in this lecture we're going to cover
anticoagulants and antiplatelet agents
so let's get right into it
anticoagulants and antiplatelet agents
are used to treat trembling disorders or
unwanted clot inside a blood vessel
which can lead to heart attack or stroke
but before we discuss their mechanism of
action let's quickly review the clotting
process so in the absence of injury the
endothelial cells that make up the inner
surface of blood vessels release
chemical mediators such as nitric oxide
and prostacyclin now nitric oxide job is
to dilate blood vessels while processing
job is to bind to receptors located on
platelet this binding triggers certain
reactions which ultimately prevent
places activation and aggregation now
what happens when there is a damaged
blood vessel let's say due to skin cut
well suddenly we have less nitric oxide
and prostacyclin around so blood vessels
become constricted and places become
activated but first in first with the
help of von willebrand factors places up
here to exposed collagen which in turn
causes them to change shape next these
activated differently shaped platelets
begin to release granules containing
chemical mediators such as ADP thrombin
from boxing a to serotonin and places
activating factor which attract and
activate even more platelets come to the
site of injury now the final step
involves activation of the glycoprotein
to b3 a receptors which bind circulating
fibrinogen the fibrinogen simultaneously
binds to these receptors on two separate
platelets thus cross-linking platelets
to form aggregates now there are several
drugs that can disrupt this platelet
plaque formation collectively we call
them places aggregation heavier
or simply and I place address one of the
most widely known drugs that belongs to
this class is aspirin in order to
understand how Aston works let's take a
closer look at the inside of a platelet
so when place it becomes activated
arachidonic acid is released from the
membrane phospholipids then it gets
converted to prostaglandin h2 by
cyclooxygenase one enzyme also known as
Cox one finally prostaglandin h2 is
further metabolized to Tom boxing a 2
which is released from the platelet to
stimulate activation of new platelets as
well promoter aggregation so what
appened does is it irreversible
inactivate Cox one enzyme that's
effectively disrupting close formation
next we have place of aggregation
inhibitor the work by blocking the
action of adp receptor specifically p2 y
12 subtype drugs that belong to this
group includes a parallel like Aguilar
Ty Cobb is speeding and Tata grill as I
mentioned before activated platelets
relief chemical mediators one of them is
ADP which binds to PT y 12 receptor
leading to activation of the
glycoprotein 2 B 3 a receptors which are
required to fibrin mediated place that
cross-linking so by blocking PT y top
ATP receptors is try to effectively
inhibits platelet aggregation and dust
cloud formation
next we had lipo protein to be 3 a
receptor blockers namely up six mat at
the sabot eyes and Tyra v n'j these
agents simply in headed platelet
aggregation by binding to the
glycoprotein to b3 a receptors on
platelets thus preventing fibrinogen
from binding to platelets and making
them unable to cross link unlike the
other drug that we discussed so far like
a protein to be three inhibitors are
administered only intravenously now the
last group of antiplatelet drugs that I
wanted to briefly
scoffs are also by astrayed inhibitors
namely diaper animal and so I saw these
two agents inhibit enzyme called
phosphodiesterase that is responsible
for breaking down cyclic MP to a MP so
by blocking this enzyme diaper animal
and two losses or increase intracellular
levels of cyclic MP which in turn leads
to decrease in intracellular calcium and
ultimately inhibition of platelet
activation furthermore this agent
inhibits phosphodiester it in the
vascular wall as well uptake of
adenosine which promotes vasodilation
for that reason Kosovo in particular is
often used to treat symptoms of
peripheral artery disease such as
narrowing of vessels that supply blood
to legs when it comes to side effects
bleeding is a major risk associated with
all antiplatelet drugs
additionally they furthermore and sauces
or due to their vapour dilated
properties can produce headaches now
let's go back to our review of clot
formation so the aggregation of
platelets acting like a plot is usually
not enough to secure the site of injury
in order to strengthen the platelet plug
a clog must form the formation of clots
involves cascade of
enzyme reactions to transform various
clotting factors to their active form
ultimately producing web-like fibrin
mesh now there are two pathways involved
with a clotting cascade the intrinsic
pathway which is activated by damage
directly to the blog that's a wall and
extrinsic pathway which is activated by
trauma to the basket wall as well as
surrounding tissue so the intrinsic
pathway starts recording factor 12 which
is activated when blood comes into
contact with a collagen in the damaged
vascular wall and here a next to the
Roman numerals spend for activated this
sets a series of reactions that leads to
activation of factor
eleven which then activates factor nine
which then activates sector ten
activated factor ten then Congress
called thrombin to thrombin and finally
turbine converts fibrinogen to fibrin
which forms mesh that strengthens the
plaited plot now let's take a look at
the extrinsic pathway so extrinsic
pathway is triggered by tissue factor
released from damaged cells outside the
circulating blood it starts with an
activation of factor seven which then
activates factor 10 so at this point the
intrinsic and extrinsic pathway converge
into a common pathway which again
resolved information of five and claw
and as a side note here keep in mind
that this is just a simplified
description of coagulation cascade and
many details were intentionally omitted
so now let's switch gears and let's talk
about anticoagulants that is drugs that
work by disrupting this coagulation
cascade let's begin by discussing one of
the most widely recognized and die
coagulants that is heparin and low
molecular weight heparin
such as an ox a pan and dog Perrin now
these agents bind to our natural
anticoagulant circulating in blood coat
antithrombin 3 the primary function of
antithrombin is to inactivate factor 10a
and thrombin so what happened drugs 2 is
they bind to antithrombin and by doing
so they accelerate its activity in case
of heparin is binding to antithrombin
results in rapid inactivation of both
factor 10a and Trumble however unlike
having low molecular weight heparin have
very little effect on an activation of
thrombin and instead they selectively
accelerate inactivation of factor 10a
another agent was mentioning here that
also selectively accelerate inactivation
of factor 10a is Fonda paradox how
unlike low-molecular-weight happens from
the pair nuts doesn't bind to any other
plasma proteins and has no direct effect
on thrombin when it comes to
side-effects bleeding is a major risk
fortunately there is a reversal agent
called protamine sulfate which can be
used to treat excessive bleeding caused
by heparin drugs protamine sulfate
simply works by binding to heparin or
low molecular weights happen to form
stable enacted complex from the panels
on the other hand doesn't have any
specific antidote at this time another
possible major side effect that is
particularly associated with the use of
heparin agents is heparin induced
thrombocytopenia head for short this is
a disorder caused by immune system
making antibodies to happen when it's
bound to platelet-derived causing
cosplays let's factor for once the
antibodies bind to these have been
plated spectre-4 complexes may begin to
activate playlists which come together
causing formation of unwanted claws and
fall in platelet count now let's move on
to another group of anticoagulants that
is direct inhibitors of factor 10a
agents that belong to this group are
effects event and rivaroxaban the
mechanism of action of these drugs is
very simple they both bind directly to
the active side of factor 10a thus
preventing it from converting
prothrombin to thrombin the biggest
advantage of these agents over the other
anti-violence that we discussed is that
they are available in oral formulation
unfortunately bleeding is still a major
risk and specific antidote is currently
not available now let's move on to the
next group of anticoagulants that is
direct thrombin inhibitors now depending
on how they interact with the trombone
molecule agents in this group can be
subdivided into two classes first we
have a univille and direct thrombin
inhibitor which binds only to the
beside example of drugs that belong to
this class are a gas oven and the bigot
ran the second class are by Valen direct
thrombin inhibitors which bind to both
the active site and the exercise one
that is fibrinogen binding site this
bivalent binding contributes to high
affinity and high specificity for
thrombin example of drugs that belong to
this class are by Valerie Rudin and desi
Rudin now one of the biggest advantages
of direct thrombin inhibitor over
indirect Raman inhibitors such as
heparin is that they don't bind to
platelet factor 4 which makes them very
useful in treatment of heparin induced
thrombocytopenia however just like with
other anticoagulants bleeding is a major
risk and there is no specific antidote
available at this time now there is one
more anticoagulant that I wanted to
discuss which is working workman is one
of the audits and Decalogue ones that
still on the market and it has its own
unique mechanism of action now in order
to understand how work and work is
important to first understand the role
of vitamin K in the coagulation cascade
so vitamin K is required for synthesis
of factors 2 7 9 and 10 these
coagulation factors are biologically
inactive until they are carboxylated by
vitamin K this carboxylation reaction
proceeds when we have reduced form of
vitamin K available in this reaction
reduced vitamin K is oxidized to the
vironment KF oxide in the presence of
oxygen and carbon dioxide yielding
carboxylated
fully active clotting factors in the
last step of this reaction oxidized
vitamin K is recycled back to the
reduced form by enzyme called vitamin K
epoxide reductase
this is where warpin comes into play
acid inhibits this enzyme and thus
disrupted vitamin K
synthesis of biologically active coding
factors as well as some other regulatory
factors now one of the biggest
disadvantages of warpin is that it has a
narrow therapeutic window and has been
associated with many drug drug and drug
to the interactions for these reasons
coalition's need to closely monitor
patient's own work and by using the
International normalized ratio
measurement also known as INR and adjust
the dose when necessary to balance the
risk of bleeding against the risk of
clotting fortunately in the event of
bleeding and dacoit on effective warpin
can be overcome by administration of
vitamin K however reversal can take up
to 24 hours therefore in the event of
emergency infusion of fresh frozen
plasma might be necessary now the last
group of drugs that I wanted to discuss
in this lecture are Trimble lytx while
antiplatelet and anticoagulant prevent
the clot from getting formed in the
first place thrombolytics act on the
existing clot causing it to dissolve and
the way they do this is by directly or
indirectly activating circulating
protein called plasminogen which then
turns into plasma now plasma is an
enzyme that breaks close link between
fibrin molecules there by dissolving the
cloth examples of thrombolytics includes
alteplase recipes and connect to place
which are produced by recombinant DNA
technology to mimic our naturally
occurring tissue plasminogen activator
another example is an agent called gyro
kinase which is a naturally occurring
tron Balearic produced some cultures
human kidney cells and lastly we have an
agent called streptokinase which is the
right from streptococcal bacteria now
one of the main differences between
these agents is their selectivity for
fibrin bound plasminogen versus
recirculating plasminogen so while
tissue plasminogen activator such as
alteplase is more close selective and
acts to dissolve the fiber
in the trembles streptokinase and
European it are less cloth selected and
thus are more likely to cause internal
bleeding into any organ system these
bleeding complications from Trimble
lytic terapy can be managed by
administration of amino caproic acid or
tranexamic acid these two agents can
stop by brenell lysis by inhibiting
binding of plasminogen to fibrin
applause conversion of plasminogen to
plasmin and with that i wanted to thank
you for watching I hope you enjoyed this
lecture and as always stay tuned for
more