1

Drugs used in coronary heart

diseases

Memy H. Hassan, PhD Associate Professor of

Pharmacology &Toxicology

College of Pharmacy,

Taibah University

Dina S. El-Agamy, PhD Associate Professor of

Pharmacology &Toxicology

College of Pharmacy,

Taibah University

Lecture ILO

• To demonstrate knowledge about drugs to

treat angina and myocardial infarction

• TOPICS COVERED IN THIS LECTURE

Rapid overview about ischemic heart diseases : basic definitions,

types and classes, risk factors

Strategies and goals of treatment of coronary heart diseases.

Different drug classes in controlling coronary heart disease

Beneficial effects of drugs used in management of coronary heart

disease

Major side effects, drug interactions and fingerprint

pharmacokinetics of drugs in management of coronary heart

diseases

Remember: What is angina pectoris?

Angina pectoris is the principal symptom of IHD.

Myocardial oxygen supply is insufficient to

meet myocardial oxygen demand

Imbalance between oxygen demand and

oxygen supply → heart muscle aches (chest

pain).

• Risk factors : Age, sex, obesity, smoking, diabetes.

RMEMBER :

NORMAL HEALTHY HEART

Heart

O2 supply O2 demand

Normal Function

Heart

O2 supply

Cardiac ischemia

O2 demand

Remember

Determinants of Cardiac O2 Demand & O2 Supply

• Four major factors of oxygen demand:

(1) Heart Rate

(2) Contractility

(3) Afterload

(4) Preload

• Oxygen Supply: Cardiac oxygen supply is determined by

myocardial blood flow.

Remember: Etiology (causes)

• O2 supply by coronary arteries (partial

obstruction) caused by: Atherosclerosis ( due to increased LDL and or

decreased HDL level)

Coronary vasospasm

Coronary thrombus formation

• in oxygen demand by the heart

- Hypertension

. Overloads on the heart

- Tachycardia

- Anxiety.

Types of Angina • Classic Angina

Atherosclerotic angina

Angina of effort

Chronic angina

stable angina

Angina that is precipitated by exertion, i.e. increase O2

demand that can not be met because of irreversible

atherosclerotic obstruction of coronary arteries

The principle way to relieve the pain of classic angina is

to decrease cardiac oxygen demand

Schematic Illustration of an Atheromatous Plaque

Stable angina

Types of Angina (cont.)

• Variant Angina

Vasospastic angina

Prinzmetal’s angina

Angina precipitated by reversible spasm of coronary vessels

NO atherosclerosis

The principle way to relieve the pain of variant angina is to increase cardiac oxygen supply

Types of Angina (cont.) • Unstable Angina

rapidly progressing increase in frequency and

severity of anginal attack, especially pain at

rest

Preinfarction or crescendo angina

It is thought to be the immediate precursor of a

myocardial infarction and is treated as a

medical emergency

Thrombosis of an Atherosclerotic Plaque

Unstable Angina

Remember: another Classification of

Angina

• Class I

• Class II

• Class III

• Class IV

• Angina only with

extreme exertion

• Angina with walking

1 to 2 blocks

• Angina with walking

1 block

• Angina with minimal

activity

Approaches used in the treatment of angina pectoris

A) Non-drug therapy: a) Avoiding smoking.

b) Avoiding fatty diet.

c) Avoiding stress and/ or emotion.

d) Weight reduction.

B) Surgical treatment (in severe cases or MI):

i- Coronary bypass graft

ii- Percutaneous transluminal ballon to dilate narrowed coronary artery.

iii- Stent placement.

C) Drugs :Treatment strategies of angina Drugs used to produce one or both of the following effects :

– Increase oxygen supply::

• Coronary vasodilators

– Reduce oxygen demand:

• Negative chrontropic drug, Vasodilators, Negative

inotropic agents.

Drugs to treat or prevent of secondary causes such

hypercholesterolemia (e.g. Atrovastatin) and thrombosis (e. g.

aspirin in low doses)

• Goals of treatment

Acute attack to relieve the spasm & pain

Prophylaxis to prevent further attack frequency & duration

Prevent or delay the worst possible outcome (MI)

Improve the patient’s functional capacity with as few side effects as

possible

Antianginal drugs classes

1) Organic nitrates:

- Nitroglycerin

- Isosorbid dinitrate

- Isosorbide mononitrate.

2) -adrenergic blockers:

- Propranolol (inderal),

- Atenolol (tenormin).

3) Ca++ channel blockers:

- Nifedipine, verapamil, diltiazem

4) K Channel Openers

- Nicorandil

- All three classes:

- relive anginal pain

- do not affect the cause

I- ORGANIC NITRATES 1- Short acting:

a) Nitroglycerine (Glyceryl trinitrate): sublingual tablets.

b) Isosorbide dinitrate : sublingual tablet.

c) Amyl nitrite: Inhalational spray.

2- Long-acting:

• Nitroglycerine, Isosorbide dinitrate & Isosorbide mononitrate,

• Erythrityl Tetranitrate.

– Orally (sustained release preparations).

– Ointment, Transdermal patch

- Direct acting smooth muscle relaxants.

- The relaxant action is non-specific

- Affect all smooth muscles.

Beneficial effects in angina: Increase O2 supply and decrease O2 demand (decrease

cardiac work) by VD that occurs in three vascular beds : i- Venodilatation: preload cardiac work O2 demand

ii- Arteriodilation: afterload oxygen demand.

iii- Coronary dilation: coronary blood flow due to epicardial or collateral

coronary artery dilation and redistribution of blood from non-ischemic area to

ischemic areas (in vasospastic angina).

N.B. Nitrates do not dilate atherosclerotic coronary arteries but dilate

normal non-sclerotic arteries.

V.D. (more selective for venous than for arteriolar B.V.)

- Mechanism of Actions

- Nitrates (enzymatic biotransformation) releasing NO.

-NO activates guanyl cyclase forming cGMP

-cGMP is a vasodilator.

-Venoselectivity is due to presence of the enzyme forming NO in veins

more than arteries.

Organic nitrates

Other Smooth Muscles Effect of Nitrates

• Nitrates relax:

– Bronchial smooth muscles

– Gall bladder smooth muscles

– Biliary duct and sphincter of oddi smooth muscles.

– GIT smooth muscles.

– Ureter and uterine smooth muscles.

Therapeutic uses of Organic nitrates A) Angina Pectoris:

• Short acting for acute attacks (SL or inhaler)

• Long acting for prophylactic (sustained release tab or transdermal

patch or oint).

• Treatment of all types of angina (exertional, vasospastic and

unstable angina) .

B) Heart Failure:

- Oral isosorbide dinitrate or nitroglycerin ointments or IV.

- Due to their V.D. effect on veins preload.

C) Hypertensive Emergency:

- I.V. Nitroglycerin (reserved for HTN emergency + IHD).

D) Diffuse Esophageal Spasm And Biliary Colics:

Sublingual nitroglycerin

Organic nitrates (cont.) • Most important side effects:

- Venodilation → Postural hypotension, reflex tachycaria,

dizzness & syncope (nitrate syncope).

Nitrates potentiate hypotension of phosphodiesterase-5 inhibitors

like viagra and may cause sudden death (not used with

sildenfil (viagra)

Arteriodilation → Throbbing headache & flushing

Methaemoglobinaemia

- Tolerance: With continuous rather than intermittent therapy.

- N.B. With tolerance headache disappear.

Monday syndrome : headache in workers of nitrates

factory.

Contraindications of organic nitrates

• Hypotension

• With phosphodiesterase-5 inhibitors as sildenafil (viagra), tadalafil.

Precautions

Start with the smallest possible dose in order to minimize side

effects.

Nitrate therapy should not abruptly stopped to avoid withdrawal

symptoms.

The patient should consult his doctor when more than 3 tablets

sublingually taken over 15 minutes without improvement for fear of

MI.

Nitroglycerine tablets should not be put in sunlight, or with cotton.

β- Blockers & Ca Channel Blockers

II- β-ADRENOCEPTOR ANTAGONISTS

Examples:

- Cardioselective Beta 1 blocker e.g. atenolol, Bisoprolol,

metoprolol,

- Non selective Beta blocker e.g. Propranolol,, nadolol.

- Non selective beta and alpha1 blocker e.g. Carvedilol

- Used in:

1- Angina P.: Prophylactic against exertional angina.

2. Post MI: Reducing the risk of sudden death or reinfarction

following acute MI.

3. Hypertension: mild-moderate types.

4. Cardiac arrhythmias (SVT) & control palpitations and

tachycardia caused by hyperthyroidism.

5- Chronic HF (Carvedilol)

β- Blockers • Beneficial effects in angina β-blockers reduce anginal pain by ↓ cardiac O2 demand

Primarily through blockade of β1 receptors cardiac output and

cardiac work

β-blockers can reduce O2 demand further by causing a modest

reduction in arterial pressure (↓ afterload)

Used for exercise angina (Exercise, emotion and cold

precipitate angina via sympathetic overactivity)

- NOT vasospastic angina : Coronary arteries contain

both α1 (VC) and β2 (VD) receptors.

- Because of unopposed -adrenoceptor- mediated more

coronary vasoconstriction

β- Blockers (cont.)

• Side Effects: most common β2 blocking → bronchospasm (asthma), disturb

blood glucose and lipid levels

Mask hypoglycemic coma hypoglycemic coma,

bradycardia

Never stop suddenly → perception of unstable

angina & myocardial infarction

• Contraindications: Important

Variant angina, Asthma, Heart block, Bradycrdia, With Ca

channel blockers,

III- CALCIUM Channel Blockers (CCBs)

1. Dihydropyridines:

– Amlodipine (Amlor, Norvasc)

– Nicardipine (Cardene)

– Nifedipine (Adalat, Epilat)

2. Non-dihydropyridines:

– Verapamil (Isoptin)

– Diltiazem (Cardizem, Cardizem SR)

Ca++ Channel Blockers

• In classic angina: Ca channel blockers reduce anginal pain by

decreasing cardiac oxygen demand

– Decrease heart rate and contractility

– Decrease arterial pressure (afterload)

• In variant angina: Ca channel blockers promote relaxation of

coronary artery spasm, thereby increasing cardiac O2 supply

Therapeutic Uses of CCBs

1) Prophylaxis of angina.

2) Post MI (Secondary prevention).

3) Treatment of hypertension

4) Antiarrhythmic (SVT); only verapamil &

diltiazem) are useful antiarrhythmics.

Ca++ Channel Blockers (cont.) • Side Effects

Arterial dilation → headache, flushing, dizziness &

ankle edema (not respond to diuretics especially

nifedipine)

↓ Contractility → poor left ventricular filling

Heart Block (especially with β- blockers &

digoxin)

Constipation: Frequently with Verapamil (effect

on calcium channels in the gut).

K Channel Openers Nicorandil

• Open potassium channel induces vascular smooth muscle

hyperpolarization results in blockade of calcium channel

induces vasodilation

• In addition it have nitrate moiety leads to more VD of

coronary and BV.

• Alternative for nitrates

• Side Effects: Headache, palpitation, dizziness, nausea &

vomiting may cause ↑ insulin release

Rational combination

1- Organic Nitrates and ß-Adrenergic Receptor Blockers (BBs)

• Nitrates (VD) reflex tachycardia myocardial oxygen

demand # by combination with BBs (bradycardia).

• ß receptor blockers coronary vasospasm while nitrates

(coronary vasodilation) and thus may prevent this undesirable

effect of beta-blockade.

2- Nifedipine or amlodipine and BBs

reflex tachycardia while BBs bradycardia (side effect

overcome the other) Beneficial interaction (rational combination).

Irrational combination or bad combination

1- Verapamil and diltiazem bradycardia & -ve inotropic, and

BBs bradycardia and –ve inotropic (addition in side effects) .

2- Ca2+ Channel Blockers and Nitrates

CCBs afterload, while nitrates preload

significant reductions in myocardial oxygen requirement.

However, hypotension with excessive vasodilation are

adverse effects

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Drugs treating secondary causes 1- Hypolipidemic agents

i) Statins (HMG-CoA reductase inhibitors):

e.g., Atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin.

ii) Bile-acid binding resins

e.g., cholestyramine and colistipole.

iii) Fibric acid derivatives

e.g., clofibrate and gemfibrozil.

iv) Niacin and estrogens

v) Dietary and cholesterol absorption inhibitors

e.g., Ezetimibe

Treatment Goals :

– Reduce total cholesterol and LDL (bad) cholesterol

– Prevent the formation of atherosclerotic plaques and

stop the progression of established plaques

– Prevent heart disease

– Prevent morbidity and mortality

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Statins (HMG-CoA reductase inhibitors)

Members:

Simvastatin (Zocor) Lovastatin ( Mevacor),

Pravastatin (Pravachol) Fluvastatin (Lescol)

Atorvastatin (Lipitor) Rosuvastatin (Crestor)

Advantages:

• Drugs of first choice in hyperlipidemia- why?

i. The best tolerated drugs; with favorable adverse effects.

ii - Most effective hypolipidemic agents.

Statins

(HMG CoA Reductase Inhibitors) Effectiveness of statins:

1. Reduce LDL cholesterol by about 40%

2. Decrease TG by about 25%

3. Raise HDL cholesterol by about 10%

4. Statins are the most effective in lowering LDL cholesterol

5. Statins are the most effective in patient who has low HDL and high LDL

Mechanism of action:

Statins inhibit HMG-CoA reductase ( enzyme activating the rate limiting step in cholesterol synthesis in the liver) thus decreasing cholesterol pool in liver production and stimulating LDL up take by liver and hence its breakdown

2- Drugs for thrombosis

1. Antiplatlet drugs (prophylactic)

2. Anticoagulants (Prevent coagulation)

3. Fibrinolytics (Dissolve clots)

Anti-Platelet drugs • Inhibit the aggregation of platelets

• Clinical use - prevents arterial thrombus

• No effect on existing thrombi

1- Low dose aspirin ( selective in platelets at low dose)

Inhibits COX -> TXA2 synthesis in platelets ( aggregation /adhesion) ; reduce reocclusion of vessels

Since platelets do not have nuclei, once cyclo-oxygenase is inhibited, no more enzyme can be made. The formation of prostacyclin, the anti-aggregatory compound, in endothelial cells is temporarily inhibited, but these cells have nuclei so can synthesize more cyclo-oxygenase.

2- Glycoprotien IIb/IIIa receptors inhibitors

– Abciximab

– Tirofiban

– Epifibatide

3- ADP receptors antagonits

– Clopidogrel and ticlopidine

4-Inhibitors of phosphodiesterase 3

– Dipyridamole and cilostazol

Anticoagulants

• Interrupt clotting cascade at various points

– No effect on platelets

• Drugs

1. Heparin & low molecular weight (LMW) Heparin

2. Warfarin

3. Direct Thrombin Inhibitors: Lepirudin

Fibrinolysis Plasminogen

Plasmin

Fibrin, fibrinogen

Activation Extrinsic: t-PA, urokinase

Intrinsic: factor XIIa, kallikrein

Exogenous: streptokinase

Fibrin, fibrinogen degradation products

Fibrinolytic drugs • Streptokinase (Kabikinase , Streptase® ) - bacterial product -

immune reaction

– Parenteral : 250000 - 1.5 million units per vial .

• Urokinase (Abbokinase) - human tissue derived – no immune

response

– Parenteral : 250000 units per vial.

• Tissue plasminogen activator (tPA) alteplase (tPA®, Activase®)

– genetically cloned , no immune reaction , EXPENSIVE

Others: anistreplase (Eminase®), reteplase (Retevase®), tenecteplase

(TNKase)

ARTERIES

OF THE

HEART

Progression of Atherosclerosis

Normal Angina

Pectoris

Myocardial

Infarction

Management of Myocardial Infarction

Acute Management

Pain Relief Thrombolysis

First choice

-Nitrates (sublingual or IV)

- Diamorphine (opioid analgesics, IV)

- β-blockers to ↓ cardiac work,

but there is no sign of heart failure

- IV thrombolytic (within 3 hours)

- - e.g. streptokinase, recombinant

tissue plasminogen activator &

alteplase ,antistreplase

Anticoagulants e.g., IV heparin to follow tPA. Followed by Antiplatelets as prophylactic e.g. Aspirin, Clopidogrel,

ticlopidine.

LETURE RESOURCES • Harvey R. A. (2012). Lippincott's Illustrated

Reviews: Pharmacology. 6th ed., Philadelphia, PA,

USA, Lippincott Williams& Wilkins. Unite IV;

chapter 18.

• Katzung B.G. (2015), Basic and Clinical

Pharmacology, 13th ed., New York, USA,

McGraw-Hill Medical. Section III; chapters 12.

• Humphrey P. R., Maureen M. D. , Ritter J.M.,

Flower R. (2011), Rang & Dale’s Pharmacology

7th ed., London, UK, Churchill Livingstone.

Section 3, chapter 18