Chapter 3: Ischemic Heart disease

1. Lesson 3
Ischemic Heart Disease(IHD)
Tsegaye Melaku (BPharm, MSc)
[Assistant Professor of Clinical Pharmacy]
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609January, 2020
Pharmacotherapy of Cardiovascular Disorders

2.  Session Hits
 Risk factors for dev’t of IHD
 Pathophysiology of chronic stable angina Vs ACS
 Clinical picture(consider specific patient)
 Appropriate lifestyle modifications & pharmacologic therapy
 Appropriate therapeutic regimen
 Monitor & evaluate
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3.  IHD:
– Aka coronary heart disease /arterial diseases(CHD) /(CAD)
– ↓ed supply of oxygenated blood to heart muscle.
– Caused by stenosis/narrowing( ≥1 major coronary arteries)
 Most commonly by atherosclerotic plaques
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4.  The major epicardial coronary arteries
a) Left main,
b) Left anterior descending,
c) Left circumflex,
d) Right coronary arteries
 Atherosclerosis  obstructive lesions(main/branch artery)
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5.  Vasospasm (no or minimal atherosclerotic plaques): may further constrict blood
flowcontribute to angina   to ACS
– Aka variant or Prinzmetal angina : uncommon
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6.  IHD: an imbalance between myocardial oxygen supply and oxygen demand
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10.  Most common
 Discomfort in the chest (↓blood supply to the myocardium)
 Chronic occurrence of chest discomfort
– Due to transient myocardial ischemia with physical exertion
or
– Other conditions that ↑MVO2.
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11.  IHD affects over 15 million Americans
 Leading cause of death : US data
 Incidence: higher in middle-aged men compared with women
– Rate ↑es 2-3 fold in women after menopause
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12.  It is initial manifestation of IHD in half of patients,
– ACS: first sign of IHD in other patients.
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13.  Hypertension, diabetes,
 Dyslipidemia, cigarette smoking
 Physical inactivity, obesity: independently ↑ the risk for IHD
 Multiple risk factors: 5- 7x risk increases
– Metabolic syndrome(MS)
 Constellation of HTN, abdominal obesity, dyslipidemia,
& insulin resistance
 Increase the risk by 2 fold
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15.  Patients must meet at least three of the following criteria: AHA definition
– Waist circumference: ≥40 inches/102 cm in men & ≥35
inches /89 cm women.
– TG ≥150 mg/dL) or active Rx to lower TG.
– Low HDL-C < 40 mg/dL in men and < 50 mg/dL in
women) or active Rx to raise HDL-C
– SBP ≥130 mm Hg, DBP≥85 mm Hg, or on antihypertensive
therapy.
– FBS ≥100 mg/dL or on antidiabetics.
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16.  Consider the determinants of oxygen supply & demand
 ↑in HR, cardiac contractility, LV wall tension  ↑MVO2
– Ventricular wall tension: BP, LV end-diastolic volume,
ventricular wall thickness.
 O 2 supply ↓ed:
– Reductions in coronary blood flow (2° to atherosclerotic
plaques/vasospasm/thrombus formation
– Arterial oxygen content (2° to hypoxia)
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17.  ↓ in diastolic filling time (e.g., tachycardia) ↓ coronary perfusion &
supply
 Anemia/CO poisoning/ cyanotic congenital HD  ↓ oxygen carrying
capacity of the blood    ischemia
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Endothelial cells : form a selective barrier between the vessel wall and blood contents.
Macrophages Lipoprotein  Foamy cells
Smooth cells migration to intima by growth factors

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24.  Distinguish b/n chronic stable from unstable angina
– The latter associated with a greater risk for MI & death
» Requires hospitalization for more aggressive treatment.
 Chronic stable angina:
– 1ºly due to↑ MVO2 rather than acute changes in oxygen
supply.
– Sxs are typically reproducible[provoked by exertion/exercise/stress.]
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25.  ACS:
– Due to an acute ↓ in coronary blood flow [inadequate
oxygen supply].
– Prolonged symptoms [often occurring at rest].
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26.  Most patients are not in acute distress
 If patients in acute distress suspect ACS
 X-rize pain: quality, location, duration, provoking/relieving factors
 Pressure/heaviness/tightness/squeezing in anterior chest area
 Sharp pain: not a typical symptom
 Pain radiate to the neck, jaw, shoulder, back, or arm.
– Accompanied by dyspnea, NV, or diaphoresis.
– Pain typically persists for several minutes
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30. 36Photo from www.google.com

31.  Sxs provoked by exertion/emotional stress
– Cold temperatures & heavy meals
– Relieved by rest or SL nitroglycerin.
 Atypical sxs[women, Elderly, DM]
– Indigestion, gastric fullness, back pain, SOB
– Diaphoresis, nausea, fatigue, and dizziness
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32.  Detailed history of symptoms
 Physical examination,
 Laboratory analysis
– FBS, HA1C, hemoglobin, lipid panel,
– Organ function (RFT, LFT, TFT)
– Cardiac biomarkers
 Diagnostic tests
– ECG, ECHO, X-ray, MRI, CT scan, angiography
– Stress testing [exercise or pharmacologic]
 Signs: abnormal heart sounds
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Canadian cardiovascular society classification system of angina

34.  Goal of therapy
– Prevent acute coronary syndrome and death
– Alleviate acute symptoms of myocardial ischemia
– Prevent recurrent symptoms of MI
– Prevent progression of the disease
– Reduce complications of IHD
– Avoid or minimize adverse treatment effects
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35.  Aggressively modify cardiovascular risk factors
 Slow the progression of coronary atherosclerosis
 Stabilize existing atherosclerotic plaques
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36.  Rx: balance between MVO2 & supply.
– Primary Rx: ↓ MVO2
– No response: revascularization by PCI & CABG: restore
coronary blood flow
 Appropriate drug dosing & monitoring: crucial
– Initiation/titration
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38.  Smoking cessation/avoidance of second-hand smoke,
 Dietary modifications,
 ↑ed physical activity,
 Weight loss
 Cigarette smoking: single most preventable cause of IHD & IHD related death
– Smoking: attenuate the antianginal effects of drug therapy.
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40.  Considered when:
– Medical therapy fails
– Symptoms are unstable, or
– Extensive coronary atherosclerosis (e.g, >70% occlusion of
coronary lumen)
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41.  Different methods:
a) Percutaneous transluminal coronary angioplasty(PTCA)
– Balloon inflation
b) Intracoronary bare metal stent placement
– Stents are thrombogenic(esp. until endothelialized
– DAPT: required till endothelized (~12 months)
c) Intracoronary drug-eluting stent placement
– Low concentrations of an anti-proliferative drug
» (paclitaxel, everolimus, sirolimus, or zotarolimus)
d) Rotational atherectomy
– Special cut away the atherosclerotic plaque
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44.  As an alternative to PCI
 May as open-heart surgery
 Considered
– In extensive coronary atherosclerosis (>70% occlusion of ≥3
coronary arteries)
– Refractory to optimal medical treatment.
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48.  High-intensity statin
– Clinical ASCVD & without clinical ASCVD LDL-C ≥190
mg/dL;
 Moderate to high-intensity
– Age >40 + diabetes
– Candidate who didn’t tolerate side effects of high intensity
– LDL-C <190mg/dL + age >40yrs +
» 10-year ASCVD risk of 7.5% in the absence of DM
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 Statin
– Anti-inflammatory effects,
– Antiplatelet effects/stabilize plaque
– Improvement in endothelial function,
– Improvement in arterial compliance and tone

50.  Hypertension
– Minimize the risk of MACE
– Goal of <140/90 mm Hg
– Rx: ACEI/ARBs ± CCB ± thiazide diuretics
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 Antiplatelet Agents
 Aspirin: prevent production of TXA2
– Considered in all patients, in no contraindications
– Dose: 75 to 162 mg
 Alternative: glycoprotein IIb/IIIa receptors inhibitors
– Clopidogrel [75mg], prasugrel, or ticagrelor
 DAPT:
– ACS
– Following PCI with stent placement [at least for 1yr, ACS +PCI)

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 Ang-II
– Potent vasoconstrictor
– Stimulates the production of aldosterone.
– HTN & Na+ & water retention increasing ventricular wall
tension),
– Cause endothelial dysfunction, promote thrombus formation,
– Cause myocardial fibrosis.

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 In absence of contraindications, ACEI
– Should be considered in all patients with IHD,
– Particularly those HTN, DM, CKD, LV dysfunction, Hx of MI,
 Side effects:
– HyperK+, deterioration in renal function, & angioedema
– Vasoconstriction of efferent arteriole
– Chronic cough
 CI: Pregnancy, AKI, renal artery stenosis

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Dosing of ACEIs and ARBs in IHD

55.  0.3 to 0.4 mg dose every 5 minutes
 To relieve acute symptoms
 Antianginal effect within 1 to 3 minutes,
 Sublingual tablets or spray
 Nitrates  NO ↑cGMP  ↑ca2+  smooth muscle relaxation
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 1˚rly venodilation  ↓preload
– ↓ventricular volume & wall tension  MVO2
 In higher dose: arterial dilation/afterload/↓BP
– ↑myocardial oxygen supply [dilate epicardial coronary
arteries & collateral vessels].
 Isosorbide dinitrate: long acting effects lasting up to 2 hours
 Don’t use with 24 to 48 hours 5-PDE inhibitors
 Side effects: hypotension, dizziness, or lightheadedness.

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 Prevent ischemic symptoms: β-blockers, CCBs, nitrates, & ranolazine
 They
– Decrease the frequency of angina
– Delay the onset of angina during exercise
 No evidence as if these agents prevent ACS or improve survival in
stable angina

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Effects of Antianginal medications

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 ↓HR & cardiac contractilityMVO2
 ↓ BP & ventricular wall tension [inhibition of renin release]
 Slow HR   prolong diastole  increasing coronary blood flow.
 Do not improve myocardial oxygen supply.
 Avoid those with ISA (e.g, acebutolol, pindolol, penbutolol): not effective
 Dosing & titration: based on HR
– Resting HR: 50-60bpm
– Exercise HR: max 100bpm/<20bpm above resting HR

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 Sidé effets: fatigue, sleep disturbances, malaise, depression, and sexual
dysfunction.
 CI: severe bradycardia (HR<50 beats/min) or AV conduction defects,
asthma, bronchospastic disease, & severe depression
 Cautions: diabetes or acute HF, Abrupt withdrawal
 DDI: digoxin, verapamil, diltiazem, etc

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Properties and dosing of Beta Blockers in IHD

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 Inhibit Ca2+ entry into vascular smooth muscle & cardiac cells  relaxation
 On vascular smooth muscle cells  systemic vasodilation  ↓ afterload
 On cardiac cells   ↓ cardiac contractility.
 ↓ MVO2 : ↓ wall tension (through reductions in afterload) & ↓ cardiac
contractility.
 All CCBs ↓supply: dilating coronary arteries
 Non-DHP: slow SA & AV nodal conduction, ↓HR  ↓MVO2
– More effective than DHP for angina(-ve inotropic effect)

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Dosing of CCBs for IHD

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 Products produce effects within 30 to 60 minutes
 Issue: tolerance with continuous use
 First 24 hours of continuous nitrate therapy  loss of antianginal effect
– Generation of free radicals that degrade nitric oxide
 Monotherapy should be avoided.
– Reflex ↑ in sympathetic activity & HR
– Add β-blocker ± CCB
 Side effects: postural hypotension, dizziness, flushing, headache

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Nitrate formulation for chronic use

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 Dose: 500 mg -1000mg Bid
 Anti-ischemic agent
 MOA: unknown/unclear
– Inhibit late inward sodium current during plateau phase of
the cardiac action potential.
 For angina refractory to other antianginal medications
 Side effects: dizziness, constipation, headache, nausea. Syncope

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 Efficacy & safety
– Clinical signs and symptoms
– Laboratory tests and investigations

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