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 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.
 Management of Hyperlipoproteinemia
Dietary Management

Dietary measures are always initiated first and may

prevent the need for drugs.
• Restricted diet rich in cholesterol and saturated
fat
• Avoid excessive alcohol

• Weight reduction and caloric restriction

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 Pharmacotherapeutic options in
hyperlipidemia
I-Agents targeting endogenous cholesterol:
• a-Statins: atorvastatin, cerivastatin, fluvastatin,
Lovastatin
Mevastatin pravastatin ,rosuvastatin and
Simvastatin
b-Fibrates. Gemfibrozil , fenofibrate , clofibrate
C-Nicotinic acid.
II-Agents Targeting Exogenous Cholesterol
a-Cholesterol Uptake Inhibitors, e.g. ezetemibe.
b- Bile acid binding resins, e.g. colestipol & holestyramine
• Lipid-regulating drugs include Statins, Fibrates, Anion-exchange resins, and
Nicotinic Acid, which may be used singly or in combination under careful
medical supervision
Statins are more effective than other classes of drugs in lowering body
concentrations of LDL-cholesterol but less effective than
fibrates in reducing triglyceride concentration.
Their use results in significant reductions in heart attacks (myocardial
infarctions) and other adverse cardiovascular events, such as STROKE.
• They should be used in conjunction with other preventive measures such as
low-fat diets, reduction in alcohol consumption, taking exercise and
stopping smoking.
Fibrates:

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 1. HMG-COA Reductase Inhibitors ("Statins")

• Example: Lovastatin, atorvastatin, fluvastatin,

pravastatin,simvastatin, and rosuvastatin

• These compounds are structural analogs of HMG-CoA (3-hydroxy-3-
methylglutaryl-coenzyme A).
HO O HO HO
COONa COOH
O OH SCoA

For example, For example, HMG CoA substrate

Mevastatin Fluvastatin
Lovastatin Atorvastatin
Simvastatin Cerivastatin
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 Chemistry & Pharmacokinetics
• Lovastatin and simvastatin are inactive lactone prodrugs that are
hydrolyzed in the GIT to the active -hydroxyl derivatives.

• Absorption of the ingested doses of the reductase inhibitors varies from

40% to 75% with the exception of fluvastatin, which is almost

completely absorbed.

• Absorption generally (with the exception of pravastatin) is enhanced

by taking the dose with food.

• All have high first-pass metabolism by the liver.

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• Most of the absorbed dose is excreted in the bile; about 5–
20% is excreted in the urine.
• Plasma half-lives of these drugs range from 1 hour to 3
hours except for atorvastatin, which has a half-life of 14
hours, and rosuvastatin, 19 hours.
• 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).

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 Bioavail. Dosage Protein Metabolites
(mg) Binding

Atorvastatin ~14% 10 – 80 >98% Active

Cerivastatin ~60% 0.2 – 0.3 >99% Active

Fluvastatin ~24% 10 – 80 98% Active

Lovastatin ~5% 10 – 80 >95%

Pravastatin ~17% 10 – 40 ~50%

Simvastatin ~5% 10 - 80 ~95%

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 Mechanism of Action
• They inhibit HMG-CoA reductase enzyme and prevent the
conversion of Mevalonic acid to cholesterol (first committed
step in sterol biosynthesis)

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 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).
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 Therapeutic Uses

• First choice drugs for primary hyperlipidaemia with raised LDL

and total cholesterols
• To treat secondary hypercholesteraemia associated with diabetes,
nephritic syndrome etc
• As cholesterol biosynthesis occurs predominantly at night,
reductase inhibitors—except atorvastatin and rosuvastatin—
should be given in the evening if a single daily dose is used.

These drugs reduce:

• Progression of atherosclerotic lesions
• Occurrence of myocardial infarction

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 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.
3. G.I.T upset.
4. Headache.
N.B: liver transaminases and CK must be regularly measured
during therapy with statins
1.
Contraindications
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.
Hypothyroidism should be managed adequately before starting treatment
with a statin
Statins should be avoided in porphyria but rosuvastatin is thought to be
safe.
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.
disease
Porphyria= a rare hereditary disorder of haemoglobin metabolism causing
mental disturbance, extreme sensitivity to light, and excretion of dark
pigments in the urine.
 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.
 2.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.
 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
• NB-The value of nicotinic acid is limited
byits side-effects, especially vasodilatation
 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).
 3. 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.

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 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.
 4. 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.
 Therapeutic Uses
• The resins are used in treatment of patients with primary
hypercholesterolemia, producing approximately 20%
reduction in LDL cholesterol in maximal dosage.
 Dosage
• Colestipol available as granular preparations and in 1 g tablets
• Cholestyramine is available as granular preparations
– Granular resins are mixed with juice or water and
allowed to hydrate for 1 minute.
• Colesevelam: available as 650 mg tablet, the maximum
dose is six tablets daily

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 Side effects
1. G.I.T complaints: Constipation , 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.( Dose of more than 30
gm/day )
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)
 5. Ezetimibe
Mechanism of action:
- Impairs dietary and biliary cholesterol absorption
at the brush border of the intestines
- 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.

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 Pharmacokinetics

Elimination half-life of ezetimibe approximately 22

hours
Long half-life:
1. Permits once-daily dosing
2. May improve compliance
 Therapeutic Uses & Dosage
• Average reduction in LDL cholesterol with ezetimibe alone in
patients with primary hypercholesterolemia is about 18%, with
minimal increases in HDL cholesterol.
• Ezetimibe is apparently synergistic with reductase inhibitors,
producing decrements as great as 25% in LDL cholesterol beyond that
achieved with the reductase inhibitor alone.
• A single daily dose of 10 mg is used

 Toxicity

• Reversible impaired hepatic function with a small increase in

incidence when given with a reductase inhibitor
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 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:
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 .
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