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Endocrine > Drugs in T2DM > Flashcards

Drugs in T2DM Flashcards

1
Q

What is the pathway of production of insulin within the beta cell?

A

Elevation of blood glucose that is transferred into the beta cell via GLUT2
Phosphorylation of glucose by glucokinase
Glycolysis of glucose-6-phosphate in mitcohondria yeilding ATP
Increased ATP/ADP ration within cell closes kATP channels causing depolarisation
Opening of voltage activated Ca2+ channels increases Ca2+ in cell triggering the release of insulin via exocytosis in storage granules

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2
Q

What is the structure of kATP channels?

A

Octomeric complex containing 4 Kir6.2 core subunits and 4 sulphonylurea receptor 1 subunitis (SUR1)

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3
Q

What is the action of SUR1?

A

Regulates potassium channel activity

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4
Q

How does ATP cause the closing of Kir6.2 channels?

A

When all 4 sites on Kir6.2 inner core are occupied by ATP the potassium channel will close causing depolarisation of the beta cell and insulin release

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5
Q

How does ADP-magnesium interact with the SUR1 subunits?

A

Opens the channel maintaining the resting potential of the beta cell and inhibits insulin secretion

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6
Q

What class of drugs are sulphonylureas?

A

Insulin secretogoues

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7
Q

What is the mode of action of SUs?

A

Cause pancreatic beta cell insulin secretion - requires functional beta cells to be effective
Displace the binding of ADP-magnesium from the SUR1 subunit closing the kATP channel and stimulatin insulin release

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8
Q

What are the different types of SU?

A

Short acting = tolbutamide

Long acting = glicazide, glipizide

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9
Q

What are the long term effects of SUs?

A

Reduce the microvascular complications of diabetes

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10
Q

What are the side effects of SU?

A

Hypoglycaemia

Weight gain

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11
Q

Who are hypos more likely with in patients who take SU?

A

Long acting agents in anyone
Elderly
Patients with reduced hepatic/renal function
CKD

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12
Q

In what patients are SUs CI in?

A

Pregnant women

Women who are breastfeeding

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13
Q

When are SUs utilised?

A

First line in patient intolerant to metformin or with weight loss
Second line with metformin
Third line with metformin and thiaolidinedione

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14
Q

How do SUs cause weight gain?

A

Anabolic effect of insulin increased
Appetite increased
Urinary loss of glucose decreased

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15
Q

What is the mechanism of action of glinides?

A

Similar to SU bu action is augmented by glycaemia

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16
Q

How are glinides metabolised?

A

Hepatic - safter than SUs in CKD

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17
Q

How are glinides absorbed?

A 
Active orally
Rapid onset (30-60mins)/ offset 4hr kinetics
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18
Q

Under what scenario are glindes prescribed?

A

In conjunction with metformin and thiazoldinediones

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19
Q

What are the incretin hormones?

A

GLP-1

GIP

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20
Q

What do GLP-1 and GIP enhance?

A

Insulin release from pancreatic beta cells (delay gastric emptying)

21
Q

What does GLP-1 decrease?

A

Release of glucagon from pancreatic alpha cells

22
Q

What does a reduced glucagon release result in?

A

Decreased hepatic gluconeogenesis

23
Q

How can the incretin effect be restored in T2DM?

A

Reducing the breakdown of the endogenous incretins

Administering exogenous incretin analogues resistant to breakdown

24
Q

What enzyme breaks down GLP-1 and GIP?

A

DDP-4

25
Q

When are DDP-4 inhibitors used?

A

In comobo with a SU or metformin but can be a monotherapy

26
Q

What is the main adverse effect of DPP-4 inhibitors?

A

Nausea
NO hypoglycaemia
Weight neutral

27
Q

What are examples of incretin analogues?

A

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

28
Q

How do incretin hormones increase the levels of insulin?

A

Bind as agonists to GPCR GLP-1 receptors that increase intracellular cAMP conc in pancreatic beta cells to stimulate insulin expression and release

29
Q

What are the additional effects of incretin analogues beside the release of insulin?

A 
Suppress glucagon secretion 
Slow gastric emptying 
Decrease appetite (hypothalamic action) 
Weight loss
Reduce hepatic fat accumulation (good for NAFLD)
30
Q

How are incretin analogues administered?

A

SC twice daily

31
Q

What are the side effects of incretin analogues?

A

Nausea

Pancreatitis

32
Q

Where can alpha-glucosidase be found?

A

Brush border enzyme that breaks down starch and disaccharides to absorbable glucose

33
Q

What are examples of alpha glucosisade inhibitors?

A

Acarbose

34
Q

When should acarbose be taken?

A

With a meal to delay the absorption of glucose and thus reduce postprandial increase in blood glucose

35
Q

What are the side effects of alphpa-glucosidase inhibitors?

A 
Flactulence
Loose stools
Diarrhoea
Abdominal pain
Bloating
36
Q

What drug is classed in the biguanide group?

A

Metformin

37
Q

When is metformin used?

A

1st line drug in T2DM irrespective of obesity with normal hepatic and renal function

38
Q

What is the mode of action of metformin?

A

Reduced hepatic gluconeogenesis by stimulating AMPK
Increases glucose uptake and utilization by skeletal muscle
Reduces carbohydrate absorption
Increases fatty acid oxidation

39
Q

What will metformin do in the long term?

A

Reduces the microvascular complications of diabetes

40
Q

How is metformin administered?

A

Orally BD or TDS

41
Q

What desirable effects does metformin have?

A

Weight loss
Prevents hyperglycaemia without causing hypoglycaemia
Combined with other agents

42
Q

What are the adverse effects of metformin?

A

GI upset - diarrhoea, nausea, anorexia

Lactic acidosis

43
Q

What is the mode of action of thiaxoldinediones?

A

Enhance the action of insulin at target tissues - do not directly affect insulin secretion i.e. reduce insulin resistance

44
Q

What transcription factor do glitazones act on?

A

PPAR gamma to promote the expression of genes that code for several proteins involved in insulin signalling and lipid metabolism

45
Q

What are the desirable effects of glitazones?

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

46
Q

What are the adverse effects to glitazones?

A

Weight gain due to the differentation of pre-adipocytes to mature adipocytes
Fluid retention - promote sodium reabsorption by the kidney causing hepatotoxicity
Increased incidence of bone fractures
SHOULD NOT BE USED IN HEART FAILURE

47
Q

What is the mode of action of SGLT-2 inhibitors?

A

Act to selectively block the reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephoron to delibratley cause glucosuria

48
Q

What are the desirable effects of SGLT-2 inhibitors?

A

Reduce hyperglycaemia with a low risk of hypoglycaemia

Calorific loss and weight loss

Endocrine (35 decks)

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