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MB2: Endocrinology > Diabetes pharmacology > Flashcards

Diabetes pharmacology Flashcards

1
Q

describe metformin mechanism of action

A

inhibits complex 1 of mitochondria respiratory chain

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

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2
Q

what cells is metformin taken up into

A

liver, kidneys and intestine

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3
Q

what effects does metformin have on GI tract

A

alters microbioma and increases gut glucose metabolism

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

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4
Q

what effects does metformin have on the liver

A

decreases lipogenesis

decreases gluconeogenesis

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5
Q

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

A

~18mmol/mol

weight neutral/loss

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6
Q

side effects metformin and how to reduce

A

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

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7
Q

true/false - metformin has no CV benefit

A

false - it is beneficial

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8
Q

what is MALA

A

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

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9
Q

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

A

1g daily

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10
Q

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

A

none, it is contraindicated

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11
Q

name 4 suplhonylureas

A

glicazide, glipizide, glimepride, glibenclamide

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12
Q

describe mechanism of action of SUs

A

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

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13
Q

most common dosage and drug used for SU therapy

A

glicazide 40-80mg OD

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14
Q

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

A

around 18mmol/mol

weight gaining due to anabolic insulin action

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15
Q

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

A

false - they are thought to be neutral

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16
Q

side effects of SUs

A

weight gain

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

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17
Q

describe the molecular mechanism of thiazolidinediones

A

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

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18
Q

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

A

reduces by 15-20mmol/mol

reduces blood pressure

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19
Q

what is the only TZD available

A

pioglitazone

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20
Q

who are TZDs most effective in

A

obese women

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21
Q

side effects of TZD

A

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

22
Q

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

A

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

23
Q

what are 2 incretins and the cells they are released from

A

GLP-1 from L cells

GIP from K cells

24
Q

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

A

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

25
Q

describe how GLP-1 augments insulin release

A

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

26
Q

what are some of the actions of GLP-1?

A

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

27
Q

mechanism of action of gliptins and their drug class?

A

DPPIV inhibitors

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

28
Q

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

A

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

29
Q

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

A

lowers around 5-8mmol/mol

weight neutral

30
Q

side effects of DPPIV inhibitors

A

not really any as they are quite well tolerated

may lead to pancreatitis

31
Q

are DPPIV inhibitors good for CV risk?

A

some studies show there is increased HF admission

32
Q

describe mechanism of action of GLP-1 agonist

A

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

33
Q

administration of GLP-1 agonist?

A

s/c but new oral preparation been developed

34
Q

risk of hypoglycaemia in pt on GLP-1 agonist

A

very low as only promotes insulin secretion in glucose dependent manner

35
Q

benefits of GLP-1 agonist?

A

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

36
Q

side effects of GLP-1 agonist

A

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

37
Q

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

A

renal outcomes are improved

reduction in CV mortality

38
Q

describe reuptake of glucose in the kidneys

A

glucose filtered by glomerus and into renal tubule

reuptake by SGLT1 and SGLT2

39
Q

describe how glucosuria occurs in the kidney

A

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

40
Q

why does phlorizin cause osmotic diarrhoea

A

non-specific blocker of SGLT1/2

SGLT1 is present in the colon and so blockage also draws water into the colon

41
Q

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

A

1/4 blood glucose

half a kilo weight loss weekly

42
Q

true/false - SGLT2i induced weight loss continues indefinitely

A

false - it has a physiological plateau

43
Q

direct side effects of SGLT2i

A

renal protective
diuretic as also blocjks Na reabsorption
increased urate excretion

44
Q

how is an SGLT2i renal protective

A

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

45
Q

indirect side effects of SGLT2i

A

reduced glucose so reduced insulin and increased glucagon

increased FFA and ketone body production

46
Q

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

A

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

47
Q

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

A

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

48
Q

name 3 SGLT2i

A

dapagiflozin, cacagiflozin, empagiflozin

49
Q

undesired side effects caused by SGLT2i

A

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

50
Q

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

A

true, as they may lead to hypovolaemia or DKA

51
Q

how are SGLT2i in terms of CV risk and renal status

A

massive CV benefit

renal protective

52
Q

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

A

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

MB2: Endocrinology (13 decks)

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