Insulinandoralhypoglycemic

drugs


 Levelsofbloodsugar

100mg/dL 80120mg/dL

140mg/dL 140180mg/dL

110mg/dL 100140mg/dL
 Diabetesmellitus
Theincidenceofdiabetesisgrowingrapidlyinthe
world.
Itisestimatedthat135million peopleworldwideare
afflictedwiththemostcommonform,Type2.
Typesofdiabetesmellitus
Type1:insulindependentdiabetesmellitus
Type2:noninsulindependentdiabetesmellitus
Type3:othertypesofdiabetes,forexample:maturity
onsetdiabetesoftheyoung(MODY)
Type4:Gestationaldiabetes(GDM) glucoseintolerance
associatedwithpregnancy
 Type1diabetesmellitus
Occuratanyage
Absolutedeficiencyofinsulincausedbymassive
cellnecrosis
Itmaybetriggeredbyaninvasionofvirusorthe
actionofchemicaltoxins.
Type1diabeticsrequireexogenousinsulin toavoid
thecatabolicstatethatresultsfromandis
characterizedbyhyperglycemiaandlifethreatening
ketoacidosis.
 Treatmentsfortype1diabetics
Purpose:maintainingbloodglucoseconcentrationas
closetonormalaspossible
Type1diabeticmustrelyonexogenous(injected)
insulintocontrolhyperglycemia,avoidketoacidosis,
andmaintainacceptablelevelsofglycosylated
hemoglobin(HbA1c)
 Type2diabetesmellitus cause
Pancreasretainssomecellfunction,butvariable
insulinsecretionisinsufficienttomaintainglucose
homeostasis
Thecellmassmaybecomegraduallyreducedin
Type2diabetes.
Type2diabetesisfrequentlyaccompaniedbythe
lackofsensitivityoftargetorganstoeither
endogenousorexogenousinsulin.
Type2diabetesmellitus treatment
Purpose:maintainbloodglucoseconcentrations
withinnormallimitsandtopreventthedevelopment
oflongtermcomplicationsofthisdisease.
Somepatients:weightreduction,exercise,and
dietarymodification
Mostpatients:oralhypoglycemicagents
 Type3diabetesmellitus
Thisdiseaseisaheterogeneousgroupofdisordersin
whichdysregulation ofglucosesensingorinsulin
secretionisduetomutationofparticulargenes.
Occursbefore25yearsofage
UnlikeType2diabetes,notobese,andinsulin
resistanceandhypertriacylglycerolemia areabsent
 Type3diabetesmellituscause
Geneticdefectsofcellfunction
Geneticdefectsininsulinaction
Diseasesoftheexocrinepancreas
Endocrinopathies
DrugorChemicalinduced
Infections
Uncommonformsofimmunemediateddiabetes
Othergeneticsyndromessometimesassociatedwith
diabetes
 Type4diabetesmellitus
Itisimportanttomaintaintightglycemic
controlclosetothenormalrangeduring
pregnancy,becausehyperglycemiacanleadto
congenitalabnormalitiesinthefetus.
Diet,exercise,and/orinsulin administration
areeffectiveinthiscondition.
FromLippincottsPharmacology4thedition
Plasmaglucoseandinsulinlevels
afteranoralglucose(75mg)

FromBrodysPharmacology4thedition


FromLippincottsPharmacology4thedition
FromKatzung 11thedition




(crystallinezinc)
(regularinsulin)
:
Humaulin:
Novolin :B30 alanine
threonine
FromKatzung 11thedition

Rapidacting
Insulinlispro
Shortacting
Crystallinezincinsulin
Intermediateacting
Insulinzincsuspension(Lente)
Isophane insulinsuspension(NPH)
Longacting
Protamine zincinsulin
Etended insulinzincsuspension
Insulinglargine
Insulindetemir
FromKatzung 12thedition
FromKatzung 12thedition
Standardandintensivetreatment
Standardtreatment
225to275mg/dL
(normal:80126mg/dL)
Intensivetreatment
(3to4times)150
mg/dL

Sideeffects:

FromLippincottsPharmacology4thedition
Sideeffectsofinsulin

FromLippincottsPharmacology4thedition
 Oralhypoglycemic
Insulinsecretagogues
Sulfonylureas( ;SU)
Meglitinide analogs
Insulinsensitizers
Biguanides ()
Thiazolidinediones (TZDsorglitazones)
Glucosidase inhibitors
 Insulinsecretagogues
Theseagentsareusefulinthetreatmentofpatients
whohaveType2diabetesbutcannotbemanagedby
dietalone.
Patientswhodevelopsdiabetesafteragefortyand
hashaddiabeteslessthanfiveyears.
Oralhypoglycemicagentsshouldnotbegivento
patientswithType1diabetes.
Sulfonylureas( ;SU)
Theypromoteinsulin releasefromthecellsofthe
pancreas.
Tolbutamide;glyburide;glipizide;glimepiride
Actions:
(1)stimulationofinsulin releasefromthecellsofthe
pancreasbyblockingtheATPsensitiveK+ channels,
resultinginCa2+ influx
(2)reductionofserumglucagonlevels
(3)increasingbindingofinsulintotargettissuesand
receptors
FromKatzung 11thedition
 Pharmacokinetics
Wellabsorbedafteroraladministration
Peakplasmaconc.within24hours
Excretedintheurine
Theiractionwillbeincreasedintheelderlyandin
patientswithrenaldisease
SUwill crosstheplacentaandenterbreast
milk
 Druginteractions
SU
NSAIDs(Aspirin)alcohol
MAOinhibitors
SU
(thiazides)
Drugsinteractingwith
sulfonylureasdrugs

FromLippincotts4thedition
 Clinicaluse
Treatmentfortype2DM
Theybanbecombinedwithinsulinsensitizers
suchasmetformin orthiazolidinediones (TZDs)
 Sideeffectsofsulfonylureas
Weightgain
Hyperinsulinemia
Hypoglycemia
NonSUdrugs:Meglitinide analogs
Action:Meglitinide




1stpeak
glucagon


8~10g

FromRangandDales6th edition
 Meglitinide analogs
Repaglinide (NovoNormPrandin,1998)
Meglitinide
Benzoicacid
92%

SU50%
150.5~4mg12mg
16mg
onemealonedosenomealnodose
Nateglinide (StarlixFastis)
DPhenylalanineRepaglinide
60~120mgtid
180mgtid
 Sideeffectsofmeglitinide
Hypoglycemia
Weightgain
Hepaticimpairment
 Insulinsensitizers
Theseagentslowerbloodsugarbyimproving
targetcellresponsetoinsulin without
increasingpancreaticinsulin secretion
Biguanides;thiazolidinediones (TZDsor
glitazones)
 Biguanides ()
Metformin
Reducedhepaticglucoseoutput,largelybyinhibiting
hepaticgluconeogenesis
Italsoslowsintestinalabsorptionofsugars(

lactate)
Likesulfonylureas,metformin requiresinsulin forits
action,butitdiffersfromthesulfonylureasinthatit
doesnotpromoteinsulin secretion
 Mechanismofaction
MetforminactivatesAMPactivatedproteinkinase
(AMPK),anenzymethatplaysanimportantrolein
insulinsignaling.
ActivationofAMPKisrequiredforanincreaseinthe
expressionofSHP(shortheterodimer partner),which
inturninhibitstheexpressionofthehepatic
gluconeogenic genesPEPCKandGLc6Pase
Metformin increasesinsulinsensitivity,enhances
peripheralglucoseuptake(byphosphorylating GLUT4
enhancerfactor)
Metformin increasesfattyacidoxidationanddecreases
absorptionofglucosefromtheGItract.
 Metformin

Liver Muscle

ActivationofAMPK ActivationofAMPK

SREPB1 Glucoseuptake
ACCActivity Gluconeogenesis
expression

Geneexpression
oflipogenic enzymes

Fattyacidoxidation AMPK=adenosinemonophosphateactivatedproteinkinase
VLDLsynthesis ACC=acetylCoAcarboxylase
SREPB1=sterolregulatoryelementbindingprotein1
VLDL=verylowdensitylipoprotein

Fattyliver
Hepaticinsulinsensitivity
FromPharmainfo.net
 Metformin
Itmodestlyreduceshyperlipidermia ()
Thepatientsoftenlosesweightbecauseofloss
ofappetite
FirstchooseforType2DMpatients
Itisonlyoralhypoglycemicagentprovento
decreasecardiovascularmortality
Metformin maybeusedaloneorcombination
withoneoftheotheragents,aswellaswith
insulin
 Adverseeffectsofmetformin
Metformin iscontraindicatedinDMwith renal
and/orhepaticdiseases,cardiacorrespiratory
insufficiency,ahistoryofalcoholabuse,severe
infection,orpregnancy
Fatallacticacidosis()
Diabeticsbeingtreatedwithheartfailure
medicationsshouldnotbegivenmetformin because
ofanincreasedriskinlacticacidosis
LongtermusemayinteractionswithvitaminB12
absorption
TakeHomeMessages

AmericanJournalofHealthSystemPharmacy,Vol.66,Issue22,20172022,2009
 Thiazolidinediones (TZDsor
glitazones)
Althoughinsulin isrequiredfortheiraction,these
drugsdonotpromoteitsreleasefromthe
pancreaticcells;thus,hyperinsulinemiadoesnot
result
Pioglitazone (Actos) ;rosiglitazone (Avandia)
Actions:bindingtoperoxisomeproliferator
activatedreceptor(PPAR;anuclearhormone
receptor)inskeletalmuscle,fatandliverto
decreaseinsulin resistance
ActionofTZDs

FromPharmainfo.net
 Pharmacokinetics
Pioglitazone [pyeohGLItazone]androsiglitazone
[roesiGLIHtazone]arehighlyproteinbound(>99%),
primarilytoserumalbumin.
Metabolizedintheliver
Pioglitazone (cytochromeP4502C8;3A4)
Rosiglitazone (cytochromeP4502C8;2C9)
Elimination
Pioglitazone (feces)
Rosiglitazone (urine)
Pioglitazone androsiglitazone arenotinfluencedby
ageorethnicity.
 TZDs(continued)
Hyperglycemia,hypertriacylgycerolemia,
hyperinsulinemiaandelevatedHbA1c levelsare
improved.
Pioglitazone canbeusedasmonotherapy orin
combinationwithotherhypoglycemics orwith
insulin.
Rosiglitazone mayalsobeusedincombinationwith
otherhypoglycemics orbutnotwithinsulin,because
edema occurswithhigherfrequency.
 TZDs(continued)
Sideeffects:weightgain,headache,anemia,
hepatotoxicity
Womantakingoralcontraceptives()
andTZDsmaybecomepregnant,becausethe
laterhavebeenshowntoreduceplasma
concentrationoftheestrogencontaining
contraceptives
Cholesterolintype2DM?
 RoleofcellABCA1ininsulin
secretion

ABC:
ATPbindingcassettetransporter

NatureMedicine13:241242,2007
 Glucosidase inhibitors
Acarbose;miglitol
Glucosidase isresponsibleforthehydrolysisof
oligosaccharidestoglucoseandothersugars.
Acarbose alsoinhibitspancreaticamylase,thus
interferingwiththebreakdownofstarchto
oligosaccharides.
 Glucosidase inhibitors(continued)
Thesedrugsaretakenatthebeginningof
meals.Theyactbydelayingthedigestionof
carbohydrates,therebydecreasingglucose
absorption.
Sideeffects
flatulence(),diarrhea,andabdominal
cramping
Theywilldecreasethebioavailabilityof
metformin;concurrentuseshouldbeavoided.
Somesideeffectsobservedwith
oralhypoglycemicagents

Meglitinides

FromLippincottsPharmacology4thedition
Summary

FromHagenforda.com
 Dipeptidyl Peptidase4Inhibitors
DPP4 GLP1 GIP
GLP1 GIP glucagon
insulin
DPP4
Sitagliptin (FDA2006;2007)
Vildagliptin (Galvus)(LAF237);
FDA
Sitagliptin
100mgHbA1c0.8%

Dipeptidyl Peptidase4Inhibitors

ByGA Herman,PP Stein,NA ThornberryandJA Wagnerfrom

ClinicalPharmacologyandTherapeutics
 PotentialnewantiDMdrugs
2adrenoceptorantagonists(pancreaticislets)
3adrenoceptoragonists(obesitywithtype2
DM)(Lipolysisthermogenesis)
Inhibitorsoffattyacidoxidation
(AccumulationoffattyacetylCoA causes
insulinresistance)

FromMedicalPhysiology,secondedition
TakeHomeMessages

FromKatzung10thedition