Antidiabetic Drugs - med.cmu.ac.th · Antidiabetic Drugs รศ. พญ. ... on fasting blood sugar) Adverse Reaction • flatulence, diarrhea, abdominal pain, releasing gas IV. Alpha-glucosidase

Antidiabetic Drugsรศ. พญ. มาลยีา มโนรถ

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Antidiabetic Drugs

รศ. พญ. มาลียา มโนรถภาควิชาเภสัชวิทยาคณะแพทยศาสตร

จุดประสงคการศึกษา

เม่ือสิ้นสุดการเรียนการสอน และการศึกษาดวยตนเองเพิม่เติม นักศึกษาสามารถ

ทราบถึงแหลงที่มาของ insulin ท่ีใชรักษาทราบถึงชนิดของ insulin ตามระยะเวลาในการออกฤทธิ์ทราบถึงผลของ insulin ตอตับ กลามเน้ือ และเนื้อเย่ือไขมันทราบถึงอาการขางเคียงจากการใช insulin รักษาทราบถึงชนิดของ oral antidiabetic agents ตลอดจนเภสัชจลนศาสตร, เภสัชพลศาสตร, ฤทธ์ิขางเคียงที่อาจเกิดขึ้น, การการประยุกตใชทางคลินิก


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Pancreatic islet cells

A cell (alpha) GlucagonB cell (beta) Insulin, C-peptide, proinsulin islet amyloid polypeptideD cell (delta) SomatostatinF cell (PP cell) Pancreaticpolypeptide

Endocrine effects of insulin

Liver:inhibits glycogenolysispromotes glucose storage

as glycogenMuscle:increased protein synthesisincreased glycogen synthesis

Adipose tissue:increased triglyceride storage


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Normal glucose and insulin level over 24 hours in people without diabetes

Diabetes Mellitus

Therapeutic classificationType 1 diabetes :

(IDDM) is a severe form associated with ketosis in the untreated state

Type 2 diabetes :(NIDDM) : milder forms, occure predominantly in adults, most patients are obese


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Insulin deficiency

Hyperglycemia Lipolysis

Glycosuria FFA

Polyuria Ketonemia

Thirst & polydipsia Acidosis

Coma, deathLong-term complications : cataract, retinopathy, nephropathy, premature atheroma


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Insulin

Proinsulin :A & B chain,C peptideInsulin :A & B chain

Regular of insulin secretionvarious nutrients, GI hormones, pancreatic hormones, autonomic neurotransmitters

• increase secretion : glucose, amino acid, ketonebodies, beta-adrenergic agonist, vagal nervestimulation

• decrease secretion : stimulate alpha-2 adrenergicreceptors

• pancreas secretes : 1 unit/h• half-life : 5-6 min (proinsulin 17 min)• degradation : liver (60% ), kidney (35-40% )

exogenous insulin kidney (60% ), liver (30-40% )


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Insulin receptor

A cell-surface receptorconsists of two heterodimers (alpha subunit, beta subunit)obesity, insulinoma :reduce concentration of insulin receptors

Species of insulin• Beef and pork insulins• Human insulins : recombinant DNA techniques

Concentration•100 units/ml (U100) : 10 mL vials•U 500 (insulin resistance)


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1. Ultra-short-acting insulin : Insulin lispro2. Short-acting insulins : Regular 3. Intermediate-acting insulins : Lente, NPH (neutral protamine Hagedorn)4. Long acting insulins : UtralenteHumulin U5. Mixtures of insulins :

20% Regular/80% NPH30% Regular/70% NPH25% Lispro/75% NPH

Insulin Preparations

Insulin PreparationsInsulin PreparationsPharmacokinetics Species type Peak (h) Duration of

action (h)

Ultra-short-acting Insulin lispro Human analog

(recombinant)0.25-0.5 3-4

Short-acting-insulins regular Human, beef, pork 0.5-3 5-7

Intermediate-acting NPH

Lente insulin

Human, pork,beef-pork mixtureHuman, pork,beef-pork mixture

8-12

8-12

18-24

18-24

Long-acting Ultralente humulin Human 8-16 24-36


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Factors that Affected Insulin Absorptionsite of injectionabdominal wall > arm > buttock > thigh

• increased subcutaneous blood flow (massage) : increase absorption

Complication of insulin therapy• Hypoglycemia• Insulin allergy and resistance• Lipodystrophy at injection site :

lipoatrophy (variant of an immuneresponse to insulin) lipohypertrophy(lipogenic action)


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Oral Antidiabetic Agents

I. Insulin secretagogues(sulfonylureas, meglitinides)

II. BiguanidesIII. ThiazolidinedionesIV. Alpha-glucosidase inhibitors


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I. Insulin secretagogues

Sulfonylureas– increase insulin release from pancreatic B cells– reduction of serum glucagon concentration– potentiate of insulin action on target tissues– First generation

tolbutamide, chlorpropamide, tolazamide– Second generation

glyburide, glipizide, glimepiride

Pharmacokinetics• effectively absorbed from GIT• 2nd gen. are approximately 100 times more

potent than 1st gen.• metabolized by the liver and the metabolites are

excreted in the urine(chlorpropamide: incompleted metabolize, 20% excreted unchanged)

Adverse Reactions• hypoglycemia• nausea, vomiting, cholestatic jaundice,

agranulocytosis, generalized hypersensitivity reactions sulfa allergy


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Sulfonylureas

ชนิด ขนาดที่ให ระยะเวลาที่ออกฤทธิ์ (ชั่วโมง)

Sulfonylureas รุนที่หนึ่ง Chlorpropamide 100-500 มิลลิกรัม/วัน นานถึง 60Tolbutamide 500-2000 มิลลิกรัม/วัน 6-12Tolazamide 100-1000 มิลลิกรัม/วัน 10-14Acetohexamide 250-1500 มิลลิกรัม/วัน 12-24

Sulfonylureas รุนที่สอง Glyburide 1.25-20 มิลลิกรัม/วัน 10-24Glipizide 5-30 มิลลิกรัม/วัน 10-24Glimepiride 1-4 มิลลิกรัม/วัน 12-24

Meglitinides

Rapaglinide• modulate B cell insulin release by regulating

potassium efflux through the potassium channel • very fast onset of action, peak effect: 1 h after

ingestion• use in controlling postprandial glucose excursions


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Adverse Reaction• hypoglycemia (if meal is delayed or skipped or

contains inadequate carbohydrate) • should be used cautiously in individuals with

hepatic impairment

• Repaglinide can be taken alone as monotherapyor incombination with biguanides

• no sulfer in the structure : may use in type 2 diabetic with sulfer or sulfonylurea allergy

II. Biguanides (metformin, buformin)act by unknown mechanism (direct stimulation of glycolysis in tissues, reduce

hepatic gluconeogenesis, slowing of glucose absorption from the GIT, reduction of plasma glucagon levels)


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Metformin (Glucophage)• half-life 1.5-3 h• not bound to plasma protein, not metabolized, excreted by the kidney

• Adverse effects : GI disturbance (dose related)• contraindicate : renal disease, hepatic disease

Clinical Use of biguanides• obesity• combination with sulfonylurea in type 2 diabetes

III. ThiazolidinedionesTroglitazone (idiosyncratic liver damage)

Rosiglitazone & pioglitazone

• mechanism of action : not fully understood , but the drug appears to reduce insulin resistance

• Both fasting and postprandial hyperglycemia are reduced)


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• carbohydrate analog that act within the intestine inhibit alpha-glucosidase slow absorption(postprandial hyperglycemia is reduced, no effect on fasting blood sugar)

Adverse Reaction

• flatulence, diarrhea, abdominal pain, releasing gas

IV. Alpha-glucosidase Inhibitors(Acarbose, Miglitol)

Antidiabetic Drugs - med.cmu.ac.th · Antidiabetic Drugs รศ. พญ. ... on fasting blood sugar) Adverse Reaction • flatulence, diarrhea, abdominal pain, releasing gas IV. Alpha-glucosidase

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