1.2 - Pharmacology of diabetes (core drugs) Flashcards
What are the four classes of diabetes drugs?
- metformin
- dipeptidyl-peptidase 4 (DPP-4) inhibitor
- sulphonylurea
- sodium-glucose co-transporter (SGLT2) inhibitor
What is the primary mechanism of action of metformin?
- metformin activates AMPK in hepatocyte mitochondria
- this inhibits ATP production
- this blocks gluconeogenesis and subsequent glucose output
- it also blocks adenylate cyclase which promotes fat oxidation
- both help restore insulin sensitivity
What is the drug target of metformin?
5’-AMP-activated protein kinase (AMPK - enzyme) in hepatocyte mitochondria
What is the primary site of action of metformin?
Hepatocyte mitochondria
What is the overall action of metformin?
Decreased gluconeogenesis
What are the main side effects of metformin?
- GI side effects (20-30%) patients, evident when very high doses given (slow increase in dose may improve tolerability)
- abdominal pain
- decreased appetite
- diarrhoea
- vomiting
What is the polarity of metformin like and how does it access tissues?
- highly polar
- requires organic cation transporter-1 (OCT-1) to access tissues
- this explains why it can accumulate in the liver (therapeutic effects) and GI tract (side effects)
When is metformin most effective?
In the presence of endogenous insulin (so when there is some residual functioning of pancreatic islet cells)
What is an example of a DPP-4 inhibitor?
Sitagliptin
What is the primary mechanism of action of a DPP-4 inhibitor?
- inhibits action of DPP-4 which is present in vascular endothelium and can metabolise incretins in plasma
- incretins (e.g. GLP-1) are secreted by enteroendocrine cells and help stimulate insulin production after eating and reduce glucagon production by liver when not needed e.g. during digestion
- incretins also slow down digestion and decrease appetite
What is the drug target and primary site of action of DPP-4 inhibitors?
DPP-4 in vascular endothelium
What is the overall effect of a DPP-4 inhibitor?
Increased plasma incretin levels
What are the main side effects of DPP-4 inhibitors?
- upper respiratory tract infections (5%)
- flu-like symptoms e.g. headache, runny nose, sore throat
- less common but serious allergic reactions
Which patients should you avoid giving DPP-4 inhibitor to?
Avoid in patients with pancreatitis
What is an advantage of DPP-4 inhibitors compared to other diabetic drugs?
Do not cause weight gain
When are DPP-4 inhibitors effective?
Act mainly by augmenting insulin secretion so are only effective when some residual pancreatic beta cell activity is present
What is an example of a sulphonylurea?
Gliclazide
What is the primary mechanism of action of sulphonylureas?
- inhibit ATP-sensitive K+ channel (KATP) on pancreatic beta cell
- this channel controls beta cell membrane potential
- inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis
What is the drug target and primary site of action of sulphonylureas?
ATP-sensitive potassium channel on pancreatic beta cell
What is the overall effect of sulphonylureas?
Insulin secretion
What are the main side effects of sulphonylureas?
- weight gain is likely
- hypoglycaemia (2nd most common)
When are sulphonylureas effective?
Act by augmenting insulin secretion so only effective when there is residual pancreatic beta cell activity
How can weight gain by sulphonylureas be mitigated?
By also giving metformin
What do we need to inform patients about if they are on sulphonylureas?
Patients need to be informed about hypoglycaemia risk, especially if they are on other glucose-lowering drugs
What is an example of a SGLT-2 inhibitor?
Dapaglifozin
What is the primary mechanism of action of SGLT-2 inhibitors?
Reversibly inhibits SGLT-2 in renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
What is the drug target and primary site of action of SGLT-2 inhibitors?
SGLT-2 in renal PCT
What is the overall effect of SGLT-2 inhibitors?
Decreased glucose reabsorption
What are the main side effects of SGLT-2 inhibitors?
- urogenital infections due to increased glucose load (5% of patients)
- slight decrease in bone formation
- can worsen diabetic ketoacidosis (stop immediately)
What can SGLT-2 inhibitors also cause/be used for?
Weight loss and reduction in BP
What is the action of SGLT-2 inhibitors dependent on?
Drug action depends on normal renal function so are less effective in renal impairment patients
How does the molecular structure of metformin influence it’s absorption into the blood and distribution to body tissues?
- metformin pKa = 12.4, so even in the most alkaline tissue (bile pH 9), metformin will be charged/ionised
- metformin is very polar - transported by organic cation transporter 1 (OCT1) - expressed in hepatocytes (liver), enterocytes (small bowel) and proximal tubules (kidney)
- SB OCT1 allows it to be absorbed
- hepatocyte OCT1 allows it to be distributed to the site
- proximal tubule OCT1 helps excretion
What are side effects of metformin, DPP-4 inhibitors, pioglitazone, sulphonylurea, and SGLT-2 inhibitors?
- metformin: GI e.g. diarrhoea
- DPP-4 inhibitor: upper RTI
- pioglitazone: heart failure
- sulphonylurea: weight gain
- SGLT-2 inhibitor: urogenital infections
How does diabetic ketoacidosis develop?
- not enough insulin: insulin not taken or insulin resistance increased e.g. infection
- glucose does not enter cells
- immediately: plasma glucose rises –> polyuria and dehydration –> patient feels awful and presents to hospital
- slowly: liver cells make ketones (starving in the midst of plenty) –> acidosis –> patient feels awful and presents to hospital
How can SGLTs affect diabetic ketoacidosis?
- early warning sign of rising glucose may be slower and even lost completely
- worse, normal glucose falsely reassures: “I don’t feel great but my glucose is normal, so it can’t be DKA, I’m probably just tired, no need for more insulin”
- normal circumstances where patients NOT on SGLTs: “Glucose is high, something must be going on, I’ll take some insulin and go to the doctor”
- take home message for SGLTs - DKA can occur with normal glucose
