B Fruitfull

Acid Reflux causes and Treatment



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 thrombotic 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 prostacyclin
job is to bind to receptors located on platelets this binding triggers certain
reactions which ultimately prevent platelet 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 platelets become activated but first things first with the
help of von willebrand factors platelets adhere 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
thromboxane A2 serotonin and platelet activating factor which attract and
activate even more platelets that come to the site of injury now the final step
involves activation of the glycoprotein 2b/3a 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 plug formation collectively we call
them platelet aggregation inhibitors or simply antiplatelet drugs one of the
most widely known drugs that belongs to this class is Aspirin in order to
understand how Aspirin works let’s take a closer look at the inside of a platelet
so when platelet it becomes activated arachidonic acid is released from the
membrane phospholipids then it gets converted to prostaglandin H2 by
cyclooxygenase-1 enzyme also known as Cox-1 finally prostaglandin H2 is
further metabolized to thromboxane A2 which is released from the platelet to
stimulate activation of new platelets as well promote their aggregation so what
Aspirin does is it irreversibly inactivates Cox-1 enzyme thus
effectively disrupting clot formation next we have platelet aggregation
inhibitors that work by blocking the action of ADP receptor specifically P2Y12 subtype drugs that belong to this group include Clopidogrel Ticagrelor
Ticlopidine and Prasugrel as I mentioned before activated platelets
release chemical mediators one of them is ADP which binds to P2Y12 receptor
leading to activation of the glycoprotein 2b/3a receptors which are
required for fibrin mediated platelet cross-linking so by blocking P2Y12
ADP receptors these drugs effectively inhibit platelet aggregation and thus
clot formation next we have glycoprotein 2b/3a
receptor blockers namely Abciximab Eptifibatide and Tirofiban these
agents simply inhibit platelet aggregation by binding to the
glycoprotein 2b/3a receptors on platelets thus preventing fibrinogen
from binding to platelets and making them unable to cross link unlike the
other drugs that we discussed so far glycoprotein 2b/3a inhibitors are
administered only intravenously now the last group of antiplatelet drugs that I
wanted to briefly discuss are phosphodiesterase inhibitors
namely Dipyridamole and Cilostazol these two agents inhibit enzyme called
phosphodiesterase that is responsible for breaking down cyclic AMP to AMP so
by blocking this enzyme Dipyridamole and Cilostazol increase intracellular
levels of cyclic AMP which in turn leads to decrease in intracellular calcium and
ultimately inhibition of platelet activation furthermore these agents
inhibit phosphodiesterase in the vascular wall as well as uptake of
adenosine which promotes vasodilation for that reason Cilostazol 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 Dipyridamole and Cilostazol due to their vasodilating
properties can produce headaches now let’s go back to our review of clot
formation so the aggregation of platelets acting like a plug is usually
not enough to secure the site of injury in order to strengthen the platelet plug
a clot must form the formation of clot involves cascade of
enzyme reactions that transform various clotting factors to their active forms
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 blood vessel wall and extrinsic pathway which is activated by
trauma to the vascular wall as well as surrounding tissue so the intrinsic
pathway starts with clotting 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 numeral stands for “activated” this sets a series of reactions that leads to
activation of factor 11 which then activates factor 9
which then activates factor 10 activated factor 10 then converts prothrombin to thrombin and finally thrombin converts fibrinogen to fibrin
which forms mesh that strengthens the platelet plug 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 7 which then activates factor 10 so at this point the
intrinsic and extrinsic pathway converge into a common pathway which again
results in formation of fibrin clot 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 anticoagulants that is Heparin and low- molecular-weight Heparin
such as Enoxaparin and Dalteparin now these agents bind to our natural
anticoagulant circulating in blood called antithrombin 3 the primary function of
antithrombin is to inactivate factor 10a and thrombin so what Heparin drugs do is
they bind to antithrombin and by doing so they accelerate its activity in case
of Heparin its binding to antithrombin results in rapid inactivation of both
factor 10a and thrombin however unlike Heparin low-molecular-weight Heparins have
very little effect on inactivation of thrombin and instead they selectively
accelerate inactivation of factor 10a another agent worth mentioning here that
also selectively accelerate inactivation of factor 10a is Fondaparinux however
unlike low-molecular-weight Heparins Fondaparinux 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-weight Heparins to form stable inactive complex Fondaparinux
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 “HIT” for short HIT is
a disorder caused by immune system making antibodies to Heparin when it’s
bound to platelet-derived protein called platelet factor-4 once the
antibodies bind to these Heparin platelet factor-4 complexes they begin to
activate platelets which clump together causing formation of unwanted clots 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
Apixaban 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 anticoagulants 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 thrombin molecule agents in this group can be
subdivided into two classes first we have univalent direct thrombin
inhibitors which bind only to the active site example of drugs that belong to
this class are Argatroban and Dabigatran the second class are bivalent direct
thrombin inhibitors which bind to both the active site and the exosite-1
that is fibrinogen binding site this bivalent binding contributes to their high
affinity and high specificity for thrombin example of drugs that belong to
this class are Bivalirudin and Desirudin now one of the biggest advantages
of direct thrombin inhibitors over indirect thrombin 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 Warfarin Warfarin is one of the oldest anticoagulants that’s
still on the market and it has its own unique mechanism of action now in order
to understand how Warfarin works its 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 vitamin K epoxide 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 Warfarin comes into play
as it inhibits this enzyme and thus disrupts this vitamin K dependent
synthesis of biologically active clotting factors as well as some other regulatory
factors now one of the biggest disadvantages of Warfarin is that it has a
narrow therapeutic window and has been associated with many drug-drug and drug-food interactions for these reasons clinicians need to closely monitor
patients on Warfarin 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 anticoagulant effects of Warfarin 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 thrombolytics while
antiplatelets and anticoagulants 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 plasmin now plasmin is an
enzyme that breaks cross-links between fibrin molecules thereby dissolving the
clot examples of thrombolytics include Alteplase Reteplase and Tenecteplase
which are produced by recombinant DNA technology to mimic our naturally
occurring tissue plasminogen activator another example is an agent called
Urokinase which is a naturally occurring thrombolytic produced from cultured
human kidney cells and lastly we have an agent called Streptokinase which is derived from streptococcal bacteria now one of the main differences between
these agents is their selectivity for fibrin-bound plasminogen versus
free circulating plasminogen so while tissue plasminogen activator such as
Alteplase is more clot selective and acts to dissolve the fibrin
in the thrombus Streptokinase and Urokinase are less clot selective and
thus are more likely to cause internal bleeding into any organ system these
bleeding complications from thrombolytic therapy can be managed by
administration of Aminocaproic acid or Tranexamic acid these two agents can
stop fibrinolysis by inhibiting binding of plasminogen to fibrin
as well as 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


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