Oral hypoglycaemic agents 2020

Lecture presentation for BDS 2nd year

1. Oral Hypoglycaemic Agents Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajgunj Medical Campus 6 July 2020 (22 Asar 2077), Monday

2. Classification Enhance Insulin Secretion Sulfonylureas (K+ATP channels blockers) First Generation: Chlorpropamide, Tolbutamide Second Generation: Glibenclamde (Glyburide), Glipizide , Gliclazide , Glimepiride Meglitinide/phenylalanine analouges : Repaglinide, Nateglinide Glucagon-like peptide (GLP-1) receptor agaonists (injectable): Exenadite , Liraglutide Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, Vildagliptin, Saxagliptin , Alogliptin , Linagliptin

3. Classification Overcome Insulin Resistance Biguanides (AMPK activators): Metformin Thiazolidinediones (PPAR γ activator): Pioglitazone Miscellaneous α-Glucosidase inhibitors Acarbose, Miglitol, Voglibose Amylin analogue Pramlintide Dopamine D2 receptor agonist Bromocriptine Sodium Glucose Co-Transport 2 (SGLT 2) inhibitor Dapagliflozine

4. Mechanism of Action: In a nutshell

5. Sulfonylureas Mechanism of action: Blocks the K + ATP channel and reduced influx of K+ ion Partial depolarization of pancreatic beta-cells  Increased influx of Ca ++ ions as well as release of Ca ++ from intracellular stores  Exocytotic release of insulin Minor action: Reduces glucagon secretion Reduced hepatic degradation of insulin Extra-pancreatic action: Sensitizes the peripheral tissues to the action of insulin Seen on prolonged use

6. Sulfonylureas Adverse Effects: Hypoglycaemia Non specific Side effects (mild and infrequent): Weight gain, nausea, vomiting, flatulence, diarrhoea, paraesthesia Hypersensitivity SU + alcohol: Flushing, disulfiram-like reaction Should not be used in pregnancy and lactating mothers

7. Repaglinide and Nateglinide : K+ATP channel blockers Quick and short lasting action Quick absorption and rapid metabolism Administered before each major meal Normalises meal time glucose levels Lower incidence of hypoglycaemia S/E: Mild headache, dyspepsia, arthralgia, weight gain Indication: Type 2 DM with pronounced postprandial hyperglycaemia Along with Metformin/long acting insulin Avoid in liver disease Meglitinide /Phenylalanine analogues ( Repaglinide , Nateglinide )

8. Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin : Competitive and selective DPP-4 inhibitor Potentiates the action of GLP-1 and GIP Body weight neutral, low risk of hypoglycaemia Well absorbed orally, little metabolised, largely excreted unchanged in urine Dose reduction needed in renal dysfunction S/E: nausea, loose stools, headaches, rashes, allergic reactions, edema

9. Biguanides (Metformin, Phenformin ) Mechanism of Action: Activation of AMPK, leading to: Suppression of hepatic gluconeogenesis Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization Retards glucose absorption of glucose, hexose, amino acids, Vit B 12

10. Biguanides (Metformin, Phenformin ) Advantages: Non-hypoglycaemic Weight loss Prevents long term complications Prolongs beta cell life

11. Biguanides (Metformin, Phenformin ) Adverse Effects: Limiting feature: gastro-intestinal intolerance Hypoglycaemia in overdose Lactic acidosis Vitamin B 12 deficiency Contraindications: Hypotensive states Heart failure Severe respiratory, hepatic and renal disease Alcoholics

12. Thiazolidinediones (PPAR γ activator): Pioglitazone Multiple actions: Enhances transcription of insulin responsive genes Reverses insulin resistance Suppresses hepatic gluconeogenesis Additional actions: lowers serum triglyceride, raises HDL Well tolerated S/E: plasma volume expansion, edema, weight gain, headache, myalgia, mild anaemia, increased risk of fracture esp. in elderly women Contraindicated in liver disease and in CHF

13. Miscellaneous OHA Acarbose : Inhibits α -glucosidases enzyme  slow down and decrease digestion and absorption of polysaccharides and sucrose. Additionally promotes GLP-1 release S/E: Flatulence, abdominal discomfort, loose stool; Poor patient acceptability Pramlintide : Synthetic amylin analogue Attenuates postprandial glycaemia and exerts centrally mediated anorectic action Reduction in body weight ++

14. Miscellaneous OHA Bromocriptine: Dopamine D2 agonist; Acts on hypothalamic dopaminergic control of the circadian rhythm of hormone (GH, prolactin, ACTH) release and reset it to reduce insulin resistance. Dapagliflozin: SGLT-2 inhibitor  glycosuria Prone to cause urinary tract infection

15. Glucagon An Hyperglycaemic agent Polypeptide chain, released as prohormone from alpha cells of pancreas Acts by: Binds to glucagon receptor  stimulates cells Liver: increased glycogenolysis, gluconeogenesis Muscle, fat cells: decreased glucose utilization Heart: increased force and rate of contraction Uses: Hypoglycaemia, Cardiogenic shock

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