Drugs for T2DM Flashcards

1
Q

what type 2 diabetes drugs are dependent upon insulin

A

increasing secretion of inulin

  • sulfonylureas
  • incretin
  • glinides
  • Gliptins (DPP4-inhibitors)

decreasing insulin resistance and reducing hepatic glucose output

  • biguanides
  • thiazolidinediones (glitazones)
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2
Q

what type 2 diabetes drugs are independent from insulin

A

slowing glucose absorption from the GI tract
-glucosidase inhibitors

enhancing glucose excretion by the kidneys
-sodium glucose type-2 inhibitors (SGLT2)

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3
Q

how does high plasma glucose lead to insulin secretion

A

high blood glucose leads to increased disunion of glutamate into the B cell by GLUT2

then glucose is phosphorylated by glucokinase

glycolysis of glucose-6-phosphate in mitochondria yields ATP

increased ATP/ADP ratio within cell closes ATP k+ channels causing membrane depolarisation

opening of voltage-activated Ca2+ channels allowing Ca++ in triggers insulin secretion

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4
Q

how does ATP cause the closing of the ATPk channel

A

high glucose means the ATP levels are high causing the closing of the K channel by ATP binging to a Kir6.2 unit in the channel leading to depolarisation and insulin release

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5
Q

how does low ATP open the Katp channel

A

low glucose means there are low ATP levels (less glycolysis) so ADP levels are high

ADP binds to the SUR1 subunit which opens the channel to maintain the resting action potential of the B cell abnd preventing insulin release

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6
Q

what do sulfonylureas do

A

bing to SUR1 and CLOSE the channel causing depolarisation and insulin release independent of plasma glucose concentration

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7
Q

what do sulfonyureas cause

A

pancreatic B cell insulin secretion - require a functional mass of B cells to be effective

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8
Q

how do sulfonyureas act

A

by displacing the ADP bound to the SUR1 unit and binding instead to close the K atp channel and stimulate insulin release

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9
Q

what is an important side effect of sulfonyureas

A

may cause hypoglycaemia by excessive insulin secretion as they are causing insulin secretion without any input from glucose levels

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10
Q

who is at greater risk of hypoglycaemia from sulfonyureas

A

the elderly
patients with reduce hepatic/renal function (particularly CKD)
those on long acting agents

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11
Q

when are sulfonyureas first line treatment

A

for patients intolerant to metformin or with weight loss

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12
Q

when are sulfonyureas second line

A

when used in conjunction with metformin

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13
Q

what affect do sulfonyureas have on weight

A

cause weight gain

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14
Q

when should you avoid long duration agents (sulfonyureas)

A

in people with CKD
elderly
pregnancy
breast feeding

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15
Q

How do glinides work

A

similar to sulfonylureas
action is augmented by glycaemia

promote insulin secretion in response to meals

bind to SUR1 to close Katp channels and trigger insulin release

less likely to cause hypoglycaemia

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16
Q

what makes glinidines safer than SUs in CKD

A

mainly metabolised by the liver

17
Q

when should you avoid glinidines

A

in severe hepatic impairment
pregnancy
breast feeding

18
Q

why is oral glucose more affective in releasing insulin than IV glucose

(the incretin effect)

A

enteroendocrine cells present in the GI tract which in response to glucose release hormones (incretins) into the blood to trigger release of insulin

19
Q

how do eneteroendocrine cells stimulate decreased glucose production and increased insulin secretion
(the incretin effect)

A

enteroendocrine cells and activated by the ingestion of food to release GLP-1 (glucagon like peptide) and GIP (insulinotropic peptide)

GLP-1 and GIP enter the portal blood causing increased insulin release from B cells and GLP-1 also decreased glucagon release

the increase in insulin increases glucose uptake and the decrease in glucagon decreased glucose production

this leads to a decrease in blood glucose

20
Q

the incretin effect is reduced in T2DM, how does the body try to restore it

A

by reducing break down of incretins

by administering exogenous incretin analogues resistant to breakdown

21
Q

What enzyme breaks down GLP-1 and GIP

A

dipeptidyl peptidase-4 (DPP-4)

22
Q

What do Gliptins do

A

inhibit the action of DPP-4 prolonging the actions of GLP-1 and GIP increasing plasma insulin (therefore only affective if insulin is preserved)

23
Q

when are gliptins used

A

in combination with SU, or metformin but can be used as mono therapy

24
Q

What are incretin analogues

A

peptides that mimic the action of GLP-1 but are much longer lasting due to resistance to breakdown by DPP-4

25
Q

Adverse affects of gliptins

A

weight neutral

nausea

26
Q

adverse affects of incretin analogues

A

modest weight loss

reduce hepatic fat accumulation

27
Q

what are alpha glucosidase inhibitors

A

glucosidase is an enzyme which breaks down starch to glucose at the brush border. Inhibition of this delays glucose absorption so reduces the post-prandial spike in blood glucose

28
Q

what is alpha glucosidase

A

brush border enzyme that breaks down starch and disaccarhides into absorbable glucose

29
Q

when are aplpha glucosidase inhibitors used

A

in T2DM patients with inadequately controlled by life style measures or other drugs eg. SUs

30
Q

adverse affects of alpha glucosidase inhibitors

A

flatulence, loss stools, diarrhoea, abdominal pain, bloating

no risk of hypoglycaemia but only moderately improve glycemic control

infrequently used in UK

31
Q

What is the first line treatment in T2DM

A

metformin (biguanide)

32
Q

how does metformin work

A

reduces hepatic gluconeogenesis (stimulates AMP-activated protein kinase (AMPK)

increases glucose uptake by skeletal muscle

reduces carbohydrate absorption

increases fatty acid oxidation

33
Q

what are the clinical pros of metformin

A

reduces microvascular complications of disease

suitable for oral administration

prevents hyperglycaemia but does not cause hypoglycaemia

causes weight loss

may be combined with other agents

34
Q

what are the adverse affects of metformin

A

GI upset (diarrhoea, nausea, anorexia)

early lactic acidosis - excessive alcohol consumption may increase incidence of lactic acidosis

35
Q

how to thiazolidinediones work (TZD, glitazones)

A

enhance the action of insulin at target tissues - but do not affect insulin secretion (so reduce insulin resistance)

36
Q

what are the desirable affects of thiazolidinediones

A

promote fatty acid uptake and storage in adipocytes rather than in skeletal muscle and liver

reduce hepatic glucose output

enhance peripheral glucose uptake

do not cause hypoglycaemia

37
Q

adverse affects of thiaxolidinediones

A

weight gain
fluid retention
serious hepatoxicity
increased incidence of bone fractures

38
Q

how do sodium-glucose cotransportat inhibitors work (SGLT2)

A

not dependent on insulin

work by acting to block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron

causes decrease in blood glucose with little risk of hypoglycaemia

39
Q

adverse affects of SGLT2

A

weight loss due to calorific loss of glucose being voided