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pharmacology 2 > glucocorticoids > Flashcards

glucocorticoids Flashcards

1
Q

corticotrophins make

A

ACTH

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2
Q

lactotrophs make

A

prolactin PRL

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3
Q

somatotropin make

A

GH

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4
Q

tyrotrophs make

A

TSH

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5
Q

gonadotrophhs make

A

FSH/LH

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6
Q

HPA axis

A

regulates synthesis and secretion of adrenal corticosteroids
hypothalamus releases CRF in a pulsatile manner
CRF acts on corticotrophins in the anterior lobe pituitary making it release ACTH
ACTH
- acts on adrenal glands to stimulate glucocorticoids
- has a trophic effects on the adrenal cortex (atrophy of the adrenal cortex without sufficient ACTH)
- negative feedback effect on the hypothalamus

glucocorticoids have a negative feedback loop to the HT and downstream effects on the body

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7
Q

3 effects of ACTH

A
  • acts on adrenal glands to stimulate glucocorticoids
  • has a trophic effects on the adrenal cortex (atrophy of the adrenal cortex without sufficient ACTH)
  • negative feedback effect on the hypothalamus
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8
Q

THE HPA axis is responsible for

A

regulating synthesis and secretion og adrenal corticosteroids

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9
Q

what does the hypothalamus do in the HPA axis

A

releases CRF in a pulsatile manner

CRF stimulated anterior lobe pituitary to produce ACTH

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10
Q

3 zones adrenal cortex

A
  1. zona glomerulosa
  2. zona fasciculata
  3. zona reticularis
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11
Q

zona glomerulosa makes

A

mineralocorticoids

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12
Q

zona fascicula makes

A

glucocorticoids

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13
Q

zona reticularis makes

A

sex hormones

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14
Q

glucocorticoids

A

cortisol/hydrocortisone - main ones
corticosterone
secreted in a circadian/diural rhythm - peak at 9am and troph at midnight

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15
Q

mineralocorticoids

A

aldosterone

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16
Q

adrenal steroidogenesis

A

synthesised from cholesterol
side chain cleavage (this is the rate limiting step)
AACTH (GC) and angiotensin 2 (MC) positively regulate conversion of cholesterol to pregnenolone
cortex zone - expression of spefici steroidogenic enzymes, required for synthesis of aldosterone of GCs or sex hormones

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16
Q

adrenal steroidogenesis

A

synthesised from cholesterol
side chain cleavage (this is the rate limiting step)
AACTH (GC) and angiotensin 2 (MC) positively regulate conversion of cholesterol to pregnenolone
cortex zone - expression of spefici steroidogenic enzymes, required for synthesis of aldosterone of GCs or sex hormones

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17
Q

cortex zone -

A

cortex zone - expression of spefici steroidogenic enzymes, required for synthesis of aldosterone of GCs or sex hormones

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18
Q

ACTH and angiotensin 2

A

increase conversion of cholesterol to pregnenolone

increases side chain cleavage

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19
Q

aminoglutethimide

A

reduced side chain cleavage

stops production of steroids

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20
Q

aaldosterone synthesis is increased by

A

angiotensin 2

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21
Q

metabolic effects of glucocorticoids

A
  • CHO metabolism
  • protein catabolism
  • adipose tissue distribution

antiinflammatory/immunosuppressive effects endogenously

resistance to stress

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22
Q

metabolic effects of mineralocorticoids

A

water and electrolyte homeostasis

  • Na retention
  • H2O retention
  • K excretion
  • H excretion

all in order to maintain blood pressure

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23
Q

glucocorticoids are bound to

A

cortisol binding globulins CBG
when they reach the plasma membrane they can cross without needing a receptor
glucocorticoid receptor is in the cytoplasm (not the plasma membrane) (GR) binds hydrocortisone and dimerises and translocates to the nucleus
binds GREs (glucocorticoid response elements) to alter transcription of target genes

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24
Q

glucocorticoid receptor

A

ligand activated transcription factor

ligand is hydrocortisol

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24
Q

glucocorticoid receptor

A

ligand activated transcription factor

ligand is hydrocortisone

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25
Q

when glucocorticoid receptor Is bound

A

it dimerises and binds glucocorticoid response elements which alter transcription of target genes

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26
Q

glucocorticoids receptor is located in

A

the cytoplasm, not plasma membrane

27
Q

transcriptional activation by glucocorticoid receptor

A

most glucocorticoid metabolic effects
represses pro inflammatory genes
transcriptional tethering - tether partner transcription factors to alter gene transcription

28
Q

GR and MR

A

highly homologous receptors
aldosterone is specific for MR does not activate GR)
cortisol binds both, binds MR with equal affinity as aldosterone
cortisol circulates at much higher levels than aldosterone

29
Q

why do MR expressing tissues response to aldosterone and not cortisol

A

because they express
11beta hydroxysteroid dehydrogenase
converts cortisol to cortisone
cortisone is inactive and doesn’t activate MR

29
Q

why do MR expressing tissues response to aldosterone and not cortisol

A

because they express
11beta hydroxysteroid dehydrogenase
converts cortisol to cortisone
cortisone is inactive and doesn’t activate MR

30
Q

Addison’s disease

A

primary adrenal insufficiency
usually autoimmune in origin in western societies causing bilateral destruction of the adrenal cortex
in third world countries it is more likely to be infection (mostly TB)
diagnosis effects mineralocorticoid producing, glucocorticoids producing and sex hormone producing layers (all three layers)

31
Q

clinical presentation of Addisons disease

A
  • fatigue and weakness
    nausea and vomiting, diarrhoea, salt craving
    hypoglycaemia and low blood pressure
    hyperpigmentation due to increase ACTH
  • GC deficiency affects CHO metabolism causing decrease in glucose (hypoglycaemia)
  • MC deficiency affects blood pressure, low blood pressure, hyponatraemic, hyperkalaemic
  • impaired stress tolerance (addisonian/adrenal crisis)
32
Q

secondary deficiency of corticosteroids causes

A
  • usually exogenous steroid use - HPA axis suppression due to low ACTH
  • hypopituitarism
  • postpartum pituitary necrosis - Sheehan’s syndrome
32
Q

deficiencies in Addison’s disease

A

GC deficiency affects CHO metabolism causing decrease in glucose (hypoglycaemia)

  • MC deficiency affects blood pressure, low blood pressure, hyponatraemic, hyperkalaemic
  • addisonian/adrenal crisis (impaired stress tolerance)
33
Q

secondary deficiency of corticosteroids

A

MC secretion is preserved
Na/K balance is normal
ACTH levels are low/normal - no hyperpigmentation
rapid ACTH test will differentiate from primary disease

34
Q

adrenal crisis in 1st and 2nd degree

A

endocrine emergency
precipitated by any stress that increases adrenal demands
treated with IV/IM hydrocortisone/cortisol

35
Q

glucocorticoid excess causes

A

Cushing’s syndrome, which can be caused by

  • cuchings disease increase in ACTH produced by a corticotrophin adenoma in the pituitary
  • increase in ACTH from ectopic source
  • increase in GCs from adrenal adenoma/carcinoma
  • increase in GCs from prescribed GCs = iatrogenic
36
Q

effects of glucocorticoids

A

CHO metabolism - hyperglycaemia, T2DM
protein - catabolism, protein breakdown, thin skin, purple stretch marks, fragile blood vessels causing bruising, fractures from osteoporosis,
fat - redistribution, face, back and abdomen
anti inflammatory/immunosuppression - infections
CNS - mood changes, cognitive impairment, psychosis

37
Q

common signs of sucking’s syndrome

A

catabolic - thin skin and striae, bruising, muscle wasting (thin arms and legs)
fat redistribution - moon faces, buffalo hump, abdomen

38
Q

clinical uses of GCs and MCs as replacement therapies

A

physiological doses - replacement therapy

adrenocortical insufficiency - IV replacement in ED
once stabilised, replaced with physiological levels
hydrocortisone to replicate diurnal rhythm (double dose in the morning)
fludrocortisone once daily (synthetic MC)
in cases of stress - surgery, infection, major trauma - double hydrocortisone dose

39
Q

clinical uses of GC as anti-inflammatory

A

supra physiological doses - GCs only

40
Q

anti inflammatory action of GC

A

inhibit inflammation

  • early during - heat, pain and swelling
  • late - during wound healing and repair

target all types of inflammation

  • infections, chemical stimuli, physical stimuli
  • inappropriate immune responses - hypersensitivity and autoimmune disease

prophylactically used to prevent allograft rejection
neoplasia - combination chemotherapy and cerebral oedema

41
Q

effects of GCs

A
  • anti inflammatory/immunosupressive

- metabolic effects - CHO metabolism, protein catabolism, adipose tissue distribution

42
Q

to isolate anti inflammatory effects of GCs

A

keep anti inflammatory effects but avoid metabolic effects
some synthetic corticosteroids have increased effect on GR and reduced effect on MR
some last longer
bioavailability altered to they can be topically administered

cannot completely seperate anti inflammatory from metabolic effects

43
Q

hydrocortisone

A

equally effective on GC
more effective on MC but inactivated
short half life, short duration of action

44
Q

prednisolone

A

oral glucocorticoid in wide use clinically
4x more potent than hydrocortisone
lower affinity for MC
intermediate half life

45
Q

triamcinolone

A

topical
relative GC receptor potency 5x as potent
doesn’t activate MC receptor
intermediate half life

46
Q

dexamethosone

A

far more potent on GC receptor
doesn’t activate MC
long half life

47
Q

fludrocortisone

A

most potent on MC

intermediate half life

48
Q

pharmacokinetics of GC

A

oral, IM, IV, inhaled, topical, intra-articular, rectal
where possible use locally due to side effects
good oral availability

49
Q

GC injectables

A

succinate/PO4 esters rapidly absorbed Solu-medrone
validate/acetate esters slowly absorbed Depo-medrone
topical/local - huge variety but all have systemic effects

50
Q

distribution, metabolism and excretion of GCs

A

lipid soluble - need to be carried by a carrier protein (some albumin)
rapidly distributed to cells through blood stream
plasma half life is short, biological half is long
sulphated and glucuronated in the liver and excreted into the bile and urine

51
Q

iatrogenic Cushing’s syndrome

A

common side effect of systemic GCs
universal with high dose, long term GC use
patients looks cushingoid

52
Q

if children are given GC

A

growth suppression if >6 months

53
Q

suppression of HPA axis in GC use

A

adrenal atrophy may occur
abrupt withdrawal causes addisionian crisis
must slowly withdraw high dose steroids

54
Q

minimising risk of GC use

A
  • use GC sparing agents
  • Lowest effectje dose for the shortest time

time dose effectively - give in the morning
- alternative days with double dose

55
Q

steroid card/bracelet

A

all patients on steroids should be wearing a bracelet carrying steroid card

56
Q

topical GC

A

vast range available

applicable for psoriasis, excess, dermatitis, allergic conjunctivitis

57
Q

inhaled GC

A

used for asthma and allergic rhinitis

metered dose inhalers e.g. fluticasone

58
Q

intra-lesional GC

A

long acting depot injection

intra/peri articular in RA for bursitis, tenditis etc

59
Q

rectal GC

A

hydrocortisone ointment/suppositories, prednisolone enema/suppositories
inflammatory bowel disease (UC, chrons)

60
Q

GC with vaccines and attenuated live virus immunisation interaction

A

failure to develop immunity

systemic infection for live virus vaccines

61
Q

insulin and oral hypoglycaemia agents with GC interaction

A

hyperglycaemia

62
Q

antacids and GC interaction

A

Impaired GC absorption

63
Q

carbamazepine, phenytoin, barbiturates with GC interaction

A

GC metabolism induction may occur

dose may need to be increased

64
Q

digoxin and GC interaction

A

can cause arrhythmias if there is hypokalaemia

pharmacology 2 (19 decks)

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