Proton Pump Inhibitors
A Curate’s Egg?
Dr John O’Malley
MA MB ChB MRCGP
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This f***ing egg is off!
This is a
fantastic drug
It has an
important role in
treating x
Why didn’t we realise
it has horrendous side
effects?
PPIs
£1 billion NHS costs
Globally £40 Billion
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
Pharmacology 2
But.... Lasts for 24 hours
No tachyphylaxis
The Proton Pump
H2 Antagonists
Atropine
Proton Pump
Inhibitors
Text
Text
Good bits
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
And the bad bits?
Side effects
Slow response
Headaches
Rashes
Diarrhoea
Abdominal pain
Flatulence
Interactions
Problems
Interstitial nephritis
Osteoporosis
Vitamin B12 absorption
C. Diff and other infections
Microscopic colitis
Inappropriate investigation and referral
And when we should, we
don’t
Underuse
•
Gastroprotection
•
Oesophageal strictures
•
? Barrett’s oesophgus
Gastroprotection
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 gastrointestinal
bleeding 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
45-64
3230
5
1 in 646
1 in
12353
1 in 3800
65-74
2280
4
1 in 570
1 in 3353
75+
1540
14
Anon. Cox-21
roundup.
Bandolier
1 in 110
in 647
2000;75
ACUTE Vs CHRONIC NSAID
USE
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 TO
HARM
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 23
years
318 (152- 979)
82 (41-181)
No previous
ulcer drug use
or
hospitalisation
Ulcer drug
18
411 (196- 1266) 106 (52-233)
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)
SSRIs and NSAIDs
Do PPIs work?
Drug
Risk of UGIB
NSAID
5.3
Rofecoxib
2.1
Paracetamol
0.9
NSAID and PPI
0.9
Number needed to treat
to avoid a peptic ulcer in
elderly NSAID/aspirin
users...........
3
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
Cost
Resource
Mean cost £
Minimum
Maximum
Diagnostic
endoscopy
Therapeutic
endoscopy
GI opd
Surgical
procedure
Rebleed
costs
435.38
282.68
650.67
1158.61
682.1
1532.73
72
3181.80
50
1731
84
3804.13
17025
14619
19964
Omeprazole cost
• 28
days of 20mg/day
=£1.62
Conclusion
•
Right person with the right drug gives the right
outcome
Problems
Interstitial nephritis
Osteoporosis
Vitamin B12 absorption
C. Diff and other infections
Microscopic colitis
Inappropriate investigation and referral
Interstitial nephritis
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?
Iron deficiency
Iron absorption
? Long term, high dose PPI link
Theoretical but not proven
Vitamin B12 Deficiency
B12 bound to protein
Pepsin needed
B12 levels reduced but significant deficiency?
Infections
PPI use and Salmonella/ campylobacter
Clostridium Difficile
infection
Gram positive bacteria
Anaerobic spore forming
Severe diarrhoea
Can lead to pseudomembranous colitis
Toxic megacolon
Absent gut flora
PPI problems
Often taken as antacids
Not all reflux is acid
Misdiagnosis
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
63%
33%
67%
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
So who do we need to
treat more?
Who should we treat
more?
NSAID
Aspirin
And who less?
Rebound hyperacidity
Prolonged treatment
Increased parietal cell mass
Peaks at 2 weeks.
Problems caused
Increased use of PPIs
Unwillingness to try step down
Gastroscopies
Overuse/ wrong use
40% ‘unknown reason’
Mean duration of use 450 days
50% taking drugs that cause or worsen GORD
18% smokers
GORD and effect of
medication
H2 blockers 30-60 minutes
PPI 24 hours
Step down
42% couldn’t be stepped down
43% reduced need for PPI or changed to
antacid/alginate or H2RA
15% stopped completely
Lifestyle
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........
PPIs
•
Used too much
•
Used not enough
•
‘Lifestyle drug’
Thank you