Proton pump inhibitors (PPI)

Discuss the mechanism of action of PPI’s?

  • PPI’s are absorbed in the proximal small bowel and then carried in the circulation and delivered to the parietal cell as prodrugs.
  • The PPI’s are activated in the parietal cell and binds covalently with the H+/K+ ATPase enzyme on the parietal cell (final common pathway for acid secretion) that results in irreversible inhibition of acid secretion by the proton pump. The parietal cell must then produce new proton pumps or activate resting pumps to resume its acid secretion
  • The elimination half-life for current PPIs is typically around 1–2 hours; however their duration of action is much longer because of the irreversible inhibition of the proton pump. Half-lives for the recovery of gastric acid secretion range from less than 15 h for lansoprazole, through around 28 h for omeprazole, to around 46 h for pantoprazole

What are the indications for the use of PPI?

  • Peptic ulcer
  • GORD
  • Hypersecretaory conditions like ZES
  • Prophylaxis for peptic ulcer in critically ill patients
  • HP infection
  • Dyspepsia

Discuss the therapeutic equivalence of PPI’s?

  • Standard doses of PPIs (esomeprazole 20 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg) are therapeutically equivalent.
  • The PPIs may be considered for therapeutic interchange because of their comparable pharmacologic properties and clinical efficacy and safety profiles.
  • However, subsets of patients may experience uncontrolled symptoms, more adverse effects, or a negative impact on health outcomes when switched from one PPI to another. This observation is expected after drug conversion, since individual variability in responses to drugs is seen even within the same therapeutic class.

Discuss the drug-drug interactions for PPI?

  • Clinically significant PPI drug-drug interactions are rare, less than one per million
  • The two main mechanisms of drug-drug interactions relevant to PPIs are
    • Inhibition or induction of CYP450 isoenzymes
    • Alteration of drug absorption.
  • The profound inhibition of gastric acid secretion by PPIs results in decreased plasma concentrations of ampicillin, iron salts, and ketoconazole.
  • There are few clinically relevant drug interactions with the PPIs. The most important interaction appears to be reduction in clearance of diazepam by omeprazole or esomeprazole via CYP2C19 inhibition. Reduction of the benzodiazepine dose, use of a benzodiazepine that is metabolized by glucuronidation (lorazepam, oxazepam, or temazepam), or the use of another PPI may be a consideration in individuals who develop an adverse interaction from the drug combination.

Interactions between warfarin or phenytoin and the PPIs, including omeprazole, do not seem to be clinically relevant when studied in controlled trials except in certain individuals.

Discuss the interaction between clopidogrel and PPI?

Clopidogrel is metabolised by the liver to an active molecule that inhibits platelet aggregation however evidence is emerging that some PPIs inhibit this pathway and may increase the risk of adverse cardiac outcomes.
The EU Committee for Medicinal Products for Human Use (CHMP) recently concluded that PPIs reduce the effectiveness of clopidogrel in preventing the recurrence of adverse cardiac events. They recommend use of these medicines together should be avoided unless considered essential.

Discuss dose adjustment for PPIs?

Dosage adjustment (reduce dose) of the PPIs may be necessary in patients with hepatic impairment.  None of the PPIs require dosage adjustment in renal impaired or elderly patients.

Discuss the side effects of PPIs?

  • The frequency of adverse effects associated with PPIs is similar to that of placebo, with an overall incidence of less than 5 percent.
  • Headache, diarrhoea, and abdominal pain were usually the most common adverse events (>= 2%) Flatulence, nausea and vomiting are other adverse GI effects besides allergic reactions.
  • Hypergastrinemia and carcinoid tumours- The rat data was the risk elevated gastrin leads to hyperplasia of gastric enterochromaffin-like (ECL) cell and carcinoid tumours.  The human data showed time- and dose-related increases in the frequency of ECL cell hyperplasia and hypergastrinemia in patients treated with PPIs for 6 months to 5 years, however no dysplastic or neoplastic changes of the ECL cells in the gastric mucosa have been detected and no patient has developed the carcinoid tumours. So, this is a
  • species-specific problem.
  • PPI and enteric infections- Achlorhydria disables the gastric barrier to ingested pathogens. In case control studies there is a small increase in enteric infections with PPIs .  PPI use is also been suggested to increase the risk of C. Difficile, however this has not been proven.
  • PPI use has also been associated with hip fractures and community-acquired pneumonia. These associations are not proven.
  • There is no documentation of increased atrophic gastritis with H Pylori infection and concomitant PPI use. Thus evaluation of H Pylori and treatment are not recommended with PPI use.

Discuss the timing of PPI treatment?
PPI are activated in the parietal cells to active moiety. This activation happens only in an acidic parietal cell environment. Thus PPI are most active when the parietal cell is stimulated to secrete acid post meals. This has important clinical implications for timing of administration. Thus PPI’s should be taken with or shortly before meals. For the same reason, PPI work poorly in those receiving other anti secretory drugs like H2RA or anticholinergic agents.

Discuss the safety of PPI in pregnancy and breast feeding?

  • The most safety data is available with omeprazole as it was the first PPI introduced. BNF mentions that it is not known to be harmful in pregnancy or breast feeding.  BNF suggests that other PPI’s should be avoided if possible in pregnancy and breast feeding.
  • European network of Teratology Information Services concluded that PPIs do not represent a major teratogenic risk in humans.

Discuss the available PPI preparations?

  • IV preparation is available for omeprazole, esomeprazole and pantoprazole
  • Orodispersible tabs (lansoprazole fast tab)-Tablets should be placed on the tongue, allowed to disperse and swallowed or may be swallowed whole. Alternatively tablets can be dispersed in a small amount of water and administered by an oral syringe or NG tube.
  • Omeprazole and lansoprazole is available in capsule forms. In cases of difficulty in swallowing- the capsules can be opened and the granules sprinkled in juice and can be administered orally or via NG tube

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