Lipitor Atorvastatin

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Lipitor (Atorvastatin)
Team E Jenna Hargens Michael Harrington Nick
Herga Ashley Holt Robert Hutchins Meagan
Jarrell
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Marketing
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Chemical Structure
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Cholesterol Biosynthesis
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Mechanism

• competitive inhibitor of HMG-CoA reductase

Part of cholesterol synthesis pathway
Mevalonate
3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA)
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Mechanism

• Decrease in cholesterol synthesis
• Increased expression of LDL receptors
  on liver cells
• Increased LDL cholesterol uptake by liver
  cells
• Reduces amount of cholesterol in blood
• WHY IS HIGH CHOLESTEROL IN THE BLOOD BAD?

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Function

• High cholesterol
• Atherosclerosis
• Cardiovascular disease, strokes, heart attacks

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Atherosclerosis
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Active Site Model

• pharmacophore of atorvastatin hydrogen bonds with
  Ser684, Asp690, Lys691, Lys692, Glu559 (red)
• fluorophenyl ring of atorvastatin forms polar
  interactions with Arg590 (yellow)
• Oxygen associated with amide also forms hydrogen
  bonds with Ser565(purple)

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Method of Administration

• 10, 20, 40, and 80 mg tablets for oral
  administration
• A patients response to their first few
  treatments can lead to a change in the dosage

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Physical Properties

• White to off-white crystalline powder
• Solubility
• Insoluble in aqueous solution with pH
• Slightly soluble in distilled water and
  acetonitrile
• Soluble in methanol
• Molecular Weight 1209.42 g/mol
• (C33H34FN2O5)2Ca23H20

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Metabolism

• Log P 4.1
• Due to hydrophobic character, absorbed quickly
  after oral administration
• Low systemic availability
• clearance in GI mucosa
• Hepatic first-pass metabolism
• Liver is the primary site of action

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Distribution

• Membrane consists of lipid bilayer
• Hydrophilic statins cannot penetrate without a
  protein
• Hydrophobic statins can diffuse across
  phospholipid bilayer
• Hydrophobic statins can enter extra-hepatic and
  hepatic cells
• Protein binding of atorvastatin is usually in the
  98 range

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Excretion

• Eliminated primarily in bile following hepatic
  metabolism
• Only 2 recovered in urine after oral
  administration

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Minor Side Effects

• Diarrhea
• Headache
• Constipation/gas
• Rash
• Upset stomach and/or stomach pain
• Muscle and joint pain

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Serious Side Effects

• muscle problems
• kidney problems/failure
• liver problems
• Breastfeeding mothers should not take Lipitor
  because of the transmission to the baby through
  the mothers milk

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Conclusion

• Pfizer reported 12.6 billion in sales in 2006
  from Lipitor alone
• Even though it is very effective in treating high
  cholesterol, many physicians are switching
  patients to other statins that are cheaper