Lipid-Lowering Agents

Basic Pharmacology Block

PDNT/PMED.PPHR -213
1

 Objectives
1.Recognize the structure and metabolism of plasma lipoproteins.
2.Differentiate between the exogenous and endogenous pathways of
lipoprotein metabolism.
3.Identify the different classes of lipid-lowering agents.
4.Recognize the mechanism of action and role of the different lipid-
lowering agents including their pharmacological effect on the
different types of lipids.
5.Identify the role of the different lipid lowering agents in clinical
practice.
6.List the major side effects and drug-drug interactions of the
different lipid lowering agents.

Lipids originate from two sources: endogenous

lipids, synthesized in the liver, and exogenous lipids,
ingested and processed in the intestine.

3
Lipid Metabolism

4
 What Are Lipoproteins?
• Lipoproteins are protein-lipid complexes.

5
 Hyperlipidemia

• Elevated concentrations of lipid (hyperlipidemia) can lead to the

development of atherosclerosis and CAD (Coronary artery
disease).

• 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.

 Hyperlipidemia
Hyperlipidemias can be:
1. Primary (diet and genetics)
• Familial hypercholesterolemia, defect of LDL receptors

2. Secondary
• Diseases

 Secondary Causes of Hyperlipidemias

• Diabetes mellitus
• Nephrotic syndrome
• Alcohol use
• Contraceptive use
• Estrogen use
• Glucocorticoid excess
• Hypothyroidism
• Obstructive liver disease

 Adult Treatment Guidelines

Desirable Borderline to High High
mg/dl (mmol/l)

Total Cholesterol <200 ( 5.2) 200 -239 (5.2-6.2) >240(6.2)

LDL Cholesterol <130(3.4) 130-159(3.4-4.1) >160(4.1)

HDL Cholesterol >60(1.55)

Men >40(1.04)

Women >50(1.30)

Triglycerides <120(1.4) 120-199(1.4-2.3) >200(2.3)

 Lipid-Lowering Drugs

1. Statins.
2. Fibrates.
3. Nicotinic acid.
4. Cholesterol absorption Inhibitors
5. Bile acid binding resins.
6. Omega 3 Fatty Acids

10

1. Statins

11
Example: Lovastatin, simvastatin , atorvastatin and rosuvastatin.
They are most effective in reducing LDL

Mechanism of action:
These drugs are competitive inhibitors of the enzyme 3-
hydoxy-3-methylglutaryl coenzyme A reductase, the rate-
limiting enzyme in cholesterol biosynthesis.

* Short acting statins such as lovastatin, pravastatin and

simvastatin are given at night to reduce peak cholesterol
synthesis in the early morning.
12

 Adverse Effects
1. Hepatotoxicity (increased serum transaminase).
2. Myopathy (increased creatine kinase) especially when
combined with other lipid lowering drugs:
i) Fibrates
ii) Niacin.
3. G.I.T upset.
4. Headache.

*CYP3A4 inhibitors, macrolide antibitiocs, ketoconazole,

verapamil also causes and increased risk of myopathy.

* These drugs are contraindicated in pregnancy and nursing

mothers.
13

 2. Fibric Acid Derivative

(Fibrates)
Examples: Gemfibrozil , fenofibrate , clofibrate and bezafibrate (the most
potent)
• Binds to peroxisome proliferator-
activated receptor-α (PPAR- α)
in the liver, heart, kidney, &
skeletal muscle. Also they
increase the activity of lipoprotien
lipase. N.B The PPAR-a are a
class of intracellular receptors
that modulate fat metabolism.

* Peroxisome proliferator response element

14

The fibrates typically lower VLDL triglyceride by 40% or

more and elevate plasma HDL cholesterol by 10% and
reduction of LDL by 10%.

Adverse effects:
•Dyspepsia
•Myopathy
•Increase hepatic enzymes

Drug-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).
15

 3. Nicotinic Acid (Niacin)

Mechanism of action:
1. Nicotinic acid decrease formation and secretion of VLDL
by the liver (1-6 gm).

2. Inhibit fatty acid mobilization (inhibit lipolysis) from the

adipose tissue.

3. In addition, nicotinic acid shifts LDL particles to larger

sizes. The larger LDL particles are thought to be less
atherogenic.

4. Nicotinic acid can also increase plasma HDL level. (Its the
most potent drug in increasing HDL level)
16

 Adverse Effects

1. Pruritus, flushing The niacin flush results from the

stimulation of prostaglandins. This flush is avoided by
low dose aspirin 325 mg ½ h before niacin.
2. Hepatotoxicity.
3. Reactivation of peptic ulcer (because it stimulates
histamine release resulting in increased gastric motility
and acid production
4. Hyperglycemia.
5. Increased uric acid level

17

4. Cholesterol Absorption Inhibitors

Ezetimibe inhibits intestinal absorption of phytosterols
and cholesterol.
• Its primary clinical effect is reduction of LDL levels.

Mechanism of Action
Ezetimibe is a selective inhibitor of intestinal absorption
of cholesterol and phytosterols

18

 5. Bile Acid Binding Resins

E.g. Colestipol , Cholestyramine

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.
2. This result in increased use of
cholesterol to replace the excreted
bile acids and lowering of hepatic
cholesterol.
3. In addition, since bile acids are
required for intestinal absorption of
cholesterol, these resins decrease
cholesterol absorption from the
G.I.T. 19



 Adverse Effects
1. Constipation, G.I.T complaints: heart burn, flatulence,
dyspepsia.
2. Impair fat soluble vitamin absorption (A,D,E,K).
3. Chronic use of cholestyramine resin may be associated with
increased bleeding tendency due to hypoprothrombinemia
associated with Vitamin K deficiency.

6. Omega 3 Fatty Acids

• Diets rich in omega 3 fatty acids from oily fish decrease
triglycerides concentrations but increase cholesterol.
• Eating fish regularly decrease ischemic heart disease.
20

 Drug Mechanism of Action Effects on Lipids Effects on Lipoproteins

Bile acid-burning !LDL Catabolism "Cholesterol "LDL , "VLDL

resins "Cholesterol
Cholestyramine absorption
Niacin "LDL and VLDL "Triglycerides "VLDL , "LDL ,
synthesis "Cholesterol !HDL
Fibrates !VLDL clearance "Triglycerides "VLDL , "LDL ,
Gemfibrozil "VLDL synthesis "Cholesterol !HDL
Statins !LDL catabolism; "Cholesterol "LDL
Lovastatin inhibit LDL synthesis

Ezetimiber Blocks cholesterol "Cholesterol "LDL

absorption across
the intestinal border

21