Pharmacology of drugs for T2DM

Question 1

how do SGLT2 inhibitors work?

Answer 1

cause a decrease in the absorption of glucose in the so that it is excreted in the urine

Question 2

what do SUs bind to?

Answer 2

SUR1

Question 3

what do SUs cause the SUR1 to do & what does this cause?

Answer 3

close the cannel causing depolarisation & insulin release

Question 4

what aspect of SUs mechanism of action could be the cause of their negative die effects?

Answer 4

the fact that insulin is released independent of plasma glucose concentration meaning there is a loss in the link between glucose & insulin secretion

Question 5

give some examples of SUs

Answer 5

tolbutamide
glibenclamide
glipizide

Question 6

how do SUs appear to act?

Answer 6

by displacing the binding of ADP-Mg2+f from the SUR1 subunit, closing the channel

Question 7

which of the SUs are more potent and longer acting?

Answer 7

glibenclamide

glipazide

Question 8

what adverse effect are the more potent & longer acting SUs more likely to cause?

Answer 8

episodes of hypoglycaemia

Question 9

when are SUs 1st line?

Answer 9

in patients who are intolerant to metformin or who are not overweight

Question 10

which other drugs can SUs be used in conjunction with?

Answer 10

metformin

thiazolidinediones

Question 11

what can SUs cause that would be undesirable in diabetics?

Answer 11

weight gain

Question 12

how do glinides work?

Answer 12

bind to SUR1 to close the Katp channel & trigger insulin release

Question 13

give some examples of glinides

Answer 13

repaglinide

nateglinide

Question 14

what is the benefit of glinides?

Answer 14

have rapid onset/offset kinetics so are less likely to cause hypos than SUs

Question 15

when are glands taken?

Answer 15

before meals to reduce postprandial rise in blood glucose

Question 16

which drugs can glinides be used in conjunction with?

Answer 16

metformin

thiazolidinediones

Question 17

GIP

Answer 17

gastric inhibitory peptide

Question 18

what do both GLP-1 & GIP do?

Answer 18

enhance insulin release from pancreatic beta cells & delay gastric emptying meaning enhanced glucose uptake & utilisation

Question 19

what does GLP-1 do that GIP doesn’t do?

Answer 19

decreases glucagon release from pancreatic alpha cells so decreased glucose production

Question 20

what stimulates the release of GLP-1 & GIP?

Answer 20

ingestion of food

Question 21

GLP-1

Answer 21

glucagon like 1

Question 22

where are GLP-1 & GIP released from?

Answer 22

enteroendocrine cells in the small intestine (L cells & K cells)

Question 23

where are L cells found?

Answer 23

ileum & colon

Question 24

where are K cells found?

Answer 24

jejunum/duodenum

Question 25

which cells release GLP-1?

Answer 25

L cells

Question 26

which cells release GIP?

Answer 26

K cells

Question 27

how do incretin analogues work?

Answer 27

mimic the action of GLP-1 but are longer lasting

Question 28

give an example of an incretin analogue

Answer 28

extenatide

Question 29

how does extenatide work?

Answer 29

binds to GPCR GLP-1 receptor that increase intracellular cAMP concentration

Question 30

what physiological effects does extenatide have?

Answer 30

increases insulin secretion suppresses glucagon secretion sloes gastric emptying decreases appetite

Question 31

what does extenatide do to the body?

Answer 31

causes modest weight loss & reduces hepatic fat accumulation

Question 32

how is extenatide administered & how often?

Answer 32

subcutaneously twice daily

Question 33

what side effects could extenatide cause?

Answer 33

nausea hypoglycaemia rarely pancreatitis

Question 34

name a longer acting incretin analogue suitable for once daily subcutaneous administration

Answer 34

liraglutide

Question 35

which ensyme rapidly terminates the actions of GLP-1 & GIP?

Answer 35

enzyme dipeptidyl peptidase-4 (DPP-4)

Question 36

what do DPP-4/gliptins do?

Answer 36

competitively inhibit DPP-4 prolonging the actions of GLP-1 & GIP

Question 37

what other drug classes are gliptins usually used in combination with?

Answer 37

thiazolidinediones | metformin

Question 38

name some gliptins

Answer 38

sitagliptin saxigliptin vildagliptin

Question 39

how is sitagliptin administered & how often?

Answer 39

orally once daily

Question 40

what is alpha-glucosidase & what does it do?

Answer 40

a brush border enzyme that breaks down start & disaccharides to absorbable glucose

Question 41

what do alpha-glucosidase inhibitors do?

Answer 41

delay absorption of glucose thus reducing postprandial increase in blood glucose

Question 42

when are alpha-glucosidase inhibitors used?

Answer 42

in T2DM patients inadequately controlled by life style measures or other drugs

Question 43

where do adverse affects of alpha-glucosidase inhibitors occur?

Answer 43

in the GI tract: | flatulence, loose stools, diarrhoea, abdominal pain, bloating

Question 44

what adverse effect do alpha-glucosidase inhibitors pose no risk of?

Answer 44

hypoglycaemia

Question 45

what type of drug is metformin?

Answer 45

biguanide

Question 46

how does metformin work?

Answer 46

reduces hepatic gluconeogenesis by stimulating AMP-activated protein kinase

Question 47

which drug is first line in the treatment of T2DM in obese patients?

Answer 47

metformin

Question 48

what does metformin do to the body?

Answer 48

increases glucose uptake & utilisation by skeletal muscle (increases insulin signalling) reduces carbohydrate absorption increases fatty access oxidation

Question 49

how is metformin administered?

Answer 49

orally

Question 50

what desirable affects does metformin have?

Answer 50

prevents hypoglycaemia but doesn't cause hypos causes weight loss may be combined with other agents

Question 51

what adverse affects an metformin cause?

Answer 51

``` GI upsets (diarrhoea, nausea, anorexia) rarely lactic acidosis due to the reduction in gluconeogenesis ```

Question 52

what do thiazolidinediones/glitazones (TZDs) do?

Answer 52

enhance the action of insulin at target tissues which reduces the amount of insulin required to maintain a given blood level of glucose

Question 53

how do TZDs work?

Answer 53

act as exogenous agonists of the nuclear receptor PPAR-gamma which associated with retinoid receptor X (RXR)

Question 54

what does an activated PRARgamma-RXR complex act as?

Answer 54

a transcription factor that binds to DNA to promote the expression of genes encoding several proteins involved in insulin signalling

Question 55

what other proteins are involved in insulin signalling?

Answer 55

lipoprotein lipase fatty acid transport protein GLUT4

Question 56

what are the desirable effects of TZD?

Answer 56

promote fatty acid uptake & storage in adipocytes rather than muscles & liver reduced hepatic glucose output

Question 57

what are the adverse effects of TZDs?

Answer 57

weight gain fluid retention increased incidence of bone fractures

Question 58

name the only TZD currently used & why?

Answer 58

pioglitazone doesn't cause hepatotoxicity

Question 59

what other drugs can pioglitazone be used in combination with?

Answer 59

metformin or SUs

Question 60

SGLT2

Answer 60

sodium-glucose contratransporter-2

Question 61

how do SGLT2 inhibitors work?

Answer 61

act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to deliberately cause glucosuria

Question 62

glucosuria

Answer 62

glucose in urine, usually there is none found

Question 63

what are the desirable effects of SGLT2 inhibitors?

Answer 63

``` cause decrease in blood glucose with little risk of hypos calorific loss (weight loss) ```

Question 64

name the currently licensed SGLT2 inhibitor

Answer 64

dapagliflozin

Question 65

what is the adverse effects of SGLT2?

Answer 65

glucosuria provides enhanced breeding ground for bacteria & fungi, increasing the incidence of lower UTIs