Antidiabetic Drugs －Insulin and Oral Antisiabetic Drugs Department of Pharmacology 2017.10

Overview diabetes mellitus A chronic condition associated with abnormally high blood sugar. Results from either deficiency of or a resistance to insulin- a hormone produced by the pancreas whose function is to lower blood sugar.

Overview morbidity： 9.7% in Chinese adultes in urban area 70,000,000 patients in China 6.4% in the world

Overview Cause by many of reasons ――chronic hyperglycemia－→metabolic disorder Hyperglycemia ―― a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Insulin: B cells ――synthesis－→secretion ――blood circulation－→target cells－→binding with insulin receptor －→intracellular substance metabolism any link going wrong －→diabetes mellitus

Overview Diabetes Mellitus ――long-term disease ――multisystem damage－→functional defect and failure Severe－→diabetic ketoacidosis－→coma Etiopathogenisis ――heredity, autoimmunity, environmental factor Diagnosis：blood glucose

Overview Therapy: early treatment, long term therapy, combined therapy and therapeutic measure individualization Purpose：blood glucose－→normal, to correct metabolic disorder, increase in life span, decrease death Principle：persevere (cannot cure)

Overview Many complications

Substance Metabolic Disorder and Clinical Situation of Diabetic glucose utilization disorder→glucose decomposition decrease→energy insufficient→starvation condition →polyphagia(多食） hyperglycemia →glucosuria →hypertonicity diuresis →polyuria（多尿） protein degradation↓dehydration thirst→polydipsia accentuation┤ athrepsy （消瘦） （多饮） lipolysis excessive hyperosmolar nonketotic diabetic coma ketonuria(酮尿) lipolysis excessive →ketoplasia excessive→Ketonemia(酮血)→acidosis coma

Classification of Diabetes Mellitus (WHO 1998) TypeⅠ: insulin dependent diabetes mellitus，IDDM TypeⅡ: non-insulin dependent diabetes mellitus，NIDDM Others： secondary diabetes

(resulting in insulin dependence) Diabetes Mellitus Type 1 Diabetes - cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30 Type 2 Diabetes - blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - effects > 90% - eventually leads to β-cell failure (resulting in insulin dependence) Gestational Diabetes （妊娠糖尿病） 3-5% of pregnant women in the US develop gestational diabetes

Diabetes - Insulin A = 21amino acids B = 30 amino acids Discovered in 1921 by Banting (Nov 14) and Best Consist of A & B chains linked by 2 disulfide bonds (plus additional disulfide in A) ~ ~ ~ A = 21amino acids B = 30 amino acids

Diabetes – Insulin (synthesis, storage, secretion) Produced within the pancreas by β cells  islets of Langerhans insulin mRNA is translated as a single chain precursor called preproinsulin removal of signal peptide during insertion into the endoplasmic reticulum generates proinsulin Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin Stored as β granules

Diabetes – Insulin (Biochemical Role) Tyrosine Kinase receptors are the locks in which the insulin key fits - Involved in signal transduction (insulin hormone being 1st messenger)

Diabetes – Insulin (Mechanism)

Insulin drug evolution Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s) Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.

Stage 3 Insert the human insulin gene into E Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®). Yeast is also used to produce insulin (trade name =Novolin®) (1987). Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.

Physiological disposition of insulin Insulin must be administered parenterally, usually by s.c. injection. It is metabolised by the liver and the kidney and has a half-life of 9-10 minutes. To extend its period of action, slow release preparations have been developed.

Types of insulin Regular insulin Insulin analogs Pre-mixed insulin Short peptide mimics

Insulin affects many organs: It stimulates skeletal muscle fibers. It stimulates liver cells. It acts on fat cells It inhibits production of certain enzyme. In each case, insulin triggers these effects by binding to the insulin receptor. protein synthesis amino acids uptake glucose uptake glycogen synthesis fat synthesis enzyme production glycogen breaking

The Pharmacological Action of Insulin It allows the active uptake of glucose and its utilisation in muscle and fat cells. It stimulates synthesis of glycogen in the liver. It inhibits formation of glucose (gluconeogensis) in the liver. It inhibits breakdown of lipids. It stimulates protein synthesis. It stimulates some cell ion transport mechanisms (e.g. Na+/K+-ATPase). Increase K+ inflow.

Who need insulin medicine? Type I (insulin dependent) diabetes patients whose body produces no insulin. Type 2 diabetes patients that do not always produce enough insulin. diabetic ketoacidosis, hypertonicity hyperglycemia coma and lactic acidosis accompany with hyperglycemia diabetes mellitus accompany with severe infection, wasting disease, hyperpyrexia, pregnancy, wound and operation. secondary diabetes is caused by pancreatectomy.

Preparations and Clinical Use of insulin Short-acting preparations. Intermediate acting preparations. Long acting preparations. New very-short- and very-long-acting insulin analogues.

Insulin Regimens Dose and choice of preparations must be determined for each patient individually. Many patients will monitor their blood glucose at home and make minor adjustments in dose accordingly.

Insulin Regimens Diabetic Ketoacidosis and diabetic coma: Insulin (S.C. Injection) will be given to lower blood sugar and to prevent further ketone formation. Once blood glucose levels have fallen to some extent, additional glucose may be given to allow continued insulin administration without hypoglycemia (low blood sugar).

Insulin Regimens Hyperpotassaemia: Insulin coadminidtrate with glucose（help K＋get into cell） (1) Prevention and Treatment of arrhythmia caused by myocardial infarction. the combination treatment of insulin, glucose and KCl (2) Insulin shock therapy has ever been used to treat schizophrenia .

Adverse Effects Hypoglycemia Allergic reaction Insulin resistance Hypokalemia (低血钾） Lipoatrophy(脂肪萎缩)

Adverse Effects 1. Allergic reaction: foreign protein enter into human body Insulin has antigenicity, the slight reaction includes local swelling, itch, ache. It rarely occurs urticaria, angioedema and anaphylactic shock. It often uses antihistamine drug and adrenal cortex hormone to treat with severe allergic reaction，and these patients should change to use high purity insulin or human insulin.

Adverse Effects 2. Hypoglycemia （the most common and serious adverse） It is the result of an imbalance between glucose intake (e.g. missing a meal), glucose utilisation (e.g. unusual exercise) and insulin dose. The result is sympathetic activation and neuroglycopenia.

Adverse Effects Patients and their families should be trained to spot the warning signs and how to treat hypoglycaemia, including possibly administration of glucagon(胰高血糖素) if the patient loses consciousness. Treatment is by administration of carbohydrate orally to a conscious patient, or i.v. glucose or i.m. glucagon.

Adverse Effects 4.Hypokalemia: may occur in the acidosis patients who use a lot of insulin and glucose, it can lead to the patient death with abnormal heart beat. 5.Lipoatrophy: is the atrophy or hypertrophy of fat at the site of injection.

Insulin Resistance (INR) Insulin resistance is a prominent feature in obese individuals and in non-insulin-dependent diabetes. Some resistance may be caused by defects in binding of insulin. Other possible mechanisms include secretion of an abnormal B-cell secretory product or the presence of circulation insulin antagonists.

Diabetes-Insulin Action Enhancers Rosiglitazone（罗格列酮） Pioglitazone（吡格列酮）

The Action of Insulin Action Enhancers The are a new class of drugs for the treatment of type 2 diabetes. They bind avidly to peroxisome proliferator-activated receptor gamma (过氧化物酶增值活化受体）in adipocytes to promote adipogenesis and fatty acid uptake (in peripheral but not visceral fat).

The Action of Insulin Action Enhancers By reducing circulating fatty acid concentrations and lipid availability in liver and muscle, the drugs improve the patients sensitivity to insulin. Thiazolidinediones（噻唑烷二酮类） favourably alter concentrations of the hormones secreted by adipocytes, particularly adiponectin（脂联素）. They increase total body fat and have mixed effects on circulating lipids.

The Action of Insulin Action Enhancers Improve insulin resistance，decrease hyperglycemia. Improve fat metabolism disorder. Prevent and treat the blood vessel complication of type II diabetes mellitus. Improve pancreatic B cell function.

Diabetes – Oral Medications Sulfonylureas (磺酰脲类) Biguanides(双胍类) Sulfonylureas and biguanide combination drugs Thiazolidinediones(噻唑烷二酮类) Alpha-glycosidase inhibitors(α糖苷酶抑制剂) Meglitinides(格列奈类)

Oral Autidiabetic Drugs Sulfonylureas Tolbutamide 甲苯磺丁脲 Chlorpropamide 氯磺丙脲 Glibouclamide 格列本脲 Glipizide 格列吡嗪 Gliclazipe 格列齐特 Glurenorm 糖适平

Oral Autidiabetic Drugs Biguanides Phenformin （苯乙双胍） Metformin（二甲双胍） α-glucosidase inhibiors Acarbose

Sulfonylureas [physiological disposition] The sulfonyureas are administered orally and undergo varying degrees of hepatic metabolism and renal elimination of the parent compound and metabolites. Most of the sulfonylureas are metabolized to inactive or less active compounds in the liver.

The Mechanism of Action Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels. This, in turn, leads to opening of calcium channels. Which leads to the production of insulin.

The Pharmacological Effect of Sulfonylureas 1. Hypoglycemic Activity Sulfonylureas act primarily by increasing the secretion of insulin and secondarily by decreasing the secretion of glucagon. 2. Antidiuresis effect: treat with diabetes insipidus（尿崩症）. 3. Decrease platelet adhesion reaction, stimulate plasminogen（纤溶酶原） synthesis.

The Clinical Application of Sulfonylureas Diabetes Mellitus：A sulfonylurea drug is often used to treat type II DM that cannot be controlled with dietary restrictions. Diabetes Insipidus：coadministrating with Hydrochlorothiazide(氢氯噻嗪) can improve the effect

Adverse Effects of Sulfonylureas Hypoglycaemia Gastrointestinal upsets Hypersensitivity: rashes etc. Weight gain: stimulation of appetite can be a problem in obese patients.

Drug Interactions Sulfonylureas are heavily protein bound and their actions may be increased by other drugs (e.g. sulfonamides, 磺胺类) that compete for the binding sites.

Glucagon-like peptide 1 (GLP-1)（胰高血糖素样肽） Glucagon-like peptide 1 (GLP-1) is produced by the proglucagon gene in L-cells of the small intestine in response. 是一种肠促胰岛素因子

Glucagon-like peptide 1 (GLP-1) It stimulates glucose-dependent into nutrientssulin release from the pancreatic islets. In addition to its insulinotropic effects, it is thought to exert antihyperglycemic effects by slowing gastric emptying, inhibiting inappropriate glucagon release, stimulating β-cell proliferation and differentiation, and improving satiety（饱胀感）.

Glucagon-like peptide 1 (GLP-1) GLP-1 exhibits a relatively short half-life (1–2 minutes) that necessitates continuous infusion to achieve steady state in pharmacological studies. This is attributed to NH2-terminal degradation by dipeptidyl peptidase IV (DPP-IV).（二肽基肽酶） Mice lacking DPP-IV exhibit reduced food intake, improved insulin sensitivity, and decreased loss of -cell mass. Numerous analogs have been developed that have a longer half-life, mediated by resistance to DPP-IV degradation

食物消化 DDP-4抑制剂(格列汀类) GLP-1 GLP-1失活 DDP-4 胰岛素合成和分泌 B细胞的增殖和分化 胰岛B细胞分泌生长抑素 抑制肝糖原输出 抑制糖原分泌

Glucagon-like peptide 1 (GLP-1) Exentiade (依克那肽） Sitagliptin phoasphate（磷酸西他替丁）

Biguanides [Physiological Disposition] Metformin is administered orally from two to four times a day and is eliminated by renal excretion of the parent compound. Its duration of action is about 18 hours.

Mechanisms and Pharmacological Effects Metformin is now considered a first-line drug for the treatment of type II DM. In patients with type II DM, it alleviates hyperglycemia primarily by decreasing the hepatic glucose output. It also appears to decrease glucose absorption from the gut and increase insulin sensitivity in skeletal muscle and adipose tissue.

Adverse Effects of Biguanides The most common adverse effects of metformin are gastrointestinal disturbances. Patients with renal or hepatic disease, alcoholism, or a predisposition to metabolic acidosis should not be treated with metformin, because they are at increased risk of lactic acidosis.

Acarbose（阿卡波糖） [Mechanisms and Pharmacological Effects] The digestion of dietary starch and disaccharides such as sucrose is dependent on the action of α-glucosidase, an enzyme located in the brush border of the intestinal tract. It thereby slows the digestion of starch and disaccharides, decreases the rate of glucose absorption, and lowers the postprandial blood glucose concentration.

The Indications of Acarbose Acarbose is used in the treatment of type II DM. It is administered with each meal and is particularly effective when given with meals containing large amounts of starch.

Adverse effects of Acarbose The most common side effect of acarbose are increased flatulence and abdominal bloating. Acarbose may increase the oral bioavailability of metformin and cause a decrease in iron absorption.

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