Pathways

Nateglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, nateglinide 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. Nateglinide 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 nateglinide therapy compared to sulfonylureas.

Nateglinide is an antihyperglycemic agent, a meglitinide one. It is used in the treatment of non insulin dependent diabetes mellitus (NIDDM). This drug had 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 the drug to the ATP-binding cassette subfamily C member 8 causes its closing. This results in the depolarization of the 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. Nateglinide is administered as an oral tablet.

Hepatic, via cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). Metabolism is via hydroxylation followed by glucuronidation. The major metabolites have less antidiabetic activity than nateglinide, but the isoprene minor metabolite has antidiabetic activity comparable to that of nateglinide. (DrugBank)

Nebivolol (also known as Bystolic or Nebivololum) is a β1-receptor blocker (selective β1-receptor antagonist) that can bind and inhibit Beta-1 adrenergic receptor in muscule and heart. Nebivolol competes with epinephrine or other beta-1 adrenergic receptor activator to bind on the receptor, which can reduce the heart rate and blood pressure that could caused by biniding of epinephrine on receptor. Nebivolol can also prevent release of renin (a hormone from kidneys), which can result in reduced level of constriction of blood vessels.

Nebivolol is a racemic mixture of 2 enantiomers where one is a beta adrenergic antagonist and the other acts as a cardiac stimulant without beta adrenergic activity. It can be administered orally, where it passes through hepatic portal circulation, and enters the bloodstream and travels to act on cardiomyocytes. In bronchial and vascular smooth muscle, nebivolol can compete with epinephrine for beta-2 adrenergic receptors. By competing with catecholamines for adrenergic receptors, it inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition of cAMP, PKA, SRC and nitric oxide synthase signaling. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower; thus, nebivolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. One potentially less than desirable effect of non-selective beta blockers like nebivolol is the bronchoconstrictive effect exerted by antagonizing beta-2 adrenergic receptors in the lungs. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Nebivolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Nebivolol is a racemic mixture of 2 enantiomers where one is a beta adrenergic antagonist and the other acts as a cardiac stimulant without beta adrenergic activity. It can be administered orally, where it passes through hepatic portal circulation, and enters the bloodstream and travels to act on cardiomyocytes. In bronchial and vascular smooth muscle, nebivolol can compete with epinephrine for beta-2 adrenergic receptors. By competing with catecholamines for adrenergic receptors, it inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition of cAMP, PKA, SRC and nitric oxide synthase signaling. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower; thus, nebivolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. One potentially less than desirable effect of non-selective beta blockers like nebivolol is the bronchoconstrictive effect exerted by antagonizing beta-2 adrenergic receptors in the lungs. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Nebivolol also reduce sympathetic activity and is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis. Nebivolol can be found under the brand name Bystolic, some side effects of use of this drug may include headache, tiredness, weakness, and dizziness.

Nebivolol is metabolized mainly by glucuronidation and CYP2D6 mediated hydroxylation. Metabolism involves n-dealkylation, hydroxylation, oxidation, and glucuronidation. Aromatic hydroxyl and acyclic oxide metabolites are active, while n-dealkylated and glucuronides are inactive. (DrugBank)