Anticoagulants Flashcards
Anticoagulants
Categories
- Anticoagulants (↓ production of fibrin)
- Anti-platelet drugs (↓ plt aggregation/function)
- Thrombolytic drugs (promote clot lysis/fibinolysis)
- venous stasis issue/slow moving blood (a-fib, DVT’s) = anticoags help
- arterial issue/fast moving blood (atherosclerotic plaque rupture, MI, stroke) = antiplatelets help
“True” Anticoagulants
(List broad categories)
- Warfarin
- Heparin
- Low-molecular-weight heparins (LMWH)
- Xa Inhibitors
- Direct Thrombin Inhibitors
List LMWH Meds
- Low-molecular-weight heparins (LMWHs)
- Enoxaparin (Lovenox)
- Daltaparin (Fragmin)
- Fondaparinux (Arixtra)
- Tinzaparin (Innohep)
Xa Inhibitors
Meds
- Xa Inhibitors
- Rivaroxaban (Xarelto)
- Apixaban (Eliquis)
Direct Thrombin Inhibitors
Meds
- Direct Thrombin Inhibitors
- Lepirudin (Refludan)
- Bilvarudin (Angiomax)
- Argatroban
- Dabigatran (Pradaxa)
Important physiologic factors that influence anti-coagulant pharmacology
- Vitamin K is required for synthesis of factors: 2, 7, 9, 10
- Anti-thrombin prevents wide-spread coagulation by inhibiting: 2a (thrombin), 9a, 10a, 11a, 12a.
- Plasmin (inactive form = plasminogen) is enzyme that breaks down a fibrin enriched clot
Warfarin
Uses
- Currently used for long term thrombosis prophylaxis
- DVT
- A-fib
- Prosthetic heart valves
- Recurrent TIA/MI
Warfarin (Coumadin)
Action
- Inhibits vitamin K epoxide reductase complex I (VKORC1) preventing synthesis of active vitamin K
- ↓ production (30-50%) of Vitamin K dependent clotting factors:
- 2, 7, 9, 10
Warfarin
Pharmacokinetics
- Absorption~ 1-2 hrs, but effect dependent on depletion of clotting factors
- Stoelting “peak effect delayed 36-72 hrs”
- E½t = 24-36 hrs
- 97% protein bound
- Has a very narrow therapeutic index
- Dose can be as minimal as 0.5 mg a day to 25-30 mg a day
Half-lives of Vitamin K-Dependent Clotting Factors
- Factor 7 = 6-8 hrs
- Factor 9 = 24 hrs
- Factor 10 = 25-60 hrs
- Factor 2 = 50-80 hrs
Lab test to monitor warfarin effectiveness & normal value
- INR/PT
- Normal value for pt not on warfarin is 0.8-1.2
- Pts w/ DVT, A-fib, PE, and other clotting issues range is 2.0-3.0
Warfarin & pregnancy
Pregnancy category X, do not use if breast-feeding
Warfarin
Adverse Reactions
- Normally well tolerated
- Bleeding is major side effect
- Bruising, bloody nose, bleeding when brushing teeth common (normal and expected)
- Blood in urine and stool, pelvic pain, headache, dizziness, low BP and/or tachycardia require immediate medication attention
- Pt should wear medic alert bracelet
Warfarin
Interactions
- Foods that contain vit K antagonize effect of coumadin; key is consistent diet
- Many meds can interfere:
- Increase or decrease anticoag effects, bleeding/thrombosis risk
- Alter protein binding (free fraction)
- Alter function of CYP enzyme
- Acetaminophen ↑ r/f bleeding (?inhibits warfarin degradation)
- Several anti-seizure meds induce CYP enzymes
- Alter synthesis or function of clotting factors and/or plts
- Heparin, NSAIDS, ASA, clopidogrel, dipyridamole, etc.
- Alter absorption of warfarin
Warfarin
Reversal
- INRs that are elevated may require varying responses
- INRs that are slightly above range (less than 6.0) we recommend to hold 1-2 doses of warfarin
- If pts have higher INRs, or showing signs of bleeding it may be appropriate to reverse effect w/ Vitamin K
- Low doses; oral route
- SQ and IM is not recommended
- IV may be used in pts w/ absorption issues
Unfractionated Heparin
- Highly sulfated glycosaminoglycans
- Potency varies always prescribed in units
- 1 unit heparin: volume of heparin solution that will prevent 1 mL of citrated sheep blood from clotting for 1 hr after addition of 0.2 ml of 1:100 calcium chloride
Heparin
Pk/Pd
- Variable PK/PD: 4X variation dose:response/ 3X variation in metabolism rate
- Baseline antithrombin activity can influence pt response
- Temp dependent (more active at higher body temps)
-
Highly polar (negatively charged) and large MW (3000-30,000 Da/ does not cross biologic membranes
- IV/SQ only
- Good choice in pregnancy and breast feeding
- Protein Binding: A lot of non-specific binding = variable free drug/unpredictable dose response
- Onset: fast, several min IV (SQ onset 1-2 hrs)
- E½t ~ 1 hr
- Precise mechanism of clearance/metabolism unclear…
- hepatic metabolism, renal excretion
Heparin
Indications
- Acute MI & stroke
- Cardio-pulmonary bypass
- DVT & DVT prevention
- Dialysis
- Disseminated intravascular coagulation (DIC)
- PE
Heparin
Labs
- Activated Partial Thromboplastin Time (aPTT)
- Typical goal: 1.5-2X normal (30-35 seconds)
- Activated clotting time (ACT) used with high dose (CPB)
- Baseline, 3-5 min after heparin, every 30 min
Heparin
Adverse Effects
- Hemorrhage
- HIT (heparin induced thrombocytopenia)
- 50% decrease in plt count <100,000 cells/mm3 w/ thrombosis
- Osteoporosis
- Hypersensitivity
- Animal tissue extraction source
Heparin
Reversal Agent
-
Reversal agent: Protamine
- Alkaline and + charged (heparin acidic and – charged)
- DOA: 2 hrs (may need a redose)
- 1 mg protamine per 100 units heparin (give slowly (over 10-15 min)! And consider how much heparin has been metabolized at time of reversal)
Heparin-induced thrombocytopenia (HIT)
- Heparin binds to PF4 (plt factor 4)
- This exposes new surface of PF4 → antibodies against complex of heparin and pf4 (body does not recognize = immune response)
- The antibody binds the PF4/Heparin complex
- The Ab binds the Fc receptor on platelets
- This activates the platelet, releasing more PF4
- And activating thrombin → blood clots!
Heparin
Contraindications & Cautions
- Liver or kidney disease
- Indwelling epidural catheter
- Traumatic placement of epidural or spinal anesthetic
- Other anti-platelet or anti-coag meds
- Peri-surgical: eye, brain, spinal cord
- Pts at high r/f bleeding:
- GI bleed risk (PUD), hemophilia, aneurysm, severe HTN, thrombocytopenia
Low Molecular Weight Heparins (all SQ)
Agents, Use, Efficacy
-
Enoxaparin (Lovenox)
- Dalteparin (Fragmin)
- Tinzaparin (Innohep)
- 1st line therapy for DVT prophylaxis and tx
- Also used in unstable angina/MI/coronary ischemia
- Equal efficacy compared w/ heparin
- Same 5 sugar sequence inactivates 10a
- Not as effective in inactivating thrombin
Low Molecular Weight Heparins (all SQ)
Pk
- More predictable pharmacokinetics
- Higher bioavailability
- Longer E½t (up to 6X that of heparin)
- No aPTT monitoring required
- No hospitalization required
Low Molecular Weight Heparins (all SQ)
Adverse Effects
- Bleeding (lower risk compared w/ unfractionated heparin)
- HIT
Low Molecular Weight Heparins (all SQ)
Contraindications/Precautions
- Effect greatly prolonged in renal failure use unfractionated heparin instead
- Spinal or epidural anesthesia (wait at least 24 hrs)
- Anti-plt or anti-coagulant drugs
- Delay surgery 12 hrs after last dose
Fondaparinux (Arixtra) subQ
- Exclusively inactivates 10a by enhancing antithrombin III activity (no direct effect on thrombin activity)
- Chemically identical to the 5 sugar active site of heparin and LMWH
- Much smaller than heparin and LMWH
Fondaparinux (Arixtra)
Pk
- Half-life is over 3x as long as LMWH
- E½t = 15 hrs
- Effect onset 2 hrs/effect lasts 2-4 days after last dose
- Eliminated unchanged by kidneys (not good for renal pts)
Fondaparinux (Arixtra)
Reversal
No reversal agent
Fondaparinux (Arixtra)
Adverse Effects
HIT does not occur but thrombocytopenia does (3%)
Fondaparinux (Arixtra)
Contraindications & Cautions
-
Contraindications (excessive risk of bleeding):
- Severe Renal Impairment (CrCl < 30 mL/min)
- Weight < 50kg for pts undergoing hip fracture, hip replacement surgery, or knee replacement surgery
-
Caution:
- Elderly pts
- CrCl (30-50 mL/min)
- Epidural or spinal anesthesia (“very hesitant unless this has been stopped at least 4-5 half lives”)
Direct Thrombin Inhibitors
Action
- Directly bind thrombin at both catalytic and fibrinogen binding site
- Useful in history of HIT
Direct Thrombin Inhibitors
Agents
- Dabigatran (Pradaxa): PO
- Desirudin: SQ
- Approved for DVT prevention in elective hip replacement
- Lepirudin (Refludan): IV infusion only
- Approved for thrombus prevention in HIT
- Argatroban: IV infusion only
- Approved for thrombus prevention in HIT
- Bilvarudin (Angiomax): IV infusion only
- Used w/ ASA in coronary angioplasty for thrombus prevention
- E1/2t = 25 min
Dabigatran (Pradaxa)
Action, Use, Pk
- Pro-drug: binds and reversibly inhibits circulating thrombin and clot integrated thrombin
- Indicated for A-fib, DVT, PE
- Rapid onset
- E½t = 13 hrs
- Not significantly metabolized by hepatic enzymes
- Primarily cleared by kidneys
- Encourage fluid intake
Dabigatran (Pradaxa)
Labs/Surgery
- Stop 48 hrs before surgery w/ normal renal function/Stop 72-96 hrs before surgery if abnormal renal function; 5 days if high risk for bleed during surgery
- Effect measured by thrombin times TT (best) or aPTT
Dabigatran (Pradaxa)
Adverse Effects
- Bleeding (17% all types with 3% major bleed)
- However warfarin > risk of life-threatening bleed
- GI (35%)
- Dyspepsia
- Gastritis
Dabigatran (Pradaxa)
Drug Interactions
- P-glycoprotein inhibitors will increase drug levels of dabigatran
- Ketoconazole, amiodarone, verapamil, quinidine
Dabigatran (Pradaxa)
Reversal
-
Praxbind® (idarucizumab) humanized monoclonal antibody fragment (Fab)
- Binds to dabigatran and metabolites w/ higher affinity than binding affinity of dabigatran to thrombin = neutralize anticoag effect immediately after admin
Highly Selective Direct Factor Xa Inhibitor
Rivaroxaban (Xarelto)
Action, Use
- Can inhibit free Factor Xa or bound Xa (heparins only bind free)
- Marketed for use in hip and knee replacement surgery as DVT/PE prophylaxis & approved in Afib
Rivaroxaban (Xarelto)
Pk
- Metabolized by CYP3A4 & Substrate for P-glycoprotein (interactions)
- ~35% eliminated unchanged by kidneys
Rivaroxaban (Xarelto)
Adverse Effects
Bleeding (potentially fatal) but lower risk compared with warfarin
Rivaroxaban (Xarelto)
Contraindications
Renal, hepatic disease, major bleeding risk, etc.
Rivaroxaban (Xarelto)
Reversal
- Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo) for reversal on fast-track status
Rivaroxaban (Xarelto)
Labs
- No blood test reliably estimates effect
- Hold 48 hrs preop; 5 days if high risk for bleed during surgery
For new direct oral anticoags, ASRA guidelines for both regional anesthesia and pain recommended interval of _______ of drug before regional or pain intervention. For resumption of drug after neuraxial procedure, ASRA regional guidelines recommended _____, whereas pain guidelines recommended ______.
For new direct oral anticoags, ASRA guidelines for both regional anesthesia and pain recommended interval of 5 half-lives of drug before regional or pain intervention. For resumption of drug after neuraxial procedure, ASRA regional guidelines recommended 6 hrs, whereas pain guidelines recommended 24 hrs.
