Drug Therapy of Diabetes Michael Veltman MBBS FANZCA
Drug Therapy of Diabetes Michael Veltman MBBS FANZCA FASE Director of Anaesthesia Joondalup Health Campus
Overview Definition and Incidence Definition, incidence, classification Physiology & Pathophysiology Medical Managment Pharmacology
Definition and Incidence
Diabetes Mellitus History Mellitus versus Insipidus Insulin treatments Definition Plasma glucose > 7 m. M, Fasting Plasma glucose > 11. 1 m. M, 2 hours post GTT
Incidence Common Disease in the western world 6% of the world’s adult population (285 million) Rising rapidly - was only 30 million people in 1985
Aetiology & Classification
Classification Type I (5%) Autoimmune Other (rare) - Pancreatitis, toxins Type II (90 -95%) Insulin Resistance Gestational
Aetiology -Type I Due to a loss of insulin secreting cells β Islet cell produce insulin Multifactorial Genetic (30 -50%) Autoimmune
Aetiology - Type II Due to insulin resistance. Compensatory hypersecretion Ultimately leading to islet cell failure
Physiology
Insulin Produced in β islet cells in pancreas
Insulin Hormone produced by pancreas. Regulates metabolism: Carbohydrate Fat Insulin is needed for uptake of glucose
Insulin Effects
Glucose Transport Location Affinity Capacity GLUT-1 RBC, Endothelium, Fetal cells 1 -2 Low * GLUT-2 Pancreatic β cells, liver, renal tubules 12 -20 High GLUT-3 Neurons, Placenta <1 Medium GLUT-4 Fat, Muscle 5 Varies GLUT-5 Fructose transport 1 -2
Cellular physiology Binds to the insulin receptor α subunit Also binds to IGF-I Causes activation of Tyrosine Kinase Phosphorylation of of cytoplasmic protiens
Insulin - Rapid Effects Rapid increases in transport of Glucose Amino Acids Potassium
Insulin - Intermediate Effects Increased protein synthesis Decreased protein degredation Glycolysis Inhibition of gluconeogenesis
Insulin - Delayed Effects Increased lipogenesis Mediated through increased production of enzymes
Pathophysiology
Diabetic Complications Acute Hyperglycaemia Polyuria. (+ loss of electrolytes) Impaired immune function Impaired injury response Myocytes Neurons Diabetic ketoacidosis
Hyperglycaemia is specifically known to be bad in certain clinical states Acute Myocardial Infarction Neurological Injury Critically unwell patients with sepsis
Diabetic Ketoacidosis Medical Emergency Acidosis is the key feature Excess production of Aceto-acetate, β Hydroxy butyrate. Fall in p. H Acidic Urine Loss of Na+ and some K+ in urine
Chronic Diabetes More a disease of fat metabolism Elevated free fatty acids Altered metabolism of Acetyl-Co. A Ketone formation (source of energy)
Diabetic Complications Chronic Accelerated Vascular Disease Peripherally Coronary Cerebral Retinopathy Neuropathy Nephropathy
Diabetes versus Hyperglycaemia The “diagnosis” of Type 2 diabetes is late Delayed diagnosis: 10 -12 years Undiagnosed illness is common This affects interpretation of many studies
Medical Management Diabetic Ketoacidosis Hypoglycaemia Hyperglycaemia Chronic management Fasting diabetics Other options
Diabetic Ketoacidosis
Critical Care Setting Aiming to prevent high (>8. 0 m. Mol) levels of glucose Intravenous insulin is the drug of choice Benefits: Critically unwell Myocardial injury Neurological injury (? )
Diabetic Ketoacidosis Aim to restore deficits in: Insulin Potassium and Sodium Water Life threatening condition 5% mortality
Critical Care Setting Insulin can be used to lower potassium Usually given with glucose Doesn’t shift potassium out of the body
Hypoglycaemia
Hypoglycaemia Medical emergency BSL < 4. 0 Treatment Glucose - Up to 50 ml of 50% Glucagon - 1 mg
Hyperglycaemia
Hyperglycaemia Aim to keep glucose < 8. 0 m. Mol most of the time. More aggressive control has uncertain benefit in most studies
DIGAMI Hyperglycaemia with AMI 620 patients follow up 3. 4 (1. 6 -5. 6) yrs. 11% reduction in mortality One life was saved for nine treated patients.
Hyperglycaemia in ICU mortality reduced 43% Hospital mortality reduced 34% Infection rate reduced 46% Antibiotic use reduced 35% at 10 days
Chronic management
Aim in the community Minimise the longer term impact of elevated glucose Day to day fluctuation is not that important Glycosylated Haemaglobin is very good measure Avoid hypoglycaemic events Reduce cardiovascular risk
Hb. A 1 c Haemoglobin has a 120 day lifespan Glycosylation happens spontaneously Glycosylation is proportional to glucose level Normal level is 4. 0 -5. 9 % Level above 6. 5% suggests diabetes Target in diabetes is < 7. 0%
Disease Progression Type II diabetes is a progressive disease
Diet control Multifactorial approach Avoid high glycaemic index agents Weight loss Exercise
Oral Agents Aim for good glycaemic control Ideally normalise BSL within 2 -4 hours of a meal Many choices of agent Metformin Sulphonylureas
Insulin Necessary with type I diabetics from onset of disease Can be combined with oral agents in type II diabetes Bedtime insulin Can be sole agent
Retinopathy Starts within a few years of diagnosis (5 -10) Leading cause of blindness in first world Generally preventable Good glucose control Laser therapy. C-peptide (? )
Fundoscopy Normal retina Left eye
Early Diabetic Retinopathy Dot blot haemorrhage
Proliferative retinopathy Cotton wool spots New vessel formation Haemorrhage
Laser Therapy Focal laser therapy
Nephropathy Looking for proteinuria Microalbuminuria is first sign Definitive Dx requires kidney biopsy (not needed)
Management Nephropathy ACE inhibition or ARB’s (not both) Diet (Protien, Potassium) Avoid NSAID’s including COX-2 inhibitors New treatments C-Peptide
Neuropathy Affects all nerve fibers, including motor, sensorty and autonomic fibres Multifactorial causes Microvascular disease Glycosylation end products Protein Kinase C activation Sorbitol / Polyol pathways
Effects Sensorimotor Loss of sensory pathways (esp vibration) Chronic pain Autonomic Diarrhoea, orthostatic hypotension, gastropariesis Cranial nerve palsy (3 rd nerve)
Treatment Pain control TCA’s (Amitriptyline, Nortriptyline) SNRI’s (Duloxitine, Venlafaxine) Gabapentinoids (Pregabalin, Gabapentin)
Other Treatments α-lipoic acid Methylcobalmin (Vit B 12 subform) C-Peptide (experimental) Photo therapies Glucose control
Vascular Disease Both peripheral and coronary vascular disease risk Control other risk factors Smoking, hypertension, cholesterol
Fasting in Diabetes
Fasting Type I diabetes Needs insulin Reduce dosage Type II diabetes Often needs no oral agents
Other Treatment Options
Other treatments Bariatric surgery Pancreatic transplantation Implantable pumps
Medical Management Diabetic Ketoacidosis Hypoglycaemia Hyperglycaemia Chronic management Fasting diabetics Other options
Oral Agents
Types of oral agents Sensitisers Biguanides (Metformin, Phenyformin) Thiazolidines (Rosiglitazone, Pioglitazone) Secretagogues Sulphonylureas (glipizide, glyburide, gliclazide) Meglitinides (repaglinide, nateglinide) α glucosidase inhibitors Peptide analogs
Sulphonylureas
Sulphonylureas Glicizide, glipizide, glibenclamide Inhibit potassium channel Increase the amount of insulin secreted. Effective, inexpensive Hypoglycaemia & Weight Gain
Mechanism of action Bind to ATP-dependent K+ channel Hyperpolarises the β cell membrane Opens voltage gated Ca++ channels Fusion of insulin granulae with membrane
Sulphonylureas Short half life - require BD or TDS dosing Metabolised by P 450 enzymes
Interactions Increased risk of hypoglycaemia Aspirin, allopurinol, sulphonylamides, fibrates Worsening glucose tolerance Steroids, isoniazide, OCP, sympathomimetics, thyroid hormones
Complications Hypoglycaemia Weight Gain Overstimulation of β cells Possible risk of disease acceleration. Teratogenic Little to no survival benefit seen
Biguanides (Metformin)
Uses Type II diabetes Prediabetes (less benefit than lifestyle Δ) Polycystic ovarian disease Gestational diabetes (? foetal safety) Reduced pancreatic cancer risk Reduced weight gain from other agents.
Mechanism of Action Inhibits gluconeogenesis to 1/3 baseline Most Type II diabetics have 3 x increase Activates AMP-activated protein kinase AMPK activation increases SHP Inhibits gluconeogenesis genes
Kinetics Bioavailable 50 -60% Peak 1 -3 hours, 8 hours with SR Minimal plasma protein binding High volume of distribution (10 L/kg) Not metabolised Cleared by tubular secretion (T 1/2 6. 2 hrs)
Advantages Reduces diabetic complications Mortality reduction of 30% c. f. insulin or sulphonylureas Mortality reduction of 40% c. f. diet control Less weight gain Lower risk of hypoglycaemia
Contraindications Lactic acidosis risks Renal, Lung, Liver, Heart disease No actual evidence of harm however Cease before iodine contrast Actual risk is 9/100 000 person years
Adverse Effects GIT Diarrhoea, GI upset, Nausea, Vomiting Hypoglycaemia Alcohol
Glitazones
Glitazones Insulin sensitiser (Binds PPAR receptor) Makes cells more sensitive to insulin Third line drug Usually in combination with metformin
Adverse effects Increased risk of AMI(Rosiglitazone) Heart failure (Pioglitazone) Stroke (Rosiglitazone) Bone fractures Bladder Cancer (Pioglitazone) Macular oedema (? ) & Acute hepatitis (? )
Adverse Effects Most glitazones have been withdrawn from some market, somewhere for some safety concern.
Advantages Low risk of hypoglycaemia Caution with alcohol or other hypoglycaemic agents. May be a better alternative than going to insulin Pioglitazone may reduce rate of atheroma progression. Raises HDL, lowers TG and hs. CRP.
Insulin
Insulin Manufacture Done with recombinant DNA USE bacteria or yeast. Species variation exists Essentially all human insulin now. Lower reaction rates to human insulins
Insulin Administration Subcutaneous Intravenous Insulin Other routes Inhalational, transdermal, intranasal, oral
Insulin Pharmacology Types of insulin Mechanisms of action Dosage
Insulin Ultra fast acting Fast Acting Intermediate Acting Long Acting
Ultra Fast Acting Lispro (Lysine and proline swap on B chain) Aspart (Aspartic Acid for Proline on B chain) Both have high soluability Rapid uptake - Onset 15 minutes Peak effect at 45 -90 minutes Duration 3 -5 hours.
Fast Acting Insulin (“Actrapid”) Standard insulin Onset 30 minutes Peak 2 -4 hours Duration up to 6 hours
Intermediate Acting Mixtard (Insulin/protamine) Onset 2 hours Peak 4 -6 Duration 12 hours
Long Acting Used to use Zinc (Ultralente insulin) Mostly now use modified insulins Glargine Adds arginine to C end of B chain Low p. Ka leads to slow absorption Detemir Binds myristic acid to the Lysine at B 29 High affinity for Albumin
Long Acting Onset slow - ? 4 hours Duration 24 hours No discernable peak.
Exogenous Versus Endogenous Insulin has different effects depending on route of administration Ideal route is into the portal vein Next best is in peritoneal dialysis bag Intravenous is better in the acute setting Subcutaneous is the easiest for most.
Summary Definition and Incidence Definition, incidence, classification Physiology & Pathophysiology Medical Managment Pharmacology
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