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Chapter 34 Insulin & Oral Antidiabetic DChapter 34 Insulin & Oral Antidiabetic Drugsrugs

Diabetes mellitus Definition: a syndrome of disordered metabolism due to a combination of hereditary and environmental causes.

Classification: Type 1: Lack of insulin.

Type 2: Cells resistance to insulin Signs & symptoms: • Very thirsty • Feeling tired • Using the toilet often to urinate • Constant hunger • High level of glucose in urine & in fasting blood

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Harms (complications)▲ Acute

Diabetic ketoacidosis (DKA)

Nonketotic hyperosmolar coma

▲Chronic

Microvascular disease: impotence & poor wound

healing

Atherosclerosis : Strokes, coronary heart diseas

e

Renal failure, retinal damage, nerve damage

Infective disease: Tuberculosis

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Treatment

Type 1: Insulin must be injected or inhaled

Type 2: Food control, exercise, medicines

(1) agents which increase insulin secretion;

(2) agents which increase the sensitivity of tar

get organs to insulin;

(3) agents which decrease glucose absorption

(4) Insulin needed for patients with serious co

mplications or an emergency.

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Section 1 InsulinSection 1 Insulin

●Chemistry: 51 aa arranged in two chains (A & B) li

nked by disulfide bridges.

● Secretion: By βcells in pancreatic islet.

● Degradation: Liver & kidney

Endogenous: Liver (60 %) & kidney (35 %-40 %)

Exogenous: Liver (35 %-40 %) & kidney (60 %)

● T1/2 in plasma: 3-5 min

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●Physiological & pharmacological actions

1.Sugar metabolism: Stimulates glucose uptake

& use by cells; inhibits gluconeogenesis →blood sugar↓

2. Fatty metabolism: Improves fatty acid transp

ortation & fat anabolism; inhibits fat catabolism & fatty acid and acetone body generation

3. Protein metabolism: Improves aa transportat

ion & protein anabolism; inhibits protein cata

bolism & aa utilization in liver

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●Physiological & pharmacological actions

4. Potassium : Stimulates K+ entering cells→blood

K+↓

5. Long-term action: Improves or inhibits the synth

esis of some enzymes.

● Mechanism of its action

＊ Insulin receptor in cell membrane mediates the effect;＊ Insulin receptor is consisted by 2αsubunits, which constitutes the recognition site, and 2β subunits, which contains a tyrosine kinase

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Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

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● Sources of exogenous insulin

＊ Bovine & porcine insulin

＊ Human insulin by replacement of porcine insulin 30-

alanine in B chain by threonine

＊ Recombinant human insulin by Escherichia coli

Clinical use

1.Diabetes mellitus

＊ The only effective drug for type 1 diabetes

＊ The following situations of type 2 diabetes

(1) Not effectively controlled by food limitatio

n & oral antidiabetic drugs;

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(2) Accompanies DKA & nonketotic hyperosmol

ar hyperglycemia coma;

(3) Accompanies serious infection, hyperpyrexi

a, injury, gestation and

consumptive diseases.

2. Others

＊ Hyperkalemia

＊ A component of GIK solution which is for limi

ting myocardial infarction & arrhythmias

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● Adverse reactions

1. Insulin allergy: itching, redness, swelling, an

aphylaxis shock

2. Insulin resistance

3.Hypoglycemia: nausea, hungry, tachycardia,

sweating, and tremulousness.

＊ First aids needed while convulsions & coma

happens

4. Lipodystrophy at injection sites: atrophy

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DurationDuration Insulin Insulin PathPathTimes on action (h)Times on action (h)

Given timeGiven timestartstart peakpeak durationduration

ShortShort RegularRegular

i.vi.v St!St! 0.50.5 22CitoCito! !

((DKA and etc.).

i.hi.h 0.5~10.5~1 2~32~3 6~86~80.5 h, a.c., t0.5 h, a.c., t..ii.d..d. or or

q.i.d.q.i.d.

MediumMedium

IsophaneIsophane i.hi.h 2~42~4 8~128~12 18~2418~241 h, a.c., q.d. or 1 h, a.c., q.d. or

b.b.ii.d. .d. Globin zinGlobin zin

cci.hi.h 2~42~4 6~106~10 12~1812~18

LongLongProtamine Protamine

zinczinci.hi.h 3~63~6

16~116~1

8824~3624~36 1 h, a.c., q.d. 1 h, a.c., q.d.

Insulin preparations and administration

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Section 2 Oral Antidiabetic DrugSection 2 Oral Antidiabetic Drugss

● Classification

Sulfonylureas

Thiazolidinediones

Biguanides

α-glucosidase inhibitors

Meglitinides

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І . Sulfonylureas

Representative DrugsRepresentative Drugs

1st generation: 1st generation:

tolbutamide chlorpropamide tolazamidetolbutamide chlorpropamide tolazamide

2nd generation: 2nd generation:

glybenclamide glyburide glybenclamide glyburide

glipizide glymeprideglipizide glymepride

3rd generation:3rd generation:

glyclazipeglyclazipe

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Pharmacological effectsPharmacological effects

1. 1. Hypoglycemic effectHypoglycemic effect

2. 2. Antidiuretic effectAntidiuretic effect

chlorpropamide & glybenclamidechlorpropamide & glybenclamide

3. 3. Antiplatelete-aggregation effectAntiplatelete-aggregation effect

glyclazipeglyclazipe

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Hypoglycemic mechanismHypoglycemic mechanism

1. 1. Rapid mechanismRapid mechanism: : stimulation of insulin secretionstimulation of insulin secretion

Sulfonylurea receptor in β-cell membrane activated

ATP-sensitive K+-channel inhibited

Cellular membrane depolarized

Ca2+ entry via voltage-dependent Ca2+ channel

Insulin release

2. Long term profit involved mechanismmechanism①①Inhibition of glucagon secretion by pancreas Inhibition of glucagon secretion by pancreas αα cells; cells;②②Ameliorating insulin resistanceAmeliorating insulin resistance③③ Increase insulin receptor number & the affinity to insulin

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Clinical useClinical use 1. 1. Type 2 diabetes mellitusType 2 diabetes mellitus 2. 2. Diabetes insipidusDiabetes insipidus: : chlorpropamidechlorpropamide

Adverse reactionsAdverse reactions 1. Gastroin1. Gastrointtestinal disorders estinal disorders 2. Allergy2. Allergy 3. Hypoglycemia3. Hypoglycemia ChlorpropamideChlorpropamide forbidden forbidden for ageds & patien for ageds & patien

ts with functional disorder in liver or kidney.ts with functional disorder in liver or kidney. 44. . GranulocytoGranulocytoppeniaenia, cholestasis & hepatic inju, cholestasis & hepatic inju

ryry

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ⅡⅡ. . Thiazolidinediones (Tzds) Representative DrugsRepresentative Drugs

rosiglitazone troglitazone

pioglitazone ciglitazone

Pharmacological effectsPharmacological effects

●●Improving function of pancreas Improving function of pancreas β cells cells

●●Ameliorating insulin resistanceAmeliorating insulin resistance

●●Ameliorating fat metabolic disorderAmeliorating fat metabolic disorder

●●Preventing and treating type 2 diabetes mellitPreventing and treating type 2 diabetes mellit

us and their cardiovascular complications us and their cardiovascular complications

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Mechanism (possible)Mechanism (possible)Peroxisome proliferator-activated receptor-Peroxisome proliferator-activated receptor-γγ((PPAR-PPAR-γγ) activated) activated

Nuclear genes involved in glucose & lipid metabolism and

adipocyte differentiation activated

Clinical useClinical use

Insulin resistance & type 2 diabetes mellitusInsulin resistance & type 2 diabetes mellitus

Adverse reactions Adverse reactions Troglitazone occasionally induces hepatic injury occasionally induces hepatic injury

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Ⅲ. Biguanides Representative DrugsRepresentative Drugs

phenforminphenformin metforminmetformin

Key pointsKey points

●●insulin secretion unchanged, and appetite unchanged insulin secretion unchanged, and appetite unchanged

●●Hypoglycemic mechanism remains unclearHypoglycemic mechanism remains unclear

●●Use for Use for obese diabetesobese diabetes and and type 2 diabetestype 2 diabetes

●●Alone or co-administered with insulin or Alone or co-administered with insulin or Sulfonylureas

●●MetforminMetformin also used to treat atherosclerosis for down-reg also used to treat atherosclerosis for down-reg

ulation of LDL& VLDLulation of LDL& VLDL

●●Ketonemia & lactic acidosis are major adverse reactions Ketonemia & lactic acidosis are major adverse reactions

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Ⅳ. α-glucosidase inhibitors

Representative DrugsRepresentative Drugs

acarbose voglibose miglitol Key pointsKey points

● ● To inhibit digestion of starch & disaccharides via competitively To inhibit digestion of starch & disaccharides via competitively ii

nhibiting intestinal nhibiting intestinal α-glucosidase (sucrase, maltase, glycoamylas

e, dextranase)

● ● Used alone or together with Used alone or together with sulfonylureas to treat type 2 diabetes to treat type 2 diabetes

● ● Main adverse reaction: flatulence, diarrhea, bellyache.Main adverse reaction: flatulence, diarrhea, bellyache.

● ● Patients with inflammatory bowel disease & kidney impaired forbiPatients with inflammatory bowel disease & kidney impaired forbi

dden.dden.

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Ⅴ. Meglitinides

Representative DrugsRepresentative Drugs Repaglinide Key pointKey point ●● To increase To increase insulin releaseinsulin release by by inhibiting inhibiting AT

P-sensitive K+-channel ●● Unlike Unlike sulfonylureas, they have no direct e

ffect on insulin releaseinsulin release ●● Used alone or together with Used alone or together with biguanides to t to t

reat type 2 diabetes reat type 2 diabetes ●● Carefully used for patients with kidney or liCarefully used for patients with kidney or li

ver impaired.ver impaired.

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Michigan lake 2007.5

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