ANTI-ANGINAL AND ANTI-ISCHEMIC DRUGS

ANTI-ANGINAL AND ANTI-ISCHEMIC DRUGS

Prof. Nelson .I. Oguanobi

Department of Pharmacology and Therapeutics
Faculty of Medical Sciences, University of Nigeria Enugu Campus.
Definitions
Ischemia: Is the inadequate blood supply to a part of the body,
even to the point of complete deprivation.

Ischemic heart disease (IHD): It is defined as acute or chronic

form of cardiac disability arising from imbalance between
between the myocardial supply and demand for oxygenated blood

Angina pectoris: It is a clinical syndrome of IHD resulting from

transient myocardial ischemia.
It is characterized by pain in the substernal or pre-cordial region of
the chest which is aggravated by an increase in the demand of the
heart and relieved by decrease in the work of the heart. Often pain
radiated to left arm, neck, jaw or right arm.
 Angina
• Is a characteristic sudden, severe, pressing-like precordial
or substernal chest pain radiating to the neck, jaw, back,
and arms.

Patients may also present with dyspnea or atypical

symptoms such as indigestion, nausea, vomiting, or
diaphoresis.
• is caused by inadequate blood flow through the coronary
blood vessels, is a consequence of myocardial O2 demand
exceeding supply.
 Angina
• Transient, self-limited episodes (15 seconds to 15 minutes)
of myocardial ischemia (stable angina) do not result in cellular
death; such as occurs in myocardial infarction (MI).

• however, acute coronary syndromes and chronic ischemia can

lead to deterioration of cardiac function, heart failure,
arrhythmias, and sudden death.
 Types of Angina

Angina pectoris has three patterns:

1. Stable, effort-induced, classic, or typical angina.

2. Unstable angina, preinfarction or crescendo angina.
3. Prinzmetal, variant, vasospastic, or rest angina. They are
caused by varying combinations of increased myocardial
demand and decreased myocardial perfusion.
 Stable Angina

Stable angina: the most common (90%)

is chest pain caused by a temporary inadequacy of blood flow
to the myocardium, The underlying cause is usually occlusion
of the coronary arteries by atherosclerosis
Usually lasts 1-15 minutes, and is provoked by exercise,
stress, extreme cold or heat, heavy meals, alcohol, or
smoking.
Rx: is promptly relieved by rest or nitroglycerin (a
vasodilator).
 Unstable angina (Acute coronary syndrome)

• lies between stable angina and MI.

• The pathology is similar to that involved in MI: a platelet-fibrin

thrombus associated with a raptured atherosclerotic plaque, but
without complete occlusion of the blood vessel.

1. chest pains occur with increased frequency, duration, and

intensity.

2. precipitated by progressively less effort.

 Unstable angina (Acute coronary syndrome)

• Any episode of rest angina longer than 20 minutes, any new-onset

angina, any increasing (crescendo) angina, or even sudden
development of shortness of breath is suggestive of unstable
angina.
• The symptoms are NOT relieved by rest or nitroglycerin.
• requires hospital admission and more aggressive therapy to prevent
death and progression to MI.
 Prinzmetal's or variant or vasospastic 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 or variant or vasospastic angina

• generally responds promptly to coronary vasodilators, such as

nitroglycerin and calcium-channel blockers.

• but β-blockers (especial non-selective) are contraindicated. ?

 Alpha-adrenergic activation enhances coronary vascular tone;

beta-blockade leaves alpha-adrenergic vasoconstriction

unopposed
Types of angina
 Determinants of the volume of oxygen required by the heart.

Determinant of myocardial O2 demand

Preload- diastolic filling pressure (blood volume and venous tone)
Afterload-peripheral vascular resistance
Heart rate
Wall tension
Ejection time
 Angina-precipitating factors:

exercise, emotional stress, sex

↑sympathetic activity ↑HR, Contraction

force, wall tension, TPR ↑ work of the
heart
↑ myocardial O2 demand ≠ myocardial O2 supply

Ischemia
 Therapeutic strategies
1. Increase blood flow to ischemic heart muscle and/or

2. Decrease myocardial oxygen demand

Four types of drugs, used either alone or in combination,

are commonly used to manage patients with stable

angina: β-blockers, CCBs, organic nitrates, and the

sodium channel blocking drug, ranolazine. These agents

help to balance the cardiac oxygen supply and demand equation by

affecting blood pressure, venous return, heart rate, and

 Therapeutic strategies

Lipid lowering drugs, particularly statins, can be given if

elevated plasma cholesterol levels are detected

Antiplatelet drugs, especially low-dose (75mg) aspirin to reduce

the possibility of thrombosis.

Fibrinolytic drugs (e.g. heparin) are used in unstable angina

Classification
1. Nitrates
a) Short acting: Glyceryl trinitrate (GNT, Nitogycerine)
b) Long acting: Isosorbide dinitrate, Isosorbide mononitrate,
Erythrityl tetranitrate
2. β- blockers: Propranolol, Metoprolol, Atenolol
3. Calcium channel blockers
a) Phenyl alkylamine: Verapamil
b) Benzothiazepine: Diltiazem
c) Dihyropyridines: Nifedipine, Nimodipine, Lacidipine,
Lercanidipine, Benidipine
4. Potassium channel opener: Nicorandil
5. Others: Dipyridamole, Trimetazidine, Ranolazine, Ivabradine,
Oxyphendrine
 Organic nitrates
Nitroglyserine, Isosorbid dinitrate, Isosorbid mononitrate
• They are effective in all types of angina pectoris.
At therapeutic doses :has 2 major effects
a)Dilation of the large veins resulting in pooling of blood
in the veins which diminish the preload and reduces the
work of the heart
b)Dilates the coronary vasculature providing increased
blood supply to the heart muscle
 ↓ Preload
 ↓ Afterload
 Relieving vasospasm
 Redistribution blood flow
• The total effect is a decrease in myocardial oxygen consumption
because of decreased cardiac work
Pharmacology of nitrates
Nitroglycerin
1. Preload reduction
2. After-load reduction
3. Redistribution of coronary flow
4. Relief in angina
Pharmacokinetics
Nitrates are lipid soluble well absorbed from buccal mucosa,
intestine and skin and is available in forms
that provide a range of durations of action from 10–20 min
(sublingual) to 8–10 h (transdermal).They undergo extensive first
past metabolism in liver. Rapidly denitrated by glutathione
reductase and mitochondrial aldehyde dehydrogenase.
Mode of action of organic nitrates
 A. Mechanism of action
• relax vascular smooth muscle
by their intracellular
conversion to nitrite ions, to
nitric oxide,
• activates guanylate cyclase
(GC) and increases the cGMP.
• dephosphorylation of the
myosin light chain, vascular
smooth muscle relaxation.

23-May-16
 A. Mechanism of action
• relax vascular smooth muscle
by their intracellular
conversion to nitrite ions, to
nitric oxide,
• activates guanylate cyclase
(GC) and increases the cGMP.
• dephosphorylation of the
myosin light chain, vascular
smooth muscle relaxation.
 Pharmacokinetics of Nitroglycerine

• Prototype: nitrate
• significant first-pass effect metabolism of nitroglycerin occurs
in the liver with PO forms
• Therefore, it is common to take the drug either sublingually or
via a transdermal patch,
• The time to onset of action varies from 1 minute for
nitroglycerin to more than 1 hour for isosorbide mononitrate.
• Isosorbide mononitrate owes its improved bioavailability and
long duration of action to its stability against hepatic
breakdown.
• Oral isosorbide dinitrate undergoes denitration to two
mononitrates, both of which possess antianginal activity.
Time to peak effect and duration of action
 Common nitrate preparations
Glyceryl trinitrate can be taken by sublingual tablet or
spray
The effects start within minutes and last ~30 min
Transdermal patches and I.V preparations are also
available
Isosorbide mononitrate is a longer acting preparation
which is given orally (half-life 4hrs), and slow release
preparations are available.

Side effects: nitrates can cause

Headache in about 30% - 60% of patients because of
the pronounced vasodilation.
High doses can cause postural hypotension, flushing &
tachycardia
 Nitrate Tolerance
• Tolerance develops rapidly. The blood vessels become
desensitized to vasodilation. Addressed by providing a
daily “nitrate-free interval” to restore sensitivity to the
drug.
• This interval is typically 10 to 12 hours, usually at night,
because demand on the heart is decreased at that time.
• Nitroglycerin patches are worn for 12 hours then
removed for 12 hours.
• However, variant angina worsens early in the morning,
perhaps due to circadian catecholamine surges. Therefore, the
nitrate-free interval in these patients should occur in the late
afternoon.
Tolerance
1. Tolerance may result from a reduced capacity of the vascular
smooth muscle to convert nitroglycerin to NO
2. Multiple mechanisms have been proposed to account for
nitrate tolerance, including
i) Volume expansion
ii) Neurohumoral activation
iii) Cellular depletion of sulfhydryl groups, and the generation of
free radicals.
iv) Inactivation of mitochondrial aldehyde dehydrogenase, an
enzyme implicated in biotransformation of nitroglycerin
Adverse drug reactions
The most common toxic effects of nitrates are the responses
evoked by vasodilation.
1. These include tachycardia (from the baroreceptor reflex)

2. Orthostatic hypotension (a direct extension of the venodilator

effect), and

3. Throbbing headache from meningeal artery vasodilatation.

Drug interaction
Nitrates + Sildenafil can lead to severe hypotension, myocardial
infarction and death
Uses
1. Angina pectoris
2. Acute coronary syndromes
3. Myocardial infarction (MI)
4. CHF and acute LVF
5. Biliary colic
6. Esophageal spasm
7. Cynaide poisoning.
 Beta Blockers

• Agents with intrinsic sympathomimetic activity (for example,

pindolol) are less effective and should be avoided in angina.
• The dose should be gradually tapered off over 5 to 10 days to
avoid rebound angina or hypertension.
 Mechanism of Action

• Suppress the activation of the heart by blocking B1 receptors

I. Decrease the HR, resulting in:
1. decreased myocardial oxygen demand.
2. increased oxygen delivery to the heart.
I. Decrease myocardial contractility, helping to conserve energy or
decrease demand
III. Reduce the work of the heart by decreasing CO and causing a
slight decrease in BP
• ↓ HR,
• ↓contractility,
• ↓systolic wall tension,
• ↑perfusion time
 Reasons for Using Nitrates and β-Blockers in
Combination in Angina

• β-Blockers prevent reflex tachycardia and contractility

produced by nitrate-induced hypotension.

• Nitrates prevent any coronary vasospasm produced by β-

Blockers.

• Nitrates prevent increases in left ventricular filling pressure or

preload resulting from the negative inotropic effects produced

by β-Blockers .
β- blockers
1. Adrenergic receptor antagonists are effective in reducing the
severity and frequency of attacks of exertional angina and in
improving survival in patients who have had an MI.
2. These agents are not useful for vasospastic angina and, if used
in isolation, may worsen the condition.
3. Timolol, metoprolol, atenolol, and propranolol have been
shown to exert cardioprotective effects. The effectiveness of
adrenergic receptor antagonists in the treatment of exertional
angina is attributable primarily to a fall in myocardial O2
consumption at rest and during exertion,
4. The decrease in myocardial O2 consumption is due to a
negative chronotropic effect (particularly during exercise), a
negative inotropic effect, and a reduction in arterial blood
pressure (particularly systolic pressure) during exercise.
 Calcium Channel Blockers (CCBs)
ex : amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil

Mechanism of Action
• Calcium is essential for muscular contraction.
• The CCBs protect the tissue by inhibiting the
entrance of Ca+2 into cardiac and smooth muscle
cells of the coronary and systemic arterial beds.
• All CCBs are therefore arteriodilators that cause a
decrease in vascular resistance. Cause peripheral
arterial vasodilation
• Reduce myocardial contractility (-ve inotropic
action)
• Result: decreased myocardial oxygen demand
Calcium channel blockers
Mechanism of Action
1. Calcium channel blockers block voltage-gated L-type calcium
channels, the calcium channels most important in cardiac and
smooth muscle.
2. By decreasing calcium influx during action potentials in a
frequency- and voltage-dependent manner, these agents
reduce intracellular calcium concentration and muscle
contractility.
Mechanism of Action
 Calcium-channel blockers

1. Verapamil mainly affects the myocardium,

2. whereas nifedipine exerts a greater effect on smooth muscle
in the peripheral vasculature.
3. Diltiazem is intermediate in its actions.
They lower blood pressure may worsen heart failure due to
their - ve inotropic effect.
Overall effects
• ↓ afterload,
• coronary vasodilation
• ↓HR,
• ↓contractility→↓O
2 demand
 Calcium Channel Blockers
a dihydropyridine derivative
A- Nifedipine
• a dihydropyridine derivative.
• functions mainly as an arteriolar vasodilator.
• This drug has minimal effect on cardiac conduction or heart
rate.
• Used in variant angina caused by spontaneous coronary
spasm
• Other members of this class, amlodipine, nicardipine, and
felodipine, have similar cardiovascular characteristics except
for amlodipine, which does not affect heart rate or cardiac
output.
 Calcium Channel Blockers
B- nondihydropyridine derivative/ Verapamil
• The diphenylalkylamine
• slows cardiac atrioventricular (AV) conduction directly,
• and decreases HR, contractility, BP, and oxygen demand.
• causes greater -ve inotropic effects than nifedipine, but it is
a weaker vasodilator.
• is extensively metabolized by the liver.
• is contraindicated in patients with preexisting depressed
cardiac function or AV conduction abnormalities.
• Drug Interaction: verapamil increases digoxin levels.
• It also causes constipation.
 Calcium Channel Blockers
C- nondihydropyridine derivative/ Deltiazem
• Its cardiovascular effects similar to verpamil
• Reduce the HR but lesser than verpamil
• Reduce BP
• Relieve coronary artery spasm so used in variant angina
• Can be used in angina in patients with concomitant diseases
I. First-line agents for treatment of:
1. angina,
2. hypertension,
3. supraventricular tachycardia
II. Short-term management of atrial fibrillation and flutter
Very acceptable side effect and safety profile, May cause:
• hypotension, palpitations, tachycardia or bradycardia, constipation,
nausea, dyspnea
Adverse drug reactions to CCB’s
1. The calcium channel blockers cause constipation, pretibial
edema, nausea, flushing, and dizziness.
2. More serious adverse effects include heart failure, AV blockade,
and sinus node depression; these are most common with
verapamil and least common with the dihydropyridines.
Use
1. Verapamil and Diltiazem may be used to treat AV nodal
arrhythmia.
2. Calcium blockers are effective as prophylactic therapy in both
effort and vasospastic angina.
3. Nifedipine has also been used to abort acute angina in severe
atherosclerotic angina, these drugs are particularly valuable
when combined with nitrates.
4. In addition to well-established uses in angina, hypertension, and
supraventricular tachycardia, some of these agents are used in
migraine, preterm labor, stroke, and Raynaud's phenomenon.
Potassium channel opener: Nicorandil
1.This novel antianginal drug activates ATP sensitive K+
channels leading to hyperpolerization of vascular smooth
muscle.
2. It also acts as a NO donor and relaxes blood vessels by
increasing cGMP.
3. Coronary blood flow is increased, dilatation of both epicardial
conducting vessels and deeper resistance vessel.
4. Mitochondrial K+ ATP channel opening exert myocardial
protection by preconditioning which appears to reduce
myocardial stunning, arrhythmias and infarct size.
Side effect
1. Flushing, palpitation, weakness, headache, dizziness
2. Large painful aphthous ulcers of mouth.
 Newer Antianginal Drugs
Sodium Channel Blocker, Ranolazine

• Ranolazine inhibits the late prolonged phase of the sodium

current (late INa), improving the oxygen supply and demand
ratio.
• Inhibition of late INa reduces intracellular sodium and calcium
overload, thereby improving diastolic function.
• It has antianginal as well as antiarrhythmic properties.
• Ranolazine is extensively metabolized, mainly by the CYP3A
family and also by CYP2D6. It is also a substrate of P-
glycoprotein. As such, Ranolazine is subject to numerous
drug interactions.
• Ranolazine can prolong the QT interval.
Newer Drugs
A) Ranolazine (contd.)

1. The decrease in intracellular sodium causes an increase in

calcium expulsion via the Na/Ca transporter and a reduction
in cardiac force and work.
2. Ranolazine is moderately effective in angina prophylaxis.

B) Dipyridamole
1. It is a powerful coronary dilator; increases total coronary
flow by preventing uptake and degradation of adenosine.
2. It dilates resistance vessels and abolishes autoregulation.
3. Inhibit platelet aggregation.
4. Not useful as an anti-anginal drug but used for prophylaxis
of Coronary and cerebral thrombosis in post-MI and post
stoke patients.
C) Trimetazidine
1. It is a novel antianginal drug acts by nonhaemodynamic
mechanism.
2. Anginal frequency is reduced and exercise capacity is
increased.
3. Mechanism of action not known .
4. But may improve cellular tolerance to ischemia by
i) Inhibiting mitochondrial long chain 3-ketoacyl-CoA-
thiolase (LC3-KAT) a key enzyme in fatty acid oxidation
and increasing glucose metabolism in myocardium.
ii) Limiting intracellular acidosis and Na+ and Ca++
accumulation during ischemia.
iii) Protecting against O. free radical induced membrane
damage
 Newer Therapeutic strategies
• Trimetazidine: Partial fatty acid oxidation inhibitors (pFOX
inhibitors). A newer strategy attempts to increase the
efficiency of oxygen utilization by shifting the energy
substrate preference of the heart from fatty acids to
glucose.
• Ivabradine: selectively reduces heart rate with no other
detectable hemodynamic effects. Acts by inhibition of the SA
pacemaker cur
ANTIPLATELET DRUGS
 ASPIRIN
 CLOPIDOGREL
 TICLOPIDINE

THROMBOLYTIC AGENTS
 STREPTOKINASE
 ALTEPLASE
 RETEPLASE-
 ASPIRIN
ANTIPLATELE T EFFECT BY INHIBITION OF THROMBOXANE A 2
NSAID, INHIBITS COX-1 AND COX -2 WHICH LEADS TO
DECREASED PROSTAGLANDIN SYNTHESIS

USES
THROMBO-EMBOLIC CVA, ISCHAEMIC HEART DISEASE-
PROPHYLAXIS (75MG/DAY) AND ACUTE TREAMENT (300 MG)

CONTRAINDICATIONS
1. THOSE UNDER AGE OF 16Y-CAN INCREASE INCIDENCE OF
REYE’S SYNDROME, LIVER/BRAIN DAMAGE
2. GASTRO-INTESTINAL ULCERS
3. BLEEDING DISORDERS
4. GOUT
5. HYPERSENSITIVITY TO ANY NSAID
6. GFR <10ML/MIN
 ASPIRIN
CAUTION
1. Asthma
2. Uncontrolled hypertension
3. Any allergic disease
4. G6pd deficiency
5. Dehydration

OTOTOXIC IN OVERDOSE

RECOMMENDATIONS ON USE OF ASPIRIN

FOR ANALGESIA- 300-900 MG 4-6 HOURLY –MAXIMUM DOSE4G/DAY

STOP 7 DAYS BEFORE SURGERY IF SIGNIFICANT BLEEDING IS EXPECTED

IF CARDIAC SURGERY OR PATIENT HAS ACUTE CORONARY SYNDROME-

CONSIDER CONTINUING
 CLOPIDOGREL
ANTIPLATELET AGENT- ADP RECEPTOR ANTAGONIST

USE
Prophylaxis of anti-thrombotic events in non—ST elevationmyocardial infarction
and in ST elevation myocardial infarction-in combination with aspirin
Myocardial infarction.
Ischaemic cerebrovascular accident.
Peripheral arterial disease.
CONTRAINDICATION
Active bleeding
Not recommended with warfarin
 CLOPIDOGREL
SIDE EFFECTS

 Haemorrhage (especially gastro-intestinal or

intra-cranial
 Gastro-intestinal upset
 Peptic ulcer
 Pancreatitis
 Headache
 Fatigue
 Dizziness
 Paraesthesia
 Rash/pruritus

Monitor full blood and for signs of occult bleeding

 STREPTOKINASE

THROMBOLYTIC AGENT
INCREASES PLASMINOGEN CONVERSION TO PLASMIN WHICH INCREASES FIBRIN
BREAKDOWN

USES
1. ACUTE MYOCARDIAL INFARCTION -1.5 MILLION UNITS INTRAVENOUS INFUSION
OVER 60 MIN
2. THROMBOEMBOLISM OF ARTERIES
3. PULMONARY EMBOLISM
4. CENTRAL RETINAL ARTERY THROMBOSIS
5. DEEP VEIN THROMBOSIS

OTHER DOSES-250,000 UNITS INTRAVENOUS INFUSION OVER 30 MIN, THEN

100,000 UNITS EVERYHOUR FOR UPTO12-72 HOURS
 ALTEPLASE
(RECOMBINANT) TISSUE-TYPE PLASMINOGEN ACTIVATOR.
RECOMBINANT FIBRINOLYTIC

USE
ACUTE MYOCARDIAL INFARCTION (TOTAL DOSE 100MG-)
REGIMEN DEPENDS ON TIME SINCE ONSET OF PAIN
0-6HOURS: 15 MG INTRAVENOUS BOLUS,FOLLOWED BY 50 MG
INTRAVENOUS INFUSION OVER 30 MINUTES AND 35 MG INTRAVENOUS
INFUSION OVER 60 MINUTES
6-12 HOURS-10 MG INTRAVENOUS BOLUS FOLLOWED BY 50 MG
INTRAVENOUS INFUSION OVER 60 MIN, AND FOUR FURTHER 10 MG
INTRAVENOUS INFUSIONS, EACH OVER 30 MIN)

DECREASE DOSE IF PATIENT WEIGHS LESS THAN 65 KG

RETEPLASE
RECOMBINANT PLASMINOGEN ACTIVATOR; THROMBOLYTIC
USED ONLY FOR MYOCARDIAL INFARCTION
DOSE-10 UNITS AS SLOW INTRAVENOUS INJECTION OVER 2 MINUTES,
REPEAT AFTER 30 MIN
Treatment algorithm for improving symptoms in patients with
stable angina.
Pharmacologic management of acute coronary syndromes