Applied Science Private University

Pharmacy Institute
Clinical Pharmacy and Therapeutics Department

Pharmacology II (906320)

Drugs for hyperlipidemia

Chapter 22

2nd semester 2022/2023

Amman-Jordan
Dr. Luai Hasoun
Dr. Rana Abu Farha
Lipid metabolism
• Triglycerides:
Normal < 150 mg/dL.
Borderline = 150 to 199 mg/dL.
High = 200 to 499 mg/dL.
Very high ≥ 500 mg/dL.
• Hyperlipidemia may be caused by:

1. Individual lifestyle (lack of exercise and high

consumption of fatty acid).

2. Inherited gene defect in lipoprotein metabolism

3. More commonly, combination of genetics and lifestyle

factors.
 Antihyperlipidemic drugs

• Coronary heart disease (CHD) is the cause of about

half of all deaths in the United States.
• The incidence of the heart diseases is correlated with
elevated levels of low density lipoproteins (LDL)
cholesterol and triglycerides & with low level of high-
density lipoprotein cholesterol (HDL).
• Atherogenicity of LDL > VLDL.
 Statins
• Mechanism of action:
(1) They are HMG CoA reductase inhibitors.
.The effect is mainly on the liver
• (2) Depletion of intracellular cholesterol causes the cell to
increase the number of cell-surface LDL receptors that can
bind and internalize circulating LDLs. Thus the end result is
a reduction in plasma cholesterol.

• (3) Also decrease triglycerides and increase HDL-C.

• Therapeutic uses:
 Effective in lowering plasma cholesterol levels in all
types of hyperlipidemias.
 reduced coronary events, ischemic stroke, & death from heart
failure.
 It has become standard practice to initiate reductase inhibitor
therapy immediately after acute coronary syndromes, regardless
of lipid levels.
 Atorvastatin, rosuvastatin, & simvastatin are the most effective
LDL cholesterol–lowering statin drugs.
 Because cholesterol synthesis occurs predominantly at night,
reductase inhibitors should be given in the evening if a single
daily dose is used, except atorvastatin and rosuvastatin because
they have much longer t1/2.
 Absorption is generally enhanced by food (with the exception of
pravastatin).
 Simvastatin is given in doses of 5–80 mg daily.
 However, patients who are homozygous for familial
hypercholesterolemia lack LDL receptors and, therefore, benefit
much less from treatment with these drugs.
 Use of statins is linked to ~50% reduction in several forms of
cancer (American Society of Clinical Oncology 2005 Annual
Meeting).
 Statins have been shown to prevent bone loss.
• Side effects:
1) Biochemical abnormalities in liver function evaluate
liver function and measure serum transaminase levels
periodically (LFTs)

2) Myopathy and rhabdomyolysis (disintegration or

dissolution of muscle).
-In most of these cases, patients usually suffered from renal
insufficiency or were taking drugs such as cyclosporine,
itraconazole, erythromycin, gemfibrozil, or niacin
Plasma creatine kinase levels should be determined
regularly
Creatine ??
Creatinine Kinase???
• Teratogenic Contraindicated during pregnancy and in
nursing mothers.
• They also should not be used in children and teenagers
except selected patients.
• Hepatic insufficiency can cause drug accumulation.

• Interactions:

• Statins elevate warfarin levels monitor INR.

• Statins are metabolized by the cytochrome P450 system;

drugs or foods (eg. grapefruit juice) that inhibit cytochrome
P450 activity increase the risk of hepatotoxicity and
myopathy.
 Niacin (vitamin B3, nicotinic acid)
Mechanism of Action:
strongly inhibits lipolysis in adipose tissue—the primary producer
of circulating free fatty acids, which is the major precursor for
triacylglycerol synthesis in the liver. Liver triacylglycerol is
required for very low density lipoprotein (VLDL) production.
Thus, both plasma triacylglycerol (in VLDL) and cholesterol (in
VLDL and LDL) are lowered.
hormone
sensitive lipase
• Niacin is the most effective agent in increasing the HDL.
-Boosts secretion of tissue plasminogen activator and lowers the
level of plasma fibrinogen.
Side effect: intense cutaneous flush (accompanied by an
uncomfortable feeling of warmth) and pruritus.
Tolerance to the flushing reaction usually develops within a few
days.
Administration of aspirin or another NSAID prior to taking niacin
decreases the flush, which is prostaglandin-mediated.
The sustained-release formulation of niacin, which is taken once
daily at bedtime, reduces bothersome initial adverse effects.
Niacin inhibits tubular secretion of uric acid and, thus, predisposes
to hyperuricemia (in about 20% of patients) and gout.
Some hepatotoxicity.
• Severe myopathy and rhabdomyolysis have been reported with
concomitant use of statins and niacin (major interaction). This
interaction is much higher in the Chinese descent compared with
those from non-Chinese descent. Yet, formulations combining
statins and niacin are available. (Pharmacogenomics)
 Fibrates
• Gemfibrozil & Fenofibrate are derivatives of fibric acid.
• They lower serum level of triglycerides, and increase the HDL. They
have little or no effect on LDL.
• Fenofibrate is more effective than gemfibrozil
MOA: Peroxisome proliferator activated receptors (PPARs) are nuclear
.receptors that regulate lipid metabolism
Fibrate binding to these receptors (activates PPARα) results in reduction
of plasma triacylglycerol concentration by increasing the expression
of lipoprotien lipase (partly extracellular).
Adverse effect
a. The most common adverse effects are mild gastrointestinal
disturbances like nausea.

b. Lithiasis: because these drugs increase biliary cholesterol excretion,

there is a predisposition to the formation of cholesterol gallstones.
 Don’t use in patients with previous gallbladder disease.

c. Myositis (inflammation of a voluntary muscle) can occur with these

drugs; thus, muscle weakness or tenderness should be evaluated.
- Severe myopathy and rhabdomyolysis have been reported during
concomitant use of statins and fibric acid derivatives, especially
gemfibrozil generally avoid (major interaction). Yet, not an
absolute contraindication.
Interactions:

Fibrates compete with the warfarin for binding sites on plasma proteins
(major interaction).
Some experts recommend that the anticoagulant dose be reduced by
approximately one-third to one-half initially, then gradually adjusted
as necessary according to INR monitoring.

Pregnancy Category C.
 Bile acid-binding resins
• Cholestyramine, colestipol, & colesevelam have significant
LDL cholesterol lowering effect, although the benefit is less
than those observed with statins.

• These agents are resins that bind bile acid in the intestine,
forming insoluble complexes that are excreted in the feces.

• Lowering bile acid level will trigger the conversion of

cholesterol into bile acid and the end result will be a
reduction in the cholesterol concentrations.

• Colesevelam produce modest reductions in HbA1c through

an unknown mechanism indicated for type 2 diabetes.
• Adverse effects:
• The most common side effect are gastrointestinal disturbances
such as constipation and nausea.
• Colesevelam has fewer gastrointestinal side effects than other
bile acid sequestrants
• At high doses they impair the absorption of fat soluble vitamins
(A,D,E, and K). Colesevelam does not have this disadvantage.

• Interactions:
• These agents inhibit the absorption of many drugs, for example,
Tetracycline, Digoxin, Warfarin, Aspirin, Pravastatin,
Fluvastatin, Thiazide diuretics.

 Drugs should be taken at least 1 to 2 hours before, or 4 to 6

hours after, the bile acid–binding resins
 Cholesterol absorption inhbitors
Ezetimibe selectively inhibits absorption of dietary and biliary
cholesterol in the small intestine, resulting in an increase in the
clearance of cholesterol from the blood.
Ezetimibe is often used as an adjunct to statin therapy or in statin-
intolerant patients to lower LDL cholesterol.

.Common adverse effects are headache and diarrhea -

May rarely increase hepatotoxicity and myopathy of statins (moderate
interaction) monitor.
No significant effect on the plasma concentrations of the fat-soluble
vitamins A, D, and E
 • Omega-3 fatty acids
• For triglyceride lowering. Found in marine sources such as tuna
and salmon.
• Cause small increases in LDL-C and HDL-C.
• Although effective for triglyceride lowering, omega-3
supplementation has not been shown to reduce cardiovascular
morbidity and mortality.
• Bleeding risk can be increased in those who are concomitantly
taking anticoagulants or antiplatelets.
 Combination therapies
- Often necessary to combine 2 antihyperlipidemics to achieve goal
plasma lipid levels.
- A combination of cholestyramine and niacin is more effective in
lowering LDL.
- A combination of a statin with bile acid-binding agent also
decreases LDL more effectively.
- Niacin + fibrate is used frequently.
- Maximum statin dose & adding
a fibrate or niacin to achieve goal
HDL & triglyceride levels.

- However, combinations increase

Liver and muscle toxicities.
Or
 Antihyperlipidemic drugs
• Must be taken indefinitely (life-long) in some cases

• Antihyperlipidimic drugs target the problem with

complimentary strategies

• In general, statins are indicated for increased LDL cholesterol,

while niacin and fibrates are indicated for high triglycerides.
Omega-3 fatty acids (fish oil) in adequate doses may also be
beneficial in lowering triglycerides.

• In some patients with a genetic condition that predisposes

them to hypertriglyceridemia and hypercholesterolemia
(familial combined hyperlipidemia), resins increase
triglycerides and VLDL, and fibrates can increase LDL
cholesterol.
• Resins may raise triglyceride levels and are contraindicated in
patients with significant hypertriglyceridemia (≥400 mg/dL).