Oral hypoglycemic agents

diabetes management... oral hypoglycemic agents

1. Oral Hypoglycemic Agents dr. Siham G. Altayib MSc . Community Pharmacy Queen’s University Belfast

2. Achieve adequate glycaemic control. Avoid short term complications:- hypoglcaemia hyper glycaemia DKA Prevent long term complications Improve quality of life Goals of diabetes management

3. The means of controlling blood glucose is 1\ Life style modifications :- 1- diet 2- exercise 3- weight loss 2\ Drugs Con.

4. The medication available to treat type 2 diabetes can be grouped according to their chemical class and function : Medications that improve insulin action : 1- biguanides 2- thiazolidenedones Medications that slow glucose absorption: Alpha – glucosidase inhibitors Options of the therapy

5. Medication that increase insulin secretion : 1- sulphonylureas 2- meglitinide 3- D- phenaylalanine drevatives Medication that restore or duplicate incretion action on insulin secretion and glucagon suppression : 1- GLP-1 agonist 2- DPP-4 inhibitors con

6. Medication that provides additional insulin exogenous pharmacological insulin It is important to note that insulin is included in this list not because oral medication faild to work or when patient is not adherent BUT insulin is typically used when 1- there is deceased endogenous insulin secretion OR 2- to decrease glucose toxicity con

7. There are many clinical markers that can reflect the predominance of the various pathophysiologic component that contributes to type2 diabetes SO this can guide the selection of the treatment by the doctor . These include : 1- body habits : Apple-shaped body suggest insulin resistance Overweight also suggest insulin resistance Medication selection for treatment of type2 diabetes

8. 2- Age : Aging promotes insulin resistance ( therefore the older the person the more likely he/she is to have insulin resistabce 3- weight change : Recent loss of weight , particularly concurrent wirth poor diabetes control suggest insulin deficiency BMI more than 27 suggest insulin resistance con

9. 4 - duration of diabetes: The longer the patient has had diabetes , the more like hood that there is insulin deficiency 5- gender: Women with type 2 diabetes lose the protection against macrovascular disease , so attention to macrovascular risk factors is important Con.

10. 6- co-existing disease: Presence of other component of the insulin resistant syndrome suggest the presence of insulin resistance ( dyslipediemia , hypertension or gout) 7- side effect profile: Development of side effect from use of medication might preclude its use e.g. metfornmin Con.

11. 1-duration of diabetes 2- age of the patient 3- Patient's Life style consideration 4- Degree of glycemic control( severity of postprandial hyperglycemia) 5- other illnesses 6- Access to drug The choice of oral therapy should be based on :

12. 7- Economic status of the person with diabetes 8- Mutual agreement between the patient & doctor ( willingness and ability to use the drug or inject insulin The choice of oral therapy should be based on :

13. The ideal OHGA is that which ; 1- conserve islets cell function . i.e . Delay the subsequent use of insulin 2- improve patient’s compliance ( single daily dosing ) 3- reduce the incidence of oral hypoglycemic events What is the ideal oral hypoglycemic agent?

14. 1- oral agents are never indicated for typ1 diabetes 2- type 2 patients with acute illness 3- surgery 4- state of gastrointestinal disorders ( nausea , vomiting or diarrhea ) Contraindications f OHGAs.

15. Monotherapy should be the initial choice The step care approach is recommended because of the progressive nature of diabetes Important points

16. 1- combination of OHGAs with different mechanisms can be indicated if MONOTHERAPY failed to control BG. NEVER use 2 drugs from the same class 2- when oral therapy failed to achieve glycemic control ISULIN should be added to the regimen OR alternatively replace treatment with OHGAs. Important points con. :

17. 1 ] sulphonylureas : Mechanism of action : Stimulates basal as well as glucose - mediated insulin secretion. Thus resulting in continuous stimulation of the beta cells to release insulin With progressive betacell failure sulphonyluras fails to control BG So additional OHGA is added or insulin may be required for glycemic contol 1\ drugs that stimulates insulin relase from pancreas ( secretogogus ):

18. 1 ] pancreatic effect : Increase insulin release from the pancreas by : stimulating the release of insulin from functioning beta cell by blocking ATP –sensitive K chanells resulting in depolarization and calcium influx which causes microtubular contraction and release of insulin b) Suppress the secretion of glucagon from alpha cells Con. Mechanism of action SU.

19. 2] Extra pancreatic effect: Potentiating of insulin action in target tissues : 1- increase the number of insulin receptors 2- increase post receptor insulin sensetivity 3- increase glycolysis 4- increase glycogenesis ( glycogen storage in liver and muscles ) 5- decrease the gluconeogensis ( glucose out put from the liver Con. Mechanism of action SU.

20. Measurement of C-peptide level gives indication of residual ß-cell function Early use of combination has been shown to reduce glucose toxicity & preserve ß-cell mass Pharmakokinetics : 1- SU. Are well absorbed orally . 2- peak plasma concentration within 2-4 hours 3- they circulate by binding to plasma protein and can be potentially interact with other drugs such as sailcylates and sulphonamides which binds to albumin Con. sulphonylureas

21. 4- elimination is through kidneys .so the half life can be significantly prolonged in the elderly and those with renal diseases 5- SU. Cross placenta & can stimulate foetal beta cell to secret insulin Clinical use of SU: SU . Is indicated for type2 D. when diet alone is insufficient to achieve glycemic control. Treatment should be commenced at low doses and titrated every 4-7 days as needed Con. sulphonylureas

22. SU. Can be used alone or in combination with other OHGA or insulin . Early use of combination has been shown to reduce glucose toxicity & preserve ß-cell mass A higher effect is observed with high fasting BG. And with high A1c levels There are 2 generations of SU. The second generation agents are more potent , have more rapid onset of action & longer duration of action Con. sulphonylureas

23. Drugs that incrase sulphonyl urease action : 1] by displacing from the protein binding : Phenylbutazone , sulphonamides ( trimethoprime ) 2} inhibit metabolism\ excretion : Cimetidin (H2 blockers) , warfarin , chlorampheincol 3 ] synergize or prolong plasma pharmacodynemic action : Salicylate ( aspirin) , probranolol , theophelline Sulphonylureas drug interactions

24. Drugs which reduce sulphonylureas action : 1] drugs which induce SU metabolism : Phenobarbitones , chronic alcohiolism 2] drugs that oppose \ suppress action ( insulin release ): Corticosteroids, thiazide diuretics , furosemide . Oral contraceptives Sulphonylureas drug interactions

25. 1] hypoglycemia : The most serious complication ( often result from law coloric intake ) Risk of HG increase in :- elderly &Those with hepatic or renal impairemnt so long acting SU. Should be avoided in this group of patients The highest incidence occures with chlorobromide & glibencalmide ( donil ) Sulphonylureas \ adverse effects

26. 2] stimulate appitaite & weight gain 3] gasteric upset ( nausea , flatulance , diarrhoea or constipation ) 4] allergic skin reaction 5] headache 6] rarely bone marrow damage Sulphonylureas \ adverse effects

27. Pregnancy Hepatic or renal insufficienty Major surgary Severe infection Sesetivity to sulpha Sulphonylureas \ contraindication

28. First generation : 1- Chloropromide 2- tolbutamide Second generation : 1- Gliclazide 2- glibenclamide ( donil ) 3- glipizide Third genteration : Glimepride Con. sulphonylureas

29. 1] Glibinclamide ( donil ) 2] Glimipride ( amary ) 3] Gliclazide ( dimicrone ) Sulphonylureas \ commonly used

30. 2] Non- sulphonylureas insulin secretogogues : [ Meglinitides ] Meglinitides stimulating the release of insulin from bancreas by binding to the SUR at a site different from the sulphonylurea –binding site . They inhibit ATP dependant potassium channels in the beta cell membrane which depolarize the cell leading to opening of calcium channels and insulin secretion . In contrast to SU this release of insulin is glucose dependant , it diminishes at low glucose concentration 1\ drugs that stimulates insulin relase from pancreas ( secretogogus ):

31. These agents stimulate first phase insulin release in glucose dependent manner {reducing the risk of hypoglycemia} Drugs in this group are : 1- repaglinide 2- Nateglinide Pharmakokinetics : Fast acting Short duration of action (2-6 hours) doses 2-4 dose per day

32. Designed to minimize meal time blood glucose peaks .( taken before the main meal) , as they help control prandial glucose) so these agents is suitable options for those who need flexible meal timing and in the elderly Patients are advised to skip dose if meal is missed Metabolize in liver ( to inactive product ) and excreted in bile Con .

33. Con. Repaglinide : Form available in sudan is NovoNorm Strength 0.5-4.0 mg tablets \ staring dose 0.5-2 mg Given just before each major meal 15 kin. Rapid & short duration of action Improve postprandial glycemia Less likely to develop repeated hunger , frequent eating and weight gain [unlike sulphonylureas ]

34. Side effects: 1- hypoglycemia { rare} 2- nausea and vomiting 3- arthralgia ( joint pain) Con.

35. Very rapid onset of action Shorter duration of action 1-10 minutes before meal Lower incidence of hypoglycemia than repaglinide Nateglinide

36. These are drugs that improve the sensitivity to insulin in muscle , liver & fat tissues Medication in this group share the following characteristics : 1- they require the presence of endogenous or exogenous insulin to have their effects 2- the patient must have insulin resistance 3- hence they reduce insulin resistance rather than insulin quantity so they have good effects in higher glucose levels ..and not likely to cause significant hypoglycemia as treatments that increase insulin levels 2\ insulin sensitizers :

37. 1- biguanides 2- thiazolidenediones 1] Biguanides : These are class of antidiabetic drugs originate from the french lilac (flower) The only one used now and is effective is metformin Con.

38. Metformin : Use alone or in combination with other drugs Recommended as first-line drug in patient with type2 diabetes ( guidelines) Approved for prevention of type 2 diabetes in high risk individuals Used for polycystic ovary syndrome : insulin resistance with ovarian hyperandrogenism Con.

39. Mechanism of action : 1- decrease the intestinal absorption of CHO 2- decrease hepatic glucose production 3- increase insulin-mediated peripheral glucose uptake 4- increase glucose utilization (glycogen synthesis 5- increase glycolysis through anaerobic pathway ( lactic acidosis) Con. Metformin

40. 6- dcrease fasting plasma glucose conc. By about 60-7-mg\dl 7- lower blood glucose but not cause hypoglycemia NB : metformin is appropriate for obese patient with type2 diabetes Con. Mechanism of action :

41. pharmakokinetics : 1- well absorbed from small intestine 2- stable 3- doesnot bind to plasma protein 4- excreted unchanged in urine 5- can be taken in 3 doses with meal 6- maximum recommended daily dose is 3g\day ( currently we don’t give more than 2g\day in divided doses with meal ) Con. Metformin

42. Secondery beneficial effects : on libids : 1\ small reduction in total cholestrol level 2- small reduction in triglycerides 3- reduction in LDL 4- increase in HDL Con. Metformin

43. Side effects : Occurs in 20-25% of patients Gastrointestinal side effects: 1- abdominal discomfort , bloating , nausea , metallic taste 2- weight loss and diarrhea observed in 10-15% of patient , depending on dose 3- decrease absorption of vit,B 12 Con. Metformin

44. adverse effects : 1- hypoglycemia : occurs only when combined with other drugs 2- rarely : severe lactic acidosis particularly in patients with CHF Drug interaction: Cimetidine , nifedipine , frusemide Con. Metformin

45. Contraindications: 1- should be avoided in patients who predisposed to lactic acidosis ( renal & hepatic disease , heart failure ..) impaired renal function serum cr. >1.4mg\dl for woman or 1.5 mg\l male 2- past history of lactic acidosis 3- chronic lung disease These conditions predespose to increase lactate production which cause hepatic lactic acidosis which is fetal. 4- all other situatios where OHGAs is contraindicated Con. Metformin

46. Contraindications: 5- type1 diabetes 6- surgary 7- myocardial infraction 8- elderly 9- pregnancy Con. Metformin

47. Metformin in market

48. Metformin in market \combination

49. Also known as : 1- PPRAs ( peroxisome prolifelator activated receptors ) 2- glitazones ( TZDs.) Untilrecently there were 3 TZDs : 1- pioglitazone ( Actos ) 2- posiglitazone ( Avandia ) 3- troglitazone ( rezulin ) 2] Thiazlidenediones

50. Mechanism of action : Antihyperglycemic : 1- increase insulin sensetivity in liver and muscle 2- do not increase insulin secretion 3- reduce hepatic glucose output 4-improve lipid profile 5- may induce weight gain Con. Thiazlidenediones

51. Rosiglitazone : Bioavailability of oral dose 99%Extenseivelly 98.5% bound to plasma protein Metabolites have no significant activity Plasma half life is 3-4 hours Excreted in urine and stool Use as single or divided to two doses per day Con. Thiazlidenediones

52. Pioglitazone : Execreted primarily in the stool Half life 3-7 h Extensively 99% bound to plasma proteins Can be given in single dose No evidence of drug induced hepato toxicity Con. Thiazlidenediones

53. Side effects : 1- weight gain because of insulin like effects 2- fluid retention ( lower limb oedema ) 3- liver enzyme elivation ( the firstTZDs troglitazone was withdrawn from market because of hepatotoxicity ) 4- most common sside effects : Headache , CHF , fatigue , slight decrease in heamoglobin , hepatic cellular injury ( rare ) Con. Thiazlidenediones

54. Contraindications 1- cardiac failure 2- impaired hepatic function 3- pregnancy and lactation Drug interaction : Not recommended to be used with oral contraceptives ) Con. Thiazlidenediones

55. Alpha glucosidase inhibitors AGIs) : Acts in the proximal small intestine They reduce the rate of digestion of polysaccarides . They reduce intestinal absorption of starch , dextrin , and disaccharides by inhibiting action of alpha glucosidase enzyme , thereby primarily lowering postprandial glucose levels . AGIs , donot prevent absorption of complex carbohydrates but delay it 3] drugs that delay glucose absoption

56. There are 2 drugs : 1- acarbose 2- miglitol Side effects : Gastric upset ( flatulanse , loose stool or diarrhae , abdominal pain tolerability can be improved by slowly titrating the dose over several days Drug interaction: Decrease metformin bioavailability when used concomitantly Con. Alpha glucosidase inhibitors AGIs) :

57. Con. Alpha glucosidase inhibitors AGIs) :

58. Are naturally occurring hormones secreted by the intestine in response to meal when BG is elevated Increased incretin levels signals : 1- incrase insulin secretion 2- stop hepatic glucose production The levels of incretins increases significantly when food is ingested 4] incretins & DPP-4 inhibitors

59. Endogenous hormones are : 1- GLP-1 ( glucagon like peptide 1) 2-,GIP ( glucose dependant insulinotropic peptide ) 1\ GIP : 42 amino acid peptide Secreted from dudenum & proximal jejenum ) 2] GLP_1: 30 amino acid peptide Secreted from the distal GI tract ( ielum & colon) Con. Incretins & DPP-4 inhibitors

60. Action : Increase insulin production from beta cells Decreas glucagon secretion ) The physiological activity of incretin is limited by the enzyme dipeptidyle peptidase-4 (DPP-4) .which rapidly degrades active incretin after its release Consequently both GLP-1 & GIP are rapidly inactivated by the enzyme dipeptidyle peptidase-4 (DPP-4) Con. Incretins & DPP-4 inhibitors

61. DPP-4 inhibitors

62. Mechanism of Action : Slow the inactivation of incretin hormones ( GLP-1 & GIP) Increased glucose stimulated insulin secretion Cause glucose stimulated glucagon suppression Primarily reduce postprandial glucose levels but also has been shown to reduce fasting BG levels DPP-4 inhibitors

63. SGLT-2 inhibitors

64. Inhibit the reabsorption of glucose by kidneys so glucose levels in urine will be increased { this is an insulin independent mechanism to lower blood glucose levels Advantages : Improve glycemic control Weight lloss Carry low risk of hypoglycemia SGLT-2 inhibitors

65. Examples : Dapagliflozin Canagliflozin SGLT-2 inhibitors

66. Life style :

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