Thursday, May 14, 2009

Statins

  • Members:
- Atorvastatin
- Lovastatin
- Fluvastatin
- Pravastatin
- Simvastatin
- Rosuvastatin
  • Chemistry:
Simvasatin and Lovastatin are prodrugs containing lactone ring which is hydrolysed in the GIT into beta-hydroxy derivatives. Pravastatin is active as given as it has an open lactone ring.
Atorvastatin, Fluvastatin and Rosuvastatin are fluorine containing cogeners and are also active as given.

  • Pharmacokinetics:
Absorption: variable from 40 - 75 %. Only Fluvastatin is absorbed 100%. All members are susciptible to 1st pass metabolism.

Excretion: Mainly hepatic excretion in bile. Only 5 -20 % are excreted in urine.

Half-life: Atorvastatin and Rosuvastatin have relatively long half-lives (14 and 19 hours respectively). Others agents have short half-lives (1-3 hours).


  • Mechanism of action:
Competetive inhibition of the enzyme HMG-CoA reductase, which is the key enzyme in cholesterol synthesis (it catalyzes the rate limiting reaction). This causes marked reduction in LDL-cholesterol level, elevation of HDL-cholesterol level and slight reduction in triglycerides level.

There is also some other actions (most are of unknown mechanisms) that do not depend on the lipid lowering effect of statins. These are called "pleotropic" actions and they include:
  1. inhibition of the inflammatory response.
  2. improvement in the endothelial function.
  3. platelet stabilization.
  4. fibrinogen lowering effect

  • Adverse effects:
  1. GIT disturbances: in the form of nausea, abdominal colic, diarrhea or constipation and flatulence.
  2. Headache.
  3. Pruritus.
  4. Fatigue, myalgia or even myopathy can occur with statins. It is advisable to do CK level and stop statin if the level is 10-times the normal. The addition of oral coenzyme Q10 may decrease the symptoms. If the patient has developped myopathy, stop the statins and rechallenge later on with lower dose. It may be preferable to shift to Simvastatin or Fluvastatin which has lower incidence of myopathy. If the symptoms recurred, statins should be avoided and non-statin lipid modifying drugs are used instead.
  5. Liver damage: it is a serious but rare side effect. transaminase level should be measured before starting treatment and after 3 months of initiation of statins. Later on, semiannual liver enzymes are advised. Elevation of liver enzymes to 3-folds the baseline is an indication to stop statins.
  6. Drug interactions: Pravastatin and Fluvastatins are not metabolized by ctochrome oxidase P450, so, they are not susciptible to major drug interactions. Other agents are dependent on this enzyme for their metabolism. Enzyme inhibitors increase the risk of myopathy when used with such statins. Examples of those enzyme inhibitors are: erytheromycin, azole antifungals, cimetedine, methotrexate, cyclosporin, gemfibrozil, verapamil and amiodarone.
  • Indications:
  1. Secondary prevention of coronary heart disease and cerebrovascular disease.
  2. Treatment of some dyslipidemias such as:
- primary hypercholesterolemia
- mixed dyslipidemias
- homozygous familial hypercholesterolemia
- selected cases of heterozygous familial hypercholesterolemia

  • Contraindications:
  1. Pregnancy and lactation: statins should not be given even to those women planning to get pregnant (statins should be stopped 6 months before getting pregnant).
  2. Active liver disease.
  3. Mypathies.
  • The following table summarizes the dosing of different statins:
Click on table to view

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