Pharmacology - DRUGS FOR HYPERLIPIDEMIA (MADE EASY)
Summary
TLDRThis lecture delves into hyperlipidemia, a condition marked by elevated blood lipids, which can lead to heart attack and stroke. It explains the role of cholesterol, triglycerides, and phospholipids, and their transport via lipoproteins. The video outlines various lipid-lowering drugs, including statins, niacin, fibrates, bile acid sequestrants, cholesterol absorption inhibitors, PCSK9 inhibitors, and omega-3 fatty acids, detailing their mechanisms and potential side effects, providing a comprehensive overview of managing hyperlipidemia.
Takeaways
- 𧬠Hyperlipidemia is a condition where there's an abnormal elevation of lipids in the blood, posing a risk for heart attack and stroke.
- π The three main lipids in the blood are cholesterol, triglycerides, and phospholipids, which serve various functions in the body.
- π Lipoproteins are protein capsules that transport lipids through the body, and they come in four main types: chylomicrons, VLDL, LDL, and HDL.
- π LDL is often called 'bad cholesterol' because high levels can lead to atherosclerosis, while HDL is known as 'good cholesterol' for its protective role.
- π Statins are HMG-CoA reductase inhibitors that lower cholesterol levels by inhibiting cholesterol production in the liver.
- π₯ Statins can have side effects such as elevated liver enzymes and muscle-related problems, including rhabdomyolysis.
- π Niacin, also known as Nicotinic Acid, reduces triglyceride levels and increases HDL by inhibiting hormone-sensitive lipase in adipose tissue.
- π Fibrates work by activating PPAR-alpha, leading to increased removal of triglycerides and higher HDL levels.
- π± Bile acid sequestrants bind bile acids in the intestine, reducing their reabsorption and leading to increased LDL receptor production in the liver.
- π« Cholesterol absorption inhibitors, like Ezetimibe, block cholesterol uptake in the intestine by inhibiting NPC1L1, thus lowering LDL cholesterol levels.
- π€ PCSK9 inhibitors are monoclonal antibodies that reduce LDL cholesterol levels by preventing the degradation of LDL receptors on liver cells.
- π Omega-3 fatty acids primarily lower triglyceride levels by inhibiting their synthesis in the liver and are associated with mild side effects.
Q & A
What is hyperlipidemia?
-Hyperlipidemia is a disorder characterized by abnormally elevated levels of fat particles, known as lipids, in the blood. These lipids can adhere to the walls of the arteries, restricting blood flow and creating a significant risk of heart attack and stroke.
What are the three major lipids found in the blood?
-The three major lipids in the blood are cholesterol, triglycerides, and phospholipids.
What is the role of cholesterol in the body?
-Cholesterol is necessary for the synthesis of bile acids, steroid hormones, and to maintain the integrity of cell membranes.
What are lipoproteins and why are they important for lipid transport?
-Lipoproteins are protein capsules that transport lipids throughout the body. They are important because lipids are insoluble in blood plasma and need to be carried in these protein packages.
How do chylomicrons and VLDL contribute to energy delivery in the body?
-Chylomicrons and VLDL deliver energy-rich triglycerides to cells throughout the body. They are composed primarily of triglycerides and some cholesterol, and they are broken down by lipoprotein lipase into fatty acids that are taken up by tissues.
Why is LDL cholesterol often referred to as 'bad cholesterol'?
-LDL cholesterol is often called 'bad cholesterol' because abnormally high levels of it can accumulate in the innermost layer of the artery wall, leading to the formation of atherosclerotic lesions.
What is the primary function of HDL cholesterol?
-HDL cholesterol, often referred to as 'good cholesterol,' prevents the formation of atherosclerotic lesions by removing cholesterol and suppressing LDL oxidation and vascular inflammation.
How do statins work to reduce cholesterol levels?
-Statins work by inhibiting the HMG-CoA reductase enzyme in the liver, which is responsible for converting HMG-CoA into mevalonic acid, a cholesterol precursor. This reduction in cholesterol production leads to an increase in LDL receptor synthesis, which in turn increases the clearance of LDL cholesterol from the blood.
What is the mechanism of action of Niacin as a lipid-lowering drug?
-Niacin works in adipose tissue by inhibiting the hormone-sensitive lipase enzyme, which is responsible for breaking down triglycerides into free fatty acids. By reducing the levels of free fatty acids available for transport to the liver, Niacin decreases hepatic VLDL synthesis and increases HDL levels.
How do fibrates affect lipid metabolism in the body?
-Fibrates work by activating the PPAR-alpha receptor, which induces the activation or inhibition of certain genes involved in lipid metabolism. This leads to increased expression of lipoprotein lipase, decreased expression of Apo-CIII, and increased expression of Apo-AI and Apo-AII, resulting in lower triglyceride levels and higher HDL levels.
What is the role of bile acid sequestrants in lowering LDL cholesterol?
-Bile acid sequestrants bind to bile acids in the small intestine, preventing their reabsorption and leading to their excretion. This increases the demand for bile acid production by the liver, which in turn increases the number of LDL receptors to bring in more LDL cholesterol, resulting in decreased circulating LDL levels.
How do cholesterol absorption inhibitors like Ezetimibe work?
-Cholesterol absorption inhibitors, such as Ezetimibe, work by binding to the NPC1L1 protein in the intestinal wall, inhibiting its interaction with the clathrin AP2 complex necessary for endocytosis. This leads to decreased delivery of intestinal cholesterol to the liver, reduced hepatic cholesterol levels, and increased clearance of LDL cholesterol from the circulation.
What are PCSK9 inhibitors and how do they lower LDL cholesterol levels?
-PCSK9 inhibitors are monoclonal antibodies that bind to and inactivate PCSK9 enzyme, which promotes the degradation of LDL receptors on liver cells. In the absence of PCSK9, more LDL receptors are available to clear LDL from the circulation, leading to decreased levels of LDL cholesterol.
What are the primary effects of omega-3 fatty acids on lipid levels?
-Omega-3 fatty acids are primarily used for their triglyceride-lowering effects, which are thought to be caused by the inhibition of VLDL and triglyceride synthesis in the liver.
Outlines
π Hyperlipidemia and Lipid-Lowering Drugs
This paragraph introduces hyperlipidemia as a disorder characterized by high levels of lipids in the blood, which can lead to atherosclerosis and increase the risk of heart attack and stroke. It explains the roles of cholesterol, triglycerides, and phospholipids, and how they are transported by lipoproteins, which are categorized into chylomicrons, VLDL, LDL, and HDL. The paragraph also differentiates between 'good' and 'bad' cholesterol and sets the stage for discussing various classes of lipid-lowering drugs.
π‘ Statins: HMG-CoA Reductase Inhibitors
The second paragraph delves into the mechanism of action of statins, which are HMG-CoA reductase inhibitors. Statins reduce cholesterol production in the liver by inhibiting the enzyme HMG-CoA reductase, leading to an increase in LDL receptors and a decrease in LDL cholesterol levels. They also have the potential to lower triglyceride levels and increase HDL levels. Common statin drugs are listed, along with potential side effects such as liver toxicity and muscle-related problems like myopathy and rhabdomyolysis.
π Niacin and Fibrates: Alternative Lipid-Lowering Agents
This section discusses two additional classes of lipid-lowering drugs: niacin and fibrates. Niacin works by inhibiting hormone-sensitive lipase in adipose tissue, reducing triglyceride breakdown and VLDL synthesis, thereby decreasing LDL and increasing HDL levels. Fibrates, on the other hand, activate PPAR-alpha, influencing gene expression related to lipid metabolism and increasing lipoprotein lipase activity. Common side effects of niacin include flushing and potential liver toxicity, while fibrates may cause GI disturbances and myopathy.
π§ͺ Bile Acid Sequestrants and Cholesterol Absorption Inhibitors
The fourth paragraph covers bile acid sequestrants and cholesterol absorption inhibitors. Bile acid sequestrants bind bile acids in the intestine, preventing their reabsorption and stimulating the liver to produce more, thereby increasing LDL receptor numbers and reducing LDL cholesterol levels. Cholesterol absorption inhibitors, such as Ezetimibe, work by blocking the interaction between NPC1L1 and clathrin AP2, reducing cholesterol uptake from the intestine. Common side effects include GI issues and potential interference with other drug absorption.
π PCSK9 Inhibitors and Omega-3 Fatty Acids
The final paragraph introduces PCSK9 inhibitors, which are monoclonal antibodies that inactivate PCSK9, allowing for more LDL receptors to clear LDL cholesterol from the circulation. This results in decreased LDL cholesterol levels. PCSK9 inhibitors like Evolocumab and Alirocumab may cause injection site reactions and neurocognitive issues. The paragraph also mentions omega-3 fatty acids, which lower triglycerides by inhibiting their synthesis in the liver, with common side effects being GI disturbances and a fishy aftertaste.
Mindmap
Keywords
π‘Hyperlipidemia
π‘Lipoproteins
π‘Statins
π‘Niacin
π‘Fibrates
π‘Bile Acid Sequestrants
π‘Cholesterol Absorption Inhibitors
π‘PCSK9 Inhibitors
π‘Omega-3 Fatty Acids
π‘Atherosclerosis
π‘Myopathy
Highlights
Hyperlipidemia is a disorder characterized by elevated levels of lipids in the blood, which can lead to heart attack and stroke.
Lipids include cholesterol, triglycerides, and phospholipids, which have essential roles in the body.
Lipoproteins transport lipids through the body, and their types include chylomicrons, VLDL, LDL, and HDL.
LDL is often called 'bad cholesterol' due to its role in atherosclerosis, while HDL is known as 'good cholesterol'.
Statins, such as Atorvastatin and Rosuvastatin, work by inhibiting HMG-CoA reductase enzyme to reduce cholesterol levels.
Statins can cause side effects like elevated liver enzymes and muscle-related problems, including rhabdomyolysis.
Niacin, or Nicotinic Acid, reduces triglyceride levels by inhibiting hormone-sensitive lipase in adipose tissue.
Common side effects of Niacin include flushing, hyperuricemia, and potential liver toxicity.
Fibrates, such as Fenofibrate, activate PPAR-alpha to influence lipid metabolism and increase lipoprotein lipase expression.
Bile acid sequestrants bind bile acids in the small intestine, leading to increased LDL receptor production and lower LDL levels.
Cholesterol absorption inhibitors, like Ezetimibe, reduce cholesterol absorption in the intestine by binding to NPC1L1.
PCSK9 inhibitors, such as Evolocumab, increase LDL receptor availability, enhancing LDL clearance from the blood.
Omega-3 fatty acids, including EPA and DHA, lower triglyceride levels and have mild side effects like GI disturbances.
Each class of lipid-lowering drugs has specific mechanisms and side effects, tailored to different patient needs.
Understanding the roles and interactions of various lipids and lipoproteins is crucial for managing hyperlipidemia.
Lipid-lowering drugs offer a range of options for treating hyperlipidemia, each with unique benefits and risks.
The lecture provides a comprehensive overview of the pharmacological management of hyperlipidemia.
Transcripts
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
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