4 Pharm-Lipid Lowering Drugs-10!13!2010

8/3/2019 4 Pharm-Lipid Lowering Drugs-10!13!2010

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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

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