Presentation on Antidiabetic agents.pdf.

Diabetes mellitus (DM) is a metabolic disorder in which person has high levels of glucose in blood.
Type I DM Occurs when the pancreas cannot produce insulin, a hormone essential for moving glucose from the blood into cells.
Type II DM is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin.

1. By-
Dr. Prerana B. Jadhav
M. Pharm, Ph.D.
Pharmaceutical Chemistry
Assistant Professor,
SanjivaniCollege of Pharmaceutical Education and
Research, Kopargaon.
ANTIDIABETIC
AGENTS

2. Introduction
•Diabetesmellitus(DM)isametabolicdisorderinwhichpersonhas
highlevelsofglucoseinblood.
•TypeIDMOccurswhenthepancreascannotproduceinsulin,a
hormoneessentialformovingglucosefromthebloodintocells.
•TypeIIDMisaformofdiabetesmellitusthatischaracterized
byhighbloodsugar,insulinresistance,andrelativelackofinsulin.
•Seriouslongtermcomplicationsinclude-
Cardiovasculardisease,nephropathy,retinopathy,andneuropathy.
•InIndia,about1.6millionpeopleareatriskofdevelopingthe
condition.
2

3. Introduction
•Somediabeticsymptomsarefrequenturination,excessivethirst,extreme
hunger,unusualweightloss,increasedfatigue,irritability,andblurredvision.
Type2DiabetesMellitus(T2DM)iscontrolledwith
Sulfonylureas,
Meglitinides,
Thiazolidinediones,
Biguanides&
α–glucosidaseinhibitors
3

4. CLASSIFICATION
1. Antidiabeticagents: Insulin and its preparations
2. Sulfonylureas: Tolbutamide, Chlorpropamide, Glipizide,
Glimepiride.
3. Biguanides: Metformin.
4. Meglitinides: Repaglinide, Nateglinide.
5. Glucosidaseinhibitors: Acrabose, Voglibose.
6. DPP IV inhibitors: Sitagliptin, Teneligliptin
7. SGLT2 inhibitors: Empagliflozin, Canagliflozin

5. INSULIN
•Insulin,apancreatichormone,isaspecific
antidiabeticagent,especiallyfortype-Idiabetes.
•Humaninsulinisadouble-chainproteinthat
contains51aminoacids(chainA-21aminoacids,
andchainB-30aminoacids),whicharebound
togetherbydisulphidebridges.

6. •Inthebody,insulinissynthesizedbyβcellsofLangerhansisletsinthepancreas.
•Inβcells,insulinissynthesizedfromtheproinsulinprecursor
molecule(pro-insulinconsistsofthreedomains:anamino-terminal
Bchain,acarboxy-terminalAchain,andaconnectingpeptidein
themiddleknownastheCpeptide)bytheactionofproteolytic
enzymes,knownasprohormoneconvertases(PC1andPC2),aswell
astheexoproteasecarboxypeptidaseE.Thesemodificationsofpro-
insulinremovethecentreportionofthemolecule(i.e.,Cpeptide)
fromtheC-andN-terminalendsofpro-insulin.
•Theremainingpolypeptides(51aminoacidsintotal),theB-andA-chains,are
boundtogetherbydisulphidebonds.

7. MOA of Insulin
•Insulinactsbybindingwithspecificreceptorsonthe
surfaceoftheinsulin-sensitivetissuessuchasskeletal
muscle,cardiacmuscle,fattytissue,andleukocytes.Insulin
lowersthesugarcontentinthebloodbyturningglucose
intoglycogen.
•Usinginsulinindiabetesmellitusleadstolowerlevelsof
sugarintheblood,andabuild-upofglycogenintissues.

8. •Insulinisusuallytakenassubcutaneous
injectionsbysingle-usesyringeswithneedles.

9. Oral hypoglycaemicagents
•Antidiabeticdrugs are drugs that lower the level of glucose (sugar)
in the blood.
•Sulfonylureas: Tolbutamide, Chlorpropamide, Glipizide,
Glimepiride.
•Biguanides: Metformin.
•Meglitinides: Repaglinide, Nateglinide.
•Glucosidaseinhibitors: Acrabose, Voglibose.
•DPP IV inhibitors: Sitagliptin, Teneligliptin
•SGLT2 inhibitors: Empagliflozin, Canagliflozin

10. Sulfonylureas
•Discovery
•Thecompound2-(p-aminobenzenesulphonamido)-5-isopropyl-thiadiazole(IPTD)
wasusedinthetreatmentoftyphoidfeverintheearly1940s.
•However,manypatientsdiedfrombeingtreatedwithheavydosesofthedrug.
•Thesedeathswereeventuallyattributedtoacuteandprolongedhypoglycaemia.
•IPTDdidnotcometobeusedashypoglycaemicagentsbecauseaseconddrug,
carbutamide,wasfoundtobeaneffectiveoralhypoglycaemicagent.
•CarbutamidewasmoreactivethanIPTDandwasthefirstsulphonylurea
hypoglycaemicagenttobemarketed.

11. Mechanism of action
•SulphonylureasbindtoanATP-dependentK+channelon
thecellmembraneofpancreaticβcells.
•Thisinhibitsoutfluxofpotassium,whichcausesthe
electricpotentialoverthemembranetobecomemore
positive.Thisdepolarizationopensvoltage-gatedCa2+
channels.
•Theriseinintracellularcalciumleadstoincreasedfusionof
insulingranulaewiththecellmembrane,andtherefore,
increasedsecretionofinsulin..

18. Biguanides: Metformin
•Thisclassofagentiscapableofreducingsugarabsorption
fromgastrointestinaltract.
•Theydecreasegluconeogenesiswhileincreasingglucose
uptakebymusclesandfatcells.Thiswillleadtolowerthe
bloodglucoselevels.

19. α-Glucosidaseinhibitors
•Theenzymeα-Glucosidaseispresentinthebrush
borderofthesmallintestineandisresponsiblefor
cleavingdietarycarbohydratesandfacilitating
theirabsorptionintothebody.
•Inhibitionofthisenzymeallowslessdietary
carbohydratetobeavailableforabsorptionandless
availableintheblood.

20. Acarbose
•Itisnaturallyoccuringoligosaccharideobtained
fromthemicroorganismActinoplanesutahensis.
•Itiscompetitiveinhibitorofα-Glucosidasewhich
reducestheintestinalabsorptionofstarch,dextrin
anddisaccharides.

21. Voglibose
•Vogliboseisan alpha-glucosidase
inhibitorusedforloweringpostprandialblood
glucoselevelsinpeoplewithdiabetes
mellitus.

22. Meglitinides: Repaglinide,
Nateglinide.
•Themetaglinidesarenonsulfonylureaoralhypoglycemicagentsusedinthe
managementoftype2diabetes.
•Theseagentsendtohavearapidonsetandashortdurationofaction.
•Muchlikethesulfonylureas,theseinduceinsulinreleasefromfunctioning
pancreaticẞcells.
•Themechanismofactionisthroughbindingspecificreceptorsin
theB-cellmembrane,leadingtotheclosureofATP-dependent
K+channels.TheKchannelblockadedepolarizestheB-cell
membrane,whichinturnleadstoCa2+influx,increased
intracellularCa2+andstimulationofinsulinsecretion.

23. •Theeffectofmetaglinidesdonotlastaslongas
effectofsulphonylureas.
•Theeffectsofthisclassappeartolastlessthan1
hour,whereassulphonylureascontinueto
stimulateinsulinproductionforseveralhours.
•Oneadvantageofshortdurationofactionisless
riskofhypoglycemia.

24. Repaglinide
•Fastonsetandshortdurationofaction.
•Itshouldbetakenwithmeal.
•ItisoxidizedbyCYP3A4.Lessthan0.2%isexcreted
unchangedbythekidneywhichisadvantageforelderly
patientswhoarerenallyimpaired.
•Sideeffects:Headache,coldsweats,anxietyandchangesin
mentalstate.

25. Nateglinide
•Itisphenylalaninederivativeandrepresentsa
noveldruginthemanagementoftype2
diabetes.
•Nateglinideisusedaloneorincombination
withothermedicationstotreattype2
diabetes.

26. •Side effects:
•Hypoglycemia
•dizziness
•sweating
•nervousness
•sudden changes in behavior or mood
•Headache
•weakness
•pale skin
•hungerCH
3
CH
3
O
NH
OH
O

27. DPP IV inhibitors
•Incretinhormones,suchasGLP-1.Thesearerapidlysecreted
fromthegutfollowingfoodintake.
•GLP-1isresponsibleformetabolismofglucoseandglucose
reuptakefrombody.Itisrapidlygetdestroyedbytheenzyme
DPPIV.
•Dipeptidyl-peptidaseIVinhibitorsinhibitthedegradationofthe
incretins,glucagon-likepeptide-1(GLP-1)andglucose-
dependentinsulinotropicpeptide(GIP).
•Prolongtheactionofincretinhormones.

28. DPP IV inhibitors
Sitagliptin TeneligliptinF
F
NH
2
O
N
N
N
N
F
F
F
F

29. Advantages of DPP IV inhibitors
•Safety
DPP-4inhibitorsaregenerallywelltoleratedandhavealowriskofhypoglycemia.
•Efficacy
DPP-4inhibitorsareeffectiveatreducingbloodglucoselevelsandimprovingglycemic
control.
•Mechanismofaction
DPP-4inhibitorsworkbystimulatingthesecretionofinsulininresponsetoglucose.
•Hearthealth
DPP-4inhibitorsmayhaveaprotectiveeffectontheheart.Forexample,sitagliptinmay
improveheartfunctionandcoronaryarteryperfusionindiabeticpatientswithcoronary
heartdisease

30. SGLT2 inhibitors: Empagliflozin,
Canagliflozin
•Sodium-glucosecotransporter2(SGLT2)inhibitorsthat
areusedtotreattype2diabetes.
•SGLT2inhibitorslowerbloodsugarbypreventingthe
kidneysfromreabsorbingglucose.Thiscausesthebodyto
removeexcessglucosethroughurine.
•SGLT2inhibitorscanimproveglycemiccontrol,reducethe
riskofcardiovascularcomplications,andslowthe
progressionofdiabetickidneydisease.

31. •Side effects:
Urinaryfrequency,dehydration,genitourinary
tractinfections,andrarely,diabetic
ketoacidosis

32. Canagliflozin
•CanagliflozinwasthefirstSGLT-2inhibitorapprovedonMarch29,
2013;
•Itisindicatedinadultpatientswithtype2DMtoimproveblood
glucosecontrolinadditiontodietandexercise.
•Itisalsoshowntodecreasetheriskofcardiovascular(CV)adverse
eventsintype2DMsubjectswithunderlyingCVillnessand
minimizetheriskofend-stagerenaldisease
•Theinitialdoseis100mgoncedailyandmaybeincreasedto300
mgdaily.

33. •Canagliflozin

34. Empagliflozin
•EmpagliflozinwasthethirdSGLTinhibitortoreceiveapprovalfrom
theFDAinAugust2014.
•Empagliflozinisindicatedinadultpatientswithtype2DMto
improvethecontrolofbloodglucoseinadditiontodietand
exercise,decreasetheriskofCVadverseeventsintype2DM
subjects.
•Theinitialdoseis10mgoncedaily;thedosemaybeincreasedto
25mgdailytoachievethetargetedglycemicgoal.

35. Empagliflozin