Tx of Hemostasis Disorders Flashcards
Aspirin inhibits the synthesis of thromboxane A2 by IRREVERSIBLE acetylation of COX-1 in platelets. How long until anti-thrombic effects are seen?
1-2 days after administration and lasts for the duration of the platelet lifespan (7-10 days)
Ticlopidine Route MOA AE Tx
Route: oral
MOA: ADP antagonist , prevents activation of GPIIb-IIIa, promotes platelet aggregation
-prevents platelet adhesion and platelet-platelet interaction
AE:
-severe bone marrow toxicity (rare cases)
-increases liver functional enzymes
-drug-drug interactions w/:
-warfarin
-heparin
-other antiplatelet drugs
-NSAIDS
Tx: limited to patients who are intolerant or unresponsive to aspirin
*Clopidogrel is usually preferred
Clopidogrel Route MOA AE Tx
Route: oral
MOA: ADP antagonist , prevents activation of GPIIb-IIIa, promotes platelet aggregation
-prevents platelet adhesion and platelet-platelet interaction
AE: less adverse cutaneous, GI, or HEMATOLOGIC rxns than ticlopidine
Tx: reduce atherosclerosis in pts w/ Hx of recent stroke, MI peripheral vascular disease, use in pts w/ stents
*It inhibits the activity of CYP2C9 and therefore may increase the plasma concentrations of drugs such as: fluvastatin many NSAIDs phenytoin tamoxifen tolbutamide Warfarin
Abciximab Route MOA AE Tx
Route: IV, monoclonal-Ab
MOA: Inhibits platelet aggregation by preventing binding of fibrinogen to glycoprotein receptor IIb/IIIa on activated platelets.
AE: bleeding
Tx: high-risk patients undergoing coronary angioplasty and patients undergoing angioplasty, atherectomy and stent placement often with clopidogrel
*expensive
Name 2 platelet-receptor glycoprotein inhibitors which are NOT monoclonal antibodies
- Tirofiban (non-peptide)
- Eptifibatide (cyclic peptide)
*These are intravenous platelet glycoprotein IIb/IIIa inhibitors similar to abciximab, but they are not monoclonal antibodies
Because decreased protein kinase A (PKA) activity leads to platelet activation via decreased cAMP levels, what drug class can be given to increase the levels of cAMP and therefore lead to inhibition of platelet activation?
Phosphodiesterase Inhibitors
- Dipyridamole
- Cilostazol
Dipyridamole
MOA
AE
Tx
MOA: phosphodiesterase inhibitor; increases cAMP and therin inhibits platelet activation
-A coronary vasodilator that also inhibits platelet aggregation
Tx:
In combination with aspirin, reduces thrombosis in patients with thrombotic disease
In combination with warfarin, inhibits embolism from prosthetic heart valves (main use)
Cilostazol
MOA
AE
Tx
MOA: Inhibits phosphodiesterase type III, and thereby, increases cAMP levels; antithrombic, antiplatelet, vasodilator
AE
Tx: Used for intermittent claudication and peripheral vascular disease
Anagrelide
MOA
Tx
MOA: Inhibits megakaryocyte development in the late postmitotic stage
Tx: Approved for the treatment of thrombocytocytosis secondary to myeloproliferative disorders, such as, polycythemia vera and chronic myelogenous leukemia to reduce the risk of stroke and myocardial infarction
What drug class inhibits blood coagulation ‘in vitro’ and can be used as coagulants for blood draws etc.?
Calcium chelators
- oxalic acid
- sodium citrate
- disodium edetate (EDTA)
Class of drugs which directly inhibit thrombin
Rudins
derivatives which interfere w/ hepatic synthesis of functional vit K-dependent clotting factors. What are the vit-K dependent factors?
Coumarin derivatives
Factors: II, VII, IX, X
also Protein C and S
What drug is a sulfated mucopolysaccharide (acidic molecule), has an immediate onset of action (due to continuous infusion pump or intermittent SubQ admin), has DOSE-DEPENDENT clearance and demonstrates extensive binding to endothelial cells/proteins?
Standard Heparin (UFH)
Warfarin and Heparin are both monitored using the PT/PTT tests, which test is used for each drug?
Heparin–PTT
Warfarin–PT
Standard Heparin (UFH) MOA
MOA: The protease inhibitor, antithrombin III, forms a 1:1 complex with clotting factor proteases
This interaction is slow, but is stimulated 1000-fold by heparin, which binds to antithrombin III
The heparin-antithrombin III complex inactivates factor IIa (thrombin); main mechanism
The heparin-antithrombin III complex also inactivates factor Xa, which occurs earlier in the cascade
AE:
Standard Heparin (UFH) Contraindications
contraindicated pts w/:
- Bleeding disorders and disorders that predispose to bleeding (e.g., hemophilia, thrombocytopenia), hemorrhage and several other diseases
- Patients with advanced liver or kidney disease, severe hypertension and certain infections (active tuberculosis, infective endocarditis)
*Preferable to other anticoagulants during pregnancy due to lack of placental transfer (contrast to warfarin)
Standard Heparin (UFH) AE:
- Bleeding/hemorrhage
* Bleeding is minimized with careful monitoring of PTT and platelet counts - Allergic reaction (heparin is an animal product)
- Osteoporosis (long-term therapy)
- Transient and occasionally severe heparin-induced thrombocytopenia (HIT)
Describe the 2 types of Heparin-induced thrombocytopenia (HIT)
-Type I = Transient and rapidly reversible.
Antibodies are generated against platelets.
Results in a decrease in platelet count.
-Type II = Severe
Antibodies decrease platelet count.
The antibodies also activate platelets.
This may produce a thromboembolism, which may be life-threatening.
Standard Heparin undergoes DOSE-RELATED clearance once binding sites are saturated. What is the antidote for this phenomena? CAREFUL!!! because excessive antidote is itself an anticoagulant
Protamine sulfate
-basic peptide that binds heparin (anion/cation interaction)
- Protamine is much less capable of reversing the effects of LMWH (disadvantage of LMWH)
- LMWH–low molecular weight heparin
Identify 3 low molecular weight heparin (LMWH)
Enoxaparin = low MW (2,000 – 6,000)
Dalteparin = low MW (2,000 – 9,000)
Tinzaparin = low MW (3,000 – 8,000)
Low molecular weight heparin (LMWH)
- indication
- kinetics
- what test is used to monitor it?
Indication: LMWH’s were first approved for primary prevention of deep vein thrombosis after hip replacement therapy
LMWH’s are being evaluated and used for the treatment of other thromboembolic diseases
Kinetics: dose-independent (1st order)
-Monitored by anti-Xa activity assay
Compare/Contrast unfractionated/standard heparin w/ its low molecular weight counterpart:
- inhibits platelet function
- increases vascular permeability
- endothelial cell/protein binding
- dose-dependent clearance
- T 1/2
1. inhibits platelet function UFH- +++++ LMWH- ++ 2. increases vascular permeability UFH- YES LMWH- NO 3. endothelial cell/protein binding UFH- extensive LMWH- minimal 4. dose-dependent clearance UFH- YES LMWH- NO 5. T 1/2 UFH- 50-90min LMWH- 3-6hr
Fondaparinux
Route
MOA
Tx
Route: SubQ–half-life is 18 hrs
MOA: synthetic pentasaccharide anticoagulant; It exerts antithrombotic activity as a result of ATIII-mediated selective inhibition of factor Xa
*should not cause HIT b/c it does not bind platelet factor 4
Tx:
–Venous thromboembolism prophylaxis following orthopedic surgery
–pulmonary embolism (PE)
–deep venous thrombosis (DVT)
–coronary artery thromboembolism; promising but still under study
- 65 amino acid peptide
- This is a specific thrombin inhibitor obtained from leeches
Hirudin
Which drug is a recombinant yeast-derived form of hirudin?
It is approved for anticoagulation in patients with heparin-induced thrombocytopenia (HIT)
Lepirudin
new recombinant hirudin analogs that may be used instead of heparins in the future
[2]
- Desirudin
2. Bivalirudin
Which drug is the 2nd agent (1st is lepirudin) to be approved for HIT?
–unlike lepirudin, it is cleared by liver and can be used in patients with end-stage renal disease
Argatroban
Warfarin T 1/2 CYP? MOA AE Tx test used to monitor
T 1/2: 36hr (extensive plasma protein binding–very low volume of distribution)
CYP2C9
MOA: Vitamin K epoxide reductase
AE: bleeding in brain, pericardium, stomach, intestine
–contraindicated in pregnancy (category X)
*fetal warfarin syndrome
*tetratogen in 1st trimester
*fetal hemorrhage during pregnancy
–contraindicated in pts w/ liver disease (impaired drug metabolism)
Tx:
–venous/arterial thrombi
–prevent blood clots in pts w/ a-fib
*test used to monitor is PT (INR)
Warfarin Drug-Drug interactions (diminished response)
- -inhibitor of warfarin absorption
- -drug class which induces hepatic microsomal enzymes
- -hormone which stimulates clotting factor synthesis
- -inhibitor of warfarin absorption
- cholestyramine (also affects vit K absorption)
- -drug class which induces hepatic microsomal enzymes
- anticonvulsants
- -hormone which stimulates clotting factor synthesis
- estrogen
- also vit K from diet and bacteria
Warfarin Drug-Drug interactions (enhanced response)
- displacement from plasma albumin
- inhibition of anticoagulant metabolism [8]
- reduction in availability of vit K
- displacement from plasma albumin
- sulfonamides
- inhibition of anticoagulant metabolism [8]
- Amiodarone
- Allopurinol
- Cimetidine
- Ciprofloxacin
- Erythromycin
- Co-trimoxazole
- Metronidazole*
- Fluconazole*
- reduction in availability of vit K
- broad-spectrum antibiotics
Novel orally bioavailable anticoagulants [3]
- Dabigatran etexilate–first oral direct thrombin inhibitor, approved for a-fib pts
- Rivaroxaban–direct FXa inhibitor, approved for post-surgical VTE (improved efficacy over LMWH)
- Apixaban
Streptokinase
MOA
AE
MOA: Facilitates thrombolysis through formation of activator complex with plasminogen results in formation of plasmin
Plasmin degrades fibrin, fibrinogen, and procoagulant factors V and VIII
AE: hypersensitivities
Urokinase
Route
AE
Tx
Route parenteral thrombolytic agent (from cultured human kidney cells)
AE: hypersensitivity occur less frequently
Tx: Indicated for lysis of pulmonary emboli, lysis of coronary artery thrombi associated with evolving transmural myocardial infarction
Recombinant Thrombolytic Agents [3]
- Alteplase–recombinant form of t-PA, expensive, no hypersensitivity rxns
- Reteplase–recombinant plasminogen activator, longer half-life than alteplase
- Tenecteplase, TNK-t-PA–modified human t-PA, prolonged half-life, increased specificity for fibrin and increased resistance to plasminogen activator inhibitor-1
Aminocaproic acid
Tx
MOA: fibrinolytic inhibitors
Tx:
–Systemic or urinary hyperfibrinolysis ( e.g., aplastic anemia, abruptio placentae, hepatic cirrhosis)
–Bleeding associated with neoplastic diseases (carcinoma of the prostate, lung, stomach, or cervix)
–Bleeding following cardiac surgery
