Hyperlipidemic drugs

Question 1

ANTIHYPERLIPIDEMIC DRUGS?

Answer 1

• HMG-CoA reductase inhibitors
• Niacin
• Bile acid-binding resins
• Fibrates
• Cholesterol absorption inhibitors

Question 2

STATINS: MECHANISM OF ACTION?

Answer 2

• Statins are analogs of 3-OH-3-methylglutarate
(HMG).
• Statins are competitive inhibitors of HMG-CoA
reductase, the enzyme that catalyzes the first
committed step of cholesterol biosynthesis.
• By inhibiting cholesterol synthesis statins deplete intracellular supply of cholesterol.
• Depletion of intracellular cholesterol leads to upregulation of HMG-CoA reductase, and upregulation
of the LDL receptor.
• Upregulation of LDL receptors results in increased clearance of LDL from the blood.

Question 3

Statin efficacy and order of potency?

Answer 3

• Statins are more effective than other drugs in
lowering LDL.
• They also cause a decrease of plasma TG and a
small increase in HDL.
• Rosuvastatin is the most potent statin in lowering
LDL.
• Atorvastatin is the next most potent, followed by
simvastatin.
• Lovastatin and pravastatin are similar in potency.
• Fluvastatin is the least potent.
• The potency of statins at lowering TG is similar to
their potency at lowering LDL.
• The largest TG reductions are seen with
rosuvastatin and atorvastatin.

Question 4

Statin uses?

Answer 4

• Drugs of choice for LDL reduction.
• Reduce cardiovascular mortality.
• Lower LDL levels in all types of hyperlipidemias.
• Homozygotes for familial hypercholesterolemia
lack functional LDL receptors and thus benefit
much less from treatment with statins.
• Contraindicated in pregnancy.

Question 5

WHO SHOULD BE TREATED WITH A STATIN

ACCORDING TO THE NEW GUIDELINES?

Answer 5

• Patients with ASCVD.
• Patients with LDL 190 mg/dL or higher.
• Patients age 40-75 years of age with diabetes and LDL 70-189 mg/dL.
• Patients without ASCVD or diabetes with LDL 70-189 mg/dL and an estimated 10-year risk of ASCVD of 7.5% or higher.

Question 6

OTHER EFFECTS OF STATINS?

Answer 6

• Improve endothelial function.
• Decrease platelet aggregation
• Stabilize atherosclerotic plaque.
• Reduce inflammation.

Question 7

STATINS: ADVERSE EFFECTS?

Answer 7

• Elevation of aminotransferases. Usually not associated with other evidence of liver toxicity.
• Myopathy and rhabdomyolysis. Rare. Rhabdomyolysis may cause myoglobinuria, leading to renal injury.

Question 8

What needs to be monitored with a statin?

Answer 8

• Aminotransferase activity should be measured
at baseline, at 1–2 months, and then every 6–12
months.
• CK should be measured at baseline. If muscle
pain, or weakness appears, CK should be
measured immediately and the drug
discontinued if activity is significantly elevated.

Question 9

Niacin’s actions?

Answer 9

• Niacin favorably affects virtually all lipid parameters.
• Decreases VLDL, LDL and Lp(a) levels.
• It increases HDL levels.
• Most effective agent for increasing HDL and the only agent that may reduce Lp(a).
• Niacin has many adverse effects which limit its use

Question 10

NIACIN: MECHANISM OF ACTION?

Answer 10

Niacin inhibits adenylyl cyclase in adipocytes. Leading to inhibition of hormone-sensitive lipase.
Decreased cAMP -> PKA inactive -> Hormone-sensitive lipase inactive
Transport of fatty acids to the liver is reduced. This
reduces liver TG synthesis.
In the liver niacin inhibits synthesis and esterification of fatty acids. VLDL production is decreased.
Niacin increases LPL activity.
• The catabolic rate for HDL is decreased → HDL
increases.

Question 11

Niacin uses?

Answer 11

• Niacin is the most effective drug for raising HDL.
• Particularly useful in patients with combined
hyperlipidemia and low HDL levels.
• Effective in combination with statins.

Question 12

Niacin AE?

Answer 12

• Intense cutaneous flush after each dose of
niacin when the drug is started or the dose
increased.
• Administration of aspirin prior to niacin
decreases the flush, which is prostaglandin mediated.
• Pruritus, rashes, dry skin.
• Acanthosis nigricans.
• Nausea and abdominal discomfort.
• Most serious adverse effects: hepatotoxicity
and hyperglycemia.
• Niacin-induced insulin resistance can cause
severe hyperglycemia.
• Niacin elevates uric acid levels and may
precipitate gout.

Question 13

Rare niacin AE?

Answer 13

• Rare adverse effects:
• Atrial arrhythmias
• Toxic amblyopia
• Toxic maculopathy

Question 14

Fibrate actions?

Answer 14

Gemfibrozil
Fenofibrate
• Fibrates lower VLDL levels and increase HDL
levels.

Question 15

Fibrate MOA?

Answer 15

• Fibrates activate peroxisome proliferatoractivated
receptor-alpha (PPAR-alpha).
• PPAR-alpha receptors are expressed primarily in
liver and brown adipose tissue.
• Activation of PPAR-α by fibrates leads to a
decrease in plasma TG levels and increase in
plasma HDL levels.
• The decrease in plasma TG levels is caused by
increased expression of lipoprotein lipase,
decreased hepatic expression of apoC-III, and
increased hepatic oxidation of fatty acids.
• Fibrates raise HDL.
• Fibrates may increase LDL, particularly if the TG
level is greater than 400 mg/dL.

Question 16

Fibrate uses?

Answer 16

• DOC in severe hypertriglyceridemia
• Reasonable consideration in moderate
hypertriglyceridemia.
• As monotherapy, fibrates offer the highest TG
reduction, followed by niacin, omega-3-fatty acids,
statins, and ezetimibe.

Question 17

Fibrate adverse effects?

Answer 17

• Mild GI disturbances.
• Myositis. Patients with renal insufficiency may be at
risk. Rhabdomyolysis has occurred rarely.
• Lithiasis. Fibrates increase biliary cholesterol
excretion, therefore they may cause gallstones.

Question 18

What are the fibrate drug interactions?

Answer 18

• Gemfibrozil inhibits hepatic uptake of statins, thus
increasing plasma concentration of statins.
• Gemfibrozil competes for the glucuronosyl
transferases that metabolize most statins.
• As a consequence, levels of both drugs may be
increased when they are co-administered. This
increases the risk of rhabdomyolysis.
• Fenofibrate does not inhibit statin metabolism, and
is much less likely to increase risk of
rhabdomyolysis.

Question 19

Describe bile binding resins?

Answer 19

Cholestyramine
Colestipol
Colesevelam
• Useful only in hyperlipidemias involving isolated
increases in LDL.
• In patients who have hypertriglyceridemia as well as elevated LDL levels, VLDL levels may increase.
• Insoluble in water.
• Large molecular weights (> 106): neither absorbed nor metabolized.
• Totally excreted in the feces.

Question 20

Bile acid binding resins MOA?

Answer 20

• Bind to anionic bile acids in the intestinal lumen
and prevent their reabsorption.
• The resin-bile acid complex is excreted in the
feces, thus preventing bile acids from returning
to the liver by the enterohepatic circulation.
• The reduction in bile acid concentration causes
hepatocytes to increase conversion of cholesterol
to bile acids.
• Consequently, intracellular cholesterol decreases.
• This leads to up-regulation of LDL receptors in
the liver.
• Liver uptake of LDL increases, leading to a
decrease in plasma LDL levels.
• This effect is partially offset by increased
cholesterol synthesis due to upregulationof
HMG-CoA reductase.
• HDL rises modestly.

Question 21

Bile acid binding resins uses?

Answer 21

• Used with statins or niacin to increase LDL
reduction.
• Drugs of choice for pregnant women and for
children.
• Little effect in individuals who completely lack
functional LDL receptors.

Question 22

BILE ACID-BINDING RESINS: ADVERSE EFFECTS?

Answer 22

• GI adverse effects: bloating, nausea, cramping
and constipation.
• Colesevelam produces fewer GI adverse effects
than cholestyramine or colestipol.
• They may increase TG: contraindicated in
hypertryglyceridemia.

Question 23

BILE ACID-BINDING RESINS drug interactions?

Answer 23

• Cholestyramine and colestipol reduce absorption

of several drugs and liposoluble vitamins.

Question 24

CHOLESTEROL ABSORPTION INHIBITORS action?

Answer 24

Ezetimibe
• Inhibits intestinal absorption of cholesterol and
phytosterols.
• Its primary clinical effect is to lower LDL.

Question 25

EZETIMIBE: MECHANISM OF ACTION?

Answer 25

• Ezetimibe inhibits an intestinal transport protein
(NPC1L1), which takes up cholesterol from the
lumen
• Cholesterol absorption is reduced by 54%.
• This triggers a compensatory increase in
cholesterol synthesis (which can be inhibited with
a statin).
• Reduced delivery of intestinal cholesterol to the
liver leads to upregulation of LDL receptors,
which enhances LDL clearance from plasma.
• The maximal efficacy of ezetimibe for lowering
LDL is about 15-20%.

Question 26

EZETIMIBE: USES?

Answer 26

• Useful in combination with a statin in patients
unable to reach their LDL goal on statin
monotherapy.
• First non-statin drug that should be considered
as an adjunct to a statin.
• Ezetimibe is only used as monotherapy in
patients who do not tolerate statins.

Question 27

Ezetimibe Adverse effects? Drug interactions?

Answer 27

• Low incidence of reversible impaired hepatic
function.
• Small increase in incidence when ezetimibe is
given with a statin.
• Myositis has been reported rarely.
• Bile-acid sequestrants inhibit absorption of
ezetimibe.
• The two agents should not be administered
together.

Question 28

ω-3 FATTY ACIDS effect?

Answer 28

• Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce TG synthesis and increase fatty acid
oxidation in the liver.
• HDL levels may modestly increase.
• Several prescription fish oil products have been
approved by the FDA.
• Indicated as an adjunct to diet to reduce TG
levels in adult patients with very high (> 500
mg/dL) TG levels.

Question 29

Lipid Profile- initial drug, additions
Elevated LDL
Elevated LDL and TG
Isolated low HDL
Isolated severe
hypertriglyceridemia

Answer 29

Elevated LDL - initial drug: Statin, Additions: Niacin, Resin,Ezetimibe

Elevated LDL and TG- initial drug: Statin, Additions: Niacin, Fibrate, omega-3 Fatty acid

Isolated low HDL- initial drug: statin, Additions: Niacin

Isolated severe hypertriglyceridemia- initial drug: Fibrate (or Niacin or omega-3 Fatty acid), Addition:Statin