2. IHD DEFINITION
Ischemic heart disease (IHD) is a condition in
which there is anadequate supply of blood and
oxygen to a portion of myocardium It tipically
occurs when there is an imbalance between
myocardial oxygen supply and demand
The most common, serious, chronic, life-
theatening disease in the developed countries
The most common cause is atherosclerotic
disease of an epicardial coronary artery
Begins early in life, often not being clinically
manifest until the middle-aged years and beyond
3. Oxygen Carrying Capacity
The oxygen carrying capacity relates to the
content of hemoglobin and systemic
oxygenation
When atherosclerotic disease is present, the
artery lumen is narrowed and
vasoconstriction is impaired
Coronary blood flow cannot increase in the
face of increased demands and ischemia may
result
4. Ischemic Heart Disease (IHD)
Three main coronary arteries:
1. Left anterior descending artery
2. Circumflex artery
3. Right coronary artery
Coronary arteries are blood vessels
that carry blood, oxygen and
other nutrients to the heart
tissue to help it work effectively
Getting older – hardened coronary
arteries & build up fatty deposits
on the inner lining of the vessel
(atherosclerosis) - narrowing of
the coronary arteries- blood
supply to heart muscle is
reduced symptoms of
coronary artery disease
5. IHD classification
Acute coronary
syndrome
Unstable angina
Myocardial infarction:
NSTEMI & STEMI
Stable angina
Non–ST-segment-elevation
myocardial infarction (NSTEMI)
ST-segment-elevation myocardial
infarction (STEMI)
Ischemia without clinical symptoms or owing to
coronary artery vasospasm
(variant or Prinzmetal’s angina)
6. 1. Atheroscheloris
Faktor risiko a.l. kolesterol, dislipidemia, DM, riwayat
keluarga, obat-obatan (kokain, marijuana, amphetamine)
2. Spasm
Spasme arteri koroner pada semua ras (Jepang)
Spasme krn mediator a.l.Angiotensin II, endotelin, dsb ;
terjadi setiap saat, sering tdk terkait dg latihan fisik
3. Embolism
Jarang terjadi krn arteri koroner pendek; dpt terjadi pd
pasien dengan riwayat endokarditis
4. Congenital
Prevalensi kecil (1-2%)
Etiology & Pathophysiology
8. Cholesterol
Everybody needs cholesterol, it serves a vital function in the body
It is a component of the nerve tissue of the brain and spinal cord as
well as other major organs
Frequently measured to promote health and prevent disease
A major component of the plaque that clogs arteries
Lipoproteins- 4 main classes
Chylomicrons
Very low density lipoproteins (VLDL)
Low Density Lipoprotein (LDL)
High Density Lipoprotein (HDL)
9. Good vs Bad Cholesterol
LDL is known as bad
cholesterol. It has a
tendency to increase risk of
CHD
LDL’s are a major
component of the
atherosclerotic plaque that
clogs arteries
Levels should be <130
HDL is known as the good
cholesterol
It helps carry some of the
bad cholesterol out of the
body
It does not have the
tendency to clog arteries
Levels should be >35
High levels of HDL >60
can actually negate one
other risk factor
11. A lesion begins as a fatty streak (a) and can develop into an intermediate lesion
(b), and then into a lesion that is vulnerable to rupture (c) and, finally, into an
advanced obstructive lesion (d)
Atherosclerosis*
*Rader DJ & DaughertyA. Nature.Vol. 451, February 2008
12. a.Atherogenic lipoproteins such as low-density lipoproteins (LDLs) enter the intima,
where they are modified by oxidation or enzymatic activity and aggregate within the
extracellular intimal space, thereby increasing their phagocytosis by macrophages.
Unregulated uptake of atherogenic lipoproteins by macrophages leads to the
generation of foam cells, which are laden with lipid.
The accumulation of foam cells leads to the formation of fatty streaks, which are often
present in the aorta of children, the coronary arteries of adolescents, and other
peripheral vessels of young adults.
Although they cause no clinical pathology, fatty streaks are widely considered to be
the initial lesion leading to the development of complex atherosclerotic lesions.
Atherosclerosis*
13. b.Vascular smooth muscle cells — either recruited from the media into the
intima or proliferating within the intima — contribute to this process by
secreting large amounts of extracellular-matrix components, such as collagen.
The presence of these increases the retention and aggregation of atherogenic
lipoproteins. In addition to monocytes, other types of leukocyte, particularlyT
cells, are recruited to atherosclerotic lesions and help to perpetuate a state of
chronic inflammation.As the plaque grows, compensatory remodelling takes
place, such that the size of the lumen is preserved while its overall diameter
increases.
Atherosclerosis*
14. c. Foam cells eventually die, resulting in the release of cellular debris and
crystalline cholesterol. In addition, smooth muscle cells form a fibrous cap
beneath the endothelium, and this walls off the plaque from the blood.This
process contributes to the formation of a necrotic core within the plaque and
further promotes the recruitment of inflammatory cells.This nonobstructive
plaque can rupture or the endothelium can erode, resulting in the exposure of
thrombogenic material, including tissue factor, and the formation of a thrombus
in the lumen. If the thrombus is large enough, it blocks the artery, which causes
an acute coronary syndrome or myocardial infarction (heart attack).
Atherosclerosis*
15. d. Ultimately, if the plaque does not rupture and the lesion continues to grow, the
lesion can encroach on the lumen and result in clinically obstructive disease.
Atherosclerosis*
*Rader DJ & DaughertyA. Nature.Vol. 451, February 2008
Plaque Rupture (Animasi 1,Animasi 2,Animasi 3)
16. Etiology & Pathophysiology
The pathophysiology that underlies this disease process is dynamic,
evolutionary, and complex.
An understanding of the determinants of MVO2, regulation of coronary
blood flow, the effects of ischemia on the mechanical and metabolic
function of the myocardium, and how ischemia is recognized is
important in understanding the rationale for the selection and use of
pharmacotherapy for IHD.
Ischemia may be defined as lack of oxygen and decreased or no blood flow
in the myocardium.
In contrast, anoxia,defined as the absence of oxygen to the myocardium,
results in continued perfusion with washout of acid by-products of
glycolysis, thereby preserving the mechanical and metabolic status of the
heart to a greater extent than does ischemia for short periods of time.
MVO2 = mixed venous oxygen saturation
17.
18. Etiology & Pathophysiology
A. Determinants of Oxygen Demand (MVO2)
1. Heart Rate
2. Contractility
3. Intramyocardial wall tension during systole
B. Regulation of Coronary Blood Flow
1. Anatomic Factors
2. Metabolic Regulation
3. Endothelial Control of CoronaryVascularTone
4. Factors Extrinsic to theVascular Bed
5. Factors Intrinsic to theVascular Bed
6. Factors Limiting Coronary Perfusion
19. Etiology & Pathophysiology
B. 1.Anatomic Factors
- Coronary System - Large epicardial or surface vessels (R1) +
Intramyocardial arteries & arterioles (R2) dense capillary network
- Total resistance – R1 + R2 (R2 >)
- Myocardial blood flow ~ coronary driving pressure & inversely to arteriolar
resistance
- Atherosclerotic lesions
R1 increase – R2 vasodilate (autoregulation)
- Diameter, length of lession + influence of pressure drop in stenosis area
- Large & small coronary arteries may undergo dynamic changes in coronary
vascular resistance and coronary blood flow
- Collateral blood flow – exists from birth as native collateral; persisting
ischemia may promote collateral growth as developed collateral.These two
type of collateral differ in anatomy and their ability to regulate coronary
blood flow. Collateral development depends on the severity of
obstruction, the presence of various growth factor, endogenous vasodilator,
hormones, exercise.
20. Etiology & Pathophysiology
B. 2. Metabolic Regulation
- Adenosine, other nucleosides, NO, prostaglandins, CO2, H+ responsible
for oxygen balance – coronary blood flow
- Adenosine (from ATP &) – potent vasodilator – links decreased
perfusion to metabolically induced vasodilation or reactive hyperemia
B. 3. Endothelial Control of CoronaryVascularTone
- Vascular smooth muscle relaxation, Inhibit trombogenesis, Inhibit
atherosclerotic plaque formation
- Large molecules – fibronectin, interleukin-1, tissue plasminogen activator,
growth hormone
- Small molecules – EDRF, prostacyclin
- EDRF – relaxation & defence mechanism of noxious stimuli
- Loss endothelial cell – PTCA, cyanide (smoking)
EDRF = endothelium-derived relaxing factor
PTCA = percutaneous transluminal coronary angioplasty
21. Etiology & Pathophysiology
B. 4. Factors Extrinsic to theVascular Bed
- Coronary vascular resistance is influenced by phasic systolic
compression of the vascular bed
- Alteration in intramyocardial wall tension throughout the cardiac
cycle
- Average global distribution of blood flow between the epicardial &
endocardial
- Extravascular resistance may decrease blood flow, primarily during
systole
B. 5. Factors Intrinsic to theVascular Bed
- Metabolic factor, myogenic responses, neural reflexes, humoral
substances within vascular bed of the coronary circulation function
B. 6. Factors Limiting Coronary Perfusion
- The extent of cross-sectional obstruction, the lenght of the lession,
lession composition, and the geometry of the obstructing lession –
affect flow across coronary arteries
- Calcium accumulation and overload secondary to ischemia impair
ventricular relaxation as well as contraction
22. Clinical Presentation & Diagnosis
Chest pain; may be painless or “silent”
Typical pain radiation anterior chest pain (96%), left
upper arm pain (83.7%), left lower arm pain (29.3%), neck
pain (22%).
Family history MI, stroke, and peripheral vascular
disease, hypertension, smoking, familial lipid disorders, and
diabetes mellitus.
Lab test: hemoglobin, fasting glucose, fasting lipoprotein
panel, resting ECG, and chest x-ray
23. Diagnostic Tests
1. Electrocardiogram (ECG)
2. ExerciseToleranceTesting
Test toleransi/treadmill
Dapat dikombinasi dengan test perfusi miokardial dgThallium
(201Tl) utk reversible/ireversible aliran darah jantung
3. Cardiac Imaging
Test radionukleid angiografi (techtenium-99m) mengukur EF
(ejection fraction)
4. Echocardiography
Pharmacologic stress echocardiography (dobutamine, dipyridamole or
adenosine) or pacing may be done to identify abnormalities during
stress
5. Cardiac Catheterization & CoronaryArteriography
24. Treatments
- Desired Outcome
- Short term: reduce & prevent anginal symptoms that limit
excercise capability & impair QOL
- Long term: prevent CHD events (MI, arrhytmias, HF, life)
- Risk Factor Modification
- Unalterable: gender, age, family history or genetic
composition, environmental influences
-Alterable: smoking, HTN, hyperlipidemia, obesity,
sedentary life style, hyperuricemia, type A behavior pattern,
drugs (progestin, corticosteroid and cyclosporine)
32. ASPIRIN SEBAGAI ANTIPLATELET
Aspirin sbgTx standar utk penyakit jantung & pembuluh darah
Aspirin dpt memberi efek antiplatelet melalui asetilasi COX di platelet shg
menimbulkan hambatan pembentukan platelet yg permanen
Hasil penelitian menunjukkan tidak diperoleh Px dgn resistensi
aspirin & hanya 2 Px termasuk aspirin semirespon
Respon Px PJK dgn hipertensi thd aspirin sbg antiplatelet masih bagus
Aspirin masih mampu memberi perlindungan dlm menurunkan risiko kekambuhan
kejadian kardiovaskular pd Px PJK akibat pembentukan agregasi platelet
Ema P.Yunita dkk, 2015, ResistensiAspirin pada Pasien Penyakit Jantung Koroner dengan Hipertensi (Penelitian
Dilakukan di Poliklinik Jantung RSUD Dr. Soetomo Surabaya), Jurnal Farmasi Klinik Indonesia,Vol. 4, No. 1,
Hlm. 28-38, ISSN: 2252-6218.)
39. Treatments
1. BetaAdrenergic BlockingAgents
- Discontinuation: due to CNS adverse effect of fatigue,
malaise & depression
- Abrupt withdrawal – tapering down for 2 days
- Drug of choice for chronic exertional angina, chronic
angina due to reduce silent ischemia, early morning peak of
ischemic activity & improving mortality after MI
- CCB as substitute – monotherapy or combination
- Prototype drug: metoprolol, propranolol, atenolol
40.
41. Treatments
2. Nitrates
- Reduction of MVO2 secondary to venodilation & arterial-
arteriolar dilation leading to reduction wall stress from
reduce ventricular volume & pressure
- Large first pass effect, short to very short t1/2, largeVd,
high CL, large interindividual variability
- Nitroglycerin concentration – route of administration
- Used for acute anginal attack, prevent effort or stress
induced attacks, or for long-term prophylaxis (combine
with beta blocker or CCB)
42. Treatments
2. Nitrates
- Side effects:
- postural hypotension, headache, flushing, nausea,
tachycardia, rash
- Keep in tightly closed glass container – avoid mixing with
other medicines – reduce nitro adsorption & vaporization
- Repeated use is not harmful or addicting
- Nitrate tolerance – reduction of tissue cyclic GMP due to
decreace production & increase breakdown of guanylate
cyclase, and increase superoxide level
- Lack of cGMP – depletion of intracellular sulfhydryl
cofactor (cystein)
43.
44.
45.
46. Nitrate Products
Product Onset (min) DurationInitial Dose
Nitroglycerin
IV 1–2 3–5 min 5 µg/min
Sublingual/lingual 1–3 30–60 min 0.3 mg
PO 40 3–6 h 2.5–9 mg tid
Ointment 20–60 2–8 h 1/2–1 in
Patch 40–60 >8h 1 patch
Erythritol tetranitrate 5–30 4–6 h 5–10 mg tid
Penterythritol 30 4–8 h 10–20 mg tid
tetranitrate
Isosorbide dinitrate
Sublingual/chewable 2–5 1–2 h 2.5–5 mg tid
PO 20–40 4–6 h 5–20 mg tid
Isosorbide mononitrate 30–60 6–8 h 20 mg qd, bida
aProduct-dependent.
47. Treatments
3. Calcium Channel Antagonist
- Modulation of calcium entry into vascular smooth muslce
and myocardium, as well as variety of other tissue
- Reduce MVO2
- Px with contraindication or intolerance to beta blockers,
Prinzmetal’s angina, PVD, severe ventricular dysfunction,
HTN
- HOPE study – suggestACEI for preventing long-term
consequenses of IHD
48.
49.
50. Calcium Channel Blocker
Dihydropyridine CCB
Used to reduce systemic vascular
resistance and arterial pressure, but
are not used to treat angina (with the
exception of amlodipine,
nicardipine, and nifedipine,
which carry an indication to treat
chronic stable angina as well as
vasospastic angina) because the
vasodilation and hypotension can lead
to reflex tachycardia
Dihydropiridine calcium channel
blockers can worsen proteinuria in
patients with nephropathy
Only the non-dihydropyridine CCBs are considered to have negative
inotropic and chronotropic effects.The dihydropyridine CCBs increase
contractility and heart rate, therefore decreasing vascular resistance
Non-dihydropyridine CCB
Phenylalkylamine CCB
are relatively selective for myocardium, reduce
myocardial oxygen demand and reverse coronary
vasospasm, and are often used to treat angina ex:
verapamil
Benzothiazepine CCB
are an intermediate class between phenylalkylamine
and dihydropyridines in their selectivity for vascular
calcium channels. By having both cardiac depressant
and vasodilator actions, benzothiazepines are able to
reduce arterial pressure without producing the same
degree of reflex cardiac stimulation caused by
dihydropyridines ex: diltiazem
52. Treatments
4. Investigational Agents
- Ranolazine – reduction in fatty acid oxidation – swift in
myocardial energy production of glucose which is less
oxygen
- Therapeutic angiogenesis – stimulate blood vessel growth
ex.Ad5FGF-4
- Selective 5-HT3 antagonists – reduce pain following MI ex.
MCI 9042
- 5-HT2A antagonists,Tedisamil
- Markers: CRP, IL-6, MMP-9
53.
54. Treatments
Effect of DrugTherapy on Myocardial Oxygen Demanda
LVWallTension
Heart Rate Myocardial Systolic LV
Contractility Pressure Volume
Nitrates ⇑ 0 ⇓ ⇓⇓
β-Blockers ⇓⇓ ⇓ ⇓ ⇑
Nifedipine ⇑ 0 or ⇓ ⇓⇓ 0 or ⇓
Verapamil ⇓ ⇓ ⇓ 0 or ⇓
Diltiazem ⇓⇓ 0 or ⇓ ⇓ 0 or ⇓
aCalcium channel antagonists and nitrates also may increase myocardial oxygen
supply through coronary vasodilation. Diastolic function also may be improved
with verapamil, nifedipine, and perhaps, diltiazem.These effects may vary
from those indicated in the table depending on individual patient baseline
hemodynamics.
Abbreviation:LV = left ventricular.
