Insulin and oral hypoglycemic drugs

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).



2-5h




1-2h 8-12h 24h


4-8h 14-20h 24-36h


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.



2-5h




1-2h 8-12h 24h


4-8h 14-20h 24-36h


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


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



(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


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)


Biguanides （双胍类）

Metformin 二甲双胍（甲福明） Phenformin 苯乙双胍（苯乙福明）


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)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.


-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


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


Aldose reductase inhibitor

Epalrestat ( 依帕司他 )

Treatment of Diabetic Neuropathy

Insulin and oral hypoglycemic drugs

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