Refluxid Duo Mechanism of Action

Pharmacology: Mechanism of Action: Pantoprazole, a benzimidazole sulfoxide derived prodrug, is an irreversible proton-pump inhibitor. Pantoprazole, being a weak base, is highly ionized at low pH and readily accumulated in the highly acidic canalicular lumen of the stimulated parietal cell in the stomach. In this acidic environment, it is protonated and rapidly converted to a cationic cyclic sulfonamide. The sulfonamide binds covalently to cysteine residues on the luminal (acidic) surface of H+/K+-ATPase to form a mixed disulfide; thus causing irreversible inhibition of the gastric proton pump. This inhibition of the gastric proton pump or H+/K+-ATPase (which represents the final step in the secretory process), suppresses gastric acid secretion.
Domperidone, a benzimidazole derivative (structurally related to the butyrophenones), acts by selectively antagonizing the peripheral dopaminergic, receptors in the gastrointestinal wall, thereby enhancing gastrointestinal peristalsis and motility and increasing lower esophageal sphincter (LES) tone.
Rationale of Combination: The mode of action of both pantoprazole and domperidone are different and complimentary to each other. Upper gastrointestinal disorders are frequently associated with a combination of hyperacidity and dysmotility. As a result, acidic chyme may either stagnate in stomach and duodenum or may be evacuated by reverse peristalsis (vomiting or nausea). Reflux of acid contents of stomach cause erosions of lower part of esophagus which may further aggravate nausea and vomiting. Since both hyperacidity and dysmotility are present at the same time in disorders like gastroesophageal reflux disease (GERD) and nonulcer dyspepsia (NUD), a combination of drugs which will take care of both would be ideal. Pantoprazole is a potent gastric acid inhibitor that blocks the final stage of acid secretion. Hence, whatever may be the stimulus, hyperacidity will be controlled by pantoprazole. In contrast, domperidone increases gastrointestinal motility, thereby facilitating the movement of acid contents further down in the intestine preventing reflux esophagitis and thereby controlling nausea and vomiting. Hence, the pharmacology of pantoprazole and domperidone corroborates their use in combined form for the treatment of GERD, NUD and related disorders. Domperidone is usually administered at a dose of 10-20 mg, 2-3 times daily before meals. In order to enhance patient compliance, without compromising on its efficacy, domperidone SR is developed. Domperidone SR (30 mg) is for once-daily administration since its plasma t½ is otherwise 12-16 hrs.
Pharmacokinetics: Pantoprazole is rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) of 1.1-3.1 (mean 2.1) mg/L occurring within 2-4 (mean 2.7) hrs (tmax) after ingestion of an enteric-coated 40 mg tablet. The volume of distribution is low (mean 0.16 L/kg at steady state) due to high degree of plasma protein-binding (-98%). Plasma pantoprazole concentrations decline monophasically after oral administration, with a mean plasma terminal t½ (ty,P) of 0.9-1.9 hrs. However, since inhibition of acid secretion is noncompetitive or irreversible, there is no correlation between plasma levels and the duration of action of pantoprazole. Concomitant intake of food has no influence on the bioavailability of pantoprazole and any possible retardant effect of food on the rate of drug absorption is not of clinical relevance, considering the prolonged antisecretory action of pantoprazole. The enteric coating does not influence the bioavailability of pantoprazole. Pantoprazole undergoes extensive hepatic metabolism via cytochrome P-450 oxidase followed by sulfate conjugation. Elimination of pantoprazole is predominantly renal, with -80% of an oral dose being excreted as urinary metabolite; the remainder is excreted in the feces and originates primary from biliary secretion.
Domperidone is rapidly and almost completely (93%) absorbed after oral administration. Peak plasma concentrations occur within 30 min after oral administration. The peak plasma concentration value after a 20-mg oral dose is in the range of 15-19 ng/mL. The mean elimination t½ ranges from 12-16 hrs for an oral dose. Oral bioavailability of domperidone is 13-17% because of extensive presystemic metabolism in gut wall and liver. Administration of domperidone 90 min after a meal increases bioavailability whereas cimetidine or alkali pretreatment reduces bioavailability. Domperidone is strongly bound to plasma proteins (90-93%). Domperidone undergoes extensive biotransformation with <1%excreted unchanged in urine.