L35: Drugs for Management of Thrombogenesis

Question 1

Arterial clots

Answer 1

Tend to be platelet-rich

Drugs that suppress platelet function lower the risk of developing intrarterial clots

Question 2

Venous clots

Answer 2

Fibrin rich

Coagulation plays an important role in venous clots

Drugs that suppress coagulation decrease the risk of developing venous clot

Question 3

What are the anticoagulants?

Answer 3

Direct acting: heparin (unfractionated), heparin (fractionated), rivaroxaban (factor Xa inhibitor), argatroban (thrombin inhibitor), dabigatran (thrombin inhibitor)

Indirect acting: warfarin

Question 4

Heparin (unfractionated)

Answer 4

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

Question 5

Potential problems with heparin

Answer 5

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

Question 6

Protamine sulfate

Answer 6

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

Question 7

Low molecular weight heparin (fractionated heparin)

Answer 7

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

Question 8

Rivaroxaban

Answer 8

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

Question 9

Argatroban

Answer 9

Direct acting anticoagulant

Thrombin inhibitor

Paraenteral

Bind to and inactivate thrombin

Therapeutic effect does not need to be monitored

Question 10

Dabigatran

Answer 10

Direct acting anticoagulant

Thrombin inhibitor

Enteral

Bind to and inactivate thrombin

Therapeutic effect does not need to be monitored

Question 11

Potential problems w/ factor Xa and thrombin inhibitors

Answer 11

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

Question 12

Andexanet alpha

Answer 12

Factor Xa inhibitor antidote

Question 13

Idarucizumab

Answer 13

Thrombin inhibitor antidote

Question 14

Warfarin

Answer 14

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

Question 15

Potential problems w/ warfarin

Answer 15

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

Question 16

Describe the variability in pharmacodynamics and pharmacokinetics of warfarin

Answer 16

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

Question 17

What are the antiplatelet drugs?

Answer 17

Aspirin, clopidogrel, vorapaxar, dipyridamole, tirofiban

Question 18

Aspirin

Answer 18

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

Question 19

Clopidogrel

Answer 19

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

Question 20

Vorapaxar

Answer 20

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

Question 21

Dipyridamole

Answer 21

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

Question 22

Tirofiban

Answer 22

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

Question 23

What are the thrombolytics? What do they do?

Answer 23

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

Question 24

Streptokinase

Answer 24

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

Question 25

Alteplase

Answer 25

Thrombolytic

Tissue plasminogen activator

Directly binds to plasminogen and accelerates its conversion to plasmin

Given intravenously

Question 26

Aminocaproic acid

Answer 26

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