Pharmacology 301.6Module 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, 10th ed. 2001

Lipoprotein classes

• Chylomicrons B48 85%

•VLDL B100/E 20% 55%

• IDL B100/E 35% 25%

• LDL B100 60% 5%

•HDL AI/II/E 20% 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

Lovastatin MEVACORLovastatin MEVACOR

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-CClofibrate ATROMID-SClofibrate ATROMID-S Fenofibrate LIPIDIL MICROFenofibrate LIPIDIL MICRO

Gemfibrozil LOPIDGemfibrozil LOPID Bezafibrate BENZALIP SRBezafibrate BENZALIP SR

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 liverNiacin tabs – 50 to 500 mg OTCNiacin tabs – 50 to 500 mg OTC

Niacin – Adverse reactionsCommon 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 myopathyNiacin + 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

Cholestyramine QUESTRAN Colestipol COLESTIDColestipol COLESTIDColesevelam WELCHOL

Colesevelam WELCHOL

Cholestyramine NOVO CHOLAMINECholestyramine NOVO CHOLAMINE

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 11-20 y of age Not used in patients with

hypertriglyceridemia (increase triglyceride synthesis)

Cholestyramine QUESTRANCholestyramine QUESTRANColesevelam WELCHOLColesevelam WELCHOL

Colestipol COLESTIDColestipol 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 20-25 normal

BMI 25-27 borderline

BMI 27-30 overweight

BMI >30 obese

Waist

male > 100 cm (40”)

female > 90 cm (36”)

weight (Kg){height (m)}2

Increased risk of diabetes

Prevalence in Canadaof BMI 27

16%

26%

36%

45%

51%

40%

32%

26%

18%16%

40%

48%

0%

20%

40%

60%

25-34 35-44 45-54 55-64 65-7418-24

age

male

female

What we have now:Glazer G Arch. Intern Med 2001; 161: 1814-24

Drug Plbo corr weight loss

(all published studies)

phentermine 7.9 kgsibutramine 4.3 kgorlistat 3.4 kgdiethylpropion 1.5 kg

Overview of studies lasting 36-52 weeks

Orlistat (XENICAL®)Davidson MH et al JAMA 1999; 281: 235-42)

• inhibits pancreatic and intestinal lipases• not absorbed (<1%) (no worry about systemic adverse effects)• reduces fat uptake of fatty acids by 30%• adverse effects: bloating 40%

oily spotting 33%

fecal urgency 30%• 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

Adipocytesstomachplacenta

Leptin receptorsHypothalamusBody wt.Endothelial cellsT-lymphocytes

Neuropeptide YHungerFood 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