Antihyperlipidemia

Antihyperlipidemia

1. Antihyperlipidemic Drugs Edson Mutandwa MBBS v

2. HYPERLIPIDEMIA Hyperlipidemia refers to increased levels of lipids (fats) in the blood, including cholesterol and triglycerides. ( uptodate ) hyperlipidemia significantly increase your risk of developing cardiovascular disease, coronary artery disease, cerebrovascular disease, and peripheral vascular disease.

3. LIPID METABOLISM

4. RISK FACTORS FOR HYPERLIPIDEMIA Family history of early heart disease (father before the age of 55 years and mother before the age of 55 years ) Cigarette smoking High blood pressure Age (men older than 45 years and women olderthan 55 years) Low HDL levels Obesity Diabetes etc

5. DIAGNOSIS OF HYPERLIPIDEMIA Diagnosis is typically based on medical history, physical examination and blood test done after overnight fasting

6. WHEN TO CHECK LIPID PANEL Two different Recommendations Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides Repeat testing every 5 years for acceptable values United States Preventative Services Task Force Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesterol levels or premature cardiovascular disease

7. Management of hyperlipidemia Management of hyperlipidemia start with therapeutic life changes ( TLC) which includes; a cholesterol-lowering diet (TLC diet), physical activity, quitting smoking ( if applicable ), weight management, a nd antihyperlipidemia drugs

8. Antihyperlipidemic drugs classification HMG-CoA reductase inhibitors Bile acid sequestrants Fibrates Nicotinic acid (Niacin) cholesterol absorption inhibitors PCSK9 inhibitors

9. HMG-CoA reductase inhibitors Examples; Lovastatin, atorvastatin, rosuvastatin (5 to 40 mg/day) Mechanism of action Analogs of HMG (3-hydroxy-3 methylglutaryl -CoA) HMG-CoA reductase catalyzes synthesis of mevalonic acid from HMG-CoA and is the rate limiting step in cholesterol biosynthesis Leads to up-regulation of LDL receptors in liver Therapeutic Uses Great for all hyperlipidemias involving increased levels of LDL or cholesterol Atherosclerosis; stroke prevention Primary prevention of CAD

10. Major side effect and drug interactions Side effects Headache nausea sleep disturbance elevations in hepatocellular enzymes and alkaline phosphatase. CI in hepatic dysfunction Myositis and rhabdomyolysis, primarily when given with gemfibrozil or cyclosporine; myositis is also seen with severe renal insufficiency (CrCl <30 mL/min). CI in pregnancy Drug interactions ; Lovastatin, atorvastatin, rosuvastatin, and simvastatin potentiate effect of warfarin; this interaction is not seen with pravastatin, fluvastatin, or pitavastatin . Most statins can also affect digoxin metabolism and levels

11. Bile acid sequestrants Examples; Cholestyramine (4 to 24 g/day), Colestipol (5 to 30 g/day), Colesevelam (3.75 g/day) Mechanism of action Anion-exchange resin – binds bile acids in intestinal lumen preventing enterohepatic circulation (this increases excretion of bile which is made from cholesterol),this causes an up-regulation of hepatic LDL receptors and increased production of cholesterol Therapeutic Uses Uses Hyperlipidemias involving ISOLATED INCREASES OF LDL

12. Major side effect and drug interactions Side effects Constipation Flatulence Dyspepsia Hypertriglyceridemia Hyperchloremic acidosis (since they exchange Cl) Bind many things (drugs, vitamins, toxins, anything fat soluble) which limits their absorption Prexisting coagulopathy is a contraindication since they prevent absorption of vit K Drug interactions Impaired absorption of fat soluble vitamins and co-administered medications including: Amiodarone , digoxin, warfarin, thiazides, β- blockers, levothyroxine, others; interaction can be minimized by taking other medications at least 1 hour before or 4 hours after bile acid sequestrant .

13. Fibrates Examples; Gemfibrozil (600 mg BID), Fenofibrate ( Nanocrystal 145 mg/day Micronized 160 to 200 mg/day0 Mechanism of action activation of nuclear transcription receptor to increase LPL synthesis (removes TGs from lipoproteins); enhanced removal of VLDL from plasma Theurapitic use DOC fro type III lipoproteinemia (familial dysbetalipoproteinemia ) Hypertriglyceridemias useful for Pruritus in biliary obstruction (↑ bile acids)

14. Major side effect and drug interactions Side effects Skin rash, gastrointestinal (nausea, bloating, cramping) myalgia; lowers blood cyclosporine levels; potentially nephrotoxic in cyclosporine treated patients. Avoid in patients with CrCl <30 mL/min. ( Fenofibrate ) Potentiates warfarin action. Absorption of gemfibrozil diminished by bile acid sequestrants . (Gemfibrozil)

15. Nicotinic acid (Niacin) Examples; Niacin (IR: 1 to 6 g/day or XR 0.5 to 2 g/day) Mechanism of action It is a potent inhibitor of lipolysis in adipose tissues which decreases mobilization of FFAs (major precursor of TGs) to the liver which in turn decreases VLDL (after few hours) Increases HDL levels Theraupetic use Uses Hyperlipidemias with very high VLDL and LDL Patients with very low HDL

16. Major side effect and drug interactions Side effects dry skin myositis Prostaglandin-mediated cutaneous flushing, warm sensation Headache Pruritus, Nausea, Vomiting, diarrhea hyperpigmentation (particularly in intertriginous regions); acanthosis nigricans ; Decreased glucose tolerance Hepatotoxicity (check AST, ALT levels) Rhabdomyolysis Hyperuricemia (inhibits tubular secretion of uric acid)

17. C holesterol absorption inhibitors Examples; Ezetimibe (10 mg/day) Mechanism of action Localizes at the brush border, selectively inhibits intestinal absorption of cholesterol and related sterols (only blocks exogenous sterol intake) Therapeutic use Used in hypercholesterolemia together with statins & diet regulation

18. Major side effect and drug interactions Side effects Diarrhea Abdominal pain CI liver dysfunction

19. PCSK9 inhibitors Examples; Alirocumab (75 to 150 mg 2/7 w), Evolocumab (140 mg 2/7 w or 420 mg 1/12 m) Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease produced predominantly in the liver that leads to the degradation of hepatocyte LDL receptors and increased LDL-C levels This category of lipid lowering therapy appears promising in a range of clinical situations. They are given subcutaneously The major side effect is injectin site reaction

20. DRUG THERAPY If no improvement within 6 weeks with a single drug therapy, the dose should be increased. If no improvement after 3 months change the drug or consider combination therapy: Bile acid resins can be safely combined with statins or nicotinic acid (↓ LDL, VLDL cholesterol levels respectively). Ezetimibe + statins → synergistic effects. Fibrates and statins are CI because of myopathy. Nicotinic acid and statins (must be cautiously used) because of myopathy.

21. EFFECTS OF ANTIHYPERLIPIDEMIC DRUGS

22. REFERENCES http://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/cholesterol-medications/art-20050958 Uptodate ; Treatment of lipids (including hypercholesterolemia) in secondary prevention; Robert S Rosenson , MD , This topic last updated: Sep 11, 2015

23. Thank you