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Antihyperlipidemic Drugs

Presentation · December 2019

DOI: 10.13140/RG.2.2.19407.30886

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Atheer S. Alsabah
Al-Bayan University
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Antihyperlipidemic Drugs Dr. Atheer S. Alsabah

Al-Bayan University / College of Pharmacy

Pharmacology & Toxicology Dept. 2020-2021
Fourth stage / Pharmacology II - Lecture 13 / Done by Dr. Atheer S. Alsabah

Antihyperlipidemic Drugs

 Hyperlipidemia is an excessive accumulation of one or more type of lipids

transported in the plasma like cholesterol or triglyceride "TG" (ester of 3 FA
with glycerol) containing lipoproteins, which are synthesized in the mucosal layer
of the intestine or liver & then transported via plasma.
- Lipids are insoluble in aqueous media so it bound to protein moiety as a carrier
forming lipoproteins "macromolecular complexes in the blood that transport
lipids". While apolipoproteins are proteins on the surface of lipoproteins, play
critical roles in the regulation of lipoprotein metabolism & uptake into cells.

• There are 4 types of lipoproteins:

1. Chylomicrons: largest, least dense lipoprotein, derived from diet & transport
triglyceride & cholesterol from intestine to other tissues.
2. VLDL "very low density lipoprotein":
Triglyceride & cholesterol rich lipoprotein, secreted by the liver & transport
triglyceride from liver to tissues (precursor of LDL).
3. LDL "low density lipoprotein":
Cholesterol rich lipoprotein, whose regulated uptake by hepatocytes & other cells
requires functional LDL receptors, transport cholesterol to tissues; elevated
LDL level associated with atherosclerosis. It considered as atherotic agent, since
it is more dangerous one contains high amount of lipid & low amount of protein.
4. HDL "high density lipoprotein":
Cholesterol rich lipoprotein, transport cholesterol from tissues to liver; low
HDL level associated with atherosclerosis.

- 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.

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 Frederickson's classification of hyperlipidemia "primary hyperlipidemia"

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 Secondary hyperlipidemia:

Disease Dominant lipid abnormality

DM ↑ TG
CRF ↑ TG
Alcohol excess ↑ TG
Thiazide ↑ TG
Hypothyroidism ↑ Cholesterol
Nephrotic syndrome ↑ Cholesterol

 Pathogenesis (consequences) of hyperlipidemia:

- Atherosclerosis occurs when LDL is oxidized in plasma to oxidized-LDL which
engulfed by macrophage forming foam cells that adhere to endothelial layer of
blood vessels causing accumulation of platelets, macrophages, in addition to
secretion of cytokines & growth factors with deposition of connective tissue
forming atheroma "plug", that causing narrowing of blood vessels & elevation of
BP, so increase the incidence of CV diseases e.g. angina pectoris, heart attack,
stroke, & peripheral arterial diseases.

 Treatment strategies:
• 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 & smocking.

• Antihyperlipidemic Drugs "lipid lowering drugs":

1. Statins (e.g. lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, &
rosuvastatin), which are HMG-CoA reductase inhibitors that modify cholesterol
synthesis.
2. Ezetimibe, which is cholesterol absorption inhibitor.
3. Niacin "nicotinic acid", that decreases secretion of lipoproteins.
4. Fibrates (e.g. clofibrate, fenofibrate, & gemfibrozil), that Increase peripheral
clearance of lipoproteins.
5. Resins (e.g. cholestyramine, colestipol, & colesevelam), which are bile acid
sequestrants that reduce bile acid absorption.

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Antihyperlipidemic Drugs Dr. Atheer S. Alsabah

1. Statins

• MOA & effects:

- Inhibit cholesterol synthesis in the liver by inhibiting conversion of hydroxyl-
methyl-glutaryl coenzyme A to mevalonate by inhibiting HMG-CoA reductase
enzyme.
- Statins have direct antiatherosclerotic effect & prevent bone loss.

• Clinical uses:
- Reduce LDL-cholesterol level dramatically specially when combined with other
lipid lowering drugs.
- Reduce the risk of coronary events & mortality in pt with IHD & ischemic stroke.
- Rosuvastatin & atorvastatin have higher efficacy, ↓TG, & ↑HDL to some extent.

• Toxicity:
- Mild elevation of serum aminotransferases are common but are often associated
with hepatic damage sp. in pt with preexisting liver disease.
- Increase creatine kinase (released from skeletal muscles), is noted in 10% of pts.
- Few cases of severe muscle pain & rhabdomylosis.
- Hepatotoxicity , myopathy, & teratogenicity (avoided in pregnancy).

2. Ezetimibe

• MOA & effects:

- Prodrug converted in the liver to the active glucuronide form that inhibit GI
uptake of cholesterol & phytosterol.
- Ezetimibe results in an increase in the synthesis of high-affinity LDL receptors
that increases the removal of LDL lipoproteins from the blood. It is more effective
when combined with statins.

• Clinical uses:
- Treatment of hypercholesterolemia & phytosterolemia "a rare genetic disorder that
results from impaired export of phytosterols".

• Toxicity:
- When combined with statins, increase the risk of hepatotoxicity.
- Serum level of active glucuronide form increased by fibrates & decreased by
cholestyramine.

3. Niacin "nicotinic acid" (water soluble vitamin B3)

• MOA & effects:

- In the liver, niacin reduces VLDL synthesis, which in turn reduces LDL levels.
- In adipose tissue, niacin inhibits lipolysis leading to decrease level of circulating
free fatty acid which precursor for TG synthesis that required for synthesis of
VLDL & LDL which are rich with cholesterol & TG.
- Niacin reduces catabolic rate for HDL & improves its level.
- Niacin decreases circulating fibrinogen & increases tissue plasminogen activator.

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• Clinical uses:
- Because it lowers serum LDL cholesterol & triglyceride levels & increases HDL
cholesterol levels, niacin has wide clinical usefulness in treatment of
hypercholesterolemia, hypertriglyceridemia, & low levels of HDL cholesterol.

• Toxicity:
- Cutaneous flushing: common S/E mediated by PG release, thus pretreatment
with aspirin or NSAIDs reduces intensity of flushing.
- Dose dependent nausea & abdominal discomfort.
- Pruritus, & hyperuricemia.
- Moderate elevation in hepatic enzymes & even severe hepatotoxicity.
- Moderately impaired carbohydrate tolerance.

4. Fibrates "fibric acid derivatives"

• MOA & effects:

- Ligands for PPAR-α "peroxisome proliferator- activated receptor alpha", that
regulates gene transcription involved in lipid metabolism.
- In the adipose tissue, they increase activity of lipoprotein lipase & enhances
clearance of triglyceride –rich lipoproteins.
- In the liver, they stimulate fatty acid oxidation, which limits the supply of
triglycerides & decreases VLDL synthesis.
- Cholesterol biosynthesis in the liver is secondarily reduced, & HDL level
increased.
- Fibrates have little or no effect on LDL levels, however, fibrates increase LDL
cholesterol in pt with genetic condition called familial combined
hyperlipoproteinemia, which associated with combined increase in VLDL & LDL.

• Clinical uses:
- Treatment of hypertriglyceridemia, & combined with other cholesterol lowering
drugs for treatment of pt with elevated levels of both LDL & VLDL.

• Toxicity:
- Nausea is most common.
- Skin rashes are common with gemfibrozil.
- Few cases of decreases in WBCs & hematocrit.
- Increased risk of myopathy when combined with statins.
- Potentiate action of anticoagulants & oral hypoglycemic drugs.
- Increased risk of cholesterol gallstones especially in pt with cholelithiasis.

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5. Resins "bile acid binding resins"

• MOA & effects:

- Resins are large nonabsorbable polymers acid that bind bile acids & similar
steroids in the intestine & prevent their absorption.
- Resins act as anionic exchange that bind to negatively charged bile acids & form
resin–bile complex which excreted via liver with feces, so ↓ bile acids plasma
level causing ↓ cholesterol level since stimulates cholesterol degradation to bile
acids & ↑ hepatic uptake of LDL causing ↓ LDL level.
- Resins cause a modest reduction in LDL cholesterol but have little effect on HDL
cholesterol or triglycerides.
- In some pts with a genetic condition called familial combined hyperlipidemia,
resins increase in triglycerides & VLDL.

• Clinical uses:
- Treatment of hypercholesterolemia.
- Reduces pruritus in pt with cholestasis & bile salt accumulation.

• Toxicity:
- Bloating, constipation, unpleasant gritty taste, & impaired absorption of vitamin k,
dietary folates, thiazides, warfarin, fluvastatin, & pravastatin.

• H.W1: What is the probucol?

• H.W2: Combination therapy of hyperlipidemia?

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