L20- Drugs Used in Disorders of Coagulation Flashcards
list the 3 steps hemostasis
1) primary hemostasis- platelet aggregation
2) secondary hemostasis- coagulation
3) fibrinolysis: via plasmin
plasmin breaks down….
- fibrinogen
- fibrin
=> degradation products
what are the types / functions of drugs used in disorders of coagulation
1) drugs used to reduce clotting
2) drugs used to reduce bleeding
what are the types of drugs used to reduce clotting
- platelet aggregation inhibitors
- anticoagulants
- thrombolytics
platelet aggregation inhibitors act on…..
- dec platelet synthesis
- inhibit actions of chemical signals
what are the 4 platelet aggregation inhibitors
- cyclooxygenase inhibitors
- ADP receptor blockers
- phosphodiesterase inhibitors
- blocker of platelet GP IIb/IIIa receptors
ASA functions as a (1) inhibitor via (2) interaction. The end goal and result is to decrease (3) levels which are responsible for (4).
1- COX (1 and 2)
2- irreversible acetylation
3- TX-A2
4- platelet degranulation and aggregation // vasoconstriction
describe the platelet aggregation interaction
1 fibrinogen binding to 2 GP IIb/IIIa on 2 different platelets
note- this reaction / interaction occurs as a result of Ca influx
ASA is used for…..
- prophylactic Tx of TIA/CVA (transient cerebral ischemia)
- reduce incidence of recurrent MI / dec mortality in post-MI patients
(1) and (2) are the ADP receptor blockers that work via a (3) interaction with (4).
- indicate whether (1)/(2) is preferred and why
1- clopidogrel (preferred b/c fewer adverse effects)
2- ticlopidine
3- irreversible
4- P2Y12 (one of two ADP receptors)
Clopidogrel is a prodrug that is converted to active metabolite via (1). List the contraindications for using clopidogrel, (2).
1- CYP2C19
2: (do not use….)
- in poor CYP2C19 metabolizers
- with Omeprazole, a CYP2C19 inhibitor
clopidogrel is used for….
reduce rate of stroke, MI, death in patients with recent MI, stroke OR with acute coronary syndrome
list the 2 phosphodiesterase inhibitors and their associated uses
- Dipyridamole: stroke prevention
- Cilostazol: intermittent claudication
list the blockers of platelet GP IIb/IIIa receptors (indicate preferred drug) and what they treat
Abciximab, Eptifibatide, Tirofiban** (preferred)
-adjuncts in PCI (stent/angioplasty) for prevention of cardiac ischemic complications
list anticoagulants
- indirect thrombin (IIa) and factor Xa inhibitors
- vitamin K antagonist
- direct thrombin (IIa) inhibitors
- direct factor Xa inhibitors
list the indirect thrombin (IIa) and factor Xa inhibitors
- unfractionated heparin (UFH)
- low molecular weight heparins (LMWH)
- fondaparinux
UFH and LMWH are administered via (1), it has a (fast/slow) action and used for (3)
1- injectable
2- rapid
3- interfere with formation of thrombi
UFH and LMWH:
1) describe structure (+ weight
(2) explain source
1- mixture of straight-chain sulfated mucopolysaccharides (highly sulfonated => very negative)
-UFH: 5000-30000 MW
-LMWH (enoxaparin): 1000-5000 MW
2- isolated from bovine lung or porcine intestinal mucosa
compare pharmacokinetic factors of UFH and LMWH
-equal efficacy
LMWH: higher bioavailability, longer half-life, requires less frequent dosing requirements
LMWH are becoming more preferred
heparin binds and accelerates the action of (1) which will inhibit (2)
1- antithrombin III
2- thrombin (IIa), IXa, Xa
(T/F) UFH and LMWH inactivate factor IIa and Xa equally
F:
- UFA inhibits both IIa, Xa (due to ternary complex formation with antithrombin III)
- LMWF inhibits Xa»_space;> IIa (does not form ternary complex with antithrombin III)
_____ is used to monitor the performance of Heparin
aPTT: activated partial thromboplastin time (integrity of the intrinsic / common pathways)
-LMWH usually doesn’t need monitoring, assessed with anti-factor Xa assays
list the uses of heparin
-DVT
-pulmonary embolism
-MI
(drug of choice during pregnancy)
list the adverse effects of heparin
- bleeding
- hypersensitivity reactions
- HIT (heparin induced thrombocytopenia: type II worse than benign type I)
how does heparin cause type II HIT
(heparin induced thrombocytopenia)
- antibodies recognize heparin and platelet protein (Platelet Factor 4) complex
- Ig binds complex and activates Fc receptor on platelet
=> platelet aggregation and release of platelet contents (positive feedback)
-thrombocytopenia and thrombosis
heparin overdose or bleeding is treated with…..
protamine sulfate (positively charged, mops up heparin)
Fondaparinux:
(1) structure
(2) binds to???
(3) inhibitor of???
1- synthetic pentasaccharide (sequence 5 carbohydrates)
2- antithrombin III
3- factor Xa specifically
(1) is the vitamin K antagonist by inhibiting (2) so that factors (3) will not have (4)
1- warfarin
2- vitamin K epoxide reductase
3- II, VII, IX, X
4- γ-carboxyglutamyl side chains
warfarin effects factor _____ the most
factor VII, extrinsic pathway (+ protein C, intrinsic pathway)
warfarin is used to treat and prevent (1) and (2) following (3) or used to treat (4) used alone
1- DVT
2- pulmonary embolism
3- heparin
4- thromboembolic AFib
list the adverse effects of warfarin
- hemorrhage
- cutaneous necrosis (due to reduced protein C activity)
- category X in pregnancy (hemorrhagic disorder in fetus, and serious birth defects)
list the parenteral DTIs, include how it is monitored and what it is used for
(direct thrombin inhibitors)
- desirudin
- bivalirudin
- argatroban
- monitor via aPTT
- used in patients undergoing PCI
list the oral DTIs, include how it is monitored and what it is used for
(direct thrombin inhibitors)
-dabigatran etexilate (prodrug converted to dabigatran)
- no monitoring necessary
- prevents and treats DVT, pulmonary embolism
list the direct factor Xa inhibitors, include route of administration, how it is monitored, and what it is used for
-apixaban, rivaroxaban
- oral
- no monitoring necessary
- prevents and treats DVT, pulmonary embolism
why are direct thrombin and factor Xa inhibitors better than Warfarin
(dabigatran, apixaban, rivaroxaban)
- equivalent antithrombotic efficacy
- lower bleeding rate
- quicker onset of action
- predictable pharmacokinetics
- wider therapeutic window
- no monitoring required
- fewer drug interactions
why are thrombolytics (fibrinolytics) useful in comparison to anticoagulants
- lyses existing blood clots –> restores vessel patency before distal tissue necrosis
- anticoagulants only prevent thrombi formation
(acts by converting plasminogen to plasmin)
list all the thrombolytics (how do they act)
- streptokinase, urokinase (non-fibrin selective)
- alteplase, reteplase, tenecteplase (fibrin selective)
- *they convert plasminogen to plasmin
streptokinase is a (1) type drug found in (2) and is used for (3)
1- thrombolytic
2- β-hemolytic streptococci
3- rarely used
urokinase is a (1) type drug found in (2) and is used for (3)
1- thrombolytic
2- human kidney (+ urine)
3- lysis of pulmonary emboli
describe the MOA of alteplase, reteplase, tenecteplase
- t-Pa: tissue plasminogen activator, serine protease produced by human endothelial
- t-Pa activates plasminogen bound to fibrin
- t-Pa is ‘fibrin selective’
list the uses for alteplase, reteplase, tenecteplase
Alteplase: recombinant t-Pa, used for acute MI, acute ischemic stroke
-Reteplase, Tenecteplase: recombinant variants of t-Pa, longer half-lives
list the drugs used to treat bleeding
- plasminogen activator inhibitors
- protamine sulfate
- vitamin K
- plasma fractions
The main plasminogen activation inhibitors are (1) and (2). They are used in (3) and (4).
1- aminocaproic acid
2- tranexamic acid
3- adjunct hemophilia therapy
4- therapy to counter bleeding via fibrinolytic therapy
(1) is a chemical antagonist of heparin because its structure is highly composed of (2)
1- protamine sulfate
2- arginine, high positive charge
vitamin K__ is administered in ______ fashion at birth
vitamin K1, injected IM at birth
Vitamin K is used to treat (1) via (2) administration. It takes (3) for the onset of effect which lasts (4). If immediate hemostasis is required then (5) can be used.
1- drug induced hypoprothrombinemia 2- oral, parenteral 3- 6 hrs 4- 24 hrs 5- fresh frozen plasma can be infused
plasma fractions are used to (1), most commonly (2) and (3)
1- replace deficient coagulation factors
2- factor VIII
3- factor IX
(2/3- mostly inherited conditions)
