Diabetes pharmacology

Question 1

describe metformin mechanism of action

Answer 1

inhibits complex 1 of mitochondria respiratory chain

fall in cell ATP and rise in AMP:ATP so stimulates AMPK so reduction in gluconeogenesis

Question 2

what cells is metformin taken up into

Answer 2

liver, kidneys and intestine

Question 3

what effects does metformin have on GI tract

Answer 3

alters microbioma and increases gut glucose metabolism

increases GLP-1 secretion to increase insulin production, delay gastric emptying and food intake

Question 4

what effects does metformin have on the liver

Answer 4

decreases lipogenesis

decreases gluconeogenesis

Question 5

how much does metformin reduce HbA1c and is it weight gaining or reductive

Answer 5

~18mmol/mol

weight neutral/loss

Question 6

side effects metformin and how to reduce

Answer 6

diarrhoea, bloating, abdo pain, dyspepsia, metallic taste in mouth
use modified release capsule or start low dose and go slowly

Question 7

true/false - metformin has no CV benefit

Answer 7

false - it is beneficial

Question 8

what is MALA

Answer 8

metformin associated lactic acidosis
metformin increases lactate production due to blocked gluconeogenesis
in AKI, often sepsis, there is raised risk

Question 9

in eGFR <45ml/min what is the max dose of metformin

Answer 9

1g daily

Question 10

in eGFR <30ml/min what is the max dose of metformin

Answer 10

none, it is contraindicated

Question 11

name 4 suplhonylureas

Answer 11

glicazide, glipizide, glimepride, glibenclamide

Question 12

describe mechanism of action of SUs

Answer 12

bind to SUR1 and cause closure of ATP sensitive K channel
rise in membrane potential causing depolarisation and opening of voltage gated potassium channel
leads to insulin exocytosis

Question 13

most common dosage and drug used for SU therapy

Answer 13

glicazide 40-80mg OD

Question 14

how much does SU lower HbA1c and is it weight gaining or losing

Answer 14

around 18mmol/mol

weight gaining due to anabolic insulin action

Question 15

true/false - SUs havea. positive impact on CV risk

Answer 15

false - they are thought to be neutral

Question 16

side effects of SUs

Answer 16

weight gain

hypoglycaemia - esp in elderly and where hypoglycaemia at risk eg work

Question 17

describe the molecular mechanism of thiazolidinediones

Answer 17

PPARy ligands that bind to co-activator and cause transactivation/transrepression of PPARy target genes
increased differentiation of pre-adiposite to adiposite to increase s/c fat mass and remove FFA from liver
increases adiponectin to increase insulin sensitivity

Question 18

clinical use of TZDs and their effect on HbA1c and blood pressure

Answer 18

reduces by 15-20mmol/mol

reduces blood pressure

Question 19

what is the only TZD available

Answer 19

pioglitazone

Question 20

who are TZDs most effective in

Answer 20

obese women

Question 21

side effects of TZD

Answer 21

weight gain
fracture risk due to fat accumulation in bone marrow, esp elderly
fluid retention, peripheral oedema and heart failure so check pt first

Question 22

describe how the incretin effect is seen on OGTT compared to IVGTT

Answer 22

in OGTT vs IVGTT isolgycaemic standardised glucose is used to demonstrate the same peak in blood glucose but in the OGTT there is a higher peak of insulin to that of IVGTT so there must be something else secreted from gut

Question 23

what are 2 incretins and the cells they are released from

Answer 23

GLP-1 from L cells

GIP from K cells

Question 24

describe the half life of incretins and how they are broken down

Answer 24

they have a very short half life and are broken down by DPPIV

Question 25

describe how GLP-1 augments insulin release

Answer 25

binds to GPCR. via camp to trigger further insulin release from beta cell, but only when the glucose trigger pathway is stimulated already

Question 26

what are some of the actions of GLP-1?

Answer 26

delays gastric emptying increases muscle glucose uptake and storage increases insulin secretion/reduces glucagon reduce appetite decrease gluconeogenesis increase beta cell proliferation

Question 27

mechanism of action of gliptins and their drug class?

Answer 27

DPPIV inhibitors | inhibit DPP4 in different ways to prevent the breakdown of GLP-1 and GIP

Question 28

true/false - DPPIV inhibitors and GLP-1 receptor agonists can cause hypoglycaemia

Answer 28

false - as they only operate when the glucose triggering pathway is already stimulated

Question 29

how much does DPPIV inhibitor lower HbA1c and is it weight losing/gaining?

Answer 29

lowers around 5-8mmol/mol | weight neutral

Question 30

side effects of DPPIV inhibitors

Answer 30

not really any as they are quite well tolerated | may lead to pancreatitis

Question 31

are DPPIV inhibitors good for CV risk?

Answer 31

some studies show there is increased HF admission

Question 32

describe mechanism of action of GLP-1 agonist

Answer 32

GLP-1 like molecule activates GLP-1 receptors but avoids breakdown by DPPIV

Question 33

administration of GLP-1 agonist?

Answer 33

s/c but new oral preparation been developed

Question 34

risk of hypoglycaemia in pt on GLP-1 agonist

Answer 34

very low as only promotes insulin secretion in glucose dependent manner

Question 35

benefits of GLP-1 agonist?

Answer 35

potent reduction in HbA1c with 11-15mmol/mol 2-3kg weight loss reduced SBP and increased HR by 3-10BPM

Question 36

side effects of GLP-1 agonist

Answer 36

nausea and vomiting increased amylase and lipase but unlikely to cause pancreatitis gallstones but slim risk

Question 37

effects of GLP-1 agonist on CV and renal outcomes?

Answer 37

renal outcomes are improved | reduction in CV mortality

Question 38

describe reuptake of glucose in the kidneys

Answer 38

glucose filtered by glomerus and into renal tubule | reuptake by SGLT1 and SGLT2

Question 39

describe how glucosuria occurs in the kidney

Answer 39

more glucose in blood enters kidney than SGLT1/2 can handle and so enters the urine instead of being filtered

Question 40

why does phlorizin cause osmotic diarrhoea

Answer 40

non-specific blocker of SGLT1/2 | SGLT1 is present in the colon and so blockage also draws water into the colon

Question 41

how much blood glucose is lost due to SGLT2i and how much weight is lost

Answer 41

1/4 blood glucose | half a kilo weight loss weekly

Question 42

true/false - SGLT2i induced weight loss continues indefinitely

Answer 42

false - it has a physiological plateau

Question 43

direct side effects of SGLT2i

Answer 43

renal protective diuretic as also blocjks Na reabsorption increased urate excretion

Question 44

how is an SGLT2i renal protective

Answer 44

increased Na delivery to distal convoluted tubule so increased Na uptake by Na/K/Cl transporter at macula densa causes increased adenosine secretion so renal afferent vasodilation and so reduces renal filtration pressure

Question 45

indirect side effects of SGLT2i

Answer 45

reduced glucose so reduced insulin and increased glucagon | increased FFA and ketone body production

Question 46

why is increased FFA and ketone body production in SGLT2i a good thing but also a bad thing

Answer 46

good for cardiac myocytes as FFA and ketone bodies act as a fuel bad as increases risk of ketosis and ketoacidosis

Question 47

how much does SGLT2i lower HbA1c, what is its effect on LDL/HDL and blood pressure

Answer 47

lowers ~11mmol/mol raises LDL/HDL modestly lowers blood pressure due to diuresis

Question 48

name 3 SGLT2i

Answer 48

dapagiflozin, cacagiflozin, empagiflozin

Question 49

undesired side effects caused by SGLT2i

Answer 49

thrush secondary to glycosuria fornier gangrene hypovolaemia/hypotension, esp if low BP or diuretics DKA, even with normal blood glucose

Question 50

true/false - avoid SGLT2i in prolonged fasting or acute illness

Answer 50

true, as they may lead to hypovolaemia or DKA

Question 51

how are SGLT2i in terms of CV risk and renal status

Answer 51

massive CV benefit | renal protective

Question 52

true/false - efficacy of SGLT2i is lost eGFR <45ml/min and glucose benefit gone <30ml/min

Answer 52

false - efficacy begins to be lost around 90ml/min and there is no glucose benefit <45ml/min, but below this it is still renal protective