Transcript PancreaticHormone&AntidiabeticDrugs

Pancreatic Hormone &
Antidiabetic Drugs
GAO Fen-Fei
Background
•
Diabetes mellitus classification:
1. insulin-dependent diabetes mellitus (IDDM):
pancreatic B cell destruction (immunemediated in most cases)
2. non-insulin-dependent diabetes
mellitus (NIDDM): ＞90%,
defects of insulin secretion
and action, insulin resistance.
Insulin
• Small protein containing 51 amino acids
arranged in two chains (A and B) linked by
disulfide bridges.
• Released from pancrearic B cells at a low
basal rate and at a much higher stimulated
rate in response to a variety of stimuli,
especially glucose.
Pharmacokinetics
• Insulin is a protein, which can be destructed
by digestive enzyme. Oral is invalid.
• Absorption is rapid when subcutaneous
injection (i.h.)
• Inactivation in liver and kidney.
Pharmacological Effects
•
1.
2.
3.
4.
Promotes the storage of fat as well as glucose within liver,
adipose(脂肪) tissue, muscle.
Promotes fat synthesis, decreases free fatty acid and
ketogensis(酮体生成), increases fatty acid and glucose
transport,
Promotes glycogen synthesis, increases glucose
catabolism(分解代谢), inhibits glycogenolysis(糖原分解)
and gluconeogenesis(糖原异生)→blood glucose↓
Promotes protein synthesis by increasing amino acid
transport and by stimulating ribosomal(核糖体) activity,
decreases protein catabolism(分解代谢).
Heart rate↑, myocardial contractility↑, blood flow of
kidney ↓
Mechanism of Action
• Insulin receptor on the membranes consists
of two heterodimers(异二聚体), each
containing
– An α subunit, entirely extracellular and
constitutes the recognition site.
– An β subunit, spans the membrane and contains
a tyrosine(酪氨酸) kinase(激酶).
Clinical Uses
• Therapy of all insulin deficient diabetes.
1. IDDM (type 1)
2. NIDDM (type 2) which cannot be controled by
diet therapy or oral hypoglycemic agents.
3. Diabetes with acute or severe complication(并发
症).
4. Diabetes accompanied severe infection, wasting
disease(消耗性疾病), high fever, pregnance,
trauma(创伤), and operation.
5. Intracellular K+ deficience.
Insulin Preparations
1. Ultra-short-acting insulins: insulin lispro(赖脯胰
岛素),
 produced by recombinant technology,
 B28 (proline脯氨酸)
B29 (lysine赖氨酸)
 Advantage: low propensity(倾向) to form hexamers(六
聚体) in contrast to human insulin, absorbed very
rapidly.
 The duration, in contrast to RI, is only minimally
prolonged by increasing the dosage of the insulin.
2. Short-acting insulins: regular insulin (RI)


The only type that can be administered intravenously.
Particularly useful for management of diabetic
ketoacidosis, after surgery or during acute infections.
As with all older insulin formulations, the duration of
action as well as the time of onset and the intensity of
peak action increase with the size of the dose.
3. Intermediate-acting insulins: NPH, GZI
4. Long-acting insulins: PZI
5. Monocomponent insulin (McI): reduce
contaminating proteins → antigenicity(抗原性)↓
Adverse Reactions
1. Hypoglycemia(低血糖症)
2. Allergic reaction
3. Insulin resistance:
 Acute resistance: induced by stress(应激).
①insulin antagonist (eg, GC, adrenaline)↑;
②pH↓→ insulin-R↓;
③free fatty acid and ketone body in blood↑→ inhibit glucose
utilization.
 Chronic resistance:
①pro-receptor abnormality: anti-insulin antibodyies;
②receptor level change: number↓, or affinity↓
③post-receptor abnormality: abnormal glucose transport system
or enzyme system in target cell.
4. Lipoatrophia(脂肪萎缩)
Oral Hypoglycemic Agents
Insulin sensitizer
Sulfonylureas(磺脲类)
Biguanides(双胍类)
Acarbose(阿卡波糖) and repaglinide(瑞格列奈)
Insulin Sensitizer
• Insulin resistance
– Acquired: type 1 diabetes —— control blood
glucose
– Hereditary: type 2 diabetes —— insulin
sensitizer
• Thiazolidinediones(噻唑烷酮类化合物):
rosiglitazone(罗格列酮), pioglitazone(吡格列酮),
troglitazone(曲格列酮), ciglitazone(环格列酮),
englitazone(恩格列酮).
Pharmacological Effects
1. Reduce insulin resistance, restore blood
glucose levels into the normal: increasing
glucose uptake and metabolism in muscle and
adipose(脂肪) tissues.
2. Ameliorate(改善) lipid metabolism:
3. Prevent and cure vascular complication of
type 2 diabetes:
4. Ameliorate function of pancreatic B cell:
Mechanism of Action
•
Competitively activate peroxisome(过氧化物酶)
proliferator-activated receptor-γ(PPAR γ) nuclear
receptor → transcription →
1. adipose cell differentiation → many small adipose
cells →insulin sensitivity↑
2. Enhance insulin signal transduction
3. Reduce gene expression of leptin(瘦素) and TNF-α
4. Ameliorate function of pancreatic B cell
5. GLUT 1 and GLUT 4↑ → glucose uptake and
transport↑
Adverse Reactions
• Incidence of hypoglycemia is low.
• Mild anemia(贫血), drowsiness(嗜睡),
muscle and skeleton pain, gastrointestinal
disorder.
• Troglitazone(曲格列酮) → idiosyncratic(特
异质的) liver damage, liver failure or death.
Sulfonylureas (磺脲类)
• First-generation: tolbutamide(甲苯磺丁脲;甲
糖宁; D860), chlorpropamide(氯磺丙脲)
• Second-generation: glyburide(格列本脲;优降
糖;降糖灵,glibenclamide), glipizide(格列吡嗪,
吡磺环己脲), glimepiride(格列美脲)
• Third-generation: gliclazide(格列齐特,达美
康)
Pharmacokinetics
• Well absorbed in gastrointestinal tract.
• Plasma protein binding rate is high → Vd↓.
• Most drug metabolized in the liver.
• Excretion from urine.
Pharmacological Effects
1. Reduce blood glucose levels:
1) Increase insulin release from pancreatic B cells:
2) Reduce serum glucagon(胰高血糖素) levels: indirect
inhibition.
3) Potentiate the action of insulin on its target tissues
2. Stimulation of ADH(抗利尿激素) secretion and
potentiation of its action at the renal tubule →
dilutional hyponatremia(稀释性低钠血症), therapy
of diabetes insipidus(尿崩症).
3. Effects on blood coagulation: platelet
adhesiveness↓, plasminogen(纤溶酶原)
synthesis↑—— third-generation sulfonylureas
sulfonylureas
+
receptor
efflux of K+ ↓
close
depolarization
B cell inward rectifier-type
ATP-sensitive potassium
channel
Voltage-gated Ca2+ channel open
Release of preformed insulin
Ca2+ influx
Clinical Uses
1. Type 2 diabetes with pancreas islet
function but invalid to diet therapy.
2. diabetes insipidus(尿崩症):
chlorpropamide(氯磺丙脲) 0.125~0.5g/d
Adverse Reactions
• Cutaneous anaphylaxis(皮肤过敏),
gastrointestinal disorder, liver damage
• Hematologic toxicity: leukopenia(白细胞减
少), blood platelet↓, hemolytic anemia
• Persistent hypoglycemia
• Contraindicated in patients with hepatic or
renal insufficiency.
Drug Interaction
1. high plasma protein binding rate of
sulfonylureas → competitive replacement by
other drugs (eg, phenylbutazone保泰松,
dicoumarol双香豆素, etc) or bilirubin(胆红素) →
hypoglycemia.
2. Alcohol inhibit gluconeogenesis(糖原异生) and
transport of liver glucose → aggravating
hypoglycemia.
3. Chlorpromazine(氯丙嗪), GC, thiazides(噻嗪类利尿
药), oral contraceptives(口服避孕药) → inhibit
blood glucose-lowering effect of sulfonylureas.
Biguanides (双胍类)
• Metformin(甲福明,二甲双胍), phenformin(苯
乙福明;苯乙双胍;降糖灵)
• Phenformin was discontinued in the USA
because of its association with lactic
acidosis(乳酸酸中毒) and because there was
no documentation of any long-term benefit
from its use.
• Not bound to plasma proteins, not metabolized,
excreted by the kidneys as the active compound.
• Mechanism of action remain elusive(难捉摸的),
maybe include:
①direct stimulation of glycolysis in tissues, with
increased glucose removal from blood;
②reduced hepatic gluconeogenesis;
③slowing of glucose absorption from the gastrointestinal
tract, with increase glucose to lactate(乳酸盐) conversion
by enterocytes;
④reduction of plasma glucagon levels.
•
Clinical Uses:
1. for patients with refractory(难控制的) obesity whose
hyperglycemia is due to ineffective insulin action.
Biguanides is an insulin-sparing agent and does not
increase weight or provoke hypoglycemia.
2. In combination with sulfonylureas in type 2
diabetics(糖尿病患者) in whom sulfonylureas therapy
alone is inadequate.
•
Adverse Reaction:
–
–
lactic acidosis, ketonemia(酮血症)
gastrointestinal (anorexia食欲减退, nausea, vomiting,
abdominal discomfort, diarrhea),
Acarbose (阿卡波糖)
• α-glucosidase(葡萄糖苷酶) inhibitors
• Mechanism: competed glycoside-hydrolase with
carbohydrate on the small intestine epithelium
brush border → hydrolysis of carbohydrate↓→
delay the absorption of glucose.
• Pharmacological Effect: lower the postprandial(餐
后) blood glucose levels.
• Adverse Reactions: gastrointestinal discomfort.
Repaglinide (瑞格列奈)
• Repaglinde is a member of the
meglitindes(氯茴苯酸) group.
• A new class of insulin secretagogues(促分
泌的).
• Advantage is to imitate the physiological
secretion of insulin.
• There is overlap with the sulfonylureas in their
molecular sites of action with two common
binding sites and one unique.
• Unlike the sulfonylureas, they have no direct
effect on insulin exocytosis.
• Repaglinide has a very fast onset and short
duration of action, and is indicated for use in
controlling postprandial glucose excursions.
• Metabolism in liver, 92% of metabolite is excreted
via bile.
• Can be taken alone as monotherapy of in
combination with biguanides.
• There is no sulfur in the structure, so
repaglinide may be indicated for use in type
2 diabetic individuals with sulfur or
sulfonylurea allergy.