Hyperlipidemia
- 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
- creates significant risk of heart attack and stroke
Content:
2. HMG-CoA reductase inhibitors
3. Lipid-lowering drugs
4. Fibrates
5. Bile acid sequestrants
6. Cholesterol absorption inhibitors
7. PCSK9 inhibitors
8. Omega-3 fatty acids
9. Reference
1. Lipids
Three major lipids in the blood
- cholesterol
- necessary for the synthesis of bile acid steroid hormones
- maintain the integrity of cell membranes
- triglycerides
- composed of glycerol and three fatty acids
- serve as an important source of energy that can be stored throughout the body
- phospholipids
- major component of all cell membranes
- function as an emulsifiers
These lipids are insoluble in blood plasma, so they have to be transported throughout the body in a protein capsule, known as lipoprotein
lipoproteins consist of
- a hydrophobic core made of cholesterol
- triglycerides surrounded by hydrophilic shell
- hydrophilic shell made of phospholipids and apolipoproteins
- apolipoproteins are specialized proteins that can control enzymes in lipoprotein metabolism
- serve as ligands for lipoprotein receptors
Lipoproteins can be divided into four major types:
- Chylomicrons
- produced in the gut from dietary lipids
- composed mostly of triglycerides and relatively small amount of cholesterol
- Very low-density lipoprotein (VLDL)
- produced in the liver
- composed primarily of triglycerides and some cholesterol in the amount relatively larger in comparison to chylomicrons
- Low-density lipoprotein (LDL)
- High-density lipoprotein (HDL)
- produced in the liver and small intestine
- composed mainly of protein with small amount of lipids
Function of Chylomicrons & VLDL
- to deliver energy rich triglycerides to cells throughout the body
- once they are secreted into the bloodstream,
- lipoprotein lipase releases the fatty acids
- lipoprotein lipase: the enzyme located on the capillary walls
- fatty acids taken up by the tissues as the triglyceride content decreases
- VLDL gets transformed into LDL which now contains relatively higher percentage of cholesterol
Function of LDL (bad cholesterol)
- 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
- uses cholesterol to synthesize bile acids
- bile acids: are necessary for normal digestion and absorption of fats and fat-soluble vitamins in the small intestine
Function of HDL (good cholesterol)
- excess cholesterol from the peripheral cells is transported back to the liver by HDL
Problem arises when
- abnormally high levels of LDL cholesterol & abnormally low levels of HDL
- accumulate in the innermost layer of the artery wall
- lead to formation of atherosclerotic lesions
- HDL prevents formation of atherosclerotic lesions by
- removing cholesterol
- suppressing LDL oxidation
- vascular inflammation
2. HMG-CoA reductase inhibitors
- commonly known as statins
- work in liver cell where HMG-CoA reductase enzyme converts HMG-CoA into mevalonic acid
- mevalonic acid is a cholesterol precursor
- is rate-limiting step
by inhibiting this enzyme,
- statins effectively reduce concentration of cholesterol within the liver cell
- liver cells sense the reduced levels of cholesterol production
- begin to compensate by synthesizing more LDL receptors
- bind and internalize LDL that circulating in the blood
- additionally low intracellular cholesterol levels lead to decreased
- secretion of VLDL
- contributes to lowering of triglyceride levels
- statins may also increase HDL levels
Drug:
- Atorvastatin
- Fluvastatin
- Lovastatin
- Pravastatin
- Rosuvastatin
- Simvastatin
Side effects
- increase risk of liver toxicity in susceptible patients
- because statins are metabolized in the liver, they may elevate liver enzymes
- muscle related problems or myopathy, in rare cases rhabdomyolysis that is destruction of skeletal muscle
- the mechanism behind that is still being investigated
- 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
3. Lipid-lowering drugs
Drug: Nicotinic Acid
- commonly known as Niacin
- works in adipose tissue where it inhibits enzyme called hormone-sensitive lipase
- responsible for breakdown of triglycerides to free fatty acid
- normally liver uses these free fatty acids to make its own triglycerides
- which then become important component of VLDL
- by reducing levels of free fatty acids available for transport to the liver,
- Niacin effectively decreases hepatic VLDL synthesis
- leads to decreased levels of LDL
- Niacin also increases HDL levels
Side effects
- flushing
- caused by Niacin induced prostaglandin release
- results in cutaneous vasodilation
- increase risk of hyperuricemia and gout
- compete with uric acid for excretion by the kidney
- liver toxicity
- at large enough doses
4. Fibrates
- work primarily by activating nuclear transcription receptor called peroxisome proliferator-activated receptor alpha (PPAR-alpha)
- 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
- increased expression of lipoprotein lipase
- increases the removal triglycerides from circulation and their breakdown to fatty acids
- fibrates decrease expression of protein called Apo-CIII
- Apo-CIII inhibits lipoprotein lipase activity
- also increase expression of proteins Apo-AI and Apo-AII which are major component of HDL
- leading to increase in HDL concentrations
Drugs:
- Fenofibrate
- Gemfibrozil
Side effects
- GI disturbances
- myopathy and rhabdomyolysis
- 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
- increase risk of gallstone formation
- because fibrates increase the cholesterol, content of bile
5. Bile acid sequestrants
- produced in the liver
- stored in the gallbladder
- excreted into the gut where they facilitate digestion and absorption of lipids
- serve as an ion exchange resins that bind negatively charged bile acids and salts in the small intestine
- formation of this insoluble complex
- prevents the reabsorption of bile acids
- increase in bile acid excretion
- creates increased demand for their production
- increase number of LDL receptors to bring in more LDL cholesterol to meet this demand
- result is decreased levels of circulating LDL
Drug:
- Colesevelam
- Colestipol
- Cholestyramine
Side effects
- limited to the GI tract, eg
- bloating
- indigestion
- constipation
- nausea
- decrease absorption of fat soluble vitamins
- have potential to form insoluble complexes with other drugs
- interfering with their absorption
6. Cholesterol absorption inhibitors
Cholesterol absorption in small intestine
Free cholesterol that comes either from bile or dietary sources
- first binds to NPC1L1 protein
- located in the plasma membrane of cells, known as enterocytes
- enterocytes line the intestinal walls
- this binding triggers endocytosis which utilizes protein complex called clathrin AP2
- clathrin AP2 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
Cholesterol absorption inhibitor
- binds to NPC1L1
- inhibits its ability to interact with clathrin AP2 complex
- that is necessary for endocytosis
- leads to decreased delivery of intestinal cholesterol to the liver causes decrease in hepatic cholesterol levels
- ultimately increased clearance of LDL cholesterol from the circulation
Drug: Ezetimibe
Side effects
- few and mild
- a good choice for patients intolerant or unresponsive to statins
7. PCSK9 inhibitors
PCSK9
enzyme circulating in the blood that binds to LDL receptors on the surface of liver cells and promotes their degradation
PCSK9 inhibitors
- monoclonal antibodies that bind to and inactivate PCSK9
- In the absence of PCSK9,
- more LDL receptors available to bind and clear LDL from the circulation
- decreased levels of LDL cholesterol
Drug:
- Evolocumab
- Alirocumab
Side effects
- injection site reactions: flu-like symptoms
- neurocognitive problems
8. Omega-3 fatty acids
- used primarily for their triglyceride lowering effects
- thought to be caused by inhibition of VLDL and triglyceride synthesis in the liver
Drug:
Components of omega-3 fatty acids
- docosahexaenoic acid (DHA)
- eicosapentaenoic acid (EPA)
Omega-3 derivative
- Icosapent ethyl
Side effects
- GI disturbances such as
- abdominal pain
- nausea
- diarrhea
- fishy aftertaste with fish-derived omega-3s
- bleeding
- at high enough doses
9. Reference
https://youtu.be/Of1Aewx-zRM
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