Acute Ischemic Heart DiseaseTherapeutics

Question 1

MONA

Answer 1

Morphine

O2

Nitro

ASA

Question 2

ABCs drugs (5 As)

Answer 2

• Anti-thrombotic/ anti-coagulant
• ASA
• (Another) Anti-platelet
• Anti-anginal
• (ACE-i)
• BB
• “Cholesterol” (Statin)

Question 3

Examples of anitplatelets

Answer 3

–Aspirin (ASA)

–P2Y12 receptor blockers

–GPIIb/IIIa receptor blockers

Question 4

Examples of antithrombotics

Answer 4

–Unfractionated heparin

–Low molecular weight heparin (LMWH)

–Direct thrombin inhibitors

–Factor Xa inhibitors

Question 5

Aspirin MOA

Answer 5

Irreversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes

Aspirin inhibits the production of thromboxane A2, thereby inhibiting platelet aggregation.

By the selective and irreversible acetylation of a single serine residue within prostaglandin G/H synthase, aspirin causes the inactivation of cyclooxygenase activity.

Question 6

Aspirin side effects

Answer 6

Upper gastrointestinal (UGI) events (eg, symptomatic or complicated ulcers): Low-dose aspirin for cardioprotectiveeffects is associated with a two- to fourfold increase in UGI events.

GI intolerance such as nausea and dyspepsia, rare

• Bleeding outside GI tract
• Salicylate sensitivity
• Tinnitus

Question 7

What is aspirin resistance

Answer 7

• Resistance = Measurable, persistent platelet activation that occurs in patients prescribed a therapeutic dose of aspirin.
• Clinical aspirin resistance, the recurrence of some vascular event despite a regular therapeutic dose of aspirin, is considered aspirin treatment failure.

Question 8

Mechanism of aspirin resistance

Answer 8

Mechanisms

–poor adherence or absorption

–drug interactions

–COX-2 activity, COX-1 polymorphism

–platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa

Question 9

Thienopyridines MOA

Answer 9

Block the adenosine diphosphate (ADP) receptor P2Y12 on platelets

Question 10

Thienopyridine Side Effects

Answer 10

•Bleeding is major side effect and contraindicated in patients with active bleeding

• Rare TTP (thrombotic thrombocytopenic purpura) reported
• Rare allergies to thienopyridines – cross reactivity reported
• Ticagrelor – 10% of patients report dyspnea

Question 11

Examples of thienopyridines

Answer 11

Clopidogrel, prasugrel, ticagrelor

Question 12

How long does clopidogrel last? Price?

Answer 12

Still commonly used, most clinical data, oldest agent, off patent (cheap)

Platelets blocked by clopidogrel are affected for the remainder of their lifespan (~7-10 days).

Question 13

Clopidogrel metabolism and drug interaction

Answer 13

• Prodrug that requires in vivo biotransformation (oxidation) by the cytochrome P450 (CYP-450) system, principally CYP2C19.
• The active metabolite irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation.
• Poor metabolizers have higher cardiovascular event rates than patients with normal CYP2C19 function (2-14% of population)
• Proton Pump Inhibitors reduce antiplatelet effect

Question 14

Why were newer thienopyridines developed?

Answer 14

•Clopidogrel has delayed onset of action, large variability in platelet response, and irreversible

• Led to development of prasugrel and ticagrelor, cangrelor (IV)
• Each induces more intense platelet inhibition and associated with higher rates of bleeding

Question 15

Prasugrel use

Answer 15

• More rapid onset, higher levels of platelet inhibition
• *Acts at same site on P2Y12 receptor as clopidogrel

•Contraindicated in patients with active bleeding, history of stroke or TIA

•High efficacy in diabetic patients

Question 16

What is unique about ticagrelor

Answer 16

•*Binds reversibly to P2Y12 receptor (only one!)

•*Acts at different site than clopidogrel/prasugrel

Question 17

Glycoprotein IIb/IIIainhibitors MOA

Answer 17

When platelets are activated, this receptor undergoes a change in conformation that increases its affinity for binding to fibrinogen.

The platelet GP IIb/IIIa receptor antagonistssterically inhibit fibrinogen from binding,preventing platelet aggregation.

Question 18

Glycoprotein IIb/IIIainhibitors side effects and contraindications

Answer 18

Major side effect is bleeding

Contraindicated in recent stroke, severe hypertension, recent major surgery

Rarely used outside of procedures, due to high bleeding risk outweighs therapeutic benefit

Question 19

Glycoprotein IIb/IIIa inhibitor examples and clearance

Answer 19

Eptifibatide (Integrillin): Renal clearance, max effect in 1hr, platelet returns to normal 4-8hr after d/c

Abciximab (ReoPro): Safe in renal disease, max effect 10 min, platelet takes 72hr to return to normal after d/c

Question 20

Antiplatelet Therapeutic Strategy

Answer 20

• All UA/NSTEMI/STEMI patients without a contraindication should receive chewable aspirin
• Most should receive P2Y12 inhibitor unless active bleeding or high risk of needing CABG
• In selected patients, IIb/IIIa inhibitors can be added at the time of angiography

Question 21

Targets for antithrombotics

Answer 21

Question 22

Use of heparin in UA/NSTEMI

Answer 22

In UA/NSTEMI, addition of heparin to aspirin likely

lowers risk of death or MI

Question 23

Unfractioned Heparin MOA

Answer 23

•Potentiates the action of antithrombin III (by binding to it) and thereby inactivates thrombin (and weakly Xa). Cannot bind or inactivate thrombin already bound within a clot (this requires lysis)

•Prevents the conversion of fibrinogen to fibrin

•Stimulates release of lipoprotein lipase (lipoprotein lipase hydrolyzes triglycerides to glycerol and free fatty acids)

Question 24

Monitoring of UFH

Answer 24

Monitor aPTT for therapeutic range, every 4-6hr

Question 25

LMHW Mechanism

Answer 25

Low molecular weight heparins have a **small effect on the activated partial thromboplastin time (aPTT) and strongly inhibit factor Xa.** Half-life elimination, plasma: 2 to 4 times longer than standard heparin, independent of dose; based on anti-Xa activity: 4.5 to 7 hours

Question 26

Example of LMWH

Answer 26

**Enoxaparin** - Given as subcutaneous injection

Question 27

Direct thrombin inhibitors MOA

Answer 27

* Bind to the catalytic site of both circulating and clot-bound thrombin. * **Prevents thrombin-mediated cleavage of fibrinogen to fibrin monomers, and activation of factors V, VIII, and XIII.** * **Specific** and **reversible,** immediate onset and labs return to normal an hour after stopping

Question 28

Direct Thrombin Inhibitors example

Answer 28

Bivalirudin

Question 29

What is Heparin Induced Thrombocytopenia (HIT)

Answer 29

•Marked by a progressive fall in platelet counts and, in some cases, thromboembolic complications –skin necrosis, pulmonary embolism, gangrene of the extremities, stroke, or MI Immunologically mediated

Question 30

Use of ACE inhibitors

Answer 30

–MUST if EF \<35% –If hypertensive, most other patients with ACS benefit

Question 31

Aldosterone receptor blocker examples and use

Answer 31

eplerenone/**spironolactone** –Must monitor for hyperkalemia! –All patients with LVEF \<35% and NYHA II symptoms

Question 32

When should Renin-Angiotensin-Aldosterone Agents not be used

Answer 32

•Should not be started in acute setting if systolic blood pressure \< 100 mmHg

Question 33

Use of Beta Blockers

Answer 33

Much larger benefit of beta blockers seen in the post-discharge setting

Question 34

Contraidications of beta blockers

Answer 34

* Any sign of heart failure (based on COMMIT): S3 gallop, rales/crackles, elevated JVP, pulmonary edema * Heart Block * Asthma * Evidence of low output state * Hypotension (SBP \< 90 mmHg) * Significant sinus bradycardia (\<50 bpm)

Question 35

Effect of nitroglycerin

Answer 35

•Reduces myocardial oxygen demand while enhancing myocardial oxygen delivery. It has both peripheral and coronary vascular effects.

Question 36

Contraindication for nitroglycerin

Answer 36

Severe aortic stenosis (USE YOUR STETHOSCOPE!), RV infarct, concurrent use of PD#5 inhibitors (Sildenafil/Viagra), Hypotension

Question 37

Morphine use

Answer 37

•Morphine should only be administered after nitroglycerin and other anti-ischemic therapies have failed to render the patient symptoms free (so almost never) ## Footnote **impairs absorption of thienopyridines**

Question 38

When should oxygen be administered

Answer 38

* Inhaled oxygen should be administered **IF the arterial oxygen saturation (SaO2)declines to less than 90%.** * Routine use in non-hypoxic patients may worsen outcomes, as hyperoxia leads to ROS formation and oxidative damage

Question 39

Different in treatment for STEMI and NSTEMI

Answer 39

–UA/NSTEMI: medical management with Percutaneous Coronary Intervention (PCI) in select patients –STEMI: emergent reperfusion!

Question 40

Time for reperfussion

Answer 40

–Thrombolytics Door to Needle \<30min –PCI Door to Balloon \<90 min

Question 41

Major contraidications for thrombolytics

Answer 41

Question 42

PCI vs lytics

Answer 42