ANTIHYPERLIPIDEMIC DRUGS Flashcards
(44 cards)
1
Q
We
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2
Q
How is hyperlipidemia and cardiovascular mortatility linked?
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Increased risk of cardiovascular mortality is most closely linked to elevated levels of LDL and decreased levels of HDL.
3
Q
Other risk factors for cardiovascular disease include?
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• Cigarette smoking
- Hypertension
- Obesity
- Diabetes
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Q
PRIMARY HYPERLIPIDEMIAS: ETIOLOGY & CLASSIFICATION?
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- Monogenic diseases
- Genetic polymorphisms
- Gene-environment interactions
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Q
What are the classications of Primary Hyperlipidemias?
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What are the secondary hyperlipidemia’s?
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7
Q
What is the agents of first choice for treatment of most patients with atherosclerotic cardiovascular disease.
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Statins are the lipid-lowering agents
8
Q
when would you use a non-statin?
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• In selected high-risk patients use of non-statinsmay be considered if statin therapy has not achieved >50% reduction in LDL.
9
Q
Why must Lipid-regulating drugs must be taken indefinitely?
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When they are stopped, plasma lipoprotein levels return to pretreatment levels.
10
Q
What are the classes of ANTIHYPERLIPIDEMIC DRUGS
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• HMG-CoA reductase inhibitors
- Niacin
- Bile acid-binding resins
- Fibrates
• Cholesterol absorption inhibitors
11
Q
Why are HMG CoA reductase inhibitors are the most important class?
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their well-demonstrated efficacy in reducing cardiovascular morbidity and mortality.
12
Q
HMG-CoA REDUCTASE INHIBITORS (Statins)?
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• Atorvastatin (2nd most potent)
- Fluvastatin ( least potent)
- Lovastatin ( similar in potency to pravastatin)
- Pravastatin( similar in potency to Lovastatin)
- Rosuvastatin ( most potent)
• Simvastatin ( 3rd most potent)
13
Q
Statins mechanism of action?
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- Statins are competitive inhibitors of HMG-CoA reductase, the enzyme that catalyzes the first committed step of cholesterol biosynthesis.
- 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.
14
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Overall summary of STATINS effect?
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- Statins are more effective than other drugs in lowering LDL.
- They also cause a decrease of plasma TG and a small increase in HDL.
15
Q
What are the uses of Statin?
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- 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.
16
Q
WHo should be recieving a statin?
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- 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.
17
Q
What are the other effects of statin?
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- Improve endothelial function.
- Decrease platelet aggregation
- Stabilize atherosclerotic plaque.
• Reduce inflammation.
18
Q
What are the adverse effects of Statin?
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- Elevation of aminotransferases. Usually not associated with other evidence of liver toxicity.
- Myopathy and rhabdomyolysis. Rare. Rhabdomyolysis may cause myoglobinuria,leading to renal injury.
19
Q
How are statins monitored?
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- 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.
20
Q
What are the common features of Niacin?
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- 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
21
Q
What is the mechanism of action of Niacin?
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- Niacin inhibits adenylyl cyclase in adipocytes. Leading to inhibition of hormone-sensitive lipase.
- 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.
22
Q
Niacin Uses?
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- 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.
23
Q
What are the adverse effects of Niacin?
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- 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: hepatotoxicityand hyperglycemia.
- 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
24
Q
What are the fibrates and what is their function?
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Gemfibrozil Fenofibrate
• Fibrates lower VLDL levels and increase HDL levels.
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What is the mechanism of action of fibrates?
* Fibrates activate peroxisome proliferator- activated receptor-a (PPAR-a).
* PPAR-a receptors are expressed primarily in liver and brown adipose tissue.
* Activation of PPAR-α by fibrates leads to adecrease in plasma TG levels and increase in plasma HDL levels.
* The decrease in plasma TG levels is caused byincreased 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.
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Mechanism of action of Fibrates map?
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What are the uses of fibrates?
* DOC in severe hypertriglyceridemia
* Reasonable consideration in moderate hypertriglyceridemia.
* As monotherapy, fibrates offer the highest TG reduction, followed by niacin, -3-fatty acids, statins, and ezetimibe.
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What are the adverse effects of fibrates?
* 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.
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What are the drug interactions of fibrates?
* 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.
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What are the bile-acid binding resins?
Cholestyramine Colestipol Colesevelam
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What are the uses of BILE ACID-BINDING RESINS?
* 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.
* • 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.
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BILE ACID-BINDING RESINS: MOA?
* • 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 adecrease in plasma LDL levels.
* This effect is partially offset by increased cholesterol synthesis due to upregulationof HMG-CoA reductase.
* HDL rises modestly.
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BILE ACID-BINDING RESINS: ADVERSE EFFECTS?
* 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.
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BILE ACID-BINDING RESINS: DRUG INTERACTIONS?
• Cholestyramine and colestipol reduce absorption of several drugs and liposoluble vitamins.
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Ezetimibe common feature?
CHOLESTEROL ABSORPTION INHIBITORS
* Inhibits intestinal absorption of cholesterol and phytosterols.
* Its primary clinical effect is to lower LDL.
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EZETIMIBE: MECHANISM OF ACTION?
* 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%.
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EZETIMIBE: USES
* 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.
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EZETIMIBE: ADVERSE EFFECTS?
* Low incidence of reversible impaired hepatic function.
* Small increase in incidence when ezetimibe is given with a statin.
* Myositis has been reported rarely.
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EZETIMIBE: DRUG INTERACTIONS?
* Bile-acid sequestrants inhibit absorption of ezetimibe.
* The two agents should not be administered together.
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ω-3 FATTY ACIDS and their common feaature?
* Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce TG synthesis and increase fatty acid oxidation in the liver.
* HDL levels may modestly increase.
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What are the effects of Antihyperlipidemias summary table?
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SUGGESTED DRUG THERAPY FOR DYSLIPIDEMIAS table?
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ANTIHYPERLIPIDEMIC DRUGS IN PREGNANCY?
* 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.
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