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Endocrinology > T2DM Pharmacology > Flashcards

T2DM Pharmacology Flashcards

1
Q

what are the insulin dependent mechanisms of treating T2DM

A

increasing insulin secretion (sulfonylureas, incretin mimetics, glinides, DPP-4 inhibitors)

decreasing insulin resistance abd reducing hepatic glucose output (glitazones)

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2
Q

what are the insulin independent mechanisms for treating T2DM

A

slowing glucose absorption from the GI tract (alpha-glucosidase inhibitors)

enhancing glucose excretion by the kidney (SGLT-1 inhibitors)

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3
Q

describe the relationship between cellular energy and insulin secretion in beta cells starting with blood glucose

A

increased blood glucose

glucose diffuses down conc gradient into B cell via GLUT2

phosphorylation of glucose by glucokinase

glycolysis of glucose - 6 - phosphate in mitochondrian making ATP

increased ATP/ADP ration

closure of ATP sensitive K+ channels

membrane depolarisation

opening of voltage activate Ca+ channels

release of intracellar Ca+

insulin secretion by exocytosis of storage granules

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4
Q

what are the components of KATP and their function

A

4 Kir6.2- form potassium channel

1 SUR1- regulates potassium channel activity

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5
Q

how does the ATP/ADP ratio determine the opening/ closing of KATP

A

ATP binds to Kir6.2- closes channel

ADP binds to SUR1 opening the channel

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6
Q

how do sulfonylureas (SU) act of KATP

A

displace ADP from SURI to close channel- cause depolarisation and the release of insulin

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7
Q

what do SU require

A

a functional mass of beta cells (to stimulate them to release insulin)

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8
Q

give exmaples of SU

A

gliclazine, glipizide

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9
Q

how do SU work

A

displace ADP from SUR1 subunit, closing KATP channel

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10
Q

what is the short ans long term effect of SU’s

A

decrease fasting and post prandial (after a meal) blood glucose

long term reduce the microvascular complications

undesirable weight gain

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11
Q

how long to peak release of insulin after SU

A

1-2 hours- some longer and shorter acting

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12
Q

what is the risk of the longer acting SU (glicazide, glipizide)

A

may cause hypos by excessive insulin secretion

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13
Q

who is most at risk of getting a hypo when using an SU

A

elderyl, reduced hepatic/ renal function, chronic kidney disease

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14
Q

when can SU be given

A

first line in those who cant tolerate metformin/ or with weight loss

second line in conjunction with metformin

third line in conjunction with metformin + thiazolidinediones/ other drugs

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15
Q

why do SUs cause weight gain

A

anabolic effect of insulin increased
appetite increased
urinary loss of glucose decreased

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16
Q

who should SUs not be given to

A

pregnant, breast feeding or elderly

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17
Q

are SUs dependent of glucose concentration

A

no work independently to it

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18
Q

how do glinides work

A

like SUs but action increased by glycaemia

bind to SUR1 to close the KATP channel and trigger insulin release

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19
Q

give examples of glinides

A

repaglininde

nateglinide

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20
Q

what is the onset of glinides

A

30-60 mins

promote insulin secretion in response to meals

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21
Q

why are glinides sometimes better than SUs

A

less likely to cause hypos (than long acting SUs)

metabolised mainly by liver- safer than SUs in CKD

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22
Q

when can and cant glinides be used

A

can be used in conjunction with metformin and thiazolidinediones

cant be given in severe hepatic impairment, pregnancy and breast feeding

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23
Q

is the insulin response greater to oral or IV glucose- why

A

oral

the incretin effect (GLP-1 and GIP)

24
Q

describe the incretin effect

A

ingestion of food stimulates release of GLP-1 and GIP from enteroendocrine cells in the small intestine
these enter the portal blood stream which goes to the pancreas
GLP-1 and GIP enhance (increment) insulin release from beta cells and delay gastric emptying (enhanced glucose uptake and utilisation)
GLP-1 decreases glucagon release from alpha cells
decreased glucose production

all together decrease the blood glucose

25
Q

what are the gliptins, give examples

A

DPP-4 inhibitors: sitagliptin and others all ending in gliptins

26
Q

what happens to the incretin effect in T2DM

A

is reduced

27
Q

what terminates the actions of GLP-1 and GIP

A

the enzyme DPP-4

28
Q

how do gliptins work

A

competitively inhibit DPP-4, prolonging the actions of endogenous GLP-1 and GIP, increasing plasma insulin

29
Q

how can gliptins be administered

A

is orally active
usually used in combo with SU, or metformin
can be given as monotherapy

30
Q

what are the effect and adverse affects of sitagliptin

A

no hypoglycaemia, weight neutral

nausea main adverse affect

31
Q

what are incretin analogues

give examples

A

peptides that mimic the action of GLP-1 but are longer lasting as can resist breakdown by DPP-4

extenatide, liraglutide

32
Q

how do incretin analogues work

A

bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP concentration in B cells to stimulate insulin secretion

also;
suppress glucagon secretion
slow gastric emptying
decrease appetite

33
Q

are incretin analogue weight neutral

A

no cause modest weight loss, reduce hepatic fat accumulation

34
Q

what are the adverse affects of incretin analogues

A

may cause nausea and pancreatitis (rare)

35
Q

how are incretin analogues given

A

subcutaneously

36
Q

what must happen to carbs before it is absorbed into the small intestine and how is this done

A

must be digested into monosaccharides

alpha-glucosidase (a brush border enzyme) breaks starch and disaccharides into absorbable glucose

37
Q

how do alpha-glucosidase inhibitors work

A

when taken with a meal, delay absorption of glucose thus reduce post prandial increase in blood glucose

38
Q

when are alpha-glucosidase inhibitors used

A

in T2DM inadequately controlled by life style measures or other drugs
(not commonly used)

39
Q

what are the adverse affects of alpha-glucosidase inhibitors

A

flatulence, loose stools, diarrhoea, abdominal pain, bloating
(all due to undigested carb)

40
Q

what are the pros and cons of alpha-glucosidase inhibitors

A

pose no risk to hypos

only moderately control glycaemia

41
Q

what is the only theraputic biguanides

A

metformin

42
Q

when is metformin used

A

is first line for T2DM irrespective of obesity, with normal hepatic and renal function

43
Q

when is metformin contraindicated

A

in severe hepatic or renal impairment

44
Q

what are the actions of metformin

A

reduce hepatic gluconeogenesis- stimulate AMP activates protein kinase

increases glucose uptake and utilisation by skeletal muscle (increases insulin signalling)

reduces carbohydrate absorption

increases fatty acid oxidation

45
Q

what are the desirable clinical effects of metformin

A

reduces microvascular complications of diabetes

doesnt cause hypos

given orally

causes weight loss

can be combines (insulin, thiazolidine, SUs)

46
Q

what are the adverse clinical effects of metformin

A

lactic acidosis (rare)- avoid in patients with severe hepatic or renal disease/ excessive alcohol consumption

47
Q

how do thiazolidineones (TZDs) work

A

enhance the action of insulin at target sites
- do not affect insulin secretion
- reduce insulin resistance
activates PPARgamma - RXR complex which is a transcription factor that promotes the expression of genes encoding proteins involved in insulin signalling and lipid metabolism

48
Q

why do TZDs have delayed onset

A

as work on transcription factors

49
Q

what are the desirable affects of TZDs

A

promote fatty acid uptake and storage of adipocytes- rather than in skeletal muscle and liver
reduce hepatic glucose output
enhance peripheral glucose uptake
dont cause hypos

50
Q

what are the adverse affects of TZDs

A

weight gain
fluid retention (Na+ absorption in the kidney)
increased incidence of bone fractures

51
Q

when should TZDs not be used

A

in heart failure- as increase circulating volume

52
Q

give an example of TZD (a.k.a glitazones) used and what it can be used in combo with

A

pioglitazone

metformin, SUs

53
Q

are SGLT2 inhibitors dependent on insulin

A

no

54
Q

how do SGLT 2 inhibitors work

A

selsctively block the re absorption of glucose by SGLT 2 in the proximal tubule of the kidney nephron
deliberately causes glucosuria
cause a decrease in blood glucose with little risk of hypos

55
Q

what are the secondary affects of SGLT 2

A

osmotic diuresus (water loss) and weight loss

56
Q

give 3 examples of SGLT 2 inhibitors

A

dapagliflozin
canaglifozin
empagliflozin

Endocrinology (46 decks)

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