Transcript Hyperlipoprotinemias Department of Pharmacology College of Medicine

Hyperlipoprotinemias
Department of Pharmacology
College of Medicine
Normal Lipid Metabolism
From Figure 36-1 Mahley RW, Bersot TP. In Goodman and Gilman’s Pharmacological Basis of Therapeutics, 10th 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

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 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

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, 6th 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, 6th 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
Statins

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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
Statins How do they work?

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
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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:

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

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
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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.
Statins

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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


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Cholestyramine QUESTRAN
Colesevelam WELCHOL
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
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
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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 (3040%)
Reduces triglycerides by 35-45% (26 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
Niacin – Adverse reactions
These 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 myopathy
Bezafibrate BENZALIP
SR
Fibrates
Gemfibrozil
LOPID

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-S
Fenofibrate LIPIDIL MICRO
Fibrates

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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
Bezafibrate BENZALIP SR
Gemfibrozil LOPID
Fenofibrate LIPIDIL MICRO
Clofibrate 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