Anticoagulation Drugs Flashcards
Clot Formation
1) vasospasm of injured blood vessel ___ passage
2) platelets release chemical making nearby platelets sticky; platelet ___forms
3) a strong clot forms by a cascade mechanism that culminates in activation of ___ , an enzyme that converts fibrinogen to fibrin
4) plasminogen is coverted to ___ by plasminogen activators
5) ___ is digested, blood flow restored
1) consitrictis
2) plug
3) thrombin
4) plasmin
5) fibrin
Clotting Factors
Serine Proteases
- ___ down-stream factors to ___ them
- Examples - Factors: XII, XI, X, IX, VII, II (pro-___)
- cleave factors ___ and ___
- Protein ___ (Anti-coagulants)
- cleave, activate
- pro-coagulants
- coagulant
- Va, VIIIa
- C
Clotting Factors
Glycoproteins
- Co-factors for activation of ___
- Examples - Factors: VIII, V, III (tissue factor), protein ___
- bind to and inhibit ___ (anti - ___ III)
- proteases
- S
- thrombin, thrombin
Clotting Factors
- Ca2+ (Factor ___ ) - links certain factors to ____
- transglutaminase - ___ fibrin fibers (Factor ___ )
- fibrinogen/fibrin - ultimately, the substrate protein for thrombin (Factor ___ ) that ___ to form clot
- IV, phospholipid membranes
- cross-links, XIII
- IIa, polymerizes
Genetic Clotting Factor Disease
Hemophilia A - deficiency in factor ___ - 1 in 5,000 males
Hemophilia B - deficiency in factor ___ - 1 in 25,000 males
Factor V Leiden - resistance to cleavage protein ___ (5% of Caucasians)
- VIII
- IX
- C
Where are clotting factors produced?
- all except for von Willebrand factor are made in the ___
- vWF is produced in the ___ , subendothelium, and megakaryocytes
- factor ___ is also produced in the endothelium
- ___ can have unpredicable effects on coagulation
- liver
- endothelium
- VIII
- liver disease
Where does coagulation occur?
Extrinsic - required a ___ factor extrinsic to the blood. Important when vessel is damaged and blood leaks out
Intrinsic - triggered when ___ in exposed on the wall of the blood vessel
- tissue
- collagen
Coagulation Cascade - Intrinsic Pathway
- all components in the blood
- initiated by contact with negatively charged collagen of diseased or injured vessel
- blood in ___ clots by this mechanism
- all
- collagen
- test tube
Coagulation Cascade - Extrinsic pathway
- relies on factors outside blood stream for activation
- release of tissue ___ initiates pathway
- rapid (about ___ secs) to start clot formation)
- thomboplastin
- 15
Activation of the Extrinsic of Tissue Factor Pathway to coagulatoin
- ___ is expressed on the surface of cells outside of but near blood vessels
- factor ___ normally resides in blood
- TF binding to factor ___ activates it
- factor ___ binds and cleaves actor ___
- tissue factor
- VII
- VII
- VIIa, X
Common Pathway
- ___ activation plays a central role in final steps of clot formation
- converts ___ into long strands of insoluble ___
- activates Factor ___ which then ___ fibrin to form a stable clot incorporated into platelet plug
- thrombin
- fibrinogen, fibrin
- XIII, crosslinks
Convergence with intrinsic pathway
Factor ___ binds Factor ___ on the surface of platelets and activates Factor ___
IXa, VIIa, X
Feedback mechanism which increase coagulation
Thrombin
- activates factor ___ and ___
- enhances platelet activation
Platelet activation - increases activation of Factor ___, Factor ___ , and cleavage of ____
- V, VIII
- VII, X, prothrombin
Feedback mechanism which decrease coagulation
Anti-thrombin
- neutralizes procoagulant serine ____ (thrombin, Xa, IXa)
- reaction acelerated by ___
Protein C system
- activated by thrombin binding to ___
- activated protein ___ complex (APC) forms a complex with protein ___ to inactivate factors ___ and ___
Factor Xa
- activates tissue factor pathway inhibitor (TFPI) to block initial activation of factor ___
- protease
- heparin
- thrombomodulin
- C, S, Va, VIIIa
- VII
Common Tests of Hemostatic Function
Platelet Count
- too low = ___ = bone marrow malfunction, nutritional deficiencies
- too high = ___
Prothrombin Time (PT/INR)
- plasma + thromboplastin + Ca - clots in 12-14 seconds
- INR (internal normalized ratio) is a normalized value for each lot of ___
- used to monitor ___ therapy
aPTT
- plasma + phospholipid (no TF) + activating agent - clots in 26-33 seconds
- used to monitor ___ therapy
Fibrinogen
- less common. range from 200-400 mg/dL
D-dimer
- product of ___ breakdown
- thombocytopenia
- thrombocytosis
- thromboplastin
- warfarin
- heparin
- fibrin
In vitro measure of coagulation
1) calcium + blood = recalcification time 2-4 min
2) calcium + partial thromboplastin (just phospholipids) + kaolin + blood = activated partial thromboplastin time (aPTT; 23-33 seconds) = ____ pathway
3) calcium + thromboplastin + blood (T.P. is tissue factor and phospholipids) - prothrombin time (PT; 12-14 seconds) = ___ pathway
- intrinsic
- extrinsic
INR
a normal PT time is 11-14 seconds. Due to differences in patches of tissue factor, producers must assign an international sensitivity index (ISI) to their product.
Normal INR = ___ - ___
Therapeutic INR ~ ___ - ___
INR > ___ = risk of hemorrhage
0.8-1.2
2-3
3
Therapeutic Indication for Anticoagulation
prevent excessing clotting that can lead to ___ of blood vessels
- stroke
- post MI
- unstable angina
- DVT
- pulmonary embolisms
- artificial surfaces
- occlusion
Vitamin K
- fat-soluble vitamin
- involved in post-translation modification of prothrombin, factors ___ , ___ , and ___ (vit K dependent)
Uses
- individuals with abnormalities in fat absorption
- reverse anticoagulant effect of excess ___
VII, IX, X
- warfarin
Vitamin K Antagonist - Warfarin
- Vitamin ___ Antagonists
- Coumarin anticoagulants
- originally found in spoiled clover hay as substances that caused hemorrhage in cattle
- all derivates are water soluble ___
- warfarin is the most commonly used
- racemic mixture ( __ isomer most potent)
- K
- lactones
- S
Warfarin - MOA
vitamin K is essential for post-translation modification of clotting factors ___ , ___ , ___ , and ___ and anticoagulation proteins ___ and ___
Warfarin acts by inhibiting the synthesis of clotting factors ___ , ___ , ___ , and ___
Vitamin K action
- carboxylase catalyzes the gama-carboxylation of Glu in ___
- Vitamin K is ___ in the process
- coumadin inhibits vit K-epoxide reductase ( ___ ), thus blocking ___of Vit K epoxide back to its active form
- VII, IX, X prothrombin II, C, S
- II, VII, IX, X
- prothrombin
- oxidized
- VKORC1, reduction
Warfarin Therapeutic actions
___ onset of action
- must deplete the pool of circulating ___
- max effect in ___ - ___ days after start of therapy
- loading dose: 5 mg/day
- maintenance dose: 2.5-5 mg/day
After discontinuing therapy
- factors must be re-synthesized to return to normal PT (several ___ )
delayed, clotting factors
- 3-5 days
- days
Warfarin Metabolism
- metabolized in the liver by CYP ___ (S-warfarin)
- t1/2 = ___ - ___ hrs
- termination of action is not correlated with plasma warfarin levels, but reestablishment of normal ___
over dose - latrogenic hemorrhage
- discontinue warfarin therapy
- administer Vit K1 (high levels can activate warfarin-inhibitied ___ )
- in serious hemorrhage - ____ replaces clotting factors faster than Vit K therapy
- CYP2C9
- 36-48
- clotting factors
- reductase
- plasma
Warfarin Necrosis
- some patients have a deficiency of protein __
- this protein is an innate ___ that requires vitamin K dependent carboxylation for its activity
- since warfarin initaitally decreases protein ___ levels faster than the coagulation factors, it can paradoxically ___ the blood tendency to coagulate when treatment is begun
- many patients when starting on warfarin are given ___ in parallel to combat this
- a deficiency in protein ___ would lead to the same necrosis
- C
- anticoagulant
- C, increase
- heparin
- S
Drugs that Diminish warfarin’s Anticoagulant Effect
- cholestyramine - inhibits warfarin absorption in the ___
- barbiturates, carbamazepine, rifampin - accelerates warfarin metabolism by ___ P450 enzymes
- Nephrotic syndrome/hypoproteinemia - decreased albumin, increased ___ warfarin, decreased t1/2
- reduced vitamin K - ___ warfarin-induced epoxide reductase inhibition
- pregnancy (bad dr) - ___ levels of clotting factors
- GI tract
- inducing
- free
- bypasses
- increased
Drugs that enhance warfarins anticoagulant effect
- chloral hydrate - displaces warfarin from plasma ___
- chloramphenicol, SSRIs, amiodarone - decreases warfarin metabolism by ___ hepatic P450
- broad spectrum antibiotics - reduce availability of vit K in the ___
- anabolic steroids - inhibits ___ and increases ___ of clotting factors
- albumin
- inhibiting
- GI tract
- synthesis, degradation
Warfarin
Adverse Effects
- hemorrhage
- drug-drug interactions
Contraindications
- when risk of ___ is greater than potential benefits (uncontrolled alcohol/drug abuse, unsupervised dementia/psychosis)
- never use in ___ (teratogen)
- hemorrhage
- pregnancy
Mechanism of Heparin
- free antithrombin can slowly inactivate Factors ___ , ___ , ___ , ___ , ___ , and ___
- heparin binding to AT changed the protein conformation; this ___ interaction of AT with target factors
- the ratio of AT activity is typically ___ (thrombin:factor Xa)
- LMWH are too small to bind AT and ___ , thus have greater specificity for inhibiton of ____
- Overall, heparin acts by accelerating AT reactions to inactivate ___ and ___
- Xa, IXa, XIa, XIIa, IIa, VIIa
- increases
- 3:1
- thrombin, Factor Xa
- thrombin, Factor Xa
Heparin - Clinical Use
administration - effective ___
- intermittenet IV inj
- Continuous IV infusion - easiest to control
- SC inj
adjust dosing according to ___ tests
- ___ therapeutic range = 1.5-2 x normal
- cleared rapidly from blood (t1/2 = 30-180 min)
anticoagulant effect disapprears within ___ of dicontinuation of therapy
- immediately
- coagulation
- aPTT
- hours
Adverse Effects of Heparin
latrogenic hemorrhage can occur at any site
risk factors:
- patients over ___
- ___ patients
- severe ___
- ___ drugs
Treatment
- stop heparin (short t1/2)
- life threatening bleeding: administer specific antagonist
- ___ - binds tightly to heparin to neutralize the anticoagulant action
- 50
- ulcer
- hypertension
- antiplatelet
- protamine sulfate
Hepatin Reversal
Heparin Inhibitor: protamine sulfate
- a low molecular weight ___ protein which forms a stable complex with ___ charged heparin through multiple electrostatic interactions
- administered IV to rapidly reverse the effects of heparins in situations of life threatening hemorrhage/great heparin excess
- not as effective with ___
- does not reverese effects of ___
- polycationic
- negatively
- LMWH
- fondaparinux
Adverse Effects - Heparin - thrombocytopenia (HIT)
type 1: mild, transient due to direct action on ___
type 2: severe, develops ___ - ___ days after starting therapy
- ___ develop to platelet (PF4)-heparin complex
- ___ - associated with extended therapy (3-6 months)
- platelets
- 7-12
- antibodies
- osteoporosis
Heparin induced thrombocytopenia
unfractionated heparin can cause thrombocytopenia and thrombosis in patients producing an ___ to a complex of heparin and platelet factor 4
- HIT risk: unfractionated heparin > LMWH > fondaparinux
antibody
Heparin Chemistry
- straight chain sulfated mucopolysaccharides - produced by ___ cells and ___
- mixture of 5-30 kDa (mean ~ ___ kDa) compounds
- extracted from ___ small intestine or ___ lung
- anticoagulant activity standardized by bioassay - expressed as units ~ 120 USP units/mg is st activity
- sulfate groups (negatively charged) required for binding to ___ are indicated in blue
- mast cells, basophils
- 15 kDa
- porcine, bovine
- antithrombin
LMWH
Examples: ___ and ____
- obtained from ___ of unfractionated porcine heparin
- equal efficacy to heparin
- increased bioavailability for ___ site of adm (only route)
- less frequent dosing (1-2x daily); ___ t1/2 than heparin
- no monitoring of ___ needed
dalteparin
enoxaparin
- depolymerization
- equal
- SQ
- longer
- clotting
Advantages of LMWH
more ___ pharmacokinetic profile
- good bioavailability from ___ injection site
- less ___ binding/more ___ dosing
- ___ t1/2 (fewer inj)
- ___ incidence of HIT/osteoporosis
predictable
- SQ
- protein, uniform
- longer
- lower
UFH - Heparin Summary
routes of administration: ___ and ___
advantages
- ___ onset and clearance
- anticoagulation effect easily ___
- ok in ___ failure
- can be rapidly reversed with ___
disadvantages
- frequent ___ required
- HIT
- IV, SQ
- rapid
- monitored
- renal
- protamine
- monitoring
LMWH - Heparin Summary
examples: ___ and ___
routes of administration: ___ only
advantages:
- ___ duration of action when administered ___ (as compared to heparin)
- monitoring is generally ___
disadvantages:
- relatively contraindicated in ___ failure
- unknown optimal dosing in morbidly ___ patients
- if monitoring is needed, it requires an ___ level (less available than aPTT)
- HIT (mixed data on whether risk is equal to or lower compared to UFH)
dalteparin, enoxaparin
SQ
- longer, SQ
- unnecessary
- renal
- obese
- anti-factor Xa
Factor Xa Inhibitor
Fondaparinux Sodium
- synthetic sulfated pentasaccharide
- mechanism: indirectly inhibits factor Xa by selectively binding ___
- route of administration: ___, can be given at home
- t1/2 ~ 17-21 hrs - can be given ___ daily
- predicatable PK and dose response; does not require monitoring
- anti-thrombin
- SQ
- once
Factor Xa Inhibitor
Fondaparinux sodium
Use:
- venous thromboembolism: acute ___ and ___
- ___ in patients undergoing hip fracture surgery, hip replacement, knee replacement or abdominal surgery
Low potential for ___
- action not reversed by ___
- DVT, PE
- prophylaxis
- HIT
- protamine sulfate
DOACs/NOACs
Direct Factor Xa Inhibitors (4)
Direct Thrombin Inhibitors
direct factor Xa inhibitors
- rivaroxaban
- apixaban
- edoxaban
- betrixaban
direct thrombin inhibitors
- dabigatran
orally available factor Xa inhibitors - rivaroxaban and apixaban
- rivaroxaban t1/2 = ___ - ___ hrs
- apixaban t1/2 = __ hrs
- treatment and prevention: ___ and ___
- prevention of thrombosis in non-valvular ___
- dose reduction with impaired ___ function
- risk of ___ and ___ in patients undergoing spinal puncture or epidural anesthesia
- increased risk of ___ upon discontinuation
- fixed dosing, monitoring not required
- 5-9 hrs
- 12 hrs
- VT, PE
- A-fib
- renal
- hematoma, paralysis
- thrombosis
orally available factor Xa inhibitors - edoxaban (Savaysa)
- t1/2 = ___ - ___ hrs
- treatment of ___ and ___ after 5-10 days with parenteral anticoagulant
- prevention of thrombosis in NV ____
- not used in patients with CrCl > ___ mL/min
- increased risk of ___ events upon premature discontinuation
- risk of ___ and ___ in patients undergoing spinal puncture or epidural anesthesia
- fixed dose, anticoagulation monitoring not required
- 10-14
- VT, PE
- A-fib
- 95 mL/min
- ischemic
- hematoma, paralysis
cant use this drug if your kidneys work too well
orally available factor Xa inhibitors - betrixaban (Bevyxxa)
- t1/2 = ___ - ___ hrs
- prevention of ___ in hospitalized patients at risk
- dose reduction in patients with severe ___ impairment
- avoid in patients with moderate to severe ___ impairment
- fixed dose, no monitoring of coagulation required
- risk of ___ and ___ in patients undergoing spinal puncture or epidural anesthesia
- increased risk of ___ events upon premature discontinuation
- 19-27 hrs
- VTE
- renal
- hepatic
- hematoma, paralysis
- ischemic
Antidote for Factor Xa inhibitors
Andexanet - reversal agent of Xa inhibitors ___ and ___.
- Recombinant protein that mimics factor ___. It can bind drug, but lacks enzymatic activity.
- under investigation or use with ___ and ___
- given ___ to patients with uncontrolled or life threatening bleeding
- black box warning: increased risk for ___ events
- apixaban, rivaroxaban
- Xa
- edoxaban, enoxaparin
- IV
- thromboembolic
Direct Thrombin Inhibitors (DTI): Mechanism
- DTIs can bind to the ___ site of thrombin, to ___ of thrombin, or both
- DTIs can inhibit both ___ and ___ bound thrombin
- direct thrombin inhibitors can also reduce platelet ___
- active, exosite
- soluble, fibrin
- aggregation
Direct Thrombin Inhibitors
non-heparinoid parenteral agents - do not act through ___. Inhibit ___ thrombin and ___ thrombin
___ - peptide from saliva gland of medicinal leach
- AT-III
- free
- fibrin bound
- Hirudin
Direct Thrombin Inhibitors
Lepirudin (Refludan)
- recombinant hirudin grown in yeast
- ___ protein (65 amino acids), given ___
- highly ___ direct inhibitor of thrombin ( ___ binding at active aite and exosite 1)
- inhibition of thrombin is ___
- ___ values increase dose-dependently
- can produce ___ reactions
- excreted via the ___
- treatment of ___
- small, IV
- specific, bivalent
- irreversible
- aPTT
- hypersensitivity
- kidney
- HIT
Direct Thrombin Inhibitors
Bivalirudin (Angiomax)
- ___ amino acid, synthetic peptide
- binds to the ___ site and ___ of thrombin
- Binding is ___ with ___ onset and ___ duration
- given ___ during percutaneous coronary angioplasty
- eliminated by ___ excretion
- t 1/2: ___
- low bleeding risk, doesn’t induce ___ formation
- 20
- catalytic, exosite I
- reversible, rapid, short
- IV
- renal
- 25 min
- antibody
Direct Thrombin Inhibitors
Argatroban
- derived from ___
- binds reversibly to the ___ site of thrombin
- does not require ___ for activity
- can ___ free and clot associated thrombin
- therapy monitored using ___
- given ___ , t1/2 ~40-50 min
- metabolized in liver (CYP ___ )
- approved treatment for ___ or coronary artery thrombosis in patients with ___
- ___ in PCI procedures
- L-arginine
- active
- anti-thrombin
- inhibit
- aPTT
- IV
- 3A4/5
- HIT, HIT
- prophylaxis
Orally administered direct thrombin inhibitor
dabigatran (Pradaxa)
- t1/2 = ___ - ___ hrs
- indicated for prevention of ___ and systemic ___ in patients with non-valvular ___
- eliminated by ___ excretion - avoid in cases of severe ___ impairment
- monitoring unnecessary
- anticoagulant activity reversed by ___ IV
- 12-14 hrs
- stroke, embolism, a-fib
- renal, renal
- idarucizumab (Praxbind)
Reversing the action of thrombin inhibitors
Idaruizumad (Praxbind)
- humanized monoclonal antibody that directly binds to ___ with ___ x greater affinity than thrombin
- does not bind other thrombin inhibitors such as ___ , ___ , or ___
- dabigatran, 350x
- hirudim, bivalirudin, argatroban
