
• observed phosphenes are reported to occur in 5.4% of patients, are mild and
transitory, and only rarely lead to treatment withdrawal (<1%).
• Treatment with ivabradine also seems to increase the absolute incidence of atrial
fibrillation by 0.7%.

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 Key points for ivabradine
• The antianginal efficacy of ivabradine is similar to that of other classes of
antianginal agents.
• Ivabradine provides additional benefits when used in combination with the other
antianginal drugs (except diltiazem and verapamil), including β-blockers.
• The synergistic effect between β-blockers and ivabradine suggests that in patients
receiving treatment with β-blockers who are still symptomatic, adding ivabradine
is more efficient than uptitration of β-blockers.

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 Trimetazidine (Vastarel)
• Trimetazidine is a metabolic modulator that does not exert haemodynamic effects.
Therefore, trimetazidine does not affect oxygen demand, but improves the
metabolic efficiency of the ischaemic myocytes.
• Trimetazidine increases cellular tolerance to ischaemia by inhibiting fatty acid
oxidation.
• trimetazidine is not recommended in patients with Parkinson disease,
parkinsonism, and other related movement disorders, or in patients with severe
renal impairment (creatinine clearance <30 ml/min).

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 Nicorandil (Adancor)
• Nicorandil is a potassium channel activator with nitric oxide donor capacity. It
causes arterial and venous dilation and improves coronary blood flow
• Additionally, as a consequence of its capacity to open ATP-sensitive potassium
channels, nicorandil exerts some metabolic effects and a form of preconditioning
on the myocardium.
• The main adverse effects of nicorandil are headache, reflux, tachycardia, facial
flushing, and hypotension. Rarely, serious skin, mucosal, and eye ulceration.

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 Key points for nicorandil
• Nicorandil is associated with some improvements in clinical outcomes.
• The concomitant use of nicorandil with aspirin might increase the risk of
gastrointestinal ulcers, perforations, and haemorrhage.

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 The antianginal impact of different classes
• Beta-blockers decrease heart rate, decrease contractility, and increase diastolic filling time.
• Nitrates decrease preload and enhance coronary arterial vasodilation, but have no direct effect
on heart rate or myocardial contractility.
• Dihydropyridine CCBs decrease afterload and enhance coronary arterial vasodilation, but may
increase contractility and heart rate due to activation of sympathetic reflexes.
• Nondihydropyridine CCBs decrease heart rate and afterload, and enhance coronary arterial
vasodilation, and decrease myocardial contractility.
• Ranolazine works by improving regional blood flow in areas of myocardial ischemia, a
different mechanism of action compared to the traditional antianginals, and it exerts little effect
on heart rate and blood pressure.
• Ivabradine works by decreasing heart rate through its action on If and has no effect on blood
pressure or contractility.

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 Antianginal drugs combination
• A combination of two or more of anti-ischaemic drugs with additive or
synergistic effects is often needed to control symptoms effectively. These
combinations should also be tailored to the type of chronic stable angina and to
the individual patient

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Possible combinations of classes of antianginal drugs according to
different comorbidities

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Possible combinations of different classes of antianginal drugs

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High heart rate (>70) BB, NDHP, Ivabradine
Low HR(<50-55) DHYP, nitrates, nicorandil

Hypertension BB, DHYP

Do not dec < 130/80

Avoid drugs lowering BP as may impair coronary

Hypotension perfusion. Ivabradine, trimetazidine, Ranolazinee

BB (+ivabradine) , trimetazidine.
LVD, HF
NDHP used wwith caution
BB, NDHP (plus ranolazine)
AF Ivabradine is ineffective & CI (selective for If)
Avoid: DHP, Nitrates, nicorandil
3rd G BB( Nebivolol, carvedilol), Trimetazidine,
DM ranolazine. Other Anttianginals
 CKD Avoid ranolazine & trimetazidine iff GFR< 30
COPD Bisoprolol (high beta 1 selectivity) is not CI

Bronchial asthma Avoid BB. If reduction of HR is needed :

ivabradine , NDHP
Avoid BB (unopposed alpha adrenergic ), VDs (CCBs,
PAD nitrates) bec acute BP lowering is deleterious

AV conduction defect Avoid: BB ,NDHP

NSBB, NDHP , ivabradine
Hyperthyroidism Avoid: DHP, Nitrates, nicorandil
Drugs that dec HR (increased diastolic filling time) : BB,
Microvascular angina NDHP, ivabradine. Ranolazine ( dec mechanical
compression of coronary microcirculation)