Comprehensive Overview of Oral Hypoglycaemic Agents: Sulfonylureas and Biguanides in Diabetes Management

Comprehensive Overview of Oral Hypoglycaemic Agents: Sulfonylureas and Biguanides in Diabetes Management

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  Oral Hypoglycaemic Agents - Sulfonylureas& Biguanides Neha Muhammed Sanad Munavair C21-393 Clinical Pharmacology Professor : Dr. Shifrin Yuri Alexandrovich
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  • A chronicmetabolicdisorder characterised by a high blood glucose concentration- hyperglycaemia • fasting plasma glucose > 7.0 mmol/l, or plasma glucose> 11.1 mmol/l 2 hours after a meal • caused by – insulin deficiency – insulin resistance Diabetes
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  Pathogenesis
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  • Oral hypoglycemicdrugs are primarily used to manage type 2 diabetes, particularly when diet and exercise alone are not enough. • They are also sometimes used for other conditions, including gestational diabetes, PCOS, and ovarian hyperstimulation syndrome. Oral hypoglycemics
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  Classification of oralhypoglycaemicagents
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  Insulinotropic diabetes medicationstreat type 2 diabetes mellitus by increasing insulin secretion, which results in decreased glucose levels. The group of medications includes sulfonylureas, meglitinides, glucagon-like peptide-1 (GLP-1) receptor agonists, and DPP-4 inhibitors. The agents are usually used in combination with other therapies for diabetes management. Sulfonylureas and meglitinides are associated with weight gain, while GLP-1 agonists may provide the added benefit of weight loss. Other side effects vary between the drug classes. None of the medications should be used in the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Insulinotropic Diabetes Drugs
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  • Lowers bloodsugarlevel in Type2 DM and normal subjects • Considered in ptn- not over weight and metformin contraindicated • Different SU has variable PK property Sulfonylureas
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  -Provoke brisk releaseof 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 actionof 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 Mechanism of Action
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  • AllSU wellabsorbed 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 Pharmacokinetics
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  Drugs enhance SUaction: •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 decreaseSU action: • Induce metabolism: phenobarbitone, phenytoin, rifampicin, chronic alcoholism • Opposite actions/ suppress insulin release: corticosteroids, thiazides, furosemide, OCP Interactions 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 Adverse effects
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  Chlorpropamide • 1st SUDiscontinued dueto long duration of action and hypoglycaemia • Also causes dilutional hyponatraemia, cholestatic jaundice Individual SU Glibenclamide • T1/2:2-4 hours • D uration 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 Gliclazid • T ½: 8-20 hours • Duration of action: 12-24 hours • Inactive metabolites • Has antiplatelet action • Dose — Initially 40-80 mg/day —Adjust according to dose upto 160mg as single dose —max 320mg/day
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  Glimepiride • T ½:5-7 hours • Duration of action: 24 hours • Long acting • Inactive metabolites • Extrapancreatic action • Lower incidence of hypoglycaemia • Dosage — 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 • Dosage —initially 2.5-5mg short before breakfast/ lunch —adjust with response —max 20mg/day —upto 15mg as single dose Tolbutamide • T1/2- 6 hours • Durationof action : 6-8 hours • Dosage—0.5-1.5g daily in divided dose with/ immediately after meals / as single dose with/ immediately after breakfast —max 2g —safer in elderly
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  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 Caution • Caution inelderly 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: • Shouldbe 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) 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
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  • Phenformin andmetformin introduced in 1950s • Phenformin had high risk of lactic acidosis and withdrawn Biguanide
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  • Little orno hypoglycaemic effect in non diabetics • Hypoglycaemia in diabetics is very rare • Does not stimulate pancreatic beta cells • Improve lipid profile in diabetics Mechanism of Action : • Does notcause insulin release • Presence of insulin essential for action • Actions are mediated through activation of AMP-dependant protein kinase Key features in MOA 1. Mainly suppress gluconeogenesis and glucose output from liver 2. Enhances insulin mediated glucose uptake and disposal in skeletal muscle and fat insulin resistance is overcome - glycogen storage in skeletal muscle - reduced lipogenesis in adipose tissue and enhanced fatty acid oxidation 3. Interferes mitochondrial respiratory chain and promotes peripheral glucose utilization by anaerobic glycolysis .Metformin retards intestinal absorption of glucose, amino acids and Vit B12 Metformin
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  Pharmacokinetics • T ½-1.5 to 3 hours • Duration of action 6-8 hours • Cleared by kidneys • Clearance of metformin approximates GFR • Accumulates in renal failure and increases the risk of lactic acidosis Uses • First choicedrug in all T2 DM except not tolerated/ contraindicated Advantages: • Nonhypoglycaemic • Weight loss promoting • Prevent micro and macro vascular DM complications • No acceleration/ failure of beta cells in T2 DM • Equivalent anti hyperglycaemic efficacy to other drugs • Can be combined with other hypoglycaemic drug • * Improve ovulation and fertility in PCOS Dose DM: Initially 500 mg at morning - After 1 wk then 500mg bd after 1 wk - Then 500mg tds - Usual max dose 2g but upto 3g used Modified release: Initially 500mg once daily - Increased every 10-15 days - Max 2g once daily with evening meal - If no control achieved 1g twice daily
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  Adverse effects • Noseriousside effects • Abdominal pain • Anorexia • Bloating • Nausea • Metallic taste • Mild diarrhea • Tiredness • Does not cause hypoglycaemia except very high doses • Lactic acidosis- rare, alcohol ingestion can precipitate • Vit B12 def rarely Contraindications • Hypotension • Heartfailure • Severe hepatic, respiratory and renal disease • Alcoholics • Ketoacidosis • Use of GA Interactions • Cimetidine andfurosemide compete with metformin excretion and enhance its toxicity
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  Thank you