Pharmacology Module 6 Lesson 2 Lipids/Obesity

Lipid cycling Chylomicron metabolism HL = hepatic lipase LPL = lipoprotein lipase FFA = free fatty acids ApoE mediated Goodman and Gilman’s Pharmacological Basis of Therapeutics, 10 th ed. 2001

Lipoprotein classes ChylomicronsB4885% VLDL B100/E20% 55% IDLB100/E35% 25% LDLB10060%5% HDLAI/II/E20%5% protein choles.triglycerides LDL is not measured but calculated: LDL-C = total cholesterol - (HDL-C + TG/5) (Triglycerides must be <4.5 mmol/L or < 400 mg/dL )

Hyperlipidemia Major CV risk factor - 25% of population LDL, Total Choles., Total Choles./HDL, and 1/HDL all predict CVD Reducing LDL with diet (10%) or drugs (20- 60%), prevents CVD, saves lives and money Generally safe, expensive (use in high risk pts.) Statins, fibrates, niacin, bile acid binding resins

Statins  Most effective and best-tolerated agents for treating dyslipidemia  Effective except when LDL receptor dysfunctional  Inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase – catalyzes cholesterol biosynthesis  Reduce cholesterol and VLDL synthesis in the liver

Statins How do they work?  LDL receptors in liver, plasma LDL- C clearance ( by 20-55%)  Higher doses of atorvastatin and simvastatin triglyceride levels (LDL receptor - Apo-E in VLDL)  Some statins may HDL-C levels

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

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.

Statins  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– erythromycin, azole antifungals, cyclosporine, antidepressants, nefazodone, protease inhibitors  Cerivastatin was withdrawn from the US market in 2001

Fibrates  Drugs of choice for hypertriglyceridemia (>1000 mg/dl) to prevent pancreatitis  Gene transcription through - peroxisomal proliferation activated receptor (PPAR-α)  Liver and adipose tissue, less in kidney, heart and skeletal muscle  Stimulates fatty acid oxidation  LPL activity, plasma triglycerides & VLDL  hepatic apoC-III – VLDL clearance  apoA-I and apoA-II – HDL-C

Fibrates  Better absorbed with meals  Side effects are uncommon - GI distress  Drug-Drug Interactions:  Fibrates plus statins myopathy  Fibrates – renal failure and hepatic dysfunction - relative contraindications  Not used in children, during pregnancy and breast-feeding

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

Niacin – How does it work? 1. Inhibits lipolysis of triglycerides in adipose tissue 2. In liver - triglyceride synthesis & hepatic VLDL production 3. Lowers LDL (comes from VLDL) 4. LPL activity, clearance of chylomicrons and VLDL triglycerides 5. HDL-C levels, clearance in the liver Niacin tabs – 50 to 500 mg OTC

Niacin – Adverse reactions Common and reduce patient compliance:  Flushing (with drop in blood pressure - syncope in some patients) (give aspirin)  Dyspepsia (take after meals)  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

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

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

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

Obesity Body mass index (BMI) = BMI 20-25normal BMI 25-27borderline BMI 27-30overweight BMI >30obese Waist male > 100 cm (40”) female > 90 cm (36”) weight (Kg) {height (m)} 2 Increased risk of diabetes

Prevalence in Canada of BMI  27 16% 26% 36% 45% 51% 40% 32% 26% 18% 16% 40% 48% 0% 20% 40% 60% age male female

What we have now: Glazer G Arch. Intern Med 2001; 161: DrugPlbo corr weight loss (all published studies) phentermine7.9 kg sibutramine4.3 kg orlistat3.4 kg diethylpropion1.5 kg Overview of studies lasting weeks

Orlistat (XENICAL®) Davidson MH et al JAMA 1999; 281: ) inhibits pancreatic and intestinal lipases not absorbed (<1%) (no worry about systemic adverse effects) reduces fat uptake of fatty acids by 30% adverse effects:bloating40% oily spotting33% fecal urgency30% 7/657 (1%) patients withdrew from study lower serum vit A,D,E,K. corrected with suppl drug interactions:  cyclosporine absorption

Sibutramine (MERIDIA®) Anon. Med Letter 1998; 40; 32 inhibits reuptake of NE, 5HT, and DA (  conc in brain) absorbed, metabolized by CYP3A4 adverse effects:dry mouth, headache, constipation increased HR and BP (dose related) drug interactions:SSRI’s, triptins, lithium, opiates

leptin insulin Most obese humans are leptin resistant energy intake energy expend Leptin Adipocytes stomach placenta Leptin receptors Hypothalamus Body wt. Endothelial cells T-lymphocytes Neuropeptide Y Hunger Food intake Reproductive function Gn-RH LH FSH

Summary Hyperlipidemia is a major cardiovascular risk factor Statins have been shown to save lives and money Fibrates likely do too Obesity is a national epidemic We have a few drugs that are useful for obesity