Anticoagulants

Front 1

Aspirin

Back 1

• Irreversible COX-1 Blocker → ↓ TXA2 → ↓ plt aggregation ↓ vasoconstriction
• @ low dose – selectively inhibits Platelet COX
• Use: arterial thrombi
• Long duration, primary and secondary prevention of MI & stroke
o Block plt activation → block release of ADP, serontonin, TXA2
• Adverse Effects:
o ↑ risk of GI bleeding & hemorrhagic stroke

Front 2

Abciximab

Back 2

• Glycoprotein 2B/3A inhibitors (GPI)
• Bind to receptor and prevent binding of glycoproteins (vWF, fibrinogen) to platelet surface
• Use:
o Patients with ischemic heart Dz
o Before PCI or thrombolysis
o Acute coronary syndrome
• Administration: IV
• Adverse Effects:
o Bleeding
o Thrombocytopenia
o Anaphylaxis

Front 3

Alteplase

Back 3

• Recombinant tPA (fibrinolytic)
• Requires fibrin for activity – more site specific, less lytic state (bad pathway)
• Administration: IV/IC infusion
• Use: approved for acute ischemic stroke (must rule out hemorrhagic stroke), Acute MI, Alternative to PCI (aka angioplasty), Pulmoanry embolism, DVT
o Administration: IV; use before 3 hours (fibrin aging)
• Adverse Effects:
o Bleeding
o Arrhythmias (reperfusion injury)

Front 4

Aminocaproic Acid

Back 4

• Hemostatic – binds reversibly to plasminogen → blocks the binding of plasminogen to fibrin → prevent activation and tranformation to plasmin
• Enhances hemostasis when fibrinolysis contributes to bleeding
• Contraindicated in patients with DIC

Front 5

Argatroban

Back 5

• Direct Thrombin Inhibitor (DTI
• DTIs do not require antithrombin, and can inhibit clot bound thrombin (heparin cannot do this)
• Use: antidote for HIT
• Administration: IV to achieve APTT ratio of 1.5-2.5
o Short t1/2 = 45 min
• Elimination: Hepatic metabolism
• No effective antidote

Front 6

Bivalirudin

Back 6

• Direct thrombin inhibitor (DTI)
• Reversible
• Mechanism: same as Lepirudin & Argatroban, but different use:
o Inactivates plt bound Xa and clot bound bound thrombin
• Use:
o NOT used for HIT
o Used as an alternative to heparin in patients with ACS & MI → better than heparin under these conditions
o Unstable angina undergoing PCI
o As effective as UFH, but safer for anticoagulation during PCI
• Monitor: Activating clotting time or APTT
• T1/2 = 25 min; ↓ dose in patients with renal impairment
• Adverse Effects:
o Bleeding (less than heparin)

Front 7

Clopidogrel & Prasugrel

Back 7

• Irreversibly blocks purinergic receptor (P2Y12) for ADP (blocks ADP receptor)
• ADP released from one Plt → activate another Plt
• Prodrug – activates by Cyp2C19
o Polymorphisms - ↓ effectiveness of this drug
o This is why Prasugrel – still a prodrug, but activated in different pathway
• Onset: 2-3 days (not used for acute treatment) – aspirin is drug of choice for acute treatment
• Max effect: takes 4-7 days
• Irreversible – takes ~5 days for plt function to return (same as aspirin)
• Indications:
o Prophylaxis before and after PCI in combo with aspirin
o Acute coronary syndrome (ACS)
o Post-MI/stroke prophylaxis
o Preven transient ischemic attacks (TIA)- stroke history
• Adverse Effects:
o Stop use before CABG to minimize risk of bleeding
o Bleeding risk

Front 8

Drug Interactions of Clopidogrel:

Back 8

o Other drugs that cause bleeding
o Omeprazole (proton pump inhibitor) → inhibits Cyp2C19 → ↓ clopidogrel effectiveness (↓ activation)

Front 9

Dipyridamole

Back 9

• Mechanism: inhibit PDE → ↑ cAMP & block uptake of adenosine (which acts at A2 receptor for adenosine to stimulate platelet adenylyl cyclase – this raising plt cAMP (SUGGESTED MECHANISMS)
• Indications: combo with low dose aspirin → stroke prevention
• Adverse Effects:
o headache

Front 10

Enoxaparinux (LMWH)

Back 10

• Most widely used LMWH
• ~50-75% is too short to inhibit thrombin, so are more selective for Factor Xa than UFH (4x more Xa inhibition than thrombin) - (less likely to cause significant bleeding)
• Administration: IV or subcutaneous (90% Bioavailability)
o CAN use in out patient setting (benefit over UFH)
o Prophylaxis in moderate/high risk patients
o Venous thromboembolism or unstable angina
• Elimination: Renal (t1/2 = 3-6 hours SC injection)
• Monitoring:
o aPTT – may be used, but not required
• Factor Xa titration
• Adverse Effects:
o Less major bleeding compared to IV UFH (one of benefits)
o Less likely to cause osteoporosis
o Less likely to cause HIT

Front 11

Eptifibatide

Back 11

• Glycoprotein 2B/3A inhibitors (GPI)
• Bind to receptor and prevent binding of glycoproteins (vWF, fibrinogen) to platelet surface
• Use:
o Patients with ischemic heart Dz
o Before PCI or thrombolysis
o Acute coronary syndrome
• Administration: IV
• Adverse Effects:
o Bleeding

Front 12

Fondaparinux
(synthetic pentasaccharide heparin)

Back 12

• Synthetic pentasaccharide binding sequence
• Factor Xa inhibitor
• Actions: Effective both in vivo and in vitro (extracorporeal circulation), Arrests thrombosis and prevents embolization, especially on the venous side of the circulation
• Inhibits factor Xa only, b/c too short to wrap around thrombin – exclusively selective for Factor Xa (less likely to cause significant bleeding)
• Administration: IV or subcutaneous (100% bioavailability)
o Can use in out patient setting (benefit over UFH)
• Elimination: Renal (t1/2 = 17-21 hours – one dose daily) – renal failure caution
• CAN use in out patient setting
• Adverse Effects:
o Less major bleeding compared to IV UFH (one of benefits)
o Less likely to cause osteoporosis
o Not associated with HIT

Front 13

Heparin (UFH)

Back 13

• Isolated from animal source
• Variable MW, Standardized units (not given in mg), GAG (1/3 has pentasaccharide sequence, other 2/3 does not - so is inactive)
• Administration: Subcutaneous (not IV)
• Uses:
o Clot in venous system
o Unstable angina
o NOT used in outpatient setting
• Mechanism: enhances antithrombin →
o inhibit coagulation proteases (esp. thrombin (2), Xa) &
o enhances TFPI (tissue factor pathway inhibitor - inhibits functions of Va & Xa)
• Elimination: Non-linear response due to dose dependence
o Cleared low dose quickly by endothelial cell & Macrophages
o Binds plasma protein (CRP) → inactive
• CRP ↑ in a lot of these patients
o Saturate these and non-saturable renal clearance takes over
o T1/2 ~ 0.5-3 hours
• Monitoring:
o aPTT – most common
o Factor Xa titration – most accurate

Front 14

Adverse Effects of Heparin:

Back 14

o Major bleeding compared to IV UFH (<3%)
o Osteoporosis w/ prolonged use – usually switch to warfarin for long-term use, but cannot give warfarin if preggers
o HIT (usually 5-10 days following drug initiation or in 24 hours is previously exposed to heparin)
• ↑ risk of clotting → DVT, DIC, thromboembolism, MI, stroke

Front 15

Lepirudin

Back 15

• Direct Thrombin Inhibitor (DTI); anticoagulant derived from leaches
• DTIs do not require antithrombin, and can inhibit clot bound thrombin (heparin cannot do this)
• Use: antidote for HIT
• Administration: IV to achieve APTT ratio of 1.5-2.5
o Short t1/2 = 1.3 h
• Elimination: renal excretion
• No effective antidote

Front 16

Phytonadione (Vitamin K)

Back 16

• Oral vitamin K
• Long duration – can complicate reestablishment of warfarin therapy
• Use: warfarin toxicity

Front 17

Protamine

Back 17

• Antidote for Heparin OD
• Basic protein (+ charge)
• UFH: Combines with UFH to form stable salt – neutralizes UFH
• LMWH: Neutralizes anti-thrombin activity, but only partially reverses the anti-Xa activity (b/c of small size)
• Fondaparinux: Does not reverse Fondaparinux
• Adverse Effects
o Over neutralization may lead to bleeding b/c protamine is a weak anticoagulant
o Anaphylactoid reaction possible – infuse slowly

Front 18

Reteplase

Back 18

• Fibrinolytic
• Nonglycoslyated mutant of wild-type tPA
• Longer half-life and faster onset and better penetration of clot than alteplase
o Administration: Bolus 2X - more beneficial for small hospitals or for use until PCI is available
• Use: Acute MI, Alternative to PCI (aka angioplasty), Pulmoanry embolism, DVT
o Administration: IV; use before 3 hours (fibrin aging)
• Adverse Effects:
o Bleeding
o Arrhythmias (reperfusion injury)

Front 19

Streptokinase

Back 19

• Fibrinolytic (thrombolytic)
• Mechanism: binds to plasminogen converting other plasminogen molecules to plasmin
• Administration: IV/IC infusion
• Use: Acute MI, Alternative to PCI (aka angioplasty), Pulmoanry embolism, DVT
• Adverse Effects:
o May have immune reaction, fever
o Bleeding
o Arrhythmias (reperfusion injury)

Front 20

Tenecteplase

Back 20

• Fibrinolytic
• Advantages:
o Slight mutation form mutant tPA → longer t1/2 and ↑ fibrin selectivity and resistance to plasminogen activator inhibitor (PAI-1)
o Less non-intracranial major bleeding than accelerated tPA
o Administration: Single bolus - more beneficial for small hospitals or for use until PCI is available
o Use: Acute MI, Alternative to PCI (aka angioplasty), Pulmoanry embolism, DVT
• Administration: IV; use before 3 hours (fibrin aging)
o Adverse Effects:
• Bleeding
• Arrhythmias (reperfusion injury)

Front 21

Warfarin (Coumadin)

Back 21

• Oral anticoagulant; patenteral available also
• Mechaninsm: Vit. K analog that competitive antagonist of the production of Factors 2, 7, 9, 10, and Protein C & S by the liver (→ ↓ gamma carboxy Glu)
• Enatiomeric mixture:
o S-warfarin – more active, metabolized by Cyp2C9, drug interactions
o R-warfarin – less potent, Cyp1A2 and Cyp3A4
• Latent Period
o 8-12 hrs for onset; 2-3 days for effect (coag factors already made); 2-5 days duration of action (to make new coag factors)
• Elimination: t1/2 ~ 40hrs; hepatic metabolism
o Initial ↑ in INR not accurate b/c of short t1/2 (~5 hrs) of factor 7 – takes to get proper anticoagulation b/c factors 2 and 10 have longer t1/2
o Protein C – short t1/2 (8 hrs) → if you ↓ too quickly – can cause recurrent skin necrosis
• Monitoring: INR (normalized PT)

Front 22

Adverse Effects of Warfarin:

Back 22

o Bleeding
• Risk factors: history or GI bleeding, age (> 60), previous stroke, A-fib, hepatic dysfunction, HTN
o Recurrent skin necrosis → Do NOT use as bolus, can cause rapid ↓ in protein C → microthrombi → ischemia → skin necrosis
o Birth defects in 1st trimester – do not use in pregnant women

Front 23

Virchow’s Triad:

Back 23

1. Endothelial Injury
2. Hypercoaguability
3. Abnormal Blood Flow

Front 24

Treatment of Heparin Overdose:

Back 24

• UFH –
o withdrawal of drug often sufficient (short T1/2)
o Give Protamine
• Transfusions are not effective to antagonize UFH
• Warfarin not substituted for UFH in HIT b/c it is associated with venous limb gangrene or multicentric skin necrosis → you can switch to warfarin after HIT is resolved, but not during HIT episode

Front 25

Warfarin Drug interactions:

Back 25

• Inhibit Cyp enzymes → ↓ Elimination → ↑ [ ] of drug
a. Fluconazole (antifungal) – inhibits S-enantiomer of warfarin
b. Amiodarone (Class 3 antiarrhythmic) – both enantiomers
c. Omeprazole (proton pump inhibitor) – blocks R-enantiomer, probable but not as significant
• Cholestyramine → ↓ intestinal absorption
• Induction of Cyps: Barbituates → ↑ elimination of drug → ↓ concentration
• Vitamin K interaction – insufficient or excess presence

Front 26

Genetic Polymorphisms effecting Warfarin

Back 26

a. Cyp2C9 – slow metabolizers of S-warfarin → ↑ sensitivity
b. VKORC1 – polymorphisms in warfarin receptor → ↑ sensitivity

Front 27

Factors involved in a patient’s response to oral anticoagulation:

Back 27

a. Vit K levels (too much or too little) – diet, fat malabsorption
b. Liver Dz (↓ metabolism)
c. CHF → hepatic congestion
d. Infection - ↑ sensitivity to warfarin
e. Following surgery - ↑ sensitivity to warfarin
f. Hypermetabolism (fever, hyperthyroidism) - ↑ sensitivity to warfarin, probably due to ↑ catabolism of vit. K dependent clotting factors. (hypothyroidism ↓ sensitivity)
g. Drug interactions
h. Genetic polymorphisms

Front 28

Treatment of Overdose of warfarin

Back 28

• Prothrombin complex concentrates – FFP, recombinant 7a
o Can use for warfarin OD, but not heparin
• Oral vitamin K (phytonadione) – antagonize warfarin – may complicate the reestablishment of warfarin b/c long duration of action

Front 29

Treatment of DVT

Back 29

1. Objectively confirm DVT
2. Short-term treatment with:
a. SC LMWH
b. IV UFH
c. Monitored SC UFH
d. Fixed-does SC UFH
e. SC fondaparinux
3. Continue parenteral therapy for 5 days or until INR (> 2) is stable for 24 hours – b/c initial change in PT does not indicate adequate anticoagulation
4. In patients with DVT – initiation of Vit. K antagonist together with one of the above drugs is recommended on the same day.