4 pharm-lipid lowering drugs-10!13!2010
TRANSCRIPT
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LIPID LOWERING DRUGS
INTRODUCTIONa) Cardiovascular diseases are the principal causes of
death in the industrialized countries.b) Most of these deaths are related to atherosclerosis.
c) Atherosclerosis is a slow progressive disease of thearteries involving the deposition of plaquescontaining cholesterol and lipid material in the intimaof arteries.
d) The development of atherosclerosis is associatedwith high levels of plasma lipoproteins involved in thecholesterol transport.
e) All lipids in human plasma are transported ascomplexes with proteins.
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Atherogenic lipoproteins include: yn: all bad cholesterols
a) LDL Low density lipoprotein
b) IDL Intermediate density lipoproteinc) VLDL Very low density lipoprotein
All of these transport () cholesterol into the artery wall.Lowering of the serum lipid concentration reduces therisk of atherosclerosis and its consequences.
Anti-atherogenic lipoprotein:
a) HDL High density lipoprotein: yn only goodcholesterol.
Retrieves () cholesterol from the artery wall andreduces () LDL oxidation.
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ACRONYMS
ACAT Acyl-CoA (cholesterol acyl transferase)Apo Apolipoprotein
HDL High-density lipoproteins yn: only good oneHMG-Co-A 3-Hydroxy-3-methylglutaryl-coenzyme AIDL Intermediate-density lipoproteinsLDL Low-density lipoproteinsLp(a) Lipoprotein(a)LPL Lipoprotein lipase yn can deal with this.can stimulate itVLDL Very low-density lipoproteinTGs Triglycerides
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CAUSES OF HYPERLIPOPROTEINEMIAS
1) Primary congenital gene defects: yn cant do anything
aboyt : cyn
2) Secondary diabetes, hypertension, hypothyroidism,
alcoholism, biliary cirrhosis and renal diseases: yn 1
glass of red wine increases HDL, 2 glasses
decrease HDL
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TREATMENT
1. Diet
a) Reduce diets high in cholesterol and saturated fats.
Cholesterol and saturated fat increase () plasmalipoproteins.b) Alcohol increase () VLDL. Yn: in some cases
increase HDL
c) Fish oil decrease () TGs and increase () HDL.Yn: Apples reduce LDL by 23%. Increase HDL by 4%.
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2. Drugs
a) Bile acid binding resins. Reduce fat absorptionfrom intestines by binding bile acids.
b) Cholesterol synthesis inhibitors (statins). Inhibit
cholesterol synthesis in the liver (de novo). Yn: Thissyntheses is night time most efective if taken atnight
c) VLDL secretion inhibitors. Reduce secretion of
VLDL from the liver.
d) Lipoprotein lipase stimulants. Increaseperipheral clearance of lipoproteins. Yn: cleavetriglycerides.
e) Lipophilic antioxidants. Inhibit oxidation of LDL
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DRUGS USED IN HYPERLIPIDEMIA
a) Bile acid binding resins
Formulas
COLESTIPOL
CHOLESTYRAMINE
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Mechanism of action
1) Downregulates () intestinal absorption of bile acids(cholesterol metabolites).
2) This increases hepatic conversion of cholesterol tobile acids ().
3) Cell membrane bound high affinity LDL receptors are
upregulated. LDL uptake from plasma increases (
).
Dosage 4 g to 5 g 20 g to 32 g per day
Toxicity
1) Interference with many other orally given drugs2) Interference with vitamins A, D, E, K.3) TG levels increase in patients with
hypertriglyceridemia.
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b) Cholesterol synthesis inhibitors (Statins)HMG-CoA reductase inhibitors
Mechanism of action
1) Inhibition of 3-HMG-CoA reductase (HMG-CoA reductase is arate limiting enzyme in the cholesterol biosynthesis).
2) Blocks hepatic synthesis of cholesterol, lowers () LDL byincreasing () LDL receptors, increases () LDL clearance andinduces as side effect 3-HMG-CoA reductase activity.
Dosage 10-80 mg per day
Toxicity1) Usually well tolerated2) Myopathy, potentially severe (death reported using Baycol
withdrawn in 2002)
Drug interactions1) Inhibitorsof CYP3A4 (e.g. ketoconazole) increase () statin
levels.2) Inducersof CYP3A4 (e.g. barbiturates) decrease () statin
levels.
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LOVASTATIN MEVASTATIN
SIMVASTATIN
PRAVASTATIN
ATORVASTATIN
FLUVASTATIN
Formulas
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c) VLDL secretion inhibitors
NIACIN (NICOTINIC ACID)Formula
Mechanism of action
1) Reduce cholesterol () via reduced () hepatic secretion of
VLDL that results from TG synthesis.2) Reduce () LDL formation3) Increase () HDL
Dosage 1.5 g to 3.5 g per day
Toxicity
1) Prostaglandin release (prevented with NSAIDs)2) GI-distress and stomach ulcers (prevented with antacids or
H2
-blockers)
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GEMFIBROZILFENOFIBRATE
CLOFIBRATE (Seldom used)
d) Lipoprotein lipase stimulants
FIBRIC ACID DERIVATIVES
Formulas
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Pharmacokinetics
Gemfibrozil.- 1.5 h plasma half-life
Fenofibrate.- 20 h plasma half-life
Mechanism of action
1) Increase (
) lipoprotein lipase which decrease (
)VLDL2) Increase () clearance of TG-rich lipoproteins3) Slightly decrease () LDL and increases () HDL
Dosage Gemfibrozil.- 600 mg twice a dayFenofibrate.- 67 mg once a day
Toxicity Few side effects (increase risk of cholesterol
gallstones). Yn dont use with statins - fatal
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e) Lipophilic antioxidants
PROBUCOLFormula
Mechanism of action
a) Inhibit () LDL oxidationb) Decrease () LDL uptake by macrophages
c) Decrease () HDL (limits overall use) yn:sideeffect. Still part of the treatment for hrtattack cyn
Dosage 2 x 500 mg per day
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DRUG COMBINATIONS: yn necessary if you donthave enough receptors and how late you start.
cyn
a) Fibric acid / Bile acid-binding resin
b) HMG-CoA reductase inhibitors / Bile acid-binding resin
c) Niacin / Bile acid-binding resin: yn resin also
binds the niocin be careful not to combine needs a few hours between the resin andthe drugs cyn
d) Niacin / HMG-CoA reductase inhibitors : ynhdl goes up, new cholesterol synthesis