1. Proton Pump Inhibitors A Curate’s Egg? Dr John O’Malley MA MB ChB MRCGP

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8. This f***ing egg is off!

9. This is a fantastic drug Why didn’t we realise it has horrendous side effects? It has an important role in treating x

12. PPIs £1 billion NHS costs Globally £40 Billion

13. Pharmacology Unstable at acid ph Parietal cell not stomach activation Act by forming a irreversible bond with cysteine residues in the proton pump Short pharmacological half life

14. Pharmacology 2 But.... Lasts for 24 hours No tachyphylaxis

15. Text Atropine H 2 Antagonists Proton Pump Inhibitors The Proton Pump

16. Good bits

17. Dyspepsia Reflux Barretts/? Prevention of cancer Prevention of strictures Diagnostic test Upper GI bleeding Ulcer prophylaxis in NSAIDs and aspirin Ulceration/ HP eradication Zollinger Ellison Syndrome

18. And the bad bits?

19. Side effects Slow response Headaches Rashes Diarrhoea Abdominal pain Flatulence Interactions

20. Problems Interstitial nephritis Osteoporosis Vitamin B12 absorption C. Diff and other infections Microscopic colitis Inappropriate investigation and referral

21. And when we should, we don’t

22. Underuse Gastroprotection Oesophageal strictures ? Barrett’s oesophgus

23. Gastroprotection

24. NICE 2001 Recommendations for patients for whom a regular NSAID is absolutely necessary: Patients at any age with existing cardiovascular disease, including patients on low dose aspirin: Standard NSAID e.g. ibuprofen, diclofenac or naproxen +misoprostol or PPI if misoprostol not tolerated. Patients aged 65+ with no cardiovascular risk factors and not onaspirin: Consider Cox-II selective inhibitor (not sure on that one!) All other patients i.e. patients < 65 with no other risk factors*: Standard NSAID e.g. ibuprofen or diclofenac

25. Risk factors for GI complications with NSAIDs Age Previous ulcer, bleed or perforation Concomitant drug treatment (steroids,anticoagulants, SSRIs) Co-morbidity (CVD, renal and hepatic impairment, etc.) Rheumatoid Arthritis NSAID dosage and duration.

26. HP eradication Maastricht -3 2005 Chronic NSAID users Naive NSAID users – test and treat Long term aspirin users – test and treat PPI is superior in preventing ulcers

27. Risk of NSAID related gastrointestinal bleeding by age for population 100,000 Age RangeNumber taking NSAIDNumber with GI bleedRisk in any one year of a GI bleed due to NSAID Risk in any one year of dying from GI bleed due to NSAID 16-44210011 in 21001 in 12353 45-64323051 in 6461 in 3800 65-74228041 in 5701 in 3353 75+1540141 in 1101 in 647 Anon. Cox-2 roundup. Bandolier 2000;75

28. ACUTE Vs CHRONIC NSAID USE Drug exposureOR (95%CI) for GUOR (95% CI) for DU Non use11 Acute use4.47 (3.19-6.26)2.39 (1.73 – 3.31) Chronic use2.80 (1.97 – 3.99)1.68 (1.22- 2.33)

29. SSRIs AND UGIH “Our meta-analysis shows that SSRIs more than double the risk of UGIH and concomitant NSAID use increase the risk of UGIH by 500%” Loke et al. Alim. Pharm. Therapeutics 2007

30. SSRIs: NUMBER NEEDED TO HARM Patient populationBaseline upper GI Event Rate NNH per year with SSRI ( 95% CI) NNH per year with SSRI AND NSAID( 95% CI) Unselected >50 years 23318 (152- 979)82 (41-181) No previous ulcer drug use or hospitalisation 18411 (196- 1266)106 (52-233) Ulcer drug42177 (85-545)46 (24- 101) Hospitalisation62121 (58 – 370)32 (17-69) Ulcer drug use and hospitalisation 10870 (34 -214)19 (10-41)

31. SSRIs and NSAIDs

32. Do PPIs work? DrugRisk of UGIB NSAID5.3 Rofecoxib2.1 Paracetamol0.9 NSAID and PPI0.9

33. Number needed to treat to avoid a peptic ulcer in elderly NSAID/aspirin users...........

34. 3

35. Compliance - GPs “In individual studies in primary care adherence to prescribing guidelines varied from 9% to 27%.”

36. Compliance - patients “...adherence to NSAID plus PPI or H2RA declined rapidly, so that after 6 months the majority of patients were not taking gastroprotection prescribed.” Moore et al. BMC Musculoskeletal Disorders 2006; 7:79

37. Cost ResourceMean cost £MinimumMaximum Diagnostic endoscopy 435.38282.68650.67 Therapeutic endoscopy 1158.61682.11532.73 GI opd725084 Surgical procedure 3181.8017313804.13 Rebleed costs 170251461919964

38. Omeprazole cost 28 days of 20mg/day =£1.62

39. Conclusion Right person with the right drug gives the right outcome

40. Problems Interstitial nephritis Osteoporosis Vitamin B12 absorption C. Diff and other infections Microscopic colitis Inappropriate investigation and referral

41. Interstitial nephritis

42. 15% of all acute admission with acute kidney damage Immune mediated? Can lead to severe kidney damage Who checks kidney function?

43. Osteoporosis UK study (GPRD) 13,556 patients with hip fracture Risk 1.4 after using PPI for >1 year Risk 2.65 if long term high dose

44. Causal? Reduces absorption of dietary calcium Inhibits magnesium absorption Also inhibit osteoclasts ? Prevent osteoporosis Coincidental?

45. Iron deficiency Iron absorption ? Long term, high dose PPI link Theoretical but not proven

47. Vitamin B12 Deficiency B12 bound to protein Pepsin needed B12 levels reduced but significant deficiency?

48. Infections PPI use and Salmonella/ campylobacter

49. Clostridium Difficile infection Gram positive bacteria Anaerobic spore forming Severe diarrhoea Can lead to pseudomembranous colitis Toxic megacolon Absent gut flora

51. PPI problems Often taken as antacids Not all reflux is acid Misdiagnosis

52. 50-60% of PPI scripts there is no or an inappropriate reason for prescribing £100 million in the NHS wrongly prescribed £2 billion worldwide Decrease in price but increase use has increased costs PPIs make up 90% of the drug budget for dyspepsia

53. 63%

54. 33%

55. 67%

56. NICE NICE Guidance 2000 Treat with healing doses then step down Shortest length of treatment with smallest dose No long term use without definitive diagnosis

57. NICE Dyspepsia Guidelines 2004 Check if PPI needed Lifestyle advice Avoid precipitants Educate Review need

59. So who do we need to treat more?

60. Who should we treat more? NSAID Aspirin

61. And who less?

62. Rebound hyperacidity Prolonged treatment Increased parietal cell mass Peaks at 2 weeks.

64. Problems caused Increased use of PPIs Unwillingness to try step down Gastroscopies

65. Overuse/ wrong use 40% ‘unknown reason’ Mean duration of use 450 days 50% taking drugs that cause or worsen GORD 18% smokers

66. GORD and effect of medication H2 blockers 30-60 minutes PPI 24 hours

67. Step down 42% couldn’t be stepped down 43% reduced need for PPI or changed to antacid/alginate or H2RA 15% stopped completely

68. Lifestyle

69. Lifestyle changes Obesity Smoking Raising the head of the bed Decrease fat intake ( chocolate, peppermint, garlic and onions) Large volume meals Rich energy dense meals Low dietary fibre Alcohol decrease

70. Lifestyle Only reduce severity and frequency Very few patients do it well And some don’t want to........

71. PPIs Used too much Used not enough ‘Lifestyle drug’

72. Thank you