Cra| hypog|ycaem|c agents

1he maln groups of oral agenLs LhaL lower blood sugar are
nsulln secreLagogues (eg sulfonylureas megllLlnldes)
2 lguanldes
3 1hlazolldlnedlones
4 lphaglucosldase lnhlblLors (eg acarbose)
% Su|fony|ureas (Insu||n secretagogues%
1hese drugs acL by sLlmulaLlng lnsulln release and Lhus requlre funcLlonal lsleL
cells
Mechan|sm of act|on
1he prlnclpal acLlon of sulphonylureas ls on Lhe cells of Lhe lsleLs sLlmulaLlng
lnsulln secreLlon and Lhus reduclng plasma glucose concenLraLlon
lghafflnlLy recepLors for sulphonylureas are presenL on Lhe 1senslLlve k
+
channels ln cell membranes
1he drugs reduce Lhe poLasslum permeablllLy of cells by blocklng Lhe 1
senslLlve poLasslum channels causlng depolarlzaLlon Ca
2+
enLry and hence lnsulln
secreLlon
asal lnsulln secreLlon and Lhe secreLory response Lo varlous sLlmull are enhanced
ln Lhe flrsL few days of LreaLmenL wlLh sulphonylurea drugs
JlLh longer LreaLmenL lnsulln secreLlon conLlnues Lo be augmenLed and Llssue
senslLlvlLy Lo lnsulln also lmproves by an unknown mechanlsm



A% I|rst generat|on su|fony|ureas
1he flrsL used LherapeuLlcally were LolbuLamlde and chlorpropamlde
1o|butam|de
Jell absorbed buL rapldly meLabollzed ln Lhe llver
Ls duraLlon of effecL ls relaLlvely shorL wlLh an ellmlnaLlon halfllfe of 43 hours
and lL ls Lherefore Lhe safesL sulfonylurea for use ln elderly dlabeLlcs
cuLe Loxlc reacLlons are rare skln rash occurs lnfrequenLly
rolonged hypoglycemla has been reporLed rarely mosLly ln paLlenLs recelvlng
cerLaln drugs (eg dlcumarol phenylbuLazone or some of Lhe sulfonamldes) LhaL
lnhlblL Lhe meLabollsm of LolbuLamlde
Ch|orpropam|de
Chlorpropamlde has a long duraLlon of acLlon and a subsLanLlal fracLlon ls
excreLed ln Lhe urlne
L can cause severe hypoglycemla ln elderly paLlenLs ln whom Lhere ls a
progresslve decllne ln glomerular fllLraLlon raLe
L causes flushlng afLer alcohol because of a dlsulflramllke effecL and has an
acLlon llke LhaL of anLldlurecLlc hormone on Lhe dlsLal nephron glvlng rlse Lo
hyponaLraemla and waLer lnLoxlcaLlon
8% Secondgenerat|on su|fony|ureas
eg (gllbenclamlde gllburlde ln uS# gllplzlde gllmeplrlde and gllclazlde)
re more poLenL (on a mllllgram basls) buL Lhelr maxlmum hypoglycemlc effecL ls
no greaLer and fallure of LreaLmenL Lo conLrol blood sugar ls [usL as common as
wlLh LolbuLamlde
1hey all conLaln Lhe sulphonylurea moleLy buL dlfferenL subsLlLuLlons resulL ln
dlfferences ln pharmacoklneLlcs and hence ln duraLlon of acLlon
llbenclamlde ls besL avolded ln Lhe elderly and ln paLlenLs wlLh even mlld renal
lmpalrmenL because of Lhe rlsk of hypoglycaemla slnce several of lLs meLabollLes
are excreLed ln urlne and are moderaLely acLlve
harmacok|net|c aspect
Sulphonylureas are well absorbed afLer oral admlnlsLraLlon and mosL reach peak
plasma concenLraLlons wlLhln 24 hours
ll blnd sLrongly Lo plasma albumln and are lmpllcaLed ln lnLeracLlons wlLh oLher
drugs (eg sallcylaLes and sulphonamldes) LhaL compleLe for Lhese blndlng slLes
,osL sulphonylureas (or Lhelr acLlve meLabollLes) are excreLed ln Lhe urlne so
Lhelr acLlon ls lncreased ln elderly paLlenLs or ln Lhose wlLh renal dlseases
Sulphonylureas cross Lhe placenLa and sLlmulaLe foeLal cells Lo release lnsulln
causlng severe hypoglycaemla aL blrLh as a resulL Lhelr use ls conLralndlcaLed ln
pregnancy and gesLaLlonal dlabeLes ls managed wlLh dleL supplemenLed lf
necessary wlLh lnsulln
Unwanted effects
1he sulfonylureas are usually well LoleraLed
Sulphonylurea drugs sLlmulaLe appeLlLe and ofLen cause welghL galn (Lhls ls a
ma[or concern ln obese dlabeLlc paLlenLs)
ypoglycaemla whlch can be severe may occur Ls lncldence ls relaLed Lo Lhe
poLency and duraLlon of acLlon Lhe hlghesL lncldence occurs wlLh chlorpropamlde
and gllbenclamlde and Lhe lowesL wlLh LolbuLamlde
bouL 3 of paLlenLs experlence gasLrolnLesLlnal upseLs
llerglc skln rashes can occur
one marrow damage Lhough very rare can be severe
lockade of 1senslLlve k
+
channels ln hearL and vascular Llssue could have
adverse effecLs
Drug |nteract|ons
-onsLeroldal anLllnflammaLory drugs (lncludlng azapropazone phenylbuLazone
and sallcylaLes) coumarlns some urlcosurlc drugs (eg sulphlnpyrazone) alcohol
monoamlne oxldase lnhlblLors some anLlbacLerlals (lncludlng sulphonamldes
LrlmeLhoprlm and chloramphenlcol) some anLlfungal drugs (lncludlng mlconazole
and posslbly fluconazole) have all been reporLed Lo produce severe
hypoglycaemla when glven wlLh Lhe sulphonylureas
2% Meg||t|n|des (Insu||n secretagogues%
Lg kepag||n|de
1hese drugs modulaLe cell lnsulln release by regulaLlng poLasslum efflux
Lhrough Lhe poLasslum channels
1he megllLlnldes have Lwo blndlng slLes ln common wlLh Lhe sulphonylureas and
one unlque blndlng slLe
8epagllnlde has a very fasL onseL of acLlon wlLh a peak concenLraLlon and peak
effecL wlLhln approxlmaLely 1 hour afLer lngesLlon
L ls hepaLlcally cleared wlLh a plasma halfllfe of 1 hour
ecause of lLs rapld onseL and shorL duraLlon of acLlon repagllnlde ls lndlcaLed for
use ln conLrolllng posLprandlal glucose excruslons
1he drug should be Laken [usL before each meal hypoglycaemla ls a rlsk lf Lhe
meal ls delayed or sklpped or conLalns lnadequaLe carbohydraLe
1hls drug should be used cauLlously ln lndlvlduals wlLh hepaLlc lmpalrmenL
1here ls no sulfur ln Lhe sLrucLure so repagllnlde may be lndlcaLed for use ln Lype
2 dlabeLlc lndlvlduals wlLh sulfur or sulfonylurea allergy
3% 8|guan|des
eg metform|n
1hey are orally acLlve hypoglycemlc agenLs LhaL do noL requlre funcLlonlng
cells
aLlenLs wlLh Lype 2 dlabeLes have conslderably less fasLlng hyperglycaemla as
well as lower posLprandlal hyperglycemla afLer blguanldes
1hese agenLs are more approprlaLely Lermed euglycemlc# raLher Lhan
hypoglycemlc agenLs
Mechan|sm of act|on
CurrenLly proposed mechanlsm of acLlon lnclude
1 ulrecL sLlmulaLlon of glycolysls ln Llssues wlLh lncreased glucose removal from
blood
2 8educed hepaLlc gluconeogenesls
3 Slowlng of glucose absorpLlon from Lhe gasLrolnLesLlnal LracL wlLh lncreased
glucose Lo lacLaLe converslon by enLerocyLes
4 8educLlon of plasma glucagon levels
,eLformln has addlLlonal meLabollc acLlons ln LhaL lL reduces plasma
concenLraLlons of low denslLy llpoproLeln and very low denslLy llpoproLeln and
very low denslLy llpoproLeln effecLs LhaL could LheoreLlcally be useful ln reduclng
aLheroma
Metabo||sm and excret|on
,eLfromln has a half llfe of 13 3 hours
-oL bound Lo plasma proLeln
-oL meLabollzed and ls excreLed by Lhe kldneys as Lhe acLlve compound
n paLlenLs wlLh renal lnsufflclency blguanldes accumulaLe and Lhereby lncrease
Lhe rlsk of lacLlc acldosls whlch appears Lo be a dose relaLed compllcaLlon
C||n|ca| use
,eLformln ls useful Lhe ma[orlLy of Lype 2 paLlenLs who are obese and who fall
LreaLmenL wlLh dleL alone (meLformln dose noL sLlmulaLe appeLlLe raLher Lhe
reverse#)
21hey used ln comblnaLlon wlLh sulfonylureas ln Lype 2 dlabeLlcs ln whom
sulfonylurea Lherapy alone ls lnadequaLe
S|de effects
1he maln unwanLed effecL ls LranslenL gasLrolnLesLlnal dlsLurbance (anorexla
nausea vomlLlng abdomlnal dlscomforL and dlarrhea)
2 acLlc acldosls (rare buL poLenLlally faLal Loxlc effecL)
3 ong Lerm use may lnLerfere wlLh absorpLlon of vlLamln
12

Contra|nd|cat|on
lguanldes are conLralndlcaLed ln paLlenLs wlLh renal dlsease alcohollsm hepaLlc
dlsease or condlLlons predlsposlng Lo Llssue anoxla (eg chronlc cardlopulmonary
dysfuncLlon) because of an lncreased rlsk of lacLlc acldosls lnduced by blguanldes
drugs ln Lhe presence of Lhese dlsease




4% 1h|azo||d|ned|ones
eg roslgllLazone and logllLazone
mechan|sm of act|on
1hey appear Lo have an acuLe posLrecepLor lnsulln mlmeLlc acLlvlLy as well as
chronlc effecLs on Lhe LranscrlpLlon of genes lnvolved wlLh glucose and llpld
meLabollsm
1helr ma[or acLlon ls Lo dlmlnlsh lnsulln reslsLance by lncreaslng glucose upLake
and meLabollsm ln muscle and adlpose Llssues
1hey also resLraln hepaLlc gluconeogenesls and exerL addlLlonal effecLs on llpld
meLabollsm ovarlan sLeroldogenesls sysLemlc blood pressure and Lhe flbrlnolyLlc
sysLem
Some of Lhe beneflclal effecLs of Lhese drugs may be due a redlsLrlbuLlon of body
faL 1hlazolldlnedlone Lherapy has been assoclaLed wlLh a decllne ln vlsceral faL
mass and enhanced developmenL of perlpheral small adlpocyLes
1hese agenLs are consldered euglycemlc# slnce when use alone Lhey can resLore
glucose levels lnLo Lhe normal or nondlabeLlc range wlLhouL causlng
hypoglycemla
ComblnaLlon Lherapy wlLh sulfonylureas and lnsulln can lead Lo low blood glucose
values and may requlre dosage ad[usLmenL
Chronlc Lherapy ls assoclaLed wlLh a drop ln Lrlglycerlde levels and a sllghL rlse ln
u and u cholesLerol values
ll are meLabollzed Lhrough Lhe hepaLlc cyLochrome p430 sysLem and Lhelr
lnducLlon of dlfferenL paLhways may affecL Lhe bloavallablllLy of oLher
medlcaLlons such as oral conLracepLlves
n adverse effecL common Lo all Lhe agenLs ls m||d anem|a
1hey are approved for use ln Lype 2 dlabeLes as monoLherapy or ln comblnaLlon
wlLh a blguanlde
logllLazone can also serve as a supplemenL Lo sulfonylurea or lnsulln Lherapy ln
Lhe Lype 2 populaLlons
% g|ucos|dase |nh|b|tors
eg carbose and mlgllLol
mechan|sm of act|on
carbose and mlgllLol are compeLlLlve lnhlblLors of Lhe lnLesLlnal glucosldase
and modulaLe Lhe posLprandlal dlgesLlon and absorpLlon of sLarch and
dlsaccharldes
,lgllLol dlffers sLrucLurally from acarbose and ls slx Llmes more poLenL ln
lnhlblLlng sucrase
C||n|ca| use
1hey can be used ln lndlvlduals wlLh Lype 2 dlabeLes as monoLherapy and ln
comblnaLlon wlLh oLher agenLs
Unwanted effects
1he commonesL adverse effecLs are relaLed Lo lLs maln acLlon and conslsL of
laLulence loose sLools or dlarrhoea and abdomlnal paln and bloaLlng
ypoglycemla may occur wlLh concurrenL sulfonylurea LreaLmenL (ypoglycemla
should be LreaLed wlLh glucose (dexLrose) and noL sucrose whose breakdown
may be blocked)
carbose has been assoclaLed wlLh reverslble hepaLlc enzyme elevaLlon and
should be use wlLh cauLlon ln Lhe presence of hepaLlc dlsease

Contra|nd|cat|ons
1hese drugs are conLralndlcaLed ln paLlenLs wlLh chronlc or lnflammaLory bowel
dlsease or any lnLesLlnal condlLlon LhaL could be worsened by gas and dlsLenLlon
&&& G|ucagon
lucagon ls synLheslzed ln Lhe cells of Lhe pancreaLlc lsleLs of langerhans
lucagon ls a pepLlde ldenLlcal ln all mammals# conslsLlng of a slngle chaln of 29
amlno aclds
lucagon ls exLenslvely degraded ln Lhe llver and kldney as well as ln plasma and
aL lLs Llssue recepLor slLes
Ls half llfe ln plasma ls beLween 3 and 6 mlnuLes
lucagon ls a fuel moblllzlng hormone sLlmulaLlng gluconeogenesls and
glycogenolysls also llpolysls and proLeolysls
L lncreases blood sugar and also lncreases Lhe force of conLracLlon of Lhe hearL
C||n|ca| uses of g|ucagon
lucagon can be admlnlsLered lnLramuscularly or subcuLaneously as well as
lnLravenously
1o LreaL hypoglycaemla ln unconsclous paLlenLs (who cannoL drlnk) or lf Lhere
ls dlfflculLy ln obLalnlng lnLravenous access
2 1o lncrease Lhe force of conLracLlon of Lhe hearL (poslLlve lnoLroplc acLlon) ln
acuLe cardlac fallure preclplLaLed by ln[udlclous use of adrenocepLor
anLagonlsLs



Adverse keact|ons
1ranslenL nausea and occaslonal vomlLlng can resulL from glucagon
admlnlsLraLlon 1hese are generally mlld and glucagon ls relaLlvely free of severe
adverse reacLlons
&&& Somatostat|n
SomaLosLaLln ls secreLed by Lhe u cells of Lhe lsleLs
L ls also Lhe growLh hormone release lnhlblLlng facLor generaLed ln Lhe
hypoLhalamus
L provldes local paracrlne lnhlblLory regulaLlon of lnsulln and glucagon release
wlLhln Lhe lsleL
Cctreot|de ls a long acLlng ocLapepLlde analogue of somaLosLaLln L lnhlblLs
release of a number of hormones and ls used cllnlcally Lo relleve sympLoms from
several uncommon gasLroenLero ancreaLlc endocrlne Lumours and for
LreaLmenL of Lhe endocrlne dlsorder caused by a funcLlonlng Lumour of cells LhaL
secreLe growLh hormone from Lhe anLerlor plLulLary and known as acromegaly