Pharmacology - DRUGS FOR HYPERLIPIDEMIA (MADE EASY)

Summary

This 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

• 🧬 Hyperlipidemia is a condition where there's an abnormal elevation of lipids in the blood, posing a risk for heart attack and stroke.
• 📈 The three main lipids in the blood are cholesterol, triglycerides, and phospholipids, which serve various functions in the body.
• 🚀 Lipoproteins are protein capsules that transport lipids through the body, and they come in four main types: chylomicrons, VLDL, LDL, and HDL.
• 🔍 LDL is often called 'bad cholesterol' because high levels can lead to atherosclerosis, while HDL is known as 'good cholesterol' for its protective role.
• 💊 Statins are HMG-CoA reductase inhibitors that lower cholesterol levels by inhibiting cholesterol production in the liver.
• 🏥 Statins can have side effects such as elevated liver enzymes and muscle-related problems, including rhabdomyolysis.
• 🍋 Niacin, also known as Nicotinic Acid, reduces triglyceride levels and increases HDL by inhibiting hormone-sensitive lipase in adipose tissue.
• 🍊 Fibrates work by activating PPAR-alpha, leading to increased removal of triglycerides and higher HDL levels.
• 🌱 Bile acid sequestrants bind bile acids in the intestine, reducing their reabsorption and leading to increased LDL receptor production in the liver.
• 🚫 Cholesterol absorption inhibitors, like Ezetimibe, block cholesterol uptake in the intestine by inhibiting NPC1L1, thus lowering LDL cholesterol levels.
• 🤒 PCSK9 inhibitors are monoclonal antibodies that reduce LDL cholesterol levels by preventing the degradation of LDL receptors on liver cells.
• 🐟 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

00:00

💊 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.

05:03

🛡 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.

10:04

🍋 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.

🧪 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.

💉 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.

Keywords

💡Hyperlipidemia

Hyperlipidemia refers to a condition characterized by abnormally high levels of lipids, such as cholesterol, triglycerides, and phospholipids, in the blood. It is a key theme of the video as it sets the stage for discussing the various drugs used to treat this disorder. The video explains that these elevated lipid levels can lead to the formation of atherosclerotic lesions, increasing the risk of heart attack and stroke.

💡Lipoproteins

Lipoproteins are protein-lipid complexes that transport lipids through the bloodstream. The video details four major types of lipoproteins: chylomicrons, VLDL, LDL, and HDL. Each type plays a specific role in lipid metabolism and has implications for cardiovascular health, with LDL often referred to as 'bad cholesterol' and HDL as 'good cholesterol'.

💡Statins

Statins are a class of drugs known as HMG-CoA reductase inhibitors. They work by reducing cholesterol production in the liver, leading to an increase in LDL receptor synthesis and a decrease in circulating LDL levels. The video mentions several statin drugs, such as Atorvastatin and Simvastatin, and discusses their side effects, including potential liver toxicity and muscle-related problems.

💡Niacin

Niacin, also known as Nicotinic Acid, is a lipid-lowering drug that operates differently from statins. It inhibits the hormone-sensitive lipase in adipose tissue, reducing the breakdown of triglycerides into free fatty acids and thus decreasing hepatic VLDL synthesis. The video notes that Niacin can increase HDL levels and discusses its common side effect of flushing.

💡Fibrates

Fibrates are a class of drugs that activate the PPAR-alpha receptor, influencing gene expression related to lipid metabolism. They increase the activity of lipoprotein lipase, reduce triglyceride levels, and can raise HDL concentrations. The video provides examples of fibrates, such as Fenofibrate and Gemfibrozil, and mentions side effects like GI disturbances and potential myopathy.

💡Bile Acid Sequestrants

Bile acid sequestrants are drugs that bind to bile acids in the intestine, preventing their reabsorption and leading to their excretion. This process increases the liver's demand for bile acid production, resulting in upregulation of LDL receptors and reduced LDL cholesterol levels. The video lists Colesevelam, Colestipol, and Cholestyramine as examples and notes GI-related side effects.

💡Cholesterol Absorption Inhibitors

Cholesterol absorption inhibitors, such as Ezetimibe, work by binding to NPC1L1 protein in the intestinal wall, inhibiting the absorption of cholesterol from the diet. This leads to decreased hepatic cholesterol levels and increased clearance of LDL cholesterol from the blood. The video highlights the mild side effects of this drug class, making it suitable for patients with statin intolerance.

💡PCSK9 Inhibitors

PCSK9 inhibitors are monoclonal antibodies that target the PCSK9 enzyme, preventing it from promoting the degradation of LDL receptors. This allows for more LDL to be cleared from the circulation, reducing cholesterol levels. The video names Evolocumab and Alirocumab as examples of PCSK9 inhibitors and mentions side effects like injection site reactions and neurocognitive issues.

💡Omega-3 Fatty Acids

Omega-3 fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are used primarily for their triglyceride-lowering effects. They are thought to inhibit VLDL and triglyceride synthesis in the liver. The video also mentions Icosapent ethyl as an omega-3 derivative and discusses common side effects such as GI disturbances and a fishy aftertaste.

💡Atherosclerosis

Atherosclerosis is a condition where plaques build up inside the arteries, restricting blood flow and increasing the risk of heart attack and stroke. The video explains that high levels of LDL cholesterol can accumulate in artery walls, leading to atherosclerotic lesions. The prevention and treatment of atherosclerosis are central to the discussion of hyperlipidemia and its management with various drugs.

💡Myopathy

Myopathy refers to muscle-related problems that can be associated with the use of certain lipid-lowering drugs, such as statins and fibrates. The video mentions that the mechanism behind myopathy is thought to be related to the inhibition of mevalonate production, which is essential for maintaining muscle cell integrity. Rhabdomyolysis, a severe form of myopathy, is also discussed as a rare side effect.

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