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Lipid metabolism and hypolipedemic drugs

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A nice presentation on lipid metabolism, HDL, LDL and drugs acting on it.

A nice presentation on lipid metabolism, HDL, LDL and drugs acting on it.

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  • 1. Lipid metabolism and Hypolipidemic drugs Dr Urmila M. Aswar, Sinhgad Institute of Pharmacy, Narhe, Pune -41
  • 2. LIPIDS • Esters of fatty acids and alcohols. • Insoluble in water • Saturated: lauric acid, palmitic acid, eg DALDA, increase LDL • Monounsaturated: oleic acid • Polyunsaturated fatty acids: arachidonic acid, abundant in corn oil, hypolipedemic. • Trans fatty acid: harmful, increase LDL
  • 3. Cont.. • Triglycerides (TG): • Cholesterol (CH): • LIPOPROTEINS: They are spherical particles that transport neutral lipids that is TG and CH in blood. • Structure: Core-TG and CE, hydrophilic surface -PL, unestrified CH and Apoprotein
  • 4. TG • Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG).
  • 5. CH • Dietary intake supplies only about 20 – 25% of the cholesterol needed everyday to build cell membranes,
  • 6. • synthesize bile acids/salts,
  • 7. • synthesize hormones of the adrenal glands (aldosterone, cortisol)
  • 8. • and synthesize the sex hormones.
  • 9. • The other 75 – 80% of our daily need for cholesterol is synthesized in the liver.
  • 10. LIPOPROTEIN • Apolipoprotein: a protein that binds to lipids • cholesteryl ester: a compound of cholesterol and a fatty acid • Triglyceride: a compound of glycerol and three fatty acids, an ordinary fat molecule • Phospholipid: a compound of glycerol, two fatty acids, and choline phospate, an emulsifier like lecithin
  • 11. Types of LP • • • • Chylomicrons, VLDL, LDL, HDL
  • 12. Density:HDL>LP(a)>LDL>IDL>VLDL>CM DM:CM>VLDL>IDL>LDL>LP(a)>HDL TG:CM>VLDL>IDL>LDL>LP(a)=HDL CE:LP (a)= LDL>IDL>HDL>VLDL>CM ATHEROGENOCITY: LP(a)>LDL>IDL>VLDL=CM HDL is antiatherosclerotic
  • 13. Apoproteins • • • • • • • • These are surface proteins on LP Gives structural stability They help in metabolism/ Fate of LP. There are 9 types APO AP-I, AP-II, AP-IV APO B-48, APO B-100 APO C-I, APO C-II, APO C-III APO E
  • 14. Normal lipid metabolism:
  • 15. Endogenous Pathway
  • 16. VLDL • Dietary TGs are packaged by the liver into a lipoprotein known as very low density lipoprotein (VLDL).
  • 17. • This lipoprotein delivers the TG to adipose tissue to be stored.
  • 18. • The primary function of low density lipoprotein (LDL) is the transport of the cholesterol synthesized in the liver to the periphery.
  • 19. • As it travels through the circulation LDL reacts with LDL receptors on various nonhepatic cells.
  • 20. • Dietary saturated fat in particular is one of the primary dietary determinants of hypercholesterolemia, as demonstrated by numerous studies.
  • 21. • These studies illustrate the importance of substituting unsaturated fat for saturated fat in the diet.
  • 22. • Saturated fats raise LDL cholesterol by decreasing the synthesis of LDL receptors, • Genetic effects involves dysfunction of LDL receptors or mutation of LDL receptors or absence of LDL receptors
  • 23. • The overall results is cholesterol is not removed from the circulation. LDL cholesterol that does not react with a LDL receptor continues to circulate.
  • 24. Why LDL is BAD and HDL is good • LDL’s are usually not particularly atherogenic • LDL gets damaged and oxidised by smoking & other factors producing free radicals • Damaged LDL is recognised by the scavenger receptor on macrophages & is engulfed by them • Because the LDL is damaged & oxidised it causes the macrophage to become poisoned & die. • They then transform into a foam cell – which is the start of the atherosclerosis process • HDL can do some repair of LDL’s to make them less damaged & less toxic to macrophages
  • 25. • The oxidation of LDL is an important step in atherogenesis as it activates further immune and inflammatory responses (i.e. entry of monocytes across endothelium).
  • 26. • These LDL foam cells accumulate in significant amounts, forming lesions called fatty streaks. Once formed, fatty streaks produce more toxic oxygen radicals and cause immunologic and inflammatory changes (production of more cytokines) resulting in progressive damage to the vessel wall.
  • 27. HDL – a good cholesterol • Nascent HDL takes CH from Foam cells and periphery. CH is converted into CE by LCAT(lecithin cholesterol acyl transferase). The CE of HDL is transported to VLDL, LDL, IDL by CETP(cholesteryl ester transfer protein) which further goes to liver via LDR receptor: Reverse cholesterol transfer
  • 28. Hyperlipedaemia • Primary: genetic • Secondary: associated with some disease, diabetes, myxoedema, nephrotic syndrome, chronic alcoholism.
  • 29. • Till 30 yrs possibility of coronary artery disease is less. • Later yrs, appearance of angina, coronary thrombosis and/or sudden death can happen.
  • 30. Factors causing CAD • Age • Obesity • Menopause
  • 31. • • • • • Hyperlipidemia, hypertension, Smoking, Diabetes Sedentary lifestyle
  • 32. WHY hyperlipedaemia occurs • The reason for this is that research from experimental animals, laboratory investigations, epidemiology and genetic forms of hypercholesterolemia indicate that elevated LDL cholesterol is a major cause of CAD and that clinical trials show that LDL-lowering therapy reduces the risk for CAD.
  • 33. Pharmacotherapy of hyperlipidaemias • Healthy Diet • HMG-CoA reductase inhibitors: Statins • Bile acid binding agents: Cholestyramine, colestipol • Fibric acid derivatives: Clofibrate, Gemfibrozil, Benzafiberate • Inhibitors of absorption of cholesterol: Stanol esters, Eztimibe
  • 34. 1. HMG-CoA reductase inhibitors The HMG-CoA reductase inhibitors, or statins are a class of hypolipidemic agents that are competitive inhibitors of HMGCoA reductase. They inhibit conversion of HMG-CoA to mevalonic acid and deplete intracellular supply of CH. • Liver compensate this biosynthesis and take up CH from blood and by increasing the no of LDR on liver.
  • 35. • They are considered to be the most potent cholesterol-lowering agents, lowering LDL-cholesterol between 20–60%. • They also increase the uptake of VLDL and IDL remenants. • Disadvantages: After prolong use only LDL reduction happens by 6% even after doubling the dose. • Ceiling dose effect: induction of HMG-CoA reductase- More synthsis of CH. This decreases LDR further.
  • 36. Lovastatin (Mevacor, Altocor) Merck • Lovastatin was the first statin approved by the FDA (August 1987). • The dosage is 20-80 mg and should be taken in the evening with food. • Shows 25-40% reduction in LDL.
  • 37. • • • • • Simvastatin (Zocor) Merck Simvastin was approved in the late 1980’s. The dosage is 20-80 mg and should be taken in the evening. Shows 35-50% reduction in LDL. Simvastatin is highly lipophilic, and there tends to be more insomnia with the lipophilic statins (unknown mechanism).
  • 38. Pravastatin (Pravachol) Bristol Meyer Squibb • Pravastatin was “discovered” in Japan in 1979, produced by a chemical modification of lovastatin. In terms of clinical trials, pravastatin is the most studied statin.The dosage is 20-80 mg and should be taken in the evening, with or without food. Pravastatin is less lipophilic than simvastatin and is also less likely to cause insomnia. • 20-35% reduction in LDL
  • 39. Atorvastatin (Lipitor) Pfizer • Atorvastatin received FDA approval in 1997 and by 2004 was the best selling drug in the world with sales of $10.9 billion. • The dosage is 10-80 mg.
  • 40. • Shows 35-60% reduction in LDL • One of the advantages of Lipitor is that it can be taken with or without food at any time of the day.
  • 41. Adverse effects of statins elevated liver enzymes 1-2% can have liver disease. Within 6 weeks of the onset of statin therapy the patient should have a blood test to determine the concentration of the liver enzymes aspartate aminotransferase, AST (normal concentration is 0 – 35 U/L) and alanine transaminase, ALT(normal concentration is 4 – 36 U/L).
  • 42. • Of these, the AST test is the most sensitive marker of the impact of statin therapy. If it is elevated more than 2-3 times the upper limit of normal, therapy should be terminated.
  • 43. • A fatty liver is the most common cause of elevated AST and ALT in patients on statin therapy.
  • 44. Muscle pain • The most commonly reported adverse effect with statin use is muscle pain. There is a serious, but rare complication associated with the breakdown of muscle proteins called rhabdomyolysis. These muscle proteins, especially myoglobin, are released into the circulation, and result in the potentially life-threatening complications of myoglobinuric acute renal failure and cardiac arrest.
  • 45. • The most common symptoms of rhabdomyolysis include: dark urine, swollen, tender muscles of the thighs and lower back.
  • 46. • Creatine phosphokinase (CPK) elevation is one of the most important diagnostic criteria of rhabdomyolysis. A value above the upper limit of normal (range of 30 – 200 U/ L), indicates a problem.
  • 47. GI problems • Common GI problems with statin therapy, which generally resolve within a couple of weeks of initiating therapy include: nausea, diarrhea, constipation, excessive flatulence. • Other effects: Headache, dizziness, taste alterations, insomnia, and photosensitivity are other reported effects.
  • 48. II. Bile acid binding resins or Bile acid sequestrants Bile acid sequestrants are a group of medications which bind bile in the GI tract. By binding bile they prevent its reabsorption, increasing its removal. As the body loses bile acids, it converts cholesterol into bile acids, thus lowering serum cholesterol levels. It reults in upregulation of LDL receptors and thus decreases LDL in serum.
  • 49. • Use of these agents has declined since the introduction of the statins. They require very large doses and need to be taken with lots of water. They are most often used as an adjunct to statins. • lowering of LDL (generally, no more than 20%) and a very slight elevation of HDL is seen with in 2-3 weeks. •
  • 50. Cholestyramine • This is the major drug in this class. • The usual dosage of this powder is 4 - 6 g, mixed with a liquid, twice a day before meals. • No more than 24 g/day
  • 51. Colesevelam • The dosage is three 625 mg tablets, twice daily, so 6 tablets/day.
  • 52. Colestipol • Dosage, if granules is 5 g, one or two times daily • Tablets, 2 – 4 g/day, tablets are 1 g each.
  • 53. Adverse effects of the bile acid sequestrants • These adverse effects are generally GI related and usually dissipate within a couple of weeks. They include: nausea, vomiting, heartburn, bloating, constipation (most common), flatulence, fecal impaction, fatty or black stools, and intestinal obstruction (most severe). •
  • 54. • Transient increases in AST, ALT and alkaline phosphatase have been observed in patients on Colestipol.
  • 55. III. Cholesterol absorption inhibitors • CH comes from diet and hepatic secretion. These drugs block dietary absorption of dietary cholesterol in the small intestine, this results in uptake of LDL and hence reduces LDL cholesterol levels. Plant stanol esters and Ezetimibe are used for this.
  • 56. Ezetimibe • A cholesterol inhibitor, Ezetimibe (Dose: 10 mg) alone generally reduce LDL between 10 – 20%. • Adverse effects include: fatigue, coughing, nausea, diarrhea, rash, pancreatitis and angioedema.
  • 57. Fibrates • The primary actions of this class of drugs is to lower triglyceride levels.
  • 58. • This occurs through stimulation of lipoprotein lipase (which hydrolyzes triglycerides) and by suppression of apoprotein C-III production (this is the protein component of VLDL, the primary carrier of triglycerides from the liver to other tissues).
  • 59. • These drugs were first introduced in 1962 and were widely used before the discovery of the statins.
  • 60. a. gemfibrozil (Lopid) • Dosage is 600 mg, bid at least 30 minutes before eating
  • 61. b. fenofibrate (Antara, Lofibra, Tricor, Triglide) • • • • Antara dosage is 43 – 130 mg/day Lofibra dosage is 67 – 200 mg/day Tricor dosage is 48 – 145 mg/day Triglide dosage is 50 – 160 mg/day
  • 62. adverse effects of fibrates • These include GI disturbances (nausea, vomiting, diarrhea, flatulence).
  • 63. • In addition, dizziness, blurred vision, muscle pain and weakness have been reported.
  • 64. • Some patients taking gemfibrozil have reported gallstone formation.
  • 65. • Combination therapy of gemfibrozil and a statin may be associated with an increased risk of rhabdomyolisis, according to the Committee on Safety of Medicines.
  • 66. • Fenofibrate may be given with a statin, but only if statin monotherapy is insufficient (very high LDL AND very high triglycerides). • Dosage: 100 – 500 mg/day, increase up to 1 – 2 g tid