MANAGEMENT STRATEGIES FOR DYSLIPIDEMIA & sitosterolemia- SUMMARIZED CATCHPOINTS

1. MANAGEMENT STRATEGIES FOR DYSLIPIDEMIA & sitosterolemia- SUMMARIZED CATCHPOINTS PRESENTED TO: DR.EMILL JAME DAVID PRESENTER DETAILS: VISHNU.R.NAIR, 5TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP).

2. PURPOSE OF THIS PRESENTATION: • This presentation aims at providing a precise insight on the do’s and dont’s while giving specific antihyperlipidemic drugs to a patient • No further details into dosage, dosage adjustments or other relevant pharmacological details have been provided • This presentation is a brief summary on important catchpoints required while dealing with DYSLIPIDEMIA cases in clinical settings • Extensive referencing skills are always recommended to get a deeper outlook into this topic. HAPPY READING!!

3. GENERAL INTRODUCTION

4. Chylomicrons(CM)  transport DIETARY TRIGLYCERIDES(TGs) & CHOLESTEROL • VLDL  carries endogenous TGs from liver to blood • In CM  TG content is greater than that of cholesterol • TGs present in CM  metabolized by LIPOPROTEIN LIPASE(LPL) inside the walls of blood vessels  free fatty acids formed  utilized by various tissues like fat & muscle • Liver surface  contains HEPATIC LIPASE(HL)  metabolizes remaining TGs  what remain inside CM is CHOLESTEROL  taken up by liver • To be precise: • DIETARY CHOLESTEROL  transported to LIVER • Free fatty acids  transported to FAT & MUSCLES.

5. During high production of TGs inside liver : • VERY LOW DENSITY LIPOPROTEINS(VLDL) formed  released into circulation • MICROSOMAL TG TRANSPORT PROTEIN(MTP)  packs TG & other components  forms VLDL • VLDL  contains more TGs than CHOLESTERYL ESTERS(CE) • TGs  metabolized by LPL • VLDL  converted to INTERMEDIATE DENSITY LIPOPROTEINS(IDL) (Remember, that in this condition, the concentration of TG & CE are the same!) • IDL can have either of the following 2 fates: • HL  metabolizes remaining TGs  converted to LDL(that contains only CE!!) • Taken up in the liver by LDL-RECEPTORS(LDL-R).

6. So basically, LDL transports its CE either to various tissues, OR is taken up in the liver(VIA LDL-R). . . • PROPROTEIN CONVERTASE SUBTILISIN KIXIN TYPE-9(PCSK-9) is a PROTEIN  binds to LDL-R  destroys it • LDL-R  transports TG & CE  sent to lysosome  broken down by LYSOSOMAL ACID LIPASE.

7. HDL CHOLESTROL: • Formed by taking cholesterol from tissues  helps in its transport to liver(Process known as REVERSE CHOLESTEROL TRANSPORT) • Thus : • HDL : GOOD CHOLESTEROL! • VLDL, LDL, IDL: BAD CHOLESTEROLS!! c. Nascent HDL  secreted by hepatocytes & enterocytes  takes free cholesterol from tissues & macrophages d. LECITHIN CHOLESTEROL ACETYL TRANSFERASE(LCAT)  converts free cholesterol to CE

8. e. MATURE HDL has either of the following 2 fates: • Taken up by liver through SCAVENGER RECEPTOR SR-B1 • CE  transferred to CMs/VLDL in exchange for TGs by the activity of CHOLESTERYL TG TRANSPORT PROTEIN(CETP)  VLDL is converted to LDL  taken up by liver, via LDL-R f. TG-rich HDL  now acted upon by HEPATIC LIPASE(HL) • Altered levels of lipoproteins may be secondary to diseases like DM, nephrotic syndrome, etc • PRIMARY HYPERLIPOPROTEINEMIA is usually FAMILIAL/GENETIC in origin.

9. VARIOUS TYPES OF HYPERLIPOPROTEINEMIAS:

10. ANTI-DYSLIPIDEMIC DRUGS

11. FIRST-LINE DRUGS include: • STATINS • BILE ACID SEQUESTRANTS • INTESTINAL CHOLESTEROL REABSORPTION INHIBITORS • SECOND-LINE DRUGS include: • FIBRATES • NIACIN.

12. STATINS

13. HMG CoA reductase  catalyzes RATE LIMITING STEP in CHOLESTEROL BIOSYNTHESIS(conversion of HMG CoA to MEVALONATE) • Statins  competitively inhibit this enzyme  reduce cholesterol synthesis in the liver  since liver requires cholesterol for bile acid & steroid hormone synthesis  LIVER responds by INCREASING LDL-receptors on its surface  increases LDL-uptake from plasma • STATINS ARE THE MOST POWERFUL LDL-LOWERING AGENTS!! • Other actions of statins include: • Lowering of TG • Lowering of IDL • Lowering of VLDL • Increase of HDL(mild).

14. Statins have no effect on LIPOPROTEIN(A) • Most potent statins : PITAVASTATIN, followed by ROSUVASTATIN • Least potent statins : FLUVASTATIN, LOVASTATIN • Since activity of HMG CoA reductase is MAXIMUM at night  these drugs are given at nighttime • ROSUVASTATIN & ATORVASTATIN can be given AT ANY TIME OF THE DAY, due to their long t1/2: • Half-life of ROSUVASTATIN: 19 hrs • Half-life of ATORVASTATIN: 14 hrs - Longest acting statin: ROSUVASTATIN.

15. Statins are responsible(to some extent) to lower the risk of stroke & MI due to its “PLEOTROPIC EFFECTS”, which include: • Antioxidant • Anti-inflammatory • Anti-proliferative. • STRUCTURAL ANALYSIS OF STATINS: • Inactive lactone prodrugs: LOVASTATIN, SIMVASTATIN • Active lactone ring: PRAVASTATIN • FLUORINE containing congeners: ATORVASTATIN, ROSUVASTATIN, FLUVASTATIN

16. All STATINS can be absorbed ORALLY • Maximum oral absorption observed with FLUVASTATIN • Food  increases absorption of all statins(except PRAVASTATIN) • LOVASTATIN & SIMVASTATIN  undergo extensive first-pass metabolism  administered as PRO-DRUGS • Drugs administered in active form: • Pravastatin • Atorvastatin • Rosuvastatin • Fluvastatin

17. All statins(except PRAVASTATIN)  metabolized by HEPATIC MICROSOMAL ENZYMES  have high chances of DRUG INTERACTIONS • PRAVASTATIN  metabolized by SULFATION(NON-MICROSOMAL) least chances of drug interactions. • Major ADRs of statins include: • MYOPATHY • HEPATOTOXICITY • Drugs + fibrates(especially GEMFIBROZIL) / NIACIN  high risk of myopathy • Myopathy  can lead to RHABDOMYOLYSIS  can lead to RENAL SHUTDOWN • Avoid statins in PREGNANCY & LACTATION.

18. Some patients taking STATINS develop DIABETES MELLITUS, but the benefits (reduced risk of cardiovascular events)  outweigh the risk (of developing DM) • STATINS are the 1st line drugs for the following conditions: • Type IIa • Type IIb • Secondary hyperlipoproteinemia • For children with HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA : a. DOC of age ≥ 8 yrs : PRAVASTATIN b. DOC of age ≥ 10 yrs: OTHER STATINS(role of PITAVASTATIN here isn’t justified yet)

19. Risk of STATIN-INDUCED MYOPATHY is INCREASED by: • Old age • Renal insufficiency • Erythromycin • Ketoconazole • Fibrates(except BEZAFIBRATE!) • Immunosuppressants.

20. SPECIAL FEATURES OF PRAVASTATIN: • Minimum drug interactions(since metabolized by non-microsomal enzymes) • Minimum food interactions • Minimum risk of myopathy • Minimum CNS penetration • Reduces fibrinogen levels.

21. INTESTINAL CHOLESTEROL ABSORPTION INHIBITOR

22. Drug includes EZETIMIBE • Drug  inhibits a transporter NPC1L1  prevents intestinal absorption of cholesterol  reduces cholesterol content of liver  liver responds by increasing LDL-R synthesis • Used as MONOTHERAPY/ in combination with STATINS for TYPE IIa & IIb HYPERLIPOPROTEINEMIA • Also reduces LDL-C in patients with SITOSTEROLEMIA

23. BILE ACID SEQUESTRANTS

24. Drugs  bind to BILE ACIDS in intestinal lumen  reduce their absorption  promotes their excretion through faeces  reduces cholesterol levels in liver  liver acquires cholesterol from plasma by increasing LDL-R • Bile acids  inhibit TG production in liver  thus deficiency of bile acids elevates TG levels • Bile acid binding agents are used ONLY FOR TYPE IIa HYPERLIPOPROTEINEMIA(since TGs are normal in this condition) • Drugs include: • Cholestyramine • Colestipol • Colesevelam.

25. CHOLESTYRAMINE & COLESTIPOL  available as SACHETS • SACHETS  mixed with water  kept for sometime(to enhance their PALATABILITY)  taken with meals • COLESEVELAM : • Available as TABLET • Has better patient compliance • Major ADR : Constipation • Cholesterol-lowering agent of choice in: • Children • Pregnancy • Lactation.

26. FIBRIC ACID DERIVATIVES

27. Drugs  activate nuclear receptor PPAR(Peroxisome proliferator activated receptor )  LPL gets activated  effects include: • Reduce TG levels • Increase HDL levels • CLOFIBRATE  not used now for the following reasons: • High risk of mortality(due to malignancies & post-cholecystectomy complications) • Did not prevent fatal MI

28. Drugs currently available include: • GEMFIBROZIL • FENOFIBRATE • BEZAFIBRATE • Fibrates reduce plasma fibrinogen levels • Important ADRs include: • GI distress • Elevation of aminotransferases • Fibrates (except BEZAFIBRATE) + STATINS  high risk of myopathy • Fibrates  potentiate effects of WARFARIN & OHAs.

29. Applications of FIBRATES: • DOC in Hypertriglyceridemia(Type III & IV) • Fenofibrate with other drugs in Type IIb(since fenofibrate has maximum LDL-lowering action) • IMPORTANT FEATURES OF FENOFIBRATE: • Prodrug • Longest t1/2 • Maximum LDL-C lowering action • URICOSURIC in nature can be used in the setting of HYPERURICEMIA

30. NICOTINIC ACID(NIACIN)

31. Another name of NIACIN is VITAMIN B3 • Drug  inhibits lipolysis in the adipose tissue • Actions of NIACIN include: • Reduces LDL-C • Reduces VLDL triglycerides • Increases HDL-C • Reduces lipoprotein(a) • Reduces fibrinogen levels

32. Major compliance limiting & side-effects of NIACIN include: • CUTANEOUS FLUSHING & PRURITUS: • Niacin  Causes release of PGs  vasodilatory action • Prevented by pre-treatment with ASPIRIN • NIACIN should be started at low doses only b. NIACIN  impairs INSULIN SENSITIVITY  avoid in DIABETICS!!! c. GI toxicity d. Hyperuricemia e. Maculopathy f. Acanthosis nigricans(dark-coloured skin lesion) g. Hepatotoxicity

33. IMPORTANT APPLICATIONS OF NIACIN: • Among all hypolipidemic drugs  NIACIN has GREATEST HDL-INCREASING PROPERTY  useful in patients with high risk of CAD!! • Type IIb • Type III • Type IV disorders.

34. MISCELLANEOUS DRUGS

35. PROBUCOL: • Has antioxidant action • Inhibits LDL oxidation • Reduces levels of both HDL & LDL • GUGULIPID: • Developed by Central Drug Research Institute, Lucknow • Causes modest reduction in LDL • Slight increment in HDL-C • ADR: Diarrhea.

36. NEWER DRUGS

37. CETP INHIBITORS: • CETP  required for exchange of TG & CE between HDL & apo-B rich lipoproteins  leads to formation of TG-rich HDL  acted upon by HEPATIC LIPASE(HL) • CETP inhibitors  increase HDL-C levels • The following CETP-inhibitors failed the clinical trials : • Torcetrapib(due to excessive mortality rates) • Dalcetrapib (due to reduced efficacy) • Evacetrapib(due to reduced efficacy) • ANACETRAPIB  currently undergoing clinical trials.

38. MTP INHIBITORS: • Drug includes LOMITAPIDE • Drug  inhibits Microsomal triglyceride transport protein(MTP)  prevents VLDL assembly & its production in liver • Indicated for FAMILIAL HOMOZYGOUS HYPERCHOLESTEROLEMIA

39. MIPOMERSEN: • Antisense oligonucleotide • Drug  targets MESSENGER-RNA for apo-B rich lipoproteins • FDA-approved for FAMILIAL HOMOZYGOUS HYPERCHOLESTEROLEMIA • Given subcutaneously ONCE A WEEK • Black-box warning by FDA on drug usage: RISK OF LIVER DISEASE.

40. PCSK-9 INHIBITORS: • Proprotein convertase subtilisin kixin type-9  protein, that binds to LDL-R  Transports LDL-R to lysosomes, causing their degradation • PCSK-9 inhibitors  prevent LDL-R destruction  reduce LDL-C levels • Monoclonal antibodies are used • Include: • ALIROCUMAB • EVOLOCUMAB * Approved for FAMILIAL HYPERCHOLESTEROLEMIA(as adjunct to diet & maximally tolerated statin therapy)

41. AVASIMIBE: • Drug  inhibits ACAT-1( Acyl coenzyme A: cholesterol acyl transferase-1)  prevents formation of cholesterol ester from cholesterol  prevents cholesterol deposition in arterial wall.

42. SITOSTEROLEMIA: A BRIEF INSIGHT

43. In normal individuals  <5% of dietary plant sterols (eg SITOSTEROL) are absorbed through GIT • Plant sterols  excreted through bile  leads to fecal excretion • Thus, in normal individuals  levels of plant sterols are kept very low in tissues • In SITOSTEROLEMIA  elevated levels of plant sterols & cholesterol occurs, due to the following reasons: • Increased intestinal absorption • Reduced biliary excretion • SITOSTEROLEMIA is an AUTOSOMAL RECESSIVE DISORDER • Caused by mutation in the following genes: • ABCG5 • ABCG8

44. Increased levels of hepatic sterols  causes DOWNREGULATION of LDL-R on hepatocytes  leads to high levels of LDL-C • Due to incorporation of plant sterols in membranes  patients can experience the following clinical episodes: • Tendon xanthoma • Premature atherosclerotic disease • Hemolysis • Splenomegaly • STATINS are ineffective in these conditions • Only effective agents include: • Ezetimibe • Bile acid sequestrants.

45. CHOLESTEROL TRANSPORT & SITES OF ACTION OF NEW ANTI-DYSLIPIDEMIC DRUGS:

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