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used in treatment of diabetes Insulin and drugs used in treatment of diabetes
Diabetes Mellitus The word Diabetes is applied to condition of excessive hunger. The other symptoms of Diabetes Mellitus are; weigh loss Hyperglycemia altered metabolism of lipids, carbohydrates, and proteins an increased risk of complications from vascular disease.
Clinical Diabetes Mellitus 1-Type 1 Diabetes: - known as insulin-dependant Diabetes Mellitus (IDDM) is caused by an absolute deficiency of insulin. This results from immune-system-mediated destruction of pancreatic β-cells. Without insulin, the body's primary source of energy and the brain's only source of energy, glucose, is unable to enter the cells. This leads to cells being energy starved as well as elevated plasma blood glucose levels. Administration of exogenous insulin currently is the only method to effectively resolve this hormone deficiency.
Clinical Diabetes Mellitus 2-Type 2 Diabetes: - known as non-insulin-dependant Diabetes Mellitus (NDDM). Type 2 diabetes is a more complex disease. If one parent has type 2 diabetes, the risk of developing it is 38%, whereas if both parents are affected then, the risk of developing diabetes before age 60 is 60%. It is characterized by end-organ insulin resistance and/or a relative deficiency in insulin secretion. Unlike the abrupt loss of β-cell function characteristic of type 1 diabetes, the pancreatic β cells in type 2 diabetes undergo progressive deterioration over a fairly long time.
Clinical Diabetes Mellitus 2-Type 2 Diabetes: - known as non-insulin-dependant Diabetes Mellitus (NDDM). At this point, blood glucose levels likely appear normal and the patient is asymptomatic. For most patients with type 2 diabetes, resolution of their metabolic disease may occur with appropriate lifestyle changes, including a well balanced diet and regular exercise. For those type 2 patients who are unable to achieve normal blood glucose levels, several classes of oral agents are available that target various biochemical processes associated with insulin secretion and/or insulin receptor sensitivity
Clinical Diabetes Mellitus 3-Gestational Diabetes It is classified as any degree of glucose-intolerance that first occurs during pregnancy, typically during the third trimester. The risk factors associated with developing GDM include previous history of GDM, obesity, glycosuria, or a family history that includes diabetes.
Oral Hypoglycimic agents
1-First and second generation sulfonylureas
Structure activity relationship There must be a reasonable bulk group on the urea nitrogen; methyl and ethyl compound are not active. There is only one (normally para substituent) on the sulfonyl aromatic ring. Many substituents are active, and the p-(β-arylcarboxamidoethyl) grouping seen in the second generation compounds is consistent with a high potency. The spatial relationship between the amide nitrogen of the substituent and the sulfonamide nitrogen is important.
Mechanism of action They stimulate the release of insulin; they interact with receptors on pancreatic β-cells to block ATP-sensitive potassium channels. This in turn leads to opening of calcium channels which produce an influx of calcium resulting in β-cells production of insulin. These drugs are effective in patients with type 2 diabetes whose insulin-secreting capacity is intact but whose ability to produce adequate insulin in the presence of elevated glucose has been lost. They can cause hypoglycemia, because these drugs can stimulate insulin secretion even when glucose levels are low.
Members of 1st generation sulfonylureas
Members of 1st generation sulfonylureas Metabolism
Members of 1st generation sulfonylureas Metabolism Chloropropamide undergoes slow hydroxylation on the propyl chain to afford 2’ and 3’-hydroxy chloropropamide. Because these processes are slow, chloropropamide is a long lasting drug.
Members of 2nd generation sulfonylureas
Members of 2nd generation sulfonylureas Metabolism
Members of 2nd generation sulfonylureas Metabolism
2- Meglitinides
Repaglinide Repaglinide is a nonsulfonylurea that binds and block the ATP-sensitive K+channels, resulting in insulin secretion from β-cells in addition to having extrapanereatic effects Repaglinide has a rapid onset and short duration of action compared to other hypoglycemic drugs.
Repaglinide It is not associated with the prolonged hyperinsulinemia seen with the sulfonylureas, and possibly for this reason, it produces fewer side effects, including weight gain and potentially dangerous hypoglycemia. Repaglinide is at least five fold more potent than glyburide on intravenous administration and nearly 10-fold more active on oral administration.
3- Biguanides
Metformin and phenoformin Mechanism of Action Metformin and the other biguanides are described as insulin sensitizers; they act in the liver by decreasing excessive, glucose production, most likely via reduced gluconeogenesis resulting from an increased sensitivity to insulin. They also improve glucose utilization by restoring tissue sensitivity to insulin They appear to have their main action in the liver mitochondria via activation of adenosine 5'-monophosphate-activated protein kinase (AMPK)
Metformin and phenoformin Mechanism of Action Metformin can lower free fatty acid concentrations by 10 to 30%. The therapeutic effect of metformin requires the presence of insulin, and metformin does not stimulate the release of insulin or other factors, such as glucagon. The drug does not induce hypoglycemia at any reasonable dose. For that reason, metformine is usually said to be an antihyperglycemic rather than a hypoglycemic agent.
4- Thiazolidinediones (Glitazones)
4- Thiazolidinediones (Glitazones)
4- Thiazolidinediones (Glitazones)
4- Thiazolidinediones (Glitazones) Like bignanides, thiazolidinediones are insulin sensitizers; however, they have a different mechanism of action from that of the biguanides. The thiazolidincdiones stimulate peroxisome proliferator-activated receptor (PPAR)-γ stimulation, leading to the transcription of insulin-sensitive genes and, subsequently, a wide variety of actions including increases in: glucose uptake (adipose, muscle, liver) lipogenesis (adipose, liver) fatly acid uptake and preadipocyte differentiation (adipose), and glycolysis and glucose oxidation (muscle) In addition to decreases in gluconeogenesis, and glycogenolysis (liver). The PPAR-γ expression is highest in adipose tissue.
4- Thiazolidinediones (Glitazones) Metabolism
4- Thiazolidinediones (Glitazones) Metabolism
4- Thiazolidinediones (Glitazones) Metabolism
5- Dual PPARα and PPARγ Coactivators
5- Dual PPARα and PPARγ Coactivators Because of weight gain can occur as an undesirable effect,a drug that activated both PPARα and PPARγ may be less prone to this side effect because of promotion of fatty acid oxidation. Activation of PPARα also is reported to reduce plasma triglyceride levels and to increase high-density lipoprotein levels; these are very desirable actions for the populations prone to type 2 diabetes.
5- Dual PPARα and PPARγ Coactivators Muraglitazar and Tesaglitazar Clinical trials demonstrated the expected benefits for muraglitazar, and it is intended as a monotherapy or in combination with metformin. Some concerns from the trials, however, is an increase, compared to placebo, in serious cardiovascular events, including death, myocardial infarction and congestive heart failure.
5- Dual PPARα and PPARγ Coactivators Muraglitazar and Tesaglitazar
6-α-glucosidase inhibitors
6-α-glucosidase inhibitors To be absorbed from the gastrointestinal tract into the blood stream, the complex carbohydrates we ingest as a part of our diet must first be hydrolyzed to monosaccharides by α-glucosidase enzyme. The rationale for the α-glucosidase inhibitors is that by preventing the hydrolysis of carbohydrate their absorption could be reduced. The oligosaccharidases responsible for final hydrolysis of these materials are all located in the brush border of the small intestine and consist of two classes: 1-The β-galaclosidases hydrolyze β-disaccharides, such as lactose, 2- α-glucosidases act on α-disaccharides, such as maltose, isomaltose, and sucrose
6-α-glucosidase inhibitors Structure activity relationship Active α-glucosidase inhibitors have a common pharmacophore, comprising a substituted cyclohexane ring and 4.6-dideoxy-4-amine-D-glucose unit known as carvosine. The secondary amino group of this structure prevents an essential carboxyl group of the α-glucosidase from protonating the glycosidic oxygen bonds of the substrate.
Acarbose (Precose) Acarbose competitvely inhibits glucoamylase and sucrase but has weak effects on pancreatic α-amylase.
Voglibose It slows the release of monosacharides from polymeric materials, and thereby lowers the glucose level.
Rimonabant
Rimonabant Obesity is a major factor leading to type-2 diabetes. As such, effective treatment of obesity may prevent or slow the onset of diabetes. Researchers hypothesized that if cannabinoids stimulate appetite in a receptor-specific fashion, then blocking, central cannabinoid receptors might lead to decreased appetite.
Rimonabant Rimonabant was found to be a selective and potent antagonist of CB1 endocannabinoid receptor. Rimonabant was found to be a selective and potent antagonist of the receptor and its administration led to the decreased consumption of fats and sugar, resulting in weight loses
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