Lecture 21: antihyperlipidimics

Question 1

Primary hyperlipidemia types

Answer 1

Question 2

ANTIHYPERLIPIDEMIC DRUGS

Answer 2

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

Question 3

HMG-CoA REDUCTASE INHIBITORS (Statins)

Answer 3

• Rosuvastatin is the most potent statinin lowering LDL.
• Atorvastatin is the next most potent,followed by simvastatin.
• Lovastat in and pravastatin are similar in potency.
• Fluvastatin is the least potent.

Question 4

STATINS: ADVERSE EFFECTS

Answer 4

• Elevation of aminotransferases. Usually not associated with other evidence of liver toxicity.
• Myopathy and rhabdomyolysis. Rare. Rhabdomyolysis may cause myoglobinuria, leading to renal injury.
• 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 5

WHO SHOULD BE TREATED WITH A STATIN ACCORDING TO THE NEW GUIDELINES?

Answer 5

• There are four major statin benefit groups:
• Patients with atherosclerotic cardiovascular disease (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

Niacin (Nicotinic acid)

Answer 6

• Niacin favorably affects virtually all lipid parameters.
• NIacin receptor activates Gai on adipocytes; require mg doses (high)
• Niacin activates Lipase -> 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

Uses

• 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.

Adverse

• 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.
• The most serious side effects are hepatotoxicity and hyperglycemia.
• Niacin should be used cautiously in patients with diabetes mellitus: niacin-induced insulin resistance can cause severe hyperglycemia.
• Niacin elevates uric acid levels and may precipitate gout.
• Rare adverse effects:
  
  • Atrial arrhythmias.
  • Toxic amblyopia.
  • Toxic maculopathy.

Question 7

Gemfibrozil, Fenofibrate

Answer 7

Fibrates lower VLDL levels and increase HDL levels.

MOA

• Fibrates activate peroxisome proliferator- activated receptor-α (PPAR-α).
• PPAR-α 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.

Only modest reductions of LDL occur in most patients.

In patients with combined hyperlipidemia, LDL often increases as TGs are reduced.

HDL increases moderately.

Uses

• DOC in severe hypertriglyceridemia
• Reasonable consideration in moderate hypertriglyceridemia.

Adverse

• 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.

Drug interactions

• 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 maybe increased when they are co-administered.
• This increases the risk of rhabdomyolysis. Exam Q
• Fenofibrate does not inhibit statin metabolism, and is much less likely to increase risk of rhabdomyolysis.

Question 8

Ezetimibe

Answer 8

CHOLESTEROL ABSORPTION INHIBITORS

Inhibits intestinal absorption of cholesteroland phytosterols.

Its primary clinical effect is to lower LDL.

MOA

• Ezetimibe inhibits an intestinal transport protein, 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 only about 15-20% when used as monotherapy.

Uses

• Useful in combination with a statin in patients unable to reach their LDL goal on statin monotherapy.
• Ezetimibe is only used as monotherapy in patients who do not tolerate statins.

Adverse

• Low incidence of reversible impaired hepatic function.
• Small increase in incidence when ezetimibe is given with a statin.
• Myositis has been reported rarely.

Drug interactions

• Bile-acid sequestrants inhibit absorption of ezetimibe.
• The two agents should not be administered together.

Question 9

ANTIHYPERLIPIDEMIC DRUGS IN PREGNANCY

Answer 9

• Statins: absolutely contraindicated in pregnancy. Category X.
• Fibrates: Category C.
• Niacin: Category C.
• Ezetimibe: Category C.
• Cholestyramine & colestipol: might interfere with absorption of nutrients. Category C.
• Colesevelam: Category B. Should be used during pregnancy only if clearly needed.

Question 10

LOVAZA

Answer 10

• FDA-approved ω-3-product.
• Ethyl esters of ω-3fatty acids.
• Adjunct to diet to reduce TG levels in adult patients with very high (> 500 mg/dL) TG levels.

Question 11

SUGGESTED DRUG THERAPY FOR DYSLIPIDEMIAS

Answer 11

only Isolated severe hypertriglyceridemia (> 500 mg/dL) require Fibrate or Niacin as initial therapy