LIPID LOWERING
AGENTS
DR. CALEB OKOTH
DEPARTMENT OF PHARMACOLOGY
UZIMA UNIVERSITY COLLEGE
Introduction
Acronyms
• ACAT: Acyl-CoA:cholesterol acyltransferase
• Apo: Apolipoprotein
• CETP: Cholesteryl ester transfer protein
• HDL: High-density lipoproteins
• HMG-CoA: 3-Hydroxy-3-methylglutaryl-coenzyme A
• IDL: Intermediate-density lipoproteins
• LCAT: Lecithin:cholesterol acyltransferase
• LDL: Low-density lipoproteins
• Lp(a): Lipoprotein(a)
• LPL: Lipoprotein lipase
• PPAR- : Peroxisome proliferator-activated receptor-alpha
• VLDL: Very low density lipoproteins
Introduction
• The lipids of human plasma are transported in
macromolecular complexes termed lipoproteins.
• Elevations in levels of any of the lipoprotein species
are termed hyperlipoproteinemias or
hyperlipidemias.
• The term hyperlipemia denotes increased levels of
triglycerides in plasma.
• The two major clinical sequelae of the
hyperlipoproteinemias are acute pancreatitis and
atherosclerosis
Introduction
• Lipoproteins that contain apolipoprotein
(apo) B100 convey lipids into the artery wall.
These are the low-density (LDL),
intermediate-density (IDL), very low density
(VLDL), and lipoprotein(a) (Lp[a])
lipoproteins.
Normal Lipoprotein Metabolism
Chylomicrons
• Are formed in the intestine and carry triglycerides of
dietary origin, unesterified cholesterol and
cholesteryl esters.
• They transit the thoracic duct to the bloodstream.
Very Low Density Lipoproteins (VLDL)
• VLDL are secreted by the liver and provide a means
for export of triglycerides to peripheral tissues.
• Major transporter of endogenous TGs and cholesterol
Normal Lipoprotein Metabolism
Low-Density Lipoproteins (LDL)
• A major pathway by which LDL are catabolized
in hepatocytes and other cells involves receptor
mediated endocytosis.
• Cholesteryl esters from the LDL core are
hydrolyzed, yielding free cholesterol for the
synthesis of cell membranes
• Normally, about 70% of LDL is removed from
plasma by hepatocytes
Normal Lipoprotein Metabolism
LP(A) Lipoprotein
• It is formed from LDL
• It can be found in atherosclerotic plaques and may also
contribute to coronary disease by inhibiting thrombolysis.
High-Density Lipoproteins (HDL)
• Delivers cholesterol from peripheral tissues to the liver.
• Much of the lipid comes from chylomicrons and VLDL
during lipolysis.
• HDL also acquire cholesterol from peripheral tissues in a
pathway
Metabolism of lipoproteins of hepatic origin
Lipoprotein Disorders
• Are detected by measuring lipids in serum after
a 10-hour fast.
• Risk of atherosclerotic heart disease increases
with concentrations of the atherogenic
lipoproteins, is inversely related to levels of
HDL, and is modified by other risk factors.
• Diagnosis of a primary lipoprotein disorder
usually requires further clinical and genetic data
as well as ruling out secondary hyperlipidemias
Lipoprotein Disorders
• Phenotypes of abnormal lipoprotein distribution
(primary hyperlipoproteinemia) include:
• Primary chylomicronemia (familial lipoprotein
lipase or cofactor deficiency): Chylomicrons,
VLDL Increased.
• Familial hypertriglyceridemia: VLDL increased;
chylomicrons may be increased in severe case.
• Familial combined Hyperlipoproteinemia: VLDL,
LDL increased
Lipoprotein Disorders
• Familial dysbetalipoproteinemia: VLDL
remnants, chylomicron remnants increased.
• Familial hypercholesterolemia: LDL increased
• Familial ligand-defective apoB: LDL increased
• Lp(a) hyperlipoproteinemia: Lp(a) increased
Lipoprotein Disorders
Secondary Hyperlipoproteinemia
• Before primary disorders can be diagnosed, secondary
causes of the phenotype must be considered.
• Causes include
Hypertriglyceridemia Hypercholesterolemia
• Diabetes mellitus Hypothyroidism
• Alcohol ingestion Early nephrosis
• Severe nephrosis Resolving lipemia
• Estrogens
Secondary hyperlipoproteinemia
Hypertriglyceridemia Hypercholesterolemia
• Uremia Anorexia nervosa
• Corticosteroid excess Cholestasis
• Myxedema Hypopituitarism
• Glycogen storage disease Corticosteroid excess
• Hypopituitarism
• Acromegaly
• Immunoglobulin-lipoprotein complex disorders
• Lipodystrophy
• Isotretinoin
• Protease inhibitors
DR. CALEB OKOTH
PHARMACOLOGICAL MANAGEMENT
OF HYPERLIPOPROTEINEMIA
Drugs used in hyperlipidemia
• Competitive Inhibitors of HMG-COA Reductase
(Reductase Inhibitors; "Statins")
• Niacin (Nicotinic Acid)
• Fibric Acid Derivatives
• Bile Acid-Binding Resins
• Inhibitors of Intestinal Sterol Absorption
Inhibitors of HMG-COA Reductase
• Are structural analogs of HMG-CoA (3-hydroxy-
3-methylglutaryl-coenzyme A).
• They are most effective in reducing LDL
Examples
• Lovastatin, atorvastatin, fluvastatin,
pravastatin,simvastatin, and rosuvastatin
Mechanism of Action
• HMG-CoA reductase mediates the first
committed step in sterol biosynthesis.
Mechanism of action
• The active forms of the reductase inhibitors are
structural analogs of the HMG-CoA intermediate that is
formed by HMG-CoA reductase in the synthesis of
mevalonate.
• These analogs cause partial inhibition of the enzyme
and thus may impair the synthesis of isoprenoids such
as ubiquinone and the prenylation of proteins.
• They induce an increase in high-affinity LDL receptors.
This effect increases both the fractional catabolic rate of
LDL and the liver's extraction of LDL precursors (VLDL
remnants), thus reducing plasma LDL.
Inhibitors of HMG-COA Reductase
Clinical applications
• Used in reducing levels of LDL alone or with
resins, niacin, or ezetimibe
Toxicity
• Hepatotoxicity
• Minor increases in creatine kinase activity in
plasma
• Rhabdomyolysis leading to myoglobinuria,
which may lead to renal shutdown.
Niacin (Nicotinic Acid)
• Niacin (but not niacinamide) decreases VLDL
and LDL levels—and Lp(a) in most patients.
• It often increases HDL levels significantly.
Mechanism of Action
• Niacin inhibits VLDL secretion, in turn
decreasing production of LDL.
• Increased clearance of VLDL via the LPL
pathway contributes to triglyceride reduction.
Niacin (Nicotinic Acid)
Therapeutic Uses & Dosage
• Normalizes LDL in most patients with heterozygous
familial hypercholesterolemia and other forms of
hypercholesterolemia in combination with a resin or
reductase inhibitor
• In severe mixed lipemia that is incompletely responsive
to diet; it reduces triglycerides.
• Treatment of combined hyperlipoproteinemia and in
those with familia dysbetalipoproteinemia
• Dose: 1.5-6g daily
Niacin (Nicotinic Acid)
Toxicity
• Harmless cutaneous vasodilation and sensation of
warmth
• Pruritus, rashes, dry skin or mucous membranes, and
acanthosis nigricans
• Hepatotoxicity; an indication for discontinuing the
drug
• Hyperuricemia
• Carbohydrate tolerance may be moderately impaired
Fibric Acid Derivatives
• Examples: Clofibrate, Gemfibrozil, fenofibrate and
bezafibrate
Mechanism of Action
• Unclear mechanism of action
• These agents function primarily as ligands for the nuclear
transcription receptor, peroxisome proliferator-activated
receptor-alpha (PPAR- ) which regulate gene transcription.
• They increase lipo-lysis of lipoprotein triglyceride via LPL.
• Intracellular lipolysis in adipose tissue is decreased. Levels of
VLDL decrease
• HDL cholesterol increases moderately
Fibric Acid Derivatives
Therapeutic Uses
• Used in hypertriglyceridemias in which VLDL
predominate
• Used in dysbetalipoproteinemia.
• Treatment of the hypertriglyceridemia
Dosage
• Gemfibrozil is 600 mg orally once or twice daily.
• Fenofibrate 54mg P.O. OD or TDS (or a single 160
mg tablet) daily
Fibric Acid Derivatives
Toxicity
• Rashes
• Gastrointestinal symptoms
• Myopathy
• Arrhythmias
• Hypokalemia
• High blood levels of aminotransferases or
alkaline phosphatase.
Bile Acid-Binding Resins
• Colestipol, cholestyramine, and colesevelam
• Are useful only for isolated increases in LDL
Mechanism of Action
• The bile acids, metabolites of cholesterol, are normally
efficiently reabsorbed in the jejunum and ileum .
• Excretion is increased up to tenfold when resins are given,
resulting in enhanced conversion of cholesterol to bile acids
in liver via 7 -hydroxylation, normally controlled by negative
feedback by bile acids.
• Increased uptake of LDL and IDL from plasma results from
upregulation of LDL receptors, particularly in liver
Bile Acid-Binding Resins
Clinical applications
• Primary hypercholesterolemia
• Relieving pruritus in patients who have
cholestasis and bile salt accumulation
• Used in combination with niacin to treat LDL
elevations in persons with combined
hyperlipidemia.
• Useful in digitalis toxicity.
Inhibitors of Intestinal Sterol Absorption
• Example: Ezetimibe
• Causes reduction of LDL levels.
Mechanism of Action
• Ezetimibe is a selective inhibitor of intestinal
absorption of cholesterol and phytosterols.
• It is effective even in the absence of dietary
cholesterol because it inhibits reabsorption of
cholesterol excreted in the bile.
Inhibitors of Intestinal Sterol Absorption
Clinical applications
• Primary hypercholesterolemia, it reduces LDL
by 18% and increase HDL
• Used in patients with phytosterolemia
DRUG COMBINATIONS
• Combined drug therapy is useful
• (1) when VLDL levels are significantly increased
during treatment of hypercholesterolemia with a
resin
• (2) when LDL and VLDL levels are both elevated
initially
• (3) when LDL or VLDL levels are not normalized with
a single agent
• (4) when an elevated level of Lp(a) or an HDL
deficiency coexists with other hyperlipidemias
DRUG COMBINATIONS
• Fibric Acid Derivatives & Bile Acid–Binding Resins
• This combination is sometimes useful in treating
patients with familial combined hyperlipidemia who
are intolerant of niacin or statins.
• HMG-CoA Reductase Inhibitors & Bile Acid–Binding
Resins
• Useful in the treatment of familial
hypercholesterolemia but may not control levels of
VLDL in some patients with familial combined
hyperlipoproteinemia.
DRUG COMBINATIONS
• Niacin & Bile Acid–Binding Resins
• This combination effectively controls VLDL levels
during resin therapy of familial combined
hyperlipoproteinemia or other disorders involving
both increased VLDL and LDL levels.
• The drugs may be taken together, because niacin
does not bind to the resins. LDL levels in patients
with heterozygous familial hypercholesterolemia
require daily doses of up to 6 g of niacin with 24–30
g of resin.
DRUG COMBINATIONS
• Niacin & Reductase Inhibitors
• This regimen is more effective than either agent
alone in treating hypercholesterolemia.
• Reductase Inhibitors & Ezetimibe
• This combination is highly synergistic in treating
primary hypercholesterolemia and has some use
in the treatment of patients with homozygous
familial hypercholesterolemia who have some
receptor function.
