30.胰島素——山東大學(xué)藥理學(xué)英文課件Insulin

1、Chapter 37Insulin and oral hypoglycemic agentsdiabetes 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 decreas

2、e in the response of peripheral tissues to insulin (insulin resistance). Characteristics of DM nhyperglycemiandisturbance in metabolism of lipids, carbohydrates and proteins Symptoms of diabetesnPolyuria (urinating frequently)nPolydipsia (very thirsty)nContinuous hungernWeight lossOther diabetes sym

3、ptomsnFatiguenDry skinnFrequent infectionsnFeet ulcerationnLoss of sensibility in inferior extremities (legs)Classification of DMtype DM (insulin-dependent diabetes mellitus, IDDM) type DM (non-insulin-dependent diabetes mellitus, NIDDM)Other type: secondery Treatment and controlnMedicationsn(insuli

4、n vs. hypoglycaemic agents)nIncrease physical activitynat least walk for 30 min. most daysnAppropriate dietnvegetablesnfruitnlow in fat and carbohydratesnLifestyle changes Classification of drugs (1) Insulin (2) Orally hypoglycemic agents Insulin sensitizers Sulfonylureas Biguanides Inhibitor of -gl

5、ycosidase Chinese herbsPART 1 insulinnChemistry :small protein with a MW of 56 KD (in human)Two chains (A and B)nsource : once from bovine and porcine pancreas, now by recombinant DNA techniquesPharmacokineticsnwill be degraded in the gastrointestinal tract if taken orally. noften administered by su

6、bcutaneous injection.nHalf life:9-10 minnElimination in liver and kindney 胰島素制劑及其作用時間分類分類制劑制劑給藥途徑給藥途徑起效起效高峰高峰持續(xù)持續(xù)給藥時間、給藥時間、次數(shù)次數(shù)短效短效正規(guī)胰島素正規(guī)胰島素皮下皮下/靜靜脈脈0.30.72458餐前餐前0.5h，34次次/日，日，急癥急癥半慢胰島素鋅混懸半慢胰島素鋅混懸液液皮下皮下0.51.0281216餐前餐前0.5h，34次次/日日中效中效低精蛋白鋅混懸液低精蛋白鋅混懸液皮下皮下126121824早餐前早餐前1h，1或或2次次/日日慢胰島素鋅混懸液慢胰島素鋅混懸液皮

7、下皮下126121824早餐前早餐前1h，1或或2次次/日日長效長效精蛋白鋅胰島素精蛋白鋅胰島素皮下皮下4614202436早早/晚餐前晚餐前1h,1次次/日日特慢胰島素鋅混懸特慢胰島素鋅混懸液液皮下皮下4616182036早早/晚餐前晚餐前1h,1次次/日日Pharmacological effectsnThe main effects of insulin are affecting metabolism of glucose, lipids and protein. n1.Effects on glycometabolism (hypoglycemia)n Increase the sy

8、nthesis and storage of glycogen n stimulating the uptake and metabolism of glucose by muscle and adipose tissue Pharmacological effects2.Effects on lipometabolismn inhibiting the hormone-sensitive lipase in adipose tissue inhibiting the hydrolysis of triglyceridesnIncreasing transfer of fatty acid s

9、timulates synthesis of fatPharmacological effects3.Effects on protein metabolism (positive nitrogen balance) nstimulating amino acids uptake and protein synthesis n inhibiting protein degradation in muscle and other tissues Pharmacological effects of insulin4.Influence on kalium in blood Decrease ka

10、lium in blood5.HR (heart rate), increase the contractility of myocardium, decrease renal blood flowMechanism of actionClinical usesnThe goal is the normalization not only of blood glucose but also of all aspects of metabolism. :the only effective drug Patient with IDDM must rely on injected insulin

11、daily in order to control hyperglycemia all his lifetime. The most common site of subcutaneous injection is abdomen.n :not adequately controlled by diet and oral hypoglycemic agents (Weight reduction, exercise and dietary modification can correct the hyperglycemia in some patients)n For NIDDM patien

12、ts, 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 coma4.DM patients under stress conditions: serious infect

13、ion, consumptive diseases, pregnancy, trauma, operation5. Hyperkalemia and intracellular hypokalemia GIK: 10GS1000mlI 20uKcl3g ivdrip Adverse reactionsn : most common may result from an inappropriately large dose of insulin or delayed food intake. Short effect agents: sweating, hunger, palpitations,

14、 tremor and anxiety, Long effect agents: neuroglycopenic symptoms (such as difficulty in concentrating, confusion, weakness, drowsiness, even loss of consciousness) Adverse reactionsn2.Insulin allergy: The most frequent allergic manifestations are IgE-mediated local cutaneous reactions. Adverse reac

15、tionsn3.Insulin Resistance Acute resistance: stress Chronic resistance: 1) AIRA (antiinsulin receptor autoantibody) 2) down regulation of receptor 3) dysfunction of glucose transfer 4. othersPreparations of insulinnPortable pen injectionnContinuous subcutaneous insulin infusion devices (CSII, insuli

16、n pumps)nInhaled insulinInjection pen 作用時間作用時間開始開始 高峰高峰 維持維持餐前半餐前半h.tid 1-2次次/日日Moderate-actingGlobin zinc insulinsc餐前半餐前半h.tid 1-2次次/日日scLong-actingPart 2 Oral hypoglycemic agents Common characteristicsn(1) Orally effective and convenientn(2) Slow and weakn(3) NIDDM insulin sensitizer Rosiglitazone

17、(羅格列酮羅格列酮) Englitazone (恩恩格列酮格列酮) ) Pioglitazone (吡格列酮吡格列酮) Troglitazone (曲格列酮曲格列酮) Ciglitazone （環(huán)（環(huán)格列酮）格列酮） Pharmacological action 1.Improve insulin resistance, lower hyperinsulinemia and hyperglycemia n Limosis and after-meal BSnBlood insulin and blood fatty acidnused in combination with other dru

18、gsnLow incidence of hypoglycemia 2.Correct lipodystrophy TGTG，TC and HDLTC and HDLC C 3.Improve complication of NIDDM anti-atherosclerosis effect delay occurrence of albuminuria 4.Improve -cell functionMechanism（PPAR )PPAR )過氧化物酶增殖體受體過氧化物酶增殖體受體Clinical use NIDDM and IRNIDDM and IRAdverse reaction ge

19、neral reactiongeneral reaction heptic toxicity heptic toxicity. Sulfonylureas（磺酰脲類）（磺酰脲類）nThe first generation: Tolbutamide(Tolbutamide(甲苯磺丁脲甲苯磺丁脲), ), chlorpropamide(chlorpropamide(氯磺丙脲氯磺丙脲).). nThe second generation: glyburide(glyburide(格列本脲格列本脲), glipizide(), glipizide(格列格列吡嗪吡嗪), gliquidone, glim

20、epiride(), gliquidone, glimepiride(格列格列美脲美脲) )nThe third generation: gliclazidegliclazidepharmacokineticsnDistribution: PPBR nElimination: livernExcretion:kidneyPharmacological effects Hypoglycemic action: weaker than Insulinn(1)Increasing the release of Insulin from pancreatic cell: n(2) Enhancing

21、the sensitivity of target cell to insulinnIncreasing the numbers of insulin receptorsnIncreasing the affinity of insulin receptorsn(3) Decreasing the release of glucagons from pancreatic A cell by stimulating the release of somatostatin2.Antidiuretic action: chlorpropamidechlorpropamide secretion of

22、 ADH3.Effects on coagulation adhesion and agregation of PLT synthesis of plasminogen sensitivity of microvessel to CA Clinical uses n ncontrol hyperglycemia in NIDDM who can not achieve appropriate control with exercise and dietary modification alone.n(1)alone (2)plus insulin2.Diabetes insipidus（尿崩癥

23、尿崩癥 ）Adverse reactions1. Hypoglycemia reactions2. Gastrointestinal tract reactions:3. Anaphylactic reaction 4.Hepatic damageDrugs interaction 1.Some drugs increase actions of sulfonylureas (1)Aspirin.butazolidin.SNS.coumarins (2) （丙磺舒）（丙磺舒）. (3) Chloromycetin（氯霉素）（氯霉素） (4) Alcohol 2.Some drugs decre

24、ase actions of sulfonylureas Glucocorticoids. glucagon. adrenaline. thiazides dilantin Biguanides n metforminnphenformin introduced in 1957 and were widely used. Phenformin was withdrawn in many countries duringthe 1970s because of an association with lactic acidosis.Metformin has been associated only rarely with thatcomplications and has been widely used in Europe andCanada. It became available in the United States in 1995. Pharmacological effectsn1.Hypoglycemic action:n(2) Slowing the absorption of glucosen(3) Promoting the use of glucosen(3) inhibiting release of glucagonn(1) Promoting the