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INSULIN DAN OBAT HIPOGLIKEMIK ORAL

DIABETES MELLITUS
syndromes characterized by hyperglycemia; altered metabolism of lipids,carbohydrates, and proteins; and an increased risk of complications from vascular disease  The American Diabetes Association (ADA)  symptoms of DM (e.g., polyuria, polydipsia, and unexplained weight loss)  a random plasma glucose concentration of greater than 200 mg/dl (11.1 mM)

DM…
a fasting plasma glucose concentration of greater than 126 ml/dl (7 mM)  a plasma glucose concentration of greater than 200 mg/dl (11 mM) 2 hours after the ingestion of an oral glucose load Classification  Type 1 diabetes mellitus = IDDM  Type 2 diabetes mellitus = NIDDM  Type 3 diabetes mellitus  Type 4 diabetes mellitus

Risk factor          Family history of diabetes Obesity Habitual physical inactivity Race/ethnicity Previously identified IFG or IGT History of GDM or delivery of baby >4 kg Hypertension HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L) Polycystic ovary syndrome .

INSULIN Insulin contains 51 amino acids  two chains (A and B) linked by disulfide bridges  precursor : preproinsulin  proinsulin  The islet of Langerhans is composed of four types of cells  in the (B) cell: insulin  in the (A) cell: glucagon  in the (D) cell: somatostatin  in the PP or F cell: pancreatic polypeptide  .

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Insulin production and regulation of secretion       Preproinsulin  proinsulin : in rough endoplasmic reticulum Proinsulin  insulin : in golgi complex Insulin stored in granules Insulin secretion mainly depends on blood glucose level The islets of Langerhans are richly innervated by both adrenergic and cholinergic nerves Intracellular Ca2+ acts as the insulin secretagogue .

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1 nM in the peripheral circulation  After ingestion of a meal.5 ng/ml (12 units/ml) or about 0. followed by a parallel but smaller rise in the peripheral circulation  . there is a rapid rise in the concentration of insulin in portal blood.Distribution and degradation of insulin Under fasting conditions  40 g (1 unit) of insulin per hour into the portal vein to achieve a concentration of insulin in portal blood of 2 to 4 ng/ml (50 to 100 units/ml)  0.

kidney.Dist…and degrade…     The half-life of insulin in plasma is about 5 to 6 minutes Degradation of insulin occurs primarily in liver. where degradation is initiated The primary insulin-degrading enzyme is a thiol metalloproteinase . and muscle The complex of insulin and its receptor is internalized into small vesicles termed endosomes.

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04 0.25 0.5–1.01–0.04 0.25 Phosphat Acetate Acetate Phosphat None 1–2 1–2 4–6 4–6 2–5 6–12 6–12 16–18 14–20 5–24 18–24 18–24 20–36 24–36 18–24 Protamine 0.25 0.5–1.03 .8 0.5 5–8 2–5 3–5 1–2.2–0.5–0.2–0.Classification of insulin type Rapid Regular Lispro Aspart Glulisine Intermedi ate Clear Clear Clear Clear 0.2–0.6–0. Zn content Buffer Onset Peak Duration NPH Lente Slow Ultra lente Protamin e zn Glargine Cloudy Cloudy Cloudy Cloudy Clear Protamine 0.5–4 0. Add.25 1.0196 None Phosphat Phosphat None 0. Prot.5 Appear.016–0.02 0.25 0.7 0.5 0.

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or dorsal arm  Affecting factors:  subcutaneous blood flow  Posture  volume or concentration of injected insulin  CSII ???  .Insulin absorption Insulin usually is injected into the subcutaneous tissues of the abdomen. buttock. anterior thigh.

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Adverse reaction     Hypoglycemia Insulin allergy and resistance Lipoathrophy and lipohipertrophy Insulin edema .

g  B Adrenergic receptor antagonists  Salicylates  Ethanol  Angiotensin-converting enzyme inhibitors  Theophylline  Calsium .Drug interaction Drugs with Hypoglycemic Effects e.

…interact Drugs with Hyperglycemic Effects  Epinephrine  Glucocorticoids  Diuretics  Atypical antipsychotics‡  HIV-1 protease inhibitors§  A Adrenergic receptor agonists        Ca2+-channel blockers Phenytoin H2-receptor blockers Morphine Heparin Marijuana Nicotine* .

Oral hypoglycemic agent .

classification INSULIN SECRETAGOGUE  Sulfonylurea  Meglitinide  Nateglinide BIGUANIDE THIAZOLIDINEDIONE α GLUCOSIDASE INHIBITOR .

Sulfonylurea .

Mechanism of action    stimulating insulin release from pancreatic β cells (may) reduce hepatic clearance of the hormone Stimulate release of somatostatin. . and they may suppress the secretion of glucagon slightly.

and for significant hepatic or renal insufficiency . fate. pregnancy. and excretion        food and hyperglycemia can reduce the absorption of sulfonylureas short half-lives largely (90% to 99%) bound to protein metabolized by the liver metabolites are excreted in the urine Adverse effect: hypoglycemia CI: type 1 DM. lactation.Absorption.

5 mg once per day. The maximal recommended daily dose is 40 mg( daily doses of more than 15 mg should be divided)  gliclazide is 40 to 80 mg/day. The daily maximal effective is 8 mg . and the maximal daily dose is 320 mg  Glimepiride : as low as 0.Dosing: (given 30 minutes before eating)  glyburide is 2.5 to 5 mg. and daily doses of more than 20 mg are not recommended  glipizide 5 mg given once daily.

Meglitinide Repaglinide  derivative of benzoic acid  stimulates insulin release by closing ATPdependent potassium channels  absorbed rapidly from the GI tract  half-life of the drug is about 1 hour  multiple preprandial use  Dose : 0.5-2 mg  CI: hepatic insufficiency .

1 to 10 minutes before a meal .Nateglinide      derived from D-phenylalanine stimulates insulin secretion by blocking ATPsensitive potassium channels Fewer hypoglycemic events CI: hepatic insufficiency dose of 120mg.

5 g given in two or three doses with meals . not hypoglycemic  reduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscle and fat  absorbed mainly from the small intestine  does not bind to plasma proteins  half-life of about 2 hours  The maximum recommended daily dose in the United States is 2.biguanide Metformin  antihyperglycemic.

   CI : renal impairment.metallic taste. or chronic hypoxic lung disease AE (acute): diarrhea. abdominal discomfort. cardiac failure requiring pharmacological therapy. and anorexia AE (chronic) : decreased absorption of vitamin B12 and folate . nausea. hepatic disease. a past history of lactic acidosis (of any cause).

thiazolidinediones (troglitazone). rosiglitazone. and pioglitazone  selective agonists for nuclear peroxisome proliferator–activated receptor.(PPAR )  activates insulin-responsive genes that regulate carbohydrate and lipid metabolism  increasing insulin sensitivity in peripheral tissue but also may lower glucose production by the liver  increase glucose transport into muscle and adipose tissue by enhancing the synthesis and translocation of specific forms of the glucose transporters .

and plasma volume expansion .     taken once a day absorbed within about 2 hours Dosing: pioglitazone  15–45mg oncedaily rosiglitazone  2–8 mg once daily CI: hepatic insufficiency AE: hepatotoxic. weight gain. anemia. edema.

and disaccharides  AE: malabsorption.to 8-week intervals to a maximum of 75 mg before each meal . dextrin.Glucosidase inhibitor Acarbose  reduce intestinal absorption of starch. and abdominal bloating  Dosing: 25 mg at the start of a meal for 4 to 8 weeks. diarrhea. followed by increases at 4. flatulence.

add another OAD (preferred:metformin. repaglinide.  Follow up closely once weekly  Start with one OAD and monitor bl gl by day curve (observe which value is exceeded)  If far from goal (>8. or pioglitazone when not contra-indicated) . acarbose.0%).Therapeutic uses Dosing Principle of Sulfonylureas  Small divided doses before meals better than large single morning dose (hypoglycemic risk>)  Obtain day curve for 2-3 days (with or without OAD).

Darmansjah. 1994 Dosing schedule of second generation sulfonylureas should be revised: “Some sulfonylureas (especially glibenclamide) have been given in single daily doses to prolong action. increase ease. and compliance…” They are prone to cause hypoglycemia. divided doses (bid or tid) is better .