Anticoagulants Flashcards
What’s the common pathway for coagulation?
Extrinsic Pathway?
Intrinsic pathway?
Factor X with cofactor 5 –> Factor 2 aka thrombin –> Factor 1 aka fibrinogen –> Clot with factor 13 that helps crosslink
Tissue damage –> Factor 7 –> common pathway
XII –> XI –> IX with co factor 8 –> Common pathway
Drug Targets for the following?
1. warfarin and citrate (6)
2. Factor Xa inhibitors
3. direct Thrombin inhibs
4. Heparins and Heparinoids
- IX, X,7, II and Proteins S and C
- Factor X
- Factor 2
- Are ATIII so they indirectly inhib factors X and II
Direct Thrombin Inhibitors
1. Name 3
2. How is it administered?
3. Dosing?
4. type of elim?
5. Half life?
- Dabigatran , Bivalirudin , Argatroban
- Oral, IV, IV
- BID, Continuous IV, continuous IV
- renal, proteolytic, hepatic
- 12-17 hrs, 25 min, 40-50 min
Factor Xa inhibitors
- Name 3
- Admin?
- Dosing
- Elim?
- Half life?
- Rivaroxaban, Apixaban, edoxaban
- ALL ORAL
- Daily or BID, BID, Daily
- Hepatic, hepatic, renal AND hepatic
- 5-9 hrs, 12 hrs, 10-14 hrs (less effective when CRCL> 95)
Heparins & Heparinoids
- Antithrombin III
- Made by ___, circulates in ? - Weakly inhibs factors __ and __ by binding in ?
- Factor Xa not inhib when bound to ?
- Factor 2a not inhib when bound to?
- liver, blood
- 2 and 10 , 1:1 complex
- platelets
- fibrin
Unfractionated Heparin (UFH)
- What is it?
MOA 1?
MOA 2?
heterogenous mix of glycosaminoglycan chains
allosteric activation of ATIII
- specific 5 saccharide sequence required
-only present in about 1/3 of heparin molecules
Ternary complex formation with ATIII and thrombin
- min 18 saccharide chain length required
Heparin Induced Thrombocytopenia (HIT)
- Caused by ?
- Ab’s bind ___ and ___ on platelets
-Leads to ?
Heparins (UFH or LMWH)
heparin + platelet factor 4
platelet activation, consumption and thrombosis
UFH
1. Has ____ to other targets which is greater for ____
- what binding causes HIT?
- what is used as reversal agent?
- binding to what causes a variable response? requires?
- binding to ___ causes ___ w/prolonged use?
- high binding, larger molecules
platelets+PF4
Protamine
Plasma proteins , PTT monitoring
osteoblasts , osteopenia
UFH is cleared by ___ which is faster for ____
-___ and ____
-Shorter ___ than ____
- no need for ___
reticuloendothelial system , larger molecules
macrophages, endothelial cells
- half life, LMWH
- renal dose adjustments
LMWH : Name 2
- a more uniform mixture of?
-MOA?
- EXCEPTION : ?
- average ___ length, but most are too short to bind
-ratio of Xa : 2a inhibition is about?
-Less effect on ___; monitored with ___ instead?
Most chains are <18 sacchs, which is why there’s less ____ inhibition?
Enoxaparin, Dalteparin
depolymerized heparin
similar to heparin
DECR INHIBITION of THROMBIN
17 sacch
3:1
PTT, anti-Xa
thrombin
LMWH : Other properties
- Decr binding to other targets
Describes what happens in the following situations when bound: plasma proteins , platelets , protamine - renal clearance
- requires?
-Longer ___, allows for? - more uniform sequence
- more consistent ____ effect , less monitoring
- More consistent half life , less monitoring required
- lower incidence of HIT
- reversal is LESS EFFECTIVE - Renal dose adjustment
half life, q12/q24 hr dosing - Anticoag
Fondaparinux
- Synthetic _____
MOA : _____ only
- Does not inhib ___
-monitoring is similar to ____ with anti ___ NOT ___
- ___ clearance ?
-Longest ____
- Does not cause _____
-Not reversed by ____
5 saccharide analog (heparinoid)
factor Xa inhibition
thrombin
LMWH , Xa, PTT
renal
half life with q24h dosing
HIT
Protamine
Protein targets for Warfarin + Citrate? (5)
Factors 9, 10, 2, protein S&C, 7
What are the vitamin K dependent clotting factors?
produced as ____
Glutamic acid (Glu) is converted to ?
factors are now functional and localize to membranes via __
II, VII, IX, X, S, C
inactive proteins
Gamma-carboxyglutamic acid (Gla)
calcium
Why are they considered Vitamin K Dependent?
Gamma carboxylation requires vitamin K
- this reaction oxidizes vitamin K to vitamin K epoxide
vitamin K must be restored by VKOR or dietary intake
Warfarin MOA
- Inhibs?
- Depletes?
- Prevents synthesis of?
half lives of factors 7, C, IX, S, X, II?
- VKOR
- vitamin K
- functional clotting factors II, VII, IX, X, S, C
4-6 hrs, 8 hrs, 24 hrs, 30 hrs, 48 hrs, 72 hrs
Day 1 of Warfarin Initiation
- Describe what happens?
Day 2-4 what begins to rise?
- factor __ has shortest half life but greatest effect on ___
-patient is NOT ____ bc factors ____ remain
-patient MAY BE ___ bc protein __ and __ are depleted
Liver produces fewer active clotting factors (30-50% less)
Factors alrdy in circulation NOT AFFECTED by warfarin
INR
7, INR
Anticoagulated, 9,10, 2
hypercoagulable, c and s
Day 5 : ____Achieved
- factor __ has longest half life and may take longer to reach steady state
anti coagulation
II
Warfarin can also cause the following (7)
S, T, S, G, D, D, D
skin necrosis
teratogenicity
stereoisomers
genetics
drug-drug interactions
disease and population interactions
dietary interactions
Teratogenicity
Category ___, Categ D for mechanical heart valves
- In 1st trimester causes what?
-2nd or third trimester causes?
X
skeletal defects, nasal and limb hypoplasia
CNS and ophthalmic defects, hearing loss, heart disease, growth restriction, hemorrhage, death
Warfarin’s Stereoisomers : S and R
1. WHich is better at VKOR inhibition?
- Describe each isomer’s CYP metabolism
- S
- S –> CYP 2C9
R –> 3A4, 1A1, 1A2
Genetics :
VKORC1 variants lead to increased?
More common in ?
Reduce dose in this way for hetero vs homozygotes ?
CYP2C9*2 or *3 lead to ?
Reduce dose how?
warfarin sensitivity
asians>caucs>africans
hetero reduce dose 25%, homo reduce dose 50%
incr warf sensitivity
25% for hetero, 50% for homozygs
Drug interactions : state what happens to INR, Clinical risk, and Examples
- CYP inducers
- CYP inhibitors
- ANticoags and antiplatelets
- decr INR
incr clotting
carbamazepine, phenytoin, rifampin, phenobarb, chronic alcohol - incr INR
-incr bleeding
amiodarone, fluconazole, ACUTE alcohol - same INR
incr bleeding
aspirin, clopidogrel, LMWH,
Disease and Population Interactions
1. Name conditions that are warfarin sensitive (6)
- Conditions that make u warfarin resistant (2)
- Catabolic conditions such as acute illness or surgery, hyperthyroidism, decompensated heart failure
- liver disease
-malnourish
-low albumin
-elevated baseline INR
- low body weight - hypothyroidism
- high body weight
