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Statin Drugs. Cholesterol lowering drugs. Individual level risk factors for cardiovascular disease. High Blood Pressure High Blood Cholesterol Tobacco Use Physical inactivity Poor nutrition Obesity Diabetes. High Cholesterol Profile.

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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

  • 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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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 Aspergillusterreus, while two (fluvastatin and atorvastatin) are synthetics


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Chemical Name

Brand Name in U.S.

Production Method

Pravastatin

Pravachol

Fermentation - modified

Simvastatin

Zocor

Fermentation - modified

Lovastatin

Mevacor

Fermentation

Fluvastatin

Lescol

Synthetic

Atorvastatin

Lipitor

Synthetic

Rosuvastatin

Crestor

Synthetic - approval pending

Cerivastatin

Baycol

Synthetic - no longer available

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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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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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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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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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 LDL’s 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


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