Hi everyone,in this video today let us discuss
the new generation drug obeticholicacid. What is this drug obeticholicacid? This is
one of the farnesoid X receptor agonist,the farnesoid X receptors are the receptors for bile
acids and when bile acid acts on these receptors, they can reduce the bile acid levels within the
hepatocytes which reduce the hepatic apoptosis and cirrhosis. This obeticholicacid is widely known as
OCA which is a derivative of chenodeoxycolic acid, the secondary bile acid present in our body.
Now this OCA can reduce the bile acid levels within the hepatocytes so it can be used in the
treatment of primary biliary cholangitis PBC, this is a condition which is increased with formation
of gallstones and decreased biliary flow, in this condition within the bile duct the biliary flow
is somewhat reduced resulting in the cholestasis. And this cholestasis can stimulate the
inflammatory response which results in the inflammation of the bile ducts, finally
it can lead to cirrhosis of biliary ducts and cirrhosis of the liver. So in such conditions,
obeticholicacid can reduce the bile acid levels within the hepatocytes and it can be used in
the treatment of primary biliary cholangitis. This OCA can be combined with another bile
acid supplement UDCA, ursodeoxycholic acid, this UDCA can also be used for the management
of PBC so both of these drugs can be combined otherwise this obeticholicacid can be given to
those patients who are not tolerated with UDCA. Since this OCA can produce severe hepatic
decompensation, this drug should be restricted in those patients who are not tolerated with UDCA.
And sometimes in order to increase the efficacy it can also be combined with UDCA. In our
previous video, we have discussed about this UDCA and today in this video we are going to
discuss obeticholicacid, how this drug acts, how it can control the bile acid levels within the
hepatocytes, what is its chemical nature, what are the important precautions, side effects, dosage,
all these things we will discuss in this video. First of all let us see the chemical nature
of this drug. So this is the structure of obeticholicacid and let us give the numbering so
we can write the suffix as cholanic acid where carboxylic acid is present at the 24th position
so we can write this as cholan- 24- oic acid. And just like the UDCA again this drug is having
hydroxyl group at third and fourth position so we can write this as 3,7-Dihydroxy but in addition
it is having a ethyl group at the sixth position, this ethyl group is attached by alpha
configuration so it is having the 6 alpha-ethyl, that is the complete name of obeticholicacid. Now
let's see how this drug acts? Within the liver, cholesterol is going to be metabolized to
produce the bile acids and this metabolic process is a multi-step process mediated
mainly by one of the metabolic enzyme CYP7A1. Now this bile acid is going to
be stored into the gallbladder and some of the bile acid can also be taken
by hepatocytes through the portal circulation and when these bile acids are excessively increase
in the liver it can produce the apoptosis and damage to the liver and the excessive bile acids
can also form the gall stones within the gall bladder which obstruct the bile flow. So in such
conditions,biliary cirrhosis as well as hepatic cirrhosis can be observed which should be treated
by reducing the bile acid levels within the liver. So here obeticholicacid can mediate this action by
acting on three types of transporters,one is the NTCP, second one is BSEP and third one is ASBT.
NTCP is the sodium taurocholate co-transporter which is responsible for uptake
of bile acids into hepatocytes through the portal circulation.So this NTCP
is expressed on the hepatocytes resulting in the uptake of bile acids which increase the
accumulation of bile acids within the liver. Second one is the BSEP, which is a bile salt
export pump which is responsible for secretion of bile acids into the bile canaliculi so that they
can reduce the bile acid levels within the liver. Third one is the ASBT, apical sodium bile acid
transporter which is responsible for absorption of bile acids at the terminal ileum. Now these bile
acids which are absorbed at the terminal ilium are going to be transported to the liver through
the portal circulation. Now this obeticholicacid can inhibit the action of NTCP so that it can
reduce the uptake of bile acids into the liver and it can promote the expression of BSEP so that bile
acid secretion is going to be promoted, finally it can inhibit the ASPT so that the absorption of
bile acid at terminal ileum is somewhat reduced. By all of these actions, obeticholicacid can
reduce the bile acid accumulation within the liver which reduce the apoptosis. This is the hepatocyte
and within the hepatocytes, the cholesterol is going to be metabolized to produce the bile
acids by one of the metabolic enzyme CYP7A1. Now another transporter is also expressed on
the hepatocytes that is the NTCP so whatever the bile acids from the portal circulation they
can be entered into the hepatocytes through this transporter. So by this way, the bile acid
levels are increased within the hepatocytes which increase the apoptosis.
Now obeticholicacid is one of the farnesoid receptor agonist, it can target
this farnesoid receptors which are present within the nuclei of hepatocytes. They can bind
to these farnesoid receptors which are going to be dimerized and they can inhibit the activity of
CYP7A1. So this reduce the synthesis of bile acids within the liver from cholesterol. And similarly
it also inhibits the another transporter NTCP, thereby the uptake of bile acids
into the hepatocytes is also reduced and finally when these farnesoid receptors are
activated, they can increase the expression of another transporter BSEP, which promotes the
secretion of bile into the bile canaliculli. In this way the bile acid concentration
within the hepatocytes is going to be reduced which reduce the apoptosis and cirrhosis of the
liver.Another target is at the enterocytes,at the enterocytes another transporter is present that
is ASBT, apical sodium bile acid transporter. Now the bile acids at the terminal ileum
can be absorbed through this ASBT pump but again at the hepatocytes, the farnesoid X
receptors are present, now OCA can bind to the farnesoid X receptors such that it can inhibit the
ASBT activity. So when this pump is inhibited,bile acid is not absorbed so bile acid absorption
and transport to the liver is somewhat reduced. Similarly the farnesoid X receptor activation
by OCA can also increase the release of another mediator FGF19, fibroblast growth factor 19.
This FGF19 can act on the corresponding receptors expressed on hepatocytes so once this FGF19 binds
to these receptors it can inhibit the activity of CYP7A1. So this can also reduce the release of
bile acids from the cholesterol thereby it can reduce the bile acid levels within the liver.
In this way, OCA can affect all these pumps thereby it can reduce the bile acid levels within
the liver. What are the precautions? One of the important precaution of obeticholicacid is that
this drug can produce some hepatic decompensation. So it is not suitable for all the patients so
it can increase the total bilirubin levels, even it can increase the ALP levels
which indicates hepatic dysfunction and few of the symptoms may be developed within the
patient such as development of jaundice,ascites formation, swelling of the abdomen and it
can also affect the gastrointestinal system resulting in the GI bleeding so if any of these
symptoms are observed then this obeticholicacid should be carefully used because it can
produce some severe hepatic decompensation. Similarly this drug can precipitate
pruritus resulting in the severe itching and this itching can be spread all over the
body resulting in the disturbance in the sleep so severe itching and sleep disturbance
can be observed with this obeticholicacid. Similarly this drug can reduce the HDL
cholesterol levels where HDL is considered as good cholesterol and it should be in the
range of 40 to 60 milligrams per deciliter, by the use of this drug the HDL cholesterol may
be reduced less than 40 milligrams per deciliter which increase the risk of atherosclerosis.
So in those patients with any risk factors for cardiovascular complications, this
drug should be carefully given. What are the side effects? The important side
effects mainly include abdominal pain, fatigue, arthralgia, joint pain, pruritus, it
can produce severe itching in the patients, dizziness, some constipation, eczema and
peripheral edema can also be observed with this obeticholicacid and it can also increase
the palpitations awareness of heartbeat and pyrexia increase in the body temperature
can also be observed with this drug. How it is given? This drug is available as
tablets at different strengths such as 5 mg,10 mg, the initial dose of the drug is
started at a very low dose such as 5 mg given once daily . After 3 months of
the treatment,the dose can be increased up to 10 mg again given as once daily. But in the
patients with any hepatic dysfunction,the dose should be somewhat reduced, instead of
giving as once daily this obeticholicacid can be given at a dose of 5mg given once weekly. So
that's about this drug, obeticholicacid which is a farnesoid receptor agonist which reduce
the uptake of bile acids into the hepatocytes and increase the biliary secretion,it also reduce
the absorption of bile acids at the terminal ileum, by all of these actions it can reduce
the hepatic apoptosis and biliary cirrhosis. This drug is restricted in those patients who
are not tolerated with UDCA and this drug can also be combined with UDCA to produce effective
treatment for primary biliary cholangitis. But in the patients with any hepatic decompensation,
this drug should be carefully given. So that's about this drug obeticholicacid,
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