Anti-thrombotic Pharmacological Treatments for Ischemic Heart Disease

Question 1

ST Segment Elevation Myocardial Infarction (STEMI)

Answer 1

• 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.

Question 2

Non ST Segment Elevation Myocardial Infarction (NSTEMI) and Unstable Angina (UA)

Answer 2

• 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.

Question 3

Standard Pharmacologic management of Acute Coronary Syndromes

Answer 3

• 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

Question 4

Antiplatelet agents

Answer 4

– Cyclooxygenase inhibitors
     • Aspirin
– ADP receptor inhibitors
     • Clopidogrel
     • Prasugrel
     •  Ticagrelor
– Glycoprotein IIb/IIIa inhibitors
     • Abciximab
     • Eptifibatide

Question 5

Antithrombotic Agents

Answer 5

– Unfractionated Heparin
– Low Molecular Weight Heparin
– Direct Thrombin Inhibitors

Question 6

Hemostasis

Answer 6

process that prevents blood loss from damaged blood vessels
– Vasoconstriction
– Adhesion and activation of platelets (platelet plug)
– Formation of fibrin

Question 7

Thrombosis

Answer 7

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

Question 8

Fibrinolytic Therapy

Answer 8

• 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)

Question 9

MOA thrombolytics (alteplase)

Answer 9

• 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

Question 10

adverse effects of thrombolytics

Answer 10

• Bleedingismost common complication
• distinction of newer drugs compared to ‘older’ streptokinase
• Systemic lytic state
– Interfere with coagulation in general circulation

Question 11

Contraindications to Thrombolytic Therapy

Answer 11

• ~ 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

Question 12

Anticoagulants

Answer 12

• Interferewith coagulation cascade
• Impairsecondary hemostasis
• Goal
     – to inhibit activation of
thrombin by Xa
     – Directly inhibit thrombin
     – Decrease production of functional prothrombin

Question 13

Unfractionated Heparin [UFH], Low Molecular Weight Heparins [LMWH] (enoxaparin, dalteparin) & Fondaparinux

Answer 13

• 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

Question 14

Direct Thrombin Inhibitor

Answer 14

• 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

Question 15

free thrombin vs fibrin-bound thrombin…

Answer 15

• 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

Question 16

Anti-Platelet Drugs

Answer 16

• Thienopyridines 
     – Clopidogrel
     – Ticlopidine 
     – Prasugrel 
     – Ticagrelor
• GP IIb/IIIa receptor
antagonists
     – Abciximab 
     – eptifibatide

Question 17

Aspirin

Answer 17

• Irreversibly acetylates cyclooxygenase-1 in platelet
• Blocksproductionof thromboxane
• Platelets lack nuclei so permanant effect of aspirin

Question 18

Why is prostacyclin less likely to decrease with aspirin administration?

Answer 18

• Endothelial cells produce prostacyclin

* prostacyclin causes platelets to not stick together–>acts opposite of thromboxane

Question 19

Aspirin use in patients with CVD Secondary Prevention

Answer 19

• 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

Question 20

Aspirin for Primary Prevention

Answer 20

-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.

Question 21

what are the aspirin recommendations?

Answer 21

• 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

Question 22

Thienopyridines

Answer 22

clopidogrel, ticlopidine, prasugrel, ticagrelor

Question 23

Thienopyridines

Answer 23

• 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`

Question 24

reversible vs. irreversible Thienopyridines

Answer 24

reversible: ticagrelor
irreversible: clopidogrel, prasugrel

Question 25

Advantage of reversible platelet inhibitor ?

Answer 25

• 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

Question 26

Thienopyridine pro-drugs which are metabolized to active metabolites

Answer 26

Clopidogrel, ticlopidine and prasugrel are pro-drugs that are metabolized to active metabolite
– Prasugrel more readily metabolized and increased potency

Question 27

side effects of thienopyridines

Answer 27

• Side effects include bleeding and GI related symptoms
– Ticlopidine associated with life- threatening adverse effects (severe neutropenia and thrombotic thrombocytopenic purpura)

Question 28

clopidogrel metabolism

Answer 28

• 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

Question 29

uses of thienopyridines

Answer 29

• 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

Question 30

Glycoprotein IIb/IIIa Receptor

Antagonists

Answer 30

abciximab and

eptifibatide

Question 31

Glycoprotein IIb/IIIa Receptor

Antagonists mechanism

Answer 31

• 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

Question 32

Abciximab

Answer 32

– Chimeric human-mouse monoclonal antibody
– blocks access of fibrinogen, vWF and other adhesive molecules to the GP IIb-IIIa receptor
– Non-competitive – IV administration

Question 33

Eptifibatide

Answer 33

– Synthetic peptide antagonist
• Contains a sequence motif that binds specifically to GP IIb-IIIa receptors
• Competitive
• IV administration
• Renal clearance

Question 34

uses of abciximab

Answer 34

• Patients undergoing PCI, including angioplasty or stent placement
• In combination with aspirin and heparin (or LMWH)
• Also used with alteplase for thrombolysis

Question 35

uses of eptifibatide

Answer 35

• Patients undergoing PCI, including angioplasty or stent placement
• Patients with unstable angina and myocardial infarction, often with LMWH

Question 36

Dipyridamole

Answer 36

• 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

Question 37

NEW Oral Anticoagulants

Answer 37

• Dabigitran

* Rivaroxaban