Statins

1. Statins Pharmacology, indications, side-effects and everything else!

2. 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

4. Lipoproteins

5. 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

6. Acetyl-CoA + Acetoacetyl-CoA HMG-CoA HMG-CoA reductase Mevalonate Isopentenyl Farnesyl Squalene Ianosterol CHOLESTEROL

8. One more difficult point, I promise!

9. Atherosclerosis …in one slide only!

11. The drugs Now we’re getting to the point!

12. 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

13. 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

14. 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

15. 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.

16. 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

17. 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

18. Clinical application On the ward round and in the clinic what does it all mean?

19. 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.

21. 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.

22. 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

23. One interesting thing I have read this week related to last weeks pharm group! Nimodipine

24. 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

25. 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.

26. 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

27. 1 2 Insulin (hormone) Insulin-specific receptor on cell surface Lysosomal enzyme 3

28. Pro-drugs

29. 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.

30. 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