Sulfonylureas

oral hypoglycaemic

1. Sulfonylureas
Dr. Sanooz Raheem

2. Objectives:
•List examples, mechanism of action,
adverse effects and clinical uses of
sulfonyl ureas

3. Introduction
•Oral drugs used for type2 DM
•Energy restriction + carbohydrate restriction + physical activity
•Insulin added if not controlled with oral therapy

4. Classification of oral hypoglycaemic agents
A.Enhance insulin secretion:
1.Sulfonylureas
-First generation: Tolbutamide
-Second generation: glibenclamide, glipizide, gliclazide, glimepride
2. Meglitinide/ phenylalanine analogues
Repaglinide, Nateglinide
3. Glucagon-like peptide-1 (GLP-1) receptor agonists  injectable drugs
Exenatide, Liraglutide
4. Dipeptidyl peptidase-4 (DPP-4) inhibitors
Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin

5. B. Overcome Insulin resistance:
1.Biguanide
Metformin
2. Thiazolidinediones
Pioglitazone

6. C. Miscellaneous antidiabetic drugs:
1.alpha-Glucosidase inhibitors
Acarbose, Miglitol, Voglibose
2. Amylin analogue
Pramlintide
3. Dopamine-D2 receptor agonist
Bromocriptin
4. Sodium-glucose cotransport-2 (SGLT-2) inhibitor
Dapagliflozin

8. Sulfonylureas
•Lowers blood sugar level in Type2 DM and normal subjects
•Considered in ptn- not over weight and metformin contraindicated
•Different SU has variable PK property
MOA:
Provoke brisk release of insulin from pancreas
Rate of insulin secretion at any glucose concentration is increased- Hypoglycaemia
Primarily augment the 2
nd
phase insulin secretion with little effect on the 1
st
phase
Indirect action through pancreas
- Minor action by reducing glucagon secretion & slowing of insulin degradation in liver

9. Extrapancreatic action:
Insulinaemic action of SU declines by few months
-Due to down regulation of sulfonylurea receptors on beta cells
-But improvement in the glucose tolerance maintained
SU sensitize the target tissue to Insulin
- Due to increases insulin receptor or post receptor action

10. MOA at pancreas
•SU block the SU receptor
•ATP sensitive K+ channel is blocked in the pancreatic beta cells
•Inward movement of potassium restricted
•Intracellular potassium falls and membrane partially depolarized
•Opening of calcium channel augmented
•Release of calcium from intracellular stores
•Calcium ion promotes fusion of insulin containing intracellular granules with plasma
membrane and exocytosis

12. Pharmacokinetic properties
•All SU well absorbed orally
•90% or more bound to plasma protein
•Low volume of distribution
•Primarily metabolized – active metabolite
•Active/ inactive metabolites excreted in urine
•Caution in kidney or liver disease

13. Interactions
Drugs enhance SU action:
-Displace from protein binding:-
Ex: phenylbutazone, sulfinpyrazone, salicylates, sulfonamides
-Inhibit metabolism/excretion:-
Ex: cimetidine, ketoconazole, sulfonamides, warfarin, chloramphenicol, acute alcohol
intake
-Synergize with/ prolong pharmacodynamics action:-
Ex: salicylates, propranolol, sympatholytic antihypertensives, lithium, theophylline,
alcohol

14. Drugs that decrease SU action:
-Induce metabolism: phenobarbitone, phenytoin, rifampicin, chronic
alcoholism
-Opposite actions/ suppress insulin release: corticosteroids, thiazides,
furosemide, OCP

15. Adverse effects
-Hypoglycaemia :
commonest problem
may last for several hours
may be severe and fatal
common in elderly, liver and renal disease / potentiating drugs added
Tolbutamide- lower risk ( low potency and shorter duration of action)
-Nonspecific side effects:
weight gain
nausea, vomiting, flatulence, diarrhea/constipation, headache, paresthesia

16. -Hypersensitivity:
rashes, photosensitivity, purpura, transient leukopenia, raraely
agranulocytosis
flushing and disulfiram like reaction with alcohol
- Occasionally disturb liver function  jaundice, hepatitis, hepatic failure

17. Chlorpropamide :-
1
st
SU
Discontinued due to long duration of action and hypoglycaemia
Also causes dilutional hyponatraemia, cholestatic jaundice

18. Individual SU
Glibenclamide :
T1/2: 2-4 hours
Duration of action: 24 hours
Potent but slow acting
Active metabolite and sequestration in beta cells
Dose – initially 5mg daily
adjust dose according to response
max 15mg/day

19. Gliclazide :
T ½ : 8-20 hours
Duration of action: 12-24 hours
Inactive metabolites
Has antiplatelet action
initially 40-80 mg/day
adjust according to dose
upto 160mg as single dose
max 320mg/day

20. Glimepiride:
T ½ : 5-7 hours
Duration of action: 24 hours
Long acting
Inactive metabolites
Extrapancreatic action
Lower incidence of hypoglycaemia
initially 1mg/day
adjust 1mg each step 1-2 wk intervals
max dose 6mg/day
taken with meal/short before

21. Glipizide:
T ½ : 3-5 hours
Duration of action – 12 hours
Fast and shorter acting
Hypoglycaemia and weight gain less likely
Preferred in elderly
initially 2.5-5mg short before breakfast/ lunch
adjust with response
max 20mg/day
upto 15mg as single dose

22. Tolbutamide:
t1/2- 6 hours
duration of action : 6-8 hours
0.5-1.5g daily in divided dose with/ immediately after meals /
as single dose with/ immediately after breakfast
max 2g
safer in elderly

23. Choosing a sulfonylurea
•Side effects
•Duration of action
•Patient’s age
•Renal function
-Glibenclamide a longer acting one and should be avoided in elderly
-Shorter acting gliclazide and tolbutamide are alternatives

24. Special situations
•Advice on hypoglycaemia when another glucose lowering drug is prescribed
•Replace with insulin during acute illness
•Omit on the morning of surgery and replace with insulin

25. Caution :
Caution in elderly
Contra-indications:
Avoid in acute porphyria
Contra-indicated in DKA
Hepatic impairment:
Reduce dose/ avoid risk of hypoglycaemia and jaundice
Renal impairment:
use with care in mild to moderate RF hypoglycaemia
Avoid in severe RF
If necessary shorter acting tolbutamide can be used with close monitoring in lower dose

26. Pregnancy and breast-feeding:
Should be avoided generally risk of hypoglycaemia
In GDM- SU can be resumed in 2
nd
and 3
rd
trimester
Generally avoided in breast-feeding risk of hypoglycaemia (glibenclamide
unlicensed usage in breast-feeding)

27. Meglitinide / D-phenylalanine analogues
Quick and short lasting insulinaemic action
Repaglinide:
Normalize meal time glucose extrusions
Quickly absorbed and quickly metabolized
Fast onset short lasting insulin release
Administered before major meal control postprandial hyperglycaemia
Omit if meals missed
SE: mild headache, dyspepsia, arthralgia, weight gain
Indication: type 2 DM with pronounced postprandial hyperglycaemia / supplement
metformin/long-acting insulin

28. Nateglinide:
Stimulates 1
st
phase insulin secretion
Faster and shorter acting than previous
Taken 10min before meal
No late phase hypoglycaemia
Little effect on FBS
SE: dizzy, nausea, flu like symptoms, joint pain
Use: type2DM with other antidiabetics to control postprandial blood glucose

29. Glucagon-like peptide-1 receptor agonists
•GLP-1 incretin released from gut in response to ingested glucose
-Induce insulin release, inhibit glucagon release, slow gastric emptying, suppress appetite
-Promote beta cell health aswell
-Tx preserve the beta cell function
-Natural GLP-1 not stable and not clinically used
-Synthetic analogues available
-Given SC injections
Ex: Exenatide ( T ½ ~ 3hrs, inactive orally, add on drug with metformin, SU,pioglit..,
lowers PPBS, FBS, body weight)
Liraglutide (longer acting than above)

30. Dipeptidyl peptidase-4 (DPP-4) inhibitors
•DPP-4 responsible for degradation of GLP-1
•Orally active inhibitors of DDP-4
•Indirectly acting insulin secretagogues
•Important adjunct drug in type 2 DM
Ex: Sitagliptin, Vildagliptin, Saxagliptin

31. Sitagliptin
•Competitive and selective DPP-4 inhibitor
•Boost post prandial insulin release, reduce glucagon secretion and lowers meal time blood
sugar and FBS
•No effect on gastric emptying and appetite
•Low risk of hypoglycaemia if given alone
•Recommended as monotherapy when metformin cannot be used
•Commonly used as adjunct drug
•Pk: well absorbed orally, little metabolized, excreted unchanged mainly in urine, T ½ - 12
hours

32. Vildagliptin
•Binds to the enzyme covalently
•Slow dissociation and persistent DPP-4 inhibition
•Longer duration of action (12-24 hours)
•T ½ : 2-4 hours
•Mainly eliminated by liver
•20- 25 % excreted unchanged in urine
•Hepatotoxicity has been reported

33. THANK YOU