1. Hyperlipoprotinemias Department of Pharmacology College of Medicine

2. Normal Lipid Metabolism Pathway of chylomicron metabolism. HL = hepatic lipase LPL = lipoprotein lipase FFA = free fatty acids ApoE mediated From Figure 36-1 Mahley RW, Bersot TP. In Goodman and Gilman’s Pharmacological Basis of Therapeutics, 10 th ed. 2001

3. Triglycerides and Cholesterol are the two most common lipids  Triglycerides – used for fat storage and as an energy source  Can be synthesized by the cells or obtained from the diet  Are the major fat in human diet because this is the most common animal and plant fat  Require bile salts to be absorbed

4. Cholesterol  Functions:  Serves as a stabilizing component of cell membranes  Serves as a precursor to bile salts  Serves as a precursor for all steroid hormones

5. Cholesterol  Metabolism  Obtained from the diet or synthesized in liver, intestine, and endocrine glands.  Acetyl CoA is its precursor  HMG-CoA reductase is the major rate- limiting enzyme in cholesterol synthesis  Cholesterol synthesis is controlled in most tissues by negative feedback to HMG-CoA reductase

6. Cholesterol in bile salts is highly recycled  Bile salts  Synthesized by liver from cholesterol.  Secreted into duodenum via gall bladder and biliary tract.  Bile salts are 95% reabsorbed, mostly in ileum.  Reabsorbed bile salts return to the liver where they are excreted again.  5% of bile salts are excreted in the feces.

7. Is Cholesterol good or bad?  Cholesterol is essential for life  All steroid hormones are formed from it including:  Calcitriol (vitamin D hormone) – essential for life  Aldosterone and mineralocorticoids (essential for life)  Androgens and estrogens (not essential for life, but many people think it is essential)  Cortisol and related glucocorticoids (essential for life)

8. Cholesterol  High levels of LDL cholesterol are atherogenic  High levels of HDL cholesterol are protective because the HDL removes cholesterol from tissues and returns it to the liver.  Cholesterol is very insoluble in water so is transported as a component of blood lipoproteins.

9. Hyperlipidemia  Hyperlipidemia is the elevation of plasma lipid concentrations.  Causes:  Most are multifactoral – they respond to drug and diet therapy combined with weight reduction, increased exercise, and stress management.  One (type I) is a rare genetic form which responds to diet therapy only.

10. Hyperlipoproteinemia  Blood lipids are combined with a protein.  In hyperlipidemias, the lipid and the protein are elevated to produce hyperlipoproteinemia.

11. Classification of Hyperlipoproteinemias From Table 23.2 in Craig CR, Stitzel RE. Modern Pharmacology with Clinical Applications, 6 th ed. Lippincott Williams & Wilkins 2004

12. Sites of Action of Antihyperlipidemic Drugs I. Stimulation of cholesterol excretion II. Stimulation of LPL activity III. Inhibition of VLDL production IV. Inhibition of cholesterol biosynthesis V. Stimulation of cholesterol secretion into bile fluid VI. Stimulation of cholesterol conversion to bile acids. VII. Increased plasma clearance of LDL From Figure 23.2 in Craig CR, Stitzel RE. Modern Pharmacology with Clinical Applications, 6 th ed. Lippincott Williams & Wilkins 2004

13. Four Groups of Antihyperlipidemic Drugs – all reduce the risk of coronary heart disease.  Statins  Resins  Nicotinic acid (niacin)  Fibrates

14. Statins  Most effective and best-tolerated agents for treating dyslipidemia  Derived from Penicillium or Aspergillus species or are synthetic.  Effective in all patients except those with homozygous familial hypercholesterolemia – dysfunctional LDL receptor (partial response due to reduced VLDL levels)

15. Statins How do they work?  Competitive inhibitors of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase – catalyzes cholesterol biosynthesis  Reduce cholesterol synthesis in the liver  LDL receptor number on hepatocytes increases and removes LDL-C from the plasma (reduce LDL-C by 20-55%)  Higher doses of more potent statins (atorvastatin and simvastatin) also can reduce triglyceride levels caused by elevated VLDL levels (LDL receptor can recognize Apo-E in VLDL). Also reduce VLDL synthesis in liver - requires cholesterol  Some statins are also indicated for raising HDL-C levels

16. Statins – other potential cardioprotective effects:  On endothelial cell function – increase NO synthesis  On plaque stability – reduce degradation of matrix by metalloproteinases  On inflammation – antiinflammatory?  On lipoprotein oxidation – reduce oxidation of LDL and uptake by macrophages  On blood coagulation – reduce platelet aggregation and alter fibrinogen levels

17. Statins - kinetics  Extensive first pass metabolism for all  Atorvastatin longer half-life (30 h) than other statins (1-4 h) – more efficacious?  Given at bedtime – cholesterol synthesis – midnight to 2 a.m., not with bile-acid seq.  Do not use during pregnancy or while breast feeding as its safety in these situations has not been established.

18. Statins  Work better in combination with bile-acid binding resins (cholestyramine & colestipol), niacin or fibrates Side effects are rare:  hepatotoxicity (ALT determinations)  myopathy (can progress to myoglobinuria and renal failure), esp. when other drugs metablized by CYP3A4 are given together – erythromycin, azole antifungals, cyclosporine, antidepressants, nefazodone, protease inhibitors  Cerivastatin was withdrawn from the US market in 2001

19. Bile-acid sequestrants (Resins)  Oldest lipid-lowering drug – second line drugs to add to statins.  Positively-charged anion-exchange resins  binding negatively charged bile acids (95% of which are normally reabsorbed)  Liver has to synthesize new bile acid and uses cholesterol – LDL receptors increase Cholestyramine QUESTRAN Colestipol COLESTID Colesevelam WELCHOL

20. Resins Maximal doses of cholestyramine and colestipol can reduce LDL-C by upto 25% (unacceptable GI side effects) Colesevelam can lower LDL-C by 18% at its maximum dose  Advantage: Probably the safest - not absorbed but remains in the intestine.  Only hypocholesterolemic drugs currently recommended for children 11-20 y of age  Not used in patients with hypertriglyceridemia (increase triglyceride synthesis) Cholestyramine QUESTRAN Colesevelam WELCHOL Colestipol COLESTID

21. Resins  Side Effects:  Interfere with absorption of fat soluble vitamins (ADEK), folic and ascorbic acids, other fat-soluble drugs (e.g., griseofulvin for tinea), thiazides, furosemide, propranolol, l-thyroxine, coumarin anticoagulants, cardiac glycosides, statins.  GI: bulk of resin causes discomfort – bloating & dyspepsia (suspend in liquid several h before ingestion)  Colesevelam better? – newer anhydrous gel-tablet form

22. Nicotinic Acid (Niacin)  Water soluble B-complex vitamin  Multiple actions  Reduces plasma LDL by 20 to 30% (4.5-6 g/d)  Best agent to increase HDL-C (30- 40%)  Reduces triglycerides by 35-45% (2- 6 g/d)  Side effects limit use

23. Niacin – How does it work? 1. Inhibits lipolysis of triglycerides in adipose tissue 2. In liver - reduces triglyceride synthesis by inhibiting the synthesis and esterification of fatty acids – reduces hepatic VLDL production 3. Since VLDL is a precursor of LDL – lowers LDL 4. Enhances LPL activity which promotes the clearance of chylomicrons and VLDL triglycerides 5. Enhances HDL-C levels reduces clearance in the liver Niacin tabs – 50 to 500 mg OTC

24. Niacin – Adverse reactions These are common and reduce patient compliance:  Flushing (with resultant sudden drop in blood pressure which may cause syncope in some patients) (give aspirin)  Dyspepsia (take after meal)  Pruritis  Skin rashes.  Hepatotoxicity (the most serious side effect)  Avoid in peptic ulcer patients & gout  Worsens diabetes  Avoid in pregnancy – birth defects Niacin + statins – watch out for myopathy

25. Fibrates  Least used of all 4 groups - a (1978) WHO report indicated increased mortality. Later studies reversed this, but the drug group never regained favour  Drugs of choice to treat severe hypertriglyceridemia (>1000 mg/dl) to prevent pancreatitis. Clofibrate ATROMID-S Bezafibrate BENZALIP SR Fenofibrate LIPIDIL MICRO Gemfibrozil LOPID

26. Fibrates  Action not clear - activate a nuclear transcription factor receptor - peroxisomal proliferation activated receptor (PPAR-α)  Primarily in the liver and adipose tissue, less in kidney, heart and skeletal muscle  Stimulates fatty acid oxidation  increased transcription of LPL gene - increased LPL activity removes plasma triglycerides and decreases VLDL levels  reduced expression of hepatic apoC-III – enhanced VLDL clearance

27. Fibrates  apoA-I and apoA-II expression increased – increases HDL-C  Increased hepatic LDL receptors?  Inhibit coagulation and enhance fibrinolysis

28. Fibrates  Better absorbed with meals  Side effects are uncommon - GI distress  Drug-Drug Interactions include  Fibrates plus statins myopathy  Displaces coumarin anticoagulants from plasma proteins. Plasma prothrombin time monitored  Fibrates – renal failure (renal clearance is the main route of excretion) and hepatic dysfunction are relative contraindications  Fibrates should not be used in children, during pregnancy and breast-feeding