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Oral hypoglycaemic drugs

Oral hypoglycemic drugs (OHAs) are used to treat type 2 diabetes by lowering blood glucose levels without the need for insulin injections. They work by either enhancing insulin secretion from pancreatic beta cells or by overcoming insulin resistance. The main classes of OHAs include sulfonylureas, meglitinides, thiazolidinediones, biguanides, DPP-4 inhibitors, alpha-glucosidase inhibitors, and newer agents like GLP-1 receptor agonists. Sulfonylureas are the oldest class and work by closing ATP-sensitive potassium channels on beta cells to stimulate insulin release. However, they can cause hypoglycemia and lose effectiveness over time. Metformin is

Health & Medicine◦
Related topics:
type-2-diabetes-mellitus• Insulin Resistance•
Oral Hypoglycaemic Drugs (OHA) Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong - 793018
Introduction D rugs which lower blood glucose level and are effective orally U sed in the treatment of Type 2 (NIDDM) diabetes mellitus not controlled by diet and modification of lifestyle alone T ype 2 diabetes: Constitutional factors and genetic factors – Decreased insulin secretion and Insulin Resistance (pre & post) I nsulin resistance is suboptimal response of body tissue – liver skeletal muscle & fat to physiological amount of insulin T hey enhance the insulin secretion or overcome Insulin resistance
Classification A.E nhance Insulin secretion  Sulfonylureas (KATP Channel Blockers): Tolbutamide, Glibenclamide, Glipizide, Gliclazide, Glimepiride  Meglitinide/phenyalanine analogues: Repaglinide, Nateglinide  Glucagon-like peptide –1 receptor agonists: Exenatide, Liraglutide  Dipeptidyl peptidase – 4 (DPP-4) inhibitors: Sitagliptin, Vidagliptin , Saxagliptin , Linagliptin B . Overcome Insulin resistance  Biguanides (AMPK activator): Metformin  Thiazolinediones (PPARȣ activator): Pioglitazone C . Miscellaneous antidiabetic drugs:  α-Glucosidase inhibitors: Acarbose, Miglitol, Voglibose  SGLT-2 inhibitor – Dapagliflozin; Amylin analogue – Pramlintide; and Bromocriptine
Sulfonylureas (SUs) • All have similar pharmacological profile - lowers blood glucose in normal person and Type 2 diabetics • Only 2nd generation drugs are used now – except Tolbutamide • Mechanismof action: In the β cells - block the SU receptor (SUR 1) of pancreas (a subunit of inwardly rectifying ATP-sensitive K+ channel (KATP ) – Insulin released at any glucose concentration (even at low conc.) – severe and unpredictable hyperglycaemia risk – Mainly the 2nd phase of insulin release – Presence of β cells is must for their action (no action on pancreatectomized subjects) - action on Type 1 diabetics (?) – 1/3rd β cells required for action – Extrapancreatic action: Action wears off after a few months – down regulation of SUR1 receptors – but improvement in glucose tolerance maintained – Sensitize target tissues (liver) to insulin action – due to increase in insulin receptors – Also inhibits gluconeogenesis
Sulfonylureas - MOA Source: Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
Sulfonylureas (SUs) – contd. •Pharmacokinetics: Well absorbed orally, highly (90%) bound to plasma proteins – low Vd –Metabolized in liver to active / inactive – liver and kidney dysfunction •Drug Interactions: –Precipitate hypoglycemia: –Displace from protein binding: Salicylates, sulfonamides –Inhibits metabolism: acute alcohol intake, Ketoconzole, Warfarin, Sulfonamides, Chloramphenicol –Prolongs action (synergism): Salicylates, Propranolol –Decrease SU action: Phenobarbitone, Rifampicin, alcoholism •Adverse effects: –Hypoglycaemia: Commonest (elderly, liver and kidney diseases) –Nausea, vomiting, flatulence, diarrhoea – Weight gain –Hypersensitivity: Rash, photosensitivity, purpura, flushing and disulfiram-like reaction
Meglitinide/phenyalanine analogues •KATP Channel Blockers – Repaglinide and Nateglinide •Repaglinide: Binds to SUR – closing of channel – depolarization – Insulin release –Rapidly metabolized, fast onset and short lasting action –Administered just before meals - control of postprandial hyperglycaemia –Lower risk of serious hypoglycaemia –Uses: Type 2 DM with severe postprandial hyperglycaemia as supplementary to metformin; Avoided in Liver diseases •Nateglinide: D-phenylalanine derivative - ` stimulates 1st phase of insulin secretion – closure of β cell KATP Channel –Shorter lasting and faster onset – less risk of hypoglycaemia than Repaglinide –Less frequent hypoglycaemia – Used in Type 2 DM with others –ADRs: Nausea, Flu like symptoms and joint pain … weight gain
Glucagon-like peptide –1 receptor agonists – injection preparations •GLP– 1 is an Incretin – induces insulin release and inhibits glucagon release –slows gastric emptying, suppresses appetite via GLP – receptors (GPCR) – in α and β cells, GIT mucosa, central neurons –Incretins promote β cells health – its dysfunction in Type 2 DM –GLP-1 not used clinically – rapid degradation by Dipeptidyl peptidase – (DPP-4) enzyme – in luminal membrane of capillary endothelial cells, kidney, liver, gut mucosa ; Also glucose- dependent Insulinotropic peptide (GIP) - insulin release • Exenatide: Synthetic DDP-4 resistant analogue of GLP-1 – similar action with GLP-1 –Ineffective orally – given SC, half life 3 hours (6-10 hours duration) – used in Type 2 DM along with others (Metformin); ADRs: Nausea and vomiting –Benefits: Lowers body weight, postprandial and fasting glucose and HbA1c •Liraglutide: Similar to Exenatide - ineffective orally – given SC –longer duration of action ( >24 hours) – only once daily dosing; Benefit – weight loss
Dipeptidyl peptidase – 4 (DPP-4) inhibitors •S itagliptin, Vidagliptin, Saxagliptin •M OA: Prevents rapid degradation of GLP-1 by DPP-4 – orally effective adjunctive drugs – indirectly acting insulin secretagogue •S iptagliptin: Competitive and selective DPP-4 inhibitor •A ctions: Potentiates action of GLP-1 and increases insulin secretion and inhibits glucagon, improves β cell health, body weight neutral, well tolerated – No effects of gastric emptying and appetite and no hypoglycaemia – Lowers HbA1c (equivalent to metformin) – Uses: as adjunctive drug with others. Monotherapy only if not controlled by Metformin/SU/Pioglitazone – Kinetics: Orally absorbed, metabolized little, excreted unchanged in urine (renal impairment!) – half life – 12 hours – ADRs: Nausea, loose stool, headache rash – cough & nasopharyngitis (Substance P)
DPP-4 inhibitors – Vidagliptin •B inds to DPP-4 covalently – complex dissociates slowly •K inetics: Short plasma half-life 2 – 3 hours, but duration of action 12 – 24 hours; Metabolized in liver – only 20 – 25% unchanged form •D ose reduction in liver and kidney diseases •D rawback: Less selective DPP-4 than Sitagliptin and hepatotoxicity
Biguanides (AMPK activator): Metformin and Phenformin •M etformin: Different action (counters insulin resistance) - no hypoglycaemia in normal, even in diabetics less episodes– no β cell stimulation •M OA: AMP dependent protein kinase (AMPK) activation …. (1) Suppresses hepatic neoglucogenesis and glucose output from liver (2) Overcome insulin resistance in Type 2: enhance insulin-mediated glucose uptake and disposal in Muscles and Fats – more glycogen storage enhanced fatty acid oxidation (3) Promotes peripheral glucose utilization through anaerobic glycolysis – mitochondrial action (4) Retards absorption of glucose and others •K inetics: half-life 1 – 3 hours and 6- 8 hours duration of action •A DRs: Frequent but less severe – Abdominal pain, anorexia, nausea, metallic taste, tiredness – but no hypoglycaemia; Lactic acidosis and Vit B12 deficiency •U ses: First choice drug in all Type 2, if tolerated
Thiazolinediones (PPARȣ activator): Pioglitazone (?Rosiglitazone) •M OA: Selective agonist of nuclear pe ro xiso m e pro life rato r-activate d re ce pto r γ (PPAR γ) – mainly in fat cells and also muscles – enhances transcription of insulin responsive genes •A ctions: (1) Enhances GLUT4 expression and translocation (2) Suppression of hepatic neoglucogenesis (3) Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue – insulin sensitizing action (4) Reduction of lipolysis and plasma fatty acid level (5) accelerated adipocyte turn over and differentiation – Lesser spectrum than SU in blood glucose lowering – Additionally – lowers triglyceride level and raises HDL •K inetics: Metabolized in Liver – half-life 3-5 hours but duration of action 24 hours; failure of OCPs (Rifampicin and Ketoconazole ?) •A DRs: Plasma volume expansion, oedema, weight gain, headache, myalgia, and anaemia – no hypoglycaemia; hepatic dysfunction and fracture •U
α Glucosidase inhibitors - Acarbose, Miglitol, Voglibose •M OA: (1) inhibits α-glucosidase enzyme – brush border of small intestine - decreases absorption of poolysaccharides (starch etc.) and sucrose (2) Release GLP-1 •R educes postprandial glycaemia – no significant increase in insulin level •R educes HbA1c level - but no effect on weight and lipid levels •A DRs: Flatulence, abdominal discomfort, loose stool – unabsorbed carbohydrate, poor patient compliance •U
Summary of OHA Source: Essentials of Medical pharmacology by KD Tripathi – 7th Edition, JAYPEE, 2013
Current status of OHA •C ontroversy – Insulin/SU/Biguanides/Diet & Exercise •I nsulin and SU Vs Metformin •I ndications of OHA (along with diet and exercise) in Type 2 DM – (1) Age > 40 years at onset of disease (2) Obesity (3) Duration of disease < 5 years (4) FBS < 200 mg/dl (6) Insulin requirement < 40 U/day (6) No ketoacidosis or history •S tart with Metformin, diet and exercise – delay progression by restoring β cells, Obese – weight reduction, reduce risk of MI and Stroke •I f monotherapy not adequate - add SU as 2nd drug – good patient compliance, high efficacy; but – prolong use β cell apoptosis and failure, weight gain, hypoglycaema, receptor desensitization •P atient with post-prandial hyperglycaemia and post meal hypoglycaemia – Meglitinide/phenylalanine analogue •P ioglitazone – 3rd choice – added to Metformin or with Metformin + SU combination
To remember D IET CONTROL S ULFONYLUREAS M ETFORMIN P IOGLITAZONE
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