PATHO/PCT LECTURE 45 DUNN [EXAM 4]

DR. DUNN ANGINA PCOL

what is myocardial oxygen supply primarily dependent on

coronary blood flow and structure and patency of coronary arteries

what are the major determinants of myocardial oxygen demand (MVO2)

HR, contractility, myocardial wall tension

to reduce myocardial oxygen demand, what general treatment options

BBs, CBBs, and organic nitrates

to improve myocardial oxygen supply what should be targeted

coronary artery dilation, enhanced coronary artery collateral flow, prolong diastole

to improve myocardial oxygen supply, what general treatment options

CCB, NTG, statins, anti-thrombotics

what is the goal of anti-anginal therapy

improve quality of life by decreasing episodes and increasing exercise capacity

what are the four options for anti-anginal therapies

BBs, CCBs, nitrates, ranolazine

what is the general MOA of BBs

-decrease HR, contractility, and BP decrease myocardial oxygen demand

· By decreasing HR, prolong diastolic fill time thus indirectly improve myocardial oxygen supply

which class of BBs should be AVOIDED with angina and why?

ISA - pindolol, acebutolol, carteolol --> avoid due to partial beta agonism not beneficial in angina

what are AE of BBs

bradycardia/heart block, worsening or acute HF, fatigue, decreased libido, ED, hypotension

what are ABSOLUTE contraindications to BBs

uncontrolled bronchospastic disease (NOT COPD) and symptomatic bradycardia

what are precautions for BBs

marked bradycardia (< 55bpm) or hypotension (SBP < 80mmHg), caution in severe COPD, avoid abrupt discontinuation, caution with HF

what is general MOA of CCBs

· Coronary vasodilation = increased blood flow

· Systemic vasodilation and reductions in afterload

· Decrease BP

what is unique action of CCBs (primarily non-dCCBs) that make it great for certain type of angina

alleviate coronary vasospasm - great for prinzmetal's

remember, which CCB class cause negative inotropic and chronotropic effects - decrease HR or AV conduction

non-dCCBs

remember, which CCB class cause more peripheral vasodilation

dCCBs

AVOID non-dCCBs in what disease state

HFrEF

what are AE of non-dCCBs

constipation with verapamil, gingival hyperplasia, edema, bradycardia (HR < 50)

what drug interactions can non-dCCBs have

with CYP3A4 - nondCCBs are moderate inhibitors of CYP3A4

remember, which dCCB should never be used

nifedipine IR

which AE of dCCBs is not good side effect with angina especially

reflex tachycardia - can combine with non-dCCB or BB to avoid if need that peripheral vasodilation of dCCB

what are some other AE of dCCBs

hypotension/dizziness, flushing, peripheral edema, HA, gingival hyperplasia, heartburn

what is the MOA of nitrates

· Prodrug that requires biotransformation to active compound converted to NO (venodilator) through denitration of nitrate

· NO increase cGMP concentration in vascular endothelium leading to reduction in cytoplasmic calcium and thus vasodilation - primarily VENOUS

at low concentrations, where is greatest action of nitrates? what about at higher doses?

At LOW concentrations, greatest action on capacitance vessels (veins) and large coronary arteries while at HIGHER doses, dilate large epicardial arteries and arterioles (but minimal effect on small arteriole)

do nitrates decrease oxygen demand or improve oxygen supply

decrease oxygen demand --> ventilation decrease preload, reduce pulmonary vascular resistance, at HIGH doses decrease afterload and arterial BP

T/F: nitrates can decrease vasospasm due to direct vasodilation effect on spastic coronary arteries

true

what dosage forms of NTG used for acute anginal attack and why

SL/spray (and IV) due to quick onset that avoids first pass hepatic metabolism

when might spray be preferred over SL NTG for angina attacks

if elderly and does not have much spit (naturally less spit or taking anticholinergics that decrease saliva production) that is necessary to dissolve SL tablet

when would we use PO nitrates

for prophylaxis before exertion to avoid angina

if taking isosorbide dinitrate TID, what dosing times should be suggested to ensure nitrate free interval

7am, 12pm, and 5pm instead of q8h

if taking isosorbide mononitrate BID, what dosing times should be suggested to ensure nitrate free interval

8am and 3pm instead of q12h

why is it important to have nitrate free intervals

to avoid loss of anti anginal properties

how fast does nitrate tolerance develop

12-24 hours

what is recommended daily nitrate free interval

8-12 hours - ideally at night when least likely to experience angina

what are AE of nitrates

HA/flushing (use APAP), dizziness, hypotension, syncope, reflex tachycardia, rash to ointment or patch

what is drug interaction contraindication for nitrates

PDE-5 inhibitor (sildenafil and vardenafil within 24 hours and tadalafil within 36 hours)

why are PDE-5 inhibitors and nitrates contraindicated

PDE-5 inhibitors block the PDE-5 mediated degradation of cGMP...if more cGMP available then NO & cGMP mediated vasodilation will increase causing too much vasodilation

what is the MOA of ranolazine

Reduces calcium overload in ischemic myocytes through selective inhibition of late sodium current --> Anti-anginal and anti-ischemic action INDEPENDENT of reduction in BP, HR, and/or inotropy and does not impact coronary blood flow

T/F: ranolazine is an ER tablet but okay to crush, break, or chew

false, do NOT crush, break, or chew

what are AE of ranolazine

Dizziness, constipation, nausea, and QT prolongation

when should ranolazine be AVOIDED

hepatic dysfunction - CI in cirrhosis

is QT prolongation effect of ranolazine a concern? why or why not?

at recommended doses, not a concern due to no sign of torsades

when would we be concerned about QT prolongation effect of ranolazine

CAUTION with doses > 1000mg BID, hepatic impairment, and concomitant QTc prolonging drugs such as Haldol with increased risk for torsades

what is ranolazine cleared by

CYP3A4 and CYP2D6

what is the MOA of ASA

irreversible COX-1 inhibitor --> prevents the formation of TXA2 by platelets --> reduce platelet activation and aggregation

how long is platelet function inhibited with ASA

7-10 days

T/F: ASA doses > 75mg provide little additional antiplatelet activity (but analgesic properties increase)

true

what is main AE of ASA

GI upset and bleeding

what are contraindications for ASA

aspirin allergy and active bleeding

what is MOA of vorapaxar/Zonitivity

competitive and selective antagonist of protease activator receptor-1 (PAR-1) [binds very tightly] --> Inhibits thrombin-induced and thrombin receptor-antagonist peptide-induced platelet aggregation

how long does recovery of platelet function take with vorapaxar/Zonitivity? what are cautions regarding this

28 days...no reversal agent...patient should inform clinician about upcoming surgeries

what are contraindications to vorapaxar/Zonitivity

history of stroke (CVA), TIA, or intracranial hemorrhage (ICH) and active bleeding

what is major AE of vorapaxar/Zonitivity

bleeding (monitor Hgb and Hct on CBC)

what are risk factors for increased bleeding risk with vorapaxar/Zonitivity

≥ 75, ≤ 60kg, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant meds with additive bleeding risk

vorapaxar/Zonitivity is NOT recommended in patients with??

severe hepatic impairment due to increased bleeding risk

what are drug interactions with vorapaxar/Zonitivity

CYP3A4 and 2J2 metabolism..antiplatelets and anticoagulant interactions

what is the MOA of P2Y12 inhibitors

bind to P2Y12 receptor and prevent its ability to activate ADP (adenosine diphosphate) --> · Blocking pro-aggregatory effect of ADP + use of aspirin = critical in ACS management

which P2Y12 inhibitors are irreversible

clopidogrel and prasugrel

which P2Y12 inhibitors are reversible

ticagrelor and cangrelor

clopidogrel is a prodrug and is activated how??

requires activation in liver via several CYP450s but mainly 2C19 causes interpatient variability in response which is not ideal

prasugrel/effient is also prodrug that requires activation in liver but has what compared to clopidogrel?

More efficient activation than clopidogrel thus has more rapid onset of action and produces greater and more predictable inhibition of ADP-induced platelet aggregation

T/F: ticagrelor/brilinta and cangrelor do not require hepatic activation as they are active drugs that produce greater and more predictable inhibition of ADP (compared to clopidogrel)

true

why is more predictable and greater inhibition of P2Y12 not always ideal

due to increased bleeding risk

By blocking binding of ADP to P2Y12 receptor on platelets, block the expression of what receptor which will indirectly inhibit what??

block the expression of GP IIb/IIIa receptors thus indirectly inhibit the formation of fibrin clot

what are AE of P2Y12 inhibitors

bleeding, thrombotic thrombocytopenia purpura (clopidogrel and prasugrel)

what are unique AE of ticagrelor and cangrelor due to interference with adenosine degradation and inhibition of adenosine uptake

o Dyspnea (SOB)

o Asymptomatic ventricular pauses/bradycardia

o Increase in SCr and uric acid

which P2Y12 is the only IV one

cangrelor

what is the GP IIb/IIIa receptor critical for

platelet aggregation --> Fibrinogen molecules bind to these receptors and form bridges between adjacent platelets, allowing them to aggregate

what is the MOA of GP IIb/IIIa inhibitors

bind to GP IIb/IIIa receptor and inhibit final common pathway in platelet aggregation

(Inhibitors block final common pathway of platelet aggregation by blocking binding of fibrinogen and vWF to GP IIb/IIIa receptor on surface of platelet)

what are AE of GP IIb/IIIa inhibitors

BLEEDING and thrombocytopenia (abciximab > eptifibatide and tirofiban)

what are the 3 GP IIb/IIIa inhibitors

Abciximab/Reopro

Eptifibatide/Integrilin

Tirofiban/Aggrastat

what is monitoring for GP IIb/IIIa inhibitors

IV lines to check for bleeding, hematoma, Scr (for dose adjustment), CBC

what are contraindications for GP IIb/IIIa inhibitors

thrombocytopenia, active bleeding, history of ICH, history of stroke within 30 days or any history of hemorrhagic stroke or TIA, recent major surgery or severe trauma, severe HTN (SBP > 180 but can bring down and then use)