ANTIHYPERLIPIDAEMIC

DRUGS
BY
DR/AZZA BARAKA
 Learning objectives
 Classify the antihyperlipidemic drugs.
 Explain the mechanism of action of drugs used
in treatment of hypercholesterolemia &
hypertriglyceridemia.
 Deduce the different antihyperlipidemic drugs in
treatment of combined hyperlipidemia.
 Tabulate the difference between the different
antihyperlipidemic drugs as regards;
mechanism of action, side effects & therapeutic
uses.
Lipids originate from two sources: endogenous lipids, synthesized in the liver,
and exogenous lipids, ingested and processed in the intestine.

Dietary cholesterol and triglycerides are packaged into chylomicrons in the

intestine, before passing into the bloodstream via lymphatics.

Chylomicrons are broken down by lipoprotein lipase (LPL) in the capillaries of

muscle and adipose tissue to fatty acids, which then enter the cells. The
chylomicron remnants, which have lost much of their triglyceride content,
are taken up by the liver for disposal.

The liver synthesizes triglycerides and cholesterol, and packages them as

VLDLs before releasing them into the blood. When VLDLs (which consist
mainly of triglyceride) reach muscle and adipose blood vessels, their
triglycerides are hydrolyzed by LPL to fatty acids. The fatty acids that are
released are taken up by the surrounding muscle and adipose cells. During
this process, the VLDLs become progressively more dense and turn into
LDLs. While most of the resulting LDLs are taken up by the liver for
disposal, some circulate and distribute cholesterol to the rest of the body
tissues.
HDLs, which are also secreted from the liver and intestine, have the task of
preventing lipid accumulation. They remove surplus cholesterol from tissues
and transfer it to LDLs that return it to the liver
 HYPERLIPIDEMIA
 Elevated concentrations of lipid
(hyperlipidemia) can lead to the development
of atherosclerosis and CAD.
 VLDLs and LDLs are atherogenic
lipoproteins, whereas HDL concentrations
are inversely related to the incidence of
CAD.
 Hence, treatments for hyperlipidemia aim to
reduce LDL levels and raise HDL levels.
 High density lipoprotiens
 Act as a reservoir for apoproteins which can be donated or received from other lipoproteins.
 Also play a vital role in scavenging “used” cholesterol (reverse cholesterol transport):

apoproteins HDL receptor mediated HDL

endocytosis by liver
HDL
HDL Liver
some cholesterol
ester transferred to
“used” cholesterol circulating VLDL
transferred to HDL and
converted to cholesterol
VLDL
ester

Cholesterol can be
LDLreceptor converted to bile salts
Peripheral mediated for excretion or
tissues LDL endocytosis LDL repackaged in VLDL
for redistribution
 Pharmacotherapeutic options in
hyperlipidemia
I-Agents targeting endogenous cholesterol:
a-Statins.
b-Fibrates.
C-Nicotinic acid.
II-Agents Targeting Exogenous Cholesterol
a-Cholesterol Uptake Inhibitors, e.g. ezetemibe.
b- Bile acid binding resins, e.g. colestipol &
cholestyramine
 H M G – COA REDUCTASE
INHIBITORS(STATINS)
Lovastatin , fluvastatin , pravastatin ,
simvastatin ,atorvastatin and rosuvastatin.
Pharmacokinetics:
They are subjected to extensive first-pass
metabolism by the liver. Greater than 95% of
most of these drugs are bound to plasma
proteins.
All statins are taken orally at bedtime because of
diurnal rhythm of cholesterol synthesis,
except atorvastatin taken at any time
because of its long half-life (14 hours).
 Mechanism of action
 These are potent reversible competitive
inhibitors of 3-hydroxy 3-methyl glutaryl
coenzyme A reductase, the rate-controlling
enzyme in cholesterol biosynthesis.
 They are extremely effective in lowering plasma
concentration of LDL-C.
 They act by inhibiting cholesterol synthesis in
the liver, so they deplete the intracellular supply
of cholesterol, which in turn triggers a
compensatory up-regulation of hepatic LDL
receptors, thus, causing increased clearance of
plasma LDL .
 Pharmacological actions
Effect on LDL-C: Statins decrease LDL-C by two
mechanisms:
Up-regulation of LDL-R with increase of clearance of LDL-C
and decrease LDL-C.
Decrease of very low density lipoprotein (VLDL) production
because cholesterol is a required component of VLDL which
is a precursor of LDL-C
Effect on VLDL: Decreased VLDL production mediated
by decreased C, a required component of VLDL.
Effect on HDL-C: Statins induce modest increase in
HDL-C, this might be due to the ability of statins to
reduce plasma CETP activity (mediates the transfer of
cholesteryl esters from HDL to apoB-containing
lipoproteins in exchange for triglycerides).
 Adverse effects
1. Hepatotoxicity (increased serum transaminase).
2. Myopathy (increased creatine kinase) especially
when combined with:
 other lipid lowering drugs: i)Fibrates. ii) Niacin.
 other drugs that are metabolized by 3A4 isoform of
cytochrome P450 e.g.: erythromycin, cyclosporine,
verapamil, ketoconazole.
1. G.I.T upset.
2. Headache.
N.B: liver transaminases and CK must be regularly
measured during therapy with statins
 Contraindications
1. Pregnancy & lactation (Cholesterol is important for normal
development, and it is possible that statins could cause serious
problems). The effects of high cholesterol do not cause
problems for many years or even decades. Therefore, if a
woman does not take her statin or other cholesterol
medications during breastfeeding, it will likely have only a
minimal impact on her long-term risks. Therefore, it is best to
wait until you have weaned your child before starting or
resuming a statin medication
2. Active liver diseases.
N.B. The American Academy of Pediatrics is recommending that
kids as young as 8 years old be given cholesterol drugs in hope
of preventing future heart disease.
 Drug interactions
 Potentiate the action of oral anticoagulant and
antidiabetic drugs (displacement from plasma
protein binding sites).
N.B. : Pravastatin and fluvastatin are the statins
of choice to be given to a patient taking other
drugs metabolized by cytochrome 3A4 system.
 (FIBRIC ACID DERIVATIVE (Fibrates
Preparations: Gemfibrozil , fenofibrate , clofibrate .
Mechanism of action:
Ligand for the nuclear transcription regulator, peroxisome proliferator-
activated receptor-α (PPAR- α) in the liver, heart, kidney, &
skeletal muscle. N.B The PPAR-a are a class of intracellular
receptors that modulate fat metabolism. It is through PPAR-a that
fibrates lead to:
 Increased LPL activity, which increases clearance of VLDL &
chylomicron in plasma.
 Increased FFA uptake by the liver.
 Decreased VLDL due to increased fatty acid metabolism( beta
oxidation), by inducing Acyl-coenzymeA synthetases , which is a crucial
enzyme that facilitate the uptake and permit the metabolism of fatty acids.
 Increased LDL-C uptake by the liver.
 Raises HDL cholesterol levels (by increasing Apo A-I and II
expression in hepatocytes).
 Increase excretion of hepatic cholesterol in bile , thus endogenous
hepatic cholesterol synthesis may be decreased.
 PPARs
 PPARs functions as a ligand-activated transcription factor.
 Upon binding to hypolipidemic drugs, PPARs are activated.
 They then bind to peroxisome proliferator response elements,
which are localized in numerous gene promoters. In particular,
PPARs regulates the expression of genes encoding for proteins
involved in lipoprotein structure and function.
 Several such genes have been identified, including those of
apoC-III, apoA-I, apoA-II, apoA-IV, acyl coenzyme A oxidase,
and possibly that of lipoprotein lipase.
 The transcriptional downregulation of apoC-III and the
upregulation of lipoprotein lipase by fibrates enhance both the
intravascular lipolysis of TG-rich lipoproteins as well as their
tissue catabolism via apoE-mediated binding to specific cellular
receptors.
 Adverse effects
 G.I.T upset,rash, urticaria
 Myopathy
 Since fibrates increase the cholesterol content
of bile, they increase the risk for gallstones.
 Drug interactions
1. Increased risk of myopathy when combined with
statins.
2. Displace drugs from plasma proteins( e.g. oral
anticoagulants and oral hypoglycemic drugs).
Contraindications:
1- Patients with impaired renal functions.
2- Pregnant or nursing women.
3-Preexisting gall bladder disease.
 NICOTINIC ACID(NIACIN)
Mechanism of action:
1. In adipose tissue: it binds to adipose nicotinic acid receptors, this
will lead to decrease in free fatty acids mobilization from
adipocytes to the liver resulting in ↓ TG and thus VLDL synthesis.
2. In liver: niacin inhibits hepatocyte diacylglycerol acyltransferase-2,
a key enzyme for TG synthesis. Thus, it decreases VLDL
production (decreased TG synthesis and estrification).
3. In plasma: it increases LPL activity that increases clearance of
VLDL & chylomicron.

4. Niacin also promotes hepatic apoA-I production and slows hepatic

clearance of apoA-I and HDL through as-yet unknown
mechanisms.
 Pharmacological actions
 Effecton VLDL: Decreased VLDL by:
1) decreased synthesis in liver;

2) increased clearance in plasma.

 Effect on LDL: Decreased LDL due to reduction in its
precursor (VLDL).
 Effect on HDL: Induces modest increase in HDL-C
(The catabolism of HDL can be inhibited by nicotinic
acid through a mechanism that is largely unknown).
Niacin also promotes hepatic apoA-I production and
slows hepatic clearance of apoA-I and HDL through
as-yet unknown mechanisms.
 Therapeutic Uses
 Niacin is the most effective medication for
increasing HDL cholesterol levels and it
has positive effects on the complete lipid
profile. It is useful for patients with mixed
dyslipidemias.
 Niacin appears to exert the greatest
beneficial effects on the widest range of
lipoprotein abnormalities
 Adverse effects
1. Pruritus, flushing The niacin flush results from the
stimulation of prostaglandins D(2) and E(2) by
subcutaneous Langerhans cells via the niacin
receptor. This flush is avoided by low dose aspirin
325 mg ½ h before niacin.
2. Reactivation of peptic ulcer (because
( it stimulates
histamine release resulting in increased gastric
motility and acid production .
3. Hepatotoxicity.
4. Hyperglycemia which is believed to be caused by an
increase in insulin resistance.
5. Increased uric acid level( due to decreased uric acid
excretion).
 Contraindications

1. Gout.
2. Peptic ulcer.
3. Hepatotoxicity.
4. Diabetes mellitus.
 Ezetimibe

Mechanism of action:
- Impairs dietary and biliary cholesterol absorption at the
brush border of the intestines without affecting fat-soluble
vitamins.
- Reducing the pool of cholesterol absorbed from the diet
results in a reduced pool of cholesterol available to the liver.
-The liver in turn will upregulate the LDL receptor,
trapping more LDL particles from the blood and result in a
fall in measured LDL cholesterol .
Adapted from van Heek M et al Br J Pharmacol 2000;129:1748-1754.
 Pharmacokinetics

Elimination half-life of ezetimibe approximately 22

hours
Long half-life:
1. Permits once-daily dosing
2. May improve compliance
 )BILE ACID BINDING RESINS(BAS
E.g. colestipol ,cholestyramine and Colesevelam
Mechanism of action:
1- When resins are given orally, they are not absorbed, they bind
to bile acids in the intestinal lumen, prevent their reabsorption
and increase their excretion, thus interrupt the enterohepatic
circulation of bile acids.
2-Since bile acids inhibit the enzyme that catalysis the rate
limiting step in the conversion of cholesterol to bile acids, their
removal results in increased breakdown of hepatic cholesterol.
3-However, a compensatory increase occurs in the rate of
biosynthesis of cholesterol which is insufficient to compensate
for the increased catabolism and up-regulation of LDL-R on
hepatocytes thus the plasma and tissue cholesterol levels
decrease.
4-In addition, since bile acids are required for intestinal
absorption of cholesterol, these resins decrease cholesterol
absorption from the G.I.T.
NB: They may produce, however, a rise in VLDL.
 Pharmacological actions
Effect on LDL-C: It decreases cholesterol
content of hepatocytes leading to up-regulation
of LDL-receptors with increased LDL-
cholesterol clearance from blood and
decreased LDL-cholesterol level.
Effect on VLDL: It produces transient increase in
TG level in normal subjects which return to
base line. In borderline patient (e.g. TG >250
mg/dl), it produces marked increase in TG,
which is dangerous.
Effect on HDL-C: Increased HDL-C
 Side effects
1. Constipation ,G.I.T complaints: heart burn, flatulence,
dyspepsia.
2. Large doses may impair absorption of fats or fat soluble
vitamins (A, D, E, and K) and other medications,
particularly warfarin and statins, that are given concurrently.
N.B. Patients on multiple drug regimens should be counseled to
administer other medications one hour before or four hours
after the BAS. Colesevelam has not been shown to interfere
with the absorption of coadministered medications and is a
better choice for patients on multiple drug regimens
1. May ↑ level of VLDL in border line patients.
2. Chronic use of cholestyramine resin may be associated with
increased bleeding tendency due to hypoprothrombinemia
associated with Vitamin K deficiency.
 Contraindications
1- Complete biliary obstruction( BECAUSE BILE
IS NOT secreted into the intestine).
2- Chronic constipation.
3-Severe hypertriglyceridemia(TG >400 mg/dL)
 Antihyperlipedemic combinations
 Indications:
1. Increased VLDL during treatment of
hypercholesterolemia with resins.
2. Combined increase in LDL & VLDL.
3. High LDL or VLDL not normalized with a
single drug.
4. Severe hypertriglycerdemia or
hypercholesterolemia.
5. To take lower doses of each drug.
Resin & Niacin:
In combined hyperlipidemia.
Advantages:
No additional side effects.
Resin decrease gastric irritation of niacin.
May be given concomitantly.
 Resin & statin: (synergistic combination) why?

Because adding statins block the compensatory increase that

occurs in the rate of biosynthesis of cholesterol induced by
resins.
 Statin & ezetimibe: (synergistic combination) why?

Because statin blocks synthesis of endogenous cholesterol

while ezetimibe blocks exogenous cholesterol.
Niacin & Statins:
 -In severe LDL elevation.
 -In combined hyperlipidemia

Statins & Fibrates:

 Contraindicated (in full dose) because the
incidence of myopathy may increase so,
use not more than ¼ maximum dose of
statin and use pravastatin .