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This is a fantastic drug
Why didn’t we realise it has
horrendous side effects?
It has an important role in treating x
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
Dyspepsia
RefluxBarretts/? Prevention of cancerPrevention of stricturesDiagnostic testUpper GI bleedingUlcer prophylaxis in NSAIDs and aspirinUlceration/ HP eradication
Zollinger Ellison Syndrome
Problems
Interstitial nephritis
Osteoporosis
Vitamin B12 absorption
C. Diff and other infections
Microscopic colitis
Inappropriate investigation and referral
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
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.
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
Risk of NSAID related gastrointestinalbleeding by age for population 100,000
Age Range Number taking NSAID
Number with GI bleed
Risk in any one year of a GI bleed due to NSAID
Risk in any one year of dying from GI bleed due to NSAID
16-44 2100 1 1 in 2100
1 in 12353
45-64 3230 5 1 in 646 1 in 3800
65-74 2280 4 1 in 570 1 in 3353
75+ 1540 14 1 in 110 1 in 647
Anon. Cox-2 roundup. Bandolier2000;75
ACUTE Vs CHRONIC NSAIDUSE
Drug exposure OR (95%CI) for GU OR (95% CI) for DU
Non use 1 1
Acute use 4.47 (3.19-6.26)
2.39 (1.73 – 3.31)
Chronic use 2.80 (1.97 – 3.99)
1.68 (1.22- 2.33)
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
SSRIs: NUMBER NEEDED TOHARM
Patient population Baseline upper GI Event Rate
NNH per year with SSRI ( 95% CI)
NNH per year with SSRI AND NSAID( 95% CI)
Unselected >50 years
23 318 (152- 979)
82 (41-181)
No previous ulcer drug use or hospitalisation
18 411 (196- 1266)
106 (52-233)
Ulcer drug 42 177 (85-545) 46 (24- 101)
Hospitalisation
62 121 (58 – 370)
32 (17-69)
Ulcer drug use and hospitalisation
108 70 (34 -214) 19 (10-41)
Compliance - GPs
“In individual studies in primary care adherence to prescribing guidelines varied from 9% to 27%.”
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
CostResource Mean cost £ Minimum Maximum
Diagnostic endoscopy
435.38 282.68 650.67
Therapeutic endoscopy
1158.61 682.1 1532.73
GI opd 72 50 84Surgical procedure
3181.80 1731 3804.13
Rebleed costs
17025 14619 19964
Problems
Interstitial nephritis
Osteoporosis
Vitamin B12 absorption
C. Diff and other infections
Microscopic colitis
Inappropriate investigation and referral
Interstitial nephritis
15% of all acute admission with acute kidney damage
Immune mediated?
Can lead to severe kidney damage
Who checks kidney function?
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
Causal?
Reduces absorption of dietary calcium
Inhibits magnesium absorption
Also inhibit osteoclasts
? Prevent osteoporosis
Coincidental?
Vitamin B12 Deficiency
B12 bound to protein
Pepsin needed
B12 levels reduced but significant deficiency?
Clostridium Difficile infection
Gram positive bacteria
Anaerobic spore forming
Severe diarrhoea
Can lead to pseudomembranous colitis
Toxic megacolon
Absent gut flora
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
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
NICE Dyspepsia Guidelines 2004
Check if PPI needed
Lifestyle advice
Avoid precipitants
Educate
Review need
Overuse/ wrong use
40% ‘unknown reason’
Mean duration of use 450 days
50% taking drugs that cause or worsen GORD
18% smokers
Step down
42% couldn’t be stepped down
43% reduced need for PPI or changed to antacid/alginate or H2RA
15% stopped completely
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
Lifestyle
• Only reduce severity and frequency
• Very few patients do it well
• And some don’t want to........