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