Lecture 12- Insulin And Oral Hypoglycaemic Agents Flashcards
Why does hyperglycaemia occur?
Because of the uncontrolled hepatic glucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis
When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine (glycosuria) + causes an osmotic diuresis (polyuria) which leads to dehydration, thirst and increased drinking
Type 1 diabetes
-common in children, adolescents/ young adults
-deficient in insulin + autoimmune destruction of pancreatic beta cells
-pancreas fails to respond to glucose
-patients require exogenous administration of insulin
*control hyperglycaemia
*avoid ketoacidosis (build up of ketones in the blood as a result of breakdown of fatty acids in the liver)
*maintain acceptable levels of glycosylated haemoglobin
Type 2 diabetes
-reduced secretion of insulin or peripheral resistance to the action of insulin or BOTH
Treatment goal= to focus on maintaining blood glucose within normal limits + to prevent development of long-term complications
Insulin and insulin analogues
-insulin= polypeptide hormone
-synthesised as= pro-insulin which undergoes proteolytic cleavage to form insulin + C-peptide secreted by the pancreatic beta cells
Insulin and insulin analogues
Treatment= aim to achieve best possible control of blood-glucose concentration
Insulin preps;
*short-acting; rapid onset of action + short duration of action (soluble insulin, insulin aspart insulin lispro)
*intermediate-acting; isophane insuline
*long-acting; slow onset of action + long-lasting effects
Insulin and insulin analogues
Clinical uses;
-patients with T1D require long-term insulin. Intermediate-acting prep is combined with soluble insulin before meals
*soluble insulin= used as IV in emergency treatments of hyperglycaemic emergencies like diabetic ketoacidosis
-short term patients with T2D/impaired glucose tolerance during intercurrent events; ops, infections, myocardial infarction
-pregnancy= gestational diabetes not controlled by diet alone
-emergency treatment of hyperkalemia
Insulin and insulin analogues
Pharmacokinetics;
-insulin is destroyed in the GIT + must be given parenterally-usually subcutaneously but IV/IM in emergencies
-usually injected into upper arms, thighs, buttocks or abdomen
Insulin administration;
-peptide; degraded in the GIT therefore= given by SC injection
-hyperglycaemic emergency= given as IV
-dose, site of injection, blood supply, temp, physical activity= affects the duration of action of various preps
-inactivated by insulin protease in liver + kidney
Insulin and insulin analogues
Side effects of insulin administration;
Hypoglycaemia, tachycardia, confusion, vertigo, anxiety, headache, blurred vision, weakness/fatigue
-lipodystrophy; local atrophy of sc fat tissue at site of injection
-allergic reactions
-local injection site reactions
Oral hypoglycaemic agents
Biguanides; (Metformin)
-only current biguanide
Mechanism of action;
-enhances peripheral glucose uptake + utilisation
-reduces hepatic glucose output; inhibiting gluconeogenesis
*excess glucose production by the liver= contributes to high blood glucose in T2D
-slows intestinal absorption of sugars
Pharmacokinetics;
-well-absorbed orally, not bound to plasma proteins + excreted unchanged in the urine
Therapeutics;
-treatment of T2D
-treatment of polycystic ovary disease; ability to lower insulin resistance in women = ovulation
Biguanides; Metformin
Side effects;
Gastrointestinal; anorexia, nausea, vomiting, diarrhoea, abdominal pain
Others; taste disturbance, decreased vit B12, absorption, erythema, pruritus + urticaria
Contraindication;
-diabetics with renal/hepatic disease, acute myocardial infarction, severe infection or diabetic ketoacidosis
-patients >80/ history of CHF/ Alcohol abuse
-X-ray contrast media
Sulfonylureas
Glibenclamide, gliclazide, glimepride, glipizide, tolbutamide
Mechanism of action;
-stimulation of increase of insuli release from the B cells of pancreas
-reduction in hepatic glucose production
-increase in peripheral insulin sensitivity
Pharmacokinetics;
-given orally
-bind to serum proteins
-metabolised by the liver
-excreted by liver/kidney
Side effects;
Weight gain
Thiazolidinediones (glitazones)
Pioglitazone, rosiglitazone
-insulin sensitisers
-lower insulin resistance by activating the peroxisome proliferator-activated receptor
-regulate glucose metabolism by increasing insulin sensitivity in adipose tissue, liver + skeletal muscle
*glitazones= rec as a second-line alternative for patients who fail/have contraindications to Metformin
Thiazolidinediones (Glitazones)
Adverse effects;
-hepatotoxicity; deaths been reported- measure liver enzymes of patients on these meds
-osteopoenia + increased fracture risk
-women= may become pregnant- reduce plasma conc of oestrogen-containing contraceptives
Uses;
-T2D
-relief of insulin resistance with glitazones = ovulation to resume in premenopausal woman with polycystic ovary syndrome
Dipeptidyl peptidase inhibitors
Saxagliptin, sitagliptin, vidagliptin
*sitagliptin= inhibits enzyme DPP-4= responsible for the inactivation of incretin hormones; glucagon-like peptide-1 (GLP-1)
-prolonging activity of incretin hormones = increased insulin release in response to meals + reduction in appropiate secretion of glucagon
*sitagliptin= treatment for T2D
-may be used as monotherapy/ in combo with Metformin
-generally well tolerated- side affects = headache
A-Glucosidase inhibitors
Acarbose
Mechanism of action;
-do not stimulate insulin release/ enhance insulin sensitivity
-taken at the beginning of meals= delay carbohydrate digestion= lower post-prandiual glucose levels
-act by reversing inhibition of a-glucosidase in the intestinal brush holder
*acarbose- inhibits pancreatic a-amylase interfering with breakdown of starch to oligosaccharides
^do not cause hypoglycaemia when used alone
