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IP1 > E3: Statins/Ezetimibe > Flashcards

E3: Statins/Ezetimibe Flashcards

1
Q

When are statins best taken?
What are the exceptions?

A

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

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2
Q

What statin has exposures that are 2x higher in Asian patients, how do you adjust the dose?

A

Rosuvastatin-Crestor, lower the dose to 5 to 10mg

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3
Q

Statins MOA

A

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

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4
Q

statins resemble _______ and are
competitive inhibitors of ______

A

mevalonate; HMG-CoA reductase

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5
Q

Statin Lactone Prodrugs (2)

A

Lovastatin and Simvastatin

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6
Q

Lipophilic statins (4)

A

Lovastatin
Simvastatin
Fluvastatin
Atorvastatin

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7
Q

Hydrophilic Statins (2)
Better selectivity for ______ tissues

A

Pravastatin
Rosuvastatin

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8
Q

3,5-dihydroxy acid ACTIVE statins

A

Fluvastatin
Atorvastatin
Pravastatin
Rosuvastatin

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9
Q

_______ statins are more widely distributed in many different tissues

A

Lipophilic

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10
Q

Drugs that contain Lactone prodrugs require ________ for activation

A

hydrolysis

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11
Q

All statins must contain 3,5-__________ acid or _________ prodrugs

A

dihydroxy; lactone

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12
Q

Statins that lowers LDL-C by ~50% or more
Examples:

A

High-intensity statins
Atorvastatin (40 or 80) mg
Rosuvastatin (20 or 40) mg

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13
Q

Statins that lowers LDL-C by ~30-50%
Examples:

A

Moderate-intensity statins
Atorvastatin (10 or 20) mg
Rosuvastatin (5 or 10) mg
Simvastatin (20 to 40) mg

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14
Q

Statins that lowers LDL-C by <30%

A

Simvastatin 10mg

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15
Q

How long to statins require to see any lipid lowering effects?
When should follow up be scheduled to measure lipid levels?

A

At least 2 weeks to see any lipid-lowering effects
4-6 week follow up to measure lipid levels

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16
Q

What additional pharmacologic benefits beyond lipid lowering have high intensity statins shown (2)

A

-Anti-inflammatory effects i.e. nitric oxide formation
-Plaque stabilization and regression
(slows progression of lipid plaques from getting bigger)

17
Q

What are the benefits of statins having anti-inflammatory/immunomodulatory characteristics?

A

↓ monocyte activation, ↓ monocyte chemotaxis and endothelial adhesion

Stabilize vulnerable coronary atherosclerotic plaques

High intensity statin use may have benefit in COVID-19 treatment

18
Q

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)

A

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

19
Q

What two statins are contraindicated with strong CYP3A4 inhibitors?
Give the statins and 4 examples of inhibitors

A

simvastatin, lovastatin

inhibitors i.e. erythromycin, ketoconazole, fluconazole cause toxicity
Inhibitor: grapefruit juice

20
Q

SAMS stands for

A

Statin associated muscle symptoms

21
Q

Define the following and state if they have +/no change in CK
Myalgia
Myopathy
Myositis
Myonecrosis w/rhabdomyolysis

A

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

22
Q

↑ Risk for SAMS w/:
(5)

A
  1. ↑ doses
  2. ↑ physical activity
  3. Age > 65
  4. CYP 3A4 inhibitors
  5. Niacin-Niaspan, gemfibrozil-Lopid
23
Q

Statin ADR: renal or hepatic toxicity?
How what lab values do you look at?

A

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

24
Q

3rd ADR of statins (that is not hepatotoxicity or SAMS)

A

New onset Type 2 Diabetes due to hyperglycemia causing an elevated A1c

25
Q

CI of Statins (2)

A
  1. Active liver disease
    Any unexplained ↑ in LFT’s
  2. Pregnancy/breastfeeding
    rare reports of congenital malformations
26
Q

Atorvastatin (Lipitor)
1. ________________ ↑ lipophilicity
2. Major or minor substrate for CYP3A4
3. _______ intensity statin
4. ________ <2% elimination
5. Long or short t1/2

A
  1. Additional aromatic rings ↑ lipophilicity
  2. Major substrate for CYP3A4
  3. High intensity statin (when at 40 or 80mg, moderate intensity for 10 & 20mg)
  4. Renal < 2% elimination
  5. Long, T1/2 = 14 hrs
27
Q

Lovastatin (Mevacor, Altoprev)
1. History fun fact
2. Highly _______ soluble- _______
3. Prodrug or active?
4. Major or minor substrate for CYP3A4

A
  1. First HMG-CoA RI (1987)
  2. highly lipid soluble-lipophyllic
  3. Prodrug- lactone hydrolyzed to
    3,5–dihydroxy acid
  4. Major substrate for CYP3A4
28
Q

Which statin:
-exhibits the least drug interactions
-more hydrophilic (↑ effect in liver)
-↓ADR observed

A

Pravastatin (Pravachol)

29
Q

Rosuvastatin (Crestor)
1. _________
-↑ hydrophilicity
-higher hepatoselectivity
-↑ receptor binding
2. Renal or hepatic elimination
3. _____ intensity statin
4. Long or short t1/2

A

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

30
Q

Simvastatin (Zocor)
1. Active or prodrug
2. Major or minor substrate for CYP3A4
3. High doses:
4. Lipophilic or hydrophilic

A
  1. Lactone prodrug
  2. Major substrate for CYP3A4
  3. High doses-(80mg) ↑ rates myopathy and rhabdomyolysis
    80 mg not recommended for use
  4. Lipophilic
31
Q

Ezetimibe-Zetia
Pharmacology:
MOA:
Pharmacologic Effect
ADR

A

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

IP1 (23 decks)

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