Drugs used in the management of Diabetes Mellitus Flashcards
Which glucose transporter is found at the pancreatic beta cells?
GLUT 2
How does an increase in glucose level stimulate insulin release?
Increased intracellular glucose
= ncreased ATP production
= increase ATP/ADP ratio
= closing of K+ channels and depolarisation of the cell
= opens voltage gated Ca2+ channels
= exocytosis of insulin containing vesicles
How does insulin regulate blood glucose levels?
1.Facilitating cellular glucose uptake (GLUT 4 receptors)
2.Regulating carbohydrate, lipid and protein metabolism (glucogenesis inhibition, glycogenolysis)
3.Promoting cell division and growth (PI3K-Akt pathway, MAPK/ERK pathway)
How is exogenous insulin mainly cleared?
Kidneys
When is insulin therapy indicated?
In all Type 1 diabetes patients, and in
Type 2 diabetes patients with
1. Severe hyperglycaemia or
2. When glycemic targets are NOT reached with 2 or more oral hypoglycaemic agents (OHAs)
What are the main types of insulins?
- Rapid
- short / intermediate/ long
- ultra long acting
Which of the insulin types has the longest peak duration of action?
NPH (Intermediate acting insulin)
since there long acting insulins have no peak
Which of the insulins are commonly used in an emergency to rapidly lower blood glucose levels?
Short acting regular human insulin
Note: It is administered intravenously
Which of the insulins have the highest risk for hypoglycaemia?
NPH (Intermediate acting insulin)
Which insulins cannot be mixed with any other insulin in a single syringe?
Glargine, detemir
Long-acting (Glargine, detemir) cannot be mixed with short or rapid-acting insulins in the same syringe
due to long acting insulins having a low pH formation
= if mixed with other insulins (neutral pH)
= premature precipitation
= incomplete insulin absorption
= unpredictable blood glucose levels
What adverse effects are associated with insulin use?
Hypoglycaemia and lipodystrophy (abnormal distribution of fat, with less fat near areas of insulin injection)
How is insulin commonly administered?
Subcutaneous injection
What factors affect the absorption of insulin?
Site of injection, Depth of injection, Volume and concentration of the dose injected, exercise, heat (e.g. sitting in a sauna), massage of insulin site
How does corticosteroids or an acute infection affect insulin demands?
It is likely to increase insulin demands as it can cause an increase in blood glucose levels (likely due to insulin resistance)
steroids:
corticosteroids cause increased gluconeogenesis
= hyperglycemia
infection:
body releases inflammatory mediators
= cytokines intefere with insulin signalling
= more glucose remain in blood stream
= increase in blood glucose
Which oral hypoglycaemic agent is commonly used as the first line of treatment in the absence of any contraindications?
Metformin
What is metformin’s mechanism of action?
Metformin decreases hepatic glucose production, increases the density of insulin receptors at the tissues and reduces intestinal glucose absorption
What factors could contraindicate the use of metformin?
Renal dysfunction, lactic acidosis, hepatic dysfunction
What is thiazolidinedione’s mechanism of action?
Primary mechanism of action is via the activation of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ).
PPAR-γ ligands
= increase trasncription of genes invovled in glucpse and lipid metabolism
= regulate glucose metabolism, adipogenesis
= improve insulin sensitivity at adipose tissues, liver and skeletal muscles
= increase glucose uptake
What are the key adverse effects associated with the use of thiazoldinediones?
Weight gain, peripheral edema, increased risk of heart failure (fluid retention) and bone fractures
increase PPAR gamma (PPAR causes more production of adipocytes and less production of osteoblasts = more succeptible to bone fracture)
= increase transcription of genes to glucose uptake
= increase glucose uptake (increase water uptake = oedema and fluid retention = weight grain & HF due to fluid retention)
Will an obese patient be suitable for thiazolidinediones?
Ideally not recommended as the drug can cause weight gain
What is sulfonylurea’s mechanism of action?
Sulfonyureas (SU) bind to the SU receptor proteins subunits of the K+ATP channels
= inhibits KATP channel mediated K+ efflux
= depolarisation of pancreatic β-cells
= calcium-dependent exocytosis of insulin granules
Name a sulfonylurea with a long duration of action
Glibenclamide - High risk of hypoglycaemia compared to the others
What are the key adverse effects associated with the use of sulfonylureas?
Weight gain, hypoglycaemia
What patient profile may have a higher risk of hypoglycaemia with sulfonyureas?
Elderly, poor renal function, or hepatic dysfunction, people with irregular eating habits
What is meglitinide’s mechanism of action?
Meglitinides bind and close the ATP-dependent potassium (KATP) channels on the pancreatic beta cells in a **glucose-dependent manner **stimulating insulin release
Why are meglitinides commonly used at meal times?
They have a rapid onset and short duration of action
What is acarbose’s mechanism of action?
The α-glucosidase inhibitors reversibly inhibit membrane-bound α-glucosidase in the intestinal brush borders
= slow down the rise in glucose levels after a meal
= inhibit post prandial hyperglycemia
**must be taken with food
What are some side effects associated with the use of acrbose?
Flatulence, GI discomfort
In which groups of patients will acarbose be contraindicated?
- GIT diseases like IBD
- severe renal and hepatic disease
What are the 2 classes of drugs that work by incretin based therapy?
Dipeptidyl peptidasae-4 inhibitors, GLP-1 receptor agonist
What are the mechanisms of action of DPP-4 inhibtors?
DPP-4 inhibitors binds and inhibits DPP-4 thus prolonging the action of the endogenous incretins, which then
1. stimulate pancreatic β-cells to increase glucose-stimulated insulin release
2. suppress α-cell mediated glucagon release
3. supress hepatic glucose production
Name 3 DPP-4 Inhibitors
Sitagliptin, Linagliptin and Vildagliptin
Name 2 examples of glucagon-like 1 peptide 1-receptor agonist
Liraglutide, Semaglutide
How are GLP-1 receptor agonists administered?
Subcutaneous injection
Semaglutide is also available as an oral tablet
What are the mechanisms of action of glucagon-like 1 peptide 1-receptor agonist?
They activate the GLP-1 receptor (membrane-bound cell-surface receptor in pancreatic beta cells)
= Increase insulin release in the presence of elevated glucose concentrations
**does not cause hypoglycemia, as insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia (normal blood glucose level)
What are the potential adverse effects associated with the use of DPP-4 inhibitors and GLP-receptor agonist?
GI related issues, pancreatitis (not recommended for patients with a history of pancreatitis
Other benefits of GLP-1 receptor agonists
Weight loss, improved cardiovascular outcomes
What are examples of sodium glucose co-transporters?
Dapagliflozin, empagliflozin, canaglifloziin
What is SGLT-2’s mechanism of action?
SGLT2, expressed in the PROXIMAL RENAL TUBULES, is responsible for 90% of the reabsorption of filtered glucose from the tubular lumen.
Inhibiting SGLT2
= decrease reabsorption of filtered glucose
= increase urinary glucose excretion
What other benefits does SGLT-2 have?
Favourable cardiac outcomes - including reduced risk of hospitalizaton due to heart failure and reduced risk of worsening renal function
What are some of the key adverse effects associated with the use of SGLT-2 inhibtors?
- Urinary tract infection
- increased urination
- female genital mycotic infections (fungal infection)
- increased risk of lower limb amputation (Canagliflozin, since it has a more potent diuretic effect = hyperviscocity = decrease oxygen to lower limbs)
- diabetic ketoacidosis
Which hypoglycaemic agents are associated with weight gain?
sulfonyureas, thiazolidinediones, meglitinides
Which hypoglycaemic agents have been found to have significant cardiovascular benefits and are favoured for patients with Atherosclerotic cardiovascular disease?
SGLT-2 inhibitors, GLP-1 receptor agonist
compare GLUT 2 vs 4
GLUT 2
- insulin INDEPENDENT
- glucose transport in and out of cells
- low affinity for glucose
GLUT 4
- insulin regulated
- glucose uptake into cells after insulin stimulation
- high affinity for glucose
what is the triad for diagnosing diabetic ketoacidosis
- hyperglucemia
- ketonemia (elevated ketones in the blood)
- metabolic acidosis
acidosis vs alkalosis
