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Pharm-Spring > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Anticoagulants

Categories

A
  1. Anticoagulants (↓ production of fibrin)
  2. Anti-platelet drugs (↓ plt aggregation/function)
  3. 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
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2
Q

“True” Anticoagulants

(List broad categories)

A
  1. Warfarin
  2. Heparin
  3. Low-molecular-weight heparins (LMWH)
  4. Xa Inhibitors
  5. Direct Thrombin Inhibitors
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3
Q

List LMWH Meds

A
  • Low-molecular-weight heparins (LMWHs)
    • Enoxaparin (Lovenox)
    • Daltaparin (Fragmin)
    • Fondaparinux (Arixtra)
    • Tinzaparin (Innohep)
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4
Q

Xa Inhibitors

Meds

A
  • Xa Inhibitors
    • Rivaroxaban (Xarelto)
    • Apixaban (Eliquis)
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5
Q

Direct Thrombin Inhibitors

Meds

A
  • Direct Thrombin Inhibitors
    • Lepirudin (Refludan)
    • Bilvarudin (Angiomax)
    • Argatroban
    • Dabigatran (Pradaxa)
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6
Q

Important physiologic factors that influence anti-coagulant pharmacology

A
  • 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
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7
Q

Warfarin

Uses

A
  • Currently used for long term thrombosis prophylaxis
    • DVT
    • A-fib
    • Prosthetic heart valves
    • Recurrent TIA/MI
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8
Q

Warfarin (Coumadin)

Action

A
  • 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
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9
Q

Warfarin

Pharmacokinetics

A
  • 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
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10
Q

Half-lives of Vitamin K-Dependent Clotting Factors

A
  • Factor 7 = 6-8 hrs
  • Factor 9 = 24 hrs
  • Factor 10 = 25-60 hrs
  • Factor 2 = 50-80 hrs
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11
Q

Lab test to monitor warfarin effectiveness & normal value

A
  • 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
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12
Q

Warfarin & pregnancy

A

Pregnancy category X, do not use if breast-feeding

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13
Q

Warfarin

Adverse Reactions

A
  • 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
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14
Q

Warfarin

Interactions

A
  • 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
    1. Alter protein binding (free fraction)
    2. Alter function of CYP enzyme
      • Acetaminophen ↑ r/f bleeding (?inhibits warfarin degradation)
      • Several anti-seizure meds induce CYP enzymes
    3. Alter synthesis or function of clotting factors and/or plts
      • Heparin, NSAIDS, ASA, clopidogrel, dipyridamole, etc.
    4. Alter absorption of warfarin
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15
Q

Warfarin

Reversal

A
  • 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
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16
Q

Unfractionated Heparin

A
  • 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
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17
Q

Heparin

Pk/Pd

A
  • 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
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18
Q

Heparin

Indications

A
  • Acute MI & stroke
  • Cardio-pulmonary bypass
  • DVT & DVT prevention
  • Dialysis
  • Disseminated intravascular coagulation (DIC)
  • PE
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19
Q

Heparin

Labs

A
  • 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
20
Q

Heparin

Adverse Effects

A
  • Hemorrhage
  • HIT (heparin induced thrombocytopenia)
    • 50% decrease in plt count <100,000 cells/mm3 w/ thrombosis
  • Osteoporosis
  • Hypersensitivity
    • Animal tissue extraction source
21
Q

Heparin

Reversal Agent

A
  • 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)
22
Q

Heparin-induced thrombocytopenia (HIT)

A
  1. Heparin binds to PF4 (plt factor 4)
  2. This exposes new surface of PF4 → antibodies against complex of heparin and pf4 (body does not recognize = immune response)
  3. The antibody binds the PF4/Heparin complex
  4. The Ab binds the Fc receptor on platelets
  5. This activates the platelet, releasing more PF4
  6. And activating thrombin → blood clots!
23
Q

Heparin

Contraindications & Cautions

A
  • 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
24
Q

Low Molecular Weight Heparins (all SQ)

Agents, Use, Efficacy

A
  • 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
25
Q

Low Molecular Weight Heparins (all SQ)

Pk

A
  • More predictable pharmacokinetics
    • Higher bioavailability
    • Longer E½t (up to 6X that of heparin)
    • No aPTT monitoring required
    • No hospitalization required
26
Q

Low Molecular Weight Heparins (all SQ)

Adverse Effects

A
  • Bleeding (lower risk compared w/ unfractionated heparin)
  • HIT
27
Q

Low Molecular Weight Heparins (all SQ)

Contraindications/Precautions

A
  • 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
28
Q

Fondaparinux (Arixtra) subQ

A
  • 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
29
Q

Fondaparinux (Arixtra)

Pk

A
  • 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)
30
Q

Fondaparinux (Arixtra)

Reversal

A

No reversal agent

31
Q

Fondaparinux (Arixtra)

Adverse Effects

A

HIT does not occur but thrombocytopenia does (3%)

32
Q

Fondaparinux (Arixtra)

Contraindications & Cautions

A
  • 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”)
33
Q

Direct Thrombin Inhibitors

Action

A
  • Directly bind thrombin at both catalytic and fibrinogen binding site
  • Useful in history of HIT
34
Q

Direct Thrombin Inhibitors

Agents

A
  • 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
35
Q

Dabigatran (Pradaxa)

Action, Use, Pk

A
  • 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
36
Q

Dabigatran (Pradaxa)

Labs/Surgery

A
  • 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
37
Q

Dabigatran (Pradaxa)

Adverse Effects

A
  • Bleeding (17% all types with 3% major bleed)
    • However warfarin > risk of life-threatening bleed
  • GI (35%)
    • Dyspepsia
    • Gastritis
38
Q

Dabigatran (Pradaxa)

Drug Interactions

A
  • P-glycoprotein inhibitors will increase drug levels of dabigatran
  • Ketoconazole, amiodarone, verapamil, quinidine
39
Q

Dabigatran (Pradaxa)

Reversal

A
  • 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
40
Q

Highly Selective Direct Factor Xa Inhibitor
Rivaroxaban (Xarelto)

Action, Use

A
  • 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
41
Q

Rivaroxaban (Xarelto)

Pk

A
  • Metabolized by CYP3A4 & Substrate for P-glycoprotein (interactions)
  • ~35% eliminated unchanged by kidneys
42
Q

Rivaroxaban (Xarelto)

Adverse Effects

A

Bleeding (potentially fatal) but lower risk compared with warfarin

43
Q

Rivaroxaban (Xarelto)

Contraindications

A

Renal, hepatic disease, major bleeding risk, etc.

44
Q

Rivaroxaban (Xarelto)

Reversal

A
  • Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo) for reversal on fast-track status
45
Q

Rivaroxaban (Xarelto)

Labs

A
  • No blood test reliably estimates effect
  • Hold 48 hrs preop; 5 days if high risk for bleed during surgery
46
Q

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 ______.

A

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.

Pharm-Spring (7 decks)

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