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 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
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hyperglycemia
disturbance in metabolism of lipids,
carbohydrates and proteins
Symptoms of diabetes
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Polyuria (urinating frequently)
Polydipsia (very thirsty)
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Continuous hunger
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Weight loss
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Other diabetes symptoms
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Fatigue
Dry skin
Frequent infections
Feet ulceration
Loss of sensibility in inferior
extremities (legs)
Classification of DM
type Ⅰ DM
(insulin-dependent diabetes
mellitus, IDDM)
type Ⅱ DM
(non-insulin-dependent diabetes
mellitus, NIDDM)
Other type: secondery
Treatment and control
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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
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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
皮下
4~6
14~20
24~36 早/晚餐前
1h,1次/日
皮下
4~6
16~18
20~36 早/晚餐前
1h,1次/日
长效 精蛋白锌胰岛素
特慢胰岛素锌混悬
液
Pharmacological effects
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The main effects of insulin are
affecting metabolism of glucose,
lipids and protein.
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1.Effects on glycometabolism
(hypoglycemia)
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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
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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
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(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.
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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)
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Adverse reactions
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2.Insulin allergy:
The most frequent allergic manifestations
are IgE-mediated local cutaneous
reactions.
Adverse reactions
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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
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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
作用时间
给药途经
开始 高峰 维持
Regular
iv
insulin
sc
Neutral protamine
Hagedorn
Short-acting
给药时间
立即 0.5 2
急救
0.5
2-3 6-8 餐前半h.tid
2-4 8-12 18-24
sc
Moderate
-acting
Long-acting
sc
Protamine
zinc insulin
Globin zinc sc
insulin
2-4
3-6
6-10
16-18
12-18
24-36
餐前半h.tid
1-2次/日
餐前1h.qd
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
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Limosis and after-meal BS
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Blood insulin and blood fatty acid
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used in combination with other drugs
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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）
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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
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Absorption: P.O
Distribution: PPBR
Elimination: liver
Excretion:kidney
Pharmacological effects
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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
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(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 ）
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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
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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
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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
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NIDDM patients with obesity
Side effects
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1.gastrointestinal
 2.Ketonuria and acidemia
phenformin： lactic acidosis
Ⅳ α-glycosidase inhibitors
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Acarbose（阿卡波糖，拜糖平）
Mechanism of action :Inhibiting α-Glycosidase
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(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
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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]
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