pharmacology of diabetes

Question 1

what is the primary mechanism of action of metformin

Answer 1

activates AMPK in hepatocyte mitochondria. this inhibits atp production and blocks gluconeogenesis and subsequent glucose output.
- also blocks adenylate cyclase which promotes fat oxidation - both help restore insulin sensitivity.

Question 2

what is the target of metformin

Answer 2

5’amp activated protein kinase (AMPK)

primary site = hepatocyte mitochondria

Question 3

what are the main side effects of metformin

Answer 3

gi side effects (30-40%) - abdominal pain, decreased appetite, diarrhoea, vomiting
- particularly evident when very high doses given

Question 4

extra info on metformin

Answer 4

*highly polar - requires organic cation transporter
can accumulate in live and gi tract
* most effective in presence of endogenous insulin

Question 5

what is an example of a dipeptidyl peptidase 4 inhibitor

Answer 5

sitagliptin

Question 6

what is the primary mechanism of action of dpp4 inhibitors

Answer 6

inhibit action of dpp4 - enzyme present in vascular endothelium and can metabolise incretins in plasma.
incretins e.g gpl1 are secreted by enteroendocrine cells and help stimulate production of insulin when needed and reduce production of glucagon by liver.
- incretins also slow down digestion and decrease appetite

Question 7

what is the main drug target of dpp4 inhibitors

Answer 7

primary site of action is vascular endothelium

Question 8

side effects of dpp4 inhibitors/ sitagliptin

Answer 8

upper resp tract infections - 5% of patients
flu like symptoms e.g headache, runny nose, sore throat
less common but serious allergic reactions-avoid in patients with pancreatitis

Question 9

extra info on dpp4/sitaglipitn

Answer 9

compared to other antidiabetics (excpt metformin)these dont cause weight gain
effective only when some residual pancreatic beta cell activity is present

Question 10

what is an example of a sulphonylurea

Answer 10

gliclazide

Question 11

what is the primary action of sulphonylureas

Answer 11

inhibits atp sensitive potassium channel on pancreatic beta cell. this channel controls beta cell membrane potential. inhibition causes depolarisation which stimulates ca2+ influx and subsequent insulin vesicle exocytosis.

Question 12

side effect of sulphonylureas e.g gliclazide

Answer 12

weight gain - likely side effect

hypoglycaemia - 2nd most common

Question 13

target site of sulphonylureas

Answer 13

atp sensitive potassium channel

primary site = pancreatic beta cells

Question 14

extra info on sulphonylureas

Answer 14

mainly act by augmenting insulin secretion therefore only effective when some residual pancreatic b cell activity is present.
weight gain mitigated by metformin
risk of hypoglycaemia should be discussed with patient

Question 15

what is an example of sodium glucose co transporter sglt2 inhibitors

Answer 15

dapaglifozin

Question 16

what is the primary action of sglt2 inhibitors

Answer 16

reversibly inhibits sodium glucose co transporter 2 in renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion

Question 17

what is the target site of sglt2 inhibitors

Answer 17

sglt2 in proximal convoluted tubule

Question 18

what are the side effects of sglt2 inhibitors

Answer 18

uro genital infections due to increased glucose load - 5% patients
slight decrease in bone formation
can worsen diabetic ketoacidosis - stop immediately

Question 19

extra info on sglt2 inhibtors

Answer 19

cause weightloss and reduction in bp

less effective in patients with renal impairment

Question 20

what can be given to adults if hbal1c rises to 48mmol/mol on lifestyle intervention

Answer 20

offer standard release metformin

support individual to aim for hba1c lower than 48

Question 21

what should be given if patient with diabetes hba1c rises to 58mmol/mol

Answer 21

consider dual therapy of metformin with one of following:
e.g ddp4 inhibitor e.g sitagliptin (100mg/dayoral)
piogiltazone (15-45mg/day oral)
sulphonylureas e.g glicazide (40-80mg/day,oral)
sglt2 inhibitors e.g dapagliflozin (5mg/day,oral)
support to lower hba1c to 53mmol/mol

Question 22

2nd intensification if hbal1c rises to 58mmol/mol after 1st intensification of meds

Answer 22

consider insulin based treatment / triple therapy with one of following combinations:
metformin, ddp4 and an su
metformin, pioglitazone and an su
metformin, pioglitazone/su and sglt2 inhibitor
support to lower hba1c to 53mmol/mol

Question 23

metformin is a very polar structure, what is its pka

Answer 23

12.4

even in alkaline tissue is charged

Question 24

why is metformin administered orally

Answer 24

small bowel oct1 allows it to be absorbed
hepatocyte oct1 allows it to be distributed to site of action
proximal tubule oct1 helps excretion