Warfarin (Vitamin K Antagonists): Pharmacology

Warfarin (Vitamin K Antagonists): Pharmacology


Hey guys, in this video we will see warfarin.
So let’s start. It’s an oral anticoagulant. Basically, it’s a vitamin K antagonist. Commercial preparation of warfarin is a mixture
of laevorotatory or S form and dextrorotatory or R form. S form is about 4 times more potent than R form. Now let’s talk about its absorption and distribution. After oral administration, almost 100% of
warfarin is absorbed. In circulation, more than 99% of warfarin binds
with plasma proteins. This binding mainly occurs with albumin. Because of this binding, warfarin has
very low volume of distribution. Now lets go to its site of action, which is mainly liver. Here it inhibits synthesis of vitamin K dependent
clotting factors. These factors are factor II, VII, IX and X. To understand how exactly this is done, lets
first see how they are synthesized normally. These clotting factors have glutamic acid residues. For proper functioning of clotting factor,
these residues need to be carboxylated. This carboxylation is responsivity of this
gamma glutamyl carboxylase enzyme. And it also requires vitamin K. Reduced form of vitamin K serves as cofactor
in this reaction. Together they carry out carboxylation of glutamic
acid residue. In the reaction reduced hydroquinone form of vitamin K is converted into oxidized or epoxide from. This form is not active. To reactivate it, there is an enzyme called
vitamin K epoxide reductase. It reduces Vitamin K back to hydroquinone form. So, vitamin K becomes active again. The clotting thus synthesized is released
into the circulation, and the cycle is repeated to synthesize more factors. Now let’s see the importance of
this carboxylation reaction. The carboxylation provides negative charge
to the glutamic acid residues. This negative charge it essential for its
binding with calcium, which associates the clotting factor to
membrane phospholipids of platelet. This allows the activation as well as subsequent
participation of clotting factor in coagulation. Thus, this carboxylation is very important
for clotting factor to do its normal job. Now if you give warfarin to the patient, it
will inhibit vitamin K epoxide reductase enzyme. So, vitamin K is not reactivated and it stays
in inactive epoxide form. Without help from vitamin K the carboxylation
of glutamic acid residues come to a halt. So now these clotting factors are released into the circulation without the carboxyl group. Without this group, their ability to participate
in coagulation is greatly reduced. So, they wonder in the circulation without
doing their job. So, coagulation is impaired. This anticoagulant effect of warfarin develops
after 3-4 days of starting therapy. That is because, although newly synthesized
clotting factors are defective, the factors that were already synthesized
earlier are fully functional. They stay in blood for few days and can contribute
in coagulation. As these factors are degraded, and defective
factors replace them, the effect of warfarin appears. If we talk about individual clotting factors,
factor VII is first to disappear. Its plasma half-life is about 6 hours, which
is shorted among all. So, its first to drop. Then factor IX with half life of about 24
hours is second to disappear. Then goes factor X who’s half-life is about
40 hours. Factor II stays the longest. Its half-life is about 60 hours. So, it takes 3-4 days for drop in its level to drop. Because of this, effect of warfarin starts
developing from the first day, but it’s completely developed only by 3 to 4 days. This is one of the reasons why we give heparin
during first 5-7 days of warfarin therapy. Its effect starts immediately, and it is given
till the effect of warfarin is completely developed. Now few more points regarding mechanism. As inhibiting synthesis of clotting factors
is possible only in living person, warfarin works only in vivo. It has no in vitro anticoagulant activity. Other vitamin K antagonists like acenocoumarol
and phenindione also work by same mechanism. So that was the mechanism of action of warfarin. Now let’s see its elimination. Half-life of warfarin is about 40 hours. Its elimination occurs mainly by CYP2C9. Now one of the most discussed topics about
warfarin, its interactions. We will see interactions of warfarin with
drugs and diseases together. First, factors that increase the effect of
warfarin. Here we have vitamin K deficiency first. It might be due to its reduced dietary intake, or due to antibiotic use which destroys
the vitamin K synthesizing bacteria or due to malabsorption from intestine. When patient is already vitamin K deficient,
it becomes easy for warfarin to inhibit its activity. Next, drugs like sulphonamide, phenytoin,
valproate and probenecid displace the warfarin from plasma protein. So, more warfarin is present in free form to work. Next. In liver diseases, capacity to synthesize
clotting factors is reduced due to disease itself. So warfarin effect is increased. Third generation cephalosporins and salicylates
inhibit activation of vitamin K, similar to warfarin. So, effect warfarin is potentiated. Salicylates for example aspirin, also have
antiplatelet activity, this further enhance the bleeding tendency in patients taking warfarin. Next, hyperthyroidism. It’s a hypermetabolic state. Clotting factors are degraded much faster
in this condition, which increases warfarin effect. Finally, enzyme inhibitors like cimetidine, amiodarone, disulfiram, erythromycin and metronidazole reduces the elimination of warfarin
and thus increase its effect. Similarly, elimination is reduced in patients
with defect in CYP2C9 enzyme. So, these are the factors that increase warfarin effect. Now factors that decrease the effect of warfarin. First increased dietary intake of vitamin K.
Obviously, if patient is secretly taking antidote of warfarin in diet, its effect will reduce. Second, with cholestyramine and habitual use
of liquid paraffin warfarin is lost in faces. I mean its absorption is reduced. Next, mutation in vitamin K epoxide reductase,
renders the enzyme incapable of binding with warfarin. So, warfarin cannot inhibit this mutated enzyme. In pregnancy and patients taking oestrogen
containing contraceptive pills synthesis of clotting factors is increased. And in patients of hypothyroidism, degradation
of clotting factors is reduced. In all these situations warfarin will have
to work harder to reduce levels of clotting factors. Next, enzyme inducers like barbiturates, rifampin,
Griseofulvin and carbamazepine increase the metabolismof warfarin. And finally, in patients of nephrotic syndrome,
protein bound drug is lost in urine. All of them reduce the effect of warfarin. So, these are the factors that affect the
warfarin response. So be cautious about this condition if your
patient is taking warfarin. Now let’s move to the uses. Warfarin is used in deep vein thrombosis and
pulmonary embolism. As venous thrombi are rich in fibrin, anticoagulants
are preferred in these conditions. It is also used in post MI patients,
unstable angina, atrial fibrillation, after cardiac valve replacement
and cerebrovascular diseases. Monitoring of warfarin therapy is done with
international normalized ration. Ideally it should be maintained from 2 to 3. It should be maintained towards
higher side like 2.5 to 3.5, in some patients with high risk prosthetic heart valves. So, these were the uses. Now let’s see the adverse events. Bleeding is a very common side effect with warfarin. It may manifest as ecchymosis, epistaxis,
haematuria, gastrointestinal bleeding etc. Yea, i know, it’s a simple side effect based
on its pharmacological action. But next one is more interesting. Skin necrosis. The mechanism behind this adverse event, is
a game of balance between procoagulant or clotting factors and anticoagulant factors. If you have seen video of vitamin K with full
concentration, you might have noticed that vitamin K is involved in synthesis of not
only clotting factors, but also in synthesis of a very important
anticoagulant factor, protein C. So, once the warfarin inhibits vitamin K activity, levels from both the sides start to drop. However, half-life of protein C is about 8 hours. This is much shorter than half lives of most
of the vitamin K dependent clotting factors. Like half of factor II is about 60 hours and
that of factor X is about 40 hours. Because of shorter half-life, protein C depletes
much faster than clotting factors. So, at this point in time, patient have more clotting factors than anticoagulant factors in his blood. This hypercoagulable state can cause thrombosis
in microvasculature sometimes leading to skin necrosis. Such lesions are common in extremities. This usually occurs from 3-10 after starting
therapy. As the clotting factors also disappear, the
risk is reduced. This is also a reason why we cover patient
with heparin during initial days of warfarin treatment. It keeps clotting factors in check when our
anticoagulant factor is gone. One more thing, as it’s a game of balance,
the risk of this adverse event is higher in patients with deficiency of protein C. So,
this was all about skin necrosis. Let’s move to the next adverse event. Purple toe syndrome. In this bottom and sides of toes turn purple
and become very painful. Next, warfarin crosses placenta and produces
deleterious effects on foetus. It can cause foetal warfarin syndrome, in
which foetus has bone abnormalities like nasal hypoplasia, stippled epiphysis etc. This may be due to reduced osteocalcin, one more protein whose synthesis is dependent on vitamin K. There can also be CNS abnormalities. And haemorrhagic complications in foetus. So, these were the adverse events of warfarin. Now let’s talk about its antidote. The overdose or excessive bleeding due to
warfarin can be treated with vitamin K. It’s a specific antidote to warfarin. However, synthesis of clotting factors takes
its time. So response of vitamin K appears after 6-24 hours. If you want immeidate response, you can give whole blood, plasma or concentrates of clotting factors to the patient. They will replenish clotting factors immediately. If you understood the treatment of overdose,
let’s move to the last section, contraindications of warfarin. Warfarin should not be given during pregnancy,
in patients with bleeding disorder, hypertension, subacute bacterial endocarditis, peptic ulcer,
bleeding piles, tuberculosis, threatened abortion, recent eye or brain surgery or lumber puncture
and hypersensitivity to warfarin. So, this was all about warfarin. Its good if you want to remember everything. But if you dont, here is a short and sweet summery. Warfarin is an oral anticoagulant. Its mechanism of action is inhibition of synthesis
of vitamin K dependant clotting factors. These factors are factor II, VII, IX and X. It is done by inhibiting vitamin K epoxide reductase. There is a delay of about 3-4 days in response
after starting the treatment. So, during this patient is covered with heparin. In pharmacokinetics, its absorption through
intestine is almost 100%. Its more than 99% protein bound. And elimination occurs mainly by CYP2C9. Its response is affected by so many factors.
among factors that increase the response are vitamin K deficiency which might be due to decreased dietary intake, antibiotic use or malabsorption, displacement of warfarin from plasma protein by sulphonamide, phenytoin, valproate, probenecid etc liver disease, third generation cephalosporines and salicylates, hyperthyroidism, enzyme inhibitors like cimetidine,
amiodarone, disulfiram, erythromycin, metronidazole etc and defect in CYP2C9. Among factors that decrease the warfarin
response are: increased vitamin K intake in diet, cholestyramine and habitual use of liquid
paraffin, mutation of vitamin K epoxide reductase, pregnancy and oestrogen containing
oral contraceptives, hypothyroidism, enzyme inducers like barbiturates, rifampin, griseofulvin, carbamazepine etc and finally nephrotic syndrome. Warfarin should be used cautiously in these situations. Now uses. Warfarin is used in pulmonary embolism, deep
vein thrombosis, post MI patients, unstable angina, atrial fibrillation, after cardiac
valve replacement and cerebrovascular diseases. Monitoring of warfarin therapy is done with INR. It should be maintained from 2 to 3. Adverse events with warfarin are bleeding,
skin necrosis due to transient imbalance between pro and anti-coagulant factors, purple toe
syndrome and foetal warfarin syndrome. Bleeding due to warfarin or its overdose can
be treated by its specific antidote, vitamin K. Response of vitamin K takes 6-24 hours to appear. Whole blood, plasma or concentrates of clotting
factors show immediate response. Contraindications of warfarin are pregnancy,
bleeding disorder, hypertension, subacute bacterial endocarditis, peptic ulcer,
bleeding piles, tuberculosis, threatened abortion, recent eye or brain surgery or lumber puncture
and hypersensitivity to warfarin. Thats it friends for this video. Check out more videos at our channel if you
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