LIPID LOWERING AGENTS
These drugs lower (LDL) lowdensity lipoprotein cholesterol
concentrations. This can prevent
formation, slow progression and
cause regression of artherosclerotic
plaques.
Serum Cholesterol
• Required for production of steroids, bile acids,
and cellular membranes. Synthesized in the
liver. Main lipid associated with CAD.
• Transported by Lipoproteins: 75% bound to
LDL 25% bound to HDL
• Increased in hyperlipidemia,
hypercholesterolemia, hypothyroidism,
uncontrolled DM, HTN, MI, CAD, and
biliary cirrhosis.
Stages of High Risk Groups
• Stage I - People with existing vascular
disease
• Stage II - A family hx of cardiovascular
disease in first degree relatives under 60
yrs.
• Stage III- Familial hypercholesterolemia
• Stage IV- Diabetes Mellitus
Lipoproteins, Triglycerides,
Apolipoproteins, and CAD
• LDL: low-density-lipoproteins.
• HDL: high-density-lipoproteins
• VLDL: very-low-density-lipoproteins ;
Triglycerides are carried in plasma this way.
• APOLIPOPROTEINS: Protein constituents
of lipoprotein.
• High LDL, VLDL, Apolipoprotein B(the
structural protein of LDL), and Low HDL
increase the risk of CAD.
INDICATIONS FOR TX
• People with a total cholesterol >240mg/dl have
a 5 times greater risk of having artherosclerotic
disease than people with a TC <200mg/dl
• Change in diet should be the primary mode of
tx unless there are contraindications, meds are
secondary mode of prevention.
• TC >350-400 is usually due to genetics. These
patients present clinically with xanthomas, and
must be tx with medications.
MAJOR CLASSES OF LIPID
LOWERING AGENTS
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HMG CoA REDUCTASE INHIBITORS
BILE ACID BINDING RESINS
FIBRATES
NICOTINIC ACIDS
ESTROGEN
OTHERS
HMG CoA REDUCTASE
INHIBITORS
OVERVIEW
• Statins are the most effective and
widely used class of lipid lowering
agents.
• At this time there are 6 HMG CoA
reductase inhibitors available
Statin drugs
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Generic Names
Atrovastin
Cerivastin
Fluvastin
Lovastin
Pravastatin
Simvastin
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Brand Names
Lipitor
Baycol
Lescol
Mevacor
Pravachol
Zocor
Mechanism of Action
• Inhibition of hepatic HMG CoA reductase, the rate
limiting enzyme in cholesterol biosynthesis.
• This reduces the cholesterol in hepatic cells, and
stimulates the synthesis of LDL receptors thereby
increasing the uptake of LDL cholesterol into the
cell.
• End result is a reduction of plasma LDL,VLDL,
and triglyceride concentration and an increase in
HDL concentrations.
Therapeutic Uses
• Statins lower elevated levels of LDL and
total cholesterol. They also reduce levels of
triglycerides and increase HDL cholesterol.
• Slows the progression of CAD, decreases
the number of cardiac events, and reduce
mortality.
• Reductions are significant with 2 weeks and
maximal within 4 to 6 weeks.
Adverse Effects
• Side effects are uncommon
• mild, transient gastrointestinal disturbances,
muscle pain, rash and headache have occurred.
• Hepatoxicitiy :
• *1-2% of patients treated one year or longer
• *increased serum transaminases (ALT , AST)
• *Assess LFT’s before use and 6 to 12 weeks for
the next 12 months
Cont’d
• Myopathy:
• * severe myalagia and muscle weakness with increases in serum CPK
levels
• *rarely, severe rhabdomyolysis and myoglobinuria leading to renal
failure have occurred.
• *risk highest with Lovastatin and simvastatin especially when
combined with gemfibrozil, nicotinic acid, cyclosporine, erythromycin,
or ketoconazole.
• Neurological
• *dysfunction of certain nerves, tremor, vertigo, memory loss,
paresthesia, peripheral neuropathy, anxiety, insomina and depression
• Reproductive:
DOSAGES
DRUGS
Atrovstatin
(Lipitor)
Cerivastin
(Baycol)
Fluvastatin
(Lescol)
Lovastatin
(Mevacor)
Pravastatin
(Pravachol)
DOSAGE
LDL
Initial: 10mg/day
MAX: 80mg/day
Initial : 0.3mg/day
MAX: 0.3mg/day
Initial: 20mg/day
MAX : 40mg/day
Initial: 20 mg/day
MAX: 80mg/day
Initial: 20mg/day
MAX : 40mg/day
DECREASE
35-40%
50-60%
30%
30%
20-25%
30-35%
25-30%
30-35%
25-30%
30-35%
COST/
MONTH
$56.36
$209.88
$39.60
$39.60
$37.70
$75.27
$69.85
$251.48
$64.95
$107.77
BILE ACID-BINDING RESINS
• OVERVIEW:
• Cholesterol is the major precursor of bile
acids.
• During normal digestion, bile acids are
secreted via the bile from the liver and
gallbladder into the intestines to emulsify
the fat and lipid materials in food, thus
facilitating absorption.
• A major portion of the bile acids secreted
are reabsorbed from the intestines and
returned via the portal circulation to the
liver, completing the enterohepatic cycle.
MECHANISM OF ACTION
• Following ingestion , bile acid sequestering resins
bind bile acids in the intestine to form an insoluble
complex that is excreted in the feces.
• The complex prevents the reabsorption of bile
acids, and thereby accelerates their excretion.
• Since bile acids are normally reabsorbed, this
increases the demand for synthesis which takes
place in the liver.
• The increased fecal loss of bile acids leads the
Cont’d
• Liver cells to obtain increased cholesterol supply.
• In order to increase bile acid production, cholesterol is
required and is obtained from the supplied LDLcholesterol.
• These drugs increase hepatic synthesis of cholesterol,
by increasing their number of LDL receptors and also
increases their capacity for LDL uptake.
• The result is an increase in LDL absorption from
plasma and a decrease in the LDL levels of blood.
Examples
• Cholestyramine (Questran, Questran Lite,
Prevalite)
• Colestipol (Colestid)
Therapeutic uses
• Bile acid-binding resins, are preferred drug
for lowering elevated LDL levels in
conjunction with diet can produce 15-20%
reduction in LDL cholesterol levels.
• In addition, a combination with nicotinic
acid, it can further reduce to a total of 50%
reduction.
Adverse effects
• The bile acid binding resins are not absorbed from
the G.I. Tract
• constipation is the principal undesired response
• other G.I. Effects include bloating, indigestion,
and nausea
• rarely, these resins decrease fat absorption and
may thereby decrease uptake of fat soluble
vitamins (A, D, E, and K)
Drug Interactions
• These drugs can form complexes with other
drugs.
• Drugs known to form complexes are
thiazide, diuretics, digoxin, warfarin, and
some antibiotics.
• To reduce formation of complexes, oral
medications should be administered either
1hour before the resin or 4 hours after.
Indications
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Diarrhea
hypercholesteremia
hyperlipoproteinemia
pruritus
Dosages
• Cholestyramine (Questran, Questran Lite) is
dispensed in powdered form
• Usual dosage is 4-12grams twice a day.
• patients should be instructed to mix the
powder with fluid, such as water, milk, fruit
juice, and soups
• pulpy fruit juices (ex.applesauce ) may be
used
Contraindications
• Cholestyramine is contraindicated in patients with
cholelithasis, biliary obstruction because in these
conditions secretion of bile acids into G.I. Tract is
impaired.
• Also contraindicated is for patients with primary biliary
cirrhosis because it can further raise serum cholestrol
• relatively contraindicated for constipated patients due to
danger of fecal impaction and patients with coronary
heart disease or hemorrhoids because constipation it can
aggravate the condition.
Cont’d
• Because cholestyramine can bind with Vitamin K, its
relatively contraindicated in patients with preexisting
coagulopathy (ex. Hemophilia)
• Cholestyramine is absolutely contraindicated in
phenylketonuria because the sugar-free preparation is
sweetened with asparatame, which contains phenylalaine.
• Relatively contraindicated for patients with renal disease.
• Cholestyramine is not absorbed systemically and is
therefore not expected to cause fetal harm during
pregnancy.
Indications
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Diarrhea
digitoxin overdose
digitoxin toxicity
digoxin overdose
hypercholesterolemia
pruritus
Dosages
• Administered orally as tablets or as a
suspension.
• To minimize drug interactions, administer
other drugs at least 1 hour before or at least
4 hours after colestipol
• tablets: do not cut, crush or chew tablets.
• Administer with a full glass of water.
FIBRATES
• They reduce triglyceride production and
remove triglycerides from circulation.
• The triglyceride lowering effect is often
associated with an increase in HDL
cholestrol.
• Fibrates include: Gemfibrozil (Lopid),
Fenofibrate (Tricor), Clofibrate (Atromid-S)
MECHANISM OF ACTION
• The mechanism by which gemfibrozil lowers
VLDL is not known
• It decreases lipolysis in adipose tissue and reduces
uptake of fatty acids by the liver.
• Both actions can decrease hepatic synthesis of
triglycerides.
• Gemfibrozil inhibits the synthesis and increases
the clearance of apolipoprotein B, a carrier
molecule for VLDL.
THERAPEUTIC USES
• The principal indication for gemfibrozil is
elevation of plasma triglycerides (VLDLs).
• Treatment is limited to patients who have
not responded adequately to weight loss and
diet modification.
• Statins and bile acid-binding resins are
more effective therapy.
ADVERSE EFFECTS
• Clofibrate and Gemfibrozil have pharmacological
similarities, the adverse findings with clofibrate may
also apply to gemfibrozil
• GI: choleliathiasis, pancreatitis, hepatoma, colitis
• CNS: dizziness, somnolence, peripheral neuritis,
decreased libido, depression, headache, confusion,
convulsions, syncope
• Cardiovascular: intracerebral hemorrhage, peripheral
vascular disease, extrasystole.
Cont’d
• Hepatoxic: can disrupt liver functions and
may also present a risk of liver cancer.
Periodic liver functions tests are required.
• Skeletal muscle effects: concomitant
therapy gemfibrozil and lovastatin has been
associated with rhabdomyolysis, markedly
elevated CPK levels and myoglobinuria
leading to acute renal failure.
CONTRAINDICATIONS
• Hepatic or severe renal dysfunctions
including primary biliary cirrhosis ,
preexisting gallbladder disease
• hypersensitivity to gemfibrozil
• pregnancy (category C)
• use with caution in patients taking statins.
DOSAGE
• Gemfibrozil (Lopid) is administered orally
30 minutes before breakfast and dinner.
• Adult dosage includes 600 mg PO bid
Overview
• Estrogen was first noticed as a possible lipid
lowering agent due to the low incidence of
artherosclerosis in females of childbearing
age.
• It was also noticed that post-menopausal
women were at equal risk for cardiovascular
disease as their male counterparts.
Mechanism of Action
• Diethylaminoethylether of estradiol is a
potent inhibitor of desmosterol reduction.
• Estrogen reduces hepatic cholesterol
synthesis and the incorporation of acetate
into cholesterol by increasing the
cholesterol content of bile and decreasing
the content of bile acids.
• Estrogen reduces plasma LDL, elevates
plasma HDL and elevates VLDL.
Therapeutic Uses
• Tx of Choice in post-menopausal women in
order to reduce LDLby 15-25% and
increase HDL by 10-15%.
• Estrogen not usually given to men due to
intolerable adverse effects.
Adverse Effects
• Variable hypercholesterolemic effect.
• Will exacerbate preexisting high VLDL’s
and further increase TC.
• In males: gynecomastia, decrease in libido,
decrease potency and penile irritation.
• Estrogen causes thromboembolic events ;
high levels increase rate of non-fatal MI due
to embolism and thrombophlebitis.
• Aggravates Types IV & V
Contraindications & Dosages
• In post-menopausal women 0.625 mg/day
PO once a day decreases LDL by 15-25%
and increases HDL by 10-15%.
• May increase the risk of gall bladder stones,
endometrial ca (if administered w/out
progestin), contraindicated for smokers and
women with hx of DVT.
Indications
• Hyperlipoproteinemia
• Hypertriglyceridemia
• Peripheral Vascular Disease
Mechanism of Action
• Unknown but unrelated to chemical role as
a vitamin.
• May decrease hepatic synthesis of LDL,
VLDL, lipolysis, and free fatty acid release
from tissue.
• Greater hypolipidemic response in women
than men. LDL reduced 40-60% w/in 7
days. VLDL reduced 20-40% w/in 4 days.
HDL increased 20%
Examples and Adverse Effects
• Niacin-regular release. (increases HDL)
• Niaspan-sustained release. (decreases LDL)
• Causes: peripheral vasodilationw/ cutaneous
flushing and warmth of upper body.
• Dizziness, pruritis, GI upset, nausea,
hyperglycemia, hyperuricemia, elevated
hepatic enzymes.
Contraindications
• Hepatic dysfunction, active peptic ulcer,
severe hypotension, hemorrhaging, arterial
bleeding.
• Minimize adverse effects with pretreatment
of aspirin 325 mg or ibuprofen 200 mg.
Administration and Dosages
• REGULAR RELEASE
• Peripheral Vascular disease: Adults 100-150
mg PO 3-5 times a day
• Hyperlipoproteinemia: Adults 1-2g PO 3
TID w/ meals. Initial doses should be small
w/ gradual increases every 4-10 days.
• Children: Initially 100-250 mg PO per day
w/ meals can increase gradually, re-evaluate
w/ ech. 500mg dose increment.
Fish Oils (Omega 3 Fatty Acids)
Indicated for hypertriglyceridemia. Studies
suggest they: inhibit secretion of VLDL,
decrease synthesis of thrombi, retard
growth of artherosclerotic plaques by
inhibiting growth factors and monocyte
migration into the intima.
Flavanoids (Tea, Red wine,
Beer, Fruits)
Indicated for hyperlipoproteinemia. There is
growing evidence that CHD events can be greatly
reduced by specific dietary supplements. Future
tx and prevention of artherosclerosis may include
targeted interventions designed to modulate
activity of vascular cell adhesion molecules
involved in inflammatory and autoimmune
disorders such as DM.