Drugs in the blood Flashcards
two stages of hemostasis and what happens during them
i. Vasospasm (vasoconstriction)
-Immediate; restricts blood flow
-Sympathetics and local factors eg. thromboxane
-Myogenic properties of vessel wall
ii. Platelet response
-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)
ii. Coagulation Phase
-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)
iv. Clot dissolution (Fibrinolysis)
-Wound healing and restoration of blood flow
-Dissolution of clot by proteolytic actions of plasmin bound to clot process of fibrinolysis
2 goals of normal hemostasis
§ Prevent prolonged hemorrhage
§ Prevent spontaneous thrombosis
prothrombogenic factors (4)
Platelet Activators
Procoagulants
Vasoconstriction
Fibrinolytic Inhibitors
antithrombogenic factors (4)
Platelet Inhibitors
Anticoagulants
Vasodilators
Fibrinolytic Activators
causes of excessive bleeding (3)
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
mechanism of action of Vitamin K for hemorrhagic diseases
Confers biological activity: factors II, VII, IX, X; post-translational modification
forms of vitamin K
-Vitamin K1: phytonadione (foods)
-Vitamin K2: menaquinone (intestinal bacteria)
uses of vitamin K
Vitamin K deficiency
-Rodenticide toxicity
-Dicumoral toxicity (sweet clover poisoning)
Warfarin overdosing
oral vs parenternal route of vitamin K administration
- Intravenous route—best to avoid; anaphylaxis possible
- IM route- hematoma possible; SC recommended route
what does vitamin K require for intestinal absorption
bile salts
desmopressin acetate (DDAVP); uses, how it works, forms
- Transiently increases von Willebrand activity in mild von Willebrand disease
- Used prophylactically to control capillary bleeding during surgery
(Effects are short lived (2 hrs); repeat dosing—reduced effect) - Available as injectable or nasal spray (can be given SC)
what is protamine sulfate used for and how does it work
to treat heparin doses
-binds to heparin neutralizing its anticoagulant effects
-More effective against large molecular weight heparin molecules in unfractionated heparins versus the low molecular weight heparins
two things to consider and why for administering protamine sulfate
- Give IV slowly to avoid adverse reactions that can include collapse
- Accurate dosing needed; high doses can produce anticoagulant
effects
how do fibrinolytic inhibitors work
- Plasmin lyses fibrin and fibrinogen
Attaches to fibrin via lysine binding sites
what is aminocaproic acid (amicar) used for and how does it work
-Synthetic agent similar to lysine; blocks lysine binding site
-Competitively inhibits plasmin action on fibrin
-Incomplete lysis can lead to thrombi formation
Uses
* Bleeding from fibrinolytic therapy
* Adjunct therapy-hemophiliacs
three drug classes for thromboembolic disease
Systemic anticoagulants
Antithrombotic drugs
Fibrinolytic drugs
venous vs arterial thrombus
-Red thrombus-fibrin rich, large # RBCs; venous
-White thrombus-platelet rich; arterial
three prothrombic factors
-Local vessel injury
-Abnormal blood flow (stasis or turbulence)
-Altered blood coagulability (Hyperactivity of hemostatic mechanisms, Hypoactivity of fibrinolytic mechanisms)
ideal systemic anticoagulant… (2)
-Prevent pathologic thrombosis
-Allow normal response to vascular injury and limit bleeding
mechanism of action of heparin (unfractionated)
-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”
uses of heparin
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)
adverse effects of heparin
-Bleeding tendencies
-Monitor aPTT; 1.8-2.5X normal mean aPTT
-Protamine sulfate can neutralize heparin in overdose
advantages of low molecular weight heparins (enoxaparin) compared to unfractionated heparin
-Less bleeding tendencies possible
-Protamine sulfate is less active against LMW heparins
-Less risk of thrombocytopenia
-Improved pharmacokinetics– can give subcutaneous
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; Heparin does not cross the placenta
how warfarin works
Oral anticoagulant by antagonizing vitamin K actions
-Reduces clotting factors (II, VII, IX and X); factor VII has shortest half-life
-Clotting not affected until existing factors used
what class is rivaroxaban
selective factor Xa inhibitors
how does rivaroxaban work
-Inactivate factor Xa directly
-Does not interact with ATIII and no thrombin activity
-Fairly quick anticoagulant activity
how does aspirin work
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
-Cat metabolizes aspirin poorly; 2X weekly dosing used
uses of aspirin
-Feline cardiomyopathy
-Heartworm disease
-Equine laminitis and navicular diseases
adverse effects of aspirin
- Gastrointestinal ulceration
- Renal damage
- Bleeding tendencies
how does clopidogrel work
Reduce platelet aggregation by inhibiting ADP pathways
-Act as P2Y 12 (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 P2Y 12 receptor
what type of drug is clopidogrel
ADP inhibitor
what is clopidogrel used for
Clopidogrel is routinely used for thromboembolic concerns in cats (HCM) and in dogs (mainly IMHA)
how do fibrinolytic drugs work
Fibrinolytics rapidly lyse thrombi by activating plasmin from clot bound
plasminogen
uses of tissue plasminogen activator
Thromboembolic therapy for canine pulmonary thromboembolism and feline saddle thrombis
adverse effects of of tissue plasminogen activator
- Reperfusion injury
- Bleeding tendencies
how tissue plasminogen activator works
-Are proteases that bind fibrin
-Can preferentially activate clot bound plasminogen (Limits activation of systemic plasmin)
-Fairly short half-life necessitates constant rate infusion
adverse effects of EPO
- Hypertension and seizure possible
- Therapeutic failure from antibody formation most common
how does EPO work
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
use of EPO
- RhuEPO used primarily in chronic anemia due to erythropoietin production in Chronic renal failure
- Has been used in anemia of other causes eg. Cancers
considerations when giving EPO
- Increase in hematocrit and hemoglobin in 2-4 weeks
- Iron supplementation is advised with EPO therapy
