in this lecture we gonna cover drugs
used for hyperlipidemia so let's get right into it
hyperlipidemia simply is a disorder in which there are abnormally elevated
levels of fat particles in the blood known as lipids these lipids can adhere
to the walls of the arteries and restrict blood flow which in turn
creates significant risk of heart attack and stroke there are three major lipids
in the blood namely cholesterol triglycerides and phospholipids
now cholesterol is necessary for the synthesis of bile acid steroid hormones
and to maintain the integrity of cell membranes triglycerides are composed of
glycerol and three fatty acids which serve as an important source of energy
that can be stored throughout the body and lastly phospholipids are a major
component of all cell membranes and function as an emulsifiers now because
these lipids are insoluble in blood plasma they have to be transported
throughout the body in a protein capsule known as lipoprotein lipoproteins
consist of a hydrophobic core made of cholesterol and triglycerides surrounded
by hydrophilic shell made of phospholipids and apolipoproteins
these apolipoproteins are specialized proteins that can control enzymes in
lipoprotein metabolism and serve as ligands for lipoprotein receptors now
depending on the variation in lipid and apolipoprotein composition as well as
their density lipoproteins can be divided into four major types that is
chylomicrons very low-density lipoprotein VLDL for short
low-density lipoprotein LDL for short and high-density lipoprotein HDL for
short now chylomicrons are produced in the gut
from dietary lipids and are composed mostly of triglycerides and relatively
small amount of cholesterol next VLDLs are produced in the liver and
are composed primarily of triglycerides and some cholesterol in the amount
relatively larger in comparison to chylomicrons now the function of these
two lipoproteins is to deliver energy rich triglycerides to cells throughout
the body once they are secreted into the bloodstream the enzyme located on the
capillary walls called lipoprotein lipase releases the fatty acids which are then
taken up by the tissues as the triglyceride content decreases the VLDL
gets transformed into LDL which now contains relatively higher percentage of
cholesterol the function of LDL is simply to deliver this cholesterol to
cells where it's used for cell membrane and synthesis of steroid hormones
however more than half of the circulating LDL is eventually taken up
by the liver which uses cholesterol to synthesize bile acids and as you may
already know bile acids are necessary for normal digestion and absorption of
fats and fat soluble vitamins in the small intestine
lastly excess cholesterol from the peripheral cells is transported back to
the liver by HDL HDL is composed mainly of protein with small amount of lipids
and it is produced in the liver and small intestine
now the problem arises when we have abnormally high levels of LDL
cholesterol which can accumulate in the innermost layer of the artery wall and
lead to formation of atherosclerotic lesions this is why LDL is often
referred to as bad cholesterol now HDL on the other hand prevents
formation of atherosclerotic lesions by removing cholesterol as well as
suppressing LDL oxidation and vascular inflammation this is why HDL is often
referred to as a good cholesterol so abnormally low levels of it can also
contribute to atherosclerosis now there are several major classes of lipid
lowering drugs so first we have HMG-CoA reductase inhibitors
commonly known as statins in order to better understand how these agents work
we need to take a closer look at the liver cell this is where HMG-CoA reductase enzyme converts HMG-CoA into mevalonic acid which is a cholesterol
precursor this is a rate limiting step so by inhibiting this enzyme statins
effectively reduce concentration of cholesterol within the liver cell now
liver cells sense the reduced levels of cholesterol production and begin to
compensate by synthesizing more LDL receptors which in turn bind and
internalize LDL that's circulating in the blood additionally low intracellular
cholesterol levels lead to decreased secretion of VLDL which also
contributes to lowering of triglyceride levels lastly statins may also increase
HDL levels by few different mechanisms that are still being investigated
example of drugs that belong to this class are Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin and Simvastatin now when it comes to side effects because statins are metabolized in the
liver they may elevate liver enzymes and thus increase risk of liver toxicity in
susceptible patients secondly use of statins has been associated with muscle
related problems or myopathy and in rare cases
rhabdomyolysis that is destruction of skeletal muscle the mechanism behind
that is still being investigated however it is thought to be related to the
inhibition of mevalonate production which happens to be essential precursor
to other compounds that are important to maintain the integrity of muscle cells
now let's move on to the next group of lipid lowering drugs which includes only
one agent that is Nicotinic Acid commonly known as Niacin
so unlike statins Niacin works in adipose tissue where it inhibits enzyme
called hormone-sensitive lipase which is responsible for breakdown of
triglycerides to free fatty acid now normally liver uses
these free fatty acids to make its own triglycerides which then become
important component of VLDL so by reducing levels of free fatty acids
available for transport to the liver Niacin effectively decreases hepatic
VLDL synthesis which in turn leads to decreased levels of LDL furthermore
Niacin increases HDL levels by few different mechanisms that are still
being investigated now when it comes to side effects one of the most common one
is flushing caused by Niacin induced prostaglandin release which results in
cutaneous vasodilation next Niacin can compete with uric acid for excretion by
the kidney which can increase risk of hyperuricemia and gout lastly at large
enough doses Niacin may also cause liver toxicity now let's move on to another
group of lipid lowering drugs that is fibrates so fibrates work primarily by
activating nuclear transcription receptor called peroxisome proliferator-activated receptor alpha or PPAR-alpha for short PPAR-alpha is found in
metabolically active tissues such as liver and adipose tissue the binding of
fibrates to PPAR-alpha induces activation or inhibition of certain
genes that code for proteins involved in lipid metabolism one of the main effects
induced by fibrates is increased expression of lipoprotein lipase which
in turn increases the removal triglycerides from circulation and their
breakdown to fatty acids furthermore fibrates decrease expression of protein
called Apo-CIII which inhibits lipoprotein lipase activity and lastly
fibrates also increase expression of proteins
Apo-AI and Apo-AII which are major component of HDL thus leading to
increase in its concentrations drugs that belong to this class include Fenofibrate and Gemfibrozil now when it comes to side effects the
most common ones are GI disturbances additionally just like with statins
myopathy and rhabdomyolysis have been reported particularly in patients
with impaired renal function the precise mechanism of myotoxicity is still yet
to be determined however it is thought to be multifactorial lastly because
fibrates increase the cholesterol content of bile they can increase risk
of gallstone formation now let's move on to the next group of lipid lowering
drugs that is bile acid sequestrants so as you already know bile acids are
produced in the liver stored in the gallbladder and they're excreted into
the gut where they facilitate digestion and absorption of lipids now bile acids
sequestrants basically serve as an ion exchange resins that bind negatively
charged bile acids and salts in the small intestine the formation of this
insoluble complex prevents the reabsorption of bile acids and thus
leads to their excretion this increase in bile acid excretion in turn creates
increased demand for their production since bile acids are made from
cholesterol liver cells increase their number of LDL receptors to bring in more
LDL cholesterol in order to meet this new demand so the end result is
decreased levels of circulating LDL example of drugs that belong to this
class are Colesevelam Colestipol and Cholestyramine now side effects are
limited to the GI tract so bloating indigestion constipation and nausea are
quite common additionally these agents may decrease absorption of fat soluble
vitamins and they also have potential to form insoluble complexes with other
drugs thus interfering with their absorption now let's move on to another
group of lipid lowering drugs that is cholesterol absorption inhibitors in
order to understand how cholesterol absorption inhibitor works it's
important to understand the basic mechanism of cholesterol absorption in
small intestine so free cholesterol that comes either from
bile or dietary sources first binds to protein abbreviated NPC1L1 which is
located in the plasma membrane of cells known as enterocytes that line the
intestinal walls this binding then triggers endocytosis which utilizes
protein complex called clathrin AP2 that works on the cell membrane to
internalize the cholesterol cargo upon endocytosis the cholesterol is released
and the NPC1L1 returns back to the plasma membrane
now the cholesterol absorption inhibitor simply binds to NPC1L1 and inhibits its
ability to interact with clathrin AP2 complex that is necessary for
endocytosis this leads to decreased delivery of intestinal cholesterol to
the liver which in turn causes decrease in hepatic cholesterol levels and
ultimately increased clearance of LDL cholesterol from the circulation
currently the only drug that belongs to this class is Ezetimibe the side effects
of Ezetimibe are few and mild which makes it a good choice for patients
intolerant or unresponsive to statins now let's move on to the next group of
lipid lowering drugs that is PCSK9 inhibitors so PCSK9 is an abbreviated
name of enzyme circulating in the blood that binds to LDL receptors on the
surface of liver cells and promotes their degradation in other words the
activity of PCSK9 reduces the removal of LDL from the circulation now the PCSK9
inhibitors are monoclonal antibodies that bind to and inactivate PCSK9 in the
absence of PCSK9 there's more LDL receptors available to bind and clear
LDL from the circulation leading to decreased levels of LDL cholesterol
example of drugs that belong to this group include Evolocumab and Alirocumab some of the side effects that have been reported with these agents are
injection site reactions flu-like symptoms and some neurocognitive
problems now before we end I wanted to briefly discuss the last major group of
lipid lowering drugs that is omega-3 fatty acids so omega-3 fatty acids are
used primarily for their triglyceride lowering effects which are thought to be
caused by inhibition of VLDL and triglyceride synthesis in the liver the
agents that fall into this class are the components of omega-3 fatty acids called
docosahexaenoic acid and eicosapentaenoic acid DHA and EPA for short as well as omega-3 derivative Icosapent ethyl the most common side effects associated with these agents are GI disturbances such as abdominal pain
nausea and diarrhea as well as fishy aftertaste with fish-derived omega-3s
lastly at high enough doses there appears to be some increased risk of
bleeding and with that I wanted to thank you for watching I hope you enjoyed this
video and as always stay tuned for more