Antianginal Drugs

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Pharmacology of Drugs

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Ischemic Heart disease

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 IHD is an umbrella term that encompasses a spectrum of cardiac disorders
caused by myocardial ischemia.
➢ Myocardial ischemia is a state of decreased perfusion during which the oxygen
supply to the myocardium is insufficient to meet its metabolic demands.

 IHD can be defined as lack of oxygen and decreased or no blood flow to the
myocardium resulting from coronary artery narrowing or obstruction.

➢ Occurs when there is imbalance between myocardial oxygen supply and demand

➢ The most common cause of IHD is atherosclerotic disease of the epicardial

coronary artery

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❑ Pathophysiology – Atherosclerosis

 Is the fundamental pathophysiological basis of IHD

 Results in the buildup of plaque in the coronary arteries which subsequently

leads to stable angina and ACS.

➢ Stable angina is caused by narrowing of the coronary artery and limitation of

the blood supply to part of myocardium

➢ On the other hand, the sudden rupture of a plaque and the subsequent
thrombosis are responsible for ACS.

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❑ Pathophysiology – Determinants of Oxygen Demand and Supply

 IHD is mainly due to an imbalance in oxygen supply and demand to

myocardial cells

 Determinant of Oxygen supply

➢ Coronary blood flow which is directly related to:

✓ Perfusion pressure (aortic diastolic pressure) &

✓ Duration of diastole

• B/c coronary flow drops to negligible values during systole, the duration of diastole
becomes a limiting factor for myocardial perfusion during tachycardia

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❑ Pathophysiology – Determinants of Oxygen Demand and Supply

 Determinants of Oxygen Demand

➢ Heart rate

➢ Myocardial contractility

➢ Peripheral vascular resistance (afterload)

➢ Intra myocardial wall tension during systole

✓ Most important determinant because during systole, coronary perfusion is largely
impaired resulting in ischemia

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❑ Symptoms of IHD – Angina Pectoris

 Is the primary symptom of IHD which characterized by paroxysmal & usually

recurrent attacks of substernal or precordial chest discomfort

➢ Variously described as constricting, squeezing, choking, or heaviness

 The pain is precipitated when the oxygen supply to the heart is insufficient to
meet oxygen demand

 Caused by transient (15sec – 15min) myocardial ischemia that falls short of

inducing myocyte necrosis

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❑ Types of Angina Pectoris – Three major Types – 1Stable/Exertional Angina

 Underlying Pathology is an atherosclerotic plaque in large coronary arteries

 Fixed obstruction (plaque) blocks ≈70% of artery (enough during rest)

➢ Episodes precipitated by exercise, cold, stress, emotion, heavy meal

➢ ↑ work of myocardium (an increase in oxygen demand)

 If blockage is >90%, pain will occur at rest

 Ischemia mostly occur at the inner most layer of myocardium because when
the heart is contracting the inner layer is most compressed by the outer layer.
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❑ Types of Angina Pectoris – Three major Types – 2Vasospastic Angina

 Also known as Variant angina or Prinzmetal’s angina

 Is a rare form of angina & common in females

 Most important cause is a transient vasospasm of coronary vessels

 Pain occurs during rest and is not related to exertion, exercise…

 Ischemia occurs through out all layers of myocardium (sub mural ischemia)

 Variant angina is relieved by nitroglycerin

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❑ Types of Angina Pectoris – Three major Types – 3Unstable Angina

 Unstable plaque/atheroma (rupture, fissure, ulceration) inititaes platelet

aggregation & adhesion with fibrin deposition →Thrombosis

 The thrombus is dynamic (↑ in size & mass) which can cause severe ischemia
( if > 20 min – may lead to Myocardial Infarction [MI])

 Can be precipitated by progressively less effort, and even at rest.

 Does not respond well with nitrates or taking rest

➢ Nitrates are given 3 times within 15min and if pain is not relieved, then it is UA

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❑ Angina Pectoris – Treatment strategies
 Drug therapy of angina has two goals:
➢ Prevention of myocardial infarction (MI) and death
✓ Cholesterol lowering drugs and antiplatelet
➢ Prevention of myocardial ischemia and anginal pain
✓ Antianginal drugs
 Stable Angina – use drugs that decrease oxygen demand
➢ Effect on HR, Contractility, preload, and afterload
 Variant Angina – use drugs that increase oxygen supply
➢ Effect on coronary blood flow
 Unstable angina – use drugs that increase oxygen supply and decrease demand as
well as antiplatelet and fibrinolytic agents

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❑ Angina Pectoris – Drug Treatment

 There are three main families of traditional antianginal agents:
➢ Organic nitrates (e.g., nitroglycerin),
➢ Beta blockers (e.g., metoprolol), and
➢ Calcium channel blockers (e.g., verapamil/DHPs)
 They ↓ Myocardial O2 requirement by ↓ing the determinants of O2 demand
(HR, ventricular volume, BP, & contractility)
 In some pts, the nitrates & the CCBs may cause a redistribution of coronary
flow & ↑ O2 delivery to ischemic tissue
➢ In variant angina, these 2 drug groups also ↑ myocardial O2 delivery by
reversing coronary artery spasm

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❑ Angina Pectoris – Drug Treatment
 Drugs may relax vascular smooth muscle in several ways:
➢ Increasing intracellular cGMP

✓ Organic Nitrates

➢ Decreasing Intracellular Ca2+

✓ Calcium channel blockers

➢ Stabilizing or preventing depolarization of the vascular smooth muscle cell

membrane

✓ Newer agents – Nicorandil, Ranolazine, Ivabradine

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates

 These agents are simple nitric & nitrous acid esters of polyalcohols
➢ Nitroglycerin (Glyceryl trinitrate, GTN),
➢ Isosorbide dinitrate (ISDN),
➢ Isosorbide mononitrate (ISMN)

 All therapeutically active agents in the nitrate group appear to have identical
MOA & similar toxicities, although susceptibility to tolerance may vary

➢ Therefore, PK factors govern the choice of agent & mode of therapy

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates - MOA

 Established mechanisms of GTN bioactivation and action include

➢ Non-enzymatic reaction with L-cysteine ➔ formation of nitrite and NO by

ALDH2 ➔ activation of soluble guanylyl cyclase ➔ generation of cGMP.

 The bio-activation of other nitrovasodilators such as ISDN and ISMN is

ALDH2 independent,

➢ May suggest the involvement of other enzymes, such as CYPs, xanthine

oxidoreductase, and cytosolic ALDH isoforms

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Effect on VSM

 Nitrates cause vasodilating effects on both peripheral veins and arteries but
with more prominent effects on the veins

➢ Veins responding at the lowest conce, and arteries at slightly higher conce

✓ Arterioles & precapillary sphincters are dilated least

➢ The major antianginal effect is mediated by preload reduction rather than

coronary artery dilation

 Direct coronary vasodilation may be the major effect of GTN in situations

where vasospasm compromises myocardial blood flow

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Other Effects

 Cardiac Effects – Tachycardia and ↑ cardiac contractility can be evoked by

baroreceptors and hormonal mechanisms responding to ↓ BP

➢ Retention of salt and water may also be significant, especially with intermediate-
and long-acting nitrates

 Other Smooth Muscles – relaxation of Bronchial, GI, and GUT

 Action on platelet – Inhibit aggregation of platelet

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – PK (ADME)

 The liver contains a high-capacity organic nitrate reductase that removes

nitrate groups and ultimately inactivates the drug

 Oral BA of the traditional agents (GTN and ISDN) is low (< 40%)

➢ For this reason, the sublingual route is used (bypass 1st pass effect)

➢ The total duration of effect is brief (15–30 minutes)

 Other routes of administration available for GTN include transdermal and

buccal absorption from slow-release preparations

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – PK (ADME)

Drugs
 The liver Preparation Onset of nitrate
contains a high-capacity organic action reductase
Duration
thatofremoves
action
Sublingual
nitrate groups tablet or spray
and ultimately 1-3 min
inactivates the drug 25min
GTN Oral, sustained release 35 min 4-8hr
 Oral BA of the traditional agents (GTN and ISDN) is low (< 40%)
Trans-dermal 30 min 10-12 hr
➢ For this reason, the sublingual route is used (bypass 1st pass effect)
ISDN Sublingual 5 min 1 hr
➢ The total duration
Oral, of effect is brief30
slow release (15–30
min minutes) 8 hr
 Other routes
ISMN Oral,ofextended
administration
release available for GTN include
30 min transdermal
>12-24 hr and
buccal absorption from slow-release preparations

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – PK (ADME)

 The liverOral
Drugs contains aElimination
high-capacity organic nitrate
half‐life reductase
Metabolism that removes
and excretion
nitrate groups
BA(%) and ultimately inactivates the drug
GTN 40 1–3 min Hepatic denitration to dinitrates and
 Oral BA of the traditional agents (GTN and ISDN) is low (< 40%)
mononitrates; renal excretion
➢ For this reason, the sublingual route is used (bypass 1st pass effect)
ISDN 25 45min; 5h for the active Hepatic denitration followed by
➢ The total durationmetabolite,5‐mononitrate
of effect is brief (15–30 minutes)
glucuronidation; renal excretion

 Other routes
ISMN ~100 of administration
5h No significant
available for GTN first‐pass effects;
include transdermal and
buccal absorption from slow-release preparationshepatic denitration and renal
excretion
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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Therapeutic Uses

 Stable Angina Pectoris

➢ Short-acting nitrates for immediate therapy (active angina)

✓ Sublingual GTN is the most commonly used for acute relief
✓ Sublingual ISDN, but not ISMN, is an alternative to GTN

➢ Longer-acting nitrates for the prophylaxis of angina

✓ Sustained-release oral preparations (ISDN, ISMN & GTN)
✓ Chronic treatment with nitrates is not associated with a prognostic benefit and may
induce tolerance and endothelial dysfunction.
• Considered 2nd choice compared to β blockers

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Therapeutic Uses

 Variant (Prinzmetal) Angina

➢ Long-acting nitrates alone are occasionally efficacious in abolishing episodes of

variant angina.

➢ Additional therapy with Ca2+ channel blockers usually is required.

✓ Ca2+ channel blockers, but not nitrates, have been shown to influence
mortality and the incidence of MI favorably in variant angina.

✓They should generally be included in therapy.

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Therapeutic Uses

 Unstable Angina Pectoris (ACS)

➢ Resistance to nitrates classifies angina symptoms as “unstable” and is a characteristic

feature of ACS,

✓ Typically caused by transient or permanent thrombotic occlusion of coronary vessels.

➢ Nitrates do not modify this process specifically and are second-line drugs.

❖ One major drawback of long-term nitrate therapy is the development of Tolerance

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Tolerance

 Refers to a decrease in the apparent effectiveness with continuous or

repeated administration of nitrates

 Mechanisms of nitrate tolerance

➢ Impaired nitroglycerin bioconversion to 1,2‐glyceryl dinitrate with decreased

formation of nitric oxide (depletion of sulfhydryl group)

➢ Reduced bioactivity of nitric oxide (decreased cellular guanylyl cyclase)

➢ Activation of the RAAS and sympathetic nervous system in response to

nitrate‐induced vasodilation

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Tolerance

 Strategies to minimize tolerance

➢ Nitrate free interval (Need 6-8 hr nitrate free time) to restart activity

✓ Exertional angina is prominent during day time: nitrate free interval during night

✓ Prinzimetal’s angina is precipitated at morning (circadian catecholamine surges,

adrenergic supply from adrenaline is more): nitrate free evening

➢ Use of alternative agents (BBs or CCBs)

➢ Partially prevented or reversed with a sulfhydryl-regenerating drug???????.

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❑ Angina Pectoris – Drug Treatment – Organic Nitrates – Adverse Effects

 The major acute toxicities of organic nitrates are direct extension of

therapeutic vasodilation

➢ Flushing and Throbbing Headache – Tx with acetaminophen or aspirin

➢ Orthostatic Hypotension – dizziness, light-headedness, syncope

➢ Reflex tachycardia and palpitation – negates Tx so pretreatment with B-blocker

❖ Contraindications

➢ Hypotension (hypovolemia), use with PDE5 Inhibitors (sildenafil), increased ICP

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❑ Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs)

 Ca2+ is essential for cardiac nodal cell activity and muscular contraction

 Ca2+ influx is increased in ischemia because of the membrane depolarization

that hypoxia produces.

➢ Ca2+ entry promotes the activity of several ATP-consuming enzymes, thereby

depleting energy stores and worsening the ischemia.

 The CCBs protect the tissue by inhibiting the entrance of Ca2+ into cardiac
and smooth muscle cells of the coronary and systemic arterial beds

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❑ Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs)

 Mechanism of antianginal effects

➢ Reduces myocardial O2 demand by

✓ ↓ myocardial contractile force – Verapamil and Diltiazem

✓ ↓ HR – Verapamil and diltiazem

✓ Arteriodilation →↓afterload – Nifedipine, Amlodipine, Verapamil, Diltiazem

➢ Increase myocardial O2 supply

✓ Coronary artery dilation – Nifedipine, Amlodipine, Verapamil, Diltiazem

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❑ Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs)

 Dihydropyridines: (amlodipine, nifedipine)

➢ Antianginal effect mainly by peripheral arterial vasodilation and afterload

reduction and not by coronary artery dilation (exception in variant angina).

✓ Their efficacy in vasospastic angina is due to relaxation of the coronary arteries.

✓ In the vascular system, arterioles appear to be more sensitive than veins

➢ Short-acting dihydropyridines should be avoided in CAD because of evidence of

increased mortality after an MI

✓ Higher risk of reflex tachycardia

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❑ Angina Pectoris – Drug Treatment – Calcium Channel Blockers (CCBs)

 Non-Dihydropyridines (Verapamil, Diltiazem)

➢ Verapamil has more direct negative inotropic and chronotropic effects

✓ Cause a reduction in myocardial O2 demand

✓ Contraindicated in patients with preexisting depressed cardiac function or AV

conduction abnormalities

➢ Diltiazem has its effect between dihydropyridines & verapamil.

✓ Can relieve coronary artery spasm and is particularly useful in patients with variant
angina.
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❑ Angina Pectoris – Drug Treatment – CCBs – Therapeutic Uses

 Variant Angina

➢ Ca2+ channel blockers are effective in about 90% of patients with variant angina.

➢ These agents are considered 1st line and may be combined with nitro-vasodilators.

 Exertional Angina

➢ CCBs are used as 2nd-line therapy when β-blockers are genuinely C/I

➢ Verapamil is a more effective antianginal agent than diltiazem or DHPs & is

considered a 1st choice – must not be combined with β-blockers

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❑ Angina Pectoris – Drug Treatment – CCBs – Therapeutic Uses

 Unstable Angina (Acute Coronary Syndrome)

➢ Verapamil and diltiazem are recommended only for patients who

✓ Continue to show signs of ischemia,

✓ Do not tolerate β blockers,

✓ Have no clinically significant left ventricular dysfunction, and

✓ Show no signs of disturbed AV conduction.

➢ Dihydropyridines should not be used without concurrent therapy with β blockers.

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❑ Angina Pectoris – Drug Treatment – CCBs – Adverse Effects

 Serious cardiac depression, including bradycardia, atrioventricular block,

cardiac arrest, and heart failure – are rare

 Relatively short-acting CCBs such as prompt-release nifedipine have the

potential to enhance the risk of adverse cardiac events

➢ Slow-release and long-acting dihydropyridine CCBs are usually well tolerated

➢ Minor toxicities include flushing, dizziness, nausea, constipation, and

peripheral edema

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❑ Angina Pectoris – Drug Treatment – β-blockers (BBs)

 Are the only drug class that is effective in reducing the severity and frequency
of attacks of stable angina and in improving survival in pts who have had MI

➢ Therefore are recommended as 1st line Tx of Pts with stable CAD and UA/ACS.

 BBs are not useful for vasospastic angina and, if used in isolation, may
worsen that condition.

 Standard compounds for the treatment of angina are β1-selective and without
ISA (e.g., Atenolol, Bisoprolol, or Metoprolol).

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❑ Angina Pectoris – Drug Treatment – β-blockers (BBs)

 Although they are not vasodilators (with the exception of labetolol, carvedilol
and nebivolol), BBs are extremely useful in the management of effort angina

 The beneficial effects of BBs are related to their hemodynamic effects—

➢ Decreased HR, BP, and contractility — which decrease myocardial oxygen

requirements at rest and during exercise

➢ Lower HR is also associated with an increase in diastolic perfusion time that may
increase coronary perfusion.

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❑ Angina Pectoris – Drug Treatment – β-blockers (BBs) – Untoward Effects

 Increase in end-diastolic volume (EDV) and an increase in ejection time,

both of which tend to increase myocardial oxygen requirement

➢ These deleterious effects of BBs can be balanced by the concomitant use of

nitrates

➢ Combination of BBs with Nitrates – prevent EDV (caused by BB) & reflex
tachycardia (caused by nitrates)

 Abrupt discontinuation may cause rebound angina and even leads to MI

➢ Dose should be gradually tapered off over 2 to 3 weeks

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❑ Angina Pectoris – Drug Treatment – β-blockers (BBs) – Untoward Effects

 Potential complications include fatigue, impaired exercise tolerance, insomnia,

unpleasant dreams, worsening of claudication, and erectile dysfunction

 Contraindications to the use of β blockers

➢ Asthma and other bronchospastic conditions, severe bradycardia, atrioventricular

blockade, bradycardia-tachycardia syndrome, and severe unstable left ventricular
failure

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❑ Angina Pectoris – Drug Treatment – Miscellaneous Agents – Nicorandil

 Has nitrate-like (cGMP-dependent) properties and acts as an agonist at ATP

sensitive potassium (KATP) channels.

 Dilates both arterial and venous vascular beds

➢ Hemodynamic profile between nitrates and dihydropyridines; decrease afterload
more than nitrates

 Second choice in the prevention of exertional angina

❖ Adverse effects: hypotension, headache, buccal and GI ulcers

 Do not combine with PDE5 inhibitor

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❑ Angina Pectoris – Drug Treatment – Miscellaneous Agents – Ranolazine

 Inhibits late Na+ and other cardiac ion currents with weak β blocking and
metabolic effects

 Second choice in the prevention of exertional angina

 Metabolized mainly via CYP3A4 and less by CYP2D6 with t1/2 of 7hrs

 Can prolong the QT interval and should be avoided with other drugs that
cause QT prolongation.

 Excretion: 75% in the urine and 25% in the feces.

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❑ Angina Pectoris – Drug Treatment – Miscellaneous Agents – Ivabradine

 Selectively decrease HR by inhibiting Hyperpolarization activated cyclic

nucleotide gated (HCN) currents in SA node.

 Second choice in the prevention of exertional angina; approved in patients not

tolerating β blockers or having HR > 75 under β blockers.

❖ Adverse effects: bradycardia, QT prolongation, atrial fibrillation, phosphenes.

 Contraindication: combination with diltiazem or verapamil

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❑ Angina Pectoris – Drug Treatment – Miscellaneous Agents – Trimetazidine

 Its effect is thought to be due to inhibition of long-chain 3-ketoacyl coenzyme

A thiolase, the final enzyme in the FFA β-oxidation pathway.

 Induce metabolic shift from fatty acid to glycolytic metabolism in the heart

➢ Provides less ATP but requires less O2 and may therefore be beneficial in
ischemia.

 Second choice in the prevention of exertional angina

 May increase the incidence of Parkinson disease.

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Pharmacology of Drugs

For

Heart Failure

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