Chapter 32 Antidiabetic drugs Diabetes mellitus (DM) 糖尿病 [,daiə‘bi:ti:z] [ ’melitəs ] Shutcm-MBL 1

DM DM consists of a group of syndromes characterized by 1 Hyperglycemia [,haipəɡlai‘si:miə]高血糖症: random plasma glucose concentration >200 mg/dl (11 mM); fasting plasma glucose concentration >126 ml/dl (7 mM); or a plasma glucose concentration >200 mg/dl (11 mM) 2 hours after the ingestion of an oral glucose load 2 Altered metabolism of lipids, carbohydrates, and proteins 3 Increased risk of complications from vascular diseases American Diabetes Association (ADA) criteria

Signs and symptoms Classic symptoms: Other signs and symptoms: Weight loss, increased urination, increased thirst, increased hunger Other signs and symptoms: blurry vision, headache, fatigue, slow healing of cuts, and itchy skin ['itʃi] 发痒的 Figure downloaded from wikipedia Shutcm-MBL

Chronic complications (1) Damage to blood vessels (the major long-term complications): coronary artery disease, stroke, diabetic retinopathy [,retin'ɔpəθi], diabetic nephropathy, diabetes-related foot problems (2) Damage to the nerves of the body: diabetic neuropathy (3) others. 视网膜病变 [ni'frɔpəθi] 肾病 [njuə'rɔpəθi] 神经病 Shutcm-MBL

Classification Comparison of type 1 and 2 diabetes Type 1, type 2, gestational diabetes, and other specific types [dʒe'steiʃənəl]妊娠期的 Comparison of type 1 and 2 diabetes Features Type 1 diabetes Type 2 diabetes Onset Sudden Gradual Age at onset Mostly in children Mostly in adults Body size Thin or normal Often obese Ketoacidosis Common Rare Autoantibodies Usually present Absent Endogenous insulin Low or absent Normal, decreased or increased Concordance in identical twins 50% 90% Prevalence ~10% ~90% 酮酸中毒 [,ki'təuæsi'dəusis] Table downloaded from wikipedia Shutcm-MBL

Insulin and DM

Pharmacological and pharmacological effects of insulin 1 Decrease blood glucose; 2 Decrease blood lipid; 3 Promote the synthesis of protein; 4 Promote K+ to enter the cell.

Insulin preparations 1. Short-acting insulin: regular insulin (RI,正规胰岛素) 2. Intermediate-acting insulin: neutral protamine hagedorn insulin, (NPH, 低精蛋白锌胰岛素) 3. Long-acting insulin: protamine zinc insulin (精蛋白锌胰岛素)

Indications of insulin 1. Type 1 DM; 2. Type 2 DM that is not controlled adequately by diet and/or oral hypoglycemic agents; 3. Postpancreatectomy diabetes; 4. Gestational diabetes; 5. Diabetic ketoacidosis, hyperglycemic, nonketotic coma; 6. Perioperative management of both type 1 and type 2 DM; 7. Intracellular potassium deficiency. [,pæŋkriə'tɛktəmi] 胰切除术 [‘kəumə] 昏迷

Adverse reactions 1. Hypoglycemia: Resulted from: (1) an inappropriately large dose; (2) a mismatch between the time of peak delivery of insulin and food intake; (3) superimposition of additional factors that increase sensitivity to insulin (e.g., adrenal or pituitary insufficiency) or that increase insulin-independent glucose uptake (e.g., exercise). Treatment: iv 20-50 mL of 50% glucose solution or sc or im 1 mg of glucagon [pi‘tju:itəri] 垂体的

Adverse reactions 2. Responsive hyperglycemia; 3. Insulin allergy: reactions to the small amounts of aggregated or denatured insulin in all preparations, to minor contaminants, or because of sensitivity to one of the components added to insulin in its formulation (protamine, Zn2+, phenol, etc.). 4. Insulin resistance; 5. Local reactions: lipodystrophy, localized infection [‘ælədʒi]过敏 [,lipədi'strəufi]脂肪代谢障碍

Drug Interactions A large number of drugs can cause hypoglycemia or hyperglycemia or may alter the response of diabetic patients to their existing therapeutic regimens. The most common drug-induced hypoglycemic states: Ethanol, β adrenergic receptor antagonists, and salicylates ['sælisileit]水杨酸盐类

Oral hypoglycemic drugs (1) Sulphonylureas Drugs: tolbutamide 甲苯磺丁脲, glibenclamide 格列本脲; Pharmacological effects: 1 Stimulating insulin release from pancreatic β cells; 2 Reducing hepatic clearance of the insulin; 3 Improving tissue sensitivity to insulin; 4 Suppressing the secretion of glucagon slightly. [,sʌlfənil‘juəriə]磺脲类 [tɔl'bju:təmaid] Pharmgenomics Pers Med. 2016; 9: 17–29. Shutcm-MBL

Clinical uses 1. Type 2 DM: in patients who cannot achieve appropriate control with changes in diet alone; β-cells activity reserved. 2. Diabetes insipidus [in’sipidəs]尿崩症: chlorpropamide (氯磺丙脲, promote the secretion of ADH) Shutcm-MBL

Adverse reactions 1. Hypoglycemic reactions, including coma: Risk factors: (1) elder patients; (2) impaired hepatic or renal function; (3) longer-acting sulfonylureas Incidence: glibenclamide: up to 20% to 30% of users; glimepiride: 2% to 4% of users 2. Others: nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions, weight gain. Shutcm-MBL

Oral hypoglycemic drugs Nateglinide & Repaglinide Pharmacological effects: Stimulating insulin secretion by blocking ATP-sensitive potassium channels in pancreatic β cells. Characteristics: Faster onset and shorter duration of action Indications: Reducing postprandial glycemic elevations in type 2 DM patients. ADME: Eliminated primarily by liver; kidney also take part in; Precautions: Used cautiously in patients with hepatic insufficiency and renal failure. Adverse reactions: Hypoglycemia with low incidence especially nateglinide. Shutcm-MBL

Oral hypoglycemic drugs (2) Biguanides Antihyperglycemic, not hypoglycemic Drugs: Metformin [met'fɔ:min] 二甲双胍 Pharmacological effects: 1. Decreasing hepatic glucose production； 2. Increasing insulin action in muscle and fat； 3. Reducing the intestinal absorption of glucose (possibility). [baɪˈɡwɑːnaɪd] 双胍类 Shutcm-MBL

Clinical uses 1. Type 2 DM (obese): Given alone or in combination with a sulfonylureas to improve glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone; 2. Hyperglycemia with refractory obesity 顽固性肥胖. Shutcm-MBL

Metformin reduced the rate of adverse cardiovascular outcomes

Adverse reactions 1. Acute side effects (up to 20% of patients): Diarrhea, abdominal discomfort, nausea, metallic taste, and anorexia [,ænə‘reksiə]厌食症. Treatment: increasing the dosage of the drug slowly and taking it with meals. Precautions: Patients with hepatic or renal impairment Shutcm-MBL

Metformin vs Sulphonylureas Better in body weight controlling? YES! A lower risk of hypoglycemia? YES! Better in reducing the rate of adverse cardiovascular outcomes in overweight patients with type 2 diabetes? May be or may not. Shutcm-MBL

Oral hypoglycemic drugs (3) α-glucosidase inhibitors Drugs: Acarbose (阿卡波糖) Pharmacological effects: Slows the intestinal absorption of carbohydrates by inhibiting the action of a-glucosidase in the intestinal brush border, thus the postprandial rise in plasma glucose is blunted and decreased. Cardiovasc Diabetol. 2007 Aug 15;6:20. Shutcm-MBL

The cardiovascular benefits of acarbose in DM. Cardiovasc Diabetol. 2007 Aug 15;6:20. Treatment with acarbose reduced the risk of any cardiovascular event by 35%, and the risk of MI specifically by 64%.   Shutcm-MBL

Clinical applications 1. Monotherapy in elderly patients or in patients with predominantly postprandial hyperglycemia. 2. In combination with other oral antidiabetic agents and/or insulin. Shutcm-MBL

Adverse reactions [,mæləb‘sɔ:pʃən] ['flætʃələns] Dose-related malabsorption, flatulence (20-30%), diarrhea (3%) 吸收障碍 胀气 Cardiovasc Diabetol. 2007 Aug 15;6:20. The stepwise-dosing regimen was associated with significantly fewer GI side-effects that were significantly less persistent than the flat-dosing regimen over the course of treatment. Shutcm-MBL

Contraindications Chronic bowel disease Inflammatory bowel disease Other intestinal condition that could be worsened by gas and distention Shutcm-MBL

Thiazolidinediones Drugs: Rosiglitazone (罗格列酮, RSG), Pioglitazone (吡格列酮, PIO) Pharmacological effects: 1. Increasing insulin sensitivity in peripheral tissues; 2. Lower glucose production by the liver Thiazolidinediones require insulin to be present for their action.

Mechanism of action Clinical applications Thiazolidinediones bind to nuclear peroxisome proliferator-activated receptor-γ (PPARγ), which activates insulin-responsive genes that regulate carbohydrate and lipid metabolism. Clinical applications Be combined with insulin or other classes of oral glucose-lowering agents. Shutcm-MBL

Adverse reactions 1 Hepatotoxicity, but rare in patients received pioglitazone and rosiglitazone; 2 Others: anemia, weight gain, edema, and plasma volume expansion. [ə‘ni:miə]贫血

大纲要求 熟悉胰岛素的作用、用途及不良反应； 掌握口服降糖药的分类、作用机理与用途。