Chapter 37Insulin and oral hypoglycemic agents

diabetes mellitus

Metabolic disorder of multiple etiology characterized by hyperglycemia with

carbohydrates, fat, and protein metabolic

alterations that result from a decrease in the circulating concentration of insulin

(insulin deficiency) and a decrease in the response of peripheral tissues to insulin

(insulin resistance).

Characteristics of DM

� hyperglycemia

� disturbance in metabolism of lipids, carbohydrates and proteins

Symptoms of diabetes

� Polyuria (urinating frequently)

� Polydipsia (very thirsty)

� Continuous hunger

� Weight loss

Other diabetes symptoms

� Fatigue

� Dry skin

� Frequent infections

� Feet ulceration

� Loss of sensibility in inferior extremities (legs)

Classification of DM

type ⅠⅠⅠⅠ DM

(insulin-dependent diabetes mellitus, IDDM)

type ⅡⅡⅡⅡ DM

(non-insulin-dependent diabetes mellitus, NIDDM)

Other type: secondery

Treatment and control

� Medications

� (insulin vs. hypoglycaemic agents)

� Increase physical activity

� at least walk for 30 min. most days

� Appropriate diet

� vegetables

� fruit

� low in fat and carbohydrates

� Lifestyle changes

Classification of drugs

(1) Insulin

(2) Orally hypoglycemic agents

Insulin sensitizers

Sulfonylureas

Biguanides

Inhibitor of αααα-glycosidase

Chinese herbs

PART 1 insulin

� Chemistry :

small protein with a MW of 56 KD (in

human)

Two chains (A and B)

� source :

once from bovine and porcine pancreas,

now by recombinant DNA techniques

Pharmacokinetics

� will be degraded in the gastrointestinal

tract if taken orally.

� often administered by subcutaneous injection.

� Half life:9-10 min

� Elimination in liver and kindney

胰岛素制剂及其作用时间

分类分类分类分类 制剂制剂制剂制剂 给药途径给药途径给药途径给药途径 起效起效起效起效 高峰高峰高峰高峰 持续持续持续持续 给药时间给药时间给药时间给药时间、、、、次数次数次数次数

短效短效短效短效 正规胰岛素正规胰岛素正规胰岛素正规胰岛素 皮下皮下皮下皮下/静静静静脉脉脉脉

0.3~0.

7

2~4 5~8 餐前餐前餐前餐前0.5h，，，，3~4次次次次/日日日日，，，，急症急症急症急症

半慢胰岛素锌混悬半慢胰岛素锌混悬半慢胰岛素锌混悬半慢胰岛素锌混悬液液液液

皮下皮下皮下皮下 0.5~1.

0

2~8 12~16 餐前餐前餐前餐前0.5h，，，，3~4次次次次/日日日日

中效中效中效中效 低精蛋白锌混悬液低精蛋白锌混悬液低精蛋白锌混悬液低精蛋白锌混悬液 皮下皮下皮下皮下 1~2 6~12 18~24 早餐前早餐前早餐前早餐前1h，，，，

1或或或或2次次次次/日日日日

慢胰岛素锌混悬液慢胰岛素锌混悬液慢胰岛素锌混悬液慢胰岛素锌混悬液 皮下皮下皮下皮下 1~2 6~12 18~24 早餐前早餐前早餐前早餐前1h，，，，

1或或或或2次次次次/日日日日

长效长效长效长效 精蛋白锌胰岛素精蛋白锌胰岛素精蛋白锌胰岛素精蛋白锌胰岛素 皮下皮下皮下皮下 4~6 14~20 24~36 早早早早/晚餐前晚餐前晚餐前晚餐前1h,1次次次次/日日日日

特慢胰岛素锌混悬特慢胰岛素锌混悬特慢胰岛素锌混悬特慢胰岛素锌混悬液液液液

皮下皮下皮下皮下 4~6 16~18 20~36 早早早早/晚餐前晚餐前晚餐前晚餐前1h,1次次次次/日日日日

Pharmacological effects

� The main effects of insulin are affecting metabolism of glucose, lipids and protein.

� 1.Effects on glycometabolism (hypoglycemia)

� Increase the synthesis and storage of

glycogen

� stimulating the uptake and metabolism of

glucose by muscle and adipose tissue

Pharmacological effects

2.Effects on lipometabolism

� inhibiting the hormone-sensitive lipase in adipose tissue→ inhibiting the

hydrolysis of triglycerides

� Increasing transfer of fatty acid →stimulates synthesis of fat

Pharmacological effects3.Effects on protein metabolism

(positive nitrogen balance)

� stimulating amino acids uptake and

protein synthesis

� inhibiting protein degradation in muscle and other tissues

Pharmacological effects of insulin

4.Influence on kalium in blood

Decrease kalium in blood

5.HR (heart rate), increase the

contractility of myocardium,

decrease renal blood flow

[Mechanism of action]

Clinical uses

� The goal is the normalization not only of blood glucose but also of all aspects of metabolism.

1.IDDM :the only effective drug

Patient with IDDM must rely on injected insulin daily in order to control hyperglycemia all his lifetime.

The most common site of subcutaneous injection is abdomen.

� 2.NIDDM :not adequately controlled by diet and oral hypoglycemic agents

(Weight reduction, exercise and dietary modification can correct the hyperglycemia in some patients)

� For NIDDM patients, the goal is to maintain blood glucose concentrations within normal limits and to prevent the development of long-term complications of the disease.

3.DM associated with acute or serious complications: Ketoacidosis, hyperosmolar nonketotic coma

4.DM patients under stress conditions: serious infection, consumptive diseases, pregnancy, trauma, operation

5. Hyperkalemia and intracellularhypokalemiaGIK: 10％％％％GS1000ml＋＋＋＋I 20u＋＋＋＋Kcl3g ivdrip

Adverse reactions� 1.Hypoglycemia : most common

may result from an inappropriately large dose of insulin or delayed food intake.

Short effect agents:

sweating, hunger, palpitations, tremor and anxiety,

Long effect agents:

neuroglycopenic symptoms (such as difficulty in concentrating, confusion, weakness, drowsiness, even loss of consciousness)

Adverse reactions

� 2.Insulin allergy:

The most frequent allergic manifestations

are IgE-mediated local cutaneous

reactions.

Adverse reactions

� 3.Insulin Resistance

Acute resistance: stress

Chronic resistance:

1) AIRA (antiinsulin receptor autoantibody)

2) down regulation of receptor

3) dysfunction of glucose transfer

4. others

Preparations of insulin

� Portable pen injection

� Continuous subcutaneous insulin infusion devices (CSII, insulin pumps)

� Inhaled insulin

Injection pen

分类分类分类分类 药物药物药物药物 给药途经给药途经给药途经给药途经 给药时间给药时间给药时间给药时间

Short-acting Regular iv 立即立即立即立即 0.5 2 急救急救急救急救

insulin sc 0.5 2-3 6-8 餐前半餐前半餐前半餐前半h.tid

Neutral protamine 2-4 8-12 18-24

Hagedorn

sc 2-4 6-10 12-18

Protamine

zinc insulin 3-6 16-18 24-36 餐前餐前餐前餐前1h.qd

作用时间作用时间作用时间作用时间

开始开始开始开始 高峰高峰高峰高峰 维持维持维持维持

餐前半餐前半餐前半餐前半h.tid

1-2次次次次/日日日日

Moderate

-acting

Globin zinc

insulin

sc

餐前半餐前半餐前半餐前半h.tid

1-2次次次次/日日日日scLong-acting

表表表表42-1 胰岛素制剂比较胰岛素制剂比较胰岛素制剂比较胰岛素制剂比较

Part 2 Oral hypoglycemic agents

Common characteristics

� (1) Orally effective and convenient

� (2) Slow and weak

� (3) NIDDM

ⅠⅠⅠⅠ insulin sensitizer

Rosiglitazone(罗格列酮罗格列酮罗格列酮罗格列酮)

Englitazone (恩恩恩恩格列酮格列酮格列酮格列酮))))

Pioglitazone (吡格列酮吡格列酮吡格列酮吡格列酮)

Troglitazone (曲格列酮曲格列酮曲格列酮曲格列酮)

Ciglitazone （（（（环环环环格列酮格列酮格列酮格列酮））））

Pharmacological action

1.Improve insulin resistance, lower

hyperinsulinemia and hyperglycemia

� Limosis and after-meal BS

� Blood insulin and blood fatty acid

� used in combination with other drugs

� Low incidence of hypoglycemia

2.Correct lipodystrophy

↓TGTGTGTG，，，，↑↑↑↑TC and ↑HDLTC and ↑HDLTC and ↑HDLTC and ↑HDL－－－－CCCC

3.Improve complication of NIDDM

anti-atherosclerosis effect

delay occurrence of albuminuria

4.Improve β-cell function

Mechanism

（（（（PPARγ )PPARγ )PPARγ )PPARγ )过氧化物酶增殖体受体过氧化物酶增殖体受体过氧化物酶增殖体受体过氧化物酶增殖体受体γγγγ

Clinical use

NIDDM and IRNIDDM and IRNIDDM and IRNIDDM and IR

Adverse reaction

general reactiongeneral reactiongeneral reactiongeneral reaction

heptic toxicityheptic toxicityheptic toxicityheptic toxicity

ⅡⅡⅡⅡ. Sulfonylureas（（（（磺酰脲类磺酰脲类磺酰脲类磺酰脲类））））

� The first generation: Tolbutamide(Tolbutamide(Tolbutamide(Tolbutamide(甲苯磺丁脲甲苯磺丁脲甲苯磺丁脲甲苯磺丁脲), ), ), ), chlorpropamide(chlorpropamide(chlorpropamide(chlorpropamide(氯磺丙脲氯磺丙脲氯磺丙脲氯磺丙脲).).).).

� The second generation:glyburide(glyburide(glyburide(glyburide(格列本脲格列本脲格列本脲格列本脲), glipizide(), glipizide(), glipizide(), glipizide(格列格列格列格列吡嗪吡嗪吡嗪吡嗪), gliquidone, glimepiride(), gliquidone, glimepiride(), gliquidone, glimepiride(), gliquidone, glimepiride(格列格列格列格列美脲美脲美脲美脲))))

� The third generation:gliclazidegliclazidegliclazidegliclazide

pharmacokinetics

� Absorption: P.O

� Distribution: PPBR

� Elimination: liver

� Excretion:kidney

Pharmacological effects

Hypoglycemic action: weaker than Insulin

� (1)Increasing the release of Insulin from pancreatic βcell:

� (2) Enhancing the sensitivity of target cell to

insulin

� ①Increasing the numbers of insulin receptors

� ②Increasing the affinity of insulin receptors

� (3) Decreasing the release of glucagons from pancreatic A cell by stimulating

the release of somatostatin

2.Antidiuretic action: chlorpropamidechlorpropamidechlorpropamidechlorpropamide↑secretion of ADH

3.Effects on coagulation

↓adhesion and agregation of PLT

↑synthesis of plasminogen

↓sensitivity of microvessel to CA

Clinical uses

� 1.NIDDM

� control hyperglycemia in NIDDM who can not achieve appropriate

control with exercise and dietary modification alone.

� (1)alone (2)plus insulin

2.Diabetes insipidus（（（（尿崩症尿崩症尿崩症尿崩症））））

Adverse reactions

1. Hypoglycemia reactions

2. Gastrointestinal tract reactions:

3. Anaphylactic reaction

4.Hepatic damage

[Drugs interaction]

1.Some drugs increase actions of

sulfonylureas

(1)Aspirin.butazolidin.SNS.coumarins (2) Penicillin.probenecid（（（（丙磺舒丙磺舒丙磺舒丙磺舒））））.

(3) Chloromycetin（（（（氯霉素氯霉素氯霉素氯霉素））））(4) Alcohol

2.Some drugs decrease actions of sulfonylureas

Glucocorticoids.

glucagon.

adrenaline.

thiazides

dilantin

ⅢⅢⅢⅢ Biguanides

� metformin

� phenformin

introduced in 1957 and were widely used.

Phenformin was withdrawn in many countries during

the 1970s because of an association with lactic acidosis.

Metformin has been associated only rarely with that

complications and has been widely used in Europe and

Canada.

It became available in the United States in 1995.

Pharmacological effects

� 1.Hypoglycemic action:

� (2) Slowing the absorption of glucose

� (3) Promoting the use of glucose

� (3) inhibiting release of glucagon

� (1) Promoting the effects of insulin

� 2.Regulating blood lipid

� 3.Antiplatelet effects

Clinical uses

� NIDDM patients with obesity

Side effects

� 1.gastrointestinal

� 2.Ketonuria and acidemiaphenformin：：：： lactic acidosis

ⅣⅣⅣⅣ α-glycosidase inhibitors

� Acarbose（（（（阿卡波糖阿卡波糖阿卡波糖阿卡波糖，，，，拜糖平拜糖平拜糖平拜糖平））））

Mechanism of action :Inhibiting α-Glycosidase

� (1)decreasing the formation of glucose

� (2) slowing the absorption of glucose

Clinical uses

used in combination with other oral anti-diabetic

agents and/or insulin

Side effects :

1.gastrointestinal reaction: 60%, mal-absorption,

flatulence, diarrhea, abdominal bloating

2.hypoglycemia: 3%

ⅤⅤⅤⅤ Other types agents:

� Repaglinide

� stimulating the pancreas to release insulin

� Mimicking physiological secretion of insulin

The others

� Chinese traditional medicinexiaokewan

[Actions]

1.Absorption2.Expansive action

3.Increase intestine peristalsis4.Nourishing action

[Uses]

Thank you !