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Transcript of Chapter 37 Insulin and oral hypoglycemic agents. diabetes mellitus Metabolic disorder of multiple...
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Chapter 37Insulin and oral
hypoglycemic agents
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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).
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Characteristics of DM
hyperglycemia disturbance in metabolism of
lipids, carbohydrates and proteins
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Symptoms of diabetes
Polyuria (urinating frequently) Polydipsia (very thirsty) Continuous hunger Weight loss
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Other diabetes symptoms
Fatigue Dry skin Frequent infections Feet ulceration Loss of sensibility in inferior
extremities (legs)
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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
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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
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Classification of drugs (1) Insulin (2) Orally hypoglycemic agents
Insulin sensitizers Sulfonylureas Biguanides Inhibitor of -glycosidase Chinese herbs
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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
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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
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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
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
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Pharmacological effects
The main effects of insulin are affecting metabolism of glucose, lipids and protein.
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1.Effects on glycometabolism (hypoglycemia)
Increase the synthesis and storage of glycogen
stimulating the uptake and metabolism of glucose by muscle and adipose tissue
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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
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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
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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]
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Clinical uses
The goal is the normalization not only of blood glucose but also of all aspects of metabolism.
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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.
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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
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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)
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Adverse reactions
2.Insulin allergy:
The most frequent allergic manifestations are IgE-mediated local cutaneous reactions.
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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
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Preparations of insulin
Portable pen injection Continuous subcutaneous insulin
infusion devices (CSII, insulin pumps)
Inhaled insulin
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Injection pen
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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
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Part 2 Oral hypoglycemic agents
Common characteristics (1) Orally effective and convenient (2) Slow and weak (3) NIDDM
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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)
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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
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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
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Mechanism
( PPARγ ) 过氧化物酶增殖体受体 γClinical use
NIDDM and IRAdverse reaction
general reaction heptic toxicity
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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
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pharmacokinetics
Absorption: P.O Distribution: PPBR Elimination: liver Excretion:kidney
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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
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(3) Decreasing the release of glucagons from pancreatic A cell by stimulating the release of somatostatin
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2.Antidiuretic action: chlorpropamide ↑secretion of ADH3.Effects on coagulation ↓adhesion and agregation of PLT ↑synthesis of plasminogen ↓sensitivity of microvessel to CA
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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
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[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
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2.Some drugs decrease actions of sulf
onylureas
Glucocorticoids. glucagon. adrenaline. thiazides dilantin
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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.
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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
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Clinical uses
NIDDM patients with obesity
Side effects 1.gastrointestinal 2.Ketonuria and acidemia phenfor
min : lactic acidosis
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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
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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%
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Ⅴ Other types agents: Repaglinide stimulating the pancreas to release i
nsulin Mimicking physiological secretion o
f insulin
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The others
Chinese traditional medicine xiaokewan[Actions] 1.Absorption 2.Expansive action 3.Increase intestine peristalsis 4.Nourishing action [Uses]
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Thank you !