drugs used in thromboembolic disease Flashcards
what is thromboembolic disease?
thrombus (platlet rich) (clot) forms when coagulation reactions are inappropriately regulated
- Red thrombus: Fibrin-rich, lots of RBCs, occurs in veins
- White thrombus: Platelet-rich, occurs in arteries
- Thromboemboli: Migration of thrombus in body; can occlude vessels distant from site of clot formation (ie. Pulmonary embolism)
Three major factors predispose one to thrombus formation: Virchow’s triad
what is the 1st main factor that predisposes one to thrombus formation in Virchow’s triad?
Endothelial injury: Dominant influence on thrombus formation in the heart and arterial circulation
Can be caused by:
- Changes in shear stress associated with hypertension * Elevated blood glucose in diabetes mellitus
- Traumatic vascular injury, smoking
Endothelial damage exposes collagen (and thus promotes platelet adhesion), activates tissue factor (and thus promotes coagulation), and inhibits t-PA (and thus reduces clot dissolution)
what is the 2nd main factor that predisposes one to thrombus formation in Virchow’s triad?
- Abnormal blood flow: Turbulent or static blood flow instead of laminar blood flow
- Atherosclerotic plaques commonly cause turbulent blood flow
Stasis is a major cause for the formation of venous thrombi in legs (deep vein thrombosis) - Abnormal blood flow allows platelets to come into proximity of vessel wall; coagulation factors are not “washed away”; promotes endothelial cell activation
what is the 3rd main factor that predisposes one to thrombus formation in Virchow’s triad?
- Hypercoagulability: Generally less important as a predisposing factor, but can be significant in some patients, can be genetic or acquired
- Oral contraception/estrogen replacement therapy: Increased synthesis of coagulation factors and/or effect of estrogen on endothelium
what are the drugs to treat/prevent thrombosis?
Prevents:
Systemic Anticoagulants (targets coagulation cascade):
- warfarin
- heparin
Anti-Platelet Agents (targets platelets):
- aspirin
- ADP inhibitors
- glycoprotein IIb/IIIa inhibitors
Treats:
Thrombolytic Agents (busts the clot - used in emergency situations):
- alteplase
Systemic Anticoagulants: warfarin
Ideal systemic anticoagulant: Prevent pathological thrombosis/emboli, limit bleeding
Warfarin (Coumadin®): Antagonizes action of Vitamin K
- Reduces clotting factor production (II, VII, IX, and X)
- Clotting not affected until existing factors used
Usually administered orally as chronic preventative anticoagulant therapy; long half-life - easy to administer
Narrow therapeutic index; monitor using international normalized ratio (INR*) → target is 2.0-3.0
- Prothrombin is a Vitamin K-dependent glycoprotein
- thrombin converts fibrinogen to fibrin
warfarin adverse effects
- Bleeding tendencies; can treat with Vitamin K1
- Serious bleeding requires fresh blood/plasma
- Warfarin crosses the placenta; contraindicated in pregnancy (heparin does not cross the placenta)
- Warfarin is metabolized by CYP450; drug-drug interactions must be carefully monitored (ie. ketoconazole co-administration)
Systemic Anticoagulants: heparin
- Heparin (deactivates thrombin): Accelerates the action of antithrombin III; inhibits activated clotting factors
(thrombin and Factor Xa) - One of the most widely used drugs in the world: Used during kidney dialysis, heart surgery, ischemia, deep vein thrombosis, pulmonary embolism, etc.
What is it? - Mixture of sulfated mucopolysaccharides; highly negatively charged
- Isolated from mast cells from bovine lung/porcine GI mucosa
contraindicated in ppl with pork allergy - from animal tissue
how does heparin work?
- Heparin forms a complex with antithrombin III (AT-III) – accelerates AT-III’s action 100-fold
- AT-III irreversibly binds to thrombin and Factor Xa
- Prevents new clot formation and prevents existing thrombi from enlarging
- Does not lyse existing clots!
heparin application
- IV/IM only – negatively charged means it cannot be absorbed from GI tract
- Acts very quickly – “acute anticoagulant”
- Often given concurrently with warfarin as warfarin takes longer to have an effect
heparin adverse effects
- Excess bleeding (caused by thin blood) and possibly thrombocytopenia
- Monitor activated PTT (aPTT) during treatment: Aim is to have ~1.8-2.5x the normal average aPTT (normal = ~30 seconds)
- Protamine sulfate can neutralize heparin in overdose
what are low molecular weight heparins? and what do they inactivate
Low molecular weight heparins
(ie. Enoxaparin [Lovenox®])
- Fractioned from the standard (unfractionated) heparin
- Inactivates Factor Xa well, but not thrombin
- Being used more frequently due to its advantages over unfractionated heparin:
* Fewer bleeding tendencies
* Less risk of thrombocytopenia
* Improved pharmacokinetics – can give subcutaneously → Longer half-life
* Monitoring with aPTT less necessary
recap: what are platelets activated by?
Platelets are activated by:
- Agents outside the platelet acting on platelets: Collagen/vWF, and Glycoprotein IIb/IIIa
- Agents produced within platelet granules that act on platelets once released: ADP, TXA2, 5-HT (serotonin) → these can target receptors on these molecules to decrease aggregation
- Agents produced within the platelet that act within the platelet: ie. COX-1 enzyme → TXA2
Anti-platelet agents target one of these three aspects of platelet activation/aggregation
recap: what does aspirin inhibit and prevent?
- Inhibits COX-1 and COX-2; Inhibition is
irreversible (acetylates the COX 1 enzyme, destroying its activity) - prevents TXA2 production in platelets, reducing platelet aggregation
- Aspirin inhibits COX-1 in platelets for their entire lifetime (10 days) → reduced platelet aggregation
- Helps prevent thrombus formation; does not lyse existing thrombus
- Useful as prophylaxis in patients with risk of clotting (heart attack, stroke, or vascular disease patients)
what are anti-platelet agents: ADP Inhibitors?
ADP Inhibitors: Clopidogrel (Plavix®)
- Reduce platelet aggregation by inhibiting ADP activity → acts as a P2Y 12 (aka P2Y ADP) receptor
antagonist, preventing binding of ADP to receptors
- Clopidogrel and Prasugrel are “prodrugs” → must be activated by P450 metabolism in liver (drug-drug interactions)
- Do not lyse existing clots; used to reduce and prevent recurrence of stroke and heart attacks; agents are fairly safe, can be used synergistically with aspirin
what are anti-platelet agents: Glycoprotein IIb/IIIa Inhibitors?
Glycoprotein IIb/IIIa Inhibitors: Abciximab (REOPRO®), Eptifibatide (Integrillin ®) → can block the binding/linkage from occurring therefore ↓ platelet aggregation via binding to glycoprotein receptors
- Glycoprotein IIb-IIIa (GPIIb-IIIa) receptors on platelets bind to fibrinogen (inhibitors ↓ this process) which links platelets together
- GPIIb/IIIa receptor expression is induced by TXA2 and ADP
- Abciximab is a monoclonical antibody directed against the GPIIa/IIIb receptor - irreversibly binds and subsequently reduces platelet aggregation
what do thrombolytic drugs do?
- bust the clot!
- used to lyse already formed clots to restore blood flow in obstructed vessel before tissue necrosis occurs
- ideally we want local thrombolysis only (dont want to lyse healthy cells) - thrombolytic therapy has the potential to dissolve fibrin clots
- used in serious medical situations: acute ischemic stroke, acute myocardial infarction, acute massive pulmonary embolism
Thrombolytic drugs: alteplase
- Alteplase: Recombinant t-PA (tissue plasminogen activator)
- T-PA is a serine protease that is normally produced by endothelial cells
- Preferentially activates clot-bound plasminogen (not systemic plasminogen)
- Fairly short half-life; requires constant infusion (IV)
- VERY RISKY: Patients with known history of hemorrhagic stroke, head trauma, aortic dissection, or any active bleeding should NOT be given alteplase
