pharmacology 301.6 module 6 lesson 2 lipids/obesity
TRANSCRIPT
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