Statin%20Drugs

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Statin Drugs

• Cholesterol lowering drugs

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Individual level risk factors for cardiovascular
disease

• High Blood Pressure
• High Blood Cholesterol
• Tobacco Use
• Physical inactivity
• Poor nutrition
• Obesity
• Diabetes

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High Cholesterol Profile

• 19 of Americans ages 20-74 have high serum
  cholesterol
• Mean level 203 mg/dl
• Most prevalent among White, non-Hispanic females
• Least prevalent among Black males

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Cholesterol

• What is cholesterol?
• Cholesterol production is controlled by a
  feedback mechanism in which cholesterol inhibits
  the enzyme b-hydroxy-b-methylglutaryl-CoA
  reductase (HMG Co-A reductase).
• By inhibiting this enzyme, the conversion of
  HMG-CoA to mevalonic acid is stopped

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Cholesterol synthesis
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Cholesterol

• Cholesterol transport by lipoproteins
• Low Density Lipoproteins LDL transports
  cholesterol throughout body Bad cholesterol
• High Density Lipoproteins- HDL removes excess
  cholesterol and carries it back to liver for
  degradation

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Lipoproteins
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Statin Drugs

• Cholesterol-lowering drugs originally isolated
  from fungi
• All terpenes
• Six statins are currently prescribed by
  physicians
• Three of these (pravastatin, simvastatin, and
  lovastatin) are derived by fermentation of the
  fungus Aspergillus terreus, while three
  (fluvastatin, atorvastatin, rosuvastatin) are
  synthetics

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Statin Drugs
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Statins

• Statins drugs act as inhibitors to HMG-CoA
  Reductase
• Can reduce blood cholesterol levels up to 60
• They specifically lower LDL cholesterol levels
  and even produce some increases in HDL
  cholesterol levels.
• The cholesterol reduction significantly reduces a
  patient's risk of heart disease

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Discovery of statins

• Some drugs available but not effective
• In 1971,Endo and Kuroda (Sankyo Pharmaceuticals
  in Japan) began search for better drugs
• Cholesterol pathway known and they wanted to find
  a HMG-CoA reductase inhibitor looked for a
  microorganism screened over 6000
• Two (3rd later) cmpds identified - one was from
  Penicillium citrinum - named mevastatin
• In 1976 isolated and crystallized
• Clinical trials started in 1978 and quickly
  stopped because of animal tumors

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Mevastatin (compactin)
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Lovastatin (Mevacor)

• Meanwhile Merck pharmaceuticals isolated a
  related cmpd - lovastatin from the fungus
  Aspergillus terreus
• Sankyo gets credit as co-discovering this cmpd
• By 1980, clinical trials began and they were
  completed in 1986
• FDA approved Aug 1987

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Lovastatin (Mevacor)
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Other Statins - Type I

• Meanwhile Sankyo and Bristol-Myers Squibb were
  entering clinical trials on another statin -
  pravastatin (Pravachol) - approved Oct 1991
• Soon after Merck came out with a second statin -
  simvastatin (Zocor) - approved Dec 91
• Simvastatin produced by chemical modification
• Simvastatin is approximately twice as potent as
  pravastatin and lovastatin
• Monascus another source of lovastatin (red yeast
  rice)

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Simvastin and Pravastatin
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Synthetics

• Soon several synthetics joined the group of
  natural statins - called Type II statins
• fluvastatin (Lescol)
• atorvastatin (Lipitor)
• rusovastatin (Crestor)
• cerivastatin (Baycol) - FDA approval withdrawn

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Fluvastatin and Atorvastatin
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Cerivastatin and Rosuvastatin
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Mode of Action

• Statins bind to the active site of HGM-CoA
  reductase - competitive inhibitor with much high
  affinity for binding the HGM-CoA
• In compensation for the inhibition, cells in
  liver begin to produce more HMG Co-A
• But they also produce more LDL receptors
• Since the liver is responsible for removing LDLs
  from plasma by the LDL receptors, blood
  cholesterol levels fall dramatically

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More on mode of action

• Statins do more than bind to active site - they
  also seem to change the active site and this
  makes these drugs very effective and specific
• Synthetic statins (Type II) are larger molecules
  and form more interactions with the active site
  and appear to be better inhibitors
• Potential for newer drugs as well because there
  is another binding site right by the active where
  NADP binds and it may be possible to develop new
  statins that will bind both places

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Benefits of statin drugs

• Prevent strokes
• Reduce coronary artery inflammation
• Affect blood vessel growth
• Some immune system expression
• Reduce risk of osteoporosis
• Reduce the risk of colon cancer when combined
  with non-steroid anti-inflammatory drugs
• Reduce risk of Alzheimers Disease
• Reduce MS symptoms

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Sales of Statin Drugs - 15.5 billion

• Lipitor (atorvastatin) 3.7b (2003 7.8b)
• Zocor (simvastatin) 2.2b (2003 - 5.5b)
• Pravachol (pravastatin) 1.2b
• Baycol (cerivastatin) 0.2b
• Lescol (fluvastatin) 0.2b
• Mevacor (lovastatin) 0.2b

Two top selling drugs in US Liptor also top
selling in world
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Effect of Statin Use on Population
Percent of Population with High Cholesterol
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Side Effects

• Side effects include muscle pain and elevated
  liver enzymes.
• In August 2001, Bayer Pharmaceuticals voluntarily
  withdrew Baycol (cerivastatin) following the
  deaths of 31 patients in the U.S. over a four
  year period

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Baycol recall

• The deaths resulted from rhabdomyolysis, which
  destroys muscle cells and causes severe muscle
  pain
• Hundreds of non-fatal cases of rhabdomyolysis
  also reported in the US
• Although this condition is a side effect of all
  statin drugs, it is exceedingly rare in the six
  approved statins and the health benefits clearly
  outweigh the slight risk

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Side effects

• The side effects may be exacerbated by
  interactions with other drugs
• A number of the Baycol deaths were patients also
  taking gemfibrozil (another class of cholesterol
  lowering drugs)
• Grapefruit juice also increases the side effects

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In the pipeline

• New cholesterol lowering drugs being developed
• Glabridin - found in the roots of licorice and
  anise plants
• Appears to inhibit the oxidation of LDL
  cholesterol, which is a factor in the build-up of
  arterial plaque

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Reserpine

• Antihypertensive drug

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Snakeroot, Rauwolfia serpentina

• Doctrine of signatures"
• Standard treatment in Ayuvedic medicine
• Root used for treating snakebites, insect stings,
  and even mental illness
• Search for schizophrenia treatment

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Rauwolfia serpentina and reserpine

• In 1952 the alkaloid reserpine was isolated from
  the roots
• Valuable tranquilizer - side effect was a
  reduction in blood pressure
• Today, this is actually the principal application
  of reserpine, as a treatment for hypertension
• What is high blood pressure?

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Reserpine mode of action

• Acts on nervous system
• Inhibits normal sympathetic activity by
  decreasing the storage of catecholamines
  (especially norepinephrine) at the pre-synaptic,
  CNS, and peripheral neurons
• Binds to the storage vesicles, causing
  catecholamines to leak into the synapse so that
  they are not available for release when the
  pre-synaptic neuron is stimulated.
• Serotonin storage also affected

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Mode of action

• These actions result in a reduction in both
  cardiac output and peripheral vascular resistance
  
• As a result heart rate decreases and blood
  pressure decreases