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 Ⅰ DM (insulin-dependent diabetes mellitu

s, IDDM) type Ⅱ DM (non-insulin-dependent diabetes me

llitus, 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 -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 s

ubcutaneous injection. Half life:9-10 min Elimination in liver and

kindney

胰岛素制剂及其作用时间分类 制剂 给药途径 起效 高峰 持续 给药时间、

次数短效 正规胰岛素 皮下 / 静

脉0.3~0.7

2~4 5~8 餐前 0.5h ，3~4 次 / 日，急症

半慢胰岛素锌混悬液

皮下 0.5~1.0

2~8 12~16 餐前 0.5h ，3~4 次 / 日

中效 低精蛋白锌混悬液 皮下 1~2 6~12 18~24 早餐前 1h ，1 或 2 次 / 日

慢胰岛素锌混悬液 皮下 1~2 6~12 18~24 早餐前 1h ，1 或 2 次 / 日

长效 精蛋白锌胰岛素 皮下 4~6 14~20 24~36 早 / 晚餐前 1h,1 次 / 日

特慢胰岛素锌混悬液

皮下 4~6 16~18 20~36 早 / 晚餐前 1h,1 次 / 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 lipa

se 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 intracellular hypokalemia GIK: 10 ％ GS1000ml ＋ I 20u ＋ Kcl3g ivdrip

Adverse reactions 1.Hypoglycemia : most common may result from an inappropriately large dose of i

nsulin or delayed food intake. Short effect agents: sweating, hunger, palpitations, tremor and anxiety, Long effect agents: neuroglycopenic symptoms (such as difficulty in co

ncentrating, 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 药物 给药途经分类 药物 给药途经 给药时间 给药时间

Short-actingShort-acting Regular iv Regular iv 立即 立即 0.5 2 0.5 2 急救 急救 insulin sc 0.5 2-3 6-8 insulin sc 0.5 2-3 6-8 餐前半餐前半 h.tidh.tid Neutral protamine 2-4 8-12 18-24Neutral protamine 2-4 8-12 18-24 Hagedorn Hagedorn sc 2-4 6-10 12-18 sc 2-4 6-10 12-18 ProtamineProtamine zinc insulin 3-6 16-18 24-36 zinc insulin 3-6 16-18 24-36 餐前餐前 1h.qd1h.qd

作用时间开始 高峰 维持

餐前半 h.tid 1-2 次 /日Moderate

-acting

Globin zinc insulin

sc

餐前半 h.tid 1-2 次 /日

scLong-acting

表表 42-1 42-1 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

Ⅰ insulin sensitizer

Rosiglitazone( 罗格列酮 )

Englitazone (恩格列酮 ) Pioglitazone ( 吡格列酮 ) Troglitazone ( 曲格列酮 )

Ciglitazone （环格列酮）

Pharmacological action

1.Improve insulin resistance, lower hyperinsuline

mia 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

↓TG ，↑ TC and ↑HDL － C 3.Improve complication of NIDDM

anti-atherosclerosis effect

delay occurrence of albuminuria

4.Improve β-cell function

Mechanism

（ PPARγ ) 过氧化物酶增殖体受体 γClinical use

NIDDM and IRAdverse reaction

general reaction heptic toxicity

Ⅱ. Sulfonylureas （磺酰脲类） The first generation: Tolbutamide( 甲苯磺丁脲 ), chlorpropamide( 氯磺丙脲 ).

The second generation: glyburide( 格列本脲 ), glipizide( 格列吡嗪 ), gliquidone, glimepiride( 格列美脲 )

The third generation: gliclazide

pharmacokinetics

Absorption: P.O Distribution: PPBR Elimination: liver Excretion:kidney

Pharmacological effects

Hypoglycemic action: weaker than Insulin (1)Increasing the release of Insulin from panc

reatic βcell: (2) Enhancing the sensitivity of target cell to i

nsulin ①Increasing the numbers of insulin receptor

s 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: chlorpropamide ↑secretion of ADH3.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 ）

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

2.Some drugs decrease actions of sulf

onylureas

Glucocorticoids. glucagon. adrenaline. thiazides dilantin

Ⅲ 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 acidemia phenfor

min ： lactic acidosis

Ⅳ α-glycosidase inhibitors

Acarbose （阿卡波糖，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%

Ⅴ Other types agents: Repaglinide stimulating the pancreas to release i

nsulin Mimicking physiological secretion o

f insulin

The others

Chinese traditional medicine xiaokewan[Actions] 1.Absorption 2.Expansive action 3.Increase intestine peristalsis 4.Nourishing action [Uses]

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