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Adv Pharm 1 > Anemia (pt 3/3) Other drugs, Fibrinolysis > Flashcards

Anemia (pt 3/3) Other drugs, Fibrinolysis Flashcards

1
Q

What is Rivaroxaban (Xarelto)?

A

Direct Acting Factor 10 (activated) inhibitor: Common Pathway.
-Inc Bioavailability
-1/2 life 5-9 hrs
-Substrate for CYP3A4 and P-glycoprotein transporter*

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2
Q

What is Apixaban (Eliquis)?

A

Direct Acting Factor 10 (activated) inhibitor: Common Pathway.
-50% Bioavailable
-1/2 life 12 hrs
-Substrate for CYP3A4 and P-glycoprotein transporter*

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3
Q

What is Edoxaban (Savaysa)?

A

Direct Acting Factor 10 (activated) inhibitor: Common Pathway.
-Once daily dosing
-62% bioavailable
-1/2 life 10-14 hrs
-No CYP issues

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4
Q

What is Betrixaban (Bevyxxxa)?

A

Direct Acting Factor 10 (activated) inhibitor: Common Pathway.
-Once daily
-34% bioavailable
-1/2 life 19-27 hrs
-Dec dose in renal fx and P-glycoprotein transporter inhibitors
-Excreted primarily by Liver (caution in Liver Dz).

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5
Q

What is important to know with Rivaroxaban (Xarelto) and Apixaban (Eliquis)?

A

Drugs inhibiting CPY3A4 and P-glycoprotein transporters, impaired renal or hepatic function increase their effects.

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6
Q

What are the uses for Rivaroxaban (Xarelto) and Apixaban (Eliquis)?

A

-Prevention of Embolic stroke in Afib without valvular disease
-Prevention of Venous embolism after hip or knee sx
-Treatment of Venous embolism = VTE

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7
Q

What are the uses for Edoxaban (Savaysa)?

A

Treatment of VTE after Heparin or LMWH

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8
Q

When is Edoxaban (Savaysa) contraindicated?

A

Edoxaban is C/I in pts with Afib and CC > 95mL/min due to ↑ risk of ischemic stroke compared to those pts taking Warfarin

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9
Q

What is important to know regarding administration of Betrixaban (Bevyxxa)?

A

Take at the same time each day
Take with food

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10
Q

What is the reversal for the Oral Direct Acting Xa Inhibitors?
Rivaroxavan (Xarelto)
Apixaban (Eliquis)
Edoxaban (Savaysa)
Betrixaban (Bevyxxa)

A

1) Andexanet alfa – FDA approved 2018 for life threatening bleeding in pts taking Rivaroxaban & Apixaban
-Factor Xa decoy molecule that lacks anticoagulant activity that completes for binding to the anti-Xa drugs
-IV dosing = rapid reversal of anti-Xa effects

Reversal dose determined by:
-Last dose of Anti-Xa
-Dose taking

Risk of thrombotic complications, cardiac arrest and sudden death

2) 4F PCC (Prothrombin Complex Concentrate) may be considered as an alternate approach to life threatening bleeding

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11
Q

How do Direct Thrombin Inhibitors work?

A

-Directly bind to the active site of Thrombin thereby inhibiting Thrombin’s downstream effects
-Oral and parenteral agents
-Work predominantly in Common Pathway (Factor 2)
-Inhibits plt activation as well (remember: Thrombin is needed to activate platelets)

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12
Q

What are the Parenteral Direct Acting Thrombin Inhibitors?

A

-Bivalirudin
-Argatroban

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13
Q

What is Bivalirudin?

A

-Large bivalent molecule that binds to the active site of thrombin and the substrate recognition site
-IV agent with rapid on/offset
-Short half-life
-Clearance 20% renal and otherwise metabolic
-Also inhibits platelet activation
-FDA approved for use in percutaneous coronary angioplasty

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14
Q

What is Argatroban?

A

-Small molecule that binds to the active site of thrombin
-IV continuous infusion
-Short half-life
-Clearance is liver dependent
-FDA approved for HIT and coronary angioplasty in pts with HIT
-↑INR = difficult transition to Warfarin

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15
Q

What lab test do you use to monitor Argatroban? (Blue Box!)

A

aPTT

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16
Q

What is Hirudin?

A

An irreversible thrombin inhibitor from leech saliva that was available in a recombinant form as Lepirudin.
-Lepuridin was approved by the FDA for use in patients with thrombosis related to HIT
-It was discontinued by the manufacturer in 2012

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17
Q

How are Direct Oral Anti-Coagulants better than Warfarin?

A

-Equivalent antithrombotic efficacy
-Lower bleeding rates
-Rapid therapeutic effect
-No monitoring
-Fewer drug interactions
-Shorter half-life (impact of non-compliance)

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18
Q

What is Dabigatran? (Dabigatran Etexilate Mesylate aka Pradaxa)

A

-The only FDA approved oral direct thrombin inhibitor
-A prodrug(!) converted to Dabigatran in the body
Dabigatran and its metabolites are direct thrombin inhibitors
-↑PTT, Thrombin time, and Ecarin Clotting Time
Ecarin Clotting Time (ECT)
-Predictable response, no monitoring needed
-Toxicity: - bleeding

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19
Q

What is Ecarin Clotting Time (ECT)?

A

Clotting test based on the use of a protein isolated from viper venom

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20
Q

How is Dabigatran Metabolized and excreted?

A

-Substrate for the P-glycoprotein transporter
-Avoid P-glycoprotein inhibitors in patients with impaired renal function.
-Renal impairment results in prolonged drug clearance
-Dec dose if creatinine clearance is 15-30 mL/min

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21
Q

What is the reversal for Dabigatran?

A

Idarucizumab: humanized monoclonal antibody Fab fragment (binding site) that binds to Dabigatran and reverses the anti-coagulant effect
-Approved for life threatening bleeding or situations requiring emergency surgery
-5gm IV, can be repeated once if bleeding recurs
-Exposes pt to the underlying thrombotic disease that they were being treated for

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22
Q

How are Fibrin clots broken down?

A

-Plasminogen (inactive) is converted to Plasmin (active)
-Plasmin breaks down fibrin into Fibrin Split Products (aka Fibrin Degradation Products). Lab = D-Dimer

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23
Q

What is Plasminogen?

A

-The inactive form of plasmin
-Enzyme synthesized in the liver
-Circulates in the blood
-Incorporated into the clot as it is developed

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24
Q

What activates Plasminogen to Plasmin?

A

tissue-type plasminogen activator and urokinase-type plasminogen activator

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25
Q

How do fibrinolytics break down clots?

A

Fibrinolytics (activators of Plasminogen) rapidly lyse thrombi by catalyzing the formation of plasmin from plasminogen

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26
Q

What do exogenous Fibrinolytics do?

A

Create a generalized lytic state when administered IV.
-Cause the destruction of both protective hemostatic thrombi as well as the target thromboemboli
-Streptokinase – a protein synthesized by streptococci that combines with plasminogen
-Urokinase – human enzyme synthesized in the kidney that directly converts plasminogen to plasmin
-t-PA – preferentially activate plasminogen that is bound to fibrin which should confine the fibrinolysis to the formed thrombus and avoid systemic activation (Altepase – recombinant human t-PA, or Reteplase)

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27
Q

What are the steps of Fibrinolysis?

A

1) Inactive Plasminogen is converted to Plasmin by TPA
-TPA is released by endothelial cells in response to injury
2) Plasmin digests Fibrin

28
Q

What is Plasmin?

A

An active fibrinolytic enzyme that degrades Fibrin to Fibrin Split Products
-Activated by Tissue Plasminogen Activator (TPA)
-Plasmin remodels a clot and limits its growth

29
Q

What does Aminocaproic Acid do?

A

Inhibits the activation of plasminogen to plasmin and is useful in some bleeding disorders.

30
Q

What are the indications for IV administration of Fibrinolytics?

A

-PE with hemodynamic instability
-DVT with superior vena caval syndrome
-Ascending thrombophlebitis of the iliofemoral vein
-Management of the acute MI
-Ischemic stroke within 3 hrs of onset of symptoms

31
Q

What would be the indication for intra-arterial administration of fibrinolytics?

A

Peripheral Vascular Disease (PVD)

32
Q

What do the IV Fibrinolytics do?

A

Create a lytic state.
-Disrupts static thrombi (protective) and target thromboemboli.
-Break down any clot in your system

33
Q

What are the 3 examples of IV Fibrinolytics?

A

1) Streptokinase: synthesized from streptococci
2) Urokinase: Synthesized in kidney, directly converts plasminogen to plasmin
3) TPA: supposedly the best, preferentially activates plasminogen already in the fibrin clot. Only breaks down target thromboemboli - Alteplase/Reteplase

34
Q

What are the 3 categories of substances that regulate platelet function?

A

1) Agents generated outside of the platelet that interact with the platelet membrane receptors
-Catecholamines, collagen, thrombin, prostacyclin
2) Agents generated within the platelet that interact with the membrane receptors
-ADP, prostaglandin D2, prostaglandin E2, serotonin
3) Agents generated within the platelet that work within the platelet
-Prostaglandin endoperoxides and thromboxane A2, cAMP & cGMP, calcium

35
Q

What are the new recommendations for ASA?

A

-2014 – FDA said that ASA for primary prophylaxis (pts without a history of MI or stroke) was not supported by available data but significantly ↑ the risk of bleeding

-2019 – American College of Cardiology and the AHA recommended low-dose ASA (75-100 mg/d) be considered for the primary prevention in adults 40-70 years old with high risk of atherosclerotic cardiovascular disease and no increased bleeding risk

36
Q

What are the 3 targets for platelet inhibitory drugs?

A

1) Inhibition of prostaglandin synthesis (ASA)
2) Inhibition of ADP-induced platelet aggregation
3) Blockade of Glycoprotein IIb/IIIa receptors on platelets (where fibrinogen attaches)

37
Q

What are the 3 Thienopyridines?

A

1) Ticlopidine
2) Clopidogrel
3) Prasurgrel

38
Q

What is Ticlopidine used for?

A

1) Prevention of stroke in pts with history of TIA or thrombic state
2) With ASA for coronary stent thrombosis

39
Q

What are the adverse effects associated with Ticlopidine?

A

-Nausea, dyspnea, diarrhea
-Hemorrhage, leukopenia
-Thrombotic thrombocytopenic purpura (TTP)
-*Recommended for pts who are intolerant or failed ASA tx.

40
Q

What is the MOA of the Thienopyridines (Ticlopidine, Clopidogrel, and Prasurgrel)?

A

-Reduce platelet aggregation by inhibiting the ADP pathway of platelets (remember: ADP is needed for plt aggregation to take cap off of GP receptor so that fibrinogen can attach to it)
-Irreversibly block the ADP P2Y12 receptor
-No effect on prostaglandin metabolism
-Standard practice in patients undergoing coronary stent placement

41
Q

What are the uses for Clopidogrel?

A

-Unstable angina or non-STEMI in combo with -ASA
-STEMI
-Recent MI, stroke or PAD

*Preferred over Ticlopidine
*80% inhibition within 5 hrs of loading dose
*Prodrug requiring CYP2C19 (use caution with drugs that impair CYP, such as Omeprazole)

42
Q

What are the adverse effects associated with Clopidogrel?

A

Fewer adv effects
Rarely causes neutropenia
TTP

43
Q

What are the uses for Prasurgrel?

A

-Unstable angina or non-STEMI in combo with -ASA
-STEMI
-Recent MI, stroke or PAD

44
Q

What are the adverse effects associated with Prasurgrel?

A

-↑bleeding risk as compared to Clopidogrel
-C/I in TIA or stroke 2/2 bleeding risk

45
Q

What do the GP IIb/IIIa Receptor Inhibitors do?

A

The GP IIb/IIIa Receptor is activated during plt aggregation, binding site for fibrinogen, vitro, fibronectin, vWF, etc. Can block this to prevent fibrin connection with platelets.
-Abciximab (Reopro)
-Dipryimadole
-Cilstazol

46
Q

What is Abciximab (Reopro)?

A

A GP IIb/IIIa Receptor Inhibitor.
-First agent in the class
-Used in percutaneous coronary intervention and acute coronary syndromes
-Short half-lives
-Administer via continuous infusion

47
Q

What is Dipyrimadole?

A

An anti-platelet directed drug.
-Vasodilator that inhibits platelet function by inhibiting adenosine update and cGMP phosphodiesterase activity
-Not effect as monotherapy
-Therapeutic use of this agent is primary in combo with ASA to prevent CVA and ischemia
-Used with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves

48
Q

What is Cilstazol?

A

An anti-platelet directed drug.
-Phosphodiesterase inhibitor that promotes vasodilation and inhibition of platelet aggregation
-Used primarily to treat intermittent claudication

49
Q

What is Vitamin K administered for?

A

-For the treatment or prevention of hypoprothrombinemia due to vitamin K deficiency and oral anticoagulant-induced hypoprothrombinemia (ex. Warfarin)
-Vit K is currently administered to all newborns to prevent hemorrhagic disease of Vit K deficiency (Common in premature infants)`

50
Q

What is Vitamin K?

A

-Fat soluble substance
-Found primarily in leafy green vegs
-Dietary requirement is low
-Synthesized in the intestines
-Require bile salts for GI absorption
-High incidence of deficiency in ICUs (Poor diet, TPN, surgery, Multiple ABX Tx, Uremia)
-Dose influenced by route, age, gender, and cause of deficiency or bleeding

51
Q

Which Vitamin K do we administer?

A

Vitamin K1

52
Q

What is Vitamin K1?

A

AKA Phytanadione
-Found in food
-Oral & parenteral forms
-Slow IV
-Rapid infusion = dyspnea, chest pain, back pain, death
-Erratic bioavailability after SQ admin
-Onset delayed for 6 hours
-Complete effect within 24 hours

53
Q

What is Vitamin K2?

A

Menaquinone
-Found in human tissues
-Synthesized by intestinal bacteria

54
Q

What is the BBW associated with Vitamin K?

A

Intramuscular administration, intravenous administration, serious hypersensitivity reactions or anaphylaxis

55
Q

Which disorders account for most of the inheritable coagulation defects?

A

Factor VIII Deficiency (Classic hemophilia/Hemophilia A) and Factor IX Deficiency (Christmas Disease/Hemophilia B)

56
Q

Which is preferred treatment, Concentrated plasma fractions or Recombinant Protein Preparations?

A

Recombinant factors are recommended for treatment whenever possible
-Pooled plasma can be pasteurized to remove Hep B, Hep C and HIV but other transmissible diseases (prions) are not removed with either solvents or detergents.

57
Q

When is FFP used?

A

For factor deficiencies for which no recombinant form of the protein is available

58
Q

What is Cryoprecipitate?

A

-Fibrinogen, Factor 8, vWF, and 13
-Plasma protein fraction obtainable from whole blood
-1 Unit of Cryo = 300mg Fibrinogen
-ABO compatible not identical
-Not treated to decrease the risk of viral exposure
-For infusion – cryo is thawed and dissolved in a small volume of sterile citrate-saline solution and pooled with other units
-Rh- women with potential for child bearing should only receive Rh- cryo b/c of the possibility of contamination with Rh+ RBCs

59
Q

What are the uses for Cryo?

A

-Deficiencies or qualitative abnormalities of Fibrinogen (ex. DIC, Liver Disease)
-VIII deficiency
-vWF disease if Desmopressin Acetate is not indicated or a pathogen-inactivated, recombinant, or plasma-derived product is not available
-Note: the concentration of VIII and vWF in cryo are not as high as those in the concentrated plasma fractions compared to recombinant

60
Q

What is Recombinant Factor VIIa used for?

A

-VIIa initiates activation of the clotting pathway by activating factor IX and factor X in association with III (Tissue Factor)
-Extrinsic pathway

Uses:
-Hemophilia A or B with inhibitors
-Treatment of bleeding associated with invasive procedures in congenital or acquired Hemophilia or Factor VII deficiency

61
Q

What are the off-label uses for Recombinant Factor VII?

A

-Bleeding with trauma
-Surgery
-Intracerebral hemorrhage
-Warfarin toxicity

Note: Concern for thrombotic events

62
Q

What are Fibrinolytic Inhibitors (Aminocaproic Acid and Tranexamic Acid) Used for?

A

-Promotes clotting
-Adjunct for Hemophilia
-Treatment of fibrinolytic therapy
-Prophylaxis for rebleeding from intracranial aneurysms

Also:
-Post surgical GI-bleed
-Postprostatectomy bleeding
-Bladder hemorrhage secondary to radiation and drug induced cystitis

63
Q

What are the adverse effects associated with Fibrinolytic Inhibitors (Aminocaproic Acid and Tranexamic Acid)

A

-Thrombosis from inhibition of plasminogen activator
-Hypotension
-Myopathy
-Abdominal discomfort
-Diarrhea
-Nasal stuffiness

64
Q

What are the C/Is associated with Fibrinolytic Inhibitors (Aminocaproic Acid and Tranexamic Acid)

A

-DIC
-Bleeding of the kidneys/ureters due to the potential for excessive clotting (Can lead to kidney/ureter destruction)

65
Q

What is Aminocaproic Acid (EACA or Amicar)?

A

-Synthetic
-Competitively inhibits Plasminogen activation
-PO admin, rapidly absorbed
-Available IV – infuse over 30 min (Avoid hypotension)
-Renal clearance

66
Q

What is Tranexamic Acid?

A

-Analog of EACA
-PO and IV

Adv Pharm 1 (28 decks)

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