1. Pharmacology of Diabetes Mellitus 2 Dr Emma Baker Consultant Physician/Senior Lecturer in Clinical Pharmacology

2. Patient 1 - 21 year old woman Drowsy and vomiting Appears breathless On examination Pulse 120 reg, BP 80/50mmHg, RR 24/min Chest clear Urinalysis Glucose +++, ketones +++ What is the most likely diagnosis? How do you explain her clinical signs?

3. Investigations Biochemistry Na 141mmol/l (135-145) K 6.0mmol/l (3.5 - 4.5) Urea 11mmol/l (2.5 - 6.5) Creatinine 120  mol/l (60-110) Bicarbonate 5mmol/l (22-28) Arterial gases pH 7.14 (7.35 - 7.45) pO 2 12 (10 - 13.1) pCO 2 2.5 (4.1 - 6.0) Do these results confirm the diagnosis? How should she be treated?

4. Treatment of diabetic ketoacidosis Insulin Route of administration? Duration of action? Metabolism and elimination? Effects on biochemistry?

5. Effects of Insulin Biochemistry Na 141mmol/l (135-145) K 6.0mmol/l (3.5 - 4.5) Urea 11mmol/l (2.5 - 6.5) Creatinine 120  mol/l (60-110) Bicarbonate 5mmol/l (22-28) Arterial gases pH 7.14 (7.35 - 7.45) pO 2 12 (10 - 13.1) pCO 2 2.5 (4.1 - 6.0) What else does he need?

6. Treatment of diabetic ketoacidosis Insulin Fluid Potassium (high in plasma, low total body) Subcutaneous heparin Careful monitoring - consider ITU

7. Patient 1 - 2 days later Considerable improvement Eating and drinking normally Biochemical abnormalities corrected Still on IV sliding scale insulin for newly diagnosed diabetes Questions What are her insulin needs going to be? What treatment regime would you suggest and why?

8. Insulin needs Normal daily pancreatic output 30-40U/day Diabetics usually need 30-50U/day (best to start lower and build up) Need continuous background level of insulin with larger amounts at the time of meals and snacks

9. Physiological Insulin Levels BreakfastLunchDinner Insulin Levels

10. Insulin regimes Soluble insulin at the time of meals Intermediate or long acting insulin to provide background cover Minimise number of injections Questions How do soluble, intermediate and long acting insulin differ?

11. Twice daily injections e.g. Humulin M3 BreakfastLunchDinner Insulin Levels

12. 3-4 daily injections - more physiological profile BreakfastLunchDinner Insulin Levels

13. Flexible insulin Insulin Lispro Change in 2 amino acids from physiological insulin Molecules dissociate and are absorbed from injection sites more quickly can be given immediately before eating rather than 30 minutes before food Injection devices Insulin pen devices

14. Patient 2 - 45 year old man Newly diagnosed diabetes mellitus 3 months on diabetic diet Fasting plasma glucose 9 mmol/l, HBA 1C 9.4% Weight 97Kg, BMI 30Kg/m 2 Questions Are you happy with his diabetic control? If necessary, which drug would you choose to lower blood sugar in this man? What else do you want to ask/ measure?

15. Diabetic control Normal HBA 1C 3.5 - 6.5% Targets

16. Choice of medication Increased body weight increases insulin resistance –Insulin is “anabolic” and will increase body weight –Diabetics on insulin or sulphonylureas (increase insulin secretion) will therefore put on weight –This could make diabetes worse Treatment of overweight diabetics –weight loss (  13.5Kg -  HBA1c 8.1% to 5.8%) –Drugs that reduce insulin resistance

17. Drugs that reduce insulin resistance Metformin (Biguanide) –oral –t 1/2 5 hours –given 3 times daily –Main side effect LACTIC ACIDOSIS Does NOT cause hypoglycaemia

18. Patient 2 - follow up On Metformin Fasting plasma glucose 7mmol/l, HBA 1C 8.4% Weight 96Kg (  1Kg) Questions Are you happy with his control? What other treatment options does he have?

19. Combination therapy for type 2 DM Sulphonylureas (gliclazide, glibenclamide, glimepiride) –oral hypoglycaemics, promote insulin secretion –variable half life and excretion –main side effect WEIGHT GAIN, HYPOGLYCAEMIA Glitazones (rosiglitazone) –oral hypoglycaemics, reduce insulin resistance –not used alone –eliminated by liver and kidney –main side effect WEIGHT GAIN, HYPOGLYCAEMIA –monitor liver function tests Acarbose

20. Drugs used to treat diabetes mellitus Gut Food Absorption Glucose Insulin Pancreas Insulin stored in  -islet cells Liver Reduced gluconeogenesis Glycogenesis Reduced lipolysis Receptor (tyrosine kinase) Complex internalised Muscle/fat cell Stimulates glucose uptake Adipose cell Insulin receptor Peroxisome proliferator- activated receptor Insulin Sulphonyl ureas Metformin Acarbose Glitazones

21. Patient 3 - 75 year old man Known type 2 diabetic on glibenclamide Ischaemic heart disease, on heart failure medication Unconscious Blood glucose stick testing unrecordable Biochemistry Urea 55mmol/l (2.5 - 6.5), Creatinine 810  mol/l (60-110) Questions –Why is he unconscious? –How would you treat this? –Why did this problem occur?

22. Diagnosis Glibenclamide is a sulphonylurea This drug increases insulin secretion from the pancreas It is eliminated via the kidney, hence can accumulate in the elderly or in renal failure Accumulation of glibenclamide causes hypoglycaemia Renal impairment may be caused by poor renal perfusion, heart failure medication in this patient

23. Patient 4 - 48 year old woman Admitted unconscious, smelling of alcohol Pulse 60bpm, blood glucose unrecordable From partner Diabetes since age 17, insulin twice daily 4th admission with hypoglycaemia in past month Recent anxiety and depression Propranolol 40mg tds,  alcohol intake Questions Why have her hypoglycaemic attacks got more frequent and required admission recently

24. Drug interactions and diabetes Increase risk of hypoglycaemia –beta blockers, alcohol, sulphonamides, monoamine oxidase inhibitors Decrease awareness of hypoglycaemia –beta blockers Raise blood glucose –corticosteroids, oral contraceptive, thiazides, loop diuretics, diazoxide

25. Special prescribing in diabetes A carefully designed insulin (+ glucose, +K+) regime is usually used in diabetics who: –are acutely ill, have had myocardial infarction –are fasting e.g. for an operation –are pregnant Care should be taken with oral hypoglycaemics in diabetics who: –are elderly –have renal/hepatic impairment

26. Summary Diabetes mellitus is a complicated spectrum of conditions Each patient requires tailored therapy depending on: –pathology of diabetes –lifestyle –special circumstances/ill health

27. Summary 2 Drugs that lower blood sugar form only part of the treatment of diabetes Attention must be paid to many other aspects including: –lifestyle –diet/alcohol consumption –cardiovascular risk factors –foot care