MOD 14: Drugs for Dyslipidemia PDF

BASIC PHARMACOLOGY 11/06/2024. MOD 14: DRUGS FOR DYSLIPIDEMIA Deo L. Panganiban MD, FPSECP...

BASIC PHARMACOLOGY 11/06/2024. MOD 14: DRUGS FOR DYSLIPIDEMIA Deo L. Panganiban MD, FPSECP Trans Group/s: 9A, 10A OUTLINE CHOLESTEROL METABOLISM, HDL, LDL, AND OTHER LIPOPROTEINS [link] I. Dyslipidemia A. CHOLESTEROL METABOLISM II. Metabolism of Lipoproteins of Hepatic Origin Despite having a bad reputation as a high-risk factor for III. Drug Therapy cardiovascular diseases, cholesterol is an essential IV. HMG-CoA Reductase Inhibitors/Statins component of all animal cells. An integral part of the cell membrane V. Bile Acid Sequestrants / Resins Provides membrane fluidity VI. Nicotinic Acid and Nicotinamide Participates in a number of cellular processes A. Nicotinic Acid (Niacin) VII. Fibric Acid Derivatives 1. SOURCES OF CHOLESTEROL A. Fenofibrate Cholesterol serves as a precursor for production of bile B. Gemfibrozil steroid hormones, and vitamin D While the body can obtain cholesterol from food, many VIII. Sterol Absorption Inhibitor cells SYNTHESIZE their own ENDOGENOUS IX. Microsomal Triglyceride Transfer Protein (MTP) Inhibitor cholesterol. X. PCSK9 Inhibitors Under negative feedback control: LOW levels of intracellular cholesterol INDUCE its own production, XI. Antisense Oligonucleotide (ASO) Inhibitor of ApoC-III while HIGH cholesterol levels INHIBIT it. XII. Angiopoietin-like-3 Inhibition MANAGEMENT OF ADULT DYSLIPIDEMIA I. DYSLIPIDEMIA It is a disease/condition wherein there is an abnormal amount of lipids (e.g. cholesterol or triglycerides) that is circulating in the blood ○ Elevated serum total cholesterol, LDL, TG levels ○ Decreased HDL Refers mostly to a condition with very elevated amounts Diagram on sources of cholesterol in Cholesterol of lipids in the blood or hyperlipidemia, which may be Metabolism due to diet or lifestyle Managing hyperlipidemia means controlling cholesterol 2. LIPOPROTEINS and triglycerides Hyperlipidemia is just a fancy word for too many lipids or Cholesterol, together with other lipids, is transported in fats in the blood that can cover many conditions blood plasma within large particles known as For most people, it comes down to two well known LIPOPROTEINS terms: high cholesterol and high triglycerides levels A lipoprotein is an assembly of lipids and proteins. Bodies make and use a certain amount of cholesterol Lipoproteins are classified based on their DENSITY. everyday, but sometimes that system gets out of quack Because lipids are LIGHTER than proteins, particles either through genetics or diet that contain MORE lipids are LARGER in size but ○ Higher levels of the “good” High Density have LOWER density. Lipoprotein (HDL) cholesterol are associated with Different types of lipoproteins have different sets of a decreased risk of heart disease and stroke proteins on their surface. These proteins serve as ○ HDL helps by removing cholesterol from your “ADDRESS tags”, determining the DESTINATION, arteries which slows the development of plaque and hence FUNCTION, of each lipoprotein There are also conditions that may lower good For example, LOW-density lipoprotein, LDL, carries cholesterol levels (e.g. drug-induced or bad dietary cholesterol FROM the liver to other tissues, while habits) HIGH-density lipoprotein, HDL, RETURNS excess The “bad” Low Density Lipoprotein (LDL) cholesterol TO the liver cholesterol can lead to blockages if there’s too much of it in the body. Pharmacology - Mod 14 Drugs for Dyslipidemia 1 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Difference between LDL and HDL Lipoproteins Common drugs used to LOWER cholesterol include: 3. CHOLESTEROL PATHWAYS Inhibitors of endogenous cholesterol Production Inhibitors of intestinal cholesterol Absorption; and Dietary cholesterol ABSORBED in the intestine and Inhibitors of bile reuptake. carried in chylomicron to the liver. The liver PACKAGES its cholesterol pool - a combination of endogenous and dietary - together with II. METABOLISM OF LIPOPROTEINS OF HEPATIC triglycerides, another type of lipid, into particles of ORIGIN VERY-LOW-density lipoprotein, VLDL. VLDL travels in the bloodstream to other organs. During circulation, muscle and adipose tissues EXTRACT triglycerides from VLDL, turning it into LOW-density lipoprotein, LDL. Peripheral cells TAKE UP LDL by endocytosis, using LDL receptor. Cholesterol is used in cell membranes and other functions. EXCESS cholesterol is exported from the cells and delivered to HIGH-density lipoprotein, HDL, to be RETURNED to the liver in a process called REVERSE cholesterol transport The liver uses cholesterol to produce BILE ○ bile is secreted to the intestine, where it helps break down fats. ○ Part of this bile is EXCRETED in feces; the rest is RECYCLED back to the liver. Lipid Synthesis and Metabolism of Hepatic Origin Legend Heavy arrows - primary pathways Dark color - donates cholesteryl esters Light blue color - triglycerides Asterisk - a functional ligand for LDL receptors Triangles - ApoE Circles - ApoC Note: Start at the upper left portion of the image Nascent VLDLs are secreted by the golgi apparatus of 1 Process of cholesterol pathways hepatocytes into the blood 4. LDL AND HDL Once in the blood, they acquire additional ApoC and 2 ApoE lipoproteins from HDL LDL has the highest cholesterol content and is the MAJOR carrier of cholesterol in the blood. VLDL are converted to VLDL remnants (also called High levels of LDL in the blood are associated with IDL) by lipolysis via lipoprotein lipase in the vessels of cholesterol plaque build-up and cardiovascular 3 peripheral tissues (i.e. capillary endothelium) diseases such as heart attacks and strokes. In the process, ApoC and a portion of the ApoE For this reason LDL, is called “BAD” cholesterol are given back to HDL On the other hand, HDL is called “GOOD” cholesterol, because it REMOVES EXCESS cholesterol from Some of the VLDL remnants (or IDL) are converted to 4 tissues and bloodstream. LDL* by further loss of triglycerides and ApoE A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver 5 (hepatocytes) and peripheral tissues Apo B-100 is the ligand * lecturer mentioned VLDL but according to the image, it should be LDL Pharmacology - Mod 14 🏠 Drugs for Dyslipidemia 2 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  III. DRUG THERAPY Cholesterol-lowering agents help in the lowering of cholesterol levels in the body ○ Resorted to when dietary and lifestyle medications have not lowered the LDLs to manageable levels ○ Resorted to if lipid levels remain elevated 6 months after consultation with intensive dietary modification These drugs are NOT a substitute for appropriate diet and exercise Hypercholesterolemia: HMG-CoA reductase inhibitors Hypertriglyceridemia: Gemfibrozil or Nicotinic acid HMG-CoA Reductase Inhibitors 1 (Lovastatin, Pravastatin, Atorvastatin) Simvastatin Structure Bile Acid Sequestrants 2 (Cholestyramine, Colestipol, Colesevelam) 3 Nicotinic Acid (or Niacin) and Nicotinamide Fibric Acid Derivatives 4 (Gemfibrozil, Fenofibrate) Sterol Absorption Inhibitor 5 Atorvastatin (Left) and Lovastatin (Right) Structure (Ezetimibe) Microsomal Triglyceride Transfer Protein (MTP) Pharmacokinetics 6 Inhibitor (Lopitamide) via CYP450 7 PCSK9 Inhibitor (Evolucumab, Alirocumab) CYP3A4: metabolizes most statins M CYP2C9: metabolizes Fluvastatin Antisense Oligonucleotide (ASO) Inhibitor of Sulfation/other pathways: Pravastatin 8 ApoC-III Primarily in bile and feces E 9 Angiopoietin-like-3 (ANGPTL3) Inhibition Renal excretion: Pravastatin 6-9 are new anti-dyslipidemia drugs T ½ 1.5-2 hrs IV. HMG-CoA REDUCTASE INHIBITORS/STATINS Adverse Effects Lovastatin, Pravastatin, Atorvastatin During the 5-year clinical trials of Simvastatin and Competitive HMG-CoA reductase inhibitors or statins Lovastatin, only a few adverse effects related to liver lower elevated LDL cholesterol levels and muscle function were reported ○ Results in a substantial reduction in coronary events and death from coronary heart disease They are the first-line drugs and more effective 1 Mild GIT Upset treatment for patients with elevated LDL cholesterol Liver function abnormalities* 2 (2-3x normal AST and ALT) Mechanism of Action These drugs inhibit the first committed enzymatic step of Muscle (myopathy and rhabdomyolysis → myoglobinuria) 3 cholesterol synthesis (10x creatine phosphokinase) Competitive inhibitor of HMG Co-A reductase → blocks cholesterol synthesis in the liver → induction of hepatic 4 Lenticular opacities LDL receptors → increased uptake of LDL from the 5 Lupus-like syndrome plasma ○ Leads to regression of atheroma in patients with 6 Peripheral neuropathy coronary artery disease (CAD) Increased bleeding risk with concomitant Therapeutic Benefits 7 administration of warfarin or coumadin Block stabilization within blood vessel lining * Note that the lecturer mentioned serum transaminases and Improvement of coronary endothelial formation serum aminotransferases separately with their elevation being 2 Inhibition of platelet thrombus formation and 3 times, respectively; it is combined by the editor since these Anti-inflammatory activity two terms are exactly the same. 1 was not thoroughly discussed Common Statins Includes Simvastatin, Atorvastatin, Lovastatin, Rosuvastatin, Fluvastatin, Pitavastatin, and Pravastatin Pharmacology - Mod 14 🏠 Drugs for Dyslipidemia 3 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 1. Liver Function Abnormalities V. BILE ACID SEQUESTRANTS / RESINS Biochemical abnormalities in liver functions have These have significant LDL cholesterol-lowering occurred with the HMG-CoA reductase inhibitors. effects, although the benefits are less than those ○ Therefore, it is prudent to evaluate liver function and observed with statins measure serum transaminase levels periodically. Drugs: Cholestyramine, Colestipol, Colesevelam Increased transaminases/aminotransferases Mechanism of Action (AST and ALT) - 2-3x normal ○ This return to normal on suspension of the drug 1 Binds to bile acids in the intestines → fecal excretion Just note that hepatic insufficiency can cause drug accumulation. 2 Inhibition of enterohepatic circulation of bile acids 2. Muscle Abnormalities (Myopathy and Rhabdomyolysis) 3 Increased conversion of bile acids from cholesterol Myopathy and rhabdomyolysis (disintegration or 4 Increased expression of LDL from the plasma dissolution of muscles) have been reported on rarely ○ Mostly seen in patients who suffer from renal Also enhances the synthesis of Triglycerides insufficiency or taking drugs such as Cyclosporine, Itraconazole, Erythromycin, Gemfibrozil, or Niacin These drugs are anion exchange resins that bind Plasma creatine kinase levels should be determined negatively charged bile acids and bile salts in the small regularly. intestines ○ Increased creatine phosphokinase (10x) The resin bile acid complex is then excreted in the May also present as arthralgia feces, thus preventing the bile acids from returning to Note that rhabdomyolysis → can lead to myoglobinuria the liver by the enterohepatic circulation Lowering the bile acid concentration causes 3. Lenticular Opacities hepatocytes to increase conversion of cholesterol to bile acids, resulting in replenished supply of these Opacification of the lens of the eyes which leads to a compounds, which are essential components of the bile decrease in vision Consequently, the intracellular cholesterol Cataracts often develop slowly and can affect one or concentration decreases, which activates increased both eyes hepatic uptake of cholesterol containing LDL particles, Symptoms may include faded colors, blurry or leading to a fall in plasma LDL receptors in some double-vision, halos around light, trouble with bright patients lights, and trouble seeing at night A modest rise in the plasma HDL levels is also observed Final outcome: Decreased total plasma cholesterol 4. Lupus-like Syndrome concentration Manifesting as fatigue, fever, joint pains, stiffness and Pharmacokinetics swelling, butterfly-shaped rash on the face that covers the cheeks and bridge of the nose, or rashes elsewhere Cholestyramine, colesevelam, and colestipol are taken on the body orally Skin lesions that appear or worsen with sun exposure or They are insoluble in water and have very large photosensitivity molecular weights Neither absorbed nor metabolically altered in the 5. Peripheral Neuropathy intestines, instead they are totally excreted in the feces Results when nerves that carry to and from the brain Function and spinal cord from and unto the rest of the body are damaged or diseases Bind to bile ACIDS in the intestines REDUCE recirculation of BILE ACIDS Drug Interactions Promote the conversion of cholesterol in hepatocytes DECREASE cholesterol in hepatocytes = enhancing May increase warfarin levels as mentioned in the LDL-receptor expression adverse effects. REMOVE LDL and VLDL which lowers LDL-C ○ It is important to evaluate INR regularly May react with Cyclosporine, Itraconazole, Therapeutic Uses Erythromycin, Gemfibrozil, or Niacin and cause adverse effects related to muscles as mentioned above Treatment of Primary Hypercholesterolemia and type Concomitant drinking of grapefruit juice increases blood 2 hypolipoproteinemia levels of atorvastatin and lovastatin In treating Type 2A and Type 2B Hyperlipidemia: DOC: Bile acid-binding Resins Contraindications ○ Often used with a combination of other drugs (Niacin) or with diet to achieve further Patients with active or chronic liver disease Hypocholesterolemic effect During pregnancy and in nursing mothers ○ Helpful in relieving patients with pruritus (Ex. cholestasis, bile salt accumulation in biliary Editor’s Notes: The lecturer read his notes on how obstruction) adverse effects on muscles are usually seen in patients Lowers LDL cholesterol (15-30%): with renal insufficiency or taking certain drugs mentioned ○ Starting daily dose = 4g above. It is unclear whether it was a mistake on the ○ Daily doses = 24g lecturer’s part or if he wanted to reiterate it as part of Decreases HDL cholesterol (3-5%) contraindications. Increases Triglycerides ○ Resins binds with digitalis glycosides = useful for digitalis toxicity Pharmacology - Mod 14 🏠 Drugs for Dyslipidemia 4 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  A. NICOTINIC ACID (NIACIN) Professor’s Notes: RESINS have LITTLE TO NO EFFECT on the plasma LDL of patients with Homozygous Niacin: a water soluble B complex vitamin familial hypercholesterolemia (Type 2A) since they lack Can reduce the bad cholesterol carrier levels by up to LDL functioning receptors 10-20% Most effective agent for increased HDL (high density lipoprotein AKA good cholesterol) Efficacy Can be used in combination with statins Bile acid sequestrants are most useful in combination ○ A fixed dose combination of lovastatin and long with a statin or niacin in aggressively lowering LDL acting niacin is available cholesterol levels ○ Useful for isolated increases in LDL Mechanism of Action ○ Reduces myocardial infarction risk “Enhances the activity of Lipoprotein Lipase → The combination of a statin and bile acid sequestrant Decreased triglyceride & hepatic synthesis of VLDL can lower LDL cholesterol levels by approximately 50% cholesterol, the precursor LDL” At gram doses, strongly inhibits lipolysis in adipose Preparation tissues, the primary producer of circulating free fatty Mix resin with water, diluted juice or soft food acids Taken with meals Inhibits lipolysis in adipose tissue at drug doses If used for combined hyperlipidemia = ↑ VLDL + another ○ Partial inhibition of release of free fatty acids from drug adipose tissue → Decrease plasma TG (triacylglycerol) synthesis in VLDL → Decreased Adverse effects cholesterol in VLDL and LDL The liver normally uses these circulating fatty Nausea, constipation, epigastric acids as a major precursor of TG synthesis, fullness, bloating (flatulence), which is required for VLDL production GIT The cholesterol-rich lipoprotein is derived from abdominal discomfort (dyspepsia) Disturbances VLDL in the plasma, therefore a reduction in Colesevelam has fewer GIT side (most common) VLDL concentration also results in a decreased effects than of the other bile acid sequestrants plasma LDL concentration Increases HDL cholesterol Impaired Cholestyramine and Colestipol, but NOT ○ Boosting secretion of tissue plasminogen activator absorption at Colesevelam, impair the absorption of and lowering the level of plasma plasminogen, high doses the fat soluble vitamins A, D, E, & K Niacin can reverse some of the endothelial cell dysfunction contributing to thrombosis associated Interferes with fat soluble vitamin absorption with hypercholesterolemia and atherosclerosis Inhibition of synthesis of Apo B-100, which is needed for Contraindications the formation of VLDL particles Increased lipoprotein lipase activity, which enhances Absolute: TG > 500 mg/dl VLDL catabolism and removal of chylomicron TG from Relative: TG> 200 mg/dl plasma Favorable LDL particle size transformation, with shift Drug interactions from small, dense to large, buoyant particles Cholestyramine and Colestipol interfere with the Reduced extraction and function of HDL particles intestinal absorption of many drugs like tetracycline, Clinical use: LIMITED by unpleasant side effects phenobarbital, digoxin, warfarin, Fluvastatin, and aspirin ○ These drugs should be taken at least 1-2 hrs before Reduction of the synthesis of VLDL, the precursor of or 4-6 hrs after the bile acid-binding resins 1 LDL Binds with anionic drugs such as: ○ Thyroxine, Digitalis glycosides, Anticoagulants, Partial inhibition of release of free fatty acids from Propranolol, Furosemide adipose tissue, leading to a decrease in TG levels Interferes with fat soluble vitamin absorption 2 Hepatic synthesis an TG content of VLDL are reduced VI. NICOTINIC ACID AND NICOTINAMIDE Inhibition of synthesis of Apo B-100, which is needed 3 for the formation of VLDL particles Increased lipoprotein lipase activity, which enhances 4 VLDL catabolism and removal of chylomicron TG from plasma Favorable LDL particle size transformation, with shift 5 from small, dense to large, buoyant particles Reduced extraction and catabolism of Apo A-1 from 6 HDL Nicotinic Acid and Nicotinamide Chemical Structure Pharmacology - Mod 14 🏠 Drugs for Dyslipidemia 5 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. Therapeutic Effects VII. FIBRIC ACID DERIVATIVES Niacin lowers plasma levels of both cholesterol and FENOFIBRATE and GEMFIBROZIL are derivatives of TAG; therefore, particularly useful in the treatment of fibric acid that lowers serum Triacylglycerol and familial hyperlipidemias increases HDL levels ○ Also used in treatment of severe ○ Both have the same mechanism of action hypercholesterolemia, often in combination with Fenofibrate is more effective than Gemfibrozil in other anti-hyperlipidemic agents lowering plasma LDL cholesterol and Triacylglycerol Most effective/potent anti-hyperlipidemic agent in levels increasing plasma HDL level ○ Most common indication for its clinical use Mechanism of Action Stimulation of Lipoprotein Lipase Activity EFFECT OF NIACIN ↓ Increased hydrolysis of VLDL and Chylomicrons LDL cholesterol ↓ (10-25%) *Moderate increase/rise in HDL HDL levels ↑↑ (15-35%) The Peroxisome Proliferator-activated Receptors TG levels ↓↓ (20-50%) (PPaRs) are members of the nuclear receptor supergene family that regulates lipid metabolism. Lp(a) ↓↓ (50%) PPaRs function as a ligand-activated transcription factor Upon binding to its natural ligands such as fatty acids, OTHER ANTI-HYPERLIPIDEMIC AGENTS COMBINED eicosanoids, or hyperlipidemic drugs, PPaRs are WITH NIACIN activated AGENT CLINICAL USE They bind to the Peroxisome Proliferator Response Elements which are localized in numerous gene Bile acid ↓ LDL in heterozygous familial promoters sequestrants + Niacin hypercholesterolemia In particular, PPaRs regulate the expression of genes encoding for proteins involved in lipoprotein Regression of atheromatous structure and function Colestipol + Niacin lesions Fibrate mediated gene expression ultimately leads to decreased triacylglycerol concentrations by increasing Pharmacokinetics the expression of Apo-A1 and Apo-A2 Fenofibrate is a prodrug producing active metabolite Niacin is administered orally Fenofibric Acid, which is responsible for the primary In the body, niacin is converted into nicotinamide which effect of the drug is incorporated into the cofactor nicotinamide adenine dinucleotide (NAD) Pharmacokinetics Niacin and its nicotinamide derivative and other metabolites are excreted in the urine. A Both drugs are completely absorbed after an oral dose ○ NOTE: Nicotinamide alone DOES NOT decrease plasma lipid levels D Both drugs distribute widely into the tissues, bound to albumin Adverse Effects of Niacin M Both drugs undergo extensive hepatic COMMON ADVERSE EFFECTS OF NIACIN biotransformation Accompanied by uncomfortable E Excreted in the urine as their glucuronide conjugates feeling of warmth and pruritus Intense This A/E is A. FENOFIBRATE cutaneous prostaglandin-mediated flushing ○ Aspirin intake prior to taking niacin decreases flushing Nausea, dyspepsia, abdominal discomfort AVOID in severe peptic disease GIT Sustained-release Niacin formulation taken once daily at bedtime reduces bothersome initial adverse effects Prevention of tubular secretion of uric acid by niacin → predisposes Hyperuricemia patient to hyperuricemia and gout May give Allopurinol Impaired glucose Hepatic and Peripheral Effects of Fibrates. tolerance These are mediated by activation of peroxisome proliferator-activated receptor alpha-1, which decreases the Hepatotoxicity secretion of VLDL and increases its peripheral metabolism Pharmacology - Mod 14 🏠 Drugs for Dyslipidemia 6 of 8 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. Mechanism of Action of Fenofibrates VIII. STEROL ABSORPTION INHIBITOR Activates peroxisome proliferator-activated receptor Representative Drug: Ezetimibe alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C3 Mechanism of Action ○ PPARα is a nuclear receptor and its activation alters Inhibits absorption of intestinal phytosterols and lipid glucose and amino acid homeostasis cholesterol ○ It targets NCP1LI, a transport protein Initial activation of peroxisome proliferator-activated ○ Inhibits the reabsorption of cholesterol excreted in 1 the bile receptor-α Increased lipolysis and elimination from plasma of Therapeutic Effects 2 TG-rich particles Daily dose = 10 mg Decreased TG produces an alteration in the size and Reduces LDL Cholesterol: 18-20% 3 composition of LDL from small, dense particles to Minimal increases = HDL cholesterol large, buoyant particles Drug of Choice = PHYTOSTEROLEMIA Synergistic with STATINS = decreases