OMEPRAZOLE

Chemistry - A substituted benzimidazole proton pump inhibitor, omeprazole has a molecularweight of 345.4 and pKa's of 4 and 8.8.

Storage, Stability, Compatibility

Omeprazole tablets should be stored at room temperature inlight-resistant, tight containers. Omeprazole pellets found in the capsules are fragile and should notbe crushed. If needed to administer as a slurry, it has been suggested to mix the pellets carefullywith fruit juices and not water, milk or saline.

Pharmacology - OMEPRAZOLE

A representative of a new class of agent, the substituted benzimidazoles, omeprazole is a gastric acid (proton) pump inhibitor. In an acidic environment, omeprazole isactivated to a sulphenamide derivative that binds irreversibly at the secretory surface of parietal cellsto the enzyme, H+/K+ ATPase. There it inhibits the transport of hydrogen ions into the stomach.
Omeprazole inhibits acid secretion during both basal and stimulated conditions. Omeprazole alsoinhibits the hepatic cytochrome P-450 mixed function oxidase system (see Drug Interactionsbelow).
Uses, Indications - Omeprazole is potentially useful in treating both gastroduodenal ulcer diseaseand to prevent or treat gastric erosions caused by ulcerogenic drugs (e.g., aspirin). Because of thedrugs recent availability and high cost, experience is limited in domestic animals.

Pharmacokinetics - OMEPRAZOLE

Omeprazole is rapidly absorbed from the gut; the commercial product is in anenteric coated granule form as the drug is rapidly degraded by acid. Peak serum levels occur within0.5 to 3.5 hours and onset of action within 1 hour. Omeprazole is distributed widely, but primarilyin gastric parietal cells. In humans, approximately 95% is bound to albumin and alpha1-acidglycoprotein. It is unknown whether omeprazole enters maternal milk.
Omeprazole is extensively metabolized in the liver to at least six different metabolites, these areexcreted principally in the urine, but also via the bile into feces. Significant hepatic dysfunction willreduce the first pass effect of the drug. In humans with normal hepatic function, serum half lifeaverages about 1 hour, but the duration of therapeutic effect may persist for 72 hours or more.

Contraindications, Precautions, Reproductive Safety

Omeprazole is contraindicated in patients hypersensitive to it. Omeprazole should be used when the benefits outweigh the risks inpatients with hepatic disease or a history of hepatic disease, as the drug's half life may be prolonged and dosage adjustment may be necessary.
Omeprazole's safety during pregnancy has not been established, but a study done in rats at dosesof up to 345 times those recommended did not demonstrate any teratogenic effects. Increasedembryo-lethality has been noted in lab animals at very high dosages. It is unknown whetheromeprazole is excreted in milk.

Adverse Effects, Warnings

While veterinary use is quite limited, the drug appears to be quitewell tolerated in both dogs and cats at effective dosages. Potentially, GI distress (anorexia, colic, nausea, vomiting, flatulence, diarrhea) could occur as well as hematologic abnormalities (rare inhumans), urinary tract infections, proteinuria, or CNS disturbances. Chronic very high doses in ratscaused enterochromaffin-like cell hyperplasia and gastric carcinoid tumors; effects occurred in doserelated manner. The clinical significance of these findings for long term low-dose clinical usage isnot known. However, at the current time in humans, dosing for longer than 8 weeks is rarelyrecommended unless the benefits of therapy outweigh the potential risks.

Overdosage, Acute Toxicity

The LD50 in rats after oral administration is reportedly >4 g/kg.
Humans have tolerated oral dosages of 360 mg/day without significant toxicity. Should a massiveoverdose occur, treat symptomatically and supportively.

Drug Interactions

Because omeprazole can inhibit the cytochrome P-450 enzyme system, omeprazole may decrease the hepatic clearance of diazepam, phenytoin or warfarin, therebyenhancing their effects and causing potential toxicity. Additional monitoring and dosage adjustments may be required.
Because omeprazole can increase gastric pH, drugs that require low gastric pH for optimal absorption (e.g., ketoconazole, ampicillin esters or iron salts) may have their absorption reduced.
Although omeprazole causes bone marrow depression only rarely in humans, use with other drugsthat cause bone marrow depression may lead to additive hematologic abnormalities.
Laboratory Considerations - Omeprazole may cause increased liver enzymes. Omeprazolewill increase serum gastrin levels early in therapy.