Lecture 33 Flashcards
What are statins?
A class of drug that is used to prevent coronary heart disease by improving the lipid profile of at risk patients They are specific reversible inhibitors of the hepatic enzyme HMG-CoA reductase
What is the mechanism of statin drugs?
Through inhibiting HMG-CoA reductase the conversion of Acetyl-CoA to mevalonate and eventually cholesterol is blocked
As cholesterol is required for certain functions such as membrane synthesis and production of steroidal hormones the LDL in the blood will be taken up to obtain the cholesterol resulting in a decrease in blood cholesterol levels
Statins also increase HDL through and unknown mechanism
What are the indirect actions of statins?
Decreased mevalonate biosynthesis has non-lipid mediated effects which cause altered localisation and activity of proteins e.g. NOS and thromboxanes
There are also independent actions where there appears to be anti-inflammatory effects and reduced bone resorption
What are the pharmacodynamic and pharmacokinetic features of statin drugs?
They are well absorbed orally reaching Cmax in 1-2h
Terminal half-lives vary from 14h to 77h
Therapeutic effect are observed in 1-2 weeks with maximal effects occur within 4-6 weeks
Lipid reduction maintained over years at close to maximal levels
Clinical effects on outcome apparent after several months
What are the dose response issues of statin drugs?
Plasma concentrations vary widely across individuals however therapeutic levels are only weakly related to plasma levels
Statins exhibit a sigmoidal curve increasing the dose above IC50 results in minor changes in effectiveness
Occurrence of side effects increases with increased dose so there is only a narrow therapeutic window
What is atorvastatin?
Lipophilic, crosses by passive diffusion
More effective/potent lipid lowering drug of the first generation of statins
What is simvastatin?
A statin which is lipophilic, crossing by passive diffusion
is a prodrug that is metabolized in the liver to the active beta-hydroxy fatty acid form
What is pravastatin?
A statin which is hydrophilic and actively pumped into the hepatocyte
Has a lower risk of myopathies and fewer significant drug interactions, longer halflife and lower protein binding profile
What are the drug interactions of statins?
CYP3A4 and 2A9 are involved in statin metabolism
Inhibitors of these can lead to toxicity
These include cyclosporin, ketoconazole, erythromycin, verapamil, grapefruit juice and protease inhibitors
Co-administration with other lipid lowering drugs can cause myopathy
What are the clinical trials that were used to show statin efficacy and safety?
Scandinavian simvastatin survival study
West scotland coronary prevention study
cholesterol and recurrent events
long-term intervention with pravastatin in ischaemic disease study
texas coronary aterhoslecorsis prevention study
What is the relationship between benefits of statin treatments and the patients baseline cholesterol?
Those with the highest baseline cholesterol and higher risk get the greatest benefit from the drug
What was determined by the landmark statin trials?
Statins reduced LDL-Cholesterol levels in various high risk populations by 30%
Statins were moderately effective in lowering triglyceride levels and raising HDL levels
Roughly linear relationship between LDL cholesterol levels and frequency of CHD events
Statins reduced the risk of coronary events by 30%, CHD mortality by 20-42% and stroke by 29%
Patients with highest risk benefit the most from treatment
Evidence for secondary prevention is much stronger than the evidence for primary prevention
What are the adverse effects of statins?
Rare cases of hepatotoxicity, Myoositis, angio-oedema, dementia, cancer, peripheral neuropathy, insomnia/headaches/memory impairment, rash/flu symptoms, GI disturbance, elevated liver ALT release
What is the relationship between dose and adverse effects for statin drugs?
A few have their incidence increase with dosage but many of the less common ones do not resulting in the idea these may be due to genetics
What are the pharmacoeconomics of statins?
Statins are very lucrative for drug companies as they are widely used with some consideration being given to if these drugs should be available over the counter
There is rising competition from generic alternatives
It is a cost effective therapy when compared to other interventions
