Browsing Pathways

Difelikefalin is a kappa opioid receptor agonist used in the treatment of moderate-to-severe pruritus (itchy skin) associated with chronic kidney disease in patients undergoing hemodialysis. It is administered via intravenous injection at the end of each hemodialysis treatment. Kappa receptors have been associated with itching sensation since 1984. In the spinal cord, Difelikefalin binds to the kappa-type opioid receptor. The Kappa-opioid receptor is coupled with G-protein receptors. Difelikefalin stimulates the exchange of GTP for GDP on the G-protein complex. The G-protein system inhibits adenylate cyclase which prevents ATP from being synthesized into cAMP which causes a decrease in intracellular cAMP. The activated G-proteins also close N-type voltage-operated calcium channels which prevents calcium from entering the neuron, and it opens calcium-dependent inwardly rectifying potassium channels which causes sodium to leave the neuron. This results in hyperpolarization and reduced neuronal excitability. This causes a neuroinhibitory effect of the itching sensation at the spinal cord level.

Metabolites of Difenoxin are predicted with biotransformer.

Diflorasone is a topical corticosteroid used to treat the symptoms of various inflammatory skin conditions. This drug is used in the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Diflorasone is a selective glucocorticoid receptor agonist. The mechanism of action of topical steroids is still unclear but it appears that by binding to the glucocorticoid receptor, diflorasone influences transcription factors AP-1 and NF-kB to block the transcription of COX-2/prostaglandin G/H synthase 2 which reduces the amount of prostanoids being produced from arachidonic acid. Prostanoids such as PGI2 and thromboxane A2 influence the effects of inflammation through vasoconstriction/dilation, pain sensitivity, and platelet aggregation. This drug also affects the promoter of annexin-1, an important inflammatory protein as it affects leukocytes and blocks phospholipase A2 which reduces the amount of arachidonic acid being cleaved from the phospholipid bilayer. Reducing the amount of arachidonic acid formed further decreases the concentrations of prostanoids mentioned calming inflammation. Diflorasone is administered as a cream or ointment.

Diflunisal (also known as Dolobid) is a prostaglandin G/H synthase inhibitor that can inhibit prostaglandin G/H synthase 1 and 2 which prevent the production of prostaglandin. Therefore, diflunisal can be used for treating prostaglandin-associated pain, fever, swelling, platelet aggregation and inflammation. Diflunisal can also inhibit the relocation of leukocytes to inflammation site and also the production of the aggregating agent of platelets: thromboxane A2.