Cardiology Test 5- Lapinsky IHD-anti-anginal agents

Angina pectoris is chest pain caused by reduced blood flow due to lack of ___ in heart muscle

oxygen

3 types of angina

1) ___ angina (exertion) (relieved at rest)

2) ____ angina (can occur at rest)

3) ____ angina (blood vessel spasm) (treated with nitroglycerin)

stable, unstable, vasospastic

Treatment goals for IHD:

1) terminate and prevent an acute ___ of angina

2) increase the ___ capacity of the patient via prophylactic/preventative drug therapy

attack, exercise

Treatment goals for IHD:

3) improve heart function by eliminating chest ___

4) prevent future CV events (like heart failure and MI)

5) reduce risk of CV ____

pain, death

MI (heart attack) occurs when an atherosclerotic plaque slowly builds up in the inner lining of a coronary artery and then suddenly ruptures, causing catastrophic ___/blood clot formation, totally occluding the artery and preventing blood flow downstream to heart muscle

thrombus

We achieve treatment goals for IHD via ___-___ drug treatment and ___-__ drug treatment

anti-platelet, anti-anginal

Anti-platelet drugs for managing stable IHD:

1) aspirin- an irreversible, covalent ___ inhibitor in blood platelets

COX

Arachidonic Acid gets coverted to Prostaglandin H2 via ___

COX

COX converts Arachidonic Acid→Prostaglandin H2.

Then, thromboxane synthase converts Prostaglandin H2→___ ___

thromboxane A2

thromboxane A2

-potent ___

-potent inducer of blood platelet aggregation toward blood clot formation

vasoconstrictor

low dose aspirin (81-162 mg QD) has a short half life of about 20 mins, however its MOA to prevent blood platelet activation and aggregation lasts for the ___ of the blood platelet (7-10 days). So it has a long functional effect !

lifespan

low dose aspirin addresses blood platelet-mediated ____ prevention (not ischemia per se)

thrombosis

low dose aspirin is part of comprehensive treatment that also includes anti-___ therapy (BBs, nitrates, CCBs), ___-lowering therapy (statins) and __ __ control

ischemic, lipid, risk factor

low dose aspirin should be used ____, unless the bleeding risk outweighs the cardioprotective benefit

lifelong

in acute coronary syndrome (ACS), we prefer non-___ coated, chewable, low-dose aspirin (81 mg/day)

enteric

____ release aspirin (Durloza) should NOT be used when a rapid onset of action is needed!! (like in ACS or pre-angioplasty)

extended

Low-dose aspirin is "___" for blood platelets even though Aspirin is not a selective COX-1 or COX-2 inhibitor itself

selective

How is low-dose aspirin "selective" for blood platelets?

1) because it is rapidly destroyed by the ___ via first pass metabolism

liver

with the 81mg Aspirin dose, only a ___ amount of aspirin survives the liver and goes into systemic circulation

tiny

with the 325mg Aspirin dose, enough aspirin survives the liver to ultimately inhibit both ___ and ___ in the systemic circulation

COX1, COX2

therefore, the ___ of aspirin determines how much gets into systemic circulation

dose

How is low-dose aspirin "selective" for blood platelets?

2) the critical anatomical trick- blood platelets are exposed to low dose aspirin ____ the liver has a chance to destroy the aspirin it sees !!

before

when you swallow aspirin

stomach/intestine → ___ ___ → liver → systemic blood circulation

portal vein

the portal blood circulation contains your ___ ___ !

blood platelets

since the portal blood circulation contains your blood platelets, these platelets "see" the ____ 81 mg dose of aspirin, but most other tissues only see the very little amount of aspirin that survived the liver

full

How is low-dose aspirin "selective" for blood platelets?

3) blood platelets CANNOT regenerate ___-__ after irreversible, covalent inhibition by low dose aspirin

COX-1

blood platelets come from "shedding off" from megakaryocytes that originate in the __ ___

bone marrow

concerning low-dose aspirins MOA, it is important to recognize that blood platelets do not have a ___. They are cell fragments (not full cells)

nucleus

blood platelets are cell fragments (not full cells). They do not have a nucleus, but they do have ___-__ because the megakaryocytes package it into the blood platelet before its release into the blood circulation

COX-1

However, once in the blood circulation, blood platelets CANNOT ____ COX-1 on their own

regenerate

since blood platelets cannot make new COX-1 , once COX-1 is acetylated by low-dose aspirin, COX-1 is ____ inactivated

permanently

unlike blood platelets, systemic endothelial cells have a nucleus, and therefore can quickly ____ COX-1 and COX-2, so can recover quickly from irreversible COX inhibition

synthesize

for cardiovascular patients, high-dose ____ (or any other reversible, non covalent COX inhibitor) should not be taken before or at the same time as low-dose aspirin for cardioprotection

ibuprofen

high-dose ibuprofen can undesirably ___ the desired cardioprotective effects of low-dose aspirin

block

when bound to the active site at COX, all NSAIDs decrease prostaglandins by preventing arachidonic acid from ___ to the active site of COX

binding

the majority of NSAIDs (like ibuprofen) are reversible, non covalent inhibitors of COX. Aspirin is the only NSAID that can act as an ____, covalent inhibitor

irreversible

low-dose aspirin's cardioprotective effect REQUIRES ____ acetylation of blood platelet COX-1 !!

irreversible

Aspirin must acetylate ___ within COX to create its cardioprotective effect

Ser530

High-dose ibuprofen sitting in the active site of COX can undesirably ___ low dose aspirin from reaching Ser530 within COX !!

prevent

if you take high-dose ibuprofen before aspirin, the aspirin will not be able to access the acetylation site to inhibit the blood platelet. Clinically, this is equivalent to missing a dose of low-dose aspirin, which can increase the risk of __ or __ in high-risk cardiovascular patients

MI, stroke

if you must use both:

-take low-dose __ first

-wait 30-60 min

-then take high-dose ___

aspirin, ibuprofen

Worst timing= taking high-dose ibuprofen ___-__ hours before taking low dose aspirin. In this case, COX blockage via high-dose ibuprofen binding outcompetes the irreversible binding of low-dose aspirin

0-4

low-dose aspirin

-causes local, irreversible covalent COX inhibition

-primary acts in the ___ ____ on blood platelets because low systemic levels and blood platelets see the full low dose before 1st pass metabolism

portal vein

high-dose NSAIDs

-systemic reversible non-covalent COX inhibition

-primary acts in ___ tissues (like endothelium, CNS, inflammatory cells)

-NOT completely destroyed by first pass metabolism, achieves therapeutic systemic concentrations

systemic

Anti-platelet drugs for managing stable IHD

2) clopidogrel (Plavix) is a _____

prodrug

Anti-platelet drugs for managing stable IHD

-clopidogrel (Plavix) is converted via ___ to its active form, which acts as a covalent, irreversible P2Y12 antagonist

CYP2C19

Anti-platelet drugs for managing stable IHD

-when clopidogrel binds to a blood platelet, the irreversible bond lasts the entire ___ of the platelet (7-10 days)

lifetime

the effectiveness of Clopidogrel to prevent thrombotic events in chronic coronary artery disease depends heavily on ____-mediated bioactivation and the patient's ___ profile

CYP2C19, pharmacogenomic

carriers of *___ or *___ are CYP2C19 poor metabolizers

2, 3

CYP2C19 poor metabolizers exhibit a reduced generation of the pharmacologically active metabolite, leading to suboptimal blood platelet inhibition, ___ clinical efficacy, and a ___ risk of ischemic events

decreased, higher

a solution for patients who are CYP2C19 poor metabolizers is ___ and ___, because they do NOT rely on CYP2C19 for their activation

prasugrel, ticagrelor

Proton Pump Inhibitors (PPIs) can function as CYP2C19 ___

inhibitors

Proton Pump Inhibitors (PPIs) can function as CYP2C19 inhibitors, therefore, they can ___ clinical efficacy of clopidogrel, and __ risk of ischemic events

decrease, increase

In stable IHD, low-dose aspirin remains first line, but clopidogrel is crucial when:

1) patient has a true aspirin ____/intolerance

allergy

In stable IHD, low-dose aspirin remains first line, but clopidogrel is crucial when:

2) a coronary ___ has been placed in patient (in this case, we use combo of aspirin+ clopidogrel)

stent

In stable IHD, low-dose aspirin remains first line, but clopidogrel is crucial when:

3) there is need to minimize ___ irritation risk

GI

We use clopidogrel if we need to minimize GI irritation risk because remember, COX inhibition by aspirin can lead to decreased production of certain _____ ____

gastroprotective prostaglandins

Anti-anginal drugs for managing stable IHD

1) ___ ____ (aka beta-1 adrenergic receptor antagonists)

beta blockers

beta blockers reduce myocardial oxygen demand via:

1) decrease heart __

2) decrease heart muscle ___

3) decrease left ventricular wall ___

rate, contractility, tension

beta blockers

-more effective than nitrates and CCBs for ____ ischemia (reduced blood flow to the heart muscle that causes no noticeable symptoms despite measurable cardiac stress)

silent

beta blockers

-avoid in ___ angina !! (chest pain caused by transient coronary artery spasms that temporarily reduces blood flow despite no significant fixed blockage)

vasospastic

beta blockers

-avoid in vasospastic angina because blocking β-1 receptors leaves the α-mediated vasoconstriction _____

unopposed

beta blockers

blocking β-1 receptors leaves the α-mediated vasoconstriction unopposed, which can ___ coronary artery spasm in patients with vasospastic angina and intensify ischemia !!

worsen

Anti-anginal drugs for managing stable IHD

2) ___ ___ ____, which are either DHP (arteriolar) or non-DHP (works in heart)

calcium channel blockers

DHP calcium channel blockers pros

-potent ___ that reduces ___

vasodilation, afterload

DHP calcium channel blockers cons

-may cause ___ ___

reflex tachycardia

non-DHP calcium channel blockers pros

-___ HR and reduce heart muscle ___

slow, contractility

non-DHP calcium channel blockers cons

-risk of ____ and __ block

bradycardia, AV

can we use DHP or non-DHP CCBs with a beta blocker?

DHP

we do not use non-DHP CCBs with a beta blocker because it can cause excessive ___

bradycardia

is DHP or non-DHP CCBs preferred for vasospastic angina?

DHP

Even though DHP CCB is preferred for vasospastic angina, non-DHP CCB can still be a solid alternative or add on depending on __ __ and patient profile

heart rate

___-release or ___-acting CCBs are effective

slow, long

AVOID nifedipine ___ because its rapid, strong vasodilation can trigger reflex sympathetic activation

IR

AVOID nifedipine IR because its rapid, strong vasodilation can trigger reflex sympathetic activation, causing __ and increased contractility, which ___ myocardial oxygen demand and can worsen ischemia or provoke adverse cardiac events

tachycardia, raises

Anti-anginal drugs for managing stable IHD

2) ___ ___, which are prodrugs of the potent, endogenous vasodilator nitric oxide (NO)

organic nitrates

organic nitrates get converted to nitric oxide via mtALDH2, which stimulates __ ___ to convert GTP to GMP, causing vascular smooth muscle relaxation and venodilation

guanylyl cyclase

vascular smooth muscle relaxation helps angina in 2 ways:

1) ___ myocardial oxygen demand (primary effect in __ angina)

decreases, stable

organic nitrates primarily dilate ___, which is the dominant benefit for angina due to fixed atherosclerotic obstruction

veins

result of decreasing myocardial oxygen demand

-increased venous __

-decrease __

-decrease left ventricular wall stress

-decrease myocardial oxygen deman

capacitance, preload

vascular smooth muscle relaxation helps angina in 2 ways:

2) ___ myocardial oxygen supply (primary effect in __ angina)

increases, vasospastic

organic nitrates can dilate large ___ coronary arteries (ie the major vessels on the heart's surface that supply oxygen-rich blood to the myocardium) including those undergoing spasm

epicardial

result of increasing myocardial oxygen supply

-relief of coronary __

-improved coronary ___

-increase in subendocardial __ __

vasoconstriction, perfusion, blood flow

organic nitrates treat vasospastic angina by "breaking the __" and restoring blood flow

spasm

How organic nitrates help in stable angina

-decrease O2 ___

-decrease wall stress

-decrease preload

demand

How organic nitrates help in vasospastic angina

-increase O2 ___

-coronary vasodilation

-relief of spasm

supply

How organic nitrates help in unstable angina

-coronary dilation + symptom relief

-does NOT fix plaque, but improves supply-demand ___

balance

Short-Acting Nitrates

-NitroSTAT (sublingual __)

-NitroMist (sublingual ___)

tablet, spray

Long-Acting Nitrates

-isosorbide ___ (ER) and isosorbide ____

-brand names are Nitro-Dur (transdermal patch) and Nitro-Bid (topical ointment)

mononitrate, dinitrate

Short-Acting Nitrates

-rapid onset (rescue med)

-onset is __-___ min

1-3

Long-Acting Nitrates

-sustained levels for chronic ____

-onset is 20-60 min for oral ER and 15-60 min for patch or ointment

prophylaxis

Short-Acting Nitrates duration is __-__ min

Long-Acting Nitrates duration is __-___+ hours

30-60, 4-12

Short-Acting Nitrates

-first line for ____ attacks

-prevent angina if taken ___ exertion

acute, before

Long-Acting Nitrates

-___-line chronic prevention

-add-on when BBs or CCBs are inadequate or contraindicated

second

Short-Acting Nitrates

-purpose of sublingual formulation is for ___ onset of action and ___ first-pass metabolism

rapid, avoids

Long-Acting Nitrates

-purpose of skin patches is to provide __ delivery

-the oral formulations are __ to first-pass metabolism

continuous, subject

Short-Acting Nitrates

-key clinical instructions is to take 1 dose every 5 min x ___.

-Call EMS if no relief after __ dose with ACS suspicion

3, first

Long-Acting Nitrates

-key clinical instructions is that you MUST include a 10-12 hour/day ___-__ interval to prevent tolerance

nitrate-free

tolerance development is not a major issue for short-acting nitrates, but is a major limitation with continuous exposure to __-acting nitrates

long

Continuous nitrate exposure leads to undesired diminished ____ !

vasodilation