Anticoagulants Flashcards by Alexis A

Q

Anticoagulants

Categories

A

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

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Q

“True” Anticoagulants

(List broad categories)

A

Warfarin
Heparin
Low-molecular-weight heparins (LMWH)
Xa Inhibitors
Direct Thrombin Inhibitors

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Q

List LMWH Meds

A

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

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Q

Xa Inhibitors

Meds

A

Xa Inhibitors
- Rivaroxaban (Xarelto)
- Apixaban (Eliquis)

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Q

Direct Thrombin Inhibitors

Meds

A

Direct Thrombin Inhibitors
- Lepirudin (Refludan)
- Bilvarudin (Angiomax)
- Argatroban
- Dabigatran (Pradaxa)

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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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Q

Warfarin

Uses

A

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

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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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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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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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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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Q

Warfarin & pregnancy

A

Pregnancy category X, do not use if breast-feeding

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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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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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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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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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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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Q

Heparin

Indications

A

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

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Q

Heparin

Labs

Study These Flashcards

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

Q

Heparin

Adverse Effects

Study These Flashcards

A

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

Q

Heparin

Reversal Agent

Study These Flashcards

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)

Q

Heparin-induced thrombocytopenia (HIT)

Study These Flashcards

A

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!

Q

Heparin

Contraindications & Cautions

Study These Flashcards

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

Q

Low Molecular Weight Heparins (all SQ)

Agents, Use, Efficacy

Study These Flashcards

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

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_**.