ORAL HYPOGLYCEMIC AGENT.ppt Sulfonylurea drugs.

Insulin secretagogues 2
:
1. Sulfonylurea drugs.
2. Meglitinides. 1
3. Incretin mimetics.
Insulin sensitizers 3
:
1. Biguanides 22. Thiazolidinediones
Agents that reduce
carbohydrate absorption:
1. Alpha glucosidase 3 inhibitors
Oral hypoglycemic drugs
( Antidiabetic drugs )
Agents that reduce glucose
renal reabsorption
(Increase glucose excretion):
1. Sodium/glucose
cotransporter 2 (SGLT2) 4
inhibitors

1. ORAL HYPOGLYCEMIC AGENT
MEDICINAL CHEMISTRY
By
Miss. Waghhrutuja
ASSISTANT PROFESSOR

2. ANTIDIABETIC AGENTS
•Agentswhichareusedinthetreatmentofdiabetesarecalled
asantidiabeticagents.
•Theyusedtolowerthebloodsugarlevelinpatientssuffering
fromhyperglycaemia.
•Thesearealsocalledasanti-hyperglycaemicagents.
•Diabetesmellitus:Itisachronicmetabolicdisorderwhichis
characterizedbyhyperglycaemia(increasedbloodsugarlevel).
Thecommonsymptomsarepolydipsia(excessthirst),
polyphagia(excesshunger),andpolyurea(excessurination).

3. Role of insulin
•Insulin:
•Itisapeptidichormonesecretedbyβ-cellsofpancreas.
•ItwasdiscoveredbyBanting&Bestin1921.
•Itregulatesmetabolismofcarbohydrate,lipidsandproteins.
•Itdecreasesbloodsugarlevelbydecreasinggluconeogenesis,
increasingglucoseuptakeandincreasingglycogensynthesis.

4. Insulin structure
•Its full structure was elucidated by Sanger in 1956.
•It is a polypeptide hormone with a molecular weight of 6000
Da.
•Inside body, the inactive pro-insulin is converted into active
insulin which is composed of 2 chains (A & B).
•A chain has 21 amino acid residues, whereas B chain has 30
amino acid residues and both the chains are attached to each
other by 2 disulphide (-S-S-) bonds.
•Sources of insulin: Bovine, Porcine, Recombinant human
insulin

5. Insulin structure

6. Classification of diabetes mellitus

11. Sulfonyl ureas:
•These are the first class of oral hypoglycaemic agents used for
treatment of diabetes. They are also called as insulin
secretagogues.
•1 st generation-Chlorpropamide, Tolbutamide, Acetohexamide
•2 nd generation-Glibenclamide, Glipizide, Glyburide
•3 rd generation-Glimepiride
•Mechanism of action-They bind to the sulfonyl urea receptors
present in pancreatic β-cells. It leads to closure of ATP-sensitive
K+ channels and depolarises the β-cell membrane. Then it
opens voltage gated Ca+2 channels and stimulates β-cells to
secrete more insulin.

12. Mechanism of action sulfonylureas

13. Mechanism of action sulfonylureas

14. Mechanism of action sulfonylureas & meglitinides

15. Mechanism of action of bigunides

16. Mechanism of action of bigunides

17. Mechanism of action thiazolidinediones

18. Mechanism of action thiazolidinediones

19. Mechanism of action of alpha –glucosidase inhibitor

26. TOLBUTAMIDE SYNTHESIS

27. •PLEASE REFER NEXT ANTIDIEBETIC DOCUMENT FOR
STRUCTURAL EXPLANATION.

35. ADMINISTRATION
•Glipizideisa2.5mgto10mgtablet,takenasasingledoseorintwodivideddoses,30minutesbeforebreakfast.
Glimepirideisavailableas1mg,2mg,or4mgtablets,takenonceadaywithbreakfastortwiceadaywith
meals.Forpatientsatincreasedriskforhypoglycemia,suchasolderpatientsorthosewithchronickidney
disease,theinitialdosecouldbeaslowas0.5mgdaily.Glyburideisavailableas1.25mg,2.5mg,or5mg
tablets,takenasasingledoseortwodivideddoses.
•Repaglinideisavailableas0.5mg,1mg,or2mgtablets,takenorallyintwotothreedivideddosesperday.
•Metforministheinitialdrugofchoiceinpatientswithtype2diabetesmellitus.Itisgivenorallyin500to1000
mgtabletstwiceaday.
•Alpha-glucosidaseinhibitorsareavailableas25mg,50mg,or100mgtablets,giventhreetimesadayjust
beforemeals.
•Pioglitazoneisgivenas15mg,30mg,or45mgtabletsdaily.Rosiglitazone,whilerarelyused,isgivenas2mg,
4mg,or8mgdaily.
•AmongtheDPP-4inhibitors,linagliptinisavailableas5mgdaily.Vildagliptinisgivenas50mgonceortwice
weekly,Sitagliptinas25mg,50mg,or100mgoncedaily,andSaxagliptinas2.5mgor5mgoncedaily.
•AmongtheSGLT2inhibitors,canagliflozinisinitiallygivenas100mgdaily,whichisgraduallyincreased
to300mgdaily,dapagliflozinas5mgor10mgdaily,andempagliflozinas10mgor25mgdaily.
•Cyclosethasaninitialdoseof0.8mgoncedaily,whichisgraduallyincreasedtotheusualdoseof1.6mgto4.8
mgoncedaily.

36. Adverse Effects
•Thefollowingareadverseeffectsofvarioushypoglycemicdrugs:
•Sulfonylureas:Syncope(lessthan3%),dizziness(2%to7%),nervousness(4%),anxiety(lessthan3%),
depression(<3%),hypoesthesia(lessthan3%),insomnia(<3%),pain(<3%),paresthesia(lessthan3%),
drowsiness(2%),headache(2%),diaphoresis(lessthan3%),pruritus(1%tolessthan3%),hypoglycemia(less
than3%),increasedlactatedehydrogenase,diarrhea(1%to5%),flatulence(3%),dyspepsia(lessthan3%),and
vomiting(lessthan3%).
•Repaglinide:Hypoglycemia(16%to31%),weightgain,headache(9%to11%),upperrespiratorytractinfection
(10%to16%),andcardiovascularischemia(4%).
•Metformin:Gastrointestinalupsetsuchasdiarrhea(12%to53%),nauseaandvomiting(7%to26%),flatulence
(4%to12%),chestdiscomfort,flushing,palpitation,headache(5%to6%),chills,dizziness,tastedisorder,
diaphoresis,naildisease,skinrash,vitaminB12deficiency.Also,inlessthan1%ofpatients,itcauseslactic
acidosis,whichcanbelife-threatening,andisprecipitatedbyconditionspredisposingtohypoperfusionand
hypoxemia,suchassevererenalfailure(eGFRlessthan30ml/min/1.73m2).
•Thiazolidinediones:Edema(lessthanorequalto27%),hypoglycemia(lessthanorequalto27%),cardiac
failure(lessthanorequalto8%),headache,bonefracture(lessthanorequalto5%),myalgia(5%),sinusitis
(6%),andpharyngitis.

37. Adverse Effects
•Alpha-glucosidaseinhibitors:Adverseeffectsincludeflatulence(74%)thattendstodecreasewith
time,diarrhea(31%),abdominalpain(19%),andincreasedserumtransaminases(lessthanorequal
to4%).
•DPP4inhibitors:
•Sitagliptin:Hypoglycemia(1%),nasopharyngitis(5%),increasedserumcreatinine,acutepancreatitis
(includinghemorrhagicornecrotizingforms),andacuterenalfailure.
•Saxagliptin:Peripheraledema(4%),headache(7%),hypoglycemia(6%),urinarytractinfection(7%),
lymphocytopenia(2%),andacutepancreatitis.
•Linagliptin:Hypoglycemia(7%),increaseduricacid(3%),increasedserumlipase(8%;morethan
threetimesupperlimitofnormal),nasopharyngitis(7%),andacutepancreatitis.
•SGLT-2inhibitors:Dyslipidemia(3%),hyperphosphatemia(2%),hypovolemia(1%),nausea,fungal
vaginosis(7%to8%),urinarytractinfection(6%),increasedurineoutput(3%to4%),dysuria(2%),
influenza(2%to3%),bonefracture(8%),andrenalimpairment.
•Cycloset:Dizziness,fatigue,headache,constipation,rhinitis,nausea,andweakness.