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

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

Cholesterol synthesis

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

Lipoproteins

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

Chemical NameBrand Name in U.S. Production Method Pravastatin(G?)PravacholFermentation - modified Simvastatin(G?)ZocorFermentation - modified Lovastatin (G)MevacorFermentation FluvastatinLescolSynthetic AtorvastatinLipitorSynthetic RosuvastatinCrestorSynthetic CerivastatinBaycolSynthetic - no longer available Statin Drugs

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

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 (3 rd 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

Mevastatin (compactin)

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

Lovastatin (Mevacor)

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)

Simvastin and Pravastatin

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

Fluvastatin and Atorvastatin

Cerivastatin and Rosuvastatin

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

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

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 Alzheimer’s Disease Reduce MS symptoms

Lipitor (atorvastatin)*$3.7b (2003 – $7.8b) Zocor (simvastatin)*$2.2b ( $5.5b) Pravachol (pravastatin) $1.2b Baycol (cerivastatin)$0.2b Lescol (fluvastatin)$0.2b Mevacor (lovastatin)$0.2b Sales of Statin Drugs - $15.5 billion * Two top selling drugs in US – Liptor also top selling in world

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

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

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

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

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

Reserpine Antihypertensive drug

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

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?

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

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