Statins

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Statins are the most commonly prescribed drugs in the UK.  The purpose is to reduce levels of low-density lipoprotein (LDL) cholesterol in the blood. By doing this it reduces the chance of developing a cardiovascular disease (CVD) or preventing heart attacks and strokes for people who already have a CVD. Primarily they have been used in secondary prevention which is when someone has already had a problem, however recent guidelines have changed and therefore it is being advised that they are now used more as a preventative to stop healthy people from contracting one of these diseases.

How they work

The way that they work is by inhibiting the synthesis of cholesterol in the liver. They impede an enzyme called HMG-CoA reductase and this interrupts the chemical pathway that leads to the production of cholesterol. This pathway can be called the mevalonate pathway, HMG-CoA reductase pathway, mevalonate-dependent (MAD) route or isoprenoid pathway. It is a complex process that involves over 30 enzymes. This is why statins can cause other effects as it does not just inhibit cholesterol but other isoprenoid proteins[1]. They attack this point because it is the slowest part of the process and non-reversible, therefore the pivotal point in the production and the natural control point for the synthesis of cholesterol. This pathway is very important and appears in all higher eukaryotes and a lot of bacteria, this is because it has a vital role in synthesising chemicals which are essential in the body. This works because 60% of all cholesterol is produced in the liver; therefore most of the cholesterol in our body is produced by us rather than it coming from food. This is why it may be more effective to take a drug than change your diet, although that would also help. The drugs are competitive inhibitors; this means that they both compete for the same active site; if the statin molecule binds with the enzyme instead of the HMG-CoA then the synthetic pathway will be prevented. This slows down production as the next molecule, called mevalonate, cannot be produced which is the next step in the pathway, nonetheless it does not stop production all together as there is still natural substrate left that is able to bind and carry on the synthesis. A competitive inhibitor means that it has a very similar structure to the HMG-CoA and generally has a higher affinity of forming a complex than the HMG-CoA. However this means that although statins reduces the amount of cholesterol made in the body it does not combat any cholesterol that is ingested in food[2].

There are many different forms of statin such as atorvastatin, lovastatin and fluvastatin, they all do the same job but have different chemical structures, they vary in their ring structure and chemical side groups, and this varies the way each statin works and their pharmacologic properties such as affinity to the active site of HMG-CoA enzyme and rate of entry into the liver. One of the main design features of statins is specific inhibition of HMG-CoA reductase in the liver, this is because non- hepatic cells still need normal cholesterol synthesis to function and if they don’t it could be very harmful. Commonly statins are divided into two groups: type 1 which are from natural sources or derived from fungi (lovastatin, pravastatin, and simvastatin), and type 2, which are synthetic and are able to be made in abundance in a laboratory (fluvastatin, atorvastatin, rosuvastatin, and cerivastatin). Type 2 can make more hydrogen bonds than type 1 therefore bond more tightly to the enzyme[3]

References

  1. Tobert, JA. (2003). Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nature Reviews Drug Discovery 2. 2 (7), p17-26
  2. Ebrahim, S Taylor, FC Brindle, P. (2014). Statins for the primary prevention of cardiovascular disease. BMJ: British Medical Journal. 348 (5)
  3. Istvan, ES Deisenhofer, J. (292). Structural Mechanism for Statin Inhibition of HMG-CoA Reductase. Science. 292 (5519), p60-64


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