Antidiabetis Drugs － Insulin and Oral Antisiabetis Drugs Department of Pharmacology, Peking Union Medical College Caiying Ye

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 ：  300,000 people － → >0.67 ％  40 years old― → 2.53 ％  ~64 years old － → 2.51 ％  ~75 years old － → 3.21 ％  1997― → 13,500,000 people (all over the word)  Prediction:2025― → >30,000,000 people

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 ： urine glucose, 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 Drink and food ： gross calorific value  Kg ＝ height － 105  Daily Kg ＝ 105 ～ 125.5K  （ 25 ～ 30Kcal ） (25 ～ 40Kcal) Therapy ： before meals

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

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

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 3-5% of pregnant women in the US develop gestational diabetes

Diabetes - Insulin Discovered in 1921 by Banting 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) Zn 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 1 st messenger)

Diabetes – Insulin (Mechanism)

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. Insulin drug evolution

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, show 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. glucose uptake glycogen synthesis protein synthesis amino acids uptake enzyme production glycogen breaking fat synthesis

The 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).

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 250 mg, additional glucose may be given to allow continued insulin administration without hypoglycemia (low blood sugar). hypoglycemia

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 been used to treat schizophrenia.

Adverse Effects Hypoglycemia Allergic reaction Insulin resistance Hypokalemia Lipoatrophy

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 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.is the atrophy or hypertrophy of fat at the site of injection. 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 Rosiglitazone Pioglitazone Pioglitazone

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

Diabetes – Oral Medications Sulfonylureas Biguanides Sulfonylureas and biguanide combination drugs Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides

Oral Autidiabetic Drugs Sulfonylureas Tolbutamide Chlorpropamide Glibouclamide Glipizide Gliclazipe Glurenorm

Oral Autidiabetic Drugs Biguanides Phenformin Metformin 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 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 Hypoglycemic Activity Sulfonylureas act primarily by increasing the secretion of insulin and secondarily by decreasing the secretion of glucagon. Sulfonylureas act primarily by increasing the secretion of insulin and secondarily by decreasing the secretion of glucagon. 2. Antidiuresis effect: treat with diabetes insipidus. 3. Decrease platelet adhesion reaction, stimulate plasminogen 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 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) that compete for the binding sites.

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 [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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