E3: Statins/Ezetimibe Flashcards
When are statins best taken?
What are the exceptions?
Statins best taken in the evening at bedtime
–atorvastatin and rosuvastatin can be dosed anytime of the day due to their long elimination half-lives which make them equally effective regardless of when they are administered
What statin has exposures that are 2x higher in Asian patients, how do you adjust the dose?
Rosuvastatin-Crestor, lower the dose to 5 to 10mg
Statins MOA
cholesterol synthesis inhibitor
reversible competitive inhibitor of HMG-CoA reductase in the synthesis of mevalonate in liver
rate limiting step in synthesis of cholesterol
causes ↑ in hepatic LDL surface receptor #’s
↓
results in ↑ uptake of plasma LDL’s
↓
[LDL]plasma falls
↓
↑ hepatic catabolism of LDL
statins resemble _______ and are
competitive inhibitors of ______
mevalonate; HMG-CoA reductase
Statin Lactone Prodrugs (2)
Lovastatin and Simvastatin
Lipophilic statins (4)
Lovastatin
Simvastatin
Fluvastatin
Atorvastatin
Hydrophilic Statins (2)
Better selectivity for ______ tissues
Pravastatin
Rosuvastatin
3,5-dihydroxy acid ACTIVE statins
Fluvastatin
Atorvastatin
Pravastatin
Rosuvastatin
_______ statins are more widely distributed in many different tissues
Lipophilic
Drugs that contain Lactone prodrugs require ________ for activation
hydrolysis
All statins must contain 3,5-__________ acid or _________ prodrugs
dihydroxy; lactone
Statins that lowers LDL-C by ~50% or more
Examples:
High-intensity statins
Atorvastatin (40 or 80) mg
Rosuvastatin (20 or 40) mg
Statins that lowers LDL-C by ~30-50%
Examples:
Moderate-intensity statins
Atorvastatin (10 or 20) mg
Rosuvastatin (5 or 10) mg
Simvastatin (20 to 40) mg
Statins that lowers LDL-C by <30%
Simvastatin 10mg
How long to statins require to see any lipid lowering effects?
When should follow up be scheduled to measure lipid levels?
At least 2 weeks to see any lipid-lowering effects
4-6 week follow up to measure lipid levels
What additional pharmacologic benefits beyond lipid lowering have high intensity statins shown (2)
-Anti-inflammatory effects i.e. nitric oxide formation
-Plaque stabilization and regression
(slows progression of lipid plaques from getting bigger)
What are the benefits of statins having anti-inflammatory/immunomodulatory characteristics?
↓ monocyte activation, ↓ monocyte chemotaxis and endothelial adhesion
Stabilize vulnerable coronary atherosclerotic plaques
High intensity statin use may have benefit in COVID-19 treatment
Statins metabolism by CYP____
Order of most metabolized to least metabolized of the following:
Rosuvastatin, simvastatin, lovastatin, pravastatin, atorvastatin
Which 3 statins are considered to have major CYP3A4 metabolism and which 3 do not have major metabolism (Use the 5 statins above plus Fluvastatin)
CYP450, CYP3A4
Most metabolized (Lipophilic): lovastatin, simvastatin > atorvastatin > rosuvastatin, pravastatin (least metabolized, hydrophilic)
3A4 Major: Atorvastatin-Lipitor, Lovastatin-Mevacor, Simvastation-Zocor
No major: Fluvastatin, Pravastatin, Rosuvastatin
What two statins are contraindicated with strong CYP3A4 inhibitors?
Give the statins and 4 examples of inhibitors
simvastatin, lovastatin
inhibitors i.e. erythromycin, ketoconazole, fluconazole cause toxicity
Inhibitor: grapefruit juice
SAMS stands for
Statin associated muscle symptoms
Define the following and state if they have +/no change in CK
Myalgia
Myopathy
Myositis
Myonecrosis w/rhabdomyolysis
myalgia: muscle soreness, tenderness w/o creatine kinase (CK) (normal 40-200 IU/L)
myopathy: muscle w/ tissue breakdown, +/- CK ↑
myositis: fibrous tissue evidence of inflammation and repair, CK ↑
Myonecrosis w/ rhabdomyolysis (rare): disintegration of muscle tissue leading to marked CK ↑, urinary myoglobin from muscle cell breakdown; excess leads to renal failure
↑ Risk for SAMS w/:
(5)
- ↑ doses
- ↑ physical activity
- Age > 65
- CYP 3A4 inhibitors
- Niacin-Niaspan, gemfibrozil-Lopid
Statin ADR: renal or hepatic toxicity?
How what lab values do you look at?
hepatotoxicity and liver abnormalities (upto 2%)
-elevations in liver enzymes:
1. AST (aspartate aminotransferase)
2. ALT (alanine aminotransferase)
Mild elevations may be expected, no need to monitor on regular basis
liver failure exceedingly rare
3rd ADR of statins (that is not hepatotoxicity or SAMS)
New onset Type 2 Diabetes due to hyperglycemia causing an elevated A1c
CI of Statins (2)
- Active liver disease
Any unexplained ↑ in LFT’s - Pregnancy/breastfeeding
rare reports of congenital malformations
Atorvastatin (Lipitor)
1. ________________ ↑ lipophilicity
2. Major or minor substrate for CYP3A4
3. _______ intensity statin
4. ________ <2% elimination
5. Long or short t1/2
- Additional aromatic rings ↑ lipophilicity
- Major substrate for CYP3A4
- High intensity statin (when at 40 or 80mg, moderate intensity for 10 & 20mg)
- Renal < 2% elimination
- Long, T1/2 = 14 hrs
Lovastatin (Mevacor, Altoprev)
1. History fun fact
2. Highly _______ soluble- _______
3. Prodrug or active?
4. Major or minor substrate for CYP3A4
- First HMG-CoA RI (1987)
- highly lipid soluble-lipophyllic
- Prodrug- lactone hydrolyzed to
3,5–dihydroxy acid - Major substrate for CYP3A4
Which statin:
-exhibits the least drug interactions
-more hydrophilic (↑ effect in liver)
-↓ADR observed
Pravastatin (Pravachol)
Rosuvastatin (Crestor)
1. _________
-↑ hydrophilicity
-higher hepatoselectivity
-↑ receptor binding
2. Renal or hepatic elimination
3. _____ intensity statin
4. Long or short t1/2
Methanesulfonamide
-↑ hydrophilicity
-higher hepatoselectivity
-↑ receptor binding
2. renal 10% elimination
3. high intensity statin at 20 & 40mg, moderate intensity at 5 & 10 mg
4. long t1/2=20hr
Simvastatin (Zocor)
1. Active or prodrug
2. Major or minor substrate for CYP3A4
3. High doses:
4. Lipophilic or hydrophilic
- Lactone prodrug
- Major substrate for CYP3A4
- High doses-(80mg) ↑ rates myopathy and rhabdomyolysis
80 mg not recommended for use - Lipophilic
Ezetimibe-Zetia
Pharmacology:
MOA:
Pharmacologic Effect
ADR
Pharmacology: reduces the amount of cholesterol your body absorbs from the food you eat
MOA:
1. cholesterol absorption/transport inhibitor
blocks intestinal absorption/transport of cholesterol thru blockage of a sterol transporter (NPC1L1)
2. GI Tract: Cholesterol normally transferred from micelles to sterol transporter
Ezetimibe inhibits cholesterol uptake through NPC1L1
3. Cholesterol stays in gut to be eliminated
Pharmacologic Effect: modest ↓ in LDL
A. ↓ TC: 12% LDL: ↓ 18% TG: ↓ 7-9 %
↑ HDL: 2%
ADR: GI: diarrhea
