Proton Pump Inhibitors

A Curate’s Egg?Dr John O’Malley

MA MB ChB MRCGP

www.pcsg.org.uk

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This f***ing egg is off!

This is a fantastic drug

Why didn’t we realise it has

horrendous side effects?

It has an important role in treating x

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

TextTextAtropine

H2 Antagonists

Proton Pump Inhibitors

The Proton Pump

Good bits

Dyspepsia

RefluxBarretts/? Prevention of cancerPrevention of stricturesDiagnostic testUpper GI bleedingUlcer prophylaxis in NSAIDs and aspirinUlceration/ 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 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)

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

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

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