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
Adverse effects: P2Y12 inhibitors
- Clopidogrel: Bleeding, Diarrhea, Rash; ~1% increase in major bleeding when added to ASA
- Prasugrel: Bleeding, Diarrhea, Rash; ~0.6% increase (Absolute risk) in major bleeding/ 0.5% increase in life-threatening bleeding (vs. clopidogrel)
- Ticagrelor: Bleeding, bradycardia, heart block, dyspnea
Anti-platelet therapy in CCD clinical scenarios
- CCD: No history of stent implantation
- CCD: Elective PCI + Stent: Bare metal stent (BMS)…..Seldom Used; Drug eluting stent (DES) - drug in stent that’s released to provide more protection
- CCD and CABG: PCI/Stent then CABG; CABG
CCD: no history of stent implantation
AKA: secondary prevention
* SAPT (Single-Antiplatelet Therapy): ALL patients with a history of CCD should receive ASA 75-
100 mg/day indefinitely (preference for 81 mg); Absolute contraindications or significant intolerance - clopidogrel 75 mg/day
* DAPT (Dual-Antiplatelet Therapy)?: “Certain high-risk patients” (i.e pt who continues to have events) may receive both
*all pts with chronic coronary disease should recieve aspirin for life
DAPT - dual antiplatelet therapy
ASA + P2Y12 inhibitor
CCD: elective PCI + stent
stent expands at site, becomes part of vessel wall in coronary artery; area becomes endothelialized, cells surround stent and leave vessel open
intracoronary artery stents:
* Bare Metal Stents: Uncommonly used - BMS and durable polymer BMS
* Drug Eluting Stents - 1st Generation: Sirolimus, Paclitaxel; 2nd Generation: Everolimus, Zotarolimus (anti-proliferative interrupt, portion of cell cycle prevents rapid inflammation around cell site); 3rd Generation (Biosorbable polymer): Biolimus, Sirolimus, Everolimus
CCD: elective PCI + drug eluting stent
- Before procedure: ASA and P2Y12 inhibitor loading dose
- After procedure: low risk bleeding - DAPT: min 6 mo, SAPT: indefinitely; high risk of bleeding/overt bleeding - DAPT: 1-3 mo; SAPT: P2Y12 inhibitor until 12 mo; SAPT: indefinitely
- New recommendations do not distinguish between choice of P2Y12 inhibitor agents: Clopidogrel 75 mg daily; Prasugrel 10 mg daily; Ticagrelor 90 mg BID
- DAPT: ASA + P2Y12 inhibitor
- SAPT: ASA 81 mg preference
SIHD: CABG
- CABG: DAPT: ASA 81 mg/day + Clopidogrel 75 mg/day; SAPT: ASA Indefinitely; Clopidogrel may be reasonable for 12 months; There is some controversy regarding the need for DAPT
ASA dose must be </= _____mg with ticagrelor
100
risk of cerebral hemorrhage + stroke are higher
RAS (ACEI; ARB) inhibitors
- Used in almost all pts with coronary disease
- Stabilize plaque, improved ET function, inhibition of VSM cell growth, decreased macrophage migration, and ?anti-ox properties, Do not improve symptomatic ischemia (don’t decrease angina, decrease risk of CV events)
- ↓ CV events in high-risk patients w/w LV dysfxn; Benefit maybe lower in lower risk patients
- Should be considered in all patients with CCD: Especially patients with LVEF <40%, HTN, DM or CKD; Ramipril 10 mg/day (HOPE) and Perindopril 8 mg/day (EUROPA) studied
- ARBs in those who are intolerant (cough/AE) to ACEIs: Telmisartan 80 mg daily (ONTARGET) studied
- Combination therapy (ACEI + ARB) NOT recommended
Colchicine
- Reduces inflammation, likely via reduction in IL-1b and IL-18
- Indicated for reducing the risks of myocardial infarction, stroke, coronary revascularization, and cardiovascular deaths in adults with established ASCVD or multiple risk factors
- Role: ?High risk with elevated hsCRP (>2) (C reactive protein anti-inflammatory marker)
- CYP3A and P-gp substrate: caution with strong inhibitors
- Contraindicated in severe renal and hepatic disease
approved for tx of chronic coronary disease
Pharmacotherapy to prevent and/or reduce ischemia and angina sxs
- Increase myocardial oxygen supply: Dilation of coronary arteries (reduce vasospasm), collateral
blood flow, prolong diastole; How do we deal with fixed stenosis or thrombus? - Decrease myocardial oxygen demand: Heart rate; Myocardial contractility; Intramyocardial wall tension
- Systolic blood pressure (afterload)
- Left-ventricular end-diastolic volume (preload)
Pharmacotherapy to relieve acute ishcemia and angina
organic nitrates
Pharmacology of organic nitrates
- Mechanism of Action: Nitric oxide donors/releasers; Activation of guanylate cyclase
- Activity: Marked venodilation (decreased
preload) - dilate veins before heart, decrease blood flow to heart; Less arteriole dilation, coronary and
peripheral; Inhibition of platelet aggregation
(minor) - NTG = GTN (glyceryl trinitrate)
NO is a physiologic mediator of vascular tone
NO produced in endothelial cells; NO accompanies vascular smooth muscle cells
how NO leads to SMC relaxation: increases cGMP
Nitrates
clinical effects: increased myocardial O2 supply - Endothelium-dependent vasodilation…dilates epicardial arteries and coronary collateral vessels; decreased myocardial O2 demand - Venous vasodilation causes reduced preload and decreased LV volume
no effect on the natural history of the disease (just treat symptoms)
Nitrates: acute agents
nitroglycerin tabs, nitroglycerin spray, nitroglycerin powder packets, nitroglycerin buccal tabs, ISDN chewable tabs, ISDN SL tabs
Nitrate products
- Selection of agents: Spray vs. tablets
- Patient information: Storage; Administration
Instructions for nitroglycerin
patient experiences chest pain/discomfort –> take ONE nitroglycerin dose SL –> unimproved/worsening 5 min after taking one tab –> call 911 and take another tab); can take up to 3 tabs before the paramedics arrive
Patient education points
tabs: Keep in original dark glass container…No plastic Rx container; no safety cap; cotton plug removal; Place under tongue, do not swallow tab; Do not store in bathroom or humid locations
spray: Spray under tongue, do not inhale; do not shake
both: Keep on person at all times; Need for Rx refills 6 mo tabs ~3 yr spray; Reinforce technique for administration: sit, time frame, etc.; preventative use instructions; 911 procedure
Nitrate adverse effects and monitoring
- Adverse effects: Headache (throbbing or pulsating sensation); Hypotension, dizziness, lightheadedness and facial flushing; Reflex tachycardia (BP is reduced –> release catacholamines –> increase HR, this could lead to reflex ischemia)
- APAP use
- Extreme caution with PDEI (potential risk of hypotension)
- Monitoring Parameters
Nitrate contraindications
sildenafil; riociguat; alpha blockers - risk of hypotension
- Vasodilatory effects of nitrates may be substantially enhanced (25 mmHg drop in SBP)….fatal events have been observed
- All package labeling states the PDEIs for ED are contraindicated
- Duration of time to avoid PDEI’s within nitrates - avanafil: 12 hr; sildenafil and vardenafil: 24 hr; tadalafil: 48 hr
Clinical recommendations for nitrates
- SL NTG tablets (0.15-0.6 mg) or SL spray delivers (0.4 mg/spray) should be utilized in all patients: Products may also be useful for the prevention of angina, when taken just prior to the initiation of exertion or some other event which precipitates angina.
Pharmacotherapy to prevent recurrent ischemia and angina sxs
beta blockers, calcium channel blockers, nitrates
Mechanism of beta-adrenergic receptors smooth muscle cells
beta blockers block catecholamines from generating an increase in HR, contractility, and conduction velocity
beta2 AR receptors: epinephrine, isoproterenol, albuterol - block Gs-R –> increase cAMP –> relaxation
Beta blockers primary effects
- Mechanism of Action: competitive, reversible inhibitors of beta-
adrenergic stimulation by catecholamines - Desired effects on myocardial oxygen demand: Reduce HR (mainly during sympathetic stimulation); Reduce myocardial contractility; Reduce arterial BP (afterload)
- Undesired effect on myocardial oxygen demand: Reduce HR → Increase diastolic filling time → Increase LVEDV →
Increase Preload (negates some of the benefits) - Effect on myocardial oxygen supply? - blood flow through coronary artery increases during diastole
- Associated with reduced ventricular arrhythmias and remodeling
Beta1 selective agents
atenolol, metoprolol
at low doses, beta1 is predominant receptor blocked, otherwise considered non-selective at higher doses
want cardioselective in pts with asthma @ low dose
Non-selective agents
propranolol, carvedilol
ISA beta blockers
pindolol, acebutolol
not a lot of rationale use with angina; contraindicated in post-MI pts
Lipid soluble beta blockers
propranolol, carvedilol
Water soluble beta blockers
atenolol, bisoprolol
Beta blockers adverse effects
- Cardiac: sinus bradycardia, sinus arrest, AV block, reduced
LVEF - Others: bronchoconstriction, fatigue, depression, nightmares, sexual dysfunction, exercise intolerance, intensification of insulin-induced hypoglycemia and peripheral vascular complication.
- β-blocker withdrawal syndrome
Beta blockers: dosage and monitoring parameters
- Initiate at lowest dose and titrate to symptom reduction
- Goal Heart Rate: Rest: 50-60 BPM; Exercise
- < 100 BPM
- 75 % of HR that typically causes angina
- Painful episodes: NTG use
Ca2+ channel blockers mechanism of action
- Cardiac: Decrease influx of trigger Ca2+ in myocytes; Decreased chronotropy in nodal cells; Inotropy in myocytes
- Vascular: vasodilation
all block L-type Ca2+ channel –> blocks effects of Ca2+, block contraction
Calcium channel antagonists myocardial vs vascular selectivity
verapamil, diltiazem (1:1) –> balanced effect on myocardium + vasculature
nifedipine, amlodipine (10:1), felodipine, isradipine, nicardipine (100:1) –> much stronger affinity effect on vasodilation
Ca2+ channel blockers adverse effects
Dihydropyridines (potent vasodilators):
Hypotension, flushing, headache and dizziness Peripheral edema, likely related to arteriolar vasodilation Reduced myocardial contractility (DHPs?)
Reflex adrenergic activation
Non-Dihydropyridines:
Reduced myocardial contractility (V>D)
AV/SA nodal conduction disturbances: bradycardia and atrioventricular block (V>D)
Hypotension, flushing, headache and dizziness Constipation (V>D)
verapamil + diltiazem contraindicated in HF - potent inducers of inotropy
Calcium channel blockers monitoring
- Initiate at lowest dose and titrate to symptom reduction
- Painful episodes: NTG use
- Monitoring parameters: DHP - edema, BP; Non-DHP - just like beta-blockers; HR 50-60 @ rest and <100 while exercising
Nitrate tolerance
- ↓ response in the presence of continuously or frequently administered nitrates.
- Not an all-or-none process
- Examples:
24-hour applications of transdermal NTG; Continuous infusions of IV NTG; ISDN administered four times daily - Prevention of nitrate tolerance: Nitrate free period of at least 10-12 hours; Biopharmaceutics and PK contribute to the amount of time required to be dosage-free
Pharmacology of nitrate tolerance
- Reversible (hours) in absence of drug
- ALDH2 inactivation in mitochondria
- ISMN and ISDN also elicit tolerance but via a slower, less understood process.
GTN activated by aldehyde dehydrogenase to become inactive
Nitrates dosing
NTG patch
ISDN tabs
ISMN tabs
ISMN SR tabs
NTG patch dosing
once daily
on for 12-14 hrs off for 10-12 hrs
on: 7am off 7-9 pm
ISDN tabs dosing
2-3 times/day
8 am, 12 pm, 4 pm
10 mg TID (8,12,4)
ISMN tabs
2 times/day 7 hours apart
8 am and 3 pm
20 mg twice daily (8am and 3pm)
ISMN SR tabs
once daily
8 am
30 mg once daily
Patient counseling: nitrate patches
- Discussion of nitrate free interval
- Patches:
Apply the patch between elbows and knees
Apply the patch to clean, dry, hairless (or nearly free) skin that is not irritated, scarred, burned, broken, or calloused.
Choose a different area each day.
You may shower while you are wearing a NTG skin
patch.
Do not cut the patch (won’t release at zero order rate)
Wash hands before and after
Patient counseling: NTG ointment
- Do not rub or massage ointment
- Do not cover the area
Nitrates
- Initiate at lowest dose and titrate to symptom reduction
- Painful episodes: NTG use
- Adverse effects: BP reduction; trying to avoid relfex tachycardia
- Monitoring parameters
Vasodilator induced tachycardia
DHP + nitrates are primary problem agents with reflex tachycardia
Cellular events during ischemia
ischemia –> decrease O2 + ATP supply and decrease LV function –> increase Na+ –> increase Ca2+ –> increase myofilament activation –> increase LVEDP/LV wall tension, increase O2 + ATP consumption –> decrease microcirculation
ranolazine prevents the increase in Na+ (inhibits INa,late)
Ranolazine MOA
- MOA: Inhibition of late inward Na+ current in ischemic myocytes, ↓ intracellular Na+ –> ↓ Ca2+ influx
- DOES NOT affect HR, BP, inotropy, or perfusion like
traditional anti-ischemic agents
Ranolazine
- Doesn’t affect BP, may have advantage in pts with low BP
- Product: Ranexa 500 mg ER tablets: Titration from 500 BID to 1000 BID over 1-2 weeks
- US Indication: treatment of chronic angina
- EMA: add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies
- Combination therapy: Add to CCBs, beta-blockers, or nitrates when inadequate response to monotherapy
- Monotherapy only when BP/HR too low with first-line agents
Ranolazine metabolism
- Metabolized via CYP3A4 (70-85%) and CYP2D6 (10-15%); Substrate for P-gp
- Prone to drug-interactions:
Should not be used with strong 3A inhibitors (KTZ, ITZ, PIs clarithromycin) or inducers (CBZ, RIF, St John’s wort, etc.); Limit dose (500 BID) with moderate inhibitors (Dilt, Ver, ERY AND FLZ)
*Ranolazine inhibits CYP3A and or P-gp - Adverse effects:
Constipation, nausea, dizziness and headache; Dose-related increase in QT-interval; should not be used with other drugs that prolong the QT interval
Selection of chronic drug therapy for stable angina
- When to initiate therapy is dependent on each individual patient (symptoms, other conditions, etc.)
- Three drug classes can be used first-line: ß-blockers, calcium channel blockers, and nitrates
- Selection of an initial drug should be based upon the patient characteristics and concomitant conditions
Place in therapy: beta-blockers
- ß-blockers should be selected as initial therapy in patients without contraindications: Compelling indications: Stable HF, History of MI; Especially useful in… Atrial Fib, high resting HR, migraine
headaches; Avoid in…vasospastic/Prinzmetal’s angina, conduction disturbances (SA nodal block/AV nodal block in absence of pace maker) - Contraindications: Bradycardia (HR < 50); High degree AV block or sick sinus syndrome (with no pacemaker)
Place in therapy: CCBs
- Non-DHP CCBs preferred, instead of ß-blockers if..: Contraindications to ß-blockers; Unacceptable side effects to ß-blockers; Potentially useful in… chronic lung diseases, HTN, DM, and peripheral vascular disease
- Contraindications: Non-DHPs: HFrEF, Bradycardia (HR < 50); High degree AV
block or sick sinus syndrome (with no pacemaker); DHPs: HFrEF (except amlodipine and felodipine)
Place in therapy: nitrates
- Monotherapy with long-acting nitrates can be challenging due to nitrate free period and tolerance. THUS, preferred as…: Combination with ß-blockers/non-DHPs (to blunt nitrate induced increase in HR); Short acting PRN nitrates to relieve discomfort or prevent ischemia before exertion
- Cautions: HOCM, severe aortic stenosis, PDI use
Clinical conditions that favor use: beta blockers
prior ACS/MI (non-ISA)
heart failure/LVD
sinus tachycardia; SV tachycardia; A fib
ventricular arrhythmias
migraines
hyperthyroidism
Clinical conditions that favor use: DHP CCB
HTN
bradycardia/AV block
diabetes
PVD/raynaud’s
severe asthma/COPD
prinzmetal’s angina
Clinical conditions that favor use: verapamil/diltiazem
HTN
sinus tachycardia; SV tachycardia; A fib
diabetes
PVD/raynaud’s
severe asthma/COPD
prinzmetal’s angina
Clinical conditions that may limit use: beta blockers
bradycarida/AV block
sick sinus syndrome
heart failure decompensation
severe depression
severe asthma/COPD
Clinical conditions that may limit use: CCBs
bradycardia/AV block
sick sinus syndrome (non-DHPs)
heart failure
severe hypertrophic obstructive CM
severe aortic stenosis
Clinical conditions that may limit use: nitrates
ED with PDE5
severe hypertrophic obstructive CM
severe aortic stenosis
What do we do when patients remain symptomatic
combo therapy:
* Nitrates and ß-blockers
* Nitrates and non DHP-CCBs
* DHP CCB and ß-blockers: also cause reflex tachycardia but beta-blockers block that effect)
* ß-blockers and non-DHP CCBs : Generally, should be avoided (b/c of HR lowering)
* Triple therapy: ß-blockers, Nitrates and CCBs
* Ranolazine: Ideal role is unclear: Combination with other agents when not effective; BP/HR “too low” to add other agents
Therapies with no benefit or are potentially harmful for CCD
- Postmenopausal HRT
- Antioxidants (Vit C, E, Beta-
carotene) - Homocysteine/Folic acid, Vit B6 or B12
- Herbal supplements (garlic, Coenzyme Q10, selenium, chromium)
- NSAIDS/COX-2 inhibitors
- Rosiglitazone
- ?Chelation therapy
ASA use with other NSAIDs
ASA is irreversible
bind, compete w/ ASA @ COX-1 site, may decrease benefits in pts w/ CV disease
all other NSAIDs do this in a competitive concentration dependent manner
can go away when stopping use
Use of NSAIDs in CV disease
- Patients and clinicians should share decision-making of the personal benefit–risk balance: Potential GI, CV and renal impacts
- Define the desired or needed therapeutic benefits
- Consider the non-pharmacological and pharmacological options available to help to achieve these benefits: When considering NSAIDs, identify the patient’s cardiovascular, gastrointestinal, renal and other physiological risks that are potentially vulnerable to NSAID-associated adverse effects; Review existing medications and the potential effect of adding NSAID therapy
- Prioritize non-pharmacological approaches and instigate them first, if
possible: Set a date to review their effectiveness, keep a patient pain/effect diary
Systemic NSAID is choden
*Use should be viewed as a temporary adjunct to non-pharmacological measures
*Use lowest dose for shortest time, single dose likely minimal impact
*Keep a patient pain/effect diary
*Select ibuprofen or naproxen as first alternatives (with gastroprotection - maybe PPI, used for shortest amount of time possible)— both have an effective analgesic dose range within the lower end of cardiovascular thrombotic risk estimates, and gastrointestinal risks can be offset to some extent with gastroprotection
*Celecoxib doses up to 200 mg per day have similar cardiovascular risk estimates but seem to have poorer analgesic effects; at doses >200 mg per day, the cardiovascular thrombotic risk escalates
* Avoid diclofenac
* Take the ASA at least 2 hours prior to NSAID - gives ASA chance to acetylate that platelet COX, NSAID can’t compete with it
* Adjunctive APAP may minimize NSAID needs
* Within 1 week, review the benefits of NSAID use and the patient’s diary record and check for AEs, aiming to down-titrate or cease the NSAID use while adjusting or up-titrating non-pharm measures
* Plan for ongoing support, prioritizing non-pharm measures to optimize the patient’s wellness, function and fitness, and to minimize the need for pharmacological measures
* If unsuccessful, consider referral to a multidisciplinary pain team for assistance
Vasospasm
Prinzmetal’s angina; Vasospastic Angina Variant Angina
* Ischemia/angina usually occurs at rest, not precipitated by physical exertion or emotional stress
* Associated with ECG ST-segment elevation
* Ischemic episodes occur most frequently in the early morning hours
* Not necessarily associated with atherosclerosis.
Management of vasospastic angina
*Acute treatment (ie SL NTG,etc.)
* Chronic treatment: Calcium channel blockers; Nitrates; ß-blockers: NO!; Combination therapy
