Pharm Antihyperlipidemics

Niacin is associated with facial flushing as its most common adverse effect.

Learning objective: describe the adverse effects of HMG-CoA reductase inhibitors.
Answer: E
The patient was most likely affected by myopathy, a rare but serious adverse effects of statins.
The disorder occurs in >0.1% of patients when statins are given alone, but can occur more
often when they are given together with niacin or fibrates (up to 5%, when given with
gemfibrozil). Myopathy can cause rhabdomyolysis with myoglobinuria, like in the present case.
A, B, C, D) These drugs do not cause myopathy.

Learning objective: describe the site of action of HMG-CoA reductase inhibitors
Answer: C
All HMG-CoA reductase inhibitors, like lovastatin acts by inhibiting the enzyme which is located
on the liver endoplasmic reticulum. Therefore liver cell cytosol is the main site of action of these
drugs.
A, D) These drugs act on plasma enzymes.
B) Aspirin inhibits thromboxane synthesis on platelets.
E) Ezetimibe acts on intestinal brush cell border.
F) Metoprolol acts on receptors located on cell membranes.

Learning objective: describe the mechanism of action of ezetimibe.
Answer: E
Ezetimibe inhibits the absorption and of cholesterol by the small intestine, apparently by
blocking a specific sterol transporter named Niemann-Pick C1-like 1 (NPC1L1) located on the
epithelial cells of intestinal mucosa.
A, B, C, D) (see explanation above)

Learning objective: describe the main drug interactions with ezetimibe
Answer: B
Ezetimibe lowers serum cholesterol concentration by selectively inhibiting the absorption of
cholesterol from the small intestine. It has a modest cholesterol lowering effect when used
alone, but the combination with HMG-reductase inhibitors can reduce LDL-cholesterol levels up
to 70%.
A) The risk of statins induced myopathy is not affected by the concomitant administration of
ezetimibe (it is worth to note that the risk is increased by the concomitant administration of
fibrates or niacin).
C, D) Ezetimibe does not affect the pharmacokinetics of lovastatin.
E) Ezetimibe does not increase appreciably the HDL-rising effect of lovastatin

Gemfibrozil is the correct answer because it activates a nuclear transcription receptor. This drug is classified as a fibric acid derivative and works by activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), which regulates the expression of genes involved in lipid metabolism. By activating this receptor, gemfibrozil helps to decrease triglyceride levels and increase HDL cholesterol levels in the blood.

Learning objective: describe the mechanism of action of HMG-CoA reductase inhibitors
Answer: C
HMG-CoA reductase inhibitors inhibit the hydroxy-methylglutaryl-CoA reductase, which is the
enzyme that catalyzes the synthesis of mevalonic acid from hydroxy-methylglutaryl-CoA. The
formation of mevalonic acid is the rate-limiting step in cholesterol biosynthesis.
A) The statin-induced inhibition of cholesterol synthesis in liver results in an up-regulation of
hepatic high-affinity LDL receptors which in turn causes an increased removal of LDL from the
blood
B) Statins have no effect on lipoprotein lipase.
D) The LDL removed from the blood fuse together in the liver, so forming larger vesicles called
endosomes. Since removal of cholesterol from blood is increased by statins, also storage of
LDL in hepatic endosomes will be increased, not decreased.
E, F) Statins can increase the plasma levels of hepatic aminotransferase and creatine
phosphokinase but this is a sign of potential toxicity, not of therapeutic efficacy of these drugs.

Learning objective: describe the clinically relevant drug interactions with niacin.
Answer: C
The cutaneous vasodilation and uncomfortable flushes are adverse effects that most persons
experience after each dose of niacin. They seem mainly prostaglandin-mediated and therefore
an aspirin (or another NSAID) can alleviate the flushing in many patients. Since these effects
undergo rapid tolerance aspirin is needed only during the first days of therapy.
A) There is no rationale for the use of warfarin. In fact niacin can cause a substantial reduction
of circulating fibrinogen levels, which actually reduces the risk of thrombosis.
B) There is no rationale for the use of atropine. Moreover the drug would worsen the
cholestyramine induced constipation.
D) Prazosin would increase the niacin induced vasodilation.
E) Gemfibrozil is used only in case of hypertriglyceridemia. In this patient triglyceride levels are
normal.

Learning objective: describe the antihyperlipidemic effects of cholestyramine.
Answer: C
Type II hyperlipoproteinemia is characterized by an elevation of LDL which may be primary or
secondary. Statins are currently used in this disease but the physician avoided them in this
case because of the patient is a woman in fertile age. Bile acid binding resins increase the
intestinal elimination of bile acids. This increased elimination causes an up-regulation of
hepatic LDL receptors which in turn reduces the plasma level of LDL.
A, B, D, E) These compounds are not consistently affected by bile acid binding resins.

Learning objective: describe the main contraindications of niacin.
Answer: B
Niacin is contraindicated in patients suffering from gout and hyperuricemia because it tends to
increase uric acid levels.
A) Cholestyramine could be appropriated in this patient since he has an isolated increase of
LDL.
C, D) Statins are effective in all disorders involving elevated levels of LDL.
E) Fibrates are useless (reduction of LDL is usually negligible) but not contraindicated in this
patient.

Learning objective: describe the main site of action of cholestiramine.
Answer: B
Cholestyramine is an acid-binding resins. These drugs act by binding bile acids and similar
steroids in the small intestine so preventing reabsorption of bile acid secreted by the liver. In
this way they increase the need of cholesterol by the liver which in turn induces an up
regulation of liver LDL receptors.
A, C, D, E) (see explanation above)

Cholestyramine is a drug that is known to sometimes cause hypertriglyceridemia. Hypertriglyceridemia is a condition characterized by high levels of triglycerides in the blood. Cholestyramine works by binding to bile acids in the intestine, which helps to lower cholesterol levels. However, one of the potential side effects of cholestyramine is an increase in triglyceride levels. Therefore, it is important to monitor triglyceride levels when using this medication.

Learning objective: explain the mechanism of action of niacin.
Answer: A
Niacin inhibits VLDL production by the hepatocyte, which in turn decreases production of LDL.
The mechanism of this action is still uncertain but seems to involve:
a) A decreased synthesis of triglycerides by the liver.
b) An inhibition of lipolysis in adipose tissue that in turn causes a decreased delivery of free
fatty acids to the liver.
c) A stimulation of lipoprotein lipase activity which enhances hydrolysis of VLDL and enhanced
delivery of triglycerides to adipose tissue.
B) Niacin actually increases the synthesis of HDL by the liver.
Niacin can cause hyperuricemia in about 20% of patients by an unknown mechanism.
D) Niacin actually inhibits lipolysis of triglycerides by hormone sensitive lipase in adipose tissue.
C) Niacin actually causes a substantial reduction of fibrinogen levels, which can be of value in
case of of atherosclerosis or thrombosis.
E) Niacin has negligible effects on exogenous cholesterol absorption.

Learning objective:: describe the adverse effects of cholestyramine.
Answer: E
The symptoms and signs of the patient indicate that he is suffering from metabolic acidosis
most likely due to cholestyramine overdose. A very high dose of cholestyramine can cause
metabolic acidosis mainly in patients at risk as in the present one, who is prone to metabolic
acidosis because of diabetes.
Cholestyramine is an anion exchange resin that binds negatively charged bile acids. Chloride is
released from binding sites in exchange from bile acids, so chloride anions can be absorbed.
When an anion other than bicarbonate is increased in plasma, HCO3- must decrease in order
to maintain electroneutrality. A reduced plasma bicarbonate concentration is defined acidosis.
Since in this case acidosis is due to an increase in chloride anion, it is named hyperchloremic.
B) Insulin protects diabetic patients from ketoacidosis so, in this case, one can suspect that an
insufficient insulin dosage or an inappropriate diet were likely contributing factors.
A, C, D) These drugs do not cause or trigger metabolic acidosis.

Learning objective: describe the site of action of gemfibrozil.
Answer: B
Fibrates bind to and activate a nuclear receptor (the peroxisome proliferator-activated receptor
alpha) in hepatocytes, skeletal muscle and the heart. Activation of this receptor in turn activates
transcription of genes which modulate protein expression. The main consequence is the
increased expression of lipoprotein lipase.
A, C, D, E, F) (see explanation above)

Learning objective: describe the antihyperlipidemic effects of niacin
Answer: D
Low HDL level is a predictor of increased coronary artery disease (CAD), independent of all
other risk factors. Therefore it is important to raise HDL, even if the other lipid fractions are
normal, especially if the patient has other risk factors for (CAD), like in the present case.
Main factors that are correlated with low HDL include cigarette smoking, obesity, androgenic or
related steroids, hypertriglyceridemia and genetic factors. Some lipid-lowering drugs can raise
HDL even if other lipid parameters are in the normal range, as in the present case. Niacin (by
an unknown mechanism) has the greatest ability to raise HDL, up to 30% and is therefore the
drug of choice in disorders associated with extremely low serum levels of HDL (these patients
ten to have premature atherosclerosis and the low HDL level may be the only identified risk
factor)
A) Gemfibrozil can raise HDL up to 10%.
B) Statins can raise HDL up to 10%
C, E) Resins and Ezetimibe have little effect on HDL.

Cholestyramine is an antihyperlipidemic drug that can cause metabolic acidosis when taken in high doses.

Learning objective: describe the main drug interactions with cholestyramine.
Answer: D
Cholestyramine is an anion exchange resin which binds bile acids in the intestinal lumen so
preventing their reabsorption. In fact the excretion of bile acid is increased up to tenfold when
the resin is given. This in turn causes an enhanced conversion of cholesterol to bile acids in the
liver, an increased uptake of LDL and IDL from plasma and an up-regulation of high-affinity
LDL receptors on cell membranes. Resins can bind many drugs (including beta-blockers and
thiazides) so reducing their intestinal absorption.
A, B, E, F) Cholestyramine does not affect the distribution or the elimination of drugs given
concomitantly.
C) Intestinal absorption of propranolol is actually decreased and therefore the oral
bioavailability is decreased, not increased.

Learning objective: explain the mechanism of action of gemfibrozil.
Answer: D
The prescribed drug was most likely a fibrate. In fact fibrates are the drugs of first choice when
there is a big, isolated increase in triglyceride level. Moreover in this patient niacin is
contraindicated because of hyperuricemia, resins can cause an increase in triglyceride level
and statins should be avoided in a woman in fertile age. The major mechanism of action
recognized for fibrates is to increase the synthesis of lipoprotein lipase.
A) Synthesis of lipids in adipose tissue is nearly undetectable in humans.
B) The antihyperlipidemic agents tend to cause an up-regulation, not a down-regulation, of LDL
receptors.
C) Statins, not fibrates, inhibit HMG-CoA reductase activity in the liver.
E) Fibrates have no effect on absorption of exogenous cholesterol.

Learning objective: describe the main contraindications of cholestyramine
Answer: B
Cholestyramine can cause severe constipation and is therefore contraindicated in case of
hemorrhoids. In addition the drug is also contraindicated in case of any coagulation defect,
since it decreases the intestinal absorption of vit K.
A, C, D, E) (see explanation above)