Proton Pump Inhibitor

PHRM 304

Proton Pump
Involve in final step of acid secretion Membrane pump: H+/K+- ATP ase Participate in exchange of hydrogen ion for potassium ion

Proton Pump Inhibitor

Act beyond the second messengers (Ca++, cAMP) Independent of the action of secretogogue (histamine, gastrin and acetylcholine)

Example
Omeprazole Esomeprazole Lansoprazole Rabeprazole Pantoprazole

 Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established racemates.

 Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.

Esomeprazole
S-enantiomer of omeprazole First proton pump inhibitor developed as a single isomer for the treatment of acid-related diseases

Esomeprazole
Eliminated 3 times slowly than R isoform, thus has prolong half life (due to slow metabolism)

http://www.nature.com/nrd/journal/v2/n2/fig_tab/nrd1010_F3.html

The large-scale production of esomeprazole is achieved by asymmetric oxidation of the same sulphide intermediate as is used in the production of omeprazole, which gives a 94% enantiomeric excess (ee). This is increased to 100% by preparing a magnesium salt of of esomeprazole and then performing a crystallization.

Proton Pump Inhibitor

2-pyridylmethylsulfinylbenzimidazole derivative: 1972

Proton Pump Inhibitor: Activation

Proton pump inhibitors (PPIs) are prodrug, that require activation in an acid environment. PPIs are lipophilic, weak base PPIs specifically concentrate in the acidic secretory canaliculi of the parietal cell. PPIs concentrated >1000 fold within parietal cell canaliculus.

Proton Pump Inhibitor: Activation

Here, it is activated by proton-catalyzed formation of a tetracyclic sulfenamide, trapping the drug so that it cannot diffuse back across the canalicular membrane.

Cysteine

Tetracyclic sulfenamide

Fig: Mechanism of action of PPIs

Ref: Wilson & Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th ed

Proton Pump Inhibitor: M/A

The sulphenamide interacts covalently with the sulphydryl groups of cysteine residues in the extracellular domain of the H+/K+-ATPase. Evidence indicates that two molecules of the intermediate from omeprazole are bound to the active site; one of these sites has been identified as cysteine-813 (and, probably, cysteine-892 and/or -822) of the cysteine-rich H+/K+-ATPase

Proton Pump Inhibitor: M/A

In the covalent binding, a disulphide bond to the proton pump is formed. Different proton pump inhibitors bind differentially to cysteines and other sulfhydryl groups. Analogous, but slightly different, results are reported for lansoprazole, pantoprazole, and rabeprazole.

Mechanism of action

Plasma

http://www.nature.com/nrd/journal/v2/n2/fig_tab/nrd1010_F2.html

PPI: Administration
Since an acidic pH in the parietal cell or acid canaliculi is required for drug activation, and since food stimulates acid production, these drugs ideally should be given about 30 minutes before meals.

PPI: Dosage Form

Activation occurs at strongly acidic pH Acid stable oral dosage form required to ensure the dissolution, release and absorption of drug in intestine Dosage form may be: enteric coated granules in capsules or enteric coated tablets If PPI release in stomach what will happen???

PPI: Kinetics
PPIs enter parietal cell from the blood, accumulate in acid space where they are activated (formation of sulfenamide). T1/2 = 1 hour Irreversibly inhibit the proton pump Long duration of acid inhibition (>24 hours) Excreted in feces and urine

PPI: CaCO3 absorption

Essential for elderly women In vitro CaCO3 disintegration and dissolution depends on pH: At pH 1: 96% At pH 6.1: 23% Omeprazole changed the stomach pH from 1.3 to 5.5 If two drugs co-administer what will happen?