Acute Ischemic Heart DiseaseTherapeutics Flashcards
MONA
Morphine
O2
Nitro
ASA
ABCs drugs (5 As)
- Anti-thrombotic/ anti-coagulant
- ASA
- (Another) Anti-platelet
- Anti-anginal
- (ACE-i)
- BB
- “Cholesterol” (Statin)
Examples of anitplatelets
–Aspirin (ASA)
–P2Y12 receptor blockers
–GPIIb/IIIa receptor blockers
Examples of antithrombotics
–Unfractionated heparin
–Low molecular weight heparin (LMWH)
–Direct thrombin inhibitors
–Factor Xa inhibitors
Aspirin MOA
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.
Aspirin side effects
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
What is aspirin resistance
- 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.
Mechanism of aspirin resistance
Mechanisms
–poor adherence or absorption
–drug interactions
–COX-2 activity, COX-1 polymorphism
–platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa
Thienopyridines MOA
Block the adenosine diphosphate (ADP) receptor P2Y12 on platelets
Thienopyridine Side Effects
•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
Examples of thienopyridines
Clopidogrel, prasugrel, ticagrelor
How long does clopidogrel last? Price?
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).
Clopidogrel metabolism and drug interaction
- 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
Why were newer thienopyridines developed?
•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
Prasugrel use
- 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
What is unique about ticagrelor
•*Binds reversibly to P2Y12 receptor (only one!)
•*Acts at different site than clopidogrel/prasugrel
Glycoprotein IIb/IIIainhibitors MOA
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.
Glycoprotein IIb/IIIainhibitors side effects and contraindications
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
Glycoprotein IIb/IIIa inhibitor examples and clearance
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
Antiplatelet Therapeutic Strategy
- 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
Targets for antithrombotics
Use of heparin in UA/NSTEMI
In UA/NSTEMI, addition of heparin to aspirin likely
lowers risk of death or MI
Unfractioned Heparin MOA
•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)
Monitoring of UFH
Monitor aPTT for therapeutic range, every 4-6hr
LMHW Mechanism
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
Example of LMWH
Enoxaparin - Given as subcutaneous injection
Direct thrombin inhibitors MOA
- 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
Direct Thrombin Inhibitors example
Bivalirudin
What is Heparin Induced Thrombocytopenia (HIT)
•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
Use of ACE inhibitors
–MUST if EF <35%
–If hypertensive, most other patients with ACS benefit
Aldosterone receptor blocker examples and use
eplerenone/spironolactone
–Must monitor for hyperkalemia!
–All patients with LVEF <35% and NYHA II symptoms
When should Renin-Angiotensin-Aldosterone Agents not be used
•Should not be started in acute setting if systolic blood pressure < 100 mmHg
Use of Beta Blockers
Much larger benefit of beta blockers seen in the post-discharge setting
Contraidications of beta blockers
- 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)
Effect of nitroglycerin
•Reduces myocardial oxygen demand while enhancing myocardial oxygen delivery. It has both peripheral and coronary vascular effects.
Contraindication for nitroglycerin
Severe aortic stenosis (USE YOUR STETHOSCOPE!), RV infarct, concurrent use of PD#5 inhibitors (Sildenafil/Viagra), Hypotension
Morphine use
•Morphine should only be administered after nitroglycerin and other anti-ischemic therapies have failed to render the patient symptoms free (so almost never)
impairs absorption of thienopyridines
When should oxygen be administered
- 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
Different in treatment for STEMI and NSTEMI
–UA/NSTEMI: medical management with Percutaneous Coronary Intervention (PCI) in select patients
–STEMI: emergent reperfusion!
Time for reperfussion
–Thrombolytics Door to Needle <30min
–PCI Door to Balloon <90 min
Major contraidications for thrombolytics
PCI vs lytics
