Pharmacology of Diabetes Mellitus 2

Dr Emma Baker

Consultant Physician/Senior Lecturer in Clinical Pharmacology

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?

Investigations• Biochemistry

Na 141mmol/l (135-145)

K 6.0mmol/l (3.5 - 4.5)

Urea 11mmol/l (2.5 - 6.5)

Creatinine 120mol/l (60-110)

Bicarbonate 5mmol/l (22-28)

• Arterial gasespH 7.14 (7.35 - 7.45)

pO2 12 (10 - 13.1)

pCO2 2.5 (4.1 - 6.0)

Do these results confirm the diagnosis?

How should she be treated?

Treatment of diabetic ketoacidosis

Insulin• Route of administration?

• Duration of action?

• Metabolism and elimination?

• Effects on biochemistry?

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 120mol/l (60-110)

Bicarbonate 5mmol/l (22-28)

• Arterial gasespH 7.14 (7.35 - 7.45)

pO2 12 (10 - 13.1)

pCO2 2.5 (4.1 - 6.0)

What else does he need?

Treatment of diabetic ketoacidosis

• Insulin

• Fluid

• Potassium (high in plasma, low total body)

• Subcutaneous heparin

• Careful monitoring - consider ITU

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?

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

Physiological Insulin Levels

Breakfast Lunch Dinner

Insulin Levels

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?

Twice daily injections e.g. Humulin M3

Breakfast Lunch Dinner

Insulin Levels

3-4 daily injections - more physiological profile

Breakfast Lunch Dinner

Insulin Levels

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

Patient 2 - 45 year old man

• Newly diagnosed diabetes mellitus• 3 months on diabetic diet

• Fasting plasma glucose 9 mmol/l, HBA1C 9.4%

• Weight 97Kg, BMI 30Kg/m2

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?

Diabetic control

• Normal HBA1C 3.5 - 6.5%

• Targets

HBA1c Fasting plasmaglucose

Lowrisk

<6.5 <5.5

Macrovascularrisk

>6.5 >5.5

Microvascularrisk

>7.5 >6.0

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

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

Patient 2 - follow up

• On Metformin

• Fasting plasma glucose 7mmol/l, HBA1C 8.4%

• Weight 96Kg (1Kg)

Questions

• Are you happy with his control?

• What other treatment options does he have?

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

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

Sulphonylureas

Metformin

Acarbose

Glitazones

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 810mol/l (60-110)

Questions– Why is he unconscious?– How would you treat this?– Why did this problem occur?

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

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

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

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

Summary

• Diabetes mellitus is a complicated spectrum of conditions

• Each patient requires tailored therapy depending on:– pathology of diabetes– lifestyle– special circumstances/ill health

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