Hyperlipoprotinemias

Department of Pharmacology

College of Medicine

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

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

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

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

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.

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)

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.

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.

Hyperlipoproteinemia

Blood lipids are combined with a protein.

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

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, 6th ed. Lippincott Williams & Wilkins 2004

Four Groups of Antihyperlipidemic Drugs – all reduce the risk of coronary heart

disease.

Statins Resins Nicotinic acid (niacin) Fibrates

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)

Lovastatin MEVACORLovastatin MEVACOR

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

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 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)

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 WELCHOLCholestyramine NOVO CHOLAMINECholestyramine NOVO CHOLAMINE

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 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

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 tissue2. 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 OTCNiacin tabs – 50 to 500 mg OTC

Niacin – Adverse reactionsThese 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 myopathyNiacin + statins – watch out for myopathy

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-SClofibrate ATROMID-S

Bezafibrate BENZALIP Bezafibrate BENZALIP SRSR

Fenofibrate LIPIDIL MICROFenofibrate LIPIDIL MICRO

Gemfibrozil Gemfibrozil LOPIDLOPID

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

apoA-I and apoA-II expression increased – increases HDL-C

Increased hepatic LDL receptors? Inhibit coagulation and enhance

fibrinolysis

Fenofibrate LIPIDIL MICROFenofibrate LIPIDIL MICRO

Gemfibrozil LOPIDGemfibrozil LOPIDBezafibrate BENZALIP SRBezafibrate BENZALIP SR

Clofibrate ATROMID-SClofibrate ATROMID-S

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