Pharmacology - Bailey Flashcards
What is the difference between insulin and glucagon?
Insulin –> Decrease plasma….glucose/AA/FFAs
So stimulates glucose utilization via glycolysis and glycogenesis
Inhibits glucose production by gluconeogenesis and glycogenolysis
Glucagon –> Increases plasma….glucose/ketones
What is the difference between T1DM and T2DM?
Type 1 –> Destruction of the B-islet cells of the pancreas
Needs injected insulin (as they produce none!)
Type 2 –> The body cannot produce enough insulin, OR the body cannot respond to the insulin correctly (“insulin resistance”)
Usually diagnosed in patients over 40yrs old
What is the IRS pathway of insulin receptor signalling?
Insulin binds to a receptor tyrosine kinase, activating insulin receptor substrate (IRS)
This causes several metabolic effects via PI3 kinase and Akt
Main effect is the expression of more GLUT receptors on the membrane of cells, allowing more glucose to be uptaken into cells (and removed from the blood) –> Eg, GLUT4 recptors in muscle and fat cells
What are some of the effects of insulin resistance?
Increased thirst/urination
Fatigue
Hypertension
Low HDL
Increased fat stores
Hyperglycemia
What are Sulfonyureas? (eg, gliclazide)
And how do they work?
Stimulate insulin secretion
They inhibit the ATP-sensitive K+ channel, causing more depolarization…..causing Ca2+ release…..which stimulates insulin secretion
Can stimulate weight gain
What are Meglitanides? (eg, rapaglinide)
“nonsulfonylureas” but act in the same way (by blocking the K-ATP channel)
They are more rapidly absorbed in the body, and so have a faster onset of action than sulfonylureas
Can be used with metformin
What are Biguanides? (eg, metformin)
Insulin sensitising molecules, so cant be used in T1DM as insulin needs to be present!!!
Main action is decreasing the hepatic glucose production (by inhibiting gluconeogensis)
Inhibits the mitochondrial respiratory complex 1 (decreased synthesis from ADP –> ATP)
Stimulates insulin receptor expression and tyrosine kinase activity
Drug of choice in overweight patients as it does not stimulate weight gain
What is the major potential side effect of metformin?
Lactic acidosis
Excessive production of lactic acid (lactate) to the blockade of the mitochondrial respiratory chain complex
So pyruvate cannot be converted back to glucose (only lactate)
What are (a)-glucosidase inhibitors? (eg, Acarbose)
They reduce the digestion of complex carbohydrates, and so slows their absorption from the gut
Adverse effects are common (flatulence/diarrohea), and so not often used in the western world
Don’t cause hypoglycemia or weight gain
What are Thiazolidinediones (TZDs/Glitazones)
An insulin-sensitising drug
Agonists at Peroxisome Proliferator-Activated Receptors (PPARs), and so decrease B-oxidation of fatty acids and cholesterol synthesis
Mechanism takes several weeks to occur
Weight gain is a major side effect!!
Metabolised by CYP450s
What are the 2 mechanisms of PPAR(y)?
Transactivation –> Activates gene transcription
Transrepression –> Represses gene transcription (including NFkB)
Therefore TZDs have anti-inflammatory effects
What are incretins?
Glucagon-like peptides (GLP-1) and gastric inhibitory polypeptides
GLP-1 affects insulin biosynthesis and secretion, but only under hyperglycaemic conditions
GLP-1 inhibits glucagon release, and is a satiety signal leading to a reduction in food intake –> So aimed at overweight patients
GLP-1 levels are reduced in T2DM!
Mimetic example = Exenatide
What are gliptins/DPP-4 inhibitors? (eg, sitagliptin)
DD4 is an enzyme responsible for rapid degradation of GLP-1 and GIP….so inhibitors potentiate GLP-1
What are the SGLT2 inhibitors? (eg, -flozin)
Reversibly inhibit the sodium glucose co-transporter 2 (SGLT2) in the renal proximal convulated tubule
This reduces glucose reabsorption and increases secretion
