Lafutidine

Lafutidine

Lafutidine (INN) is a second generation H2 receptor antagonist having multimodal mechanism of action. It is currently marketed in Japan (Stogar) [1] China (Lemeiting) [2] and India (Lafaxid) [3] It not only suppresses gastric acid secretion, but also has cytoprotective properties by the virtue of its property to induce the collagen synthesis in the gastric mucosa.[4] It has a novel mechanism of action in addition to blocking the H2 receptors , it decreases inflammation by modulating Capsaicin- sensitive gene-related peptide (CGRP) [5] and vanilloid receptors [6] It is also found to stimulate mucin biosynthesis and promote the restitution of damaged mucosa.[7]

Mechanism of Action

Acid Suppressive action

Lafutidine is absorbed in the small intestine, reaches gastric cells via the systemic circulation, and then directly and rapidly binds to gastric cell histamine H2 receptors, thereby inhibiting the stimulation of cAMP and a resultant decrease in acid production (antisecretory action).[8] It causes a sustained increase in intracellular Ca2+ ion concentration in endothelial cells resulting in the release of Calcitonin Gene Related Peptide (CGRP), which causes acid suppression by decreasing the vagal tone.[9] Lafutidine also increases plasma somatostatin levels which decreases secretion of gastrin from G cells. This decrease in gastrin causes inhibition of parietal cells, resulting in decrease in gastric acid secretion.[10][11]

Gastroprotective action

Lafutidine induced CGRP release stimulates nitric oxide (NO) production in endothelial cells, where NO participates in the regulation of gastric mucosal blood flow through vasodilation in the gastric microvasculature and increases mucin biosynthesis resulting in gastroprotection.[12][13] Lafutidine inhibits secretion of interleukin-8, which in turn inhibits sequestration of neutrophils at the site of inflammation, thereby preventing mucosal inflammation [14] It also inhibits neutrophil activation which reduces damage caused by free radicals, thereby reducing inflammation [5] Additionally, Lafutidine has been found to block the attachment of H. pylori with the gastric cells, thereby preventing diseases like peptic ulcer.[14]

Pharmacokinetics

When 10 mg of lafutidine was orally administered to healthy adult males in fasting conditions, peak plasma concentration of 265.15 ± 49.84 ng/ml was achieved at 0.95 ± 0.24 hours. The plasma half life was 1.92 ± 0.94 hours.[15] Among the elderly, there was no difference in pharmacokinetics parameters between those with normal renal function (Ccr average 88.0±9.4 mL/min) and those with deteriorating renal function (Ccr 20~60ml/min, average 45.2±7.8 ml/min).[14] In dialytic patients when administered without hemodialysis, the Cmax, AUC and the t1/2 values were 336±40 ng/ml, 2278±306 ng.hr/mL and 6.71±0.30 hours respectively while those after hemodialysis were 226±36 ng/ml, 853±128 ng.hr/mL and 4.57±0.2 hours respectively.[16] Therefore lafutidine should be administered carefully with lower dosage in dialytic patients.

Adverse effects

Antacid preparations such as lafutidine by suppressing acid mediated break down of proteins, leads to an elevated risk of developing food or drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use as well.[17]

References