Pharmacology of diabetes

Question 1

what is the primary mechanism of action of metformin

Answer 1

metformin activates AMPK in hepatocyte mitochondria, this inhibits ATP production which blocks gluconeogenesis and subsequent glucose output
It also blocks adenylate cyclase which promotes fat oxidation. Both help to restore insulin sensitivity.

Question 2

what is the drug target for metformin

Answer 2

5′-AMP-activated protein kinase (AMPK)

The primary site of metformin action is the hepatocyte mitochondria

Question 3

what are main side effects of metformin

Answer 3

GI side effects eg abdominal pain, decreased appetite, diarrhoea, vomiting
particularly in high doses, slow dose increase may improve tolerability

Question 4

what does metformin require to access tissues

Answer 4

it is highly polar and needs ogranic cation transporter-1 (OCT-1)
which is why it can accumulate in the liver and GIT

Question 5

when is metformin most effective

Answer 5

in the presence of endogenous insulin so is most effective with some residual functioning pancreatic islet cells

Question 6

give an example of DDP-4 inhibitors

Answer 6

sitagliptin

Question 7

what does DDP4 stand for

Answer 7

dipeptidyl-peptidase 4

Question 8

what are the different drugs you can give for diabetes

Answer 8

metformin, DPP4 inhibitors, sulphonylureas, SGLT2 inhibitors

Question 9

what is the primary mechanism of action of DPP4 inhibitors

Answer 9

work by inhibiting the action of DPP4, which is in vascular endothelium and can metabolise incretins in the plasma

Question 10

what are incretins

Answer 10

eg GLP-1
are secreted by enteroendocrine cells and help stimulate the production insulin when it is needed eg after eating and reduce the production of glucagon by the liver when it is not needed, they also slow down digestion and decrease appetite

Question 11

what is the drug target of DPP4 inhibitors

Answer 11

vascular endothelium where the DPP4 enzyme is found

Question 12

what are the side effects of DPP4 inhibitors

Answer 12

upper RTIs, flu like symptoms eg Upper respiratory tract infections (5% of patients) Flu-like symptoms e.g. headache, runny nose, sore throat
Less common but serious:
Serious allergic reactions/ avoid in patients with pancreatitis

Question 13

do DPP4 inhibitors cause weight gain

Answer 13

no, unlike other anti diabetic drugs (apart from metformin)

Question 14

how do DPP4 inhibitor’s mainly act

Answer 14

mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present

Question 15

give an example of a sulphonylurea

Answer 15

gliclazide

Question 16

what is the primary mechanism of action of sulphonylureas

Answer 16

Inhibit the ATP-sensitive potassium (KATP) channel on the pancreatic beta cell. This channel controls beta cell membrane potential. Inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

Question 17

what is the target for sulphonylureas

Answer 17

ATP sensitive potassium channel
primary site of SUs inhibitor action is pancreatic beta cell

Question 18

side effects of sulphonylureas

Answer 18

Weight gain is a likely side effect
Hypoglycaemia (2nd most common)

Question 19

how do sulphonylureas mainly act

Answer 19

by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present

Question 20

how is weight gain by sulphonylureas mitigated

Answer 20

by the concurrent administration with metformin

Question 21

what should be considered when prescribing sulphonylureas?

Answer 21

The risk of hypoglycaemia associated with sulfonylureas should be discussed with the patient, especially when concomitant glucose-lowering drugs are prescribed.

Question 22

give an example of a sodium glucose co-transporter (SGLT2) inhibitor

Answer 22

dapaglifozin

Question 23

what is SGLT2 inhibitors primary mechanism of action

Answer 23

Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion

Question 24

what is the drug target for SGLT2 inhibitors

Answer 24

SGLT2
The primary site of SGLT2 inhibitor action is the proximal convoluted tubule

Question 25

what are side effects of SGLT2 inhibitors

Answer 25

uro genital infections due to increased glucose load
slight decrease in bone formation
can worsen DKA (stop immediately)
weight loss and reduction in BP

Question 26

SGLT2 inhibitor action depends on what

Answer 26

normal renal function so they are less effective in patients with renal impairment

Question 27

what are the steps for diabetes treating in the UK

Answer 27

first try lifestyle intervention

if HbA1C rises to 48mmol offer standard release metformin, support to aim for HbA1C of 48

if it rises to 58: consider dual therapy with DPP4 inhibitor, pioglitazone, SU, SGLT2 inhibitor, support to aim for 53

if it rises to 58: consider insulin based treatment or triple therapy with metformin DPP4i and SU, metformin pioglitazone and SU, metformin pioglitazone or SU and SGLT2i; support to aim for 53

Question 28

what is more effective metformin of lifestyle

Answer 28

lifestyle at the start then metformin catches up after 3/4y

Question 29

metformin’s pKa is 12.4 so what does this mean in the most alkaline tissue

Answer 29

bile pH is 9, bc of pKa even here metformin will still be charged

Question 30

why is it relevant that OCT-1’s are expressed in hepatocytes, enterocytes (small bowel) and proximal tubules (kidneys)

Answer 30

Small bowel OCT-1 allows metformin to be absorbed

Hepatocyte OCT-1 allows it to be distributed to the site of action.

Proximal tubule OCT-1 helps excretion

Question 31

what is a side effect of pioglitazone

Answer 31

heart failure

Question 32

what is a take home message about DKA for those taking SGLT2i’s

Answer 32

can occur with a normal glucose measurement
normally in DKA a rising glucose is an early warning sign but it is slower or just not there in these patients taking SGLT2i’s

Question 33

how does metformin administration change based on kidney function

Answer 33

if eGFR is over 45 no change (between 45-60 monitor in 3-6 months)
if between 30-45 if taking already then consider 50% decrease do not newly initiate
if less than 30 then contraindicate

Question 34

why does renal impairment cause problems for diabetic patients on metformin

Answer 34

metformin does not leave the system and stays at high plasma levels