Anti hyperlipidemic agents ppt

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1. ANTI-HYPERLIPIDEMIC AGENTS Subject: Medicinal Chemistry-II Semester: 5 Sem. Indraj Saini B Pharma 3 rd year Create a ppt in Exam preparation time [email protected] College- Alwar pharmacy College ( IET GROUP ) 5 th sem notes

2. 2 Introduction. Classification . Drugs used in Anti Hyperlipidaemics Agents Mechanism of action . SAR. Structure Adverse Drug Reactions . Uses.

3. 3 Lipids are naturally fat like components of cells in the body. Although body synthesis the required amount of lipids additional amount is derived from food and can be harmful. These plas m a l i p i ds a re water i nso l u b le a n d h e nce ne e d to transported through carriers known as lipoproteins. An increase in lipid particularly cholesterol a condition involving damage of heart.

4. Lipoproteins are of 4 types: 4 High density lipoprotein (HDL) Low density lipoprotein (LDL) Intermediate density lipoprotein (IDL) Very low density lipoprotein (VLDL)

5. 1. HMG-COA reductase inhibitors: Simvatain Lovastatin 5 Met a st a tin

6. 6 Pravastatin Atorvastatin Rosu v a s tatin

7. 2. Fabric acid derivative: 7 Clof i brate Gemfibrozil

8. 8 benzafibrate Fenofinrate Ciprofribrate

9. 3. Bile acid Sequestrantes 9 Cholestyramine Colestip ol

10. 4. Inhibition of LDL oxidation 10 P r obucol 5. Lypolysis/ Triglyceride synthesis inhibitor Nicotinic acid

11. 6. Miscellaneous drugs 11 Ezetimibe Dextrothyroxine β-sitosterol

12. 7. New Drugs 12 Patavastain

13. HMG-COA REDUCTASE INHIBITORS 13

14. 1. HMG-COA reductase inhibitors: T h i s c l a ss o f d r ug i s known t o b e t he m ost e f fic i e nt a nd best tolerated among all other antihyerlipidaemic drugs. Mechanism of action: Cholesterol is synthesizes in the liver by the conversion of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonic acid by the enzyme HMG-CoA reductase. Statins act by inhibiting this rate limiting enzyme, thereby resulting in reduced hepatic cholesterol synthesis. This in turn results in compensatory increase in synthesis of high affinity LDL receptors on the surface of liver cells and consequent increase in the uptake and catabolism of plasma IDL and LDL. Thus a significant decrease in plasma LDL cholesterol levels is achieved. 14

15. SAR of HMG-COA reductase inhibitors : Mevastatin and Lovastatin are the lead compounds in the development of HMGRIs. Lactone ring, bicyclic rings Ethylene Bridge are very important for the activity. Provastatin is the ring opened dihydroxyacid with a 6 hydroxyl group is more hydrophilic. So it has the low penetration to the peripheral tissues and less side effects.

16. Common for all statins The 3,5 dihydroxycarboxylate is essential for inhibitory activity. Compounds containing a lactone are prodrugs requiring in vivo hydrolysis. The absolute stereochemistry of the 3-and 5-hydroxyl groups must be same as the Mevastatin and Lovastatin. A double bound between C6 and C7 can either increase or decrease activity. The ethyl group provides optimal activity for compounds containing ring A and some heterocyclic rings (pyrrole ring of atorvastatin). The ethenyl group is optimal for compounds with other rings such as indole and pyrimidine rings seen in fluvastatin and cerivastatin.

17. Ring A sub class- the decline ring is essential for anchoring the compound to the enzyme active site. Replacement with the cyclohexane ring resulted in 10,000 fold decrease in activity. Stereochemistry of the ester chain is important for activity, the conversion of this ester to an ether resulted in a decrease in activity. Methyl substitution at R2 position increases activity (simvastatin is more potent than Lovastatin). β h y dr o xyl g r oup su b st i t ut i on a t R 1 posi t i on e nhanc e s hydrophilicity and provides some cellular specificity.

18. Simvatain

19. Pharmacokinetics: All strains of oral administration get absorbed to the extent of 40- 90% except fluvastatin which is completely absorbed. Lovastatin and simvastatin are prodrugs which get hydrolysed to active metabolites in the GIT while atorvastatin, fluvastine, rosuvastatin are fluorinated compounds which are activate drugs. All statins undergo first pass metabolism and excreted mainly through bile. Adverse Drug Reactions: Nausea, headache, rashes, and bowel upset Sleep disturbances Memory loss, impotence, gynaecomatia, peripheral neuropathy Liver damage

20. Therapeutic Uses: Statins are useful in both primary and secondary hypercholesterolaemia. They cause reduction in the progression of atherosclerotic lesions and occurrence of myocardial infarction. Statins are the first line drugs for primary hyperlipidaemics which de creased LDL and total cholesterol level. They are used to reduce the incidence of myocardial infarction in patients

21. Lovastatin Structure: IUPAC: 8-{2-[-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl- hexahydronaphthalen-1-yl -2-methylbutanoate Properties: white or almost white crystalline powder, insoluble in water, soluble in acetone and sparingly soluble in ethanol, practically insoluble in hexane. Molecular formula: C 24 H 36 O 5

22. Therapeutic Uses: Lovastatin is used to decrease the amount of cholesterol and other fatty substances in your blood. If cholesterol builds up in your arteries, it may block the flow of blood to your heart, brain, or other parts of your body. This raises your risk of serious problems, such as a heart attack or stroke. Lowering your cholesterol level lowers these risks Dose: 10-80 mg/ day Adverse Drug Reactions: pain in your stomach area, constipation Nausea, headache Heartburn, memory loss/forgetfulness weakness/lack of energy, muscle pain Confusion, inability to fall asleep

23. F ABRIC ACID DERIVATIVE 24

24. 2. Fabric acid derivative This groups of drugs are derivatives of fibric acid like isobutyric acid and include gemfibrozil, benzafibrate, fenofibrate. Mechanism of action: They enhance the activity of lipoprotein lipase (LPL) which is responsible for the hydrolysis of VLDL triglycerides. Hence incorporation of fatty acids into VLDL in the liver is decreased and there by synthesis and secretion of VLDL is inhibited.

25. SAR of Fabric acid derivative: Isobutyric acid group is essential for activity. Compounds containing an ester, such as clofibrate and fenofibrate are prodrugs and require in vivo hydrolysis. Substitution at para position of the aromatic ring with a chloro group or a chlorine containing isopropyl ring produce compound with significantly longer half life. Most of drugs contain a phenoxyisobutyric acid, the addition of an m-propyl spacer as seen in gemfibrozil results in an active drug. Gemfibrozil

26. Pharmacokinetics: They are completely absorbed from the gastrointestinal tract. They mostly exist in protein bound form and are mainly excreted through urine. Adverse Drug Reactions: Allergic reactions, nausea, diarrhea are common side effects. Weight gain Increase in serum amino transferases or alkaline phosphatase levels and reversible myopathy have also reported. Chronic therapy may increases the risk of gall stone formation.

27. Therapeutic Uses: Fibrates are the first line drugs used in the treatment of hypertriglyceridaemic especially those associated with low HDL level. They are effective in decreasing genetic hypertriglyceridaemic and dysbetalipoproteinaemia. They are also effective in treating familial combined hypertriglyceridaemia and hyperlipidaemics associated with type-2 diabetes.

28. Clofibrate Structure: IUPAC: ethyl 2-(4-chlorophenoxy)-2-methylpropanoate Properties: C olorl e ss t o pale y e l l ow l i qu i d, f a i nt c h a ract e ri s t ic o d o r , f a int ch a ract e ris t ic t a st e , i n so l uble i n wa t e r , s o l uble i n a l c oho l , chloroform, miscible with acetone and ether. Molecular Formula: C 12 H 15 ClO 3

29. Therapeutic Uses: Used in the treatment of hyperlipidaemics They are also effective in treating familial combined hypertriglyceridaemia and hyperlipidaemics associated with type-2 diabetes. Adverse Drug Reactions: Head ache, Nausea , Vomiting Fever Blood in urine Sweating of feet Increase of appetite, Stomach pain, gastric problems Weight gain Chest pain Dose: 5 to 2 grams a day. This is divided into two to four doses.

30. BILE ACID SEQUESTRANTES 32

31. 3. Bile acid Sequestrantes Mechanism of actions: They are insoluble non-absorbable basic anion exchange resins which bind with bile acids and form insoluble complexes in the intestine which gets excreted in faces. Adverse Drug Reactions: Head ache, Vomiting Constipation, Heart burn are common Therapeutic Uses: Cholestyramine is used as an anti-hyperlipidaemic in children and pregnant women. It is also used in treating pruritus associated with biliary cirrhosis and cholestatic jaundice.

32. SAR of Bile acid Sequestrantes: Cholestyramine is a copolymer consisting primarily of polystyrene with small amount of divinyl benzene as a cross linking agent. In addition it contains some fixed quaternary ammonium groups. These positively charged groups function as binding sites for anions. Colestipol is a copolymer of tetraethylenepentamine and chlorhydrin . It contains basic secondary and tertiary amines. Total nitrogen content of Colestipol is greater than Cholestyramine the functional ion exchange capacity of the resin depends upon intestinal pH and may be less than Cholestyramine. The adsorption capacity of Cholestyramine for bile salts is more than the Colestipol.

33. Cholestyramine Structure: IUPAC: [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium Properties: White or almost white fine powder, hygroscopic insoluble in water, methylene chloride, ethanol. Molecular Formula: C 21 H 30 ClN

34. Pharmacokinetics: Oral route of administration, metabolized through bile acids. Cholestyramine resin adsorbs and combines with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. Adverse Drug Reactions: Constipation. Upset stomach or stomach pain. Diarrhea or loose stools. Nausea. Vomiting. Loss of appetite. Skin irritation.

35. Therapeutic Uses: Cholestyramine is used to reduce high cholesterol levels. It's given to people with high cholesterol who haven't been able to lower their cholesterol enough with diet changes. This drug is also used to treat itching due to partial bile obstruction. Dose: 4 to 16g/day

36. Colestipol Structure: IUPAC: N'-[2-[2-(2-aminoethylamino)ethylamino]ethyl]ethane-1,2- diamine;hydrochloride Properties: Yellow to orange beads, hygroscopic in nature, it does not dissolve in water, dilute aqueous solution of acids and alkali, insoluble in ethanol, dichloromethane. Molecular Formula:C 8 H 24 ClN 5

37. Adverse Drug Reactions: Constipation, Diarrhea stomach/abdominal pain, gas, Nausea and vomiting may occur. Weakness Confusion Rashes Therapeutic Uses: It is used along with a proper diet to lower cholesterol in the blood. Lowering cholesterol helps decrease the risk for strokes and heart attacks. Dose: 5-30 mg day

38. T HA N K YOU 42