PharmacologyTier 2Medical Sciences concept

Proton pump inhibitor adverse effects (hypomagnesaemia, B12 deficiency, fracture risk)

Core concept

PPIs irreversibly inhibit the gastric H+/K+-ATPase in the parietal cell canaliculus
- Prodrugs, activated only in an acid compartment -> take 30-60 min before food when pumps are being recruited
- Covalent binding -> effect outlasts the plasma half-life (~1 h); new pump synthesis takes 24-48 h
Almost all adverse effects follow from one of two consequences
- Loss of gastric acid -> impaired absorption, impaired barrier to ingested organisms
- Compensatory hypergastrinaemia -> ECL cell hyperplasia, rebound acid hypersecretion on withdrawal

Effect	Mechanism	Strength of evidence
Hypomagnesaemia	dec active TRPM6/7-mediated intestinal Mg uptake	Established; often after >1 year
B12 deficiency	Acid and pepsin needed to release B12 from dietary protein	Established, long-term use
Iron deficiency	Acid needed to reduce Fe3+ to absorbable Fe2+	Established
Enteric infection	Loss of the gastric acid barrier	Established - C. difficile, campylobacter, salmonella
Hypocalcaemia	Secondary to refractory hypomagnesaemia (Mg needed for PTH release and action)	Established
Fracture	Ca absorption, and confounding	Association only; modest
Acute interstitial nephritis	Idiosyncratic, T-cell mediated	Established, uncommon
CKD, dementia, pneumonia, mortality		Confounded observational associations

Refractory hypocalcaemia and hypokalaemia that will not correct -> check the magnesium, and ask about the PPI
- Low Mg -> dec PTH secretion and PTH resistance; also inc ROMK activity -> renal K wasting
- Correcting Mg is the only thing that fixes it; the PPI usually has to stop
Interactions
- dec absorption of drugs needing acid - ketoconazole, itraconazole, atazanavir, mycophenolate, iron salts
- Omeprazole and esomeprazole inhibit CYP2C19 -> theoretical dec clopidogrel activation; pantoprazole is the preferred PPI with clopidogrel
Rebound acid hypersecretion on abrupt withdrawal after >8 weeks - taper, or step down to an H2 antagonist
PPIs mask gastric cancer symptoms and reduce the yield of H. pylori testing (stop 2 weeks before urea breath test or antigen)

Deprescribing is the clinical point - a large proportion of long-term PPI use has no ongoing indication
- Continue indefinitely: Barrett oesophagus, severe erosive oesophagitis, Zollinger-Ellison, long-term NSAID or antiplatelet with high GI risk, previous bleeding ulcer
- Step down or stop: uncomplicated reflux, dyspepsia, "stress ulcer prophylaxis" continued after discharge
Monitor magnesium (and B12, iron) in anyone on long-term therapy, especially with a diuretic, digoxin or diarrhoea
A patient with hypomagnesaemia, hypocalcaemia and hypokalaemia on a PPI and a thiazide is a stock exam vignette
Post-ICU and post-surgical PPIs are a common source of unintentional lifelong prescriptions - review at discharge

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.