Oral Hypoglycemic Agent (1).pdf

Classification, Mode of Action

1. Oral Hypoglycemic
Agents
By
Dr. Jasmine Chaudhary
Associate Prof.
MMCP

2. Oral hypoglycemic agents
Classification
Insulin secretagogues
Sulphonylureas : Tolbutamide, Glipizide, Glibenclamide
Meglitinides: Repaglinide, Nateglinide
Insulin sensitizers
Thiazolidinediones : Pioglitazone, Rosiglitazone
Biguanide: Metformin, Phenformin
Alpha-glucosidase inhibitors : Acarbose
Dipeptidyl Peptidase-IV inhibitors

3. Insulinsecretagogues
•Calledbecausetheypromoteinsulinreleasefromtheβcellsof
pancreas.
•UsefulinthetreatmentofpatientswhohaveType2diabetesbut
whocannotbemanagedbydietalone.
•BestresponsetoOHAisseeninonewhodevelopsdiabetesafter
age40andhashaddiabeteslessthan5years.
•Patientswithlong-standingdiseasemayrequireacombinationof
hypoglycemicdrugswithorwithoutinsulintocontroltheir
hyperglycemia.
•OralhypoglycemicagentsshouldNOTbegiventopatientswith
Type1diabetes.

4. •Sulfonylureas
•Firstgeneration:Tolbutamide,Chlorpropamide
•Secondgeneration:Glipizide,Glimepiride
•Thirdgeneration:Glyclazipe
Firstgenerationsulfonylureasareexcretedmainlythroughurine
andarelesspotentthan2
nd
generationwhile2
nd
generationare
mainlyexcretedthroughbiliaryexcretionandaremorepotent

5. Modeofaction
Actsbybindingtosulfonylureareceptoroncellmembraneof
pancreaticbetacells
DepolariztionofATPsensitiveK+channels
InfluxofCalciumions
DegranulationofstoragevesiclescontaininginsulinandInsulinis
released.

6. SAR
R’
•R’ Must be lipophilic and should have an aromatic ring next to the sulfoxide
group
•Should have a substitutent at the para position.
•Methyl, amino, acetyl, chloro, bromo, and trifluorometyl enhance
hypoglycemic activity.
•The larger, more complex, para substituents comprise the 2nd generation
which are more potent.
•R’ also governs duration of action e.g Tolbutamide is having short DOA
than chlorpropamide.

7. R’’
•R’’ should also be lipophilic. For maximum activity, R’’ should be
between 3-6 C atom chain. It can also be replaced by heteroaromatic
or aromatic group.
3. Benzene ring is essential for activity.
4. Sulfonyl group and R’ should be p-to each other.

8. 1-butyl-3-(4-methylphenyl)sulfonylurea/ Tolbutamide
Chlorpropamide

9. 1-cyclohexyl-3-(4-[2-{5-methyl pyrazine carboxamide} ethyl] phenyl)sulfonyl urea
1-(4-methylcyclohexyl)-3-(4-[2-{3-ethyl-4-methyl-2-oxo) pyrrolidinecarboxamide}
ethyl] phenyl)sulfonylurea

10. Side effects include
•Skin rashes and photosensitivity
•GIT disturbances like nausea, anorexia
•Cardiac dysfunction
4-methyl benzene sulfonamide
Butyloxy cyanide

11. Meglitinides
•The meglitinide are nonsulfonylurease oral hypoglycemic agents used
in the management of type 2 diabetes (NIDDM).
•Mechanism of action is similar to that of sulfonylurease.
•There are two major difference between these two classes –
•These agents tends to have rapid onset and short duration of action.
•Meglitinide cause must faster insulin production than sulfonylurease
Effects of meglinides do not last as long as the effect of sulfonylurease
--The effect of these class appear to last less than one hrs while
sulfonylurease continue to stimulate insulin production for several
hrs.

12. •Incontrasttothesulfonylureas,themeglitinideshavearapid
onsetandashortdurationofaction.Theyarearecategorized
aspostprandialglucoseregulators.Asaresultmeglitinide
shouldbetaken5to10minsbeforemeal.Thesearethedrugs
whichnormalizemealtimeexcursions.(Premealtherapyto
controlpostprandialhyperglycemia)
•Thereislessriskofhypoglycemiaduetoshortdurationof
action.

13. AdverseEffects:
•Incidenceofhypoglycemiaislowerthanthatofthe
sulfonylureas.
•Weightgainislessofaproblemwiththemeglitinidesthanwith
thesulfonylureas.

14. 2-ethoxy-4-(2-[3-methyl-1-[2-piperidyl)phenyl]
butyl ]amino-2-oxoethyl benzoic acid
3-phenyl-2-[4-(1-methylethyl)cyclohexylcarbonyl) aminopropanoic
acid

15. Insulin sensitizers
•Include biguanides and thiazolidinediones
•Lower blood sugar level by improving target cell response to
insulin without increasing pancreatic insulin release.
Biguanides
DiscoverystartedfromplantGalegaofficinaliswhichwasonce
usedtotreatdiabetesanditwasobservedtohaveguanidine
moeitywhichwasresponsibleforitsaction.
Thus guanidines were the prototype of this class but possess toxic
effects, therefore biguanides were synthesized. First phenformin
came into market but cause lactic acidosis so withdrawn from
market.
Require insulin for its action but doesn’t promote insulin secretion.

16. •Side effects include
•Mainly GIT disturbances like Anorexia, Abdominal Pain,
•Fatigue, Metallic taste
Metformin/ 1,1-Dimethylbiguanide
Phenformin/ N-
Phenethylbiguanide

17. Thiazolidinediones
•Also known as glitazones.
•Troglitazonewasthefirstdrugapprovedofthisclassbutlaterfound
tocausehepatotoxicitysowithdrawnfrommarket.
•TheothertwodrugsbelongingtothisclassisPioglitazoneand
Rosiglitazone.
MOA
SelectiveagonistofPPAR-γreceptorwhichisinvolvedin
transcriptionofgenesinvolvedincontrolofglucoseand
lipidmetabolisminmuscle,adiposetissueandliver.So,it
reducesinsulinresistancebystimulatingGLUT-4
expression.

18. Pioglitazone/ 5-(4-(2-(4-ethylpyridin-2-yl)ethoxy) benzyl) thiazolidine-2,4-dione
Rosiglitazone/
5-[[4-[2-[N-methyl(pyridin-2-yl)amino]ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione
Side effects include Fluid retention, Weight gain, Hypoglycemia, Respiratory Tract Infection

19. Alpha glucosidase inhibitors
•E.g include Agarbose and Voglibose
•Inhibits alpha glucosidase enzyme which convert complex sugar
(carbohydrates) into simple sugar.
•Used to lower post prandial blood glucose level.

20. Dipeptidyl Peptidase-IV (DPP-IV) inhibitors
•Sitagliptin, Vildagliptin, Saxagliptin
•Selective and reversible competitive inhibitor of DPP-4 enzyme
and potentiate secretion of insulin in beta cells and suppress
glucagon release by alpha cells of Islets of Langerhans of
pancreas.