Statins Pharmacology, indications, side-effects and everything else!
What is cholesterol?What is it’s function? A ‘sterol’ that is mainly synthesised in the liver but is also obtained in the diet Cell membranes, precursor of steroids and steroid hormones, component of bile salts
Lipoprotein Lipase • Lipoproteins are catabolised (taken apart) by lipoprotein lipase • The remnant lipoproteins are removed by the liver through apolipoprotein E receptors or LDL receptors
Acetyl-CoA + Acetoacetyl-CoA HMG-CoA HMG-CoA reductase Mevalonate Isopentenyl Farnesyl Squalene Ianosterol CHOLESTEROL
Atherosclerosis …in one slide only!
The drugs Now we’re getting to the point!
What are the statins? • HMG-CoA reductase(3-hydroxy-3-methylglutaryl – coenzyme A) inhibitors • The rate limiting enzyme in cholesterol synthesis • Catlyses the conversion of HMG-CoA to mevalonic acid • The statins are specific, reversible, competitive inhibitors
Remember this? Statins knock off the production of cholesterol ↓ There is less available for bile acid synthesis ↓ Upregulation in the number of LDL receptors on hepatocyte surfaces ↓ Increased clearance of circulating LDL cholesterol ↓ Fatties can eat cake – not exactly
Other actions of statins • Some products of the mevalonate pathway (prenylate or farnesylate) are components of important membrane-bound enzymes • These fatty groups serve as anchorsand help with cell-signalling • This means they have other effects additionally to LDL-C effects • Some of these actions are undesireable • HMG-CoA reductase guides migrating primordial germ cells and therefore if we inhibit HMG-CoA reductase we may harm our baby – CI’d in pregnancy) • The mechanisms for these are either widely unknown or far too complicated For a GOLD STAR (to really suck up): Sometimes called their pleiotropic effects
Pleiotropic effects • Improved endothelial function • Reduced vascular inflammation • Reduced platelet aggregability • Increased neovascularisation of ischaemic tissue • Increased circulating endothelial progenitor cells • Stabilisation of atherosclerotic plaque • Atherothrombotic actions • Enhanced fibrinolysis • Inhibition of germ cell migration during development • Immune suppression • Protection against sepsis. The extent to which these effects contribute to the antiatheromatous actions of statins is unknown.
Pharmacokinetics (ADME) • Short-acting – given by mouth at night • Reduces peak cholesterol synthesis in the early morning • Well absorbed and extracted by the liver, their site of action • Metabolised via cytochrome P450 presystemically • Simvistatin is a pro-drug • Metabolised in the liver to it’s active form by cytochrome P450
Side-effects/Adverse effects • Mostly well tolerated, however…. • Myalgia and myositis • Dose related • Cervistatin was withdrawn due to severe myositis • Possibly due to those pesky bits we didn’t read about in the mevalonate pathway being needed for activation of muscle regulatory proteins • GIdisturbance (N&V, flatulence, diarrhoea) • Liver enzymes disturbed • NICE: Measure these before treatment, at 3 and 12 months • Don’t use in alcoholics and liver disease • CNS - Insomnia, dizziness and blurred vision • Rash • Serious, uncommon complications: • Rhabdomyolysis • Angio-oedema
Clinical application On the ward round and in the clinic what does it all mean?
In the clinic… • Secondary prevention – of MI and Stroke in those who have symptomatic disease • Primary prevention – arterial disease in patients with risk factors • NICE: “Statin therapy is recommended as part of the management strategy for the primary prevention of CVD for adults who have a 20% or greater 10-year risk of developing CVD calculated using an appropriate calculator”….”it is recommended that therapy should usually be initiated with a drug with a low acquisition cost” – as always it is not whether the treatment is effective but whether it is cost-effective that matters.
On the ward round… “Name me some trials that showed that statins can reduce mortality and morbidity?” • Scandinavian Simvistatin Survival Study (4S) • Patients with IHD and PlsChol 5.5-8.0 mmol/L – lowered death by 30% • CARE trial • Pts with established ischaemic heart disease reduced mortality • WOSCOPS (West of Scotland Coronary Prevention Study) and ASCOT • Mortality was reduced in healthy people at risk of CAD with a wide range of cholesterol levels and risk factors.
Drug flash-card • Name:STATINS (atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvistatin) • Action:HMG-CoA reductase inhibitors – HMG-CoA reductase is the rate-limiting step in the manufacturing of cholesterol within the liver. • Reducing the amount of cholesterol produced causes up-regulation of LDL receptors causing a reduction in free LDL levels (also reduced VLDL and mild increase in HDL) • Also has pleiotropic effects – mechanisms unknown • Clinical application: Primary and secondary prevention of atheromatous disease (MI and Stroke); Treatment of Familial Hypercholesterolaemia • ADME:short-acting, taken orally, well-absorbed in the liver, metabolised by CYP450 • Side-effects:GI, CNS, Muscle, liver enzyme disturbance (monitor LFTs) • Severe – rhabdo + AE • Other info: Trials - 4S’s, CARE, WOSCOPS, ASCOT
One interesting thing I have read this week related to last weeks pharm group! Nimodipine
Nimodipine • Dihydropyridine calcium channel blocker (CCB) origionallydeveloped for controlling HTN • Not used for this indication anymore • Used for preventing major complications of subarachnoid haemorrhage, specifically vasospasm (which causes the ischaemiaand resulting permanent brain injury) • This is because it is SELECTIVE for the cerebral vasculature • Remember CPP=MAP-ICP
Catabolism and anabolism • Metabolism referes to biochemical processes that occur within any living organism to maintain life. • Greek metabole meaning ‘change’ • Anabolism and catabolism are what make metabolism up – they are the 2 phases of metabolism • All organisms simultaneously conduct anabolism and catabolism • As with every body system – it’s all about balance! • Anabolism is the BUILDING of simpler molecules to form complex compounds • Amino acids →proteins→cells→tissues→systems→organisms • Catabolism is the BREAKDOWN of molecules into smaller units • Usually releases energy during this process.
Upregualtion and downregulation • Downregualtion – the process by which a cell decreases the quantity of a cellular component in response to an external variable • Upregulation - the process by which a cell increases the quantity of a cellular component in response to an external variable • Example: • Decrease in the number of receptors to a molecule such as a hormone or neurotransmitter which reduces the cell’s sensitivity to the molecule. • Locally acting negative feedback mechanism • Increased numbers of NMDA glutamate receptors found in alcoholics (thereby inhibiting those same receptors) • Pregnancy receptors cause the uterus to become more sensitive to oxytocin
1 2 Insulin (hormone) Insulin-specific receptor on cell surface Lysosomal enzyme 3
Chlyomicrons • Chylomicrons are one of the five major groups of lipoproteins. • They are produced in absorptive cells of small intestines. • They transport exogenous lipids to liver, adipose, cardiac and skeletal muscle tissue where their triglyceride components are unloaded by the activity of lipoprotein lipase. • As a consequence, chylomicron remnants are left over and are taken up by the liver.
An interesting read! AtherosclerosisVolume 177, Issue 2, December 2004, Pages 219–234 Review:Pharmacogeneticsof HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management