Statin Drugs

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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

• Percent of Americans ages 20-74 with high serum
  cholesterol 19
• Mean serum cholesterol level, mg/dl 203
• High serum cholesterol is most prevalent among
  white, non-Hispanic females
• High serum cholesterol is least prevalent among
  Black males

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Cholesterol

• Vital constituent of all cells since it is part
  of the cell membrane
• Also used in the synthesis of sex hormones
• Also used to make bile salts
• Synthesized in liver from saturated fatty acids
  and also absorbed by small intestines from animal
  foods
• If diet low in cholesterol liver responds and
  makes more

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Cholesterol

• However, if the diet is rich in cholesterol then
  synthesis within the body virtually stops
• 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 transported in the blood by a special
  complex that consists of cholesterol, lipids and
  proteins - called lipoproteins
• Several different types of lipoproteins - two
  most significant High Density Lipoproteins-HDL
  and Low Density Lipoproteins - LDL
• LDL transports cholesterol throughout body, HDL
  removes excess cholesterol and carries it back to
  liver for degradation

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Lipoproteins
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LDL

• LDL - bad cholesterol - can be taken up by
  cells lining arteries - deposits called plaque
• Resulting deposition of cholesterol can block
  arteries and restrict blood flow - condition
  called artherosclerosis
• Can lead to heart attacks when coronary arteries
  are blocked
• Can lead to strokes if arteries to brain blocked

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HDL

• HDL - good cholesterol
• Can prevent artherosclerosis by preventing the
  build up of cholesterol deposits on the lining of
  the arteries

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Statin Drugs

• Statins are cholesterol-lowering drugs that were
  originally isolated from fungi and have been
  widely used for the past decade
• All terpenes
• Five statins are currently prescribed by
  physicians
• Three of these (pravastatin, simvastatin, and
  lovastatin) are derived by fermentation of the
  fungus Aspergillus terreus, while two
  (fluvastatin and atorvastatin) are synthetics

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Statin Drugs
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Statins

• Statins drugs act as inhibitors to HMG-CoA
  Reductase which is necessary for cholesterol
  synthesis
• 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 cholesterol lowering drugs available in
  1950s and 60s - not all that 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
• They wanted to find a microorganism that produced
  an HMG-CoA reductase inhibitor as a defense
  mechanism against attack by other microbes which
  relied on sterols as part of their biochemical
  make up

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Discovery of mevastatin

• Endo and Kuroda screened over 6,000
  micro-organisms - took over 2 yrs
• Screened culture broth for cmpds that would
  inhibit lipid synthesis
• Found 2 cmpds (later a 3rd) - one was from
  Penicillium citrinum called it 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 for marketing in 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) - FDA approval pending
• 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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Other modes of action

• It is possible that statins have additional modes
  of action because, statin drugs do more than
  lower cholesterol
• More and more reports are appearing about other
  benefits of statin drugs

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Benefits of statin drugs

• Statins appear to be effective in preventing
  strokes, especially in patients with known heart
  disease
• They reduce coronary artery inflammation, which
  has recently been found to be a major cause of
  heart attacks and strokes
• Can also affect blood vessel growth
• Some immune system expression helps prevent
  rejection of transplanted organs with much fewer
  side effects than cyclosporin may be able to
  reduce levels of cyclosporin

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Statins and Osteoporosis

• Decrease the risk of fractures by increasing bone
  density (actually showing bone formation)
• Therefore decreases the risk of osteoporosis
• Statins reduce the risk of colon cancer when
  combined with non-steroid anti-iflammatory drugs.

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Statins and Dementia

• Recent studies also show a reduced risk of
  Alzheimer's disease
• In fact, patients taking lovastatin or
  pravastatin had a 60 to 73 lower risk of
  developing Alzheimer's
• Researchers suggest that these drugs possibly
  prevent dementia by dilating blood vessels and
  increasing blood flow to the brain

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The new wonder drug

• The medical community is saying that the use of
  statin drugs should be expanded since many more
  people could benefit from their use
• The expanding role of statins has already been
  called one of the top ten medical advances of the
  new millenium

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Sales of Statin Drugs

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

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Effect of Statin Use on Population
Percent of Population with High Cholesterol
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Side Effects

• Nothing is perfect
• 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 five
  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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Hypertension - High Blood Pressure

• Adds to the workload of the heart and arteries
• If it continues for a long time, the heart and
  arteries may not function properly
• Can damage the blood vessels of the brain, heart,
  and kidneys, resulting in a stroke, heart
  failure, or kidney failure
• Also increases risks of heart attacks.
• These are less likely to occur if blood pressure
  is controlled

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Snakeroot and Schizophrenia

• Snakeroot, Rauwolfia serpentina
• "doctrine of signatures"- because long coiled
  roots resembled a snake, healers believed that
  the root could be used for treating snake bites
• For over 4000 years, Hindu healers in India used
  the root for the treatment of snakebites, insect
  stings, and even mental illness
• Standard treatment in Ayuvedic medicine

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Rauwolfia serpentina and reserpine

• In 1952 the alkaloid reserpine was isolated from
  the roots
• Later dozens of alkaloids found
• The sedative effects of reserpine made it
  valuable as a tranquilizers - side effect was a
  reduction in blood pressure
• Today, this is actually the principal application
  of reserpine, as a treatment for hypertension

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Reserpine mode of action

• Acts on nervous system
• Inhibits normal sympathetic activity by
  decreasing the storage of catecholamines 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

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Dietary control of heart disease

• French Paradox - red wine
• Mediterranean diet - olive oil
• Garlic
• Soy isoflavones