Blood Drugs Flashcards
Goal of normal blood hemostasis
§ Prevent prolonged hemorrhage
§ Prevent spontaneous thrombosis
Stages of hemostasis
- vasospasm
- platelet response
- coagulation phase
- clot dissolution (fibrinolysis)
what is the vasospasm stage of hemostasis? how does it work?
Stage 1
§ Immediate; restricts blood flow
§ Sympathetics and local factors eg. thromboxane
§ Myogenic properties of vessel wall
what is the platelet response stage of hemostasis and how does it work?
Stage 2
§ Within seconds; forms initial plug
§ Platelets adhere to exposed collagen of damaged endothelium, and each other
§ Platelet plug releases chemical mediators (TXA2, 5-HT and ADP)
> recruit more platelets
> promote vasoconstriction
> initiate the coagulation cascade
what is the coagulation phase of hemostasis and how does it work?
Stage 3
§ Occurs thru sequential conversion of inactive proteins into catalytically active proteases
§ Tissue factor-factor VIIa pathway is main initiator
§ Result—conversion of soluble fibrinogen to insoluble fibrin—net of organized protein around platelet plug
§ Result of coagulation phase is clot proper (thrombus)
what is the clot dissolution phase of hemostasis and how does it work?
Stage 4
(Fibrinolysis)
§ Wound healing and restoration of blood flow
§ Dissolution of clot by proteolytic actions of plasmin bound to clot—process of fibrinolysis
Excessive bleeding may be caused by…..
- Platelet deficiency
> Thrombocytopenias (quantitative consumption)
>von Willebrand’s (qualitative disorder) - Clotting factor deficiency
> Single factor eg. hemophilia (VIII, IX)
> Multiple factors ie. vitamin K deficiency - Fibrinolytic hyperactivity
Excessive bleeding may be caused by…..
- Platelet deficiency
> Thrombocytopenias (quantitative consumption)
>von Willebrand’s (qualitative disorder) - Clotting factor deficiency
> Single factor eg. hemophilia (VIII, IX)
> Multiple factors ie. vitamin K deficiency - Fibrinolytic hyperactivity
treatments for hemorrhagic diseases
- Vitamin K
- Other agents (DDAVP, Protamine sulfate, antifibrinolytics)
what two natural forms of vitamin K exist?
Vitamin K1: phytonadione (foods)
Vitamin K2: menaquinone (intestinal bacteria)
mechanism of action of vitamin K for hemorrhagic diseases? how should it be administered and is it safe? what does it require for intestinal absorption?
- Confers biological activity: factors II, VII, IX, X; post-translational modification
-Vitamin K1 available for oral and parenteral use
* Intravenous route—best to avoid; anaphylaxis possible
* IM route- hematoma possible; SC recommended route
-Fat soluble vitamin; considered very safe
* Requires bile salts for intestinal absorption
mechanism of action of vitamin K for hemorrhagic diseases? how should it be administered and is it safe? what does it require for intestinal absorption?
- Confers biological activity: factors II, VII, IX, X; post-translational modification
-Vitamin K1 available for oral and parenteral use
* Intravenous route—best to avoid; anaphylaxis possible
* IM route- hematoma possible; SC recommended route
-Fat soluble vitamin; considered very safe
* Requires bile salts for intestinal absorption
uses of vitamin K for hemorrhagic diseases
Vitamin K deficiency
>Rodenticide toxicity
>Dicumoral toxicity (sweet clover poisoning)
Warfarin overdosing
what is desmopressin acetate used for? how is it administered?
hemorrhagic disease
* Transiently increases von Willebrand activity in mild von Willebrand disease
* Used prophylactically to control capillary bleeding during surgery
* Available as injectable or nasal spray (can be given SC)
what is protamine sulfate? what is it used for and what is its use in cases of hemorrhagic disease?
- Low molecular weight strongly basic (cationic) protein produced by recombinant technology
- Used to treat heparin overdoses
> binds to heparin neutralizing its anticoagulant effects
> More effective against large molecular weight heparin molecules in unfractionated heparins versus the low molecular weight heparins
how should we administer protamine sulfate? what do we need to keep in mind in terms of dosing?
- Give IV slowly to avoid adverse reactions that can include collapse
- Accurate dosing needed; high doses can produce anticoagulant effects
what substance lyses fibrin and fibrinogen? where does it attach to fibrin?
- Plasmin lyses fibrin and fibrinogen
> Attaches to fibrin via lysine binding sites
what is aminocaproic acid? what does it do? what are its uses
fibrinolytic inhibitor
- Synthetic agent similar to lysine; blocks lysine binding site so that plasmin cannot bind to cause lysis
- Competitively inhibits plasmin action on fibrin
- Incomplete lysis can lead to thrombi formation
Uses:
* Bleeding from fibrinolytic therapy
* Adjunct therapy-hemophiliacs
what is a thrombus? what does red vs white mean?
“blood clot proper”
-Red thrombus - fibrin rich, large # RBCs; venous
-White thrombus - platelet rich; arterial
what is a thromboemboli?
migration of thrombus in body
what are the 3 contributors to thrombosis?
endothelial injury
abnormal blood flow
hypercoagulability
Pathogenesis of thrombosis requires prothrombic factors such as:
Local vessel injury
Circulatory stasis
Altered blood coagulability
>Hyperactivity of hemostatic mechanisms
>Hypoactivity of fibrinolytic mechanisms
drug classes used to treat thrombosis
Systemic anticoagulants
Antithrombotic drugs
Fibrinolytic drugs
what would an ideal systemic anticoagulant do?
Prevent pathologic thrombosis
Allow normal response to vascular injury and limit bleeding
what is heparin? where does it come from?
Systemic anticoagulant
-Mixture of sulfated mucopolysaccharides
-Isolated from mast cells: bovine lung/porcine GI mucosa
mechanism of action of heparin
Enhances (accelerates 100-fold) the action of Antithrombin III (AT-III) >forms heparin-ATIII complex
AT- III inhibits activated clotting factors especially thrombin (IIa) and Xa—acts as a “suicide substrate”
primary use of heparin and other uses, generally (no specific diseases)
Primarily used in the initial treatment of thrombosis and thromboembolic disease
- Rapid onset of action renders it useful as an “acute anticoagulant” >Oral anticoagulant usually given concurrently
-Prevents new thrombus formation only!!
>Does not lyse existing thrombus
what are some diseases where heparin would be useful?
-Feline cardiomyopathies
-DIC, venous thrombosis, pulmonary thromboembolism
-Canine IMHA
-Equine laminitis
adverse effects of heparin? how can we neutralize an overdose?
-Bleeding tendencies
-Monitor aPTT; 1.8-2.5X normal mean aPTT
-Protamine sulfate can neutralize heparin in overdose
what are low molecular weight heparins and how are they made? what is the most commonly used of these?
Are fractioned from standard (unfractionated) heparin or chemically
synthesized
-Enoxaparin is the most common low molecular weight heparin
what clotting factors does enoxaparin inactivate well? what does it not do that unfractionated heparins can?
Enoxaparin inactivates Xa well, but not thrombin (factor IIa)
what are advantages of low molecular weight heparins over unfractionated heparins?
Being used more commonly due to advantages over unfractionated heparin
- Less bleeding tendencies possible
- Protamine sulfate is less active against LMW heparins
- Less risk of thrombocytopenia
- Improved pharmacokinetics– can give subcutaneous
- Longer half-life
what is warfarin? how does it work?
-Oral anticoagulant by antagonizing vitamin K actions
-Reduces clotting factors (II, VII, IX and X); factor VII has shortest half-life
-Clotting time not affected until existing factors used
how is warfarin administered?
Injectable and oral formulations available
what is the traditional use for warfarin in veterinary medicine? is it still used?
Was used as an oral chronic preventative anticoagulant, but less use in veterinary medicine now with availability of other drugs
- Dosing usually begun with heparin administration
what should we monitor while administering warfarin?
Monitor using international normalized ratio (INR)
> patient PT/mean normal PT for the lab
> increase INR value to 2.0-3.0
adverse effects of warfarin?
-Bleeding tendencies; can combat with Vitamin K1
-Serious bleeding requires fresh blood/plasma
-Warfarin crosses the placenta; don’t use in pregnancy
is it better to use warfarin or heparin during pregnancy? why?
- Heparin does not cross the placenta so use it
- Warfarin crosses the placenta; don’t use in pregnancy
what is an important selective factor Xa inhibitor? how does it work and how fast?
Rivaroxaban
- Inactivate factor Xa directly
- Does not interact with ATIII and no thrombin activity
- Fairly quick anticoagulant activity
advantage of rivaroxaban over warfarin/heparins
Predictable pharmacokinetics and a fixed dosage can be used without monitoring as with warfarin or heparins
route of admin for rivaroxaban
oral
adverse effect of Rivaroxaban and how to possibly mitigate
Bleeding can occur
> Reversing agents are available but limited data in veterinary patients
primary use of Rivaroxaban in vet med
Being used more in veterinary medicine
- Use primarily in dogs with IMHA thus far
common systemic anticoagulants
heparin
low molecular weight heparins
warfarin
selective factor Xa inhibitors
common antithrombotic drug? how does it work?
Aspirin (Less commonly used with clopidogrel available)
-cyclooxygenase inhibitors-
Irreversibly binds (acetylates) cyclooxygenase-1
-COX-1 selective over COX-2 at low doses; selectivity lost at higher doses
-Prevents TXA2 production in platelets reducing platelet aggregation
-Other NSAIDs can inhibit cyclooxygenase-1 but not irreversibly; hence a shorter duration of action
what animal metabolizes aspirin poorly? what do we need to do as a result?
Cat metabolizes aspirin poorly; 2X weekly dosing used
what does aspirin prevent?
Prevents thrombus and re-thrombosis formation
>Feline cardiomyopathy
>Heartworm disease
>Equine laminitis and navicular diseases
adverse events related to aspirin use?
- Renal damage
- Bleeding tendencies
- Gastrointestinal ulceration
types of antithrombotic drugs?
-cyclooxygenase inhibitors- (Aspirin)
-ADP Inhibitors- (Clopidogrel)
what is clopidogrel and how does it work?
Antithrombotic Drugs -ADP Inhibitors-
-Reduce platelet aggregation by inhibiting ADP pathways
* Act as P2Y12 (aka P2YADP) receptor antagonists; prevent binding of ADP to receptors
- May be synergistic with aspirin as work by different mechanisms of action
- Clopidogrel is irreversible inhibitor of the P2Y12 receptor
how is clopidogrel activated? what are drugs like this called?
Clopidogrel is a “prodrug”—must be activated by liver P450 metabolism
what is clopidogrel mainly used for?
Clopidogrel is routinely used for thromboembolic concerns in cats (HCM) and in dogs (mainly IMHA)
is clopidogrel safe?
fairly safe
how do fibrinolytic drugs work? what are two common examples?
-Fibrinolytics rapidly lyse thrombi by activating plasmin from clot bound plasminogen
> Studies have shown that interventional angioplasty is superior to these agents in human medicine for myocardial infarction
Tissue Plasminogen Activators
what are tissue plasminogen activators? how do they work? what are their properties and route of admin?
-Are proteases that bind fibrin
-Can preferentially activate clot bound plasminogen
>Limits activation of systemic plasmin
- Fairly short half-life necessitates constant rate infusion
uses of tissue plasminogen activator
Thromboembolic therapy for canine pulmonary thromboembolism and feline saddle thrombis
adverse effects of tissue plasminogen activator
- Reperfusion injury
- Bleeding tendencies
what is erythropoietin? how is it made? how does it work and what does it do?
Drug used in anemia
Growth Factor
* Glycoprotein made by kidney in response to hypoxia
-Prepared by recombinant technology (rHuEPO)
-EPO receptor is member of JAK/STAT superfamily
-Stimulates proliferation-differentiation of red cell progenitors and release of reticulocytes
result of erythropoietin use? what should we take with it?
- Increase in hematocrit and hemoglobin in 2-4 weeks
- Iron supplementation is advised with EPO therapy
