PHARM 117 Agents Used in Dyslipidemia PDF 2024-2025

PHARM 117: Pharmacology II B.S. in Pharmacy | A.Y. 2024-2025 Level III - Semester 1 | Instructor: Princess Rabago Chapter 4: Agents Used in Dyslipidemia...

PHARM 117: Pharmacology II B.S. in Pharmacy | A.Y. 2024-2025 Level III - Semester 1 | Instructor: Princess Rabago Chapter 4: Agents Used in Dyslipidemia Patients whose blood cholesterol levels place them at a severe risk TOPIC OUTLINE of CAD will most likely require one of these drugs in addition to dietary changes. UNIT 1: Hematologic Pharmacology Part 2 Clinical Uses CHAPTER 4: Agents Used in Dyslipidemia Part 1 Used in treatment of elevated cholesterol level. This class of drugs acts to decrease LDL. I. Antihyperlipidemic Drugs There is generally no significant effect on HDL. II. Classes Of Antilipemic Drugs used to treat pruritus associated with liver failure and diarrhea after III. Drugs Restricted to Patients with Homozygous Familial gallbladder removal. Hypercholesterolemia Drug interaction They may bind with acidic drugs in the GI tract, decreasing their I Antihyperlipidemic Drugs absorption and effectiveness. Acidic drugs likely to be affected include barbiturates, phenytoin, penicillin, Cephalosporins, thyroid Antihyperlipidemic drugs are used to lower abnormally increase hormones, digoxin, and thiazide diuretics blood levels of lipids such as cholesterol, triglycerides and Decreased absorption of propranolol, tetracycline, furosemide, phospholipids. penicillin G, hydrochlorothiazide, and gemfibrozil. The risk of developing CAD increases when serum lipid levels reduce absorption of lipid-soluble vitamins, such as vitamins ADEK. are elevated. Poor absorption of vitamin K can affect prothrombin times Drugs are used in combination with lifestyle (such as proper significantly, increasing the risk of bleeding. diet, weight loss, and exercise) and treatment of an underlying disorder causing the lipid abnormality to help lower lipid levels. Adverse reaction Short-term adverse reactions to these drugs are relatively mild and II Classes Of Antilipemic Drugs severe reactions can result from long-term use. long-term therapy includes GI upset like severe diarrhea, bleeding, 1. Bile Acid Sequestrants hemorrhoids and vomiting. 2. Fibric Acid Derivative It has a bile taste of medication. 3. 3-Hmg Coa Reductase decreased absorption of fat- soluble vitamins (A, D, E and K) and 4. Nicotinic Acid folic aid 5. Cholesterol Absorption Inhibitors 6. Omega-3-Fatty Acids (Miscellaneous) impaired absorption of a variety of other drugs (e.g., warfarin, digoxin, tetracycline, thiazide diuretics). Rarely, peptic ulcers, bleeding, gallstones and inflammation of the I Bile Sequestering Drugs gallbladder may occur cholestyramine, colestipol and colesevelam. Resins that remove excess bile acids from the fat deposits under 2 Fibric Acid Derivatives the skin. Fibric acid is produced by several fibrates. MOA Two derivatives of this acid are gemfibrozil, and fenofibrates. Used to reduce high triglyceride levels and, to a lesser extent, high inhibit the reabsorption of bile acids in the jejunum and ileum. LDL levels. Lower levels of bile acid result in the increased conversion of cholesterol to bile acids, thereby leading to lower levels of Peroxisome Proliferator-Activated Receptor-Alpha (PPAR-) intracellular cholesterol. The cell responds to lower levels of member of a family of nuclear transcription regulators that participate intracellular cholesterol by increasing the concentration of LDL in the regulation of metabolic processes; target of fibrate drugs and receptor on the cellular surface, thereby resulting in increased omega-3 fatty acids uptake of serum LDL into the cell with a resulting decrease in serum LDL. MOA Pharmacokinetics This class of drugs acts to stimulate lipoprotein lipase. Lipoprotein lipase is the enzyme responsible for breaking down TG are not absorbed from the GI, they remain in the intestine, where into VLDL and CHYLOMICRONS, which are then removed from they combine with bile acids for about 5 hours. circulation. Excreted in stools The fibrates have also been implicated in decreasing hepatic Pharmacodynamics cholesterol biosynthesis. lower blood levels of low-density lipoproteins (LDLs). Pharmacokinetics combine with bile acids in the intestines to form an insoluble Fenofibrates and gemfibrozil are absorbed readily from the GI tract compound that’s then excreted in stool. and are highly protein based. decreasing level of bile acid in the gallbladder triggers the liver to Fenofibrate is hydrolyzed while gemfibrozil undergoes extensive synthesize more bile acids from their precursor, cholesterol. metabolism in the liver. Both drugs are excreted in the urine. Pharmacotherapeutics Pharmacodynamics drugs of choice for treating type 2 -A hypercholesterolemia (familial Although the exact mechanism of action for these drugs isn’t hypercholesterolemia) when the patient can’t lower his LDL levels known, researchers believe that fibric acid derivatives may: through diet alone. o reduce cholesterol production early in its formation o mobilize cholesterol from the tissues o increase cholesterol excretion Frances Keisha M. Acoba | III-B 1 PHARM 117 CHAPTER 4: Agents Used in Dyslipidemia o decrease synthesis and secretion of lipoproteins Lovastatin, rosuvastatin and simvastatin may increase the risk of o decrease synthesis of triglycerides. bleeding when administered with warfarin. All of these drugs should be administered one hour before the administration of Pharmacotherapeutics bile-sequestering drugs (cholestyramine, colesevelam, and used primarily to reduce triglyceride levels, especially VLDL colestipol) triglycerides, and secondarily to reduce blood cholesterol levels. Adverse reaction typically used to treat patients with types II, III, IV and mild type V hyperlipoproteinemia may alter liverfunction studies, increasing AST, ALT, alkaline phosphate, and bilirubin. Other hepatic effects may include Clinical Uses pancreatitis, hepatitis, and cirrhosis. Used in treatment of elevated cholesterolemia and decreased TG Myalgia is the most common musculoskeletal effect. Myopathy and levels. rhabdomyolysis are rare, but potentially severe, reactions that may mildly decrease LDL levels and mildly increase HDL levels. occur with these drugs. Possible adverse GI reactions include nausea, vomiting, diarrhea, Drug interaction abdominal pain, flatulence, and constipation. Fibric acid drugs may displace acidic drugs such as barbiturates, Teratogenic malformation phenytoin, thyroid derivatives, and cardiac glycosides. After 6 months, ptx lipid profile has improved (cholesterol level of The risk of bleeding increases when fibric acid derivatives are 199 mg/dL; LDL of 100 mg/dL but HDL remained low at 28 mg/dL). taken with oral anticoagulant. You tell the ptx that you could prescribe another Fibric acid derivatives can lead to adverse GI effects. The cholesterol-lowering medication, which is also a water soluble hypoglycemic effects of repaglinide may be increased and prolonged vitamin that may help raise HDL levels, but you also inform that if taken with gemfibrozil. recent trials have failed to show a clinical benefit from this Use of fibric acid derivatives and HMG CoA reductase inhibitors medication. may increase the risk of rhabdomyolysis. Adverse reaction 4 Nicotinic Acid GI upset Also known as niacin/Vit B3, nicotinic acid is a water-soluble Gallstone formation vitamin that decreases cholesterol, triglyceride, and apolipoprotein B myalgias levels and increases the HDL level. abnormal liver available in immediate-release and extended-release tablets. MOA I HMG-CoA Reductase Inhibitors It has been shown to decrease lipolysis in adipose tissue, thereby HMG-CoA reductase inhibitors (also known as the STATINS lower decreasing the lipid levels by interfering with cholesterol synthesis. concentration of precursors for VLDL and LDL production. These drugs include Atorvastatin, Fluvastatin, Lovastatin, It has also been shown to inhibit triglyceride synthesis in the Pravastatin, Rosuvastatin, and Simvastatin. hepatocyte. MOA Lastly, it may inhibit lipase breakdown, thereby increasing HDL levels. This class of drugs acts by inhibiting HMG-CoA reductase which is the enzyme that catalyzes the first step in cholesterol biosynthesis in Pharmacokinetics the liver (the conversion of HMG-CoA to mevalonic acid). Nicotinic acid is rapidly and extensively absorbed following oral an increase in the concentration of LDL receptor on hepatocytes, administration. thereby increasing the liver’s ability to extract LDL and very-low- moderately bound to plasma proteins (60-70%) density lipoprotein (VLDL) from the serum. undergoes rapid metabolism by the liver to active and inactive Pharmacokinetics metabolites. About 75% of the drug is excreted in urine. Each drug has slightly different pharmacokinetic properties. All are highly bound to plasma proteins and undergo extensive Pharmacodynamics first-pass metabolism except pravastatin. However, plasma levels The mechanism of action by which nicotinic acid lowers triglyceride don’t correlate with the drugs’ abilities to lower cholesterol. and apolipoprotein levels is unknown. However, it may work by Pharmacodynamics inhibiting hepatic synthesis of lipoproteins that contain apolipoprotein B-100, promoting lipoprotein lipase activity, reducing free fatty acid HMG-CoA reductase inhibitors inhibit the enzyme responsible for mobilization from adipose tissue, and increasing fecal elimination of the conversion of HMG-CoA to mevalonate, an early step in the sterols. synthesis of cholesterol. Pharmacotherapeutics Pharmacotherapeutics Nicotinic acid is usually used in combination with other drugs to used primarily to reduce LDL cholesterol and total blood cholesterol lower triglyceride levels in patients with type IV or V hyperlipidemia levels and produce a mild increase in HDL cholesterol levels. who are at high risk for and to lower cholesterol and LDL levels in used to treat primary hypercholesterolemia (types IIa and IIb). patients with hypercholesterolemia. Because of their effect on LDL and total cholesterol, these drugs are It may also be used with other antihyperlipidemic to boost HDL also used to reduce the risk of CAD and to prevent MI or stroke in levels patients with high cholesterol levels. Nicotinic acid is contraindicated in patients who are hypersensitive Drug interaction to nicotinic acid and in those with Hepatic dysfunction, active peptic ulcer disease, or arterial bleeding. Taking a statin drug with amiodarone, clarithromycin, cyclosporine, erythromycin, fluconazole, gemfibrozil, itraconazole, ketoconazole, Adverse reaction or niacin increases the risk of myopathy or (a potentially fatal High doses of nicotinic acid may produce vasodilation and cause breakdown of skeletal muscle, causing renal failure). flushing. Extended release forms tend to produce less severe vasodilation than immediate-release forms. Frances Keisha M. Acoba | III-B 2 PHARM 117 CHAPTER 4: Agents Used in Dyslipidemia Nicotinic acid can cause hepatotoxicity; the risk of this adverse 6 Omega-3-Fatty Acids (Miscellaneous) reaction is greater with extended release forms. eczema or acanthosis nigricans; hyperuricemia Docosahexanoic Acid (Dha), Eicosapentaenoic Acid (Epa) & Other adverse reactions include nausea, vomiting, diarrhea, and Omega-3 Derivative Icosapent Ethyl epigastric or substernal pain. They are used primarily for their triglyceride lowering effects which are thought to be caused by inhibition of VLDL and triglyceride Drug interaction synthesis in the liver. The most common side effects associated with Together, nicotinic acid and an HMG-CoA reductase inhibitor may these agents are GI disturbances and diarrhea as well as fishy after increase the risk of myopathy or rhabdomyolysis. taste with fish-derived omega-3s. BSD can bind with nicotinic acid and decrease its effectiveness. When given with nicotinic acid, may increase the risk of hepatotoxicity III Drugs Restricted to Patients with Homozygous Familial Hypercholesterolemia Familial hypercholesterolemia is a genetic condition where high 5 Cholesterol Absorption Inhibitors levels of cholesterol, particularly low density lipoprotein (LDL) inhibit the absorption of cholesterol and related phytosterols from cholesterol, are inherited. the intestine. PCSK9 Inhibitors Ezetemibe is the drug in this class. Evolocumab & Alirocumab humanized antibodies to the enzyme MOA proprotein convertase subtilisin/kexin type 9 (PCSK9). The function decreases the absorption of cholesterol in the intestine. of PCSK9 is to transport the LDL receptor to the lysosome for Decreased intestinal cholesterol absorption leads to a decrease in degradation. LDL reductions of up to 70% have been achieved with hepatic cholesterol stores. these agents. The hepatocyte responds to lower levels of intracellular cholesterol Adverse effects include local reactions at the injection site and by increasing the concentration of LDL receptors on the cellular upper respiratory and flu-like symptoms. surface, thereby resulting in increased uptake of serum LDL into the cell with a resulting decrease in serum LDL. Proprotein Convertase Sublitisin/Kexin type 9 (PCSK9) they transport the LDL receptors to the lysosome for degradation; PCSK9 Pharmacokinetics is the target of Evolocumab & Alirocumab (antibodies used in Ezetimibe is rapidly and extensively absorbed following oral Familial Hypercholesterolemia/HF) administration. readily absorbed and is highly bound to plasma proteins. primarily metabolized in the small intestine and excreted by the liver and kidneys. Pharmacodynamics Ezetimibe reduces blood cholesterol levels by inhibiting the absorption of cholesterol by the small intestine. This leads to a decrease in delivery of intestinal cholesterol to the liver, reducing hepatic cholesterol stores and increasing clearance from the blood. Pharmacotherapeutics Ezetimibe may be administered alone or with dietary changes to treat primary hypercholesterolemia and homozygous. The drug is also used in combination with HMG-CoA reductase inhibitors to treat primary hypercholesterolemia and homozygous familial hypercholesterolemia. Ezetimibe may also help lower total cholesterol and LDL cholesterol, and increase HDL cholesterol, when maximum-dose HMG-CoA reductase inhibitor therapy has been ineffective. Adverse reaction fatigue Abdominal pain and diarrhea pharyngitis Back pain cough sinusitis When these drugs are given with an HMG-CoA reductase inhibitor, the most common adverse reactions are chest pain, dizziness, headache, abdominal pain, diarrhea, pharyngitis, sinusitis, upper respiratory tract infection, arthralgia, back pain, and myalgia. Drug interaction Ezetimibe administered with cholestyramine may lead to decreased effectiveness of ezetimibe. Ezetimibe administered with cyclosporine, fenofibrates, or gemfibrozil leads to increased levels of ezetimibe. Frances Keisha M. Acoba | III-B 3 PHARM 117 CHAPTER 4: Agents Used in Dyslipidemia B Lipoproteins TOPIC OUTLINE Macromolecular complexes in the blood that transport lipids UNIT 1: Hematologic Pharmacology Part 2 Consist of a hydrophobic core made of cholesterol and triglycerides surrounded by hydrophilic shell made of CHAPTER 4: Agents Used in Dyslipidemia Part 2 phospholipids and apolipoproteins Apolipoproteins IV. Hyperlipidemia/Dyslipidemia V. Agents Used in Dyslipidemia are specialized proteins that can control enzymes in lipoprotein metabolism - important in lipid metabolism and uptake into cells IV Hyperlipidemia/Dyslipidemia serve as ligands for lipoprotein receptors A. Three Major Lipids in the Blood B. Lipoproteins A disorder which there are abnormally elevated levels of fat particles in the blood known as lipids - lipids: for cell integrity, steroid hormone synthesis - hyperlipidemia: abnormal increase levels of lipids in the blood - accumulate in blood vessels and build up B Four Major Types of Lipoproteins (atherosclerosis) which increase risk for heart attack and stroke 1. Chylomicrons 2. Very-low-density lipoprotein (VLDL) 3. Low-density lipoprotein (LDL) 4. High Density Lipoprotein (HDL) A Three Major Lipids in the Blood 1. Cholesterol 2. Triglycerides 3. Phospholipids - they are insoluble in blood plasma - need to be transported into the bloodstream by lipoprotein capsule (protein-capsule) 1. Chylomicrons 1. Cholesterol produced in the gut from dietary lipids Necessary for the synthesis of bile acid steroid hormones - secreted from the gut - hypercholesterolemia: increase level of cholesterols composed mostly of triglycerides and small amount of cholesterol - risks: eating fatty foods 2. Very-low-density lipoprotein (VLDL) Maintain the integrity of cell membranes triglyceride and cholesterol-rich lipoprotein secreted by the liver that transports - synthesized from the liver triglycerides to the periphery; precursor of LDL - composed of high amount of triglycerides (higher amount 2. Triglycerides than chylomicrons) and cholesterol Are composed of glycerol and free fatty acids which serve as an - When these two transport into the bloodstream, the chylomicrons important source of energy that can be stored throughout the body. are converted to chylomicron remnants while VLDL is converted into - in heavy drinker: there is a tendency for patient to always intermediate density lipoprotein (IDL) and LDL. have high triglycerides - In the bloodstream, lipoprotein lipase stimulates free fatty acids. Triglycerides are converted to free fatty acids. The free fatty acids are taken up by adipose tissues and even skeletal muscle. The free fatty acids are stored in adipose while on skeletal it is converted to ATP. Cholesterol remains since trigly was converted to free fatty 3. Phospholipids acids. LDL (bad cholesterol) happens. - LDL (cholesterol) is accumulated in the blood vessels and causes Major component of all cell membranes and function as an atherosclerosis that may increase risk of cardiovascular events. LDL emulsifiers will go to peripheral cells and some in the liver depending on cell requirements (bile acid synthesis, etc.) - Small amounts of LDL (cholesterol) are synthesized in the liver. - bile acid synthesis: aid in absorption and absorption of fat soluble vitamins such as A,D,E,K - Increased level of LDL, lesion occurs. - In the small intestines, there is synthesized HDL (High Density Lipoprotein). HDL is the good cholesterol and takes the excess Frances Keisha M. Acoba | III-B 4 PHARM 117 CHAPTER 4: Agents Used in Dyslipidemia cholesterol from peripheral cells and livers and dissolves it. It also Increased bile acid secretion in turn creates increased demand for suppresses LDL oxidation. their production, since bile acids are made from cholesterol liver - LDL oxidation: increase levels of LDL cells increase their number of LDL receptors to bring in more LDL cholesterol in order to meet this new demand Lipoprotein lipase (LPL) an enzyme found primarily on the surface of endothelial cells that releases free fatty acids from triglycerides in lipoproteins 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 3. Low-density lipoprotein (LDL) Side Effects cholesterol-rich lipoprotein whose regulated uptake by hepatocytes Indigestion and other cells requires Decrease absorption of fat-soluble vitamins functional LDL receptors; an elevated LDL concentration is Form insoluble complexes with other drugs thus interfering with associated with atherosclerosis their absorption 4. High Density Lipoprotein (HDL) - alter absorption would lead to inhibit or increase effectiveness Intermediate-Density Lipoproteins (IDL) B Fibric Acid Derivatives/Fibrates intermediate in triglyceride and cholesterol content between VLDL and LDL Gemfibrozil - formed from degradation of VLDL Fenofibrates Clofibrates transient form as VLDL is converted to LDL bezafibrates delivers triglycerides and cholesterol to cells V Agents Used in Dyslipidemia Mechanism of Action Work primarily by activating nuclear transcription receptor called A. Bile Sequestering Drugs/Bile Acid Sequestrants peroxisome proliferator-activated receptor alpha or PPAR-alpha B. Fibric Acid Derivatives/Fibrates (found in metabolically active tissues such as liver and adipose C. HMG-CoA Reductase Inhibitors D. Nicotinic Acid/Niacin tissue) E. Cholesterol Absorption Inhibitors (Ezetimibe) - activate PPAR alpha F. Omega-3 Fatty Acids - PPAR alpha: example of encoding protein G. PCSK9 Inhibitors - encoding protein: may increase expression of certain proteins - ex. lipoprotein lipase A Bile Sequestering Drugs/Bile Acid Sequestrants The binding of fibrates to PPAR-alpha induces activation or inhibition of genes that code for proteins involved in lipid metabolism Colesevelam Stimulates expression of lipoprotein lipase which in turn increases Colestipol the removal of triglycerides and their breakdown to fatty acids cholestyramine Decrease expression of protein Apo-CIII which inhibits lipoprotein lipase activity - when binded with PPAR, it can either activate lipoprotein Mechanism of Action lipase (LPL) or inactivates protein APOCIII Serve as an ion exchange resin that bind negatively charged bile - lipoprotein lipase: converts trigly to free fatty acids and salts in the small intestine acids - bile acid: synthesized from liver - low levels of free fatty acids = - one of the components together with cholesterol downregulation (no tissue activation, that makes up the bile low energy) - may increase LDL - tissue activation: FFA aids in The formation of this insoluble complex prevents the reabsorption plasminogen to plasmin conversion of bile acids and leads to their excretion - protein APOCIII: degrades LPL - 95% of bile acid gets reabsorbed into the liver while 5% - degradation: no free fatty acids are only excreted - stimulates APO AI and APO AII - 5% are only excreted because of enterohepatic - APO A1 and APOA2: precursor in HDL recycling - from the liver, they go into the gut for reabsorption - the reabsorbed bile acid, the bile acid sequestrants or resins bind - may produce insoluble complexes - Inhibits enterohepatic recycling - the excreted bile acid will decrease LDL (lowers cholesterol) - best taken with meals - bile acid is excreted in feces - laxatives: induce diarrhea - oil content in feces is the cholesterol Frances Keisha M. Acoba | III-B 5 PHARM 117 CHAPTER 4: Agents Used in Dyslipidemia Side Effects Gastric irritation Myopathy & rhabdomyolysis - myopathy: coQ10 in muscles stimulates ATP in muscles. Fibric acid decreases CoQ10. - Rhabdomyolysis: muscle death Gallstone formation - gallstone formation - in skeletal muscle, creatinine kinase increases and - 7 alpha hydroxylase: when inhibited the Side Effects creatinine kinase leaks out - deposits of creatinine kinase Liver toxicity (supersaturation) may lead to - metabolized in the liver and elevation of aminotransferase increase in cholesterol (ex. aspartate) - patients with CKD cannot excrete and storage of Muscle related problems or myopathy cholesterol happens in lumen and painful - no mevalonic acid (inhibited) sensation happens which lead to cholelithiasis - mevalonic acid is used for contraction in skeletal (gallstone formation) muscle - Fluvastatin and - are less likely to cause myopathies C HMG-CoA Reductase Inhibitors Rhabdomyolysis (rare) - destruction of skeletal muscle Acute kidney injury ( increase myoglobulin levels) Modern Intensity Statins Rosuvastatin (40 mg) - inhibit hormone sensitive lipase - first line agents in treatment of hyperlipidemia - HSL: converts trigly to free fatty acids Mechanism of Action - decreased free fatty acids Niacin effectively decreases hepatic VLDL synthesis which in turn Acts by inhibiting HMG-CoA reductase enzyme that catalyzes the leads to decreased levels of LDL first step in cholesterol biosynthesis in the liver (conversion of - in liver, the FFA becomes triglycerides HMG-CoA to mevalonic acid) - increase triglycerides = increase VLDL = - production of cholesterol happens during night time decrease LDL - statins should be taken before 6 PM - synthesis of FFA= increase LDL By inhibiting this enzyme statins effectively reduce concentration of receptors = endocytosis cholesterol within the liver cell - in liver the hepatocytes, there is HMG-CoA reductase which converts HMG CoA to mevalonic acid (one of the precursor in making cholesterol) - HMG-CoA reductase: inhibits the enzyme to decrease cholesterol Liver cells sense the reduced cholesterol level production and begin to compensate by synthesizing more LDL receptors which in turn bind and internalized LDL that circulating in the blood - the liver sense levels of cholesterol in patient taking Statins - the liver will synthesize and get cholesterol into Side Effects the bloodstream to increase LDL receptors - LDL receptors will get the LDL found Flushing the bloodstream Eczema - LDL will bind to receptors (internalization of - triggers arachidonic pathway LDLs) - prostaglandin releases which results in - gets taken up by cells and vasodilation and allergic reactions endocytosis happens Hyperuricemia - vesicles: separates the Hepatotoxicity LDL and LDL receptors Acanthosis nigricans - the LDL will go to the skeletal muscle, E Cholesterol Absorption Inhibitors (Ezetimibe) adipose tissue, and cell membranes so as to not - good in patients with i tolerance with statins accumulate in the Mechanism of Cholesterol Absorption in Small Intestine bloodstream - decrease LDL, increase HDL, decrease VLDL, Free cholesterol that comes from dietary sources or bile first binds decrease TG to protein abbreviated NPCIL1 which is located in the plasma Frances Keisha M. Acoba | III-B 6 PHARM 117 CHAPTER 4: Agents Used in Dyslipidemia membrane of cells that line the intestinal wall, this binding then G PCSK9 Inhibitors triggers endocytosis which utilizes protein complex called clathrin AP2 to internalized the cholesterol cargo Upon endocytosis the cholesterol is released and the NPC1L1 Mechanism of Action returns back to the plasma membrane Are monoclonal antibodies that bind to and inactivate PCSK9 - treatment with patients with familial hypercholesterolemia - impaired LDL receptors - high LDL cholesterol is not removed - PCSK9: responsible in the degradation of LDL receptors - higher LDL cholesterol 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 - inhibits the enzyme and inhibits the degradation of LDL receptors - decrease LDL and no accumulation of LDL in Mechanism of Action the blood vessels - ex. MABs Binds to NPC1L1 and inhibits its ability to interact with clathrin AP2 complex that is necessary for endocytosis, this leads to decreases delivery of intestinal cholesterol to the liver which in turn causes decrease in hepatic cholesterol levels and ultimately increases clearance of LDL cholesterol from the circulation - the bile (from liver and dietary sources) and cholesterol bind with NPCIL1 (located in plasma membrane) binds Side Effects with clathrin AP2 Flu-like symptoms - clathrin AP2: endocytosis happens and gets Neurocognitive problems the cholesterol cargo - after endocytosis, the cholesterol is becomes ATP/stored energy or into the bloodstream - inhibits binding NPL1 = no endocytosis and lowers cholesterol in bloodstream and stored energy Side Effects Diarrhea Fatigue Back pain - high cholesterol = no back pain - decrease ATP stored energy in skeletal muscle = Lower ATP F Omega-3 Fatty Acids Mechanism of Action inhibition of VLDL and triglyceride synthesis in the liver - lower TGs = lowers VLDL = decrease LDL, IDL, and increase HDL Side Effects Diarrhea GI disturbance Fishy aftertaste Frances Keisha M. Acoba | III-B 7