Week 4 Pharmacology - Endocrine Flashcards
What does autocoid refer to?
Drug class consisting of serotonin, histamine, prostaglandins, leukotrienes
What is the proposed mechanism of action of triptans?
Activation of 5-HT receptors on presynaptic trigeminal nerve endings to inhibit release of vasodilation peptides (thought to be the cause of migraine)
Where are the different histamine receptors located?
H1 = smooth muscle, endothelium, brain
H2 = gastric mucosa, cardiac muscle, mast cells, brain
H3 = presynaptic autoreceptors, brain
H4 = granulocytes, CD4 T cells
What receptor is targeted in treating allergic/hypersensitivity induced histamine release?
H1 receptor antagonists
What is the difference between first generation and second generation antihistamines?
First generation are more likely to block autonomic receptors (prevent adrenergic activity) and have a stronger sedative response
PK of antihistamines?
Peak plasma concentration 1-2 hours, effective 4-6 hours.
Reversible antagonism of H1 receptors
Is insulin initially produced as a pro-hormone?
Yes! - Proinsulin
What occurs to pro-insulin when inside granules (within beta cell)?
Hydrolysed to Insulin and C-peptide (which are secreted in equimolar amounts in response to activation of insulin secretion)
Stimulates insulin secretion?
Glucose
Amino acids
GLP-1
Glucagon
CCK
Fatty acids
Beta adrenergic activity
Glucagon
What inhibits insulin secretion?
Insulin
Somatostatin
Alpha adrenergic activity
Leptin
Phenytoin
Colchicine
What are the steps that lead to release of insulin from islet cells?
- Increased intracellular glucose via GLUT 2 transport
- Increased ATP synthesis and presence within cell
- ATP binds and closes ATP dependent K+ cells, preventing K+ efflux
- Depolarisation and opening of voltage gated Ca2+ channels
- Calcium as cellular messenger acts to trigger exocytosis of preformed vesicles of insulin
What is the half life of circulating insulin?
3-5 minutes
What type of receptor is insulin receptor on peripheral cells?
Tyrosine kinase
What are the general metabolic effects of insulin on liver, adipose and muscle?
Liver:
- Reversal of catabolism
- Induction of anabolism
Muscle:
- Increased protein synthesis
- Increased glycogen production
Adipose:
- Increased triglyceride storage
Where is GLUT-1 found?
All tissues, all for one - and one for all! Basal uptake of glucose
Where is GLUT-2 found?
Beta cells pancreas
Liver
Kidney
GIT
Where is GLUT-3 found? (Three is an odd number)
Brain, placenta
Where is GLUT 4 found? (May the four be with you)
Muscle, adipose (this is insulin mediated uptake)
Where is GLUT-5 found? (Five, ffff)
Gut, Kidney - absorption of fructose
What effect does insulin binding have on insulin sensitive cells?
Translocation of GLUT-4 transporters to cell membrane
Where is insulin metabolised?
65% liver, 35 kidney (reversed for exogenous insulin)
What are the rapid effects of insulin administration?
Increased glucose and amino acid transport
Potassium uptake into insulin sensitive cells
What the intermediate effects of insulin administration (minutes)?
Stimulation of protein synthesis/inhibition of degradation
Activation of glycolytic enzymes and glycogen synthase
Inhibition of gluconeogenesis
What are the delayed effects of insulin administration (hours)?
Increase in mRNAs for lipogenic / other enzymes
What medications antagonise the effect of insulin?
Steroids
Thyroxine
Sympathomimetics
Thiazides
Where is glucagon synthesised?
Pancreatic islet alpha cells
Where are the target cells for glucagon metabolically? Effects?
Liver - GPCR binding that causes increased gluconeogenesis and ketogenesis and glycogenolysis
What are the cardiac effects of glucagon?
Potent inotropy and chronotropy (not requiring functioning beta receptors, reason why useful in beta blocker poisoning)
What is the half life of glucagon?
3-5 minutes
Compare onset and duration of novorapid with glargine?
Novorapid: Onset 5-15 mins, peak 1.5 hrs, duration 5 hrs
Glargine: Onset 30mins-1hr, peak is flat, duration 24 hours
What are the two main categories of oral hypoglycaemic?
Insulin secretagogues vs non secretagogues
What are the different types of insulin secretagogues?
- Sulphonylureas
- Incretins
- DPP-4 Inhibitors
What is the mechanism of sulphonylureas?
Act directly on ATP sensitive K+ channels in pancreatic beta cells to close –> depolarisation and insulin release in the same manner as physiological insulin release
What are examples of sulphonylureas?
Gliclazide
What are adverse effects of sulphonylureas?
Weight gain, hypoglycaemia
What are incretins?
Hormones released by GIT following meal that leads to increased insulin release, i.e. GLP-1
What two medication classes mimic the action of incretins?
- Glucagon-Like-Peptide-1 Agonists, i.e. semaglutide, liraglutide, exendatide
- DPP4 Inhibitors: Sitagliptin, Linagliptin
What is the mechanism of action of DPP4 inhibitors?
Act to inhibit the enzymes that break down GLP-1, which has the effect of facilitating its function –> which is binding to beta cells and increasing insulin release
What are the extra-pancreatic effects of GLP-1 agonists?
Increased satiety, decreased gastric emptying rate, lower glucagon levels
What is the mechanism of metformin/biguanide?
Activation of AMP Kinase (liver enzyme) which acts to inhibit hepatic gluconeogenesis, as well as intestinal absorption of glucose.
What are adverse effects of metformin?
GI upset
Lactic acidosis
What is the mechanism of SGLT-2 inhibitors?
Direct inhibition of transporters in PCT of nephron to reduce glucose absorption
What are adverse effects of SGLT-2 inhibitors?
UTI
Euglycaemic ketoacidosis
Osmotic diuresis
Is carbimazole a pro-drug?
Yes! Converted to methimazole, which accumulates in thyroid gland
How does carbimazole act?
Major mechanism = inhibition of thyroid peroxidase reactions, as well as coupling of iodotyrosines
How long after commencing carbimazole does it take for effect?
3-4 weeks (as it only interferes with synthesis of thyroid hormone, NOT release)
What role does propranolol have in management of hyperthyroidism?
Inhibition of beta adrenoceptors manages symptoms, as well as decreased peripheral conversion of T4 –> T3
