Antihyperlipidemic Drugs

❖ Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the

blood like cholesterol or triglyceride .

• Lipids are insoluble in aqueous media so ,they are bound to proteins forming
lipoproteins , which are water soluble and can be transported in plasma. These
proteins are synthesized by the liver and called Apo-liporoteins .

• There are 4 types of plasma lipoproteins(according to density):

1. Chylomicrons:
2. VLDL
3. LDL
4. HDL

Hyperlipidemia either primary due to genetic defect or secondary as a

consequence to other diseases like D.M, hypothyroidism, or liver cirrhosis.
• Normal level of cholesterol < 200 mg/dl, triglyceride < 160 mg/dl, LDL < 130
mg/dl, VLDL < 30 mg/dl, HDL > 35 mg/dl.
❖ Acquired hyperlipidemia(also called secondary dyslipoproteinemias):
This may increase the risk of atherosclerosis, pancreatitis and other complications of
chylomicronemia syndrome.
The most common causes of secondary hyperlipidemia are:
Disease Dominant lipid abnormality
Diabetes M. ↑ TG
Chronic renal failure ↑ TG
Alcohol excess ↑ TG
Drugs such as Thiazide, B-blockers and estrogens ↑ TG
Hypothyroidism ↑ Cholesterol
Nephrotic syndrome ↑ Cholesterol
❖ Management :
•Non-pharmacological management:
Diet control by increase intake of fruits, vegetables, & unsaturated fatty
acids (e.g. fish oil, & olive oil) since they are not oxidized easily like
saturated fatty acids. In addition to exercise, weight reduction , avoid
alcohol & smoking.
•Pharmacological management:
Antihyperlipidemic drugs "lipid lowering agents":
1. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors:
Statins (e.g. lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin,
pitavastatin & rosuvastatin).
2. Niacin "nicotinic acid“: decrease secretion of lipoproteins.
3. Cholesterol absorption inhibitor: Ezetimibe.
4. Fibrates: (e.g. clofibrate, fenofibrate, Etofibrate, Bezafibrate& gemfibrozil),
that Increase peripheral clearance of lipoproteins.
5. Bile acid sequestrants :Resins (e.g. cholestyramine, colestipol, &
colesevelam), they are reduce the bile acid absorption.
6. Omega-3 fatty acids: Eicosapentaenoic acid , docosahexaenoic acid and
Icosapent ethyl
1. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase
inhibitors: Statins:(e.g. lovastatin, fluvastatin, pravastatin,
simvastatin, atorvastatin, pitavastatin & rosuvastatin).

❖ Mechanism of action: They act by:

• inhibition the HMG CoA reductase enzyme → inhibition de novo cholesterol
synthesis→ depletes the intracellular supply of cholesterol.
• Increasing the number LDL receptors →due to depletion of intracellular cholesterol →
promote uptake of LDL from blood.
• Decreasing triglyceride levels and may increase HDL-C in some patients.
Thus, plasma cholesterol is reduced, by both decreased cholesterol synthesis and
Increased circulating LDL catabolism.
❖ Therapeutic uses:
• Hyperlipidemias : by reduction the total and LDL-cholesterol levels.
• They are used to reduce the risk of atherosclerotic cardiovascular disease(ASCVD ): like
stroke and MI

❖ Adverse effects:
• Myopathy and rhabdomyolysis (disintegration of skeletal muscle)
• Hepatotoxicity & teratogenicity (avoided in pregnancy).
❖ Contraindications: Pregnancy, lactation and children.
2. Niacin "nicotinic acid" (water soluble vitamin B3)

❖ Mechanism of action:
• Niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of
free fatty acids (from triglyceride ) →reduce liver triglyceride levels →decrease
hepatic VLDL production → reduces plasma LDL-C concentrations.
• Note: The liver normally uses circulating free fatty acids as a major precursor for
triglyceride synthesis.
❖ Therapeutic uses:
• Treatment of familial hyperlipidemias by lowering plasma levels of both cholesterol
and triglycerides.
• Treatment of other severe hypercholesterolemias in combination with other agents.
❖ Adverse effects:
• Cutaneous flushing: common S/E mediated by PG release, thus pre treatment with
aspirin or NSAIDs reduces intensity of flushing.
• Dose dependent nausea & abdominal discomfort.
• Pruritus, hyperuricemia and gout.
• Impaired glucose tolerance and hepatotoxicity.
3. Cholesterol absorption inhibitor : Ezetimibe

❖ Mechanism of action:
• Ezetimibe selectively inhibits absorption of dietary and biliary cholesterol in
the small intestine→ leading to a decrease in the delivery of intestinal
cholesterol to the liver→ causes a reduction of hepatic cholesterol stores
and an increase in clearance of cholesterol from the blood.
❖ Therapeutic uses:
• Treatment of hypercholesterolemia
❖ Adverse effects:
• Hepatotoxicity, especially when combined with statins.
4. Fibrates "fibric acid derivatives“:
They are derivatives of fibric acid that lower serum triglycerides and increase
HDL-C. (e.g. clofibrate, fenofibrate, Etofibrate, Bezafibrate& gemfibrozil),
❖ Mechanism of action:
• Fibrates →activate PPARs→ leads to decreased triglyceride concentrations by increasing the
expression of lipoprotein lipase and decreasing apolipoprotein (apo) CII concentration.
• Fibrates also increase HDL-C by increasing the expression of apo AI and apo AII.
Note: The peroxisome proliferator–activated receptors (PPARs) are members of the nuclear receptor
family that regulate lipid metabolism.

❖ Therapeutic uses:
• Treatment of hypertriglyceridemias.
• Treatment of type III hyperlipidemia .
❖ Adverse effects:
• Gastrointestinal (GI) disturbances..
• Gallstones: because these drugs increase biliary cholesterol excretion.
• Myositis, and muscle weakness or tenderness.
❖ Drug interaction:
• Statins :Increase the risk of myopathy when combined with statins.
• Warfarin: Increase the action of warfarin .
❖ Contraindications: Fibrates should not be used in patients with gallbladder disease , biliary
cirrhosis ,severe hepatic or renal dysfunction.
5. Bile acid sequestrants (Resins ):(e.g. cholestyramine, colestipol &colesevelam)
Resins are large non absorbable polymers have significant LDL-C lowering effects.
❖ Mechanism of action:
They are anion-exchange resins that bind negatively charged bile acids and bile salts in the small
intestine →forms a non-absorbable resin/bile acid complex which excreted in the feces→
decrease the bile acid concentration→ increase conversion of cholesterol to bile acids in
hepatocytes→ Consequently, decrease the intracellular cholesterol concentrations→ increased
hepatic uptake of cholesterol containing LDL-C particles→ leading to a decrease in plasma LDL-C.
❖ Therapeutic uses:
• Treatment of type IIA and type IIB hyperlipidemias(hypercholesterolemia).
• Relieve pruritus caused by accumulation of bile acids in patients with biliary stasis.
• Colesevelam is indicated for type 2 diabetes due to its glucose-lowering effects.
❖ Adverse effects:
• GI disturbances, such as constipation, nausea, and flatulence( Colesevelam has fewer GI side
effects).
• They impair the absorption of the fat-soluble vitamins (A, D, E, and K).
❖ Drug interaction:
They interfere with the absorption of many drugs (digoxin, warfarin, thiazide diuretics, pravastatin,
fluvastatin and thyroid hormone). Therefore, other drugs should be taken at least 1 to 2 hours before,
or 4 to 6 hours after, the bile acid sequestrants.
❖ Contraindications and cautions:
• They are contraindicated in patients with significant hypertriglyceridemia, complete biliary
obstruction and used with caution in pregnancy and in liver or kidney disease
6-Omega-3 fatty acids:
Eicosapentaenoic acid and docosahexaenoic acid are an essential polyunsaturated fatty acids in fish oil
used for lowering triglyceride by inhibiting the VLDL and triglyceride synthesis in the liver.
❖ Therapeutic uses: Used as adjunct to other lipid-lowering therapies for Treatment of
hypertriglyceridemias.
❖ Adverse effects: GI effects (abdominal pain , nausea, diarrhea) and a fishy aftertaste.
❖ Drug interaction: increase bleeding risk when used concomitantly with anticoagulants or
antiplatelet agents.