L35: Drugs for Management of Thrombogenesis Flashcards
Arterial clots
Tend to be platelet-rich
Drugs that suppress platelet function lower the risk of developing intrarterial clots
Venous clots
Fibrin rich
Coagulation plays an important role in venous clots
Drugs that suppress coagulation decrease the risk of developing venous clot
What are the anticoagulants?
Direct acting: heparin (unfractionated), heparin (fractionated), rivaroxaban (factor Xa inhibitor), argatroban (thrombin inhibitor), dabigatran (thrombin inhibitor)
Indirect acting: warfarin
Heparin (unfractionated)
Direct acting anticoagulant
Very long chain of repeating subunit of sulfated d-glucuronic acid and d-glucosamine; 40 repeated units on average
Big and water-soluble; can’t be administered orally
Given intravenously in hospital or sometimes subq but absorption is inconsistent
Mechanism: binds to anti-thrombin III and helps it to more rapidly inactivate a series of clotting factors (IIa, IXa, Xa, XIa, XIIa, XIIIa)
Thrombnin is factor IIa
Get an immediate effect
Potential problems with heparin
Zero order elimination: don’t have well characterized dose response relationship; have to monitor the therapeutic effect w/ APTT (at least daily)
Hemorrhage: if dose is too excessive, pt may start to hemorrhage
Heparin-induced thrombocytopenia:
Type I - 10% incidence; inconsequential; mild and transient; usually done within first 4 days of heparin administration
Type II - Serious and life-threatening; heparin binds to PFIV and forms a complex; this complex binds to Fc receptor on platelets and causes platelet activation; develop platelet-rich blood clots; in response, have to stop heparin and substitute another anticoagulant (argatroban) which is given intravenously and is thrombin inhibitor that will inhbit thrombin; pt can’t ever receive heparin again since they have the antibodies
Protamine sulfate
Antidote for heparin in case of hemorrhage
Will combine w/ one molecule of heparin to get a protamine-heparin-sulfate complex and heparin is excreted in urine
Low molecular weight heparin (fractionated heparin)
Direct acting anticoagulant
Average length of 16 repeating units of sulfate d-glucuronic acid and d-glucosamine
Undergoes first order elimination - have well characterize dose response relationship and thus don’t have to monitor therapeutic effect
Risk of developing type II thrombocytopenia is reduced
Disadvantage is that when it combines w/ anti-thrombin it will not accelerate the inhibition of thrombin
Administered by IV or subq (absorption more consistent than unfractionated heparin); some outpatients will be given unfractionated heparin bc they can be taught to give subq injections
Rivaroxaban
Direct acting anticoagulant
Factor Xa inhibitor
Oral administration
Binds to factor Xa and inhibits it (factor Xa combined w/ Va is needed to convert prothrombin to thrombin)
Will inhibit prothrombinase activity by binding to Xa
Therapeutic effect does not need to be monitored
Argatroban
Direct acting anticoagulant
Thrombin inhibitor
Paraenteral
Bind to and inactivate thrombin
Therapeutic effect does not need to be monitored
Dabigatran
Direct acting anticoagulant
Thrombin inhibitor
Enteral
Bind to and inactivate thrombin
Therapeutic effect does not need to be monitored
Potential problems w/ factor Xa and thrombin inhibitors
Hemorrhage
Should not be used in renal disease - since these drugs are eliminated primarily by renal excretion
Missing doses - they have relatively short half lives, so drug levels may fall below therapeutic levels if doses are missed
Monitoring therapeutic effect? - due to a number of deaths from excess hemorrhage
Increased risk of MI? - don’t know if real or not
Andexanet alpha
Factor Xa inhibitor antidote
Idarucizumab
Thrombin inhibitor antidote
Warfarin
Indirect acting anticoagulant
Inhibits production of clotting factors 2, 7, 9, and 10 by the liver (the vitamin K-dependent clotting factors)
These factors require reduced vitamin K as cofactor for synthesis; this is oxidized to produce vitamin K epoxide
For reaction to continue, have to convert it back to reduced vitamin K by vitamin K epoxide reductase
Will not see effect on blood coagulation until 8 - 12 hours after administration since plenty of factors are already circulating
Action is not directly on clotting factor, but by inhibiting their synthesis in the liver
Therapeutic effect must be monitored by PT when initiated; after PT starts to stabilize, can do so less frequently
Potential problems w/ warfarin
Hemorrhage (vitamin K is antidote)
Dietary concerns (cruciferous vegetables are high in vitamin K; pt can’t change their dietary habits when taking warfarin)
Interactions w/ other drugs (Cyp2C9) - is biotransformed by Cyp2C9, which also metabolizes many other drugs; if they are given another drug metabolized by this, that will compete with warfarin and warfarin levels will go up and you will start to see hemorrhage
Antibiotics that reduce gut bacteria - some gut bacteria produce vitamin K that we absorb; if antibiotics kill these bacteria, vitamin K will go down and dose of warfarin will need to be digested
Variability in pharmacodynamics/kinetics
Describe the variability in pharmacodynamics and pharmacokinetics of warfarin
Required dose can vary 20-fold
Blood levels at same dose can vary 50-fold
Genetic polymorphisms in Cyp2C9 (slow metabolizers and fast metabolizers) and epoxide reductase (very sensitive and moderately sensitive variants)
These genetic polymorphisms can be tested before warfarin administration and initial dose is assigned to whatever category that pt is in
As a result of these effect, therapeutic effect of warfarin must be monitored by PT
When initiated, monitored several times in first week; after PT starts to stabilize, can be done less frequently
What are the antiplatelet drugs?
Aspirin, clopidogrel, vorapaxar, dipyridamole, tirofiban
Aspirin
An antiplatelet
Inhibits platelet cyclooxygenase 1, thus inhibiting production of thromboxane A2; without that, won’t get much platelet activation
Low-dose aspirin therapy is used to prevent MI and ischemic stroke
Increases risk of hemorrhagic stroke
Clopidogrel
Antiplatelet
Prodrug (needs to be metabolically activated)
Active metabolite binds to and inactivates the ADP receptor, thereby inhibiting the activation of the GP2b/3a receptor
Given orally
Is activated by Cyp2C19, for which there are genetic polymorphisms - some people are hyporesponders and have low activity form of Cyp2C19; those individuals produce active metabolite at a slow rate and have to be given a larger dose
Vorapaxar
Antiplatelet
Binds to PAR1 and prevents its activation by thrombin
Inhibits binding of thrombin to its receptor (PAR1) and thus inhibits platelet activation
Decreases risk of MI and ischemic stroke but increases risk of hemorrhagic stroke
Given orally
Dipyridamole
Antiplatelet
Elevate cAMP by inhibiting platelet phosphodiesterase and by increasing prostacyclin release from endothelial cells
High platelet cAMP lowers free calcium; low free calcium inhibits events leading to platelet activation and granule release
Not a commonly used drug
Used in combination w/ warfarin in pts with prosthetic heart valves since these are synthetic and when blood comes into contact with it, it increases risk of intravascular clot formation; these pts have to take warfarin and dipyridamole for the rest of their lives
Tirofiban
Antiplatelet
Binds to the GP2b/3a receptor, blocking cross-linking of platelets
Only effective with intravenous administration, so only used in hospitals
Used during procedures, such as when stents are put in
Advantage of this is that it acts immediately
What are the thrombolytics? What do they do?
Streptokinase and alteplase
Dissolve already existing clots
Accelerate conversion of plasminogen to plasmin which will break down fibrin and fibrinogen, leading to dissolving of clots
Given to help dissolve clots responsible for MI and ischemic stroke
Effective if given within 6 - 9 hours after initial infarction has occurred
Streptokinase
Thrombolytic
A molecule of streptokinase binds to a molecule of plasminogen; this complex then binds to another plasminogen and accelerates its conversion to plasmin
Given intravenously
Alteplase
Thrombolytic
Tissue plasminogen activator
Directly binds to plasminogen and accelerates its conversion to plasmin
Given intravenously
Aminocaproic acid
Antidote for thrombolytics
Given if excessive hemorrhaging due to thrombolytics
Blocks activation of plasminogen and the interaction of plasmin w/ fibrin and fibrinogen
Pretty dangerous itself and is used carefully and only in hospital setting
