3rd unit anti-hyperlipidemic agents ppt

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

1. 3 rd UNIT ANTI-HYPERLIPIDEMIC AGENTS Prepared by G. Nikitha, M.Pharmacy Assistant Professor Department of Pharmaceutical Chemistry Sree Dattha Institute Of Pharmacy Hyderabad 1 Subject: Medicinal Chemistry-II Year: B.Pharmacy 3 rd Year Semister: 1 st Semister

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

3. Introduction 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 plasma lipids are water insoluble and hence need to transported through carriers known as lipoproteins. An increase in lipid particularly cholesterol a condition involving damage of heart. 3

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

5. Classification 1. HMG-COA reductase inhibitors: 5 Simvatain Metastatin Lovastatin

6. 6 Pravastatin Atorvastatin Rosuvastatin

7. 2. Fabric acid derivative: 7 Clofibrate Gemfibrozil

8. 8 benzafibrate Fenofinrate Ciprofribrate

9. 3. Bile acid Sequestrantes 9 Cholestyramine Colestipol

10. 4. Inhibition of LDL oxidation 10 Probucol 5. Lypolysis / Triglyceride synthesis inhibitor Nicotinic acid

11. 6. Miscellaneous drugs 11 Ezetimibe D extrothyroxine β- sitosterol

12. 7. New Drugs 12 Patavastain

13. HMG-COA reductase inhibitors 13

14. HMG-COA reductase inhibitors: This class of drug is known to be the most efficient and 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. 15

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 . 16

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 hydroxyl group substitution at R1 position enhances hydrophilicity and provides some cellular specificity. 17

18. Ring B sub class- either zero or one (five or six member heterocyclic). The para-flurophenyl cannot be coplanar with the central aromatic ring. (Structural restraints to cause coplanarity have resulted in a loss of activity). R substitution with aryl groups of hydrocarbon chains enhances lipophilicity and inhibitory activity. 18

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 19

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 increased LDL and total cholesterol level. They are used to reduce the incidence of myocardial infarction in patients 20

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. 21 Molecular formula: C 24 H 36 O 5

22. Pharmacokinetics: Oral route of administration, Lovastatin is given as a lactone prodrug and thus, in order to produce its mechanism of action, it is required to be converted to the active beta- hydroxy form. This drug activation process does not seem to be related to CYP isoenzyme activity. but rather to be controlled by the activity of serum paraoxonase , Following an oral dose of 14C-labeled lovastatin to man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug excreted in bile, together with unabsorbed drug. 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 22

23. 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 23

24. Fabric acid derivative 24

25. 2. Fabric acid derivative This groups of drugs are derivatives of fibric acid like isobutyric acid and include gemfibrozil , benzafibrate , fenofibrate . Mechanism of action: These are known to simulate the nuclear transcription receptor called peroxisome proliferator activated receptor-α (PPAR-α) which controls the expressions of genes mediating triglyceride metabolism. 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

26. 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. 26

27. Pharmacokinetics: They are completely absorbed from the gastrointestinal tract. They mostly exist in protein bound form and are mainly excreted in an unchanged 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

28. Therapeutic Uses: Fibrates are the first line drugs used in the treatment of hypertriglyceridaemic especially those associated with low HDL-C 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

29. Clofibrate Structure: IUPAC: ethyl 2-(4-chlorophenoxy)-2-methylpropanoate Properties: Colorless to pale yellow liquid, faint characteristic odor, faint characteristic taste, insoluble in water, soluble in alcohol, chloroform, miscible with acetone and ether. 29 Molecular Formula: C 12 H 15 ClO 3

30. Pharmacokinetics: Oral route of administration, Hepatic and gastrointestinal: rapid de- esterification occurs in the gastrointestinal tract and/or on first-pass metabolism to produce the active form, clofibric acid ( chlorophenoxy isobutyric acid [CPIB]), eliminated through urine. 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 30

31. Therapeutic Uses: Used in the treatment of III, IV, V hyperlipidaemics They are also effective in treating familial combined hypertriglyceridaemia and hyperlipidaemics associated with type-2 diabetes. Dose: 5 to 2 grams a day. This is divided into two to four doses. 31

32. Bile acid Sequestrantes 32

33. 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. 33

34. 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 epichlorhydrin . 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 . 34

35. Cholestyramine Structure: IUPAC: [4-[3-(4-ethylphenyl)butyl]phenyl]- trimethylazanium Properties: White or almost white fine powder, hygroscopic insoluble in water, methylene chloride, ethanol. 35 Molecular Formula: C 21 H 30 ClN

36. 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. Belching. Loss of appetite. Skin irritation. 36

37. 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 37

38. 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. 38 Molecular Formula:C 8 H 24 ClN 5

39. Pharmacokinetics: Oral route of administration, Colestipol hydrochloride binds bile acids in the intestine forming a complex that is then ultimately excreted in the feces. In humans, less than 0.17% of a single 14C-labeled colestipol hydrochloride dose is excreted in the urine when given following 60 days of chronic dosing of 20 grams of colestipol hydrochloride per day. The increased fecal loss of bile acids due to colestipol hydrochloride administration leads to increased oxidation of cholesterol to bile acids, it is not absorbed into the systemic circulation nor is it hydrolyzed by any digestive enzymes. Its action is ultimately limited to the lumen of the gastrointestinal tract, where it is eventually passed into the feces  39

40. 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 40

41. Reference books Text book of Medicinal chemistry volume-1-3 rd edition by V.Alagarasamy. Text book of Medicinal chemistry volume-2-3 rd edition by V.Alagarasamy. Medicinal chemistry by Rama Rao Nadendla. 41

42. Tha nk You 42