STABLE ISCHEMIC HEART DISEASE 2.0 Flashcards
Vascular Protection
Angiotensin Converting Enzyme Inhibitors (ACEI)
Rationale?
• Rationale:
- ↓ progression of atherosclerosis
- plaque stabilization
- ↓ neo-intimal formation
- ventricular remodeling
- endothelial function
- fibrinolysis
• properties thought to be independent of blood
pressure lowering effects
- controversial
Vascular Protection
Angiotensin Converting Enzyme Inhibitors (ACEI)
Place in therapy?
• Meta-analysis of 6 trials (n = 33,500)
- Follow-up x 4.4 yr
- High risk patients (CAD with preserved LV function)
- 16% RRR in nonfatal MI
- 17% RRR in CV mortality
- 13% RRR in all-cause mortality
• Place in therapy
- Consider in all patients with IHD in the absence of CI
- Especially in those with other indications:
- Post-MI
- Systolic heart failure (HFrEF)
- DM nephropathy / CKD
- ARBs are a reasonable alternative (ONTARGET trial)
Vascular Protection
Angiotensin Converting Enzyme Inhibitors (ACEI)
Adverse Effects?
CNS Lightheadedness, dizziness, fatigue BP, postural BP
ENT Angioedema (rare, but life threatening) symptoms
CVS Hypotension +/- orthostasis BP
RESP Dry cough (20%) symptoms
GI Nausea/vomiting, taste disturbance symptoms
GU Renal dysfunction (expect up to 30%↑Scr) SCr, BUN
DERM Rash symptoms
Lytes Hyperkalemia K
Vascular Protection
Angiotensin Converting Enzyme Inhibitors (ACEI)
Contraindications?
- History of angioedema
- Bilateral renal artery stenosis
- Hypersensitivity
- Pregnancy
Medical Therapy - Symptom Control
Needs Assessment
Does my patient need symptons control?
- frequency of attacks
- sSeverity of attacks
- impact on exercise tolerance
- impact of ADL
- impact on QOL
Medical Therapy - Symptom Control
What are the goals?
Goals: • Frequency of symptoms • Intensity of symptoms • Functional capacity • Improve quality of life
Medical Therapy - Symptom Control
Options?
Options:
• First line:
- β-blockers
• Second line:
- Calcium channel blockers (CCB) - Long acting Nitrates
• Third line:
- Ranolazine ( New to Canada 2021 – refractory
angina)
- Ivabradine (Not indicated in Canada for SIHD)
Medical Management of IHD
Summary
see slide 14
Beta-blockers:
anti-ischemic effects
HR, cardiac contractility, myocardial tension = oxygen demand
regional flow distibution, O2 extraction, coronary blood flow = supply
• Reduction in HR and contractility = lowering MvO2
• Slight decrease in BP (through reduction in CO,
inhibition of renin) = reduced afterload, lowering
myocardial wall stress and MvO2
• Does not generally improve oxygen supply, although
increased diastolic time may improve coronary
perfusion
• Note: unopposed alpha stimulation may lead to
worsening vasoconstriction in vasospastic angina
(see slide 15 for reference)
Beta-blockers:
anti-ischemic effects
Cardiac effects?
Cardiac effects:
B1-receptors in cardiac nodal tissue, conducting system and contracting myocytes
• ↓Cardiac sympathetic tone:
- Chronotropy (heart rate)
- Inotropy (contractility)
- Dromotropy (electrical conduction)
- Lusitropy (relaxation)
• Vascular effects (minor):
- Mild vasoconstriction (unopposed alpha effects)
- Blocking beta-2 receptors removes vasodilatory
influence that normally opposes the alpha
mediated vasoconstriction
(see slide 16 for reference)
Beta-blockers:
Clinical effects?
• Delays or eliminates angina during exercise
- limits in HR & BP during exercise
- Decreases the needs for short acting NTG
- Decrease frequency of angina
• No specific agent has proven to be superior
- avoid those acebutolol with intrinsic sympathomimetic
activity (ISA) and sotalol (anti-arrhythmic)
- may worsen vasospastic angina
* Unopposed alpha-blockade
Beta-blockers:
Why high dose beta-blockers should never be stopped abruptly?
High dose beta-blockers should never be stopped abruptly because:
A) rebound tachycardia
B) rebound hypotension
C) rebound broncospasm
D) A and B
A) rebound tachycardia
(beta blockers cause hypotension)
- Upregulate beta receptors, when you take them away, you have too mmuch receptors and there is too much stimulaion
Never abruptly stop in the community
Beta-blockers:
Place in therapy?
Place in therapy:
• BB are the initial choice in the absence of CI in all
patients
- post-MI patients = ↓ death and recurrent MI
- extrapolate data to patients without MI
• Initiation
- Baseline:
* BP(SBP >100), HR (>60 bpm), euvolemic (HF), no
contraindications
- Titration:
* to HR (55-60 or lower if no symptoms of
bradycardia) or symptom relief
* Avoid abruptly stopping therapy, especially high
doses
> Rebound tachycardia secondary to upregulation of
beta receptors
Beta-blockers:
Contraindications
• Reactive airway disease (e.g., asthma)
- Caution in COPD (use β1 selective)
- 2° or 3° heart block
- Decompensated HF
- Severe PAD
• Pheochromocytoma (without αlpha blockade)
neuroendocrine tumor that grows from cells called chromaffin cells
• Hypersensitivity
Beta-blockers:
Adverse Effects
see slide 21
CNS Fatigue, insomnia, vivid dreams,
depression symptoms
CVS Bradycardia, hypotension, decreased
exercise tolerance, heart block BP, HR, ECG
RESP Bronchospasm (> non-selective agents) symptoms
ENDO Mask hypoglycemia, increase blood
glucose and triglycerides, lower HDL-C symptoms
Other Impotence, decreased libido, cold
extremities symptoms
Beta-blockers:
Benefits of Cardio-Selectivity
• What you can minimize by using cardio-selective
agents:
- Beta-2 blockade in:
* lungs: bronchospasm
* pancreas: potential hyperglycemia (transient, little
clinical significance)
* liver: blunt the recovery from hypoglycemia
* vascular smooth muscle: potential aggravation of
intermittent claudication or Raynaud’s phenomenon
• Cardio-selectivity is dose-dependent; at higher doses,
cardio-selective agents lose their relative selectivity for
beta-1 receptors and can block beta-2 receptors as
effectively.
• The dose at which cardio-selectivity is lost varies from
patient to patient.
Is metoprolol a good choice for Mr. Smythe?
Is metoprolol a good choice for Mr. Smythe?
A) Yes
B) No
C) Maybe
Is metoprolol a good choice for Mr. Smythe?
Yes, he doesnt have contraindications
Calcium Channel Blockers (CCB):
Anti-Ischemic Effects
• Non-DHP: ↓HR and contractility = ↓MvO2
• DHP: ↓ arterial resistance and afterload = ↓ lowering
myocardial wall stress and MvO2.
Coronary artery dilation, improving oxygen supply
(mainly in vasospastic angina)
• Competitive antagonist of L-type calcium channels
- vascular smooth muscle, cardiac myocytes, nodal
tissue (SA and AV node)
- decreased calcium available for contractile elements,
smooth muscle relaxation and vasodilation
• Depending on the agent may have:
- ↓ inotropy (demand)
- ↓ chronotrophy (supply and demand)
- ↓ dromotropy, conduction velocity (supply and
demand)
- vasodilation, coronary and systemic (supply and
demand)
(see slide 25 for reference)
Calcium Channel Blockers (CCB):
Properties
see slide 27
NDHP CCB: Verapamil, Diltiazem
DHP CCB: Nifedipine, Amlodipine, Felopidine
dilt and verapamil will slow the heart rate. affect cardiac specifically
DHP affect peripheral vasodilation, no effects on heart rate (sig vasodilation that can cause reflex tachcardia by nifedipine)
Calcium Channel Blockers (CCB):
Cardiac vs Vascular Selectivity
• Non-DHPs:
- higher selectivity for L-type calcium channels in heart
contractile cells (verapamil > diltiazem), as they prefer
channels undergoing increased frequency of
depolarization.
• DHPs:
- higher selectivity for the more inactivated L-type
calcium channel in vascular smooth muscle
• All bind to different areas of the alpha 1 subunit in the
L-type calcium channel
Calcium Channel Blockers (CCB):
Which CCB would be the best choice to combine with metoprolol in the symptom treatment of SIHD?
Which CCB would be the best choice to combine with metoprolol in the symptom treatment of SIHD?
A) diltiazem
B) amlodipine
C) verapamil
D) A and C
Avoid diltiazem and verapamil in combo with metoprolol
Additive effects on HR, cause bradycardia
amlodipine
Calcium Channel Blockers (CCB):
Place in therapy
Place in therapy:
• second-line agent ( but equally as effective as BB in
symptoms)
• combination treatment
• useful for coronary spasms (Prinzmental’s or variant)
Short-acting dihydropyridine CCB may ↑ risk of adverse CV events (MI/CVA) from rapid BP drops
Long-acting CCB are effective at relieving symptoms
Initiation:
• Baseline:
- BP(SBP >100), HR (>60 bpm), no contraindications
• Titration:
- to HR (55-60 or lower if no symptoms of
bradycardia) or symptom relief
- NB: only verapamil and diltiazem significantly effect
HR
Calcium Channel Blockers (CCB):
Adverse Effects
see slide 32
CNS Dizziness, fatigue, headache symptoms
CVS Hypotension, brady-/tachycardia,
heart block, decreased exercise tolerance BP, HR, ECG
GI Constipation (verapamil) symptoms
DERM Rash (diltiazem), flushing (DHP) symptoms
Other Peripheral edema (DHP) (Dose related,
20%) symptoms
Calcium Channel Blockers (CCB):
Contraindications
• 2nd or 3rd degree heart block or sick sinus syndrome
without a pacemaker (NDHP)
- Hypotension
- Bradycardia (NDHP)
• Heart failure with reduced ejection fraction [HFrEF]
(except amlodipine)
Calcium Channel Blockers (CCB):
Drug Interactions
see slide 34
see slide 35
Digoxin ↓HR, ↑digoxin (verapamil/diltiazem)
Monitor HR, monitor digoxin
β-blockers ↓HR (verapamil, diltiazem), ↓BP
Avoid use, monitor HR, BP
Diltiazem 3A4 substrate and
inhibitor Potential for multiple drug interactions
Verapamil 3A4 substrate and inhibitor, 1A2 and 2C substrate, Pglycoprotein
Felodipine 3A4 inhibitor
Nitrates:
Anti-Ischemic Effects
• Venous dilation -> ↓ preload -> ↓ myocardial wall
tension -> ↓ MvO2 (Myocardial oxygen consumption )
• Lower preload -> ↓ diastolic wall stress -> improved
subendocardial blood flow -> improved regional flow
distribution
- Mild coronary vasodilation -> may improve O2 supply
- Mild afterload reduction
(see slide 36 for reference)
Nitrates:
MOA?
Clinical effects?
MOA:
• Vasodilation:
- Converted to nitric oxide by vascular endothelium
- Activates cGMP -> ↓ cellular calcium -> smooth
muscle relaxation and vasodilation
Clinical effects:
• improve exercise tolerance
• time to onset of angina
• ischemic threshold
Nitrates:
Place in therapy
Place in therapy:
• rescue treatment (rapid-acting)
- all patients with angina should have rapid-acting
NTG
• prophylaxis (long acting)
- econd line - combination treatment - may be useful in vasospasm
Nitrates:
Tolerance
- MOA unknown
- tolerance to anti-anginal and hemodynamic effects
• require a “nitrate-free” period
- 8-12 hours
• counseling required
- Always inquiry about patch use
Nitrates:
Use of rapid acting NTG
Instructions?
Other use?
Instructions:
• Stop and sit down (avoids presyncope/ syncope)
• After one dose, if NO relief or gets worse → call 911
• If improves, but does not resolves wait 5 minutes,
take a second dose, if NOT resolved in 5 minutes →
call 911 and take another dose
• Can continue to take q5min until EMS arrives
Other use:
• prophylactic use prior to activities known to cause
angina in individual patients
Nitrates:
Adverse Effects
see slide 42
CNS Headache, dizziness symptoms CVS Hypotension, reflex tachycardia, palpitations, syncope BP, HR GI Nausea, vomiting, diarrhea symptoms MSK Weakness symptoms DERM Flushing, rash symptoms
Nitrates:
Contraindications?
Drug interactions?
Contraindications:
• Severe aortic stenosis (pre-load dependent)
Drug interactions:
• sildenafil (Viagra®, Revatio®), vardenafil (Levitra®),
tadalafil (Cialis®)
- Inhibits the breakdown of NO by PDE5 inhibitor
- coadmin = ↑ risk of life-threatening hypotension
(↑ ↑NO)
- Contraindicated
* At least 24h: sildenafil, vardenafil
* At least 3-4 days: tadalafil
- ALWAYS ask before prescribing NTG
RANOLAZINE (Corzyna®)
• Approved second line anti-anginal (available in Canada,
$260/mo)
• Inhibits late sodium channel influx during repolarization
in myocytes
-> reduces intracellular sodium concentrations -> lowers
calcium influx -> lowers ventricular diastolic wall
tension -> lowers MvO2
- Does not impact HR or BP (ideal add-on agent)
- Can prolong QTC at higher doses
• Dosing: ranolazine ER 500 mg po BID, increased to
1000 mg BID in 2-4 weeks based on symptoms
RANOLAZINE (Corzyna®)
Adverse Effect?
Contraindications?
Drug interaction?
ADverse Effects:
• constipation, nausea, dizziness, headache, prolong
QTc
Use with caution in CrCl < 50ml/min, contraindicated
in hepatic cirrhosis
Drug interaction:
• Avoid with concomitant QTc-prolonging agents:
antipsychotics, class 1a and III antiarrhythmic
(other than amiodarone), quinolones, macrolides,
azole antifungals
• Substrate of CYP 3A4 (major) and p-glycoprotein
(minor)
- Contraindicated with strong CYP 3A4 inducers:
phenytoin, carbamazepine, rifampin
- Contraindicated with strong CYP 3A4 inhibitors:
ketoconazole, clarithromycin, antitertovirals
• Inhibitor CYP 3A4 (weak) and p-glycoprotein:
dabigatran, simvastatin, cyclosporine, sirolimus
IVABRADINE (Lancora®)
• Off-label, second line anti-anginal (available in
Canada, $50/mo)
• Inhibits sinus node HCN channel -> slower
generation of ‘funny’ current (spontaneous electrical
activity) -> reduction in HR -> reduction in MvO2
• Does not impact contractility
• Of note, increase death/nonfatal MI in CCS class 2-4 angina (SIGNIFY trial subgroup analysis)
• Dosing: 2.5-7.5mg BID
IVABRADINE (Lancora®)
Adverse Effect?
Contraindications?
Drug interaction?
Adverse Effect:
• visual disturbances (reversible), headache, dizziness,
bradycardia, afib, heart block
Contraindication:
• HR <70, severe hepatic disease
Drug interaction:
• Avoid with concomitant QTc-prolonging agents:
antipsychotics, class 1a and III antiarrhythmic (other
than amiodarone), quinolones, macrolides, azole
antifungals)
• Metabolized by CYP 3A4 (major)
- Contraindicated with strong CYP 3A4 inducers:
phenytoin, carbamazepine, rifampin
- Contraindicated with strong CYP 3A4 inhibitors:
ketoconazole, clarithromycin, anti-retrovirals,
diltiazem, verapamil,
Treatment Approach
Summary
see slide 49
see slide 50
• Mr. Smythe comes to the pharmacy 1 week later after getting his new prescriptions: - EC ASA 81mg daily - Metoprolol 25mg BID - Nitroglycerin spray prn
• He reports that he is feeling better on his new
medications. He notices that he is only getting the
chest pressure weekly (was 2-3x per week) and only if
he ‘over does it’
• He reports his BP at 110 ∕ 70 and his HR = 70
• He states that he is feeling a little sluggish when he
walks and wonders if it is from the medications. He
states he is sleeping fine and has no other symptoms.
Mr. Smythe’s sluggishness could be from?
Mr. Smythe’s sluggishness could be from?
A) hypotension
B) bradycardia
C) exercise intolerance
D) All of the above
