Anti-diabetics

1、12DIABETES MELLITUSAffects approx. 5 8 %Mostly asymptomaticTendency increase with obesityOne of the leading cause of death by diseaseOne of the leading cause of blindness One of the leading cause of renal failure3CharacteristicType 1 ( 10% )Type 2Onset (Age)Usually 40 Type of onsetAbruptGradualNutri

2、tional statusUsually thinUsually obeseDietMandatory with insulinMandatory with or without drugHypoglycemic drugsShould not be usedClinically indicatedClinical symptomsPolydipsia, polyphagia, polyurea, Wt lossOften asymptomaticKetosisFrequentUsually absentEndogenous insulinAbsentPresent, but relative

3、ly ineffectiveRelated lipid abnormalitiesHypercholesterolemia frequent, all lipid fractions elevated in ketosisCholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia commonInsulin therapyRequiredRequired in only 20 - 30% of patients4EFFECTS OF INSULIN CARBOHYDRATE

4、S FAT GLUCOSE UPTAKEGLYCOGEN SYNTHESIS( STORAGE)GLUCONEOGENEIS(LIVER)GLYCOLYSIS (MUSCLE) CONVERSION OF CARBOHYDRATE TO FAT (LIPOGENESIS)LIPOLYSISPROTEINAMINO ACID UPTAKE (PROTEIN SYTHESIS)K+ UPTAKE INTO CELLSPOTASSIUM5INSULIN DEFICIENCY DIABETES MELLITUS GLUCOSE UPTAKE HYPERGLYCEMIA GLYCOSURIA DEHYD

5、RATION, AA mobilization PLASMA AA LIPOLYSIS PLASMA FFA KETOSIS ACIDOSIS 6 Insulin Degradation Hydrolysis of the disulfide linkage between A&B chains. 60% liver, 40% kidney(endogenous insulin) 60% kidney,40% liver (exogenous insulin) Half-Life 5-7min (endogenous insulin) Delayed-release form( inj

6、ected one) Category B ( not teratogenic) Usual places for injection: upper arm, front& side parts of the thighs& the abdomen. Not to inject in the same place ( rotate) Should be stored in refrigerator& warm up to room temp before use. Must be used within 30 days.78TYPES OF INSULIN PREPAR

7、ATIONS1. Ultra-short-acting 2. Short-acting (Regular)3. Intermediate-acting4. Long-acting 9Short-acting (regular) insulins e.g. Humulin R, Novolin RUsesDesigned to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosisPhysical characteristicsClear solution at neutral pHChe

8、mical structureHexameric analogueRoute & time of administrationS.C. 30 45 min before mealI.V. in emergency (e.g. diabetic ketoacidosis)Onset of action30 45 min ( S.C )Peak serum levels2 4 hrDuration of action6 8 hrUsual administration2 3 times/day or moreUltra-Short acting insulins e.g. Lispro,

9、aspart, glulisineSimilar to regular insulin but designed to overcome the limitations of regular insulinClear solution at neutral pHMonomeric analogueS.C. 5 min (no more than 15 min) before mealI.V. in emergency (e.g. diabetic ketoacidosis)0 15 min ( S.C )30 90 min3 4 hr2 3 times / day or more10 3. I

10、ntermediate - acting insulins e.g. isophane (NPH) Turbid suspension Injected S.C.(Only) Onset of action 1 - 2 hr Peak serum level 5 - 7 hr Duration of action 13 - 18 hrInsulin mixtures75/25 70/30 50/50 ( NPH / Regular )11 3. Intermediate - acting insulins (contd.) Lente insulin Turbid suspension Mix

11、ture of 30% semilente insulin 70% ultralente insulin Injected S.C. (only) Onset of action 1 - 3 hr Peak serum level 4 - 8 hr Duration of action 13 - 20 hr12 3. Intermediate - acting insulins (contd.) Lente and NPH insulins Are roughly equivalent in biological effects. They are usually given once or

12、twice a day. N.B: They are not used during emergencies (e.g. diabetic ketoacidosis). 13 4. Long acting insulins e.g.Insulin glargineOnset of action 2 hrAbsorbed less rapidly than NPH&Lente insulins.Duration of action upto 24 hrDesigned to overcome the deficiencies of intermediate acting insulins

13、 Advantages over intermediate-acting insulins:Constant circulating insulin over 24hr with no pronounced peak.More safe than NPH&Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia).Clear solution that does not require resuspention before administration.1415Profile of In

14、sulin Glargine vs NPHGlargine NPH 16Methods of AdminisrationInsulin SyringesPre-filled insulin pensExternal insulin pump Under Clinical TrialsOral tabletsInhaled aerosolIntranasal, Transdermal Insulin Jet injectorsUltrasound pulses1718COMPLICATIONS OF INSULIN THERAPY 1. Severe Hypoglycemia ( 50 mg/d

15、l ) Life threatening Overdose of insulin Excessive (unusual) physical exercise A meal is missed How it is treated ? 2. Weight gain 3. Local or systemic allergic reactions (rare) 4. Lipodystrophy at injection sites 5. Insulin resistance 6. Hypokalemia19Severe insulin reaction(Hypoglycemic Shock)Diabe

16、tic coma(Diabetic Ketoacidosis)OnsetRapidSlow- Over several daysInsulinExcessToo littleAcidosis & dehydrationNoKetoacidosisSigns and sympsB.P.Normal or elevatedSubnormal or in shockRespirationNormal or shallowDeep & air hungerSkinPale & SweatingHot & dryCNSTremors, mental confusion,

17、sometimes convulsionsGeneral depressionBlood sugarLower than 70 mg/100ccElevated above 200 mg/100ccKetonesNormalElevated20Oral Hypoglycemics All taken orally in the form of tablets.Pts with type11 diabetes have two physiological defects:Abnormal insulin secretion1. Resistance to insulin action in ta

18、rget tissues associated with decreased number of insulin receptors21 Oral Anti-Diabetic Agents2223Tolbutamid short-actingAcetohexamideintermediate-acting Tolazamide intermediate-acting Chlorpropamide long- acting AbsorptionWellWellSlowWellMetabolismYesYesYesYesMetabolitesInactive*Active + *Active +

19、*Inactive *Half-life4 - 5 hrs6 8 hrs7 hrs24 40 hrsDuration of actionShort (6 8 hrs)Intermediate (12 20 hrs)Intermediate (12 18 hrs)Long( 20 60 hrs)ExcretionUrineUrineUrineUrineFIRST GENERATION SULPHONYLUREA COMPOUNDS* Pts with renal impairment can expect long t1/2 24GlipizideShort- actingGlibenclami

20、de(Glyburide)Long-actingGlimepirideLong-actingAbsorptionWellWellWellMetabolismYesYesYesMetabolitesInactiveInactiveInactiveHalf-life3 4 hrsLess than 3 hrs5 - 9 hrsDuration of action10 16 hrs12 24 hrs12 24 hrsExcretionUrineUrineUrineSECOND GENERATION SULPHONYLUREA COMPOUNDS25MECHANISM OF ACTION OF SUL

21、PHONYLUREAS1) Release of insulin from -cells2) Reduction of serum glucagon concentration3) Potentiation of insulin action on target tissues26SIDE EFFECTS OF SULPHONYLUREAS1) Nausea, vomiting, abdominal pain, diarrhea2) Hypoglycaemia3) Dilutional hyponatraemia & water intoxication (Chlorpropamide

22、)4) Disulfiram-like reaction with alcohol (Chlorpropamide)5) Weight gain 27SIDE EFFECTS OF SULPHONYLUREAS (contd.) 6) Blood dyscrasias (not common; less than 1% of patients)- Agranulocytosis- Haemolytic anaemia- Thrombocytopenia 7) Cholestatic obstructive jaundice (uncommon) 8) Dermatitis (Mild) 9)

23、Muscle weakness, headache, vertigo (not common) 10) Increased cardio-vascular mortality with longterm use ?28CONTRAINDICATIONS OF SULPHONYLUREAS1) Type 1 DM ( insulin dependent)2) Parenchymal disease of the liver or kidney3) Pregnancy, lactation4) Major stress29DRUGS THAT AUGMENT THE HYPOGLYCEMIC AC

24、TION OF SULPHONYLUREAS WARFARIN SULFONAMIDES SALICYLATES PHENYLBUTAZONEPROPRANOLOLALCOHOLCHLORAMPHENICOLFLUCONAZOLE30DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE CORTICOSTEROIDS ORAL CONTRACEPTIVES PHENYTOIN, PHENOBARB., RIFAMPIN ALCOHOL

25、( chronic pts )3132MEGLITINIDESe.g. Repaglinide, Nateglinide PHARMACOKINETICSTaken orallyRapidly absorbed ( Peak approx. 1hr )Metabolized by livert1/2 = 1 hrDuration of action 4-5 hr 33MEGLITINIDES (Contd.)MECHANISM OF ACTIONBind to the same KATP Channel as do Sulfonylureas, to cause insulin release

26、 from -cells.34MEGLITINIDES (Contd.)CLINICAL USEApproved as monotherapy and in combination with metformin in type 2 diabetesTaken before each meal, 3 times / dayDoes not offer any advantage over sulfonylureas;Advantage: Pts. allergic to sulfur or sulfonylureaSIDE EFFECTS:HypoglycemiaWt gain ( less t

27、han SUs )Caution in pts with renal & hepatic impairement.35BIGUANIDES e.g. Metformin PHARMACOKINETICS Given orally Not bind to plasma proteins Not metabolized Excreted unchanged in urine t 1/2 2 hr36BIGUANIDES (Contd.) MECHANISM OF ACTION1. Increase peripheral glucose utilization2. Inhibits gluc

28、oneogenesis3. Impaired absorption of glucose from the gut37Advantages of Metformin over SUsDoes not cause hypoglycemia ( why ? )Does not result in wt gain ( why ? ) ( Ideal for obese pts )38BIGUANIDES (Contd.) SIDE EFFECTS1. Metallic taste in the mouth2. Gastrointestinal (anorexia, nausea, vomiting,

29、 diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use)4. Lactic acidosis ( rare 01/ 30,000-exclusive in renal & hepatic failure)391. Hepatic impairment2. Renal impairment3. Alcoholism4. Heart failureBIGUANIDES (Contd.) CONTRAINDICATIONS40 Obese patients with type 11 diabetes

30、 2. Alone or in combination with sulfonylureas BIGUANIDES (Contd.) INDICATIONS41-GLUCOSIDASE INHIBITORSe.g. AcarbosePHARMACOKINETICSGiven orallyNot absorbed from intestine except small amountt1/2 3 - 7 hrExcreted with stool42MECHANISM OF ACTIONInhibits intestinal alpha-glucosidases and delays carboh

31、ydrate absorption, reducing postprandial increase in blood glucose-GLUCOSIDASE INHIBITORS(Contd.)43-GLUCOSIDASE INHIBITORS (Contd.) MECHANISM OF ACTION44-GLUCOSIDASE INHIBITORS (Contd.) MECHANISM OF ACTION45SIDE EFFECTSFlatulenceLoose stool or diarrheaAbdominal painAlone does not cause hypoglycemia-GLUCOSIDASE INHIBITORS(Contd.)46INDICATIONS Patients with Type 11 inadequately controlled by diet wit