Anti-thrombotic Pharmacological Treatments for Ischemic Heart Disease Flashcards
ST Segment Elevation Myocardial Infarction (STEMI)
• Result of complete thrombotic occlusion of the infarct related artery at the site of plaque rapture
• Reperfusion therapy
– Mechanical
– Pharmacological with thrombolytic
• In addition to immediate re‐perfusion, STEMI patients should receive standard pharmacologic treatment for ACS with antiplatelet/antithrombotic agents, statin, aspirin, beta‐adrenergic blockers, and nitrates.
Non ST Segment Elevation Myocardial Infarction (NSTEMI) and Unstable Angina (UA)
- UA and NSTEMI result from plaque rupture with partial thrombotic occlusion of the vessel lumen.
- NSTEMI and UA patients should receive standard pharmacologic treatment for ACS with antiplatelet/antithrombotic agents, statin, aspirin, beta‐adrenergic blockers, and nitrates.
Standard Pharmacologic management of Acute Coronary Syndromes
• The pharmacologic treatment of NSTEMI, UA, and STEMI is similar, and is consists of antithrombotic/antiplatelet agents, statins, beta adrenergic blockers and nitrates.
EXCEPTION: STEMI may also be Treated with a thrombolytic
Antiplatelet agents
– Cyclooxygenase inhibitors
• Aspirin
– ADP receptor inhibitors
• Clopidogrel
• Prasugrel
•  Ticagrelor
– Glycoprotein IIb/IIIa inhibitors
• Abciximab
• EptifibatideAntithrombotic Agents
– Unfractionated Heparin
– Low Molecular Weight Heparin
– Direct Thrombin Inhibitors
Hemostasis
process that prevents blood loss from damaged blood vessels
– Vasoconstriction
– Adhesion and activation of platelets (platelet plug)
– Formation of fibrin
Thrombosis
pathological formation of a
‘hemostatic’ plug within the vasculature in the
absence of bleeding
– Injury to blood vessel wall ~ atherosclerosis, plaque rupture
– Altered blood flow ~ veins of leg after sitting for long time
– Abnormal coagulability of blood ~pregnancy, certain drugs, inheritable disease
Fibrinolytic Therapy
• Accelerate lysis of occlusive intracoronary thrombosis in STEMI
– Restore coronary blood flow
– Limit myocardial damage
– Translate to increased survival rate and fewer complications
• Patients with UA or NSTEMI do not benefit from fibrinolytic therapy
• Recombinant tissue-type plasminogen activators – Alteplase (tPA)
MOA thrombolytics (alteplase)
- Transforms the inactive precursor plasminogen into active protease plasmin, which lyses fibrin clots
- No matter which thrombolytic is used, the key point is that need to be administered ASAP, ideally within 30 min of patient’s presentation at hospital
adverse effects of thrombolytics
• Bleedingismost common complication
• distinction of newer drugs compared to ‘older’ streptokinase
• Systemic lytic state
– Interfere with coagulation in general circulation
Contraindications to Thrombolytic Therapy
• ~ 30% of patients may be unsuited for thrombolytics
• Situations where drug therapy could impair necessary fibrin clots w/i circulation
• Where would you not want bleeding to occur???
– Active peptic ulcer
– Recent stroke
– Recovering from recent surgery
Anticoagulants
• Interferewith coagulation cascade
• Impairsecondary hemostasis
• Goal
– to inhibit activation of
thrombin by Xa
– Directly inhibit thrombin
– Decrease production of functional prothrombinUnfractionated Heparin [UFH], Low Molecular Weight Heparins [LMWH] (enoxaparin, dalteparin) & Fondaparinux
• Administered parenterally (not absorbed from GI tract)
• Most important side effect is bleeding
• UFH has additional side effect of heparin-induced thrombocytopenia (HIT)
• LMWH (also fondaparinux) advantage over UFH is longer half-life and more predictable bioavailablity (less bleeding, less risk of HIT)
– UFH is heterogenous mixture, binds plasma proteins, contributes to patient variability and less predictable response
Direct Thrombin Inhibitor
• Bivalirudin • Inhibits independently of antithrombin • Acts on both circulating and clot-bound- thrombin • No thrombocytopenia • Unstable angina patients undergoing percutaneous coronary intervention • Major adverse effect is bleeding
free thrombin vs fibrin-bound thrombin…
- thrombin bound to fibrin within a thrombus remains enzymatically active and protected from inactivation by antithrombin
- fibrin-bound thrombin can locally activate platelets and trigger coagulation thereby causing thrombus growth
- Heparin only inactivates circulating thrombin
- Direct thrombin inhibitors inactive free and fibrin-bound
Anti-Platelet Drugs
• Thienopyridines
– Clopidogrel
– Ticlopidine
– Prasugrel
– Ticagrelor
• GP IIb/IIIa receptor
antagonists
– Abciximab
– eptifibatideAspirin
- Irreversibly acetylates cyclooxygenase-1 in platelet
- Blocksproductionof thromboxane
- Platelets lack nuclei so permanant effect of aspirin
Why is prostacyclin less likely to decrease with aspirin administration?
- Endothelial cells produce prostacyclin
* prostacyclin causes platelets to not stick together–>acts opposite of thromboxane
Aspirin use in patients with CVD Secondary Prevention
• Used in patients with unstable angina, acute myocardial infarction (MI), history of MI
– Reduces incidence of future fatal and nonfatal coronary events
• Used in patients with chronic stable angina without a history of MI
– Decreases occurrence of subsequent MI and mortality
• Used in patients who have had a minor stroke or transient cerebral
ischemic attack
– Reduces rate of future stroke and CV events
• Used in patients who have undergone coronary artery bypass surgery
– Decreases chance of graft occlusion
Aspirin for Primary Prevention
-multiple randomized trials and several high-quality systematic reviews and meta-analyses
-But still significant debate remains about which patients, if any, should be offered aspirin for primary prevention
– Some are in favor of aspirin use for primary prevention in people with increased CVD risk who are not at high risk for aspirin’ s adverse effects.
– Others have recommended against aspirin use for most patients without a prior history of CVD events
-US Food and Drug Administration issued a statement reaffirming that “ [it] has reviewed the available data and does not believe the evidence supports the general use of aspirin for primary prevention of a heart attack or stroke.
what are the aspirin recommendations?
• Low dose (75 to 325 mg/day) to patients with clinical manifestation of coronary artery disease
– No contraindications in patient
• Should not be prescribed routinely for primary prevention purposes to
completely healthy individuals
– Many physicians recommend aspirin use in men and women older than 50 who have at least one major atherosclerosis risk factor
– Elevated LDL, reduced HDL
– Tobacco smoker
– Hypertension
– Diabetes, Metabolic syndrome
– Lack of physical activity
Thienopyridines
clopidogrel, ticlopidine, prasugrel, ticagrelor
Thienopyridines
• Inhibit ADP-mediated activation of platelets
• ADP simultaneously activates two purinergic receptors, P2Y1 and P2Y12
– P2Y1–>increase PLC–> increase calcium
– P2Y12–>decrease cAMP–> increase calcium
• Drugs inhibit P2Y12 receptor`
reversible vs. irreversible Thienopyridines
reversible: ticagrelor
irreversible: clopidogrel, prasugrel
Advantage of reversible platelet inhibitor ?
• If patient requires surgery (like coronary bypass surgery) and is taking drug like clopidogrel (or aspirin), waiting period is necessary to prevent platelet function to return to normal.
– 7-10 days
• Prevents perioperative bleeding complications
Thienopyridine pro-drugs which are metabolized to active metabolites
Clopidogrel, ticlopidine and prasugrel are pro-drugs that are metabolized to active metabolite
– Prasugrel more readily metabolized and increased potency
side effects of thienopyridines
• Side effects include bleeding and GI related symptoms
– Ticlopidine associated with life- threatening adverse effects (severe neutropenia and thrombotic thrombocytopenic purpura)
clopidogrel metabolism
• Clopidogrel is metabolized by CYP2C19
– Variability of response in patients with CYP2C19 polymorphisms
– Co-administration with protein pump inhibitor (omeprazole) a concern since PPI inhibit CYP2C19
uses of thienopyridines
• As monotherapy, drugs are modestly superior to aspirin in reducing risk of myocardial infarction
– Increased risk of side effects
– Increased cost
• Combination of clopidogrel with aspirin has increased benefit compared to aspirin alone
– Increased bleeding risk
Glycoprotein IIb/IIIa Receptor
Antagonists
abciximab and
eptifibatide
Glycoprotein IIb/IIIa Receptor
Antagonists mechanism
• Reversibly inhibit the final common pathway of platelet aggregation – binding of GPIIb/IIIa receptors to fibrinogen and vWF
• So platelets can’t ‘stick’ to each other, don’t get formation of the hemostatic plug
• Abciximab
– Chimeric human-mouse monoclonal antibody
• Eptifibatide
– Synthetic peptide antagonist
Abciximab
– Chimeric human-mouse monoclonal antibody
– blocks access of fibrinogen, vWF and other adhesive molecules to the GP IIb-IIIa receptor
– Non-competitive – IV administration
Eptifibatide
– Synthetic peptide antagonist • Contains a sequence motif that binds specifically to GP IIb-IIIa receptors • Competitive • IV administration • Renal clearance
uses of abciximab
- Patients undergoing PCI, including angioplasty or stent placement
- In combination with aspirin and heparin (or LMWH)
- Also used with alteplase for thrombolysis
uses of eptifibatide
- Patients undergoing PCI, including angioplasty or stent placement
- Patients with unstable angina and myocardial infarction, often with LMWH
Dipyridamole
• Occasionally prescribed to patients that cannot tolerate aspirin; relatively ineffective
• Mechanism of action-unclear
– Increase in platelet cAMP
• Blocking phosphodiesterase
• Blocking cellular uptake and destruction of adenosine
• Given alone, the drug has no proven cardiac benefits
NEW Oral Anticoagulants
- Dabigitran
* Rivaroxaban
