Transcript Chapter 36 Insulin and oral hypoglycemic agents
Chapter 37 Insulin and oral hypoglycemic agents
diabetes mellitus
Metabolic disorder of multiple etiology characterized by hyperglycemia (insulin resistance).
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
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 type
Ⅰ
DM (insulin-dependent diabetes mellitus, IDDM)
Ⅱ
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
-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 制剂 短效 中效 半慢胰岛素锌混悬 液 低精蛋白锌混悬液 长效 正规胰岛素 慢胰岛素锌混悬液 精蛋白锌胰岛素 特慢胰岛素锌混悬 液 给药途径 皮下 脉 皮下 皮下 皮下 皮下 皮下
/
静 起效
0.3~0.
7 0.5~1.
0 1~2 1~2 4~6 4~6
高峰
2~4 2~8 6~12 6~12 14~20 16~18
持续
5~8 12~16 18~24 18~24 24~36 20~36
给药时间、 次数 餐前
0.5h
，
3~4
次
/
日， 急症 餐前
0.5h
，
3~4
次
/
日 早餐前
1h
，
1
或
2
次
/
日 早餐前
1h
，
1
或
2
次
/
日 早
/
晚餐前
1h,1
次
/
日 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 lipase in adipose tissue→ inhibiting the hydrolysis of triglycerides Increasing transfer of fatty acid →stimulates synthesis of fat
Pharmacological effects of insulin
Pharmacological effects
3.Effects on protein metabolism
(positive nitrogen balance) stimulating amino acids uptake and protein synthesis inhibiting protein degradation in muscle and other tissues
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 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
表
42-1
胰岛素制剂比较 分类 药物 给药途经 作用时间 开始 高峰 维持 给药时间
Short-acting Moderate -acting Regular iv
立即
0.5 2
急救
insulin sc 0.5 2-3 6-8
餐前半
h.tid
Neutral protamine 2-4 8-12 18-24 Hagedorn sc
餐前半
h.tid 1-2
次
/
日
sc 2-4 6-10 12-18 Protamine zinc insulin 3-6 16-18 24-36
餐前
1h.qd
Long-acting insulin
餐前半
h.tid 1-2
次
/
日
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 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 ↓
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γ
Clinical use
NIDDM and IR
Adverse 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
美脲) : glyburide(格列本脲), glipizide(格列 吡嗪), gliquidone, glimepiride(格列
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 pancreatic βcell: (2) Enhancing the sensitivity of target cell to insulin ① Increasing the numbers of insulin receptors ② Increasing 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 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 ）
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 sulfonylureas 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 phenformin
：
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 insulin Mimicking physiological secretion of insulin
The others
Chinese traditional medicine xiaokewan [Actions] 1.Absorption
2.Expansive action 3.Increase intestine peristalsis 4.Nourishing action [Uses]