Dyslipidemia antihyperlipidemic pptv4.pptx

Atherosclerosis is the leading cause of death for both men and
women in the Western world. Drugs discussed in this chapter
prevent the sequelae of atherosclerosis (heart attacks, angina,
peripheral arterial disease, ischemic stroke) and decrease
C H A P T E R
mortality in patients with a history of cardiovascular disease and
hyperlipidemia. Although the drugs are generally safe and effective,
they can cause problems, including drug-drug interactions
and toxic reactions in skeletal muscle and the liver.

1. Agents used in dyslipidemia

2. Introduction Hyperlipidemia is a major cause of atherosclerosi s and atherosclerosis-associated conditions , such as: Coronary heart disease (CHD), Ischemic cerebrovascular disease, Peripheral vascular disease It is also the major cause of acute pancreatitis

3. Plasma lipids are transported in complexes called lipoproteins. Lipoproteins are macromolecular complexes that contain lipids and proteins The hydrophobic core region contain cholesteryl ester , and triglycerides… Surrounded by unesterified cholesterol , phospholipids and apoprotein (provide structural stability , and function as ligands in lipoprotein-receptor inter actions) According to the amount and the composition of stored lipids , as well as the type of apolipoprotein , one distinguishes four transport forms: Chylomicrons Very low-density lipoprotein (VLDL) particles Low-density lipoprotein LDL-C particles High density lipoprotein (HDL) particles Introduction

4. Apo B-48 : formed in the intestine and found in chylomicrons Apo B-100 : synthesized in the liver and found in VLDL, ILD, LDL, and Lp (a) Apo A : found in HDL Each class of lipoprote in has a specific role in lipid transp ort Introduction

5. Review (self-reading)

6. Review (self-reading)

7. Hyperlipoproteinemia/Pathogenesis Premature or accelerated development of atherosclerosis is strongly associated with elevated concentrations of certain plasma lipoproteins, especially LDL . A depressed level of HDL is also associat ed with increased risk of atherosclerosis. In some families , h ypertriglyceri demia is similarly correlate d with atherosclerosis. Chylomicronemia , the occurrence of chylomicrons in the serum while fasting , is a recessive trait that is correlated with a high incidence of acute pancreatitis and managed by restriction of total fat intake

8. Drugs Used in Hyperlipidemia Antihyperlipidemic drugs target the problem of elevated serum lipids with complementary strategies The main agents used clinically are: Statins: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors Nicotinic acid Fibrates Bile-acid binding resin Inhibitors of cholesterol absorption

9. HMG-CoA Reductase inhibitors (statins) Agents: Lovastatin , atorvastatin , fluvastatin , pravastatin , simvastatin , and rosuvastatin , pitavastatin The statins are: the most effective in reducing LDL and best-tolerate d for dyslipidemia They decr ease oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions . It has become standard practice to initiate high dose reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels.

10. Statins- Pharmacokinetics After oral administration , intestinal absorption of the statins varies between 40% and 75% with the exc eption of fluvastatin , which is almost completely absorbed All have high first-pass extraction by the liver….. systemic bioavailability of the statins varies between 5% and 30% of administered doses Half life is 1-3 hrs , except atorvastatin (14 hrs ) and rosuvastatin (19 hrs ) pitavastatin ( 12 hrs ) Absorption generally (with the exception of pravastatin and pitavastain ) is enhanced by food

11. HMG-CoA Reductase inhibitors (statins) These drugs are competitive inhibitors ( structural analogs of HMG-CoA) of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase , which catalyzes an early, rate-limiting ste p in hepatic cholesterol biosynthesis Lovastatin and simvastatin are prodrugs , whereas the other HMG-CoA reductase inhibitors (atorvastatin, fluvastatin , pravastatin, and rosuvastatin ) are active as given

12. Statins- Mechanism of action Inhibition of HMG CoA reductase competitively. Reduce the conversion of HMG-CoA to mevalonate ….inhibit an early and rate-limiting step in cholesterol biosynthesis Increase in LDL receptors: depletion of intracellular choleste rol causes the cell to increase the number of specific cell-surfa ce LDL receptors that can bind and internalize circulating LDLs. Thus, plasma cholesterol is reduced, by both decreased cholesterol synthesis and increased LDL-C catabolism. Modest decreases in plasma triglycerides (VLDL ) and small increases in HDL also occur

13. Statins- Mechanism of action

14. Statins- Clinical uses These drugs are effective in lowering p lasma cholesterol levels in all types of hyperlipidemias alone or with resins, fibrates, niacin, or ezetimibe Large clinical trials have shown that they reduce the ri sk of coronary events and mortality in patients with ischemic heart disease, and they also reduce the risk of ischemic stroke . Thus they are indicated in the p revention of atherosclerotic cardiovascular disease

15. Statins- ADEs Liver: Mild elevations of serum aminotransferases are common but are not often associated with hepatic damage . Patients with preexisting liver disease may have more severe reaction Medication should be discontinued immediately if symptomatic or asymptomatic whose aminotransferase activity is persistently elevated Evaluate liver function and measure serum transaminase levels periodically

16. Statins- ADEs Contraindicated in patients with active liver disease or decompensated cirrhosis. Muscle: An increase in creatine kinase (released from skeletal muscle) is noted in about 10% of patients ; in a few , severe muscle pain and even rhabdomyolysis may occur. If the drug is not discontinued , myoglobinuria can occur , leading to renal injury

17. Statins- ADEs The risk of statin-induced rhabdomyolysis increases with older age , use of interacting medications such as fibrates and hypothyroidism.   Discontinue therapy in any patient in which CPK levels are markedly elevated (>10 times ULN) or if myopathy is suspected/diagnosed. C. Dysglycemia : Increases in HbA1c and fasting blood glucose have been reported in diabetic patients with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia .

18. Statins - drug interactions HGM-CoA reductase inhibitors are metabolize d by the cytochrome P450 system. Drugs or foods ( eg , grapefruit juice) that inhibit cytochrome P450 activity increase the risk of hepatotoxicity and myopathy.

19. Statins - drug interactions Lovastatin , simvastatin , and atorvastatin are primarily metabolized by CYP3A4 Drug that increase plasma concetration of statin…. macrolide antibiotics, cyclosporine , ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus , nefazodone, & fibrates Conversely, drugs such as phenytoin , griseofulvin, barbiturates , rifampin , and thiazolidinediones increase expression of CYP3A4 Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily

20. Statins - drug interactions The metabolism of fluvastatin and rosuvastatin is mediated by CYP2C9 Inhibitors of CYP2C9 such as ketoconazole , metronidazole, sulfinpyrazone , amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin Pravastatin is catabolized through other pathways, including sulfation . Pravastatin appear to be the statin of choice for use with verapamil, ketoconazole, macrolides, and cyclosporine

21. Statins - C ontraindications Statins are usually contraindicated in women with hyperlipidemia who are pregnant, lactating , or likely to become pregnant ( Because of evidence that the HMG-CoA reductase inhibitors are teratogenic, these drugs should be avoided in pregnancy (see next slide)). These agents should not be used in children or teenagers ( their use is restricted to selected patients with familial hypercholesterolemia or familial combined hyperlipidemia )

22. Niacin (Nicotinic acid) Niacin , nicotinic acid is one of the oldest drugs used to treat dyslipidemia It is primarily used to treat hypercholesterolemia and pellagra (niacin deficiency). It favorably affects virtually all lipid pa rameters; it decreases VLDL and LDL levels , and Lp (a) , & increases HDL levels significantly It is clearly the most effective agent for increasing H DL and the only agent that may reduce Lp (a)

23. Niacin ( Nicotinc acid)-MOA Niacin decrease the hormone-sensitive lipase activity in adipocytes, triglyceride lipolysis , and release of free fatty acids and t hus decreases plasma fatty acid and triglyceride levels ( decreasing the flux of free fatty acids to the liver) In the liver , niacin reduces triglyceride synthesis by inhibiti ng both the synthesis and esterification of fatty acids. Thus, niacin causes a decrease in liver triacylglycerol synthesis , which is r equired for VLDL production

24. Niacin (Nicotinc acid)-MOA A reduction in the VLDL concentration also results in a decreased plasma LDL concentration. Thus, both plasma triacylglycerol ( in VLDL) and cholesterol ( in VLDL and LDL) are lowered Niacin raises HDL-C levels This effect is due to a reduction in the hepatic catabolism of HDL- apoA -I rather than by enhancing HDL synthesis

25. Niacin (Nicotinc acid)-ADEs Most common ADE is intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) after each dose when niacin is starte d or the dose increased Administration of aspirin (or other NSAID ) prior to taking niacin decreases the flush , which is prostaglandin mediated Pruritus, rashes, dry skin or mucous membranes Acanthosis nigricans , which requires the discontinuance of niacin use because of its association with insulin resistance Some patients also experience nausea and abdominal pain. Many can continue the drug at reduced dosage, with inhibitors of gastric acid secretion.

26. Niacin (Nicotinc acid)-ADEs Niacin should be avoided in patients with significant peptic disease. Impaired glucose/carbohydrate tolerance (niacin-induced insulin resistance), which is usually reversible except in some patients with diabetes Reversible elevation s in aminotransferases up to twice normal may occur…...not associated with liver toxicity…. liver function should be monitored at baseline and at appropriate intervals Rarely, true hepatotoxicity may occur, and the drug should be discontinued. Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout …… allopurinol can be given if needed

27. Acanthosis nigricans: is a cutaneous skin disorder typically characterized by hyperpigmented, velvety, hypertrophic plaques

28. Clinical use Niacin is no longer considered a primary or secondary agent for dyslipidemias . Although niacin consistently affects surrogate markers, it has not been shown to reduce cardiovascular disease outcomes beyond that achieved with statin use and may be associated with harm May consider use in patients with very high triglyceride levels (>500 mg/dL) or in dyslipidemia for patients who do not achieve the desired response or have intolerance to a statin or other alternative therapy 

29. Fibric Acid Derivatives (Fibrates)- MOA Agents: gemfibrozil and fenofibrate   Fibrates are agonists for the peroxisome proliferator-activated recepto r (PPAR- α ) expressed primarily in the liver and brown adipose tissue and to a lesser extent in kidney, heart, and skeletal muscle Fibrate-mediated gene expression ultimately leads to: Increase in oxidation of fatty acids in liver and striated muscle Increase t he level of HDL cholesterol by increasin g the expression of apo AI and apo AII Decrease TG conc. by increasing the expression of lipoprotein lipase (in muscle and adipose) and decreasing apo C-III concentration ( an inhibitor of lipolysis ) Levels of VLDL decrease , in part as a result of decreased secretion by the live r ; only modest reductions of LDL occur in most patients

30. Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor- α , which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

31. Fibric Acid Derivatives (Fibrates) All of the fibrate drugs are absorbed rapidly and efficiently (>90%) More than 95% of these drugs in plasma are bound to protein, nearly exclusively to albumin The half-lives of fibrates differ significantly, ranging from 1-2 hours (gemfibrozil) to 20 hours (fenofibrate) 70% of gemfibrozil is eliminated through the kidneys , mostly unmodified Fenofibrate is mainly 60% excreted in the urine as the glucuronide ( Contraindicated in patients with active liver disease )

32. Fibric Acid Derivatives (Fibrates)- Clinical uses Hypertriglyceridemias in which VLDL predomina te and in dysbetalipoproteinemia in which chylomicron and VLDL remnants increase Hypertriglyceridemia that results from treatment with viral protease inhibitors The combination of fenofibrate with rosuvastatin is particularly effective

33. Fibric Acid Derivatives (Fibrates)- ADEs The most common adverse effects are mild gastrointestinal disturbances , which occur in up to 5% of patients. These lessen as the therapy progresses. Cholelithiasis : because these drugs increase biliary cholesterol excretion , there is a predisposition to the formation of gallstone ( cholelithiasis) Fibrates should be used with caution in patients with biliary tract disease or in those at high ris k such as women , obese patients , and Native Americans.

34. Fibric Acid Derivatives (Fibrates)- ADEs Myopathy and rhabdomyolysis have been reported with fibrates, including fenofibrate when used as monotherapy or in combination with other agents (usually a statin). There is an increased risk of myopathy and rhabdomyolysis with gemfibrozil compared to fenofibrate, especially when used in combination with a statin ( Fenofibrate is the fibrate of choice for use in combination with a statin )

35. Fibric Acid Derivatives (Fibrates)- ADEs Drug interactions: Both fibrates c ompete with the coumarin anticoagulan ts for binding site s on plasma proteins , thus transiently potentiating their anticoagulant activity Contraindications: . They should not be used in patients with severe hepatic and renal dysfunction or in patients with preexisting gallbladder disease

36. Bile Acid–Binding Resins Agents: Colestipol , cholestyramine , & colesevelam They have significant LDL cholesterol–lowering effects, although the benefit s are less than those observed with statins They are large polymeric cationic exchange resins that are insoluble in water that bind negatively charged bile acids and bile salts in the small intestine . The resin-bile acid complex is excreted in the feces , thus preventing the bile acid s from returning to the liver by the enterohepatic circulation

37. Drug of choice in patients with familial heterozygous hyper cholesterolemia Interruption of reabsorption depletes the pool of bile acids , and hepatic bile-acid synthesis increases . As a result, hepatic cholesterol content declines , stimulating the production of LDL receptors…… increase LDL clearance Useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with combined hyperlipidemia Cholestyramine is also sed for pruritis associated with cholestasis Bile Acid–Binding Resins- Clinical uses

38. Other medication (except niacin) should be given at least 1 hour befor e or 4-6 hours afte r the resin to ensure their absorption VLDL levels increases during treatment of hypercholesterolemia with a resin, requiring the addition of a second agent such as niacin (may be taken together , because niacin does not bind to the resins ) Because the resins bind digitalis glycosides , they may be useful in digitalis toxicity ( except colesevelam ) Bile Acid–Binding Resins- Clinical uses

39. Bile Acid–Binding Resins (ADEs) Gastrointestinal effects: The most common side effects are GI disturbances, such as constipation, bloating, diarrhea, & heartburn Impaired absorptions: malabsorption of vitamin K Drug interactions: intestinal absorption of certain drugs, including those with neutral or cationic charge as well as anions , may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin , tetracycline, thyroxine, iron salts, pravastatin , fluvastatin , folic acid, aspirin, and ascorbic acid Colesevelam does not bind digoxin, warfarin, or reductase inhibitors.

40. Inhibitors of Intestinal Sterol Absorption Ezetimibe is a prodrug that is converted in the liver to the active glucuronide form Is the first member of a group of drugs that selectively inhibits a transporter that mediates gastrointestinal uptake of cholesterol and phytosterols It acts by blocking a transporter protein, NPC1L1 , in the brush border of enterocytes By preventing absorption of dietary cholesterol and cholesterol that is excreted in bile , ezetimibe reduce the cholesterol in the tightly regulated hepatic pool

41. Ezetimibe A compensatory increase in the synthesis of LDL receptors increases the removal of LDL lipoprotein from the blood. Added to statin therapy, it provides an additional effect, decreasing LDL levels and further reducing the dimensions of atherosclerotic plaques Ezetimibe is administered P.O and is absorbed into intestinal epithelial cel ls, where it localizes to the brush border…….the presumed site of action Approximately 80% of the drug is excreted in feces Plasma concentrations are reduced when given with cholestyramine

42. Ezetimibe binds to the NPC1L1 protein on epithelial cells, blocking the absorption of cholesterol

43. Ezetimibe- Clinical uses Primary hypercholesterolemia : Ezetimibe lowers LDL cholesterol by 17% and slightly increases in HDL concentration Is synergistic with reductase inhibitors , producing decrements a s great as 25% in LDL cholesterol Useful in patients with phytosterolemia : rare inherited   lipid metabolic disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols leading to  hypercholesterolemia

44. Ezetimibe- ADE Ezetimibe is generally well tolerated Low incidence of reversible impaired hepatic func tion with a small increase in incidence when given with a HMG-CoA reductase inhibitor Bile acid sequestrants inhibit absorption of ezetimibe , and the two agents should not be administered together

45. Proprotein convertase subtilisin kexin type 9 inhibitors PCSK9I PCSK9 is an enzyme predominately produced in the liver. It binds to the LDL receptor on the surface of hepatocytes, leading to the degradation of LDL receptors. By inhibiting the PCSK9 enzyme, more LDL receptors are available to clear LDL-C from the serum. Alirocumaband , evolocumab are PCSK9 inhibitors, which are fully humanized monoclonal antibodies.

46. Proprotein convertase subtilisin kexin type 9 inhibitors PCSK9I Indications Familial hypercholesterolemia Clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. Side effects PCSK9 inhibitors are generally well tolerated. The most common adverse drug reactions are injection site reactions, allergic reactions, nasopharyngitis, and upper respiratory tract infections

47. Dietary Management of Hyperlipoproteinemia Dietary measures are initiated first and may obviate the need for drug Patients with familial hypercholesterolemia or familial combined hyperlipidemia always require drug therapy Cholestero l and saturated and trans -fats are the principal factors that increase LDL , whereas total fat , alcohol , and excess calories increase triglycerides Weight reduction, caloric restriction, and avoidance of alcohol are especially important for patients with elevated VLDL and IDL (increase HDL) Omega-3 fatty acids found in fish oils activate PPAR- α and can induce profound reduction of t riglycerides in some patients They also have anti-inflammatory and antiarrhythmic activities

48. QUESTION 1 1. Increased serum levels of which of the following is associated with a decreased risk of atherosclerosis? (A) Cholesterol (B) LDL (C) HDL (D) Triglyceride (E) VLDL

49. A 58-year-old man with a history of hyperlipidemia was treated with a drug. The chart below shows the results of the patient’s fasting lipid panel before treatment and 6 mo after initiating drug therapy. Normal values are also shown. Which of the following drugs is most likely to be the one that this man received? (A) Colestipol (B) Ezetimibe (C) Gemfibrozil (D) Lovastatin (E) Niacin QUESTION 2

50. Which of the following drugs is most likely to increase this patient’s triglyceride and VLDL cholesterol concentrations when used as monotherapy? (A) Atorvastatin (B) Cholestyramine (C) Ezetimibe (D) Gemfibrozil (E) Niacin QUESTION 3

51. The patient is started on gemfibrozil. Which of the following is a major mechanism of gemfibrozil’s action? (A) Increased excretion of bile acid salts (B) Increased expression of high-affinity LDL receptors (C) Increased secretion of VLDL by the liver (D) Increased triglyceride hydrolysis by lipoprotein lipase (E) Reduced uptake of dietary cholesterol QUESTION 4

52. Consumption of alcohol is associated with which of the following changes in serum lipid concentrations? (A) Decreased chylomicrons (B) Decreased HDL cholesterol (C) Decreased VLDL cholesterol (D) Increased LDL cholesterol (E) Increased triglyceride QUESTION 5

53. Which of the following is a major toxicity associated with gemfibrozil therapy? (A) Bloating and constipation (B) Cholelithiasis (C) Hyperuricemia (D) Liver damage (E) Severe cardiac arrhythmia QUESTION 6

54. If the patient has a history of gout, which of the following drugs is most likely to exacerbate this condition? (A) Colestipol (B) Ezetimibe (C) Gemfibrozil (D) Niacin (E) Simvastatin QUESTION 7

55. After being counseled about lifestyle and dietary changes, the patient was started on atorvastatin. During his treatment with atorvastatin, it is important to routinely monitor serum concentrations of which of the following? (A) Blood urea nitrogen (B) Alanine and aspartate aminotransferase (C) Platelets (D) Red blood cells (E) Uric acid QUESTION 8

56. Six months after beginning atorvastatin, the patient’s total and LDL cholesterol concentrations remained above normal, and he continued to have anginal attacks despite good adherence to his antianginal medications. His physician decided to add ezetimibe. Which of the following is the most accurate description of ezetimibe’s mechanism of an action? (A) Decreased lipid synthesis in adipose tissue (B) Decreased secretion of VLDL by the liver (C) Decreased gastrointestinal absorption of cholesterol (D) Increased endocytosis of HDL by the liver (E) Increased lipid hydrolysis by lipoprotein lipase QUESTION 9

57. Which of the following nonstatin drugs lowers LDL-C most effectively? A. Niacin B. Alirocumab C. Cholestyramine D. Ezetimibe QUESTION 10