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Sulfonylureas

Sulfonylureas are oral hypoglycemic drugs that enhance insulin secretion from the pancreas. They work by blocking ATP-sensitive potassium channels in pancreatic beta cells, which leads to insulin release. Common side effects include hypoglycemia and weight gain. Examples include glibenclamide, glipizide, and glimepiride. Choice of sulfonylurea depends on factors like duration of action, renal function, and patient age. They are generally effective treatments for type 2 diabetes but require caution in elderly patients or those with kidney/liver problems.

Healthcare◦
Sulfonylureas Dr. Sanooz Raheem
Objectives: •List examples, mechanism of action, adverse effects and clinical uses of sulfonyl ureas
Introduction • Oral drugs used for type2 DM • Energy restriction + carbohydrate restriction + physical activity • Insulin added if not controlled with oral therapy
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
B. Overcome Insulin resistance: 1.Biguanide Metformin 2. Thiazolidinediones Pioglitazone
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
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 2nd phase insulin secretion with little effect on the 1st phase Indirect action through pancreas - Minor action by reducing glucagon secretion & slowing of insulin degradation in liver
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
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
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
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
Drugs that decrease SU action: -Induce metabolism: phenobarbitone, phenytoin, rifampicin, chronic alcoholism -Opposite actions/ suppress insulin release: corticosteroids, thiazides, furosemide, OCP
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
- Hypersensitivity: rashes, photosensitivity, purpura, transient leukopenia, raraely agranulocytosis flushing and disulfiram like reaction with alcohol - Occasionally disturb liver function  jaundice, hepatitis, hepatic failure
Chlorpropamide :- 1st SU Discontinued due to long duration of action and hypoglycaemia Also causes dilutional hyponatraemia, cholestatic jaundice
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
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
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
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
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
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
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
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
Pregnancy and breast-feeding: Should be avoided generally risk of hypoglycaemia In GDM- SU can be resumed in 2nd and 3rd trimester Generally avoided in breast-feeding risk of hypoglycaemia (glibenclamide unlicensed usage in breast-feeding)
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
Nateglinide: Stimulates 1st 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
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)
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
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
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
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