PHARMACOTHERAPY OF

ISCHEMIC HEART DISEASE

Girum Sebsibe(B.pharm, MSC)
 Learning Objectives
• Define ischemic heart disease

• Identify risk factors for the development of ischemic heart disease.

• Differentiate between the Pathophysiology of chronic stable angina and acute coronary

syndromes

• Recognize the symptoms and diagnostic criteria

• Identify treatment goals of IHD, appropriate lifestyle modifications, and pharmacologic

therapy to address each goal.

• Design an appropriate therapeutic regimen for the management of IHD based on

patient-specific information

• Formulate a monitoring plan to assess effectiveness and adverse effects of drug

regimen
Coronary artery
 IHD, CAD,CHD
• IHD:- imbalance between oxygen supply and demand
caused by the narrowing of one or more of the major
coronary arteries most commonly by atherosclerotic
plaques.

• Angina pectoris is the most common symptom of IHD

• Angina is discomfort in the chest that occurs when the

blood supply to the myocardium is compromised
IHD may present as
 Epidemiology
• IHD affects over 16 million Americans
• The leading cause of death for both men and women in the United
States.
• The incidence of IHD is higher in middle-aged men compared to
women ???.
• because premenopausal women are protected by natural oestrogen
hormones.
• However, the rate of IHD increases two- to three-fold in women after
menopause
• IHD was responsible for 52% of deaths from CVD.
RISK FACTORS
 Major risk factors
• The risk of developing IHD and related complications is two-
fold higher in patients with metabolic syndrome

• To diagnose metabolic syndrome, patients must meet at least

three of the following criteria:
1. Increased waist circumference (greater than 40 inches or 102 cm in
males and greater than 35 inches or 89 cm in females)

2. Triglycerides of 150 mg/dL (1.70 mmol/L) or greater or active

treatment to lower triglycerides
 Major risk factors
3.Low HDL cholesterol (less than 40 mg/dL in males and less than 50 mg/dL

in females) or active treatment to raise HDL cholesterol

4. Blood pressure of 130/85 mm Hg or greater or active treatment with

antihypertensive therapy.

5. Fasting blood glucose of 100 mg/dL (5.55 mmol/L) or greater or active

treatment for diabetes.

• Early detection and aggressive modification of risk factors are among the

primary strategies for delaying IHD progression and preventing IHD-

related events including death

 Chronic stable angina
• Chronic stable angina is defined as a chronic
occurrence of chest discomfort due to transient
myocardial ischemia with physical exertion or
other conditions that increase oxygen demand
• Chronic stable angina is the initial manifestation
of IHD in about 50% of patients, whereas ACS is
the first sign of IHD in other patients
Pathophysiology
 Determinant of oxygen supply
• Reductions in coronary blood flow (secondary to atherosclerotic plaques,

vasospasm, or thrombus formation) or arterial oxygen content (secondary to

hypoxia) decrease myocardial oxygen supply.

• Decreases in diastolic filling time (e.g., tachycardia) can also reduce coronary

perfusion and myocardial oxygen supply.

• vascular endothelium
– Protects surface of the artery wall

– Promotes smooth muscle relaxation and inhibits thrombogenesis

• Loss of the vascular endothelium due to physical injury, cigarette, oxidized LDL,

HTN, or atherosclerosis results in loss of NO(impaired endothelium dependent

vasodilatation) and the defense me

 Determinants of demand (MVO2
1.Heart rate (HR)

2.Myocardial contractility

3. Ventricular wall tension

– Left ventricular wall tension is a function of blood pressure, left ventricular
end-diastolic volume, and ventricular wall thickness –
• Increased pressure or enlargement of the ventricle will increase systolic wall force and
increase MVO2

• Increases in heart rate, left ventricular wall tension, and cardiac

contractility increase the rate of myocardial oxygen consumption
(MVO2)
 Pathophysiology of stable angina
• In chronic stable angina, established atherosclerotic plaque that
obstructs coronary blood flow to the extent that myocardial
oxygen supply can no longer meet increases in myocardial
oxygen demand

• Over time, an established plaque may become unstable and

rupture, with subsequent thrombus formation causes abrupt
reductions in coronary blood flow and oxygen supply.
– this is the hallmark feature in the Pathophysiology of unstable angina
and MI(ACS).
Non-atherosclerotic Conditions that Can
Cause Angina like Symptom
 Laboratory and diagnostic test
• Cardiac biomarkers: ( CK-MB, Troponin I and T) are normal in chronic stable angina

and unstable angina but elevated in MI

• Hemoglobin, Fasting blood glucose and fasting lipid profile should be determined for

assessing CV risk factor and establishing differential diagnosis

• ECG –
– A resting ECG is indicated in all patients with angina-like symptoms.

– Exercise ECG testing using either a treadmill (most commonly) or bicycle ergometer is a

common non-invasive test to evaluate the patient with suspected IHD

– A 12-lead ECG should be done within 10 minutes of presentation to the emergency department in

patients with symptoms of ischemia

• Echocardiography – useful if physical examination suggests valvular, pericardial

disease, ventricular dysfunction

Criteria for Determination of the Specific
Activity Scale Functional class
 Treatment: Desired Outcome
• The major goals for the treatment of IHD are to:
– Alleviate acute symptoms of myocardial ischemia
– Risk factor identification/modification
– Prevent recurrent symptoms of myocardial ischemia
– Prevent acute coronary syndrome and death
– Reduce complications of IHD
– Avoid or minimize adverse treatment effects
 Treatment
• Short term goals:
-reduce/prevent angina symptoms that limit exercise
capability & impair quality of life (QOL)

• Long-term goals:
-Prevent recurrent symptoms of myocardial ischemia
- Prevent IHD events :ACS ,arrhythmias, HF
 Non pharmacological Treatment

• Initiate and/or maintain Lifestyle modifications including

– Smoking cessation

– Dietary modification

– Increased physical activity- facilitates both weight loss and BP reduction

– Avoidance of stress (emotional, physiologic, cold)

– Taking rest during symptoms

• Reduction of risk factors for IHD such as dyslpidemia,

hypertension, diabetes…. etc(statin,ACEI….)

 Principle of Pharmacotherapy
Treatment of angina can involve two strategies:

1. Increase supply

– Most effective treatments to improve myocardial oxygen supply are surgical

revascularization
– PCI, and coronary artery bypass graft (CABG) surgery . drug such as nitrate, CCB

2. Reduce cardiac workload

-by reducing heart rate and/or force of contraction

-drug treatment is primarily aimed at reducing oxygen demand.

-Short-acting nitrates are indicated to acutely relieve angina.

-Β-blockers, calcium channel blockers (ccbs), and long-acting nitrates are traditionally used to

reduce the frequency of angina and improve exercise tolerance.

-Statin, ACEI risk reduction

 Treatment: Stable angina pectoris
• Sublingual nitroglycerin for immediate angina relief (Class I, Level B)

• ß-blockers with prior MI (Class I, Level A)

• Calcium antagonists or long-acting nitrates for symptom reduction when ß-

blockers contraindicated (Class I, Level B)

• Calcium antagonists or long-acting nitrates in combination with ß- blockers

when initial ß-blocker treatment is inadequate (Class I, Level C)

• Calcium antagonists or long-acting nitrates as substitutes for ß-blockers if initial

ß-blocker treatment leads to intolerable side effects (Class I, Level A)

• Use of long-acting non dihydropyridine calcium antagonists instead of ß-blockers

as initial therapy (Class IIa, Level B)

 Treatment: Stable angina pectoris
• ACEI for patients with CAD & diabetes or LV systolic dysfunction

(Class I, Level A)

• LDL-lowering therapy with CAD & LDL > 130 mg/dL (Class I, Level

A)
– target LDL < 100 mg/dL

– < 70 mg/dL in patients with CHD & multiple risk factors

• ASA (Class I, Level A) –

– May substitute clopidogrel when ASA contraindicated (Class IIa, Level B)

• Therapies to avoid: – dipyridamole (Class III, Level B

 Treatment: Stable exertional angina pectoris
• Nitrate :MOA ????

• Dilate peripheral veins -leads to decreased blood return to the heart - reductions in

preload
– which lead to decrease in ventricular volume and wall tension-> reduction in myocardial oxygen

demand

• Dilate peripheral arteries

– Decreased peripheral resistance (afterload), Decreased O2 demand

• Dilate coronary arteries and increase myocardial blood flow.

• dilation of large & small intramural coronary arteries, collateral dilation, coronary

artery stenosis dilation, abolition of normal tone in narrowed vessels, spasm

 Treatment: Stable angina pectoris
Nitrate place in therapy
– Terminate acute anginal attack

– Prevent effort/stress-induced attacks

– long-term prophylaxis usually in combination with ß-blockers or CCBs

• Route of administration :
– Inhalation, sublingual, oral, transdermal, intravenous

• Nitrate therapy for acute attacks

– sublingual , buccal , spray products

• Symptom prophylaxis when undertaking activities that precipitate attacks

– oral or transdermal products – 0.3 to 0.4 mg SL ~5 min prior to activity

• Chronic prophylaxis
– long-acting forms
General Approach to Treatment
relieve acute symptoms
Nitroglycerin

• Short-acting nitrates are first-line treatment to terminate

acute episodes of angina (Class I, Level B)

• At the onset of an angina attack, a 0.3 to 0.5 mg dose of

nitroglycerin (tablet or spray) should be administered
sublingually, and repeated every 5 minutes until symptoms
resolve
Nitrate product
 Nitrate
• Nitrate therapy adverse effects

– extension of pharmacologic effects

• Postural hypotension with CNS symptoms, headaches, flushing 2°to vasodilation

• occasional nausea from smooth muscle relaxation

– Reflex tachycardia, but bradycardia has been reported

– Rash with all products (particularly with patches)

– Production of methemoglobinemia with high doses for extended periods

• Measurable ethanol & propylene glycol concentrations with IV nitroglycerin

• Tolerance
Long-term Treatment Anti angina therapy
Pharmacotherapy to Prevent Recurrent Ischemic
Symptoms

Drugs used to prevent ischemic symptoms are

• β-blockers,

• CCBs, and

• Nitrates or

• Combination of two or more of these agents

– Improve balance between myocardial oxygen supply and demand

– Decrease the frequency of angina and delay the onset

 β-Blockers
• They are effective as monotherapy or with nitrates, CCBs, or a
combination.

• β-blockers are preferred (first-line therapy if not contraindicated )

in patients with
– Prior MI

– Coexistent hypertension

– History of supraventricular arrhythmias or post-MI angina

– Anxiety associated with angina

– Physical activity figures prominently in anginal attack

 β-Blockers
How???

• β-Blockers decrease myocardial oxygen demand

– Decrease HR

– Decrease contractility

– Reduce BP and wall tension

• Effects on oxygen supply are as follows:

– β-blockers cause no direct improvement of oxygen supply decreased HR

→ increase diastolic perfusion time (coronary arteries fill during diastole), which

may enhance left ventricle (LV) perfusion

 Beta blockers
• Selection of β-blockers is based on the following factors

• consider frequency of dosing and drug cost

• β-blockers with cardioselectivity have fewer adverse effects

– ISA may not be as effective because
• Reduction in HR would be minimal; therefore, there is a small reduction in oxygen

demand

• Other β-blockers appear equally effective at controlling symptoms of

angina Selection of β-blockers.

Properties and Dosing of β-Blockers in
Ischemic Heart Disease
Start low, go slow

• Avoid Abrupt β-blocker withdrawal may increase the frequency and

severity of angina, possibly because of

– increased receptor sensitivity to catecholamines after long term β-blockade

Contraindications

• Severe bradycardia (heart rate less than 50 beats per minute)

• AV conduction defects

• Caution:- combination with other agents that depress AV conduction (e.g.,

digoxin, verapamil, and diltiazem) = increased risk for bradycardia and

heart block
 Calcium Channel Blockers
• Effective monotherapy (usually used if patients are intolerant of ß- blockers)

• Generally used in combination with ß-blockers when initial treatment is unsuccessful

• Ideal candidates

– Concurrent HTN

– Prinzmetal angina

– Peripheral vascular disease

– Severe left ventricular dysfunction(long acting CCB prefered)

• Amlodipine and felodipine possess less negative inotropic effects and appear to be safe in

patients with left ventricular systolic dysfunction

• Non dihydropyridine (Ex-verapamil and diltiazem (due to their negative chronotropic effects)

are generally more effective anti- anginal agents than the dihydropyridine CCB
 Calcium Channel Blockers
• HOW????

• CCB reduce myocardial oxygen demand by

– Reduction in cardiac contractility, HR

– Reduction in wall tension.

– CCB increase myocardial oxygen supply through vasodilatation= decrease

preload

• Finally, there is some evidence shows that short acting CCBs (particularly short

acting nifedipine and nicardipine) may increase the risk of cardiovascular events.

• Therefore, short-acting agents should be avoided in the management of IHD.

 Calcium Channel Blockers
• Calcium channel blockers (CCBs)
– large, variable, 1st-pass metabolism

• ~20 to 50% bioavailability for diltiazem, nicardipine,

nifedipine, verapamil, felodipine, isradipine
• amlodipine bioavailability ~60 to 80%
• most CCBs eliminated via CYP 3A4 & other CYP
isoenzymes
 Long-Acting Nitrates
• Long-acting nitrates should be used as initial therapy to reduce

symptoms only if β-blockers or CCBs are contraindicated.

• In combination with β-blockers can be used when initial treatment

with β-blockers is ineffective.

• Nitrates are used in patients with CAD or other vascular disease

• Nitrates are preferred agents in the treatment of vasospastic angina.

• Nitrates improve exercise tolerance

• Sitting or standing enhances the effectiveness of nitroglycerin.

 Long-Acting Nitrates
• The loss of anti-anginal effects may occur within the
first 24 hours of continuous nitrate therapy
– depletion of the sulfhydryl groups necessary for the
conversion of nitrates to nitric oxide, and

• generation of free radicals that degrade nitric oxide

Solution
• Allow a daily nitrate-free interval of at least 8 to 12 h
Nitrate Formulations and Dosing for
Chronic Use
 Combinations
Combination therapy:
β-blockers and CCBs

– β-blockers and long-acting dihydropyridine CCBs are usually efficacious and well

tolerated.

– CCBs, especially the dihydropyridines, increase sympathetic tone and may cause reflex

tachycardia.
• β-blockers attenuate this effect.

– β-blockers and nondihydropyridine CCBs should be used together cautiously because

• Combination can lead to excessive bradycardia or AV block.

• also precipitate symptoms of heart failure in susceptible patients.

β-blockers and nitrates.

– Nitrates increase sympathetic tone and may cause a reflex tachycardia.

• β-blockers attenuate this response.
 Newer therapies
Ranolazine

• How???
– The MOA is unclear, but it is believed to Inhibits the late phase of the inward sodium channel in ischemic cardiac

myocytes during cardiac repolarization reducing intracellular sodium concentrations and thereby reducing

calcium influx via Na + -Ca 2+ exchange.

– Decreased intracellular calcium reduces ventricular tension and myocardial oxygen consumption

• Ranolazine has minimal effects on HR or BP(without changing HRor BP.); thus it may be an

option in IHD patients with low baseline BP or HR

• In clinical trials, ranolazine reduced angina and increased exercise capacity when added to

other antianginal therapy

• Ranolazine does not relieve acute angina attacks

 Prevent acute coronary syndrome and death
• The primary strategies for preventing ACS and death (eg,
primary or secondary prevention) are to:
– Aggressively modify cardiovascular risk factors;
• Lifestyle modifications and

• reduce cardiovascular risk factors, slow the progression of IHD, and

decrease IHD-related complications.

• Pharmacologic therapy

– Slow the progression of coronary atherosclerosis; and

– Stabilize existing atherosclerotic

 Pharmacotherapy to Prevent Acute Coronary Syndromes and Death

Antiplatelet Agents

Asprin

• Prevent platelet aggregation.

• Use for prophylaxis of blood clots particularly in unstable angina

Mechanism ???
– Causes irreversible inhibition of cyclooxygenase (enzyme responsible for synthesize
thromboxane A2)

– Through its effects on thromboxane, aspirin inhibits platelet activation and aggregation

• In patients with stable or unstable angina, aspirin has been consistently shown
to reduce the risk of major adverse cardiac events, particularly MI
 Antiplatelet Agents
• Aspirin (75-162 mg daily) is recommended in all patients with chronic IHD (with or

without symptoms) in the absence of contraindications

• Aspirin is contraindicated (e.g., aspirin allergy, active peptic ulcer disease, or active

internal bleeding)

• Clopidogrel (75 mg daily) is chosen when aspirin is absolutely contraindicated

• Combination of aspirin and clopidogrel 75 mg daily for up to 9 months was more

effective than aspirin alone in decreasing the risk of death, MI, and stroke

• Aspirin Contraindication: Documented hypersensitivity, Gastrointestinal disease, liver

damage; ; bleeding disorders; asthma, Because of association with Reye syndrome, do

not administer to children

 Lipid lowering drugs
Statin (HMG-CoA) reductase inhibitor

• Statin therapy should be considered in all patients with IHD, particularly in those with elevated

LDL cholesterol or DM

• Effective for both primary and secondary prevention of IHD-related events.

– improving atherosclerotic plaque stability

– Shift LDL cholesterol particle size from highly atherogenic particles to less atherogenic particles

– Prevent inflammation by lowering C-reactive protein and other inflammatory mediators thought to be

involved in atherosclerosis.

– Improve endothelial function leading to more effective vasoactive response of the coronary arteries.

• A meta-analysis showed the risk of major adverse cardiac events is reduced by 21% with the

use of statins in patients at high risk for IHD-related events

– Simvastatin, P.O, 10-40mg/day, Atorvastatin, P.O., 10-80mg/day ,Rosuvastatin,P.O.,5-20mg/day

Lovastatin,P.O., 20-80 mg/day

 ACE Inhibitors
• ACE inhibitors should be considered in IHD patients who also
have diabetes mellitus, left ventricular dysfunction

• How??
– ACE inhibitors antagonize the effects of angiotensin II and
aldosterone

– Decrease BP and sodium and water retention (decrease ventricular

wall tension)

– Improve endothelial function

– Prevent myocardial fibrosis

Doses of ACE inhibitors and Angiotensin Receptor
Blockers Indicated in Ischemic Heart Disease (IHD)
 Coronary revascularization

• In most patients with IHD, the most effective

treatments to improve myocardial oxygen
supply are Invasive mechanical interventions
• Percutaneous coronary intervention (PCI)
• coronary artery bypass grafting
 Percutaneous coronary intervention (PCI)
• is appropriate for when optimal medical therapy fails or

• if extensive coronary atherosclerosis is present

• high risk patients (Low exercise capacity,large area of ischemia, EF

– Reduced stenosis due to
• Compression, redistribution of plaque

• Embolization of plaque contents

• Disruption of plaque & arterial wall

– Patients usually heparinized during PCI to prevent immediate thrombus formation at site of arterial injury
• anticoagulation up to 24 hrs

• Prevention of restenosis:
– combination therapy with acetylsalicylic acid, heparin, GP IIa/IIIa receptor antagonists

– bivalirudin

– drug-eluting & bare metal stents

 Coronary artery bypass graft surgery
• Involves using a leg vein or mammary artery
to form a channel around an atherosclerotic
plaque.
– Reduces symptomatic angina not controlled by
medical management or PCI
– Improves patient lifestyle
– Reduces CAD mortality
– Reduces need for nitrates, ß-blockers
 PTCA Vs CABG
• Low-risk patients have greater alleviation of
symptoms with PCI
• Moderate-risk patients had equal mortality &
MI rates with PCI or CABG
• High-risk patients showed improved survival
with CABG than medical therapy
 Outcome Evaluation
• Assessing for Drug Effectiveness and Safety

• Monitor symptoms of angina at baseline and at each clinic visit to assess the

effectiveness of antianginal therapy.

• If angina is occurring with increasing frequency or intensity, adjust anti-anginal

therapy

• Improved cardiac performance

• Risk factor reduction

• Increased exercise capacity

• May use coronary angiography to assess extent of stenosis or restenosis after

angioplasty or CABG
 Outcome Evaluation
• Closely monitor heart rate in patients treated with
– Drugs that have negative chronotropic effects
• e.g.ß-blockers, verapamil, or diltiazem) or

– Drugs that may cause reflex tachycardia

• e.g., nitrates or dihydropyridine CCBs).

• Routinely monitor renal function and potassium levels at

baseline, after drug initiation and post dose titration,and
periodically thereafter(ACE inhibitors and/or ARBs,)
 Variant angina or Prinzmetal’s
• Results from spasm (or vasoconstriction) of a coronary artery
in the absence of significant atherosclerosis

• Is characterized by recurrent episodes of chest pain (angina)

that usually occur when a person is at rest, between midnight
and early morning

• Vasospasm is generally transient, in some instances may

persist long enough to infarct the myocardium.
– Commonly resolves without progression to MI
 Variant Angina Pectoris
Causes

• The cause of variant angina is unclear but appears to involve endothelial dysfunction
– Imbalance between endothelium-produced vasodilator factors (prostacyclin, nitric oxide) & vasoconstrictor

factors (endothelin, angiotensin II) results in impaired endothelium dependent vasodilatation

• Adrenoreceptor polymorphisms may predispose patients to developing vasospasm

• Imbalance of autonomic control characterized by parasympathetic dominance of inflammation

• Precipitants of variant angina include

– Cigarette smoking,

– Stress

– Cocaine or amphetamine use,

– Exposure to cold temperatures.

 Diagnosis
• ST-segment elevation during transient chest discomfort
(usually at rest) that resolves when chest discomfort
diminishes in patients with normal or non-obstructive lesions

• In absence of ST-segment elevation, may use provocative

tests to precipitate coronary artery spasm
– ergonovine, acetylcholine, methacholine

– withdraw nitrates & CCB prior to testing

 Treatment
Treatment strategy

• Treat all patients for acute attacks

• Maintain prophylactic treatment 6 to 12 months following initial episode

– Using vasodilators
• Nitrate(Sublingual, long acting nitrate)

• Calcium channel blocker

• Eliminate aggravating factors

– Alcohol

– Stimulant ex-ocaine

– cigarette smoking
 Treatment
• Nitrates for acute attacks (Sublingual)
– Effective, fast-acting ,inexpensive

– Relaxes or prevents spasm in coronary arteries, thus increasing oxygen supply

• CCBs
– cause the blood vessels to relax, making them wider and letting more blood pass through to the

heart

– Nifedipine, verapamil, diltiazem equally effective single agents for initial treatment

– Dose titration needed

– Combination therapy with nifedipine-diltiazem or nifedipine- verapamil useful for patients

unresponsive to single-drug regimens

• ß-blockers should be avoided in patients with variant angina because of

– their potential to worsen vasospasm due to unopposed α -adrenergic receptor stimulation
 YOU
NK
T HA