Hypolipidemic agents


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This is a wonderful presentation on hypolipidemic drugs by Dr.Sachin Kuchya.
Kudos for him.

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Hypolipidemic agents

  1. 1. Hypolipidemic Agents Sachin Kuchya, MD Assistant Professor, Department of Pharmacology NSCB Medical College, Jabalpur
  2. 2. Why do we need them? <ul><li>Low HDL & elevated LDL-c are known risk factor for CHD. </li></ul><ul><li>Elevated TG’s are known to cause Pancreatitis. </li></ul><ul><li>In well controlled clinical trials ,fatal & nonfatal CHD events & strokes was reduced by as much as 30-40% as per Scandinavian Simvastatin Survival Study. </li></ul>
  3. 3. Overview of Presentation <ul><li>Physiology </li></ul><ul><li>Pharmacological targets </li></ul><ul><li>Drugs </li></ul><ul><li>Clinical states </li></ul><ul><li>Special populations </li></ul><ul><li>Combination Drug Regimens </li></ul>
  4. 4. GLOSSARY <ul><li>Lipid – water insoluble compounds, comprising of FFA, TG, CHL, CHL- esters. </li></ul><ul><li>LIPOPROTEIN - complex of lipids + apoproteins </li></ul><ul><li>Chylomicrons – largest of lipoproteins, carry TG & CHL- esters from the gut to other tissues </li></ul><ul><li>VLDL - very low density lipoprotein, principal form secreted by liver, represents triglyceride content in lipid profile. </li></ul><ul><li>LDL - low density lipoprotein, derived from VLDL, represents CHL. </li></ul><ul><li>HDL - high density lipoprotein, extracts CHL from body tissues. </li></ul><ul><li>Lp(a)- LDL + apoprotein a, is known to be atherogenic . </li></ul><ul><li>CETP - Cholesteryl Ester Transfer Protein . </li></ul>
  5. 5. PHYSIOLOGY Enterohepatic circulation - Bile acids CHL Pool Dietary CHL De novo CHL synthesis HMG CoA reductase enz. VLDL Chylomicrons 50% 50% VLDL LDL TG CHL <ul><li>Adipose tissue (Storage) </li></ul><ul><li>Skeletal M </li></ul><ul><li>Cardiac M </li></ul><ul><li>Breast tissue during lactation </li></ul>To various body tissues, Gut HDL2 HDL3 CHL ester TG LDL CETP Tightly regulated Diurnal variation
  6. 6. <ul><li>Dietary restriction </li></ul><ul><li>Cholesterol absorption inhibitor </li></ul><ul><li>Bile acid binding resin </li></ul><ul><li>HMG CoA reductase inhibitor </li></ul><ul><li>VLDL secretion inhibitor </li></ul><ul><li>Fibric acid derivatives </li></ul><ul><li>CETP inhibitor </li></ul>Non Pharmacological & Pharmacological targets 1 2 3 4 5 6 7 Dietary Atheroma HDL2 CHL Pool CHL VLDL Chylomicrons 50% 50% VLDL LDL TG CHL Gut HDL3 CHL ester TG LDL CETP Bile acids
  7. 7. Statins – effect on lipids <ul><li>LDL-c </li></ul><ul><li>Lowers LDL-c by 20-50% </li></ul><ul><li>TG </li></ul><ul><li>If >250 mg/dl, then significant reduction is seen. </li></ul><ul><li>HDL-c </li></ul><ul><li>Increases HDL levels by 5- 10%. </li></ul><ul><li>Lp(a) </li></ul><ul><li>No effect is seen . </li></ul>
  8. 8. Statins – additional effects <ul><li>Improved endothelial function </li></ul><ul><li>Prevents weakening & rupture of atherosclerotic plaque. </li></ul><ul><li>Reduces platelet aggregation. </li></ul><ul><li>Lowers C- Reactive protein levels – anti-inflammatory action. </li></ul>
  9. 9. Statins – Clinical Pharmacokinetics <ul><li>Should be administered orally </li></ul><ul><li>Lo – sim – pra – fluvastatin, should be administered in evening / with dinner. </li></ul><ul><li>Ator – Rosuvastatin, can be given at any time of day. </li></ul><ul><li>All statins will need dose adjustments with gemfibrozil, cholestyramine, niacin. </li></ul><ul><li>Role of CYP3A4 & CYP2C9 enz. </li></ul>
  10. 10. Statins – adverse effects <ul><li>Major side effects </li></ul><ul><ul><li>Myopathy (Diabetes, Advancing age & Drug) </li></ul></ul><ul><ul><li>Hepatotoxicity </li></ul></ul><ul><ul><li>Teratogenicity (Lo - Fluvastatin). </li></ul></ul><ul><li>Minor </li></ul><ul><ul><li>Dyspepsia </li></ul></ul><ul><ul><li>Generalized eczematous rash (Simvastatin) </li></ul></ul>
  11. 11. Statins – indications <ul><li>Effective in almost all patients with elevated LDC-c levels </li></ul><ul><li>Exception – familial homozygous hypercholesterolemia . </li></ul>
  12. 12. Bile acid binding resins <ul><li>LDL-c </li></ul><ul><li>Lowers LDL-c by 12 –28 %. </li></ul><ul><li>TG </li></ul><ul><li>May increase transiently . </li></ul><ul><li>HDL-c </li></ul><ul><li>Increases HDL levels by 4 –5%. </li></ul>
  13. 13. Bile acid binding resins – adverse effects <ul><li>No systemic absorption, no systemic toxicity. </li></ul><ul><li>Only local GI side effects </li></ul><ul><li>Bloating </li></ul><ul><li>Dyspepsia </li></ul><ul><li>Constipation </li></ul>
  14. 14. Bile acid binding resins <ul><li>Indications – safest , </li></ul><ul><li>Hypolipidemic of choice during pregnancy. </li></ul><ul><li>As a second line agent, if elevated LDL-c is not adequately controlled with statins . </li></ul><ul><li>Drug interactions – </li></ul><ul><li>Inhibits GI absorption of thiazides, furosemide, thyroxine, statins, ezetimibe, fibrates, warfarin etc. </li></ul><ul><li>Any additional drug should be administered 1 hr before or 4 hrs after the resins. </li></ul>
  15. 15. Ezetimibe <ul><li>Lowers LDL-c by 15- 20%. </li></ul><ul><li>(should be combined with a statin) </li></ul><ul><li>Increases HDL levels by 1- 2%. </li></ul><ul><li>Lowers TG’s by 5%. </li></ul>
  16. 16. Ezetimibe <ul><li>Adverse effects – almost none, well tolerated. </li></ul><ul><li>No enzyme induction /inhibition is seen. </li></ul><ul><li>Precaution : should not be simultaneously administered with bile acid binding resins. </li></ul>
  17. 17. Niacin <ul><li>LDL-c </li></ul><ul><li>Lowers LDL-c by 20- 30% </li></ul><ul><li>TG </li></ul><ul><li>Lowers TG levels by 35-45% </li></ul><ul><li>HDL-c </li></ul><ul><li>Increases HDL levels by 30- 40%. </li></ul><ul><li>Lp(a) </li></ul><ul><li>Lowers Lp(a) level by 40%. </li></ul>Physiologic dose, as vitamin B3– 50mg/ day Pharmacologic dose, as hypolipidemic agent – 2 – 6gm/day.
  18. 18. Niacin <ul><li>Adverse effects </li></ul><ul><ul><ul><li>Cutaneous flushing </li></ul></ul></ul><ul><ul><ul><li>Dry skin, itching </li></ul></ul></ul><ul><ul><ul><li>Gastritis </li></ul></ul></ul><ul><ul><ul><li>Hepatitis </li></ul></ul></ul><ul><ul><ul><li>Precipitation of acute gout </li></ul></ul></ul><ul><ul><ul><li>Hyperglycemia </li></ul></ul></ul><ul><li>Contraindications </li></ul><ul><li>H/o of gastric ulcer, gout, diabetes milletus </li></ul>
  19. 19. Niacin - indications <ul><li>Hypertriglyceridemia </li></ul><ul><li>Elevated LDL-c, </li></ul><ul><li>Especially in those with low HDL-c levels. </li></ul>
  20. 20. Fibric acid derivatives <ul><li>LDL-c </li></ul><ul><li>Increases LDL-c by upto 10-30%. </li></ul><ul><li>TG </li></ul><ul><li>Lowers TG’s by upto 50% </li></ul><ul><li>HDL-c </li></ul><ul><li>Increases HDL levels by 15%. </li></ul>
  21. 21. Fibric acid derivatives <ul><li>Adverse effects </li></ul><ul><ul><li>Gallstone (Clofibrate) </li></ul></ul><ul><ul><li>Dyspepsia & abdominal pain </li></ul></ul><ul><ul><li>Increased risk of myopathy (gemfibrozil + statins) </li></ul></ul><ul><li>Contraindications </li></ul><ul><ul><li>Hepatic & renal dysfunction </li></ul></ul>
  22. 22. Fibric acid - indications <ul><li>Hypertriglyceridemia </li></ul><ul><li>Chylomicronemia </li></ul><ul><li>Type III dysbetalipoproteinemia </li></ul>
  23. 23. CETP inhibitor - Torcetrapib <ul><li>Increases HDL levels by 45- 100%. </li></ul><ul><li>Under clinical trial. </li></ul>
  24. 24. ω3 – fatty acids <ul><li>EPA & DHA, found primarily in fish oils, when given in high doses upto 6 gm/day, result in inhibition of VLDL secretion. </li></ul><ul><li>TG level falls upto 75% </li></ul><ul><li>Are very useful in treatment of severe hypertriglyceridemia’s ( > 1000mg/dl). </li></ul><ul><li>However, these often raise LDL-c levels , in a manner similar to that seen with fibric acid derivatives, the clinical impact is however unclear. </li></ul><ul><li>Commonest side effect is belching with a fishy odour </li></ul>
  25. 25. Clinical states <ul><li>In this section, we will have some clinical states. </li></ul><ul><li>This exercise shall rationalize the use of hypolipidemic agents. </li></ul>
  26. 26. Chylomicronemia Dietary restriction 1 Clinical state - 1 CHL Pool Dietary CHL VLDL Chylomicrons 50% 50% VLDL LDL TG CHL To various body tissues, Gut HDL2 HDL3 CHL ester TG LDL CETP 1 Bile acids
  27. 27. Hypercholesterolemia 2 5 4 3 Cholesterol absorption inhibitor Bile acid binding resin HMG CoA reductase inhibitor VLDL secretion inhibitor Clinical state - 2 CHL Pool Dietary CHL De novo CHL synthesis HMG CoA reductase enz. VLDL Chylomicrons 50% 50% VLDL LDL TG CHL To various body tissues, Gut HDL2 HDL3 CHL ester TG LDL CETP 2 5 3 4 Bile acids
  28. 28. CHL Pool Dietary CHL VLDL Chylomicrons 50% 50% VLDL LDL TG CHL atheroma Gut HDL2 HDL3 CHL ester TG LDL CETP 6 5 Hypertriglyceridemia 6 5 VLDL secretion inhibitor Fibric acid derivatives Clinical state - 3
  29. 29. Low HDL-c levels VLDL secretion inhibitor CETP inhibitor 5 7 Clinical state - 4 CHL Pool Dietary CHL VLDL Chylomicrons 50% 50% VLDL LDL TG CHL Atheroma Gut HDL2 HDL3 CHL ester TG LDL CETP 7 5
  30. 30. Special Population <ul><li>Children </li></ul><ul><li>Women – Adolescence / Pregnancy/ Lactation/ Postmenopausal. </li></ul>
  31. 31. Special population – Children <ul><li>Less than 2 yrs of age – no dietary restriction & no drug therapy. </li></ul><ul><li>> 2yrs – 10yrs – Dietary restriction of saturated and total fats ; CHL restricted diet only. </li></ul><ul><li>10 yrs & above – Diet therapy </li></ul><ul><li>Drug therapy is indicated only after an adequate trial of dietary control for 6mo – 1 yr. </li></ul>
  32. 32. Special population – Children <ul><li>Drugs </li></ul><ul><ul><li>Bile acid sequestrants (resins) are the first line agents of choice. </li></ul></ul><ul><li>If not - tolerated then, </li></ul><ul><ul><li>Statins can be given, </li></ul></ul><ul><ul><li>Ator – lova – sim, approved for 11yrs & above. </li></ul></ul><ul><ul><li>Pravastatin, for 8 yrs & above . </li></ul></ul>
  33. 33. Women <ul><li>Statins should be used with caution in adolescent girls / females, likely to conceive. </li></ul><ul><li>Bile acid binding resins are the only CHL – lowering drugs used during pregnancy . </li></ul><ul><li>In post menopausal women, who wish to have HRT, elevated TG’s if any should be controlled with Dietary restriction, weight control and fibrates/ statins + fibrates, prior to initiation of HRT. </li></ul>
  34. 34. Combination regimens – why? <ul><li>Maximize reduction of LDL & VLDL. </li></ul><ul><li>Minimize side effects by using smaller doses of drugs. </li></ul><ul><li>Allow use of resins, patients with elevated TG’s & LDL. </li></ul><ul><li>Treat increased LDL, found consequent to treatment of elevated TG with fibric acid derivatives. </li></ul>
  35. 35. Combination regimens – when? <ul><li>After diet & a single drug have been found insufficient. </li></ul><ul><li>Statins, being the most effective & well tolerated, should be the first drug. </li></ul><ul><li>Effect on Plasma lipoprotein levels & side effects should be assesed only after 4 –8 weeks of therapy. </li></ul>
  36. 36. LDL-c reduction <ul><li>Statin + Fenofibrate </li></ul><ul><li>Statin + Niacin </li></ul><ul><li>Statin + Resins </li></ul>
  37. 37. VLDL reduction <ul><li>Nicotinic acid + fibric acid </li></ul><ul><li>Addition of fish oils, may be helpful. </li></ul>
  38. 38. Minimize doses and side effects <ul><li>Statin + Ezetimibe is the safest combination. </li></ul>
  39. 39. Diabetic patient <ul><li>The defect, </li></ul><ul><li>Elevated TG’s / LDL </li></ul><ul><li>Low HDL-c </li></ul><ul><li>Glycosylated LDL </li></ul><ul><li>The treatment, </li></ul><ul><li>Adequate glycemic control & dietary restrictions. </li></ul><ul><li>Drugs </li></ul>
  40. 40. Diabetic patient - drugs <ul><li>Niacin – impairs glycemic control </li></ul><ul><li>Resins – increases TG </li></ul><ul><li>Fibric acid level – increases LDL </li></ul><ul><li>So, combination of hypolipidemics is must, </li></ul><ul><li>Statin + fenofibrate, is the ideal combination . </li></ul>
  41. 41. Thank you Topic is open for queries