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Pharmacology Of Anticoagulants Flashcards

1
Q

Steps in hemostasis (4)

A
  1. Vessel injury
  2. Vessel spasm
  3. Platelets adhere to injury site and aggregate to form plug
  4. Formation of insoluble fibrin strands and coagulation
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2
Q

General MOA of antiplatelet agents, anticoagulants, thrombolytics/fibrinolytics

A

Antiplatelet agents: prevent platelet aggregation
Anticoagulants: interfere with the clotting cascade
Thrombolytics/fibrinolytics: clot-dissolving agents

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3
Q

What are the 2 substances that are responsible for platelet aggregation?

A
  1. Thromboxane (TxA2)

2. ADP

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4
Q

Steps of platelet activation (3)

A
  1. Attached platelets activate
  2. Release substances to stimulate the attachment of other platelets
  3. Platelets attach to one another using the GPIIb-IIIa receptors
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5
Q

Platelet inhibitor agents and their general MOA (3)

A
  1. Aspirin: blocks formation of TxA2
  2. ADP receptor antagonists: Blocks ADP receptors on platelets
  3. Glycoprotein IIb-IIIa receptor antagonists (GP IIb/IIIa): Blocks the receptors used for platelet aggregation
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6
Q

Aspirin (MOA, PK, Pregnancy category, Indications)

A

MOA: Irreversibly inhibits COX-1 and COX-2 in platelets and inhibits the production of TxA2, a potent platelets aggregator

PK: Half-life of 20-30 minutes for aspirin and 6 hours for salicylic acid (active metabolite)

Pregnancy category: D

Indications: Thromboembolic disorder, OA, RA, fever, pain, prophylaxis of stroke and MI

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7
Q

Aspirin (ADRs [2 common/3 serious] and Considerations)

A

Common ADRs:

  1. GI disturbance
  2. Tinnitus

Serious ADRs:

  1. GI ulcer
  2. Hemorrhage
  3. Reye’s syndrome (rare progressive encephalopathy usually seen in children recovering from a viral infection that was treated with aspirin)

Considerations: 81 mg minimum but no more than 325 mg to prevent thrombi, MI, or stroke. Avoid use with other anticoagulants unless provider-approved. Irreversible effects means platelet inhibition may last up to 1 week. Allergic reactions/hypersensitivity. Possible Reye’s syndrome in children/teens with chickenpox or flu symptoms.

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8
Q

ADP Receptor Antagonists [Clopidogrel, Prasugrel, Ticagrelor] (MOA, PK, Pregnancy category, Indications)

A

MOA: Irreversibly inhibits the ADP receptor on the surface of platelets that is necessary for platelet aggregation. Used to prevent thrombotic events. Ticagrelor has a reversible agent.

PK: Prasugrel - half-life of 7-8 hours

Pregnancy category: B

Indications: Used to prevent thrombotic events in patients with acute coronary syndromes (unstable angina), and those at high risk for stroke, clots, and MI

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9
Q

ADP Receptor Antagonists [Clopidogrel, Prasugrel, Ticagrelor] (ADRs [2 common/1 serious] and Considerations)

A

Common ADRs:

  1. Hemorrhage
  2. Easy bruising

Serious ADRs:
1. GI hemorrhage

Considerations: Reversal agent for Ticagrelor in clinical trials. Currently no reversal agent and resultant platelet inhibition lasts for the lifespan of the platelet (7-9 days). Clopidogrel and Prasugrel are prodrugs that must be activated by 2 liver reactions, including CYP2C19. Omeprazole is a potent CYP2C19 inhibitor.

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10
Q

Advantage of using Ticagrelor over Clopidogrel?

A

Ticagrelor is not metabolized in the liver and is much less likely to have DDIs. Clopidogrel is metabolized in the liver by CYP2C19, which can be inhibited by omeprazole, a common PPI used for GERD.

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11
Q

GP IIb/IIIa Receptor Antagonists [Abciximab, Eptifibatide, Tirofiban] (MOA, PK, Pregnancy category, Indications)

A

MOA: Blocks the GP IIb/IIIa receptor that is necessary for platelet aggregation. Most potent platelet inhibitors.

PK: All administered IV

Pregnancy category: B

Indications: Used for patients with recent MI, stroke, or PCI

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12
Q

GP IIb/IIIa Receptor Antagonists [Abciximab, Eptifibatide, Tirofiban] (ADRs [1 common/1 serious/ and Considerations)

A

Common ADRs:
1. Hemorrhage

Serious ADRs:
1. Thrombocytopenia

Considerations: Major and minor events have occured; increased risk with a history of bleeding disorders, and concomitant use with drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, NSAIDs)

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13
Q

Why are GP IIb/IIIa Receptor Antagonists so efficacious?

A

Platelets have multiple GP IIb/IIIa receptors along their surface and creating an agent that blocks them all produces a very strong inhibitory effect against aggregation; prevents bridging between adjacent platelet since fibrinogen is not able to bind.

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14
Q

Anticoagulant agents [Inhibitors of the blood clotting cascade] (4)

A
  1. Heparin
  2. Factor Xa Inhibitors
  3. Direct thrombin inhibitors
  4. Warfarin
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15
Q

Primary use of anticoagulants?

A

To prevent formation of clots in veins to treat thromboembolic disorders

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16
Q

Heparin (General and Commercial Preparations)

A

General: Sulfated mucopolysaccharide. Negatively charges, acidic. Found in the secretory granules of mast cells.

Commercial preparations: Unfractionated (HMW) - bovine lung and porcine gut (5-30 kDa). LMW Heparin (Enoxaparin) - gel filtration (1-5 kDa). Fondaparinux - synthetic pentasaccharide.

17
Q

Heparin (General MOA)

A

MOA: Enhances the actions of the protease Anti-thrombin III, which inactivates Factor X and thrombin. Heparin acts as a co-factor. Heparin increases the inactivation reaction rate by 1000x.

Different heparins have differing anticoagulant actions!

18
Q

Unfractionated heparin [HMW] (MOA)

A

MOA: Binds to anti-thrombin III and thrombin unit for inactivation. Also binds to anti-thrombin III via pentasaccharide (sufficient to inactivate Xa). Effectively catalyzes the inactivation of both Thrombin and Factor Xa.

19
Q

Low molecular weight heparin [LMW - Enoxaparin] (MOA)

A

MOA: Binds to anti-thrombin III without binding to thrombin (poorly inactivates thrombin). Also binds to anti-thrombin III via pentasaccharide (sufficient to inactivate Xa). Increases inactivation of Factor Xa, less effect on thrombin.

20
Q

Heparin [Fondaparinux] (MOA)

A

MOA: No effect on thrombin. Binds to anti-thrombin III via pentasaccharide (sufficient to inactivate Xa).

21
Q

Unfractionated heparin [HMW] (Considerations)

A

Considerations/Drawbacks: Unpredictable response. Short half-life. May cause HIT (heparin-induced thrombocytopenia). May cause unwanted bleeding.

22
Q

Low molecular weight heparin [LMW - Enoxaparin] (Considerations)

A

Considerations: Enoxaparin (Lovenox) is a shorter heparin molecule. More predictable response. No lab monitoring required. Longer half-life. Less risk for HIT. Still may cause unwanted bleeding.

23
Q

Heparin ADRs (3)

A

ADRs:

  1. Generally well tolerated
  2. Major concern is unwanted bleeding
  3. HIT (Heparin-induced thrombocytopenia): 1-4% of patients treated with UFH (unfractionated heparin) for 7 days, autoimmune activation and destruction of platelets, could also cause thrombotic disorder.
24
Q

Treatment of Heparin ADRs (2)

A
  1. For unwanted bleeding: Stop heparin, effects reverse in several hours; give protamine sulfate (used to reverse the effects of heparin, give IV 1 mg for every 100 U of heparin, also works against LMW heparins)
  2. For HIT: Stop heparin. Replace with a direct thrombin inhibitor.
25
Factor Xa Inhibitors [Rivaroxaban, Apixaban] (MOA, PK, Pregnancy category, Indications)
MOA: Inhibitor of Factor Xa PK: Rivaroxaban half-life 5-11 hours. Apixaban half-life 6-12 hours. Pregnancy category: C Indications: Treatment or prophylaxis for DVT
26
Factor Xa Inhibitors [Rivaroxaban, Apixaban] (ADRs [2 common/1 serious] and Considerations)
Common ADRs 1. Hemorrhage 2. Easy bruising Serious ADRs 1. GI hemorrhage Considerations: Given as fixed dose and no monitoring required. More rapid onset and shorter half-life than warfarin. Andexanet alfa (Andexxa) approved as reversal agent for Xa inhibitors in 2018. No dietary restrictions.
27
Direct Thrombin Inhibitors [Argatroban, Dabigatran] (MOA, Indications, ADRs [4])
MOA: Inhibits the actions of thrombin by blocking its activation site. Other agents like Lepirudin also block the substrate recognition site. No effect on Factor Xa. Indications: PCI clot prevention, DVT prevention, and HIT. Pradaxa is used orally to prevent stroke in patients with atrial fibrillation. ADRs: 1. Hemorrhage 2. Nausea 3. Fever 4. Hepatic impairment
28
Warfarin (General, MOA, PK, Pregnancy category, Indications)
General: Form of 4-hydroxycoumarin (Vitamin K antagonist). MOA: Inhibits liver Vitamin K reductase. Inhibits the regeneration of Vitamin K, an essential cofactor for synthesis of clotting factors in the liver, factors II, VIII, IX, and X. PK: Half-life is 1 week. Pregnancy category: X and D for patients with mechanical heart valve. Indications: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE). Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.
29
Warfarin (ADRs [1 common/1 serious/BBW] and Considerations)
Common ADRs: 1. Hemorrhage Serious ADRs: 1. GI hemorrhage Black Box Warning: Can cause major or fatal bleeding. Regular monitoring of INR should be performed on all treated patients. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin therapy. Considerations: Avoid aspirin during treatment. Monitored by PT-INR. Highly protein-bound, interacts with many medications (ASA, NSAIDs). CYP metabolized; caution with CYP inducers or inhibitors. Avoid foods high in Vitamin K (collard greens, kale, spinach).
30
Drugs that diminish warfarin’s anticoagulant effects (decreased INR) [3]
1. Cholestyramine: inhibits warfarin absorption in the GI tract 2. Barbiturates, carbamazepine, phenytoin, rifampin: Accelerate warfarin metabolism by inducing hepatic P450 enzymes 3. Vitamin K (reduced): Bypasses warfarin’s inhibition of epoxide reductase
31
Drugs that enhance warfarin’s anticoagulant effects (increased INR) [4]
1. Chloral hydrate: Displace warfarin from plasma albumin 2. Amiodarone, clopidogrel, ethanol, fluconazole, fluoxetine, metronidazole, sulfamethoxazole: Decrease warfarin metabolism by inhibiting hepatic P450 enzymes 3. Broad-spectrum antibiotics: Eliminate gut bacteria and thereby reduce availability of vitamin K and GI tract 4. Anabolic steroids (testosterone): Inhibit synthesis and increase degradation of coagulation factors
32
Warfarin (Pharmacogenomic Considerations - 2)
Genetic variants in: 1. CYP2C9 will vary rates of activity 2. Vitamin K epoxide reductase (VKOR) will vary response to warfarin
33
Warfarin Reversal (2)
1. INR > 10 and there is no bleeding: hold dose and give oral Vitamin K (2.5-5 mg) 2. If significant bleeding (regardless of INR): stop warfarin, administer 4 factor prothrombin complex concentrate (Kcentra)
34
PT-INR values on Warfarin Therapy
INR should be 2-3 to prevent DVT and 2.5-3.5 to prevent arterial thrombosis. High INR values indicate a risk for bleeding and that anticoagulant dose may need to be reduced.
35
Fibrinolytics/Thrombolytic [Alteplase, Reteplase] (MOA and Indications)
MOA: Activates plasminogen and converts it to plasmin, which can digest fibrin that holds the clot together. Alteplase (t-PA) is a recombinant tissue plasminogen activator. Reteplase is a genetically engineered variant of t-PA; more rapid onset; longer half-life; less ADRs than t-PA. Indications: Used IV to dissolve life-threatening clots (MI, CVA, DVT, PE). Also used to clear IV catheters.
36
Other Plasminogen Activators [Streptokinase] (General, MOA, and Indications)
General: Derived from beta-hemolytic streptococci MOA: Converts circulating plasminogen to plasmin. Powerful thrombolytic, but is antigenic and non-specific. Indications: Approved for use in STEMI and PE.
37
Where does each drug class work in the coagulation cascade?
See slide 50.
38
Hemostatics [Aminocaproic acid, Thrombin, Tranexamic acid] (MOA and ADRs [2 common/4 serious])
MOA: Used to treat or prevent excess bleeding from surgical sites. Prevents fibrin dissolution. Common ADRs: 1. Allergic skin reactions 2. Headache Serious ADRs: 1. Anaphylaxis 2. Thrombosis 3. Bronchospasm 4. Nephrotoxicity

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