Dr Sharon Rees @reesprescribe
Day 1, #atorvastatin: In the 1970s, a Japanese scientist, Akira Endo reviewed thousands of fungal ‘broths’, ultimately discovering Penicillium citrinum, which causes the blue-green mould on citrus fruit. An active metabolite ‘compactin’ was found. ‘Compactin’ was found to be structurally similar to HMG-CoA reductase, one of the enzymes needed for liver cholesterol synthesis. Compactin was discovered to be a competitive inhibitor of this enzyme, which controls the rate of cholesterol synthesis #prescribing
Dr Sharon Rees @reesprescribe
Day 2: Lovastatin was the first commercial statin licensed c.1987 (FDA), followed by simvastatin (semi-synthetic) and synthetic versions, such as #atorvastatin. Indications are primary and secondary prevention of cardiovascular events and primary and familial hypercholesterolaemia. All statins reduce triglycerides. #atorvastatin is 1st line for primary (20mg) and secondary (80mg) hypercholesterolaemia, despite primary dose unlicensed & secondary prev being an unlicensed indication. Nonetheless, there is grade A evidence for each #prescribing
Dr Sharon Rees @reesprescribe
Day 3: Mechanism of action: Cholesterol is made in the liver for use in bile salts, fat soluble vitamins, transport to cells etc. A key step is the conversion of HMG CoA to mevalonate by HMG CoA reductase. Statins such as #atorvastatin all inhibit this enzyme, halting cholesterol production. Sensing the reduced cholesterol level, liver cells up-regulate their cell surface low-density lipoprotein (LDL) receptors, extracting more LDL from blood. This lowers circulating cholesterol, ultimately helping to decrease atheroma formation and lower risk of heart attack and stroke #prescribing
Dr Sharon Rees @reesprescribe
Day 4: Metabolism of #atorvastatin is important, as primarily phase 1 liver CYP3A4 + substrate (drug and metabolites) of hepatic transporters. Hence multiple drug-drug interactions from inhibitors of CYP3A4 or transport proteins which increases ADR risk such as myopathy. Elimination in bile is also relevant for #atorvastatin re hepatic impairment cautions. Liver function tests are central to safe initiation & monitoring for duration of treatment; stop drug if transaminases > × 3 upper limit #prescribing
Dr Sharon Rees @reesprescribe
Day 5: Multiple adverse drug reactions possible. ‘Common' ones include myalgia, constipation, diarrhoea, headache and sleep disorders. MHRA state mild muscle pain 190 cases, myopathy five cases and rhabdomyolysis 1.6 cases each per 100,000 patient years. Statin enzyme breakdown begins in the GI tract by CYP3A4 enzymes. Grapefruit juice disables these enzymes for three days (time to replace CYP3A4 levels), so more statin drug is absorbed, increasing bioavailability & therefore increase the risk of ADRs. Volume of grapefruit juice to affect #atorvastatin is >1.2L #prescribing
Dr Sharon Rees @reesprescribe
Day 6: Why myalgia? Theories include low vit D (fat-soluble vitamin), myocyte membrane dysfunction, co-enzyme Q10 derivative of mevalonate, so decreased levels in high energy tissues such as muscle could cause fatigue/myalgia etc. Risk factors include renal impairment, elderly, alcohol abuse, low body mass. There are many branches from mevalonate pathway, so interference from statins/#atorvastatin has potential for numerous positive & negative effects. Could be anti-inflammatotry (augments CVD benefit?) and anti-tumour effect. Of note is increased diabetes risk, although the mechanism for this is unclear #prescribing
Dr Sharon Rees @reesprescribe
Day 7: Statins are a good example of the ‘nocebo' effect (opposite to placebo). Prior knowledge of an expected outcome e.g muscle pain, increases the risk of it happening. The pain/problem is real & can happen even when experiments include subjects who are not exposed to the drug! The nocebo issue is NOT a reason to withhold key safety information re adverse drug reactions. Patients are advised to report muscle pain, cramps, weakness, especially if also malaise/fever. The patient decision aid (NICE publication) is an excellent aid for statin understanding/concordance #prescribing