INSULIN DAN OBAT HIPOGLIKEMIK ORAL

DIABETES MELLITUSsyndromes characterized by hyperglycemia; altered metabolism of lipids,carbohydrates, and proteins; and an increased risk of complications from vascular diseaseThe 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)

DMa 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 ClassificationType 1 diabetes mellitus = IDDM Type 2 diabetes mellitus = NIDDMType 3 diabetes mellitusType 4 diabetes mellitus

Risk factorFamily history of diabetes ObesityHabitual physical inactivity Race/ethnicityPreviously identified IFG or IGTHistory of GDM or delivery of baby >4 kg Hypertension HDL cholesterol level 250 mg/dL (2.82 mmol/L) Polycystic ovary syndrome

INSULINInsulin contains 51 amino acidstwo chains (A and B) linked by disulfide bridgesprecursor : preproinsulin proinsulinThe 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

Insulin production and regulation of secretion Preproinsulin proinsulin : in rough endoplasmic reticulumProinsulin insulin : in golgi complexInsulin stored in granulesInsulin secretion mainly depends on blood glucose levelThe islets of Langerhans are richly innervated by both adrenergic and cholinergic nervesIntracellular Ca2+ acts as the insulin secretagogue

Distribution and degradation of insulinUnder fasting conditions40 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) 0.5 ng/ml (12 units/ml) or about 0.1 nM in the peripheral circulationAfter ingestion of a meal, there is a rapid rise in the concentration of insulin in portal blood, followed by a parallel but smaller rise in the peripheral circulation

Distand degrade The half-life of insulin in plasma is about 5 to 6 minutesDegradation of insulin occurs primarily in liver, kidney, and muscleThe complex of insulin and its receptor is internalized into small vesicles termed endosomes, where degradation is initiatedThe primary insulin-degrading enzyme is a thiol metalloproteinase

Classification of insulin

typeAppear.Add. Prot.Zn contentBuffer Onset Peak Duration Rapid Regular Clear0.010.04None 0.50.71.54 58LisproClear0.02Phosphat0.250.51.525AspartClear0.0196Phosphat0.250.60.835GlulisineClear None 0.51.5 12.5Intermediate NPHCloudyProtamine0.0160.04 Phosphat126121824Lente Cloudy0.20.25Acetate12612 1824SlowUltra lenteCloudy0.20.25Acetate461618 2036Protamine znCloudyProtamine 0.20.25 Phosphat46 14202436Glargine Clear 0.03None 25 5241824

Insulin absorptionInsulin usually is injected into the subcutaneous tissues of the abdomen, buttock, anterior thigh, or dorsal arm Affecting factors:subcutaneous blood flowPosturevolume or concentration of injected insulinCSII ???

Adverse reactionHypoglycemiaInsulin allergy and resistanceLipoathrophy and lipohipertrophyInsulin edema

Drug interactionDrugs with Hypoglycemic Effects e.gB Adrenergic receptor antagonistsSalicylatesEthanolAngiotensin-converting enzyme inhibitorsTheophyllineCalsium

interactDrugs with Hyperglycemic EffectsEpinephrineGlucocorticoids Diuretics Atypical antipsychoticsHIV-1 protease inhibitorsA Adrenergic receptor agonists

Ca2+-channel blockersPhenytoin H2-receptor blockersMorphineHeparinMarijuanaNicotine*

Oral hypoglycemic agent

classificationINSULIN SECRETAGOGUESulfonylureaMeglitinide NateglinideBIGUANIDETHIAZOLIDINEDIONE GLUCOSIDASE INHIBITOR

Sulfonylurea

Mechanism of actionstimulating insulin release from pancreatic cells(may) reduce hepatic clearance of the hormoneStimulate release of somatostatin, and they may suppress the secretion of glucagon slightly.

Absorption, fate, and excretionfood and hyperglycemia can reduce the absorption of sulfonylureasshort half-liveslargely (90% to 99%) bound to proteinmetabolized by the livermetabolites are excreted in the urineAdverse effect: hypoglycemiaCI: type 1 DM, pregnancy, lactation, and for significant hepatic or renal insufficiency

Dosing: (given 30 minutes before eating)glyburide is 2.5 to 5 mg, and daily doses of more than 20 mg are not recommendedglipizide 5 mg given once daily. 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, and the maximal daily dose is 320 mgGlimepiride : as low as 0.5 mg once per day. The daily maximal effective is 8 mg

MeglitinideRepaglinidederivative of benzoic acidstimulates insulin release by closing ATP-dependent potassium channelsabsorbed rapidly from the GI tracthalf-life of the drug is about 1 hourmultiple preprandial useDose : 0,5-2 mgCI: hepatic insufficiency

Nateglinide derived from D-phenylalaninestimulates insulin secretion by blocking ATP-sensitive potassium channelsFewer hypoglycemic eventsCI: hepatic insufficiencydose of 120mg, 1 to 10 minutes before a meal

biguanideMetforminantihyperglycemic, not hypoglycemicreduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscle and fatabsorbed mainly from the small intestinedoes not bind to plasma proteinshalf-life of about 2 hoursThe maximum recommended daily dose in the United States is 2.5 g given in two or three doses with meals

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

thiazolidinediones(troglitazone), rosiglitazone, and pioglitazoneselective agonists for nuclear peroxisome proliferatoractivated receptor- (PPAR ) activates insulin-responsive genes that regulate carbohydrate and lipid metabolismincreasing insulin sensitivity in peripheral tissue but also may lower glucose production by the liverincrease glucose transport into muscle and adipose tissue by enhancing the synthesis and translocation of specific forms of the glucose transporters

taken once a dayabsorbed within about 2 hoursDosing:pioglitazone 1545mg oncedailyrosiglitazone 28 mg once dailyCI: hepatic insufficiencyAE: hepatotoxic, anemia, weight gain, edema, and plasma volume expansion

Glucosidase inhibitorAcarbosereduce intestinal absorption of starch, dextrin, and disaccharidesAE: malabsorption, flatulence, diarrhea, and abdominal bloatingDosing: 25 mg at the start of a meal for 4 to 8 weeks, followed by increases at 4- to 8-week intervals to a maximum of 75 mg before each meal

Therapeutic usesDosing Principle of SulfonylureasSmall divided doses before meals better than large single morning dose (hypoglycemic risk>) Obtain day curve for 2-3 days (with or without OAD). Follow up closely once weeklyStart with one OAD and monitor bl gl by day curve (observe which value is exceeded)If far from goal (>8.0%), add another OAD (preferred:metformin, repaglinide, acarbose, or pioglitazone when not contra-indicated)

Darmansjah, 1994Dosing 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