1 HYPOLIPIDAEMICS or LIPID LOWERING DRUGS

2 Hypolipidaemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidaemias. They are called Lipid Lowering Drugs (LLD) or agents Lipids in human plasma are transported in complexes with lipoproteins.

3 A lipoprotein is a biochemical assembly that contains both proteins and lipids. The lipids or their derivatives may be covalently or non-covalently bound to the proteins Many enzymes, transporters, structural proteins, antigens, adhesins and toxins are lipoproteins

4 Elevation of plasma lipoprotein is termed hyperlipidaemia. Increased levels of plasma triglycerides is termed hyperlipemia. Increased levels of plasma cholesterol is termed hypercholesterolemia Hyperlipidaemia or hyperlipo-proteinaemia can result in acute pancreatitis or artherosclerosis. Acute pancreatitis results in patients with hyperlipemia. In such patients control of triglycerides can prevent recurrent attacks.

5 Lipoprotein Transport in the Blood Lipids and cholesterol are transported through the blood stream as macromolecular complexes of lipid and protein known as lipoproteins. These consists of a central core of hydrophobic lipid (triglycerides or cholesteryl esters) encased in more hydophillic coat of polar substances- phosholipids, free cholesterol and associated apolipoproteins.

6 The lipoproteins differ in the relative proportion of the core lipids, the type of apoprotein, size and density. There are four main classes of lipoprotein basing on the density property:  Chylomicrons  Very low density lipoproteins (VLDL)  Low density lipoproteins (LDL)  High density lipoproteins (HDL)

7 These are the vehicles that transport lipids in the bloodstream between sites of absorption, synthesis (liver), storage (adipose tissue), and utilization (other tissues). (1) Chylomicrons transport triglycerides and cholesterol from the g.i.t to the tissues, where they split by lipoprotein lipase, releasing free fatty acids. These are taken up in muscle and adipose tissue.

8 Chylomicron remnants are taken up in the liver, where cholesterol is stored, oxidised to bile acids or released into VLDL (2) VLDL transport cholesterol and newly synthesized triglycerides to the tissues, where triglycerides are removed as before, leaving:

9 (3) LDL with a large component of cholesterol, some of which is taken up by the tissues and some by the liver, by endocytosis via specific LDL receptors (4) HDL adsorb cholesterol derived from cell breakdown in tissues (including arteries) and transfer it to VLDL and LDL.

10 HDL exert several anti-artherogenic effects. Low levels of HDL are an independent risk factor for coronary disease. The higher the plasma concentration of LDL-cholesterol, and the lower the concentration of HDL-cholesterol, the higher the risk of ischaemic heart disease

11 DIETARY MANAGEMENT OF HYPER-LIPOPROTEINAEMIA : The diet is restricted in cholesterol and saturated fat and provide calories to achieve and maintain the ideal body weight.

12 Total fat calories should be %, with saturated fats less than 8 % of total calories and cholesterol less than 200mg/day. This regimen produces a % reduction in serum cholesterol. Increase in complex carbohydrates and fibre are recommended and mono-unsaturated fats should predominate within the fat allowance. Weight reduction and calorie restriction are especially important in patients with elevated VLDL. Patients with hypertriglyceridemia should avoid alcohol.

13 LIPID LOWERING DRUGS

14 Lipid-lowering Drugs Several drugs are used to decrease plasma LDL-cholesterol. Drug therapy to lower plasma lipids is only one approach to treatment and is used in addition to dietary management and correction of other modifiable cardiovascular risk factors

15 Lipid Lowering Drugs The main classes of drug used clinically are:  Bile acid-binding resins (bile acid sequestrants)  Fibrates  Statins: HMG-CoA (3-hydroxy-3- methylglutaryl-coenzyme A) reductase inhibitors  others

16 LIPID LOWERING DRUGS (I) BILE ACID-BINDING RESINS (BILE ACID SEQUESTRANTS)-:  Cholestyramine  Colestipol Are resin which bind bile salts in the gut and thus interrupt the enterohepatic circulation. How?

17 When taken by mouth, they sequester bile acids in the intestine and prevent their reabsorption and enterohepatic recirculation. The result is decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acids in the liver.

18 This leads to increased expression of LDL receptors on liver cells, and hence to increased removal of LDL from the blood and a reduced concentration of LDL- cholesterol in plasma

19 Summary: Are resin which bind bile salts in the gut and thus interrupt the enterohepatic circulation. They increase hepatic cholesterol synthesis and promote receptor mediated uptake of LDL cholesterol from plasma. The resin lower LDL-cholesterol with marked increase in HDL and no effect on triglycerides.

20 Unwanted Effects Since resins are not significantly absorbed, systemic toxicity is low Folic acid deficiency may occur. Gastro-intestinal side effects (nausea, abdominal bloating, constipation or diarrhoea) are not uncommon and compliance may be poor. Cholestyramine is unpalatable and must be given in large doses [ gm ] daily.

21 Unwanted effects They interfere with the absorption of fat- soluble vitamins, [ especially vitamin K ] and to a lesser extent fats. Also interfere with absorption of drugs such as chlorothiazide, digoxin and warfarin, therefore should be taken at least 1 hour before or 4-6 hours after the resin

22 Clinical uses of acid binding resins For hypercholesterolaemia when statin is contraindicated As an addition to a statin when response has been inadequate Uses unrelated to atherosclerosis include: -pruritis in patients with partial biliary obstruction -bile acid diarrhea (e.g. caused by diabetic neuropathy)

23 (II) FIBRATES Several fibric acid derivatives (‘fibrates’) are available including: gemfibrozil Clofibrate Bezafibrate

24 Gemfibrozil and Bezafibrate lower LDL cholesterol by % by activation of lipoprotein lipase and may also inhibit HMGCoA reductase. They also raise HDL cholesterol. Clofibrate has less effect on LDL but reduces triglycerides by promoting lipolysis of triglyceride rich particles. Long term clofibrate therapy has been associated with an increase in hepatobiliary diseases particulary cholesterol cholelithiasis.

25 Gallstones result from increased cholesterol saturation of the bile. Fibrates as a group are completely absorbed and largely excreted unchanged by the kidney. Extensive plasma protein binding to albumin is one mechanism of drug interaction with these drugs. Gemfibrozil and clofibrate may potentiate the effect of oral anti-coagulants. Fibrates may be used alone or combined with resin or other agents.

26 (III) STATINS: 3-HYDROXY-3- METHOXYGLUTARYL-COENZYME A [HMGCoA ] REDUCTASE INHIBITORS Lovastatin. Simvastatin. Pravastatin

27 HMG-CoA reductase is the rate limiting enzyme in the hepatic synthesis of cholesterol, which catalyses the conversion of HMG-CoA to mevalonic acid. Blockade of this enzyme leads to increased in LDL- cholesterol uptake by the liver. Thus the statins are specific, reversible and competitive inhibitors The resulting decrease in hepatic cholesterol synthesis leads to increased synthesis of LDL receptors and increased clearance of LDL.

28 Substantial falls [30-40 % ] in LDL- cholesterol may occur especially if the drug is combined with resin. Lovastatin is well tolerated, it can be taken once or twice daily. Long term experience with these inhibitors is lacking.

29 (IV) OTHER LIPID LOWERING DRUGS a) Probucol This lowers LDL cholesterol by % but also inhibits the production of HDL cholesterol. b) Nicotinic acid [ or Niacin is a vitamin B ]. It is a potent inhibitor of LDL and VLDL formation.

30 Nicotinic acid and its derivative Nicofuranose lower LDL and raise HDL cholesterol. Nicotinic acid is not well tolerated, severe facial flushing is common and is a dose limiting effect. This is prostaglandin mediated and may be alleviated in part by co-administration of aspirin.

31 c) Fish oils high in un-saturated acids such as eicosapentaenoic and docosahexaenoic acids may be used particulary to reduce high triglycerides. These preparations are not palatable. Raised cholesterol, especially LDL-cholesterol is an important determinant of cardiovascular risk.

32 Diet alone may control mild hypercholesterolemia but diet combined with drug therapy is indicated for moderate and severe hypercholesterolemia. Treatment of raised cholesterol should be part of an overall plan in individual patient for prevention of cardiovascular disease.

33 Assignment Giving examples, classify the lipid lowering drugs Describe their actions, mechanism of action, pharmacokinetics, unwanted effects and clinical uses.