Dr. drg. Nur Permatasari, MS.

dr. Dian Nugrahenny, M.Biomed.

LIPID
 Lipids are necessary for human life
 Cholesterol
 Essential component of cell membrane
 Precursor to the sterol and steroid compounds
 Triglycerides (TG)
 Composed of 3 fatty acids and glycerol
 Main storage form of fuel, generate high-energy
compound such as ATP, that provides energy for
muscle contraction and metabolic reactions
Hyperlipidemia and Hyperlipoproteinemia

 Hyperlipidemia: an elevation of one or more of

cholesterol, cholesterol esters, phospholipids, or
triglycerides.
 Hyperlipoproteinemia: an increased concentration of the
lipoprotein macromolecules that transport lipids in the
plasma.
 The density of plasma lipoproteins is determined by their
relative content of protein and lipid.
 Hypercholesterolemia, elevated LDL, and low HDL are
unequivocally linked to increased risk for coronary heart
disease and cerebrovascular morbidity and mortality
 LDL is the primary target
 Lipoprotein
Metabolism
1. Exogenous/
chylomicron
pathway
(dietary fat)
2. Endogenous
pathway
(lipids
synthesized by
the liver)
HDL Metabolism and Reverse Cholesterol Transport
DYSLIPIDEMIA

Dyslipidemia can be primary or secondary.

The primary forms are genetically determined
Secondary forms are a consequence of other conditions
such as diabetes mellitus, alcoholism, nephrotic syndrome,
chronic renal failure, administration of drug.
Lipid Lowering Drugs
 HMG-CoA
reductase
inhibitors

Low-Density Lipoprotein
(LDL) Cholesterol High-Density Lipoprotein (HDL) Total Triglyceride
Therapy Concentration Cholesterol Concentration Concentration Other Effects

HMG-CoA ↓20-50% ↑10% ↓10-40% Increase in

reductase hepatic LDL
inhibitors receptors.

It's postulated that one mechanism by which statins decrease triglycerides is through the
stimulation of lipoprotein lipase
 HMG-CoA Reductase inhibitors

Adverse effects
Abdominal cramps, constipation, diarrhea, heartburn
Elevate serum levels of hepatic enzymes
Liver transaminases (ALT and AST) should be checked before
starting therapy, at 8 weeks, and then every 6 months.
Severe myopathy (myalgia, myositis) and even rhabdomyolysis 
rarely.
The risk of myopathy is increased by the presence of renal
insufficiency and by coadministration of drugs that interfere
with the metabolism of HMG-CoA reductase inhibitors, such
as erythromycin, antifungal agents, immunosuppressive drugs.
Niacin
 It's a water-soluble B complex vitamin commonly found in plant
and animal foods.
 Mechanisms of Action:
 Niacin inhibits triglyceride in VLDL synthesis by:
 Decreasing the supply of nonesterified fatty acids going from
adipose tissue to the liver,
 Decreasing hepatic esterification of triglycerides.
 Niacin inhibit lipolysis with a decrease in free fatty acids in
plasma.
 Niacin have possible direct effect on the hepatic production of
apolipoprotein B.
 Niacin also increases HDL by reducing its catabolism.
 At 2 to 3 grams/day: 5% to 25% reduction in LDL cholesterol, 20%
to 50% reduction in triglyceride, and a 15% to 35% increase in HDL.
Niacin
 Frequent side effect and a major problem: prostaglandin-
mediated skin flushing.
Reduce flushing:
Start at a low dose and taken with meals to delay
absorption. Dose should be increased every 4 to 7 days.
Taking an aspirin 30 min prior to the niacin.
Use the extended-release niacin.
 Adversely affects glycemic control in type 2 diabetic
patients.
 Elevated liver function tests (mild, 15% of patients),
hyperuricemia, and hyperglycemia  laboratory tests
before and after 1 month therapy.
Niacin
 Niacin potentiates the effect of warfarin, and these two
drugs should be prescribed together with caution.
 Acanthosis nigricans and maculopathy are infrequent side
effects of niacin.
 Niacin is contraindicated in patients with peptic ulcer
disease and can exacerbate the symptoms of esophageal
reflux.

Achantosis nigricans
Bile Acid Resin/Sequestrants
 The primary action of BARs is to bind bile acids in the
intestinal lumen, with a concurrent interruption of
enterohepatic circulation of bile acids and a markedly
promote their excretion in the feces.
 This decreases the bile acid pool size and stimulates hepatic
synthesis of bile acids from cholesterol.
 Depletion of the hepatic pool of cholesterol results in:
 An increase in cholesterol biosynthesis, and
 An increase in the number of LDL receptors on the
hepatocyte membrane.
 The increased number of receptors stimulates an enhanced
rate of catabolism from plasma and lowers LDL levels.
Bile Acid Resin/Sequestrants

 BARs may aggravate hypertriglyceridemia in patients

with combined hyperlipidemia.
 Activation of phosphatidic acid phosphatase promotes
hepatic TG synthesis, induces secretion of TG-rich, very
low density lipoprotein particles, and consequently,
increases plasma TG levels.
Bile Acid Resin/Sequestrants

 Bile acid sequestrants are not systemically absorbed and

are very safe.
 Cholesterol-lowering drug of choice in children and in
women of child-bearing age who are lactating, pregnant,
or could become pregnant.
Bile Acid Resin/Sequestrants
Adverse Effects
Gastrointestinal complaints of constipation, bloating, epigastric fullness,
nausea, and flatulence are reported most commonly.
These adverse effects can be managed by increasing the fluid intake,
modifying the diet to increase bulk, and using stool softeners.
Hypernatremia and hyperchloremia, gastrointestinal obstruction,
Impaired absorption of fat-soluble vitamins A, D, E, and K,
Reduced bioavailability of acidic drugs such as coumarin anticoagulants,
digitoxin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone,
hydrochlorothiazide, loperamide, and possibly iron.
All other medications should be taken either 1 h before or 4 h after the
bile acid sequestrants.
Fibrates
 Fibrates are agonists for PPAR alpha.
 3 major effects of PPAR alphas on triglyceride:
 Increase in secretion of Apo A-1.
 Increase in lipoprotein lipase, which catalyzes a
breakdown of TG component of chylomicrons in VLDL.
 Inhibition of the synthesis in secretion of Apo C-III.
 Apo C-II stimulates lipoprotein lipase.
 Apo C-III inhibits of lipolysis catalyzed by lipoprotein
lipase.
Fibrates

 Fibrates are generally very well tolerated.

 Most common side effect: dyspepsia.
 Myopathy and hepatitis occur rarely in the
absence of other lipid-lowering agents.
PHARMACOLOGIC THERAPY

 Initial therapy for any lipoprotein disorder is therapeutic

lifestyle changes with restricted intake of total and
saturated fat and cholesterol and a modest increase in
polyunsaturated fat intake, along with a program of
regular exercise and weight reduction if needed.

 Low HDL cholesterol is addressed with lifestyle

modifications such as smoking cessation and increased
exercise; niacin and gemfibrozil can increase HDL
cholesterol significantly as well.
PHARMACOLOGIC THERAPY

 If pharmacologic therapy is insufficient after therapeutic

lifestyle changes, lipid-lowering agents should be chosen
based on the specific lipoprotein disorder presentation and the
severity of the lipid abnormality.

 Primary hypercholesterolemia is treated with the bile acid

resins (BARs) or sequestrants (colestipol, cholestyramine, and
colesevelam), HMG-CoA reductase inhibitors (statins), niacin,
or eztimibe.

 Of these choices, statins are first choice because they are the
most potent LDL-lowering agents.
PHARMACOLOGIC THERAPY

 Considering compliance, adverse effects, and effectiveness,

statins are the drugs of choice for patients with
hypercholesterolemia because they are the most potent form
of monotherapy and are cost-effective in patients with known
coronary artery disease (CAD) or multiple risk factors and in
high-risk primary prevention patients.

 Patients not responding to statin monotherapy may be

treated with combination therapy for hypercholesterolemia
but should be monitored closely because of an increased risk
for adverse effects and drug interactions.
PHARMACOLOGIC THERAPY

 Hypertriglyceridemia should be treated by achieving desirable

body weight, consumption of a low saturated fat and
cholesterol diet, regular exercise, smoking cessation, and
restriction of alcohol.

 Hypertriglyceridemia usually responds well to niacin,

gemfibrozil, or high-dose/potency statins (e.g., atorvastatin or
simvastatin).
 Niacin should be used cautiously in diabetics because of
worsening glycemic control.
 Fibrates may increase LDL, and their use in borderline high
triglyceridemia requires careful.