Department of Pharmacology
College of Medicine

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

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

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

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

Cholesterol in bile salts is highly recycled
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Bile salts
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Synthesized by liver from cholesterol.
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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.

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

Cholesterol
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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.

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

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

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

Sites of Action of Antihyperlipidemic Drugs
From Figure 23.2 in Craig CR, Stitzel RE. Modern Pharmacology with
Clinical Applications, 6 th ed. Lippincott Williams & Wilkins 2004
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

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

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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)
Lovastatin MEVACOR

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Competitive inhibitors of 3-hydroxy-3methylglutaryl 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

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

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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.

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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

Bile-acid sequestrants (Resins)
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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 NOVO CHOLAMINE
Colestipol COLESTID

Resins
Colesevelam WELCHOL
Cholestyramine QUESTRAN
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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)
Colestipol COLESTID

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Side Effects:
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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.
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GI: bulk of resin causes discomfort – bloating & dyspepsia (suspend in liquid several h before ingestion)
Colesevelam better? – newer anhydrous gel-tablet form

Nicotinic Acid (Niacin)
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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 - 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

These are common and reduce patient compliance:
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Flushing (with resultant sudden drop in blood pressure which may cause syncope in some patients) (give aspirin)
Dyspepsia (take after meal)
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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

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

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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

Fibrates
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 apoA-I and apoA-II expression increased – increases HDL-C
Increased hepatic LDL receptors?
Inhibit coagulation and enhance fibrinolysis
Bezafibrate BENZALIP SR
Gemfibrozil LOPID
Fenofibrate LIPIDIL MICRO
Clofibrate ATROMID-S

Fibrates
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Better absorbed with meals
Side effects are uncommon GI distress
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Drug-Drug Interactions include
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Fibrates plus statins myopathy
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Displaces coumarin anticoagulants from plasma proteins. Plasma prothrombin time monitored
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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