hyperlipoprotinemias department of pharmacology college of medicine
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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