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PHA 332 > diabetes therapies steve darby > Flashcards

diabetes therapies steve darby Flashcards

1
Q

what is diabtes? what happens?

A

Disorder characterised by hyperglycaemia–
Impaired carbohydrate metabolism
–Changes in fat and protein metabolism
–Chronic vascular damage

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2
Q

what is the m/a of insulin on glucose levels?

A

glucose gets transported into cell by GLUT-2 transporter
it gets metabolised by the mitochondria
ATP is generated
this ATP inactivates the k+ channel and it becomes depolarised
this activates the calcium channel
an influx of calcium serves as a trigger for insulin release

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3
Q

what happens when glucose decreases in a normal person?

A

insulin increases

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4
Q

how does insulin affect the metabolism of different tissues?

A

adipose tissue: increases glucose uptake and lipogenesis
decreases lipolysis

striated muscle: increases glucose uptake, glycogen synthesis and protein synthesis

liver: decreases glucogenesis, increases glycogen synthesis and lipogeneiss

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5
Q

how does insulin act to produce its action on glucose levels?

A 
1-Insulin binds Insulin Receptor
2.Receptor is phosphorylated
3.Activates cell signalling
4.Releases Glucose Transporter 4 (GLUT4)
5.GLUT4 imports glucose
•Lowers blood Glucose
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6
Q

what is the structure of insulin?

A

it consists of two peptide chains of 21 and 30 amino acid resides linked by 22 disulfide bonds

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7
Q

what is used now to produce insulin?

A

PA S T– Bovine or Porcine origin

NOW – human origin– recombinant technology

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8
Q

what are the phases of normal insulin release?

A

1st- rapid release of stored insulin

2nd- slow release following synthesis

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9
Q

what is the half life of endogenous circulating insulin ? what clears it?

A

3-5 min
60% is cleared by the liver from the pancreas
kidneys remove 35-40% of insulin

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10
Q

what happens when insulin is subcutaneously injected? how is it cleared?

A

•Therapeutic sub-cutaneous injection is direct into circulation – the ratio is then actually the reversed–Kidneys remove 60% –Liver 30-40%

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11
Q

how is insulin prepared?

A

zinc is used in preparations to helpform the zinc-insulin hexamer

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12
Q

what are the benefits to using zinc as a preparation for a hexamer?

A
  • increases stability of insulin

- delays site of absorption

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13
Q

what is protamine?

A

is a protein (from salmon) that forms insoluble complexes with insulin. Produces prolonged release when administered

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14
Q

what are the 4 classes of injectable insulin’s? and their onset/peak time

A
  1. Rapid Acting – 5-15 min onset
  2. Short Acting– peak 2-3h
  3. Intermediate Acting– peak 6-12h
  4. Long Acting– peak 10-24h
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15
Q

what is the goal for insulin preparations?

A

to replicate the normal physiological insulin secretion patterns

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16
Q

how do you prolong the absorption of insulin to avoid frequent injections?

A

This is achieved by formulating insulin either as a soluble preparation (also called neutral insulin) or as a complex with protamine and/or zinc

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17
Q

what are the different types of insulin formulation?

A

insulin neutral or soluble-short
isophane insulin-intermediate
insulin zinc suspension
protamine zinc insulin both long

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18
Q

how do we make recombinant insulin?

A

we put human insulin genes in a bacteral plasmid
we use ebdinucleases to cut at a specific point
undergoes cell division to make a new copy
bacterial cells produce human insulin protein in bulk
simply purify protein from culture

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19
Q

how can we change the insulin sequence?

A

by modifying the DNA

Simply use enzymes to CUT/CHANGE any DNA base you wish to change the amino acid sequence to make any DESIGNER insulin

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20
Q

what are the 3 commercially available rapid insulins?

A

Insulin -LISPRO, -ASPART, -GLULISINE

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21
Q

when are rapid acting insulins taken?

A

taken before a meal to minimise elevated blood glucose 5-15 min onset

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22
Q

how does lispro differ from normal human insulin?

A

he amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline
this prevents dimer or hexamer formation.

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23
Q

what are the features of short acting insulin?

A
  • Regular Insulin – made as recombinant molecule, Less immune issues than animal insulin
  • Hexamericin nature which means it has a delayed onset compared to Lispro
  • Should be injected 30-45 minsbefore a meal
  • Used especially for IV administration in managing diabetic Ketoacidosis
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24
Q

give an example of an intermediate acting insulin?

A

Neutral Protamine Hagedorn(NPH) Insulin – bound to protamine.

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25
Q

what needs to occur when NPH is injected?

A

Once injected, enzymes need to break down protamine and release insulin (2-5h)

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26
Q

what is an example of a long acting insulin? how does it act?

A

Insulin Glargine – insertion of 2 arginine molecules on chain B and substitution of Glycine with Asparagine at A21 position–Soluble in more acidic conditions (pH4)–Micro precipitates in blood–Provide low level continuous insulin

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27
Q

how does insulin detemir work?

A

it is a newly developed long acting insulin
A myristic acid is attached at B29 – increases self aggregation and albumin binding
•The most reproducible effect of the intermediate/long acting insulins

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28
Q

what are some of the undesirable effects of insulin?

A

Too much = Hypoglycaemia > brain damage > Cardiac arrest
•Diabetic Ketoacidosis – undertreatment with Insulin
•Insulin Allergy •Lipodystrophy at site of injection (animal insulin)
•Cancer risk (contentious)

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29
Q

what are the 3 fundamental stratigies of oral antidiabetic drugs to lower blood glucose?

A

1- increase cellular sensitivity to insulin
2-increase insulin release
3- reduce/delay glucose absorption into the blood

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30
Q

what are the agents that lower glucose by actions on liver, muscle and adipose?

A

metformin and glitazones

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31
Q

what does biguanides do?

A

lowers postprandial hyperglycaemia

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32
Q

how was metformin developed?

A

guanidine was the active ingredient isolated from biguanides. it was then altered to form metformin by adding methyl group

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33
Q

what is the most widely used T2DM antiglycaemc drug?

A

metformin

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34
Q

what is the plasma half life of metformin?

A

1-5hr short

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35
Q

is metformin metabolised?

A

NOT metabolised and is 100% renally eliminated

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36
Q

would metformin be good for obese people?

A

yes, •Metformin can suppress appetite and causes less weight gain than the sulfonylureas, which is useful in overweight people

37
Q

is metformin prone to causing acidosis?

A

•Early biguanides Phenformin and buformin more prone to causing acidosis than metformin so now replaced by metformin

38
Q

is metformin an insulin secretagogue?

A

Is not an insulin secretagogue, It is an insulin sensitiser (MANY mechsanisms)

39
Q

do biguanides affect the output of insulin?

A

no- biguanides are effective mainly in late stage disease where beta cell decline has occurred

40
Q

what effects does metformin produce?

A

lowers hyperglycaemia via multiple mechanisms
does not cause hypoglycaemia
does not cause weight gain
reduces diabetes related death by 42% versus sulphonylurea or insulin alone

41
Q

how does metformin produce its insulin sensitisation?

A

there are many mechanisms - still not fully understood

42
Q

how does the organic cation transporter (OCT1) produce its affect?NB

A

OTC 1 transports metformin into cell in the liver
it works in complex with mitochondrial electron complex 1
this increases AMP levels which is detected by the system.
AMPK detects this increase caused by metformin. this triggers a series of events
It causes increased ammount of lactate in cells and decreased pyruvate which in turn decreases hepatic glucose production.
AMPL also decreases some of these transcription factors in the nucleus which decrease glucogenesis gene expression which also decreases glucose production

43
Q

what is the serious clinical consequence of decreased pyruvate?

A

lactic acidosis
we are forcing cells to produce more lactate
must have 100% renal elimation

44
Q

what are the most common side effects of metformin?

A

diarrhoea and dyspepsia

45
Q

what is lactate a substrate of?

A

gluconeogenesis

46
Q

what renal function tests are required for metformin?

A

Renal Function Test Required–Not prescribed if GFR <45 ml/min
–Treatment should be immediately stopped if GFR drops < 30ml/min

47
Q

how do you test for creatine?

A

orange colour

48
Q

what are glitazones also called?

A

thiazolidinediones (TZD)

49
Q

what role do glitazones play?

A

insulin sensitiser
increase glucose uptake
agonist of PPARY

50
Q

what is the MOA of glitazones?

A

1-goes into cell binds to PPARY.
2- transcription and ttranslation occurs of tarfet genes
3- decreasein IL6 and increase in adiponectin
this decrease in cytokines that interfere with the insulin signalling cascade
4- increase in glucose transporter expression eg.g GLIT 1 and 4

THIS ALL REQUIRES INSULIN

51
Q

what metabolises glitazones?

A

metabolised in the liver to give active and inactive metabolites -CYP3A4- drugs effecting CYP3A4 may impact glitazone levels

52
Q

what is the half life and duration of glitazones?

A

half life=5-6hr

duration=16-24hr= gene transcription mechanism

53
Q

what are the s/e of glitazones?

A

Weight gain, Liver dysfunction (rare), fluid retention (kidneys)

54
Q

what are the drugs that bind suphonylurea receptor and stimulate insulin secretion?

A

secretagogues:

sulphonylurea

55
Q

what is a sulphonylurea made up of?

A

aryl-sulfonyl-urea

56
Q

how does the SUR1 work?

A

sulfonylurea binds to SUR1.
This depolarises the K+ channel.
this leads to an influx of calcium from the voltage dependent calcium channel
insulin is secreted

57
Q

what is the mode of action of sulphonylureas?

A

stimulates beta cells of the islet of Langerhans in the pancreas to release insulin= lowers blood glucose

58
Q

how does the second generation sulfonylurea differ?

A

increased potency, shorter half life, longer duration of action
-much improved binding to sulfonylurea receptor

59
Q

when should sulfonylureas be considered?

A

for diabetic patients who are:
not overweight
where metformin is contraindicated

60
Q

how are sulfonylureas metabolised?

A

Sulfonylureas are extensively metabolized in the liver, primarily by the cytochrome P450 - CYP2C9 –no active metabolites

61
Q

what is the half life of sulfunylureas?

A

short with the exception of chlorpropamide 24-48hr

62
Q

when are sulphonylureas typically used in treatment?

A

typically used in the earlier course of the disease process as they are dependednt on the proper function of beta cells- they may not be present in later stage diabetes

63
Q

when would you not use sulphonylureas?

A

type 1 DM

post-pancreatectomy

64
Q

what does gliclazide not interact with?

A

EPAC2- less hypoglycaemia

65
Q

what are some of the side effects ?

A

nausea, vomiting, diarrhoea, constipation
hypoglycaemia
hypersensitivity reactions
dilutional hyponatraemia

66
Q

what is the MOA of rapid acting meglitnides?

A

insulin releasing agents

Bind to the SUR1 receptor on the β-cell, stimulate insulin release in the same way

67
Q

how are insulin releasing agents metabolised?

A

Metabolised in the liver (CypC28 and Cyp3A4) and have short half-lives (1–2 h)

68
Q

what are the adverse reactions to rapid-acting meglitinides?

A

hypoglycaemia, visual disturbances, diarrhoea, vomiting

69
Q

following food intake what hormones does the body release in order to tell the pancrease to release insulin?

A

GLP-1 and GIP

70
Q

how does increatin mimicing agents produce insulin?

A

GIP/GLP-1 secrete activate cAMP which act upon epac 2 and rap1 to produce insulin

71
Q

what are the two licensed GLP-1 Agonists in the UK?

A

exenatide

liraglutide

72
Q

what do GLP-1 agonists do?

A

increase insulin

decrease glucagon

73
Q

when are GLP-1 agonists used in therapy?

A

3rd line in place of insulin, glitazones or DPP4 inhibitors

74
Q

what are the s/e of GLP-1 agonists?

A

acute pancreatitis

75
Q

what is exenatide?

A

its an injectable therapy that mimics GLP-1 to lower blood glucose

76
Q

how is exenatide excreted?

A

Excreted by the kidneys so not approved for patients with a GFR <30ml/min

77
Q

what does the DPP4 enzyme do?

A

The enzyme dipeptidylpeptidase-4(DPP4) inactivates and degrades incretin hormones

78
Q

what are the gliptins?

A

The ‘gliptins’ are competitive inhibitors of DPP-4, bind directly to the DPP-4 enzyme •Reduce the inactivation of the incretin hormones GLP-1 and GIP. •Prolongs GLP-1 and GIP activity to help reduce glucose levels

79
Q

how is sitagliptin (gliptin) excreted and metabolised?

A
  • Sitagliptinis excreted by the kidney

* Saxagliptinis cleared mainly by CYP450 metabolism in the liver

80
Q

why is the duration of DPP4 inhibitors so long?

A

is unrelated to the plasma half-life due to prolonged binding to the target enzyme

81
Q

what are the side effects of gliptins?

A
  • nausea, vomiting, dyspepsia,
  • oedema,
  • headache, dizziness, fatigue, nasopharyngitis.
82
Q

what are agents that slow intestinal absorption of glucose?

A

alpha-glucosidase inhibitors

83
Q

how do acarboses work?

A
  • Glucose is broken down in stomach
  • If we slow down these snzymes so slow down release of sugars into body
  • Bind and block enzymes in the stomach preventing glucose release
  • Slowing down digestion and release into blood stream
84
Q

what are the side effects of acarbose?

A

diarrhoea and Flatulence(undigested carbohydrates in the colon

85
Q

what are the agents that inhibit glucose reabsorption in the kidney?

A

SGLT2 inhibitors- glifozins
ound in the proximal convoluted tubule of the kidney
•Major role = 90% of glucose reabsorption in the kidneys

86
Q

is SGLT2 insulin dependent?

A

yes

87
Q

give an example of an SGLT2 INHIBITOR and how it works?

A

dapagliflozin

reabsorption of glucose in kidneys

88
Q

who would dapagliflozin be suitable for?

A

SGLT2 inhibitors may be suitable for people with type 2 diabetes
•High blood glucose levels even if taking metformin and insulin

89
Q

who would dapagliozin not be suitable for?

A

patients with renal insuffiency

PHA 332 (42 decks)

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