Hyperlipidemia
• Lipids of human plasma are transported as
complexes with proteins, such macromolecular
complexes are term...
• The major complications are acute
pancreatitis and atherosclerosis
• Those which contain apolipoprotein (apo)
B100 act a...
• Cellular components in atherosclerotic plaque
are foam cells, derived form macrophages and
smooth muscle cells filled wi...
RISK FACTORS
1) Cigarette is a major risk factor for coronary disease
– Associated with reduced HDL levels
– Impaired chol...
• Normally EDRF, nitric oxide are responsible for
vessels regulation but it is impaired in
hyperlipidemia.
• So natural an...
Pathophysiology of
hyperlipoproteinemia
•
1.
2.
•

Major lipoproteins are:
Cholesteryl esters and
Triglycerides
A monolaye...
• Chylomicrons:
– Lagest type;formed in intestine and carry dietary lipids
–triglycerides
– Responsible for transport of l...
• Low density lipoproteins:
– Further removal of triglycerides by hepatic
lipaseresults in its formation.
– Hepatocytes pl...
• High density lipoproteins:
– Secreted by the liver and intestine
– Comes from surface of chylomicrons and VLDL
during li...
• Atherosclerosis: It is a disease which affects large and
medium size arteries, and a leading cause of death.
• consists ...
Classification of anti-hyperlipidemics:
• HMG-CoA reductase inhibitors ( statins)
– Lovastatin
– Atorvastatin
– Simvastati...
• Bile acid sequestrants (resins):
– Cholestyramine
– Colestipol
• lipoprotein lipase inducers (fibric acid derivative)
– ...
HMG-CoA reductase inhibitors
• Mechanism of action
The de novo synthesis of cholesterol involves a
pathway in which mevalo...
• Pharmacokinetics:
– Given orally except fluvastatin
– Upto 90% available
– Undergoes first pass metabolism and secreted ...
• Adverse effects:
–
–
–
–
–
–

Headache, nausea, bowel upsets, rashes
Sleep disturbances
Rhabdomyolysis
Myalgia , myopath...
• Drug interactions :
– Gemfibrogil
– Cyt P450 enzymes
Cholestyramine
• Also known as bile acid binding resin.
• Bile acid binding resins are cholesterol lowering
drugs that are...
• Resulting in decreased enterohepatic
circulation of causing the liver to increase
production of bile acids utilizing cho...
• Pharmacokinetics:
– Orally (chewed)
– No systemic effects as it is retained in the GI tract
– Usual dose of 12-36g of re...
• Side-effects:
– Increased VLDL and triglycerides
– Usually causes GI symptoms like constipation and
flatulence.
– May in...
Nicotinic acid
• Inhibition of VLDL synthesis( inhibiting
ApoB100 gene expression and resulting in:
– Decreased plasma VLD...
Fibric acid derivatives
• Prototype: Gemfibrozil
• Others : clofibrate , benzafibrate
• Mechanism of action:
– Induction o...
• Indications:
– Hypertriglyceridemias in which VLDL predominate
& in dysbetalipoproteinemia.
– Treatment of hypertriglyce...
• Pharmacokinetics:
– absorbed from the GI tract & undergoes
enterohepatic circulation
– most (70%) is eliminated unchange...
• Side Effects:
–
–
–
–
–
–
–
–

rare cases of rash
GI symptoms
Gall stones
Myositis
Myopathy
Arrhythmias
Hypokalemia &
Hi...
Lab findings

Drugs

Hypercholesteremia

Cholestyramine ,
colestipol, ezetimibe

Hypertriglyceridemia

Gemfibrozil

Combin...
6anti hyperlipidemic drugs
6anti hyperlipidemic drugs
6anti hyperlipidemic drugs
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6anti hyperlipidemic drugs

  1. 1. Hyperlipidemia • Lipids of human plasma are transported as complexes with proteins, such macromolecular complexes are termed lipoproteins; except fatty acids which are bound to albumin. • Any metabolic disorders involving the elevations in plasma concentrations of any lipoprotein species known as hyperlipoproteinemias or hyperlipidemias. • Hyperlipidemia is generally restricted to conditions that involve increased level of triglycerides in plasma.
  2. 2. • The major complications are acute pancreatitis and atherosclerosis • Those which contain apolipoprotein (apo) B100 act as vehicles by which cholesterol are transported into artery wall. • Those are low-density (LDL), intermediate density (IDL), very low density (VLDL) and Lp(a) lipoproteins.
  3. 3. • Cellular components in atherosclerotic plaque are foam cells, derived form macrophages and smooth muscle cells filled with cholesteryl esters. • The atheromatous plaque grows over time with the accumulation of increased no. of foam cells and of collagen and fibrin. • High-density lipoproteins (HDL) exert antiatherogenic effects.
  4. 4. RISK FACTORS 1) Cigarette is a major risk factor for coronary disease – Associated with reduced HDL levels – Impaired cholesterol level – Cytotoxic effects on endothelium – Increased oxidation of atherogenic lipoproteins – Stimulates thrombogenesis 2) Hypertension 3) Diabetes 4) LDL levels
  5. 5. • Normally EDRF, nitric oxide are responsible for vessels regulation but it is impaired in hyperlipidemia. • So natural antioxidants such as tocopherol and ascorbic acid can reduce such impairment.
  6. 6. Pathophysiology of hyperlipoproteinemia • 1. 2. • Major lipoproteins are: Cholesteryl esters and Triglycerides A monolayer of unesterified cholesterol and phospholipids surrounds the hydrophobic core of above lipoproteins. • Specific proteins (apolipoproteins) are located on the surface. • Also certain lipoproteins contain large mol. wt apolipoproteins(B lipoproteins) which don’t migrate like smaller ones. • Subtypes of B apolipoproteins: – – B-48 formed in intestine with chylomicrons B100 synthesized in liver and found in VLDL, VLDL remnants,LDL and the Lp(a) lipoproteins.
  7. 7. • Chylomicrons: – Lagest type;formed in intestine and carry dietary lipids –triglycerides – Responsible for transport of lipids • Very low density lipoproteins (VLDL) : – Secreted by liver; means for transporting triglycerides to peripheral tissues – Hydrolyzed by lipoprotein lipase yielding free fatty acids for oxidation and storage. – Intermediate particles called IDL are formed after the VLDL is depleted of triglycerides.
  8. 8. • Low density lipoproteins: – Further removal of triglycerides by hepatic lipaseresults in its formation. – Hepatocytes play a major role for its catabolic activity. • Lp(a) lipoprotein: – Formed form an LDL-like moiety – The Lp(a) lipoprotein complex can be found in atherosclerotic plaques and contribute to coronary disease by inhibiting thrombolysis.
  9. 9. • High density lipoproteins: – Secreted by the liver and intestine – Comes from surface of chylomicrons and VLDL during lipolysis.
  10. 10. • Atherosclerosis: It is a disease which affects large and medium size arteries, and a leading cause of death. • consists of localized plaque in the intima, and is composed of cholesterol esters, proliferation of smooth muscle, deposition of fibrous proteins and calcifications. • Effects: – Narrowing of the arterial lumen – Ulceration of arterial lumen and thrombosis of artery and embolization. – Weakens arterial wall and formation of aneurysms.
  11. 11. Classification of anti-hyperlipidemics: • HMG-CoA reductase inhibitors ( statins) – Lovastatin – Atorvastatin – Simvastatin – Pravastatin – Rosuvastatin
  12. 12. • Bile acid sequestrants (resins): – Cholestyramine – Colestipol • lipoprotein lipase inducers (fibric acid derivative) – Clofibrate – Gemfibrozil – Benzafibrate • Inhibit lipolysis and triglycerides synthesis – Nicotinic acid ( niacin) • Inhibit intestinal cholesterol absorption – Ezetimibe • Others – Probucol – gugulipid
  13. 13. HMG-CoA reductase inhibitors • Mechanism of action The de novo synthesis of cholesterol involves a pathway in which mevalonic acid is formed and by the enzyme hydroxymethylglutaryl co-enzyme reductase (HMG-Co A reductase); the statins inhibits this step resulting in decrease hepatic cholesterol synthesis. Resultantly synthesis of high affinity LDL receptors on the liver occurs and increased clearance of plasma LDL. • Decrease liver cholesterol • Increase LDL gene expression • Decrease plasma LDL • Decrease VLDL synthesis • Decrease TGLs
  14. 14. • Pharmacokinetics: – Given orally except fluvastatin – Upto 90% available – Undergoes first pass metabolism and secreted in bile – 5-10% excreted in urine
  15. 15. • Adverse effects: – – – – – – Headache, nausea, bowel upsets, rashes Sleep disturbances Rhabdomyolysis Myalgia , myopathy Rise in LFTs particularly serum transaminases Muscle weakness • Indications: – Hyperlipidemia with raised LDL and Cholesterol level – Progression of atherosclerotic lesion – Ischemic heart disease of elderly
  16. 16. • Drug interactions : – Gemfibrogil – Cyt P450 enzymes
  17. 17. Cholestyramine • Also known as bile acid binding resin. • Bile acid binding resins are cholesterol lowering drugs that are man made resins. They are gritty, insoluble granules which are available in the form of a bar that has to be chewed thoroughly or comes in the form of a powder and needs to be mixed with a liquid. • These prevent re-absorption of cholesterol into the body when they bind with the cholesterolrich bile acids secreted by the liver.
  18. 18. • Resulting in decreased enterohepatic circulation of causing the liver to increase production of bile acids utilizing cholesterol • Decrease LDL levels • Increase LDL receptor gene expression. • It significant effect on LDL levels by utilizing the LDL receptors but no effect on the HDL levels.
  19. 19. • Pharmacokinetics: – Orally (chewed) – No systemic effects as it is retained in the GI tract – Usual dose of 12-36g of resin per day in divided doses with meals.
  20. 20. • Side-effects: – Increased VLDL and triglycerides – Usually causes GI symptoms like constipation and flatulence. – May interfere with the absorption of fat-soluble vitamins and may bind with other drugs if taken concurrently. Drug interactions – Orally administered drugs Contraindication: – Hypertriglyceridemia
  21. 21. Nicotinic acid • Inhibition of VLDL synthesis( inhibiting ApoB100 gene expression and resulting in: – Decreased plasma VLDL – Decreased plasma LDL – Increased plasma HDL Side effects : – Flushing , pruritus , rashes – hepatotoxicity
  22. 22. Fibric acid derivatives • Prototype: Gemfibrozil • Others : clofibrate , benzafibrate • Mechanism of action: – Induction of lipoprotein lipase – Activation of the nuclear transcription receptor “peroxisome proliferator - activated receptor alpha” (PPARα). –mediate effects of insulin – class of intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation. – PPAR-α activation by fibrates results in numerous changes in lipid metabolism that act together to decrease plasma triglyceride levels & increase plasma HDL. – Decrease VLDL and IDL
  23. 23. • Indications: – Hypertriglyceridemias in which VLDL predominate & in dysbetalipoproteinemia. – Treatment of hypertriglyceridemia resulting from treatment with viral protease inhibitors. Contraindication: Hypercholesteremia
  24. 24. • Pharmacokinetics: – absorbed from the GI tract & undergoes enterohepatic circulation – most (70%) is eliminated unchanged through the kidneys – half life : 1.5 hrs.
  25. 25. • Side Effects: – – – – – – – – rare cases of rash GI symptoms Gall stones Myositis Myopathy Arrhythmias Hypokalemia & High aminotransferase or alkaline phosphatase levels, risk of cholesterol gallstones.
  26. 26. Lab findings Drugs Hypercholesteremia Cholestyramine , colestipol, ezetimibe Hypertriglyceridemia Gemfibrozil Combined hyperlipidemia (Statins and niacin) + ezetimibe

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