Med Chem - Venous Thromboembolism + Anticoagulants Flashcards
causes of clots
injury to vasculature, tissue, blood hypercoaguability, blood stasis (not moving)
3 general steps to coagulation
explain them
-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
3 steps of blood coagulation
- generation of factor x (intrinsic and extrinsic)
- thrombin formation (from prothrombin)
- fibrin formation (from fibrinogen)
name the 5 major classes of anticoagulants
vitamin k antagonists
heparins
direct factor Xa inhibitors
direct thrombin inhibitors
antiplatelet drugs
name the 2 chemical classes of vitamin K antagonists
coumarins
1,3-inandiones
how were coumarins discovered as anticoagulants
naturally - from cattle who were fed fermented hay - they got a bleeding disorder
**which isomer of warfarin is more active
the S isomer is 4x more active
explain the mechanism of action of coumarins***
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
name the 4 coagulation factors that coumarins reduce the numbers of
II (prothrombin), VII, IX, X
true or false
warfarin is 100% metabolized to inactive metabolites
true
***what are the R and S isomers of warfarin metabolized by
S isomer - majorly by CYP2C9
R isomer - by 3A4, 2C19, 1A2
introduce OH groups
polymorphisms in which CYP enzyme can affect the metabolism of warfarin
2c9
2 drugs that are 1,3-indandione vitamin K antagonists
phenindione
anisidione
true or false
1,3-indandiones have more pharmacological activity than coumarins
TRUE - they are also analgesics, uricosuric, anti-inflamm, etc
HOWEVER, warfarin is still preferred over them bc they have singnificant renal and hepatic toxicities
***unfractionated heparin s a polysaccharide composed of sulfated D-glucosamine and D-glucuronic acid residues LINKED BY ________
alpha 1,4 bonds
unfractionated heparins are highly _____ in nature
they are similar to what other molecule(s)?
HIGHLY acidic
hyaluronic acid, chondroitin
explain the dual MOA of unfractionated heparin
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
HOW does heparin bind to AT (what specific bonds)
by its anionic COO- and SO3- to the cationic aa’s (lysine and arginine) in AT
2 ways heparin can be administered
subq or IV
NOT IM (hematomas) or oral - degraded by gastric acid
MAJOR ADR of heparin
THROMBOCYTOPENIAS
Type 1 - non immune (HAT - heparin associated thrombocytopenia)
type 2 - immune (LIFE THREATENING) - HIT (heparin induced thrombocytopenia)
**3 major drugs that are low MW heparins
enoxaparin
dalteparin
tinzaparin
**all 3 low MW heparins show slight selectivity for…
which has highest ratio? which has lowest?
ALL have higher selectivity for Xa inhibition over thrombin
enoxaparin has highest for Xa
tinzaparin has lowest, but still more than thrombin
how are low molecular weight heparins produced
from heparin by chemical or enzymatic depolymerization
3 major advantages of low molecular weight heparin over unfractionated heparin
-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)
name 4 factor Xa inhibitors
fondaparinux
rivaroxaban
apixaban
edoxaban
**briefly explain the structure of fondaparinux
a synthetic pentasaccharide (5 sugars) + an OCH3 group at the reducing end
**incidence of HIT in fondaparinux
even lower incidence of HIT than the low molecular weight heparins!!
while there is a lower risk of HIT in fondaparinux than LMWH’s, however….
fondaparinux has a risk of thromboembolic issues when used for epidural or spinal hemotoma
can get long term/permanent paralysis :(
3 indications for rivaroxaban (xarelto)
-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
xarelto is not recommended for use in what patients
severe renal issues (cr crl less than 30)
2 indications for apixaban
-reduce risk of stroke and systemic embolism in a fib
-lower risk venous thromboembolism post orthopedic surgery
2 indications for edoxaban
-reduce risk stroke and systemic embolism in pts with non valvular a fib
-lower risk of venous thrombosis post orthopedic surgery
which are hydrolyzed faster – esters or amides
esters much faster
***name 6 direct thrombin inhibitors
hirudin
lepirudin
desirudin
bivalirudin
argatroban
dabigatran (NOAC)
**name 1 direct thrombin inhibitor that is REVERSIBLE and 2 that are IRREVERSIBLE
reversible - hirudin
irreversible - lepirudin, desirudin
explain the MOA of hirudin
forms non covalent stable complex with alpha thrombin.
(REVERSIBLE inhibition)
therefore, thrombin can’t cleave fibrinogen and initiate the clotting cascade!
MOA bivalirudin
direct thrombin inhibitor
works by binding BOTH the catalytic site and the allosteric site (anionic-binding exosite I) of thrombin
argatroban is synthetic or natural?
synthetic thrombin inhibitor
derived from L-arginine (has highly basic guanidine gorup!!!!!****
how is argatroban able to exert anticoagulation effects
inhibits thrombin-catalyzed reactions like fibrin formation, activation of coagulation facotrs (5,8,13), protein C, platelet aggregation
indication for argatroban
for prevention or treatment of thrombosis in patients with HIT
2 indications for dabigatran
-prevent venous thromboembolism in pts underwent hip or knee replacement
-prevent stroke and embolism in pts with a fib
3 contraindications to dabigatran
-severe renal impairment (cr cl <30)
-concimitant tratment w p-glycoprotein inhibitors
-mechanical or prosthetic heart valves
