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Biguanide
This document discusses biguanides and thiazolidinediones as oral hypoglycemic drugs. It describes metformin as the main biguanide currently used, noting its mechanism of action involves suppressing glucose production in the liver and enhancing glucose disposal in muscles. Pioglitazone is the only available thiazolidinedione, which works by enhancing insulin sensitivity. Potential side effects and appropriate uses are provided for both classes. Acarbose is also summarized as an alpha-glucosidase inhibitor that reduces glucose absorption from the gut. Clinical uses of glucagon for treating hypoglycemia are briefly mentioned.
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Biguanide
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- 2. Objectives • List examples,mechanism of action, adverse effects and clinical uses of biguanides • List examples, mechanism of action, adverse effects and clinical uses of thiazolidinediones • Describe the uses and effects of acarbose as an oral hypoglycemic • List clinical uses of glucagon
- 3. Biguanide • Phenformin andmetformin introduced in 1950s • Phenformin had high risk of lactic acidosis and withdrawn
- 4. Metformin • Little orno hypoglycaemic effect in non diabetics • Hypoglycaemia in diabetics is very rare • Does not stimulate pancreatic beta cells • Improve lipid profile in diabetics
- 5. MOA • Does notcause insulin release • Presence of insulin essential for action • Actions are mediated through activation of AMP-dependant protein kinase
- 6. Key features inMOA 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
- 7. PK • 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
- 8. Adverse effects • Noserious side 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
- 9. Contraindications • Hypotension • Heartfailure • Severe hepatic, respiratory and renal disease • Alcoholics • Ketoacidosis • Use of GA
- 10. Interactions • Cimetidine andfurosemide compete with metformin excretion and enhance its toxicity
- 11. 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
- 12. Dose DM: Initially 500 mgat 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
- 13. Pioglitazone • Only onethiazolidinedione available • Rosiglitazone withdrawn due to increased risk of MI,CHF, stroke and death
- 14. MOA • Selective agonistfor nuclear peroxisome proliferator- activated receptor gamma • Mainly expressed in fat cells, also in muscle and other cells • Enhances transcription of several insulin responsive genes • Tend to reverse insulin resistance by enhancing GLUT4 expression and translocation • Glucose entry into muscle and fat improved hepatic gluconeogenesis suppressed • Activation of genes regulating fatty acid metabolism and lipogenesis in adipose tissue contributes to insulin sensitizing action • Reduction in lipolysis and plasma fatty acid level • Increased turnover and differentiation of adipose tissue
- 15. • Degree ofblood sugar reduction is less than SU and metformin • Lowers TG, raises HDL, no significant change in LDL • Due to induced expression of reverse cholesterol transporter and some apoproteins
- 16. PK • Well tolerated •T ½ : 3-5 hours • Duration of action – 24 hours • Metabolized in liver • Interact with OCP and contraceptive failure occurs • Keatconazole inhibits and rifampicin induces metabolism
- 17. AR • Plasma volumeexpansion • Edema • Weight gain • Headache • Myalgia • Mild anaemia • Monotherapy not associated with hypoglycaemia • Rarely hepatic dysfunction • CHF worsened or precipitated • Increases the risk of fracture in elderly CI- liver disease, CHF
- 18. Indications • Type 2DM - Reduce blood glucose and HbA1C - Do not increase insulin - Do not work in low insulin base line - Stooped if <0.5% reduction in HbA1C in 6 months • Supplement SU/Metformin and in case of insulin resistance • Monotherapy in mild cases • When used with insulin- greater fluid retention, weight gain, precipitation of CHF • Should not be used during pregnancy
- 19. Dose : 15- 30mg initially once daily Increased upto 45mg
- 20. Alpha glucosidase inhibitors Acarbose •Complexoligosaccharide •Reversibly inhibits alpha glucosidase ( final enzyme for digestion in the brush border of small intestine mucosa) MOA -Slows down and decreases digestion and absorption of polysaccharides and sucrose - Increases GLP-1 release -Postprandial glycaemia is reduced -Regular use lowers HbA1C modestly , change in body weight and lipid level minimal -In diabetics reduces CVS events
- 21. Uses : •Mild antihyperglycaemicand a hypoglycaemic •Used as adjuvant with diet/ SU/ metformin in obese PK: Only a small fraction of the dose absorbed AR: Flatulence, abdominal discomfort, loose stools Patient’s acceptability is poor due to GIT side effects ++ other alpha glucosidase inhibitors: Ex: Miglitol, Voglibose
- 22. Contra indications- IBD, predispositionto partial intestinal obstruction, hernia and previous abdominal surgery Dose: Initially 50mg daily Then 50mg tds After 6-8 weeks 100mg tds Max 200 mg tds
- 23. Advice: Chew with mouthfulof food or swallow whole with little fluid immediately before food
- 24. Miscellaneous drugs Amylin analogue: -Islet amyloid polypeptide, produced in beta cells -Acts in brain to reduce glucagon secretion, delay gastric emptying, retard glucose absorption, promote satiety Ex: pramlintide- synthetic, S.C injection before meal, used in Type 1 and 2 DM Bromocriptine: Quick release oral formulation used Adjunctive in T2 DM treatment Act on hypothalamic dopaminergic control of circardian rhythm of hormones (GH, Prolactin, ACTH) Used alone/ with metformin or SU or both
- 25. Oral hypoglycaemics mainlypreferred in • Age above 40 at disease onset • Obesity at the time of presentation • Duration of disease < 5 years when starting treatment • FBS < 200mg/dl • Insulin requirement < 40 U/day • No ketoacidosis or history of it
- 26. Glucagon • Single chainpolypeptide • Secreted by alpha cells • Secretion regulated by glucose levels, other nutrients, paracrine hormones, nervous system • GLP-1, FFA, ketone bodies inhibit glucagon release • Enhance glycogenolysis and gluconeogenesis in liver • Increases the force and rate of cardiac contraction
- 27. Uses: 1.Hypoglycaemia – duringemergency, not useful when hepatic glycogen is depleted Dose 0.5-1mg IV or IM 2.Cardiogenic shock- not very marked action 3.To facilitate radiographic examination of upper/lower GIT tract by relaxing stomach and intestines Other hyperglycaemics: Diazoxide, Somatostatin, Streptozocin
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