Pathways

Remimazolam is an ultra short-acting benzodiazepine used for the induction and maintenence of procedural sedation during short procedures. Recent trends in anesthesia-related drug development have touted the benefits of so-called "soft drugs" - these agents, such as remifentanil, are designed to be metabolically fragile and thus susceptible to rapid biotransformation and elimination as inactive metabolites. These "soft drugs" are useful in the context of surgical procedures, wherein a rapid onset/offset is desirable, enabling anesthesiologists to manipulate drug concentrations as needed. Remimazolam was the first "soft" benzodiazepine analog to be developed and was approved for use by the FDA in July 2020 under the brand name Byfavo. Like other benzodiazepines, remimazolam exerts its therapeutic effects by potentiating the effect of gamma-aminobutyric acid (GABA) on GABA(A) receptors, the main inhibitory neurotransmitter receptors in the mammalian brain. GABA(A) receptors are a component of GABA-gated ionotropic chloride channels that produce inhibitory postsynaptic potentials - following activation by GABA, the channel undergoes a conformational change that allows the passage of chloride ions through the channel. The inhibitory potentials produced by GABA neurotransmission play an integral role in the suppression and control of epileptiform nerve firing such as that seen in epilepsy, which makes the GABA system a desirable target in the treatment of epilepsy. Benzodiazepines are positive allosteric modulators of GABA(A) function. They bind to the interface between alpha (α) and gamma (γ) subunits on the receptor, commonly referred to as the benzodiazepine binding site, and modulate the receptor such that its inhibitory response to GABA binding is dramatically increased. Some side effects of using remimazolam may include drowsiness, dizziness, lightheadedness, and confusion.

Remoxipride is an atypical antipsychotic dopamine D2 antagonist. Chronic use upregulates the expression of D2 receptors, while downregulating the expression of D1 and D5 receptors in the prefrontal cortex. This activity may be related to the antipsychotic activity of remoxipride. Remoxipride displays weaker binding to D2 dopaminergic receptors that dopamine. This weaker binding is thought to account for the reduced incidence of Parkinsonism. Remoxipride also increases expression of the protein Fos in the nucleus accumbens but not the dorsolateral striatum, which may be responsible for a reduced incidence of extrapyramidal symptoms.

Metabolites of Remoxipride are predicted with biotransformer.

Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic activity. (DrugBank)

Repaglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, repaglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Repaglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with repaglinide therapy compared to sulfonylureas.

Repaglinide is an antihyperglycemic agent, a meglitinide one. It is used in the treatment of non insulin dependent diabetes mellitus (NIDDM). This drug has the function to increase the insulin release by the pancreas to the blood. It does this by inhibiting the ATP-sensitive potassium channels in a glucose-dependent manner. This drug does not act on the insulin level without the presence of glucose, which differentiates it from sulfonylurea drugs. The mechanism of action starts with the need for functioning beta cells in the pancreas and glucose in the blood. Since the release of insulin is controlled by the beta cells membrane potential, the binding of repaglinide to the ATP-binding cassette subfamily C member 8 causes its immediate closing. This results in the depolarization of the beta cell and the opening of the L-type calcium channels. In consequence, the increased concentration of calcium results in the stimulation of the calcium-dependent exocytosis of insulin granules. An overdose of this drug may result in the development of hypoglycemic symptoms. Repaglinide is administered as an oral tablet.