Insulin and oral hypoglycemic drugs. §A group of diseases characterized by high levels of blood...
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Transcript of Insulin and oral hypoglycemic drugs. §A group of diseases characterized by high levels of blood...
Insulin and oral hypoglycemic drugs
A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both
194 million people worldwide 90% cases are Type 2
Diabetes Mellitus
CLASSIFICATION
TYPE 1 (IDDM,10%) Deficiency of insulin secretion Genetic predisposition and possible links to
viral infections and environmental factors Possible autoimmune process with
destruction of beta pancreatic cells Require insulin supplementation, prone to
develop DKA ( 酮症酸中毒)
CLASSIFICATION
TYPE 2 (NIDDM,90%) Resistance to action of insulin on target organs Decrease in insulin production Increased risk with obesity high fat, high caloric
diets Stronger genetic predisposition Variety of initial presentations: HHNKS ( 高血糖高渗
性非酮症综合征 ), nephropathy, retinopathy, neuropathies
Disease can be delayed or prevented with life style changes
CLINICAL FEATURES
PolyuriaPolydipsiaPolyphagiaWeight loss
TYPE 1 DM-- acute, severeTYPE 2 DM-- chronic, less severe
Therapy of Diabetes Mellitus
DietExerciseInsulin and its enhancers Oral hypoglycemic drugs
Insulin and its action enhancers
Structure of insulin
Insulin
1. Pharmacological effects(1) Carbohydrate metabolism: reducing blood glucose levels by glucose
oxidation and glycolysis , glycogenolysis , glycogen synthesis , gluconeogenesis
(2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids , ketone bodies
(3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism
(4) HR , myocardial contractility , renal blood flow
Mechanism of insulin actions Interacting with insulin receptor
Insulin
1. Pharmacological effects(1) Carbohydrate metabolism: reducing blood glucose levels by glycose
oxidation and glycolysis , glycogenolysis , glycogen synthesis , gluconeogenesis
(2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids , ketone bodies
(3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism
(4) HR , myocardial contractility , renal blood flow
Mechanism of insulin actions Interacting with insulin receptor
Interaction between insulin and its receptorIRS: insulin receptorsubstrate
tyr: tyrosine
P: phosphate
2. Clinical uses(1) Type 1 diabetes mellitus
(2) Type 2 diabetes mellitus: failure to other drugs or diet control
(3) Diabetic complications: diabetic ketoacidosis ( 酮症酸中毒 ), hyperosmotic nonketotic coma (高渗性非酮症性昏迷)
(4) Critical situations of diabetic patients: fever, severe infection, pregnancy, trauma, operation
(5) Others: intracellular lack of K+
Insulin
3. Preparations Properties Preparations Onset Peak duration
Rapid Lispro, aspart 5-15min 30-60min
2-5h
Fast Regular insulin 0.5-1h 2-4h 5-7h
Fast Novolin R, Humulin R 0.5-1h 2-4h 5-7h
Intermediate Neutral protamine hagedorn (NovolinN, Humulin N)
1-2h 8-12h 24h
Long Protamine zinc insulin suspension
4-8h 14-20h 24-36h
Long Glargine 1-2h no 20-24h
Rapid Acting Insulin Analogues Current agents include lispro ( 赖脯胰岛素 ), aspart
( 门冬胰岛素 ), and glulisine ( 赖谷胰岛素 ). (人胰岛素类似物)
Remain monomeric after injection, resulting in rapid absorption, and relatively rapid onset and offset.
Onset of action is 5-15 minutes, with peak action at 30-60 minutes and duration of ~2-5 hours.
Advantages include: increased convenience- can take just prior to meal. better postprandial glycemic control.
Disadvantages include: short duration of action- can be problematic in Type 1
diabetic without basal insulinization, as with bedtime NPH.
more expensive than regular insulin (~double the cost).
3. Preparations Properties Preparations Onset Peak duration
Rapid Lispro, aspart 5-15min 30-60min
2-5h
Fast Regular insulin 0.5-1h 2-4h 5-7h
Fast Novolin R, Humulin R 0.5-1h 2-4h 5-7h
Intermediate Neutral protamine hagedorn (NovolinN, Humulin N)
1-2h 8-12h 24h
Long Protamine zinc insulin suspension
4-8h 14-20h 24-36h
Long Glargine 1-2h no 20-24h
Regular InsulinReferred to as clear or unmodified insulin.Onset of action 30-60 minutes, Peak action
2-4 hours, Duration of action: 5-7 hours.Advantages:
Inexpensive Long track record of safety.
Disadvantages: Need to take doses 30-45 minutes prior to eating a meal. Effect is not truly rapid… it is delayed which can result in
postprandial hyperglycemia, late hypoglycemia.
3. Preparations Properties Preparations Onset Peak duration
Rapid Lispro, aspart 5-15min 30-60min
2-5h
Fast Regular insulin 0.5-1h 2-4h 5-7h
Fast Novolin R, Humulin R 0.5-1h 2-4h 5-7h
Intermediate Neutral protamine hagedorn (NovolinN, Humulin N)
1-2h 8-12h 24h
Long Protamine zinc insulin suspension
4-8h 14-20h 24-36h
Long Glargine 1-2h no 20-24h
Glargine (Lantus 甘精胰岛素 )
Long acting insulin analogue.Onset is ~90 minutes, and it is virtually
peakless. Duration is 20-24 hours.Provides ~flat basal insulinization.More expensiveCannot be mixed with other insulins.
The Medical Letter, Vol 43, August 6, 2001
Mixed insulin
70-30: human monocomponent insulin ( 单组份人胰岛素 ) 30% , Human Insulin Isophane Suspension ( 精蛋白锌人胰岛素) 70%.
50-50: human monocomponent insulin ( 单组份人胰岛素 ) 50% , Human Insulin Isophane Suspension ( 精蛋白锌人胰岛素) 50%.
Onset:0.5h, peak 2-12h, duration:16-24h. 30min before breakfast.
4. Adverse effects
(1) Hypersensitivity: treated with H1 receptor antagonist, glucocorticoids, replaced by human or high purity insulin
(2) Hypoglycemia: (sweating, hunger, weakenss, tachycardia, blurred vision, headache, coma, shock, etc.), drink glucose contained water, or treated with 50% glucose
(3) Lipoatrophy: localized in injection sites
(4) Insulin resistance: Acute: stress etc. induced, need large dose of insulinChronic: need >200U/d and no complication
Insulin
4. Adverse effects
(5) Increase body weight
(6) Ametropic eye 屈光不正
(7) Edema
Insulin
Thiazolidinediones (TDs) 噻唑烷酮类化合物
Biguanides ( 双胍类 )
Insulin action enhancers(oral hypoglycemic drugs)
Thiazolidinediones (TDs) 噻唑烷酮类化合物
Rosiglitazone 罗格列酮
Pioglitazone 吡格列酮
Troglitazone 曲格列酮
Insulin action enhancers
Rosiglitazone 罗格列酮
Pioglitazone 吡格列酮
Insulin action enhancers
1. Pharmacological effects
Selective agonists for nuclear peroxisome proliferator-activated receptor- (PPAR, 过氧化物酶增殖体激活受体 ).
(1) Fat cells differentiate to a lot of small fat cells, and increase GLUT-4 expression (2) Increase signal transmission of insulin (Rosiglitazone increase insulin receptors)(3) Decrease leptin, IL-6 and TNF-alpha expression in fat cells(4) increase GLUT1,4 transcription and expression(5) Inhibit VEGF mediated angiogenesis, to prevent the complications.(6) Increase adiponectin level, recover the function of B cells
Insulin action enhancers
1. Pharmacological effects
(1) Lowering insulin resistance(2) Lipid metabolism regulation: TG, free fat acid, LDL (3) Antihypertensive effects(4) Effect on vascular complications in type 2 patients(5) Recover the function of B cells
Insulin action enhancers
2. Clinical uses
Used for treatment of insulin-resistant diabetic patients or type 2 patients
3. Adverse effects
Edema, headache, myalgia, GI reactions, hepatic damage (troglitazone)
Insulin action enhancers
Biguanides (双胍类)
Metformin 二甲双胍(甲福明) Phenformin 苯乙双胍(苯乙福明)
Insulin action enhancers
Biguanides
1. Pharmacilogical effects increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut, gluconeogenesis, and glucagon release.
2. Clinical uses mild insulin-independent patients with obesity
3. Adverse effects severe lactic acidosis (less for metformin),
malabsorption of vitamin B12 and folic acid
Other oral hypoglycemic drugs
Oral insulin secretagogues
Sulfonylureas ( 磺酰脲类 )RepaglinideIncretin (GLP-1) MimeticsDipeptidylpeptidase IV (DPP-IV) Inhibitors
Oral hypoglycemic drugs
Sulfonylureas (磺酰脲类)
Tolbutamide (D860) 甲磺丁脲Chlorpropamide 氯磺丙脲Glibenclamide 格列本脲 ( 优降糖 ) Glipizide 格列吡嗪Gliclazide 格列齐特 ( 达美康 )
Sulfonylureas
1. Pharmacological effects
(1)Hypoglycemic effect: blocking ATP-sensitive K+ channel: Ca2+ inflow , insulin
release , stimulating insulin secretion increase the binding of insulin and its receptors (still effective
after long-term use to recover insulin level) glucose utilization, glycogen and fat synthesis, insulin
receptor number and affinity , insulin metabolism↓
(2) Antidiuretic effect
(3) Effect on coagulation function
Action of sulfonylureas
Sulfonylureas
1. Pharmacological effectsHypoglycemic effect: blocking ATP-sensitive K+ channel: Ca2+ inflow , insulin
release , stimulating insulin secretion, increase the binding of insulin and its receptors (still effective
after long-term use to recover insulin level) glucose utilization, glycogen and fat synthesis, insulin
receptor number and affinity , insulin metabolism↓
(2) Antidiuretic effect (chlorpropamide): effect of
antiuretic hormone (ADH)
(3) Effect on coagulation function (gliclazide)
2. Clinical uses
(1) Insulin-indenpedent diabetic patients (type 2): alone or combined with insulin
(2) Diabetes insipidus ( 尿 崩 症 ): Chlorpropamide ( 氯 磺 丙脲 )
Sulfonylureas
3. Adverse effects
(1) GI reactions
(2) CNS reactions
(3) Hypoglycemia: especially in elderly, hepatic or renal insufficiencies
(4) Others: cholestatic jaundice, hepatic damage (Chlorpropamide), leukopenia.
Sulfonylureas
4. Drug interactions
(1) Potentiation of hypoglycemic effects replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. inhibition of hepatic microsomal enzymes: chloramphenicol, warfarin
(2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucocorticoids, thiazides,
etc.
Sulfonylureas
Pharmacological effects Repaglinide lowers blood glucose by stimulating the release of
insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels
in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion
Protect beta cell
Clinical uses Type2 DM, diabetic nephropathy, elder DM patient less hypoglycemia
Repaglinide ( 餐时血糖调节剂 )
Incretin (GLP-1) Mimetics
Mechanism of Action: Act as an incretin enhance insulin secretion in response
to an oral glucose load. Suppress post-prandial glucagon secretion Increase insulin secretion in a glucose-dependent manner Increase somatostatin secretion which inhibit glucagon
release Delay gastric emptying Centrally suppress appetite Preserve beta cell mass by reducing apoptosis and
increased neogenesis (animal models).
Keating, Drugs. 65(12):1681-92, 2005.Riddle and Drucker. Diabetes Care 2006; 29:435-49.
Incretin (GLP-1) Mimetics Exenatide (Byetta) is first incretin mimetic on market. Synthetic version of salivary protein found in the Gila monster53%
overlap with human GLP-1.
Must be taken as a BID injection w/in 60 mins prior to meal Major side effects: nausea, vomiting, diarrhea. Increases the risk of
Acute pancreatitis. Use not recommended in severe renal impairment. Not recommended as monotherapy
To be used as add on therapy with SU, metformin, or TZD’s Increases the risk of Hypoglycemia when added to SU treatment.
Major advantage is weight loss (~5 kg) as well as maintained effect (?preserved beta cell function).
Efficacy: decreases A1C ~1.0%.
Keating, Drugs 2005 65(12):1681-92
Site of DPP-IV Inactivation
Exenatide
A SYL GQ AKE RVKAH G F VEA T TSD S SY LE GQAA KE F I AW LVKGR -NH2GLP-1Human
Dipeptidylpeptidase IV (DPP-IV) Inhibitors
Mechanism of Action: Acts to prevent breakdown of intrinsic GLP-1, thereby increasing
portal GLP-1 levels
Sitagliptin (Januvia) is first DPP-IV inhibitor on market. Effective as monotherapy or when used in conjunction
with metformin or a thiazolidinedione. Efficacy: decreases A1C ~0.8%.
Riddle and Drucker. Diabetes Care 2006; 29:435-49.
Oral hypoglycemic drugs
-Glucosidase inhibitors (葡萄糖苷酶抑制药)
Acarbose 阿卡波糖
Reducing intestinal absorption of starch ( 淀粉 ), dextrin ( 糊精 ), and disaccharides ( 二糖 ) by inhibiting the action of intestinal brush border -glucosidase
Oral hypoglycemic drugs
Pramlintide acetate ( 醋酸普兰林肽 ) • an analogue of amylin, a small peptide hormone that is released
into the bloodstream by the β-cells of the pancreas along with insulin, after a meal.
• delay glucose absorption, inhibit secretion of glucagon
• Symlin has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin. Symlin allows patients to use less insulin, lowers average blood sugar levels, and blood sugar after eating.
• Apart from insulin analogs, symlin is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s
Oral hypoglycemic drugs
Aldose reductase inhibitor
Epalrestat ( 依帕司他 )
Treatment of Diabetic Neuropathy