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

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Esomeprazole

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

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.

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

Proton Pump Inhibitor

• 2-pyridylmethylsulfinylbenzimidazole derivative: 1972

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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

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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?