Oral hypoglycemic agents

Oral hypoglycemic agents

1. Dr.
Oral Hypoglycemic Agents
Dr. Kumbhare Manoj R.
Professor, Head Dept. of Pharmaceutical Chemistry
S.M.B.T. College of Pharmacy,
Dhamangaon Tal-Igatpuri
Dist. Nashik (M.S.).
[email protected]
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2. Insulin & Oral Antidiabetic Drugs
Diabetes mellitus
Definition: a syndrome of disordered metabolism due
to a combination of hereditary and environmental causes.
Classification:
Type 1: Lack of insulin.
Type 2: Cells resistance to insulin
Signs & symptoms:
• Very thirsty
• Feeling tired
• Using the toilet often to urinate
• Constant hunger
• High level of glucose in urine & in fasting blood
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3. Treatment
Type 1: Insulin must be injected or inhaled
Type 2: Food control, exercise, medicines
(1) agents which increase insulin secretion;
(2) agents which increase the sensitivity of
target organs to insulin;
(3) agents which decrease glucose absorption
(4) Insulin needed for patients with serious
complications or an emergency.
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4. Pathophysiology
•Insulinsecretedbybetacells
•Insulinbindswithandactivates80%ofcells
•Liver,muscle,andfatcellsareprimarytissues
forinsulinaction
•Withinsulinreceptorbinding,cellmembranes
permeabletoglucoseintothecells
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5. What is insulin ?
Insulin is a peptide hormone produced by beta
cells present in langerhansislets in pancreas
Chemistryofinsulin
Insulinisasmallpeptide(protein)consistingof
fifty-oneaminoacidssynthesizedandstored
withinthepancreas
Theproteinitselfconsistsoftwochains,denoted
AandB,linkedbydisulfide(sulfur-sulfur)bridges
betweencysteineresidues
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6. molecular weightof 5808Da
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7. howinsulinworks
Elevatedlevelsofglucoseinthebloodstimulates
cellsofthepancreastoincreaseinsulinsecretion
intotheblood.
Theinsulincirculatesthebody,andwithin
minutes,stimulatestheliverandmusclecellsto
takeupglucosefromtheblood.Asglucoseis
removedfromtheblood,obviouslybloodlevels
fall.
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8. Classification of Antidiabetic Agents
•Biguanidese.g. Metformin, phenformin
•Sulfonylureas
First generation agents -Tolbutamide, acetohexamide, tolazamide,
chlorpropamide
Second generation agents –glyburide, glypizide,
Glimepride, gliclazide, glycopyramide
Third generation agents-glybormuride
•Thiazolidinedionese.g. rosiglitazone( withdrawn
market due to elevated cardiovascular risks, ) pioglitazone
troglitazone(withdrawn due tohepatitis and liver damage risk)
•Meglitinides-repaglinide, nateglinide.
•Alpha-glucosidaseinhibitors –Miglitol, acarbose, etc.
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9. Sulfonyl ureas
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10. ThiazolidinedionesN
CH
3
N
NH
S
O
O
O
Rosiglitazone H
3C N
NH
S
O
O
O
Pioglitazone
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11. Structure and Properties of Hypoglycemic Sulfonylureas
1.TheArandRportionsofthisgeneralstructureprovidelipophilic
characterwhereasthe-SO2-NH-CO-NH-moietyishydrophilic.Allof
thesefunctionalgroupsarerequiredforactivity,butthelipophilicArand
Rgroupsaccountforthedifferencesinpotency(SUreceptorbinding),
metabolism,duration,androutesofelimination.
2.Thearylsulfonylureasareweakorganicacids(pKas=5-6)andarelargely
ionizedatphysiologicalpH.
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12. Mechanismofactioningeneral
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13. Mechanism(s)ofSulfonylureaHypoglycemia
Thesulfonylureasproducetheirhypoglycemicactionsviaseveralmechanismsthatcan
bebroadlysub-classifiedaspancreaticandextra-pancreatic:
A.PancreaticMechanism:AllsulfonylureahypoglycemicsinhibittheeffluxofK+(K+
channelblockers)frompancreaticß-cellsviaasulfonylureareceptorwhichmaybe
closelylinkedtoanATP-sensitiveK+-channel.TheinhibitionofeffluxofK+leadsto
depolarizationoftheßcellmembraneand,asaconsequence,voltage-dependent
Ca++-channelsontheß-cellmembranethenopentopermitentryofCa++.The
resultantincreasedbindingofCa++tocalmodulinresultsinactivationofkinases
associatedwithendocrinesecretorygranulestherebypromotingtheexocytosisof
insulin-containingsecretorygranules
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15. Uses
Sulfonylureasareusedprimarilyforthetreatmentofdiabetesmellitustype2.
Sulfonylureasareineffectivewherethereisabsolutedeficiencyofinsulin
productionsuchasintype1diabetesorpost-pancreatectomy.
Sulfonylureascanbeusedtotreatsometypesofneonataldiabetes.While
historicallypatientswithhyperglycemiaandlowbloodinsulinlevelswere
diagnosedwithTypeIDiabetesbydefault,ithasbeenfoundthatpatientswho
receivethisdiagnosisbefore6monthsofageareoften,infact,candidatesfor
receivingsulfonylureasratherthaninsulinthroughoutlife.
Althoughformanyyearssulfonylureaswerethefirstdrugstobeusedinnew
casesofdiabetes,inthe1990sitwasdiscoveredthatobesepatientsmight
benefitmorefrommetformin.
Morerecently,apharmaceuticalstartup,RemedyPharmaceuticals,Inc.has
begundevelopingintravenousglyburide
[
asatreatmentforacutestroke,
traumaticbraininjuryandspinalcordinjurybasedontheidentificationofanon-
selectiveATP-gatedcationchannelwhichisupregulatedinneurovasculartissue
duringtheseconditionsandclosedbysulfonylureaagents.
Somediabetesexpertsfeelthatsulfonylureasacceleratethelossofbetacells
fromthepancreas,andshouldbeavoided.
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16. Glipizide
Glimepiride
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17. MEGLITINIDES: Repaglinide
Repaglinide is a non-sulfonylurea hypoglycemic agent that consists
structurally of the nonsulfonylurea moiety of glyburide and a salicylic
acid derivative
Nateglinide is a derivative of the amino acid D-phenylalanine related
somewhat to repaglinide. 17

18. Combination therapy with repaglinide and metformin resulted
in synergistic improvement in glycemic control compared with
either repaglinide or metformin monotherapy
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19. •Biguanides
• Guanidine found to lower blood glucose in animals in 1918, but too toxic.
• Alkyl-diguanides synthalin A and B were introduced into diabetes therapy in
1920s. Displayed efficacy comparable to insulin, but renal and hepatic
damage resulted upon prolonged administration. Discontinued in the 1930s
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20. Phenformin was initially regarded as the most potent biguanide and was
used more extensively until its withdrawal in most countries by
1977. This withdrawal was prompted largely by the association of
phenformin therapy with lactic acidosis (rare, but potentially fatal).
Alpha-Glucosidase Inhibitors: Acarbose
Voglibose, a simple amine substituted cyclohexane polyol is
in development
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22. Alternative medicine
•Medicinal plants have been studied for the
treatment of diabetes, however there is
insufficient evidence to determine their
effectiveness
•Examples:
Cinnamon
Chromium supplements
Vanadyl sulfate a salt of vanadium
Thiamine
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23. Conclusion
•Research
•Life style
•Food habits
•Exercise
•Insulin
•Drugs
•Biguanides ,
•Sulfonyl ureas ,
•Thiazolidinediones ,etc.

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