Med Chem - Venous Thromboembolism + Anticoagulants

Question 1

causes of clots

Answer 1

injury to vasculature, tissue, blood hypercoaguability, blood stasis (not moving)

Question 2

3 general steps to coagulation

explain them

Answer 2

-platelet adhesion - platelets adhere to injured cells and tissue

-platelet aggregation - platelets adhere TO EACH OTHER under influence of TxA2 (released from platelet)

-blood coagulation - strengthens the “plug” of platelets

Question 3

3 steps of blood coagulation

Answer 3

1. generation of factor x (intrinsic and extrinsic)
2. thrombin formation (from prothrombin)
3. fibrin formation (from fibrinogen)

Question 4

name the 5 major classes of anticoagulants

Answer 4

vitamin k antagonists

heparins

direct factor Xa inhibitors

direct thrombin inhibitors

antiplatelet drugs

Question 5

name the 2 chemical classes of vitamin K antagonists

Answer 5

coumarins
1,3-inandiones

Question 6

how were coumarins discovered as anticoagulants

Answer 6

naturally - from cattle who were fed fermented hay - they got a bleeding disorder

Question 7

**which isomer of warfarin is more active

Answer 7

the S isomer is 4x more active

Question 8

explain the mechanism of action of coumarins***

Answer 8

they are competitive inhibitors of BOTH vitamin K reductase AND vitamin K epoxide reductase

this results in inhibition of vitamin-K dependent carboxylation of proenzymes – LEADING TO REDUCED COAGULATION FACTORS SUCH AS II (prothrombin), VII, IX, and X

Question 9

name the 4 coagulation factors that coumarins reduce the numbers of

Answer 9

II (prothrombin), VII, IX, X

Question 10

true or false

warfarin is 100% metabolized to inactive metabolites

Answer 10

true

Question 11

***what are the R and S isomers of warfarin metabolized by

Answer 11

S isomer - majorly by CYP2C9

R isomer - by 3A4, 2C19, 1A2

introduce OH groups

Question 12

polymorphisms in which CYP enzyme can affect the metabolism of warfarin

Answer 12

2c9

Question 13

2 drugs that are 1,3-indandione vitamin K antagonists

Answer 13

phenindione
anisidione

Question 14

true or false

1,3-indandiones have more pharmacological activity than coumarins

Answer 14

TRUE - they are also analgesics, uricosuric, anti-inflamm, etc

HOWEVER, warfarin is still preferred over them bc they have singnificant renal and hepatic toxicities

Question 15

***unfractionated heparin s a polysaccharide composed of sulfated D-glucosamine and D-glucuronic acid residues LINKED BY ________

Answer 15

alpha 1,4 bonds

Question 16

unfractionated heparins are highly _____ in nature

they are similar to what other molecule(s)?

Answer 16

HIGHLY acidic

hyaluronic acid, chondroitin

Question 17

explain the dual MOA of unfractionated heparin

Answer 17

antithrombin III (AT) is formed in the liver. it slowly inactivates thrombin

heparin binds to AT causing a conformational change in AT

this conformational change causes ACCELERATED BINDING to thrombin (MOA1) AND to Factor Xa (MOA2)

heparin is then released from the complex leaving behind an inactive form of thrombin/Xa – therefore heparin is a catalyst — can leave and do the process again by binding another antithrombin III

Question 18

HOW does heparin bind to AT (what specific bonds)

Answer 18

by its anionic COO- and SO3- to the cationic aa’s (lysine and arginine) in AT

Question 19

2 ways heparin can be administered

Answer 19

subq or IV

NOT IM (hematomas) or oral - degraded by gastric acid

Question 20

MAJOR ADR of heparin

Answer 20

THROMBOCYTOPENIAS

Type 1 - non immune (HAT - heparin associated thrombocytopenia)

type 2 - immune (LIFE THREATENING) - HIT (heparin induced thrombocytopenia)

Question 21

**3 major drugs that are low MW heparins

Answer 21

enoxaparin
dalteparin
tinzaparin

Question 22

**all 3 low MW heparins show slight selectivity for…

which has highest ratio? which has lowest?

Answer 22

ALL have higher selectivity for Xa inhibition over thrombin

enoxaparin has highest for Xa

tinzaparin has lowest, but still more than thrombin

Question 23

how are low molecular weight heparins produced

Answer 23

from heparin by chemical or enzymatic depolymerization

Question 24

3 major advantages of low molecular weight heparin over unfractionated heparin

Answer 24

-lower incidence of HIT - bc more selective for Xa

-longer half life - only need q12

-predictable dose response - so no need to monitor aPTT (activated partial thromboplastin time)

Question 25

name 4 factor Xa inhibitors

Answer 25

fondaparinux rivaroxaban apixaban edoxaban

Question 26

**briefly explain the structure of fondaparinux

Answer 26

a synthetic pentasaccharide (5 sugars) + an OCH3 group at the reducing end

Question 27

**incidence of HIT in fondaparinux

Answer 27

even lower incidence of HIT than the low molecular weight heparins!!

Question 28

while there is a lower risk of HIT in fondaparinux than LMWH's, however....

Answer 28

fondaparinux has a risk of thromboembolic issues when used for epidural or spinal hemotoma can get long term/permanent paralysis :(

Question 29

3 indications for rivaroxaban (xarelto)

Answer 29

-prevention venous thromboembolism in pts undergone total hip replacement and knee replacement -prevention stroke and systemic embolism in pts with afib -TREATMENT DVT and PE

Question 30

xarelto is not recommended for use in what patients

Answer 30

severe renal issues (cr crl less than 30)

Question 31

2 indications for apixaban

Answer 31

-reduce risk of stroke and systemic embolism in a fib -lower risk venous thromboembolism post orthopedic surgery

Question 32

2 indications for edoxaban

Answer 32

-reduce risk stroke and systemic embolism in pts with non valvular a fib -lower risk of venous thrombosis post orthopedic surgery

Question 33

which are hydrolyzed faster -- esters or amides

Answer 33

esters much faster

Question 34

***name 6 direct thrombin inhibitors

Answer 34

hirudin lepirudin desirudin bivalirudin argatroban dabigatran (NOAC)

Question 35

**name 1 direct thrombin inhibitor that is REVERSIBLE and 2 that are IRREVERSIBLE

Answer 35

reversible - hirudin irreversible - lepirudin, desirudin

Question 36

explain the MOA of hirudin

Answer 36

forms non covalent stable complex with alpha thrombin. (REVERSIBLE inhibition) therefore, thrombin can't cleave fibrinogen and initiate the clotting cascade!

Question 37

MOA bivalirudin

Answer 37

direct thrombin inhibitor works by binding BOTH the catalytic site and the allosteric site (anionic-binding exosite I) of thrombin

Question 38

argatroban is synthetic or natural?

Answer 38

synthetic thrombin inhibitor derived from L-arginine (has highly basic guanidine gorup!!!!!******

Question 39

how is argatroban able to exert anticoagulation effects

Answer 39

inhibits thrombin-catalyzed reactions like fibrin formation, activation of coagulation facotrs (5,8,13), protein C, platelet aggregation

Question 40

indication for argatroban

Answer 40

for prevention or treatment of thrombosis in patients with HIT

Question 41

2 indications for dabigatran

Answer 41

-prevent venous thromboembolism in pts underwent hip or knee replacement -prevent stroke and embolism in pts with a fib

Question 42

3 contraindications to dabigatran

Answer 42

-severe renal impairment (cr cl <30) -concimitant tratment w p-glycoprotein inhibitors -mechanical or prosthetic heart valves