Pathophysiology, Pharmacology and Pharmacotherapy of Coronary Artery Disease Flashcards
chronic coronary disease
Stable angina/Stable ischemic heart disease
Post-ACS or revascularization
Angina with coronary artery spasm/microvascular angina
Acute coronary syndromes
Unstable Angina
Non ST Segment Elevation MI
ST Segment Elevation MI
Impact of CV disease in US
Atherosclerotic CAD is the number one cause of death in both men and women
Increases with age, greater in men than women until menopause
Clinical syndromes of chronic coronary disease
- Stable angina pectoris: “macrovascular disease”
- Post-ACS; post-revascularization
- Variant or Prinzmetal’s angina: “vasospastic disease”
- Cardiac syndrome X: “microvascular disease”
- Silent myocardial ischemia
Types of angina
prinzmetal’s variant angina (vasospasm) - supply ischemia: angina associated with artery closure by a spasm, alteration in supply of blood to muscle
chronic stable angina (fixed stenosis) - demand ischemia: fixed threshold type, blockage from exercise, get ischemia
unstable angina (thrombus) - supply ischemia: atherosclerosis progresses to have thrombus form, causes vessel to fully close
Myocardial ischemia oxygen supply/demand imbalance
fixed stenosis, vasospasm, thrombus –> decreased coronary blood flow –> ischemia –> angina, anginal equivalents
increase in heart rate, contractility, afterload, preload –> increased oxygen consumption –> ischemia –> angina, anginal equivalents (SOB, change in color of tissue, due to some other disease i.e HF)
Factors impacting myocardial O2 supply/demand ratio
contractility
heart rate
preload
afterload
Contractility
decrease will decrease O2 consumption
Heart rate
- decreased HR will decrease O2 consumption
- decreased HR will increase coronary perfusion
Preload
- Decreased by venodilation
- Decrease leads to decrease in O2 consumption
- Decrease leads to increase in myocardial perfusion
Afterload
- Decreased by dilation of arteries
- Decrease leads to decrease in O2 consumption
Pathophysiology of stable angina
- Stable angina pectoris is usually associated with large single to multivessel ASCAD - Ischemia → CP caused by a fixed obstruction in epicardial artery
- Approximately 85 % of patients with angina pectoris have significant coronary artery disease (defined as > 70-75% atherosclerotic reduction) in a major epicardial coronary vessel. - Reductions between 50-70 % usually do not cause ischemia
Epicardial vessels
1,2,3: RCA (right coronary artery)
11: LM (left main, right off the aorta)
12, 13, 14: LAD (the widow maker; left anterior descending artery)
18,19: LCX (left circumflex)
Myocardial ischemia
Imbalance between myocardial oxygen supply and demand
* Usually, secondary to increased myocardial work (EFFORT INDUCED) in the setting of a fixed decrease in myocardial oxygen supply.
Produces disturbances in myocardial function without causing myocardial necrosis.
* Mechanical, Biochemical and Electrical
Angina
Resulting symptoms from ischemia…is a clinical syndrome of chest discomfort.
Stable angina pectoris definition
- Discomfort in the chest and/or adjacent areas
- Caused by myocardial ischemia and associated with a disturbance in myocardial function without myocardial necrosis.
- “Stable”: characteristics of an anginal episode (quality, frequency, severity, duration of symptoms, time of day, etc.) have not changed recently.
Clinical presentation: typical PQRST
- Precipitating factors: Exertion (walking, gardening, ADOL….etc.)
- Palliative measures: Rest and/or SL NTG
- Quality and quantity of the pain: Squeezing, heaviness,
tightening - Region and radiation: Substernal
- Severity of the pain: ~Subjective, > 5 (out of 10)
- Timing and temporal pattern: Lasts <20 min, usually relieved in 5-10 min
Classic clinical characteristics
- Typical angina:
Substernal
Duration: 0.5-20 min (usually short)
NTG/Rest relief - ECG findings:
ST-segment depression (during event)
women + pts with diabetes have more silent episodes of ischemia and describe pain in diff way
Diagnostic procedures
- History and physical examination - Risk factors
- Electrocardiogram - ST segment depression (during ischemia); ST segment elevation in variant angina
Diagnostic procedures for CHD exercise tolerance testing
- Treadmill or bicycle exercise testing
- Endpoints: duration, workload achieved, ECG changes, BP and HR responses and Sxs.
- Double product: HR·SBP is used as an index of MVO2
- Assessment of drug therapy
- Beta-blockers and CCBs may complicate interpretation by ↓HR
Diagnostic procedures for CHD
- Cardiac Imaging
Pharmacologic stress testing (drug increases HR if unable to use treadmill)
Nuclear imaging
Electron beam computerized tomography (EBCT) - Calcium score (non-invasive CT scan, allows you to quantify calcification associated with plaque, higher score, more significant - Echocardiography
- Cardiac catheterization and coronary angiography - Definitive assessment of coronary anatomy; Invasive
Treatment of chronic coronary disease
desired outcome #1: risk factor modification, prevent ACS and death
desired outcome #2: managment of anginal episodes, alleviate acute sxs and prevent recurrent sxs of ischemia
avoid/minimize adverse treatment effects
Treatment algorithm for #1
stable ischemic heart disease –> risk factor modification –> lifestyle modifications: diet, exercise, weight reduction, smoking cessation –> annual flu vaccine –> management comorbidities: HTN BP goal </= 130/80 mm Hg, DM Hgb A1C goal </=7%, moderate to high intensity statins –> antiplatelet therapy: aspirin 81 mg/day OR clopidogrel 75 mg/day is aspirin allergy; DAPT may be reasonable in certain high-risk patients –> ACE-I: if HTN, DM, LVEF </=40% or CKD OR ARB if intolerant to ACE-I
Treatment algorithm for #2
stable ischemic heart disease –> management of angina –> SL NTG for acute attacks –> vasospastic angina? –> yes - BP <130/80 mm HG, add LA nitrate, BP >/=130/80 mm Hg, add CCB; no - heart rate >60 bpm - beta blocker, non-DHP CCB –> angina sxs controlled? –> yes - continue therapy and monitor; no - BP <130/80 mm Hg? –> yes - add ranolazine or LA nitrate; no - add DHP
CCB –> continued angina –> consider PCI or CABG surgery
Cardiovascular risk factor reduction goals and strategies
risk factor: dyslipidemia, HTN, DM, smoking, weight management, physical activity
Dyslipidemia treatment goal and preferred treatment
treatment goal: >50 % reduction in LDL
preferred treatment: Lifestyle modifications; Low (< 7%) saturated fat, Low (<200 mg/dL) C; Moderate-High Intensity Statins
HTN treatment goal and preferred treatment
treatment goal: BP < 130/80 mmHg
preferred treatment: Lifestyle modifications; Therapy based on compelling indications with b- blockers, ACEIs, ARBs + others as necessary
DM treatment goal and preferred treatment
treatment goal: HbA1c < 7 %
preferred treatment: Individualize to reach goal
T2DM with ASCVD: SGLT2 or GLP-1
Smoking treatment goal and preferred treatment
treatment goal: Complete Smoking Cessation/Exposure
preferred treatment: Systematic strategy, pharmacotherapy
Weight management treatment goal and preferred treatment
treatment goal: BMI 18.5-24.9; Waist circumference (40 men, 35 women); Wt loss 5-10 % initially
preferred treatment: Diet/lifestyle counseling, printed educational materials and encourage
Physical activity treatment goal and preferred treatment
treatment goal: 30-60 min mod intensity activity 5-7 days/wk; Cardiac Rehab/Supervised
preferred treatment: Brisk walking, swimming, cycling; Increased daily activities
Other risk factor modifications
- Influenza vaccination
- Alcohol consumption
- Exposure to air pollution
- Management of psychological factors
Pharmacotherapy to prevent ACS and death
- Anti-platelet therapy
- Statin therapy: See dyslipidemia lectures
- RAS Inhibitors: ACE inhibitor/ARB therapy
- Colchicine? (may decrease CV risk)
- Beta-blockers
Aspirin: platelet COX-1 inhibition
- Acetylation and irreversible inactivation of platelet COX-1
- Antiplatelet activity: Blocking TXA2 synthesis: Interferes with platelet aggregation; Prolongs bleeding time; Blocks arterial thrombi formation
COX-1 vs COX-2
COX-1 promotes clotting: aspirin –> TXA2 –> increases platelet aggregation + vasoconstriction –> aspirin prevents platelet aggregation
COX-2 has protective anti-coagulative effect: coxibs –> prostacyclin, PGI2 –> inhibits platelet aggregation + vasodilation –> higher thrombotic risk
want to maximize COX-1 inhibition and minimize COX-2 inhibition; high dose aspirin also blocks COX-2, why we use low dose aspirin
Anti-platelet therapy
aspirin: loading dose - 162-325 mg
P2Y12 inhibitors: Clopidogrel (Plavix): loading dose - 300-600 mg; Prasugrel (Effient): loading dose - 60 mg; Ticagrelor (Brilinta): loading dose 180 mg; Cangrelor (Kengreal)
Aspirin (soluble or EC) MOA
Beneficial (low dose): Irreversibly inhibits COX-1, blocking the formation of TXA2 (potent platelet aggregant and vasoconstrictor)
Detrimental (higher dose): Inhibits COX-2, blocking formation of PGI2 (opposite of above)
take aspirin tab during MI –> prevent thrombus from progressing, can’t take EC, not fast enough
EC protects against gastric distress (only dissolves in SI)
ASA decreases platelet aggregation; low dose - reduces risk of future CV events
P2Y12 inhibitors MOA
Selectively inhibit adenosine diphosphate induced platelet aggregation with no direct effect on TXA2
Adverse effects: aspirin
- Gastrointestinal: bleeding
- Hematologic: bleeding (intracranial and extracranial)
- Hypersensitivity
- Major bleeding: 2-3 % in year 1
P2Y12 inhibitors
clopidogrel
prasugrel
ticagrelor
Clopidogrel
CYP dependent; conversion to active
Prasugrel
less CYP dependent; conversion to active
Ticagrelor
direct acting
Pharmacology of P2Y12 inhibitors
block P2Y12 receptor; no more ADP stimulated mechanism