DRUG EFFECT ON BLOOD LIPIDS

DRUG EFFECT ON BLOOD LIPIDS

            The drugs which lower the levels of lipoprotein in the blood are called hypolipoprotein drugs. They potentially present cardiovascular disease by retarding the accelerated atherosclerosis in hyperlipoproteinmic individual. Lipids are carried in plasma in lipoprotein after getting associated with several apoproteins. Plasma lipids concentrations are dependent on concentration of lipoproteins. The core of lipoprotein globules consists of TGS or CHES (cholesterol esters) while the outer polar layers has phospholipids, free cholesterol (CH) and apoproteins. The lipoproteins have been divided into six classes on the basis of their particle size and density. They also differ in the nature of apoprotein, the ratio of TG and CHE, tissue of origin and fate.

Lipoprotein class	Diameter (mm)	Lipid content	Source of lipid	Function
Chy	100-500	TG>>CHE	Diet	Dietary TG transport
Chy reminants	30-50	CHE>>TG	Diet, chy	Dietary CH transport
VLDL	40-80	TG>>CHE	Liver	Endogenous TG transport
IDL	30-35	CHE>TG	VLDL	Transport CHE and TG to liver source of LDL
LDL	20-25	CHE	IDL	Transport CH to tissue and liver
HDL	5-10	Phospholipids CH	Tissue cell membrane	Removal of CH from tissue

Hyperlipoproteinemia

1. Secondary associated with diabetes, myxedema, neptrotic syndrome, chronic alcoholism, drugs (corticosteroids, oral contraceptives, b blocker) etc
2. Primary due to
1. A single gene defect is familial and called monogenic or genetic
2. Multiple genetic, dietary and physical activity related causes ‘polygenic’ or multifactorial

      LDL is the primary carrier of plasma CHE and VLDL that of TGs

Drug (daily dose)	MOA	Effect on lipids (%)
HMG – COA reductase inhibitor Lovastatic (10-80mg) Simvastatin (5-40mg)	Decreases cholesterol synthesis by inhibition of rate limiting HMG-CoA reductase	LDL decrease 20-40% HDL increase 5-15% TG decrease 10-20%
Bile acid sequestrants Cholesthyramine (4-16g) Colestipol (5-30g) CETP inhibitor TORCETRAPIB	Decreases bile acid absorption Increases hepatic conversion of CH bile acids Increases LDL receptors on hepatocytes	LDL decreases 10-30% HDL increases 3-5% TG not affected may increase in some
Fibricacid derivatives Gemfibrozil (1200mg) Benzafibrate (600mg)	Increases activity of lipoprotein lipase Decreases release of fattyacids from adipose tissue	LDL decrease 10-15% May increase when TG is high HDL increase 10-15% TG decrease 20-50%
Nicotinicacid (2-6g)	Decrease production of VLDL Decrease lipolysis in adiposite	LDL decrease 10-20% HDL increase 15-30% TG decrease 20-50%

            Statins are first choice drugs for primary hyperlipidimia with raised LDL and total cholesterol levels, with or without raised TG levels (Type IIa, IIb, V) as well as for secondary (diabetes, nephrotic syndrome) hyper cholestremia. Simvastatin reduced total cholesterol by 25% LDL-CH by 35% raised HDL by 8% over a period of 6 years CAD mortability was < by 42% overall mortality by 30% cerebrovascular events by 30% in simvastin group.

            Pravastatin to lower risk of MI by 31% and all cause mortality by 22%. The beneficial effects, who have raised CH levels relative to improved coronary artery compliance and atheromatous plaque stabilization (in no evidence of CAD) reducing chances of plaque rupture and thrombus formation. Thus used for primary and secondary hypercholesterolemia with or without raised TG levels. Cholestyramine and colestipol relieve itching of obstructive jaundice and in certain bile salt mediated diarrhea.

Fibric Acid Derivative

            Gemfibrozil reduce VLDL secretion by liver and increase the production of HDL apoprotein LDL composition may also be altered. Gemfibrozil and benzafibrate shift small dense LDL particles to large less dense particles.

            Clofibrate has a specific action in type III hyperlipoproteinimia mobilizes the abnormal lipoprotein; markedly reduce VLDL and IDL with a mild effect on LDL. This plasma, TG and CH are both drastically reduce. Clofibrate enhances ADH secretion and reduces urine volume in nephrogenic diabetes insipidus.

            Gemfibrozil in a dose of 600mg BD taken before meals. It is the drug of choice for patient with raised TG levels. Whether or not CH levels are also increased. It is most effective in type III hyperlipoproteinimia also a first line of drug in type IV and type V disease. It may be used as an adjuvant drug in type II b patients.

            Benzafibrate alternative for gemfibrozil in mixed hyperlipidemia (III, IV, V) it has been indicated in hypercholestrolemia (type II) it is inferior to statins and resins. It has greater action in LDL – CH decrease level of circulating fibrinogen and glucose.

            Fenofibrate as an adjunctive drug in raised LDL CH levels in addition to raised TG levels.

            Nicotinic acid reduces plasma lipids in higher doses. TG and VLDL decreases rapidly, followed by modest fall in LDL and CH. HDL rises by 15-30%. It reduces production of VLDL by liver, it degradation produces IDL and LDL are subsequently reduced. It inhibits lipolysis in adipose tissue and increases activity of lipoprotein lipase. No effect on CH and bile acid metabolism.

            It is wide spectrum hypolipoproteinemic drug and is highly efficacious in hypertriglyceridemia (type III, IV, V) associated with increased CH levels or not. Used to lower VLDL and raised HDL level and as an adjunctive drug.

            It is most effective drug in reducing plasma TG levels and controlling pancreatitis in genetic type IV and V disorders. Long term use prevents further attacks of pancreatitis. Given continuously in port – MI patient, it reduces recurrence of MI and overall mortality. However, because of marked side effects, use of nicotinic acid is restricted to high risk cases only.

Azetidinone

            Ezetimibe – selective and effective 2 azetidinone cholesterol absorption inhibitor. It localizes and act a brush border of small intestine and inhibits absorption of both biliary and disease cholesterol lead to decrease in delivery of intersinal cholesterol to liver. Causes reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from blood. Reduce LDL cholesterol 16.9% increase 0.4% placebo in prihypercholesterolemia. Ezetimibe + Statin à Lower Total Cholesterol LDL-C and TG, increase HDL-C.

Miscellaneous

            Orlistat, a pancreatic lipase inhibitor reduces total cholesterol, LDL, TG, Apo B in obese II DM patient. Pramlintide, a synethetic amylin analogue. Acipimox, a nicotinic acid congener decreases TG with decrease total cholesterol decrease Apo B. Fish oil containing eicosapentaenoic acid and dicosahexanoid and (n3 PUFA) decreases TG. (large dose increases LDL and worsen glycemic control)Guargum (dietary soluble fibre) and pectin mild lowering of cholesterol. Oral estrogen in post menstrual female lower LDL 10% increase HDL 15%.

Note:

            General guidelines for use of hypolipidimic drugs, Life style modification, Low fat low cholesterol diet, Regular exercise, Body weight control, Smoking cessation, Restrict of alcohol. All subjects should be considered for drug therapy if LDL-CH is ³ 190 mg/dl. While in those with existing CAD drugs are recommended even at ³ 130mg/dl

Guidelines

Hyperlipidemia	Monotherapy drugs	Drug combination
Elevated LDL and normal TG (<200mg/dl)	HMG – CoA reductane inhibitor bile acid sequestant nicotinic acid HRT (in female)	HMG – CoA reductane inhibitor + bile acid sequestant + nicotinic acid; HMG CoA + Nicotinic acid
Elevated LDL and TG (200-400mg/dl)	HMG CoA Gemfibrozil Nicotinic acid	HMG + Gemfibrozil HMG + nicotinic acid Bile acid and requestant + nicotinic acid Gemfibrozil + Nicotinic acid
TG ³ 400mg/dl	Gemfibrozil Nicotinic acid	-

REFERENCE:

RSSDI Text Book of Diabetes Mellitus