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B4T1 (L 1,2): Antihyperlipidemics

Terms in this set (60)

Statin mechanism of action
Inhibit HMG-CoA reductase (catalyzes the rate limiting step in cholesterol synthesis) → ↓ hepatic cholesterol production → ↑ LDL receptors, which then clear LDL and VLDL from the blood.

The incrase in LDL receptors in the primary mechansim. VLDL secretion is also decreaed. Effects occur mainly at the liver.
Statins are the most effective at lowering ____ cholesterol
LDL (↓ ~20-50%, depending on dose)
Aside from improving cholesterol profile, what other effects do statins have? (3)
"Decrease oxidative stress

Decrease vascular inflammation

Increase stability of atherosclerotic lesions Result = significant reduction of new coronary events (MI) and stroke"
Statin adverse effects (~4)
"GI upset (Abdominal pain, nausea, diarrhea)
Increased blood glucose (Diabetes)
Myopathy/Rhabdomyolysis (Simvastatin 80 mg!)
Increased liver enzymes - Liver failure (very rare) - Discontinue if transaminase levels (AST/ALT) increase > 3 times upper limit of normal (ULN)"
Drug interactions that ↑ myopathy/rhabdo risk with statins (4)
"Gemfibrozil (avoid combo!)
Amiodarone (inhibits 3A4 and 2C9)
Colchicine
Niacin "
Which statins (3) are metabolized via CYP3A4 and therefore interact with CYP3A4 inducers/inhibitors?
Lovastatin, simvastatin, atorvastatin
Which statins (3) are metabolized via CYP2C9 and therefore interact with CYP2C9 inducers/inhibitors?
Fluvastatin, rosuvastatin, ~pitavastatin
What dietary supplement may contain a chemical structure similar to lovastatin and should not be used with a statin due to increased risk of adverse effects?
Red yeast rice
Niacin is also known as (2)
Vitamin B3 and Nicotinic Acid
Niacin products are available OTC as _______ and by ______.
Dietary supplements and by prescription.
Niacin is the most effective agent for ↑ _____ cholsterol and ↓ _______.
HDL; triglycerides
What did the FDA recently say about the coadministration of niacin (ER tablets) and statins?
Benefits do not outweigh the risks
Mechanisms of action of niacin (3)
"1. inhibits hepatic VLDL secretion, which decreases LDL production.

2. inhibits lipolysis in adipose tissue, reducing production of free fatty acids that would normally be used by the liver to produce triglycerides (which would be incorporated into VLDL).

3. Inhibits metabolism/breakdown of HDL."
Niacin contraindications (3)
"Liver impairment
Peptic ulcer
Arterial bleeding"
Niacin adverse effects (6)
"Cutaneous vasodilation and warm sensation (i.e., flushing)
Pruritus
Nausea
abdominal pain
Hyperuricemia → gout
Impaired glucose tolerance
Hepatotoxicity"
Niacin drug interactions (1)
Statins (myopathy/rhabdo)
3 ways to reduce frequency/intensity of statin flushing
"1. Take with food (not spicy food)
2. Pre-medicate with aspirin 30 minutes before dose
3. Initiate low dose and titrate over weeks as tolerated"
Bile acid sequestrants (3)
"Colestipol (Colestid)
Cholestyramine (Questran)
Colesevelam (Welchol)"
Mechanism of Bile acid sequestrants
Bind bile acids in the intestine, preventing their reabsorption.
Complex is then excreted in the feces.
Results in enhanced hepatic conversion of cholesterol to bile acids.
This leads to a decrease in intracellular cholesterol concentrations, causing an up-regulation in LDL receptors, primarily in the liver.
Increased LDL receptors leads to increased uptake of LDL the plasma.
What negative impact on lipid profile might bile acid sequestrants have?
May ↑ LDL Bile acid sequestrants contraindications (2) "Fasting triglyceride level ≥ 300 mg/dL History of bowel obstruction"
Main adverse effect of bile acid sequestrants
"GI upset (constipation, nausea, flatulence) Colesevelam has least GI effects"
Drug interactions with bile acid sequestrants (~1). What can you do to avoid these interactions?
"Impair absorption of fat-soluble vitamins and other drugs

Other drugs/supplements should be taken 1-2 hours before or 4-6 hours after bile acid sequestrant"
Mechanism of ezetimibe
Inhibits absorption of dietary and biliary cholesterol from intestine to liver
Ezetimibe contraindication (1)
Liver impairment
Ezetimibe adverse effect (1)
Reversible hepatic impairment (rare)
Ezetimibe drug interacton (1)
Gemfibrozil (combo ↑ risk of cholelithiasis = gallstones)
Fibrates (aka fibric acid derivatives (3)
"Gemfibrozil (Lopid) Fenofibrate (Tricor, Lofibra) Fenofibric Acid (Trilipix)"
Fibrates mechanism of action
"Activate PPAR-α ↑ lipoprotein lipase = ↓ triglycerides ↓ apo C-II & C-III = ↓ VLDL ↑ apo A-I & A-II = ↑ HDL"
Fibrates contraindications (4)
"Hepatic dysfunction
Renal dysfunction
Gallbladder disease
Nursing/breastfeeding"
Fibrates adverse effects (3)
"Mild GI upset (Most common)
Myopathy / Rhabdomyolysis (rare)
Predisposition to form gallstones"
Why did FDA say use of niacin (extended release) or fibrates (fenofibric acid delayed release) with a statin should be avoided?
"Scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL levels in statin-treated patients results in reduction in risk of cardiovascular events" - FDA
Omega-3 fatty acids (fish oil) is availabe over the counter as _______ and by ________.
Dietary supplements and by prescription.
Mechanism of omega-3 fatty acids
"Activate PPAR-α. Similar to fibrates."
Omega-3 fatty acids adverse effects (~2)
"GI upset (pain, nausea, diarrhea) Fishy aftertaste"
Omega-3 fatty acids drug interactions
May increase bleeding risk with anticoagulants (e.g., heparin, warfarin) or antiplatelet agents (e.g., clopidogrel)
Which medications are most effective at lowering triglycerids (~2 classes)
Fibrates and niacin
Which medications are most effective at lowering LDL?
Statins
Which medicaiton is most effective at raising HDL?
Niacin
Lopitamide mechanism
Inhibits microsomal triglyceride transfer protein. Inhibition of MTTP (1) decreases hepatic VLDL secretion (2), leading to decreased LDL in plasma (3).
Lopitamide indication
Restricted to homozygous familial hypercholesterolemia (results in lack of functional LDL receptors)
Lopitamide contraindications (3)
"Liver impairment Use with moderate-strong CYP3A4 inhibitors Pregnancy"
Lopitamide adverse effects (2)
"Accumulation of triglycerides in liver in some individuals
Hepatotoxicity (Black Box Warning)"
Mipomersen mechanism
Inhibits apo B-100 synthesis → ↓ LDL & VLDL
Mipomersen indication
Restricted to homozygous familial hypercholesterolemia (results in lack of functional LDL receptors)
Mipomersen contraindication
Liver impairment
Mipomersen adverse effects (3)
"Hepatotoxicity - BBW! Injection site pain/reaction Flu-like symptoms"
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (2)
evolucumab (repatha) | alirocumab (praluent)
PCSK9 inhibitors mechanism
"Inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) from binding to and mediating the breakdown of hepatic LDL receptors. ↑ LDL receptors = ↑ LDL uptake into liver"
PCSK9 inhibitors indication
Approved for use in addition to diet + max-tolerated statin
PCSK9 inhibitors adverse effects (~3)
"Injection site pain/reaction
Upper respiratory tract infection
Flu"
Cholesterol ester transfer protein (CETP) inhibitors currently in phase 3 clinical trials (2)
"Anacetrapib and evacetrapib . Not that torcetrapib was withdrawn from clinical trial due to ↑ cardiovascular events and deaths. We'll see how these turn out..."
4 major statin benefit groups (i.e., these people should definitely be on a statin, unless there's a contraindication or they are statin-intolerant, to decrease ASCVD risk)
"1. Clinical ASCVD 2. LDL ≥ 190 mg/dL 3. Diabetes aged 40 to 75 years with LDL 70-189 mg/dL 4. Without clinical ASCVD or diabetes aged 40-75 years with LDL 70-189 mg/dL and estimated absolute 10-year ASCVD riskk** >7.5% "
What is "Clinical ASCVD"?
Acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin
Points about the use of non-statin in dislipidemia
"Target high risk patients with: - Inadequate response to statins OR - Unable to tolerate statin or recommended intensity of statin Before non-statin is considered: - Rule out secondary causes of hyperlipidemia - Re-emphasize adherence to lifestyle recommendations - Re-emphasize adherence to statin therapy "
Mild to moderate hypertriglyceridemia. How is it classified? How is it treated?
"Triglycerides of 150-999 mg/dL Increased cardiovascular risk Initial treatment = lifestyle modification (e.g,. diet, exercise) Suggested drugs, if needed: - Fibric acid derivatives - Niacin - Omega-3 fatty acids" Severe hypertriglyceridemia. How is it classified? What's the risk? And how is it treated? "Triglycerides ≥ 1,000 mg/dL Increased risk for acute pancreatitis Fibric acid derivative = first line Statins are not recommended as monotherapy"
HMG-CoA reductase
Enzyme catalyzing rate-limiting step in cholesterol biosynthesis. Inhibited by statins.
Proliferator-activated receptor-alpha (PPAR-α)
Nuclear transcription regulator that regulates metabolic processes. Target of the fibrate drugs and omega-3 fatty acids
Name the 7 statins (aka HMG-CoA reductase inhibitors)
Atorvastatin (Lipitor) | Fluvastatin (Lescol) | Lovastatin (Mevacor) | Pitavastatin (Livalo) | Pravastatin (Pravachol) | Rosuvastatin (Crestor) | Simvastatin (Zocor) | *Prodrug
Statin contraindications (3)
"Active liver disease or unexplained persistently elevated liver function tests Pregnancy Breast feeding"
Statin mechanism of action
Inhibit HMG-CoA reductase (catalyzes the rate limiting step in cholesterol synthesis) → ↓ hepatic cholesterol production → ↑ LDL receptors, which then clear LDL and VLDL from the blood. The incrase in LDL receptors in the primary mechansim. VLDL secretion is also decreaed. Effects occur mainly at the liver.
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