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bioregulatory systems y2 > endocrinology > Flashcards

endocrinology Flashcards

1
Q

what are the anterior pituitary hormones

A

growth hormone - somatotrophin
prolactin
thyroid stimulating hormone - thyrotrophin (TSH)
lutenising hormone (LH)
follicle stimulating hormone (FSH)
adrenocorticotropic hormone (ACTH, corticotrophin)

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2
Q

what travels in the portal circulation to the anterior pituitary to regulate the anterior pituitary hormone production

A

hypothalamic releasing or inhibitory factors

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3
Q

what are the hormones produced in the hypothalamus

A

corticotrophin releasing hormone
dopamine
growth hormone releasing hormone
somatostatin
gonadotrophin releasing hormone
thyrotrophin releasing hormone

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4
Q

what does prolactin do

A

milk production

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5
Q

what is LH and FSH responsible for

A

oestrogen and progesterone and testosterone

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6
Q

what is TSH responsible for

A

triiodothyronine (T3)
thyroxine (T4)

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7
Q

what is ACTH responsible for

A

cortisol production

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8
Q

what is primary disease

A

an issue or failure with the gland itself eg thyroid gland, adrenal cortex or gonads

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9
Q

what is secondary disease

A

when there are no signals from the hypothalamus or anterior pituitary - problem is further away from the hormone itself?

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10
Q

what is primary hypothyroidism

A

eg autoimmune destruction of thyroid gland
T3 and T4 fall but TSH increases (TRH would also be high but we cannot measure hypothalamic hormones)

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11
Q

what is secondary hypothyroidism

A

eg pituitary tumour damaging thyrotrophs
issue with the pituitary gland or hypothalamus
cannot make TSH
TSH falls
T3 and T4 also fall as there is no TSH to stimulate their production

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12
Q

what is primary hypoadrenalism

A

eg destruction of adrenal cortex (eg autoimmune)
cortisol falls and ACTH increases (CRH also high but we do not measure this)

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13
Q

what is secondary hypoadrenalism

A

eg pituitary tumour damaging corticotrophs
cannot make ACTH > ACTH falls > cortisol falls

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14
Q

what is primary hypogonadism

A

eg destruction of testes (mumps) or ovaries (eg chemotherapy)
testosterone (men) or oestrogen (women) falls
LH/FSH increases (GnRH would also be high but we cannot measure this)

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15
Q

what is secondary hypogonadism

A

eg pituitary tumour damaging gonadotrophs
cannot make FSH/LH > LH/FSH falls > testosterone/oestrogen falls

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16
Q

what are the congenital causes of hypopituitarism

A

(rare btw)
mutations of transcription factor genes needed for normal anterior pituitary development eg PROP1 mutation

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17
Q

what does deficient in GH and at least 1 more pituitary hormone
lead to

A

short stature
hypoplastic (underdeveloped) anterior pituitary gland on MRI

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18
Q

what are the acquired (more common) causes of hypopituitarism (remember TRISTAn)

A

Traumatic brain injury
Radiotherapy (hypothalamic/pituitary damage)
Inflammation (hypophysitis) or infection (eg meningitis)
Surgery or Sheehan’s syndrome
Tumours (adenomas, metastases, cysts)
Apoplexy (incapacity due to haemorrhage or stroke)

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19
Q

what can also cause posterior pituitary dysfunction too

A

inflammation (hypophysitis)
surgery

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20
Q

what is total loss of anterior and posterior pituitary function called

A

panhypopituitarism

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21
Q

what is radiotherapy induced hypopituitarism

A

as the pituitary and hypothalamus both sensitive to radiation
radiotherapy directly or indirectly to the pituitary can induce hypopituitarism
(extent depends on total dose of radiotherapy delivered)

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22
Q

what are the most sensitive to radiotherapy

A

GH and gonadotrophins

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23
Q

what hormone can increase after radiotherapy

A

prolactin (loss of hypothalamic dopamine)

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24
Q

for how long do risks persist after radiotherapy

A

10years

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25
Q

what are the presentations of hypopituitarism for FSH/LH

A

reduced libido
secondary amenhorrhoea
erectile dysfunction
reduced pubic hair

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26
Q

what are the presentations of hypopituitarism for ACTH

A

fatigue (not a salt losing crisis bc aldosterone exists)

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27
Q

what are the presentations of hypopituitarism for TSH

A

fatigue

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28
Q

what are the presentations of hypopituitarism for GH

A

reduced QoL
short stature only in children

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29
Q

what are the presentations of hypopituitarism for PRL

A

inability to breastfeed

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30
Q

what is Sheehan’s syndrome and where is it most commmon

A

post partum hypopituitarism secondary to hypotension (post partum haemorrhage PPH)
most common in developing countries

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31
Q

what is normally seen in a pregnancy that is otherwise abnormal

A

anterior pituitary enlargement due to lactotroph hyperplasia

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32
Q

what does a post partum haemorrhage lead to

A

pituitary infarction

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33
Q

what are some common presentations of Sheehans syndrome

A

lethargy, anorexia and weight loss - due to TSH/ACTH/GH deficiency
failure of lactation - due to PRL deficiency
failure to resume menses post delivery

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34
Q

is the posterior pituitary affected in Sheehans

A

usually not affected

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35
Q

what is the best way to radiologically visualise the pituitary gland

A

MRI scan

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36
Q

what is pituitary apoplexy

A

intra-pituitary haemorrhage or less commonly infarction
often dramatic presentation in patients with pre-existing pituitary tumours (adenomas)

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37
Q

what are the symptoms of pituitary apoplexy

A

severe sudden onset headache (can be the first presentation of a pituitary adenoma)
visual field defect - compressed optic chiasm - bitemporal hemianopia
can be precipitated by anticoagulants

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38
Q

what may the cavernous sinus involvement lead to

A

diplopia (IV, VI), ptosis (III)

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39
Q

what are the biochemical diagnoses’ of hypopituitarism (tests)

A

caution in interpreting basal plasma hormone concs
cortisol - what time of day
T4 - circulating t1/2 6 days
FSH/LH cyclical in women
GH/ACTH - pulsatile

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40
Q

how do we test/diagnose hypopituitarism (specific test) and how does it work

A

dynamic pituitary function test:
ACTH/GH are known as stress hormones so we induce stress
stress = hypoglycaemia (<2.2 mM) = stress
insulin induced hypoglycaemia > stimulates GH and ACTH release and cortisol is measured
TRH stimulates TSH release
GnRH stimulates FSH/LH release

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41
Q

why do we use MRI to visualise pituitary gland

A

pituitary MRI (CT not so good at delineating pituitary gland)
may reveal specific pituitary pathology eg haemorrhage (apoplexy), adenoma
empty sella (turcica) - thin rim of pituitary tissue

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42
Q

what hormones can you treat for in hypopituitarism

A

GH
TSH
LH/FSH
ACTH

NOT PROLACTIN

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43
Q

what are the treatments for GH deficiency

A

NICE guidance
confirm GH deficiency on dynamic pituitary function test
assess quality of life (QoL) using specific questionnaire
daily injection
measure response by
improvement in QoL
plasma IGF-1

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44
Q

what are the treatments for TSH deficiency

A

straightforward
replace with 1 daily levothyroxine
TSH will be low so you cannot use to adjust dose as you do in primary hypothyroidism
aim for a fT4 above the middle of the ref range

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45
Q

what are the treatments for ACTH deficiency

A

replace cortisol rather than ACTH
difficult to mimic diurnal variation of cortisol
2 main options in the UK using synthetic glucocorticoids
prednisolone once daily AM - eg 3mg // hydrocortisone 3x per day eg 10/5/5mg

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46
Q

what is very important to tell patients who have ACTH deficiency

A

sick day rules

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47
Q

what are the sick day rules

A

patients with ACTH deficiency (or Addison’s primary adrenal failure) are at risk of adrenal crisis’ triggered by intercurrent illness
adrenal crisis features - dizziness, hypotension, vomiting, weakness - collapse/death
patients who take replacement steroid eg prednisolone, hydrocortisone must be told sick day rules
steroid alert pendant/bracelet
double steroid dose if fever/intercurrent illness
unable to take tablets eg vomiting inject IM or straight to A&E

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48
Q

what is the treatment for FSH/LH deficiency in men if no fertility is required

A

replace testosterone - topical or intramuscular (most pop)
measure plasma testosterone
replacing testosterone does not restore sperm production (dependent on FSH)

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49
Q

what is the treatment for FSH/LH deficiency in men if fertility is required

A

induction of spermatogenesis by gonadotrophin injections
best response if secondary hypogonadism has developed after puberty
measure testosterone and semen analysis
sperm production may take 6-12 months

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50
Q

what is the treatment for FSH/LH deficiency in women if no fertility is required

A

replace oestrogen
oral or topical
will need additional progestogen if intact uterus to prevent endometrial hyperplasia - risk of endometrial cancer

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51
Q

what is the requirement for FSH/LH deficiency in women if fertility is required

A

can induce ovulation by carefully timed gonadotrophin injections (IVF)

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52
Q

what are the main 3 things you need to know about how a drug exerts its effect on the body

A

where is the effect produced
what is the target for the drug
what is the response that is produced after interaction with the target

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53
Q

are drugs limited to 1 effect

A

NO
drugs can have more than 1 effect and these effects can be produced in different parts of the body
important to be specific as to where the effect would be produced
for a drug to produce an effect it must be bound to a target

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54
Q

for eg where would the effect of cocaine be produced

A

the dopaminergic neurons in the nucleus accumbens is the specific site for drug effect
the target for the drug is the dopamine reuptake protein on the presynaptic terminal
dopamine is not removed from the synapse as quickly and more is available to bind the dopamine D1 receptor, activation of this receptor causes euphoria

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55
Q

what are the 4 drug target classes (proteins)

A

transport proteins
ion channels
receptors
enzymes

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56
Q

what is the drug target for aspirin and how does it work

A

enzyme (cyclooxygenase) and blocks production of prostaglandins

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57
Q

how do local anaesthetics work and what are their drug targets

A

ion channel (sodium) prevents nerve conduction

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58
Q

what is the drug target for prozac and how does it work

A

anti depressant - transport proteins (serotonin carrier proteins) prevents serotonin removal from the synapse

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59
Q

what is the drug target for nicotine

A

receptor (nicotinic acetylcholine receptor)

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60
Q

what does a drug need to show to be an effective therapeutic agent

A

it must show a high degree of selectivity for a particular drug target

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61
Q

example for selectivity

A

consider 3 endogenously produced chemicals : dopamine, noradrenaline and serotonin (structurally similar) - each have a high degree of specificity for specific receptors, but since they look similar they have some degree of specificity for the other receptors - side effects can be produced

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62
Q

why is drug dose important

A

at a low dose, the effect you see is more specific, due to the fact that Pergolide will only interact with one target. As the dose increases, the effect becomes less specific, because Pergolide starts to interact with other drug targets producing other unwanted effects
but it is hard to accurately predict how much drug might arrive at your specific drug target

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63
Q

what are the 4 drug receptor interactions

A

electrostatic interactions
hydrophobic interactions
covalent bonds
stereospecific interactions

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64
Q

what are electrostatic interactions

A

most common mechanism and involves hydrogen bonds and Van der Waal forces

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65
Q

what are hydrophobic interactions

A

this is important for lipid soluble drugs

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66
Q

what are covalent bond interactions

A

these are the least common as the interactions tend to be irreversible

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67
Q

what are stereospecific interactions

A

many drugs exist as stereoisomers and interact stereospecifically with receptors

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68
Q

what is the equation for a drug + receptor

A

drug + receptor ←→ drug receptor complex
for a specific conc of the drug, a specific no. of drug receptor complexes are formed

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69
Q

what happens to the drug receptor complexes when you increase drugs

A

↑ drug + receptor ←→ ↑↑ drug receptor complex
increase the conc of the drug > equilibrium strongly shifted to the right - more drug available to bind to free receptors

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70
Q

what happens to drug receptor complexes when you decrease drugs

A

↓↓ drug + receptor ←→ ↓ drug receptor complex

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71
Q

what 2 categories are drugs classed into

A

agonists and antagonists

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72
Q

what is the difference between agonist and antagonist action

A

both agonists and antagonists possess the ability to bind to receptors - only agonists can bind and activate receptors
agonist - fits into the lock and activates the receptor
antagonists can fit into the lock but jams the mechanisms and prevents the lock from opening (activated)

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73
Q

what determines strength of binding of the drug to the receptor

A

affinity

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74
Q

what is affinity linked to

A

receptor occupancy

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75
Q

fill in this blank
each individual drug receptor is — with many interactions only lasting milliseconds

A

transient

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76
Q

if you have 2 drugs that could be added to the tissue (same numbers of receptors available) which drug would form stronger drug receptor complexes

A

drug with the higher affinity will form stronger drug receptor complexes and thus at any given movement it is more likely that more of this drug will be bound to receptors

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77
Q

what is efficacy

A

refers to the ability of an individual drug molecule to produce an effect once bound to a receptor

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78
Q

what happens after a drug occupies a receptor

A

it does not necessarily produce one standard unit of response
may produce a complete/no/partial response

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79
Q

what is A if Drug A - has affinity for the receptor but no efficacy

A

therefore acts as a receptor antagonist. When bound to the receptor, it is effectively ‘blocking’ that receptor and preventing an agonist from binding to the receptor and inducing activation

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80
Q

what is B if Drug B - has affinity for the receptor and sub-maximal efficacy

A

therefore acts as a partial agonist. When bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor

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81
Q

what is C if Drug C - has affinity for the receptor and maximal efficacy

A

therefore acts as a full agonist. When bound to the receptor, it can produce the maximal response expected from that receptor

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82
Q

what is potency

A

refers to the conc or dose of a drug required to produce a defined effect
potency is related to dose
less drug required to produce an effect - the more potent the drug is

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83
Q

what is the standard measure of potency

A

is to determine the conc or dose of a drug required to produce a 50% tissue response

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84
Q

what is the standard nomenclature for potency

A

EC50 (half maximal effective conc) or the ED50 (half maximal effective dose)

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85
Q

what is the difference between EC50 and ED50

A

the conc that produced a 50% response would be the EC50
dose of drug that produced the desired effect in 50% of the individuals tested would be ED50

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86
Q

which is used to compare potencies, ED50 or EC50

A

ED50

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87
Q

what does a highly potent drug produce

A

large response at relatively low concs

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88
Q

what does a highly efficacious drug produce

A

a maximal response and this effect is not particularly related to drug conc

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89
Q

what is the diff between a partial and full agonist

A

diff in efficacy

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90
Q

is efficacy or potency related to dose

A

potency

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91
Q

which is more important, efficacy or potency

A

efficacy is more important, you want to know if the drug can produce a maximal response
potency simply determines the dose that you will need to administer to produce a response - if you have 2 drugs that have the same efficacy then it doesn’t matter if 1 is more potent than the other as you can still produce maximal response with the less potent drug but you will just need to administer a higher conc

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92
Q

what is the posterior pituitary anatomically continuous with

A

hypothalamus

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93
Q

what do hypothalamic magnocellular neurons contain

A

AVP and oxytocin

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94
Q

where do hypothalamic magnocellular neurons originate

A

long, originate in supraoptic and paraventricular hypothalamic nuclei
nuclei → stalk → posterior pituitary

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95
Q

what is another name for vasopressin

A

ADH (antidiuretic hormone)

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96
Q

what does diuresis mean

A

production of urine

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97
Q

what is the main physiological action for ADH

A

stimulation of water reabsorption in the renal collecting duct > concentrates urine (smaller vol)

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98
Q

what does ADH act through

A

the V2 receptor in the kidney
also a vasoconstrictor (via V1 receptor)
stimulates ACTH release from anterior pituitary

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99
Q

what is the mechanism for ADH/AVP action

A

AVP through bloodstream to collecting duct to V2
intracellular mechanism leading to aquaporin 2 migration to apical membrane and insertion
water can go through Aq2 to Aq3 on basolateral membrane
therefore less water (reabsorbed into plasma) and more conc of urine

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100
Q

how can we visualise the posterior pituitary on MRI

A

sagittal MRI
posterior pituitary = bright spot on MRI
not visualised in all healthy individuals so absence may be normal variant

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101
Q

what are the physiological effects of vasopressin (3)

A

antidiuretic effect
vasoconstriction via V1 receptor
stimulation of reabsorption of water in collecting duct
(also stimulates ACTH)

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102
Q

what is the difference between osmotic and non osmotic stimuli for vasopressin release

A

osmotic (increase in conc)
rise in plasma osmolality sensed by osmoreceptors
non osmotic
decrease in atrial pressure sensed by atrial stretch receptors

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103
Q

where are osmoreceptors found

A

hypothalamic nuclei
organum vasculosum and subfornical organ
both nuclei which sit around the 3rd ventricle (circumventricular)

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104
Q

why is it beneficial for there being no blood brain barrier between the circumventricular nuclei

A

neurons can respond to changes in the systemic circulation
highly vascularised
neurons project to the supraoptic nucleus - site of vasopressinergic neurons

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105
Q

STEPS for how osmoreceptors regulate vasopressin

A

1) increase in extracellular NA+
2) H2O leaves osmoreceptor
3) osmoreceptor shrinks
4) increased osmoreceptor firing
5) AVP release from hypothalamic neurons

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106
Q

STEPS for non osmotic stimulation of vasopressin release

A

1) atrial stretch receptors detect pressure in the right atrium
2) inhibit vasopressin release via vagal afferents to hypothalamus
3) reduction in circulating volume eg haemorrhage means less stretch of these atrial receptors so less inhibition of vasopressin

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107
Q

why is vasopressin released following a haemorrhage

A

reduction in circulating volume after haemorrhage
vasopressin release results in increased water reabsorption in the kidney (some restoration of circulating volume) V2 receptors
vasoconstriction via V1 receptors
renin aldosterone system will also be important, sensed by JG apparatus

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108
Q

what happens when you have increased plasma osmolality

A

1) increased plasma osmolality
2) stimulation of osmoreceptors
3) thirst and increased AVP release
4) increased water reabsorption from renal collecting ducts
5) reduced urine volume and increase in urine osmolality
6) reduction in plasma osmolality

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109
Q

what is diabetes insipidus

A

a problem with AVP
either insufficiency or resistance (cranial or nephrogenic)

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110
Q

what are the symptoms of diabetes insipidus

A

polyuria
nocturia
thirst - often extreme
polydipsia
in diabetes mellitus (hyperglycaemia), these symptoms are due to osmotic diuresis
in diabetes insipidus, these symptoms are due to a problem with arginine vasopressin
most common cause of polyuria, nocturia and polydipsia is diabetes mellitus not insipidus

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111
Q

what are the 2 types of DI

A

cranial DI
nephrogenic DI

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112
Q

what is cranial DI

A

cranial (central) diabetes insipidus - problems with hypothalamus and or posterior pituitary - unable to make arginine vasopressin

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113
Q

what is nephrogenic DI

A

nephrogenic diabetes insipidus - can make arginine vasopressin (normal hypothalamus and posterior pituitary)
kidney (collecting duct) - unable to respond to it

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114
Q

what are the acquired (more common) causes of cranial DI

A

STIGMA
pituitary Surgery
pituitary Tumour
traumatic brain Injury
Granulomatous infiltration of pituitary stalk e.g. TB or sarcoidosis
Metastasis e.g. from breast cancer
Autoimmune

there are some congenital rare causes

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115
Q

what are the congenital causes of nephrogenic diabetes I

A

rare (mutation in gene encoding V2 receptor, aquaporin 2 type water channel)

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116
Q

what are the acquired causes of nephrogenic DI

A

drugs eg lithium (damages the collecting duct - reduces ability to respond to AVP)

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117
Q

what is the presentation for DI

A

polyuria
nocturia
thirst - often extreme
polydipsia (thirsty)
urine = very dilute (hypo-osmolar) and large volumes
plasma = increased conc (hyperosmolar) patient becomes dehydrated, increased sodium (hypernatraemia), glucose normal, always check a patient with these for DM

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118
Q

why do people with DI present with high serum sodium

A

passing large volumes of dilute urine
less water retained therefore salty blood

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119
Q

STEPS for how DI works/why these symptoms occur

A

1) AVP problem (not enough - CDI, not responding - NDI)
2) impaired conc of urine in renal collecting duct
3) large volumes of dilute (hypotonic) urine
4) increase in plasma osmolality (and sodium) - dehydrated
5) stimulation of osmoreceptors
6) thirst polydipsia (could lead to death if no water available)
7) maintains circulating volume as long as patient has access to water

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120
Q

what are the clinical features of DI (No PPE)

A

nocturia
polyuria
polydipsia
extreme thirst

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121
Q

what is psychogenic polydipsia

A

similar presentation to diabetes insipidus
polydipsia
polyuria
nocturia
unlike diabetes insipidus - no problem w arginine vasopressin
problem is that the patient drinks all the time so passes large volumes of dilute urine
psychological

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122
Q

STEPS for psychogenic polydipsia and how it affects patients

A

increased drinking
plasma osmolality falls
less AVP secreted by posterior pituitary
large volumes of dilute (hypotonic) urine
plasma osmolality returns to normal

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123
Q

how do we distinguish between DI and PP

A

water deprivation test

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124
Q

what is the water deprivation test

A

no access to anything to drink
measure urine volumes over time
measure urine conc (osmolality) over time
measure plasma conc (osmolality) over time
weigh regularly - stop test if lose >3% of body weight (a marker of significant dehydration which can occur in diabetes insipidus and low urine osmolality)

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125
Q

explain the water deprivation test

A

DI patients cannot concentrate their urine despite not having any water intake bc they either do not have enough or are resistant to AVP
PP patients will be able to concentrate their urine because they have AVP

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126
Q

how do we distinguish between cranial and nephrogenic diabetes insipidus

A

give ddAVP

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127
Q

how does giving ddAVP help us distinguish between CDI and NDI

A

work “like” vasopressin
cranial diabetes insipidus - response to ddAVP - urine concentrates
nephrogenic diabetes insipidus - no increase in urine osmolality with ddAVP as kidneys cannot respond
ddAVP (desmopressin, synthetic AVP) - fixes the issue in CDI but not in NDI

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128
Q

what is the treatment for cranial DI

A

want to replace vasopressin
desmopressin
selective for V2 receptor (V1 receptor activation would be unhelpful)
different preparations = tablet // intranasal

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129
Q

what is the treatment for nephrogenic DI

A

this is rare but difficult to treat successfully
thiazide diuretics eg bendrofluazide
paradoxical - mechanism unclear

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130
Q

what is SIADH

A

syndrome of inappropriate antidiuretic hormone

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131
Q

what happens when you have too much AVP

A

reduced urine output
water retention
high urine osmolality
low plasma osmolality
dilutional hyponatremia

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132
Q

what are some causes of SIADH

A

CNS
- head injury, stroke, tumour
pulmonary disease
- pneumonia, bronchiectasis
malignancy
- lung cancer (small cell)
drug related
- carbamazepine, serotonin reuptake inhibitors (SSSRIs)
idiopathic

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133
Q

other expensive treatments of SIADH

A

common cause of prolonged hospital stay
fluid restrict
can use a vasopressin antagonist (vaptan) - binds to the V2 receptors in the kidney (£££)
when sodium goes down - feel light headed

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134
Q

what happens at the kidney regarding sodium in SIADH

A

water reabsorption happens at the kidney so sodium will be low not high

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135
Q

what does thyroxine do to cells in the body

A

binds to cells
increases basal metabolic rate
speeds up processes in those cells
“warms” cells up

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136
Q

what is the control of thyroid activity

A

TRH released by thyrotrophs in the hypothalamus
stimulates pituitary to produce TSH
stimulates thymus to produce T3 and 4
negative feedback

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137
Q

what is the level of TSH in a patient with primary hypothyroidism and how do we treat this

A

high TSH
increase dose till TSH falls back to normal

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137
Q

what is the level of TSH in a patient with primary hypothyroidism and how do we treat this

A

high TSH
increase dose till TSH falls back to normal

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138
Q

what is Graves disease

A

autoimmune
antibodies bind to and stimulate the TSH receptor in thyroid
cause goitre (smooth) and hyperthyroidism

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139
Q

what are some symptoms of Graves disease

A
  • perspiration
  • facial flushing
  • SoB
  • loss of weight
  • goiter
  • exophthalmos
  • diarrhoea
  • tremor
  • pretibial myxoedema
  • increased appetite
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140
Q

what causes exophthalmos

A

other antibodies bind to muscle behind the eye and cause this

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141
Q

what causes pretibial myxoedema

A

other antibodies
(hypertrophy)

142
Q

what is the swelling (non-pitting) that occurs on the shins of patients w/Graves disease

A

growth of soft tissue

143
Q

what is Plummer’s disease

A

more common than Graves (esp in older people)
toxic nodular goitre
benign adenoma that is overactive at making thyroxine
NOT autoimmune
NO pretibial myxoedema
NO exophthalmos

144
Q

what are the effects of thyroxine on the SNS

A

sensitises beta adrenoreceptors to ambient levels of adrenaline and noradrenaline
there is apparent sympathetic activation
tachycardia, palpitations, tremor in hands, lid lag

145
Q

what are the features of hyperthyroidism

A

weight loss despite increased appetite
breathlessness
palpitations, tachycardia
sweating
heat intolerance
diarrhoea
lid lag and other sympathetic features

146
Q

what is a thyroid storm/symptoms of a thyroid storm

A

blood results confirm hyperthyroidism
hyperpyrexia > 41 degrees celsius
accelerated tachycardia/arrhythmia
cardiac failure
delirium/frank psychosis
hepatocellular dysfunction : jaundice (bc liver cannot cope)
2 signs = storm
needs aggressive treatment

147
Q

what are treatment options for hyperthyroidism

A

surgery (thyroidectomy)
radioiodine
drugs (thionamides - antithyroid drugs)

148
Q

symptoms of hyperthyroidism

A

weight loss despite increased appetite
SoB
palpitations, tachycardia
sweating
heat intolerance
diarrhoea
lid lag and other sympathetic features
fatigue/tiredness

149
Q

what is the daily treatment of hyperthyroidism

A

thionamides

150
Q

how do thionamides affect thyroid hormone synthesis

A

inhibits the enzyme thyroid peroxidase and therefore T3 and 4 synthesis and secretion
(biochemical effect = hours)
(clinical effects = weeks)
treatment regimen may include propranolol - rapidly reduces tremor/tachycardia (as it is a beta blocker)

151
Q

what are some unwanted actions of thionamides

A

agranulocytosis (usually reduction in neutrophils) - rare and reversible on withdrawal of drug
rashes (common)

152
Q

what does the follow up of thionamides consist of

A

aim to stop antithyroid drug treatment after 18 months
review patient periodically including thyroid function tests for remission/relapse

153
Q

what are the roles of beta blockers in thyrotoxicosis

A

several weeks for ATDs to have clinical effects eg reduced tremor, slower heart rate, less anxiety
non selective (ie beta1 and beta2) beta blocker
eg propranolol
achieves these effects in the interim

154
Q

describe the treatment of KI

A

(doses at least 30x the average daily requirement)
prep of hyperthyroid patients for surgery
severe thyrotoxic crisis (thyroid storm)
only lasts for 10 days - not long term treatment

155
Q

what is the mechanism action of KI

A

inhibits iodination of thyroglobulin
inhibits H2O2 generation and thyoperoxidase
hyperthyroid symptoms reduce within 1-2 days
vascularity and size of the gland reduces within 10-14 days

156
Q

why does KI only work for about 10 days

A

eventually the iodide is taken up
activated and makes thyroxine

157
Q

what are some problems with surgery

A

risk of voice change - recurrent laryngeal nerve
risk of also losing parathyroid glands
scar
anaesthetic

158
Q

how does radioiodine work as a treatment

A

swallow a capsule containing about 370 MBq (10mCi) of the isotope I (131)
contradicted in pregnancy
need to avoid children and pregnant mums for a few days!!
for scans only (not treatment) - 99-Tc pertechnetate is an option
ACTIVELY AVOID PEOPLE

159
Q

what are the drug treatment options

A

drugs
- beta blockade is v important
- propranolol
antithyroid drugs
- carbimazole
- propylthiouracil

160
Q

what is the mechanism for Viral (de Quervains) thyroiditis

A

viral attacks thyroid gland causing pain and tenderness
thyroid stops making thyroxine and makes viruses instead
thus no iodine uptake (none at all)
virus releases ALL thyroxine
radioiodine uptake zero
stored thyroxine released
toxic with zero uptake
4 weeks later - stored thyroxine exhausted - hypothyroid
after 1 more month - resolution occurs (like all viral diseases)
patient = euthyroid again

161
Q

what are some symptoms for viral (de Quervains) thyroiditis

A

painful dysphagia
hyperthyroidism
pyrexia
thyroid inflammation

162
Q

what is post partum thyroiditis

A

similar to viral thyroiditis but no pain and only occurs after pregnancy
immune system modulated during pregnancy

163
Q

summary of viral thyroiditis

A

neck becomes painful
all stored thyroxine released
free T4 levels rise
TSH level drops
1 month hyperthyroidism
but NO new thyroxine synthesis
so Ft4 slowly falls:
patient = hypothyroid - gland stops making thyroxine and replicates virus only
hypothyroidism lasts a 2nd month
after 3 months slow recovery

164
Q

what do somatotrophs make

A

GH
somatotrophin

165
Q

what do lactotrophs make

A

PRL

166
Q

what do thyrotrophs make

A

TSH
thyrotrophin

167
Q

what do gonadotrophs make

A

LH and FSH

168
Q

what do corticotrophs make

A

ACTH
corticotrophin

169
Q

what are functioning pituitary tumours of somatotrophs called

A

causes acromegaly

170
Q

what are functioning pituitary tumours of lactotrophs called

A

prolactinomas

171
Q

what are functioning pituitary tumours of thyrotrophs called

A

TSHoma

172
Q

what are functioning pituitary tumours of gonadotrophs called

A

gonadotropinoma

173
Q

what are functioning pituitary tumours of corticotrophs called

A

corticotroph adenoma
Cushing’s disease

174
Q

how do we classify pituitary tumours

A

radiologically (MRI)
function
benign

175
Q

how do we describe the radiological classification of a pituitary tumour

A

microadenoma <1cm
macroadenoma >1cm
sellar or suprasellar
compressing optic chiasm or not
invading cavernous sinus or not

176
Q

how do we describe classification of a pituitary tumour using function (of the tumour)

A

excess secretion of a specific pituitary hormone eg prolactinoma
no excess secretion of pituitary hormone eg non functioning adenoma

177
Q

how do we describe the classification of a pituitary tumour using whether it is benign (not cancer)

A

pituitary carcinoma very rare <0.5% of pituitary tumours
mitotic index measured using ki67 index - benign is <3%
pituitary adenomas can have benign histology but display malignant behaviour

178
Q

how does hyperprolactinaemia inhibit kisspeptins

A

PRL binds to PRL receptors on kisspeptin neurons in hypot.
inhibits kisspeptin release
decrease downstream GnRH therefore > LH/FSH/T/Oestrogen
leading to oligoamenorrhoea, low libido, infertility, osteoporosis
flattens GnRH pulsatility
(secondary hypogonadism)

179
Q

describe prolactinomas

A

commonest functioning pituitary adenoma
usually serum [prolactin] >5000mU/L
serum [PRL] proportional to tumour size

180
Q

what is the presentation for patients with a prolactinoma

A

menstrual disturbance
erectile dysfunction
reduced libido
galactorrhoea (more common in women)
subfertility

181
Q

what are the physiological causes of an elevated PRL

A

pregnancy/breastfeeding
stress : exercise, seizure, venepuncture (as it is a stress hormone)
nipple/chest wall stimulation

182
Q

what are the pathological causes of an elevated PRL

A

primary hypothyroidism (high TSH = high PRL)
polycystic ovarian syndrome
chronic renal failure

183
Q

what are iatrogenic causes of an elevated PRL

A

antipsychotics
selective serotonin reuptake inhibitors
anti-emetics
high dose oestrogen
opiates

184
Q

why is it important to confirm TRUE elevation in serum PRL

A

(lot of false positives) order MRI
no diurnal variation - not affected by food
where you see a mild elevation in serum prolactin - if patient has no clinical features consistent with this (and review of medication list has occurred) think of 2 things:
macroprolactin
stress of venepuncture

185
Q

describe macroprolactin

A

majority of circulating prolactin is monomeric and biologically active
this prolactin = “sticky”
a polymeric form of PRL
an antigen-antibody complex of monomeric PRL and IgG
recorded on assay as elevation of PRL (needs alternative method to confirm)
limited bioavailability and bioactivity

186
Q

describe how stress of venepuncture causes high PRL

A

exclude by cannulated PRL series
sequential serum [PRL] measurement 20 mins apart with an indwelling cannula to minimise venepuncture stress

187
Q

what do you do when confirmed true pathological elevation of serum PRL

A

organise pituitary MRI

188
Q

what are treatments of prolactinoma

A

1st line = medical not surgical
dopamine receptor agonists!!!!! mainstay of treatment
cabergoline (bromocriptine) - safe in pregnancy
aim = normalise serum PRL and shrink prolactinoma
microprolactinomas = smaller doses than macroprolactinomas

189
Q

how do dopamine receptor agonists reduce PRL and shrink prolactinomas

A

lactotroph has D2 receptors (job = make PRL)
PRL has an off but not an on switch
dopamine (from hypothalamic dopaminergic neurones) binds to D2 receptor and therefore no PRL
dopamine receptor agonists work like dopamine - bind to D2 and turns off PRL

190
Q

what do pituitary tumours secreting excess GH cause in adults and children

A

gigantism = children
acromegaly = adults
acromegaly
often insidious presentation - mean time to diagnose from onset of symptoms = 10y

191
Q

what is menorrhagia a feature of

A

primary hypothyroidism

192
Q

what are the symptoms of acromegaly

A

sweatiness!!
headache!!
coarsening of facial features
macroglossia
prominent nose
large jaw - prognathism
increased hand and feet size
snoring and obstructive sleep apnoea
hypertension
impaired glucose tolerance/diabetes mellitus

193
Q

what are the mechanisms of growth hormone

A

released by AP
acts on liver which produces IGF-1 (somatomedin)
IGF-1 also causes increased metabolic actions > growth and development

194
Q

how do we diagnose acromegaly

A

as GH is pulsatile, random measurement is not helpful
elevated serum IGF-1
failed suppression (paradoxical rise) of GH following oral glucose load - oral glucose tolerance test

prolactin can be raised - secretion of GH and PRL

195
Q

what do you do once you confirm GH excess

A

pituitary MRI to visualsies pituitary tumour

196
Q

what are the treatments for acromegaly - increased CV risk in untreated acromegaly

A

1st line = surgical - transsphenoidal pituitary surgery - through sella turcica to access pituitary
aim = normalise serum GH and IGF-1
can use medical treatment prior to surgery to shrink tumour or if surgical resection incomplete
somatostatin analogues eg octreotide - endocrine cyanide - not specific for GH (side effects)
dopamine agonists eg cabergoline (GH secreting pituitary tumours frequently express D2 receptors)
radiotherapy (slow)

197
Q

what is Cushings syndrome

A

occurs due to an excess of cortisol or other glucocorticoid
excess cortisol
cushings disease is due to a corticotroph adenoma secreting ACTH

198
Q

what are causes of Cushings syndrome

A

taking steroids by mouth (common)
pituitary depending Cushings disease (pituitary adenoma)
Ectopic ACTH (lung cancer)
adrenal adenoma or carcinoma

199
Q

what are some symptoms of Cushings syndrome

A

red cheeks
fat pads (buffalo hump)
thin skin
osteoporosis
impaired glucose tolerance
high BP
proximal myopathy (muscle weakness)
thin arms and legs
purple striae
easy bruising
moon face
pendulous abdomen
poor wound healing
mental changes

200
Q

what are ACTH dependent causes

A

cushings disease (corticotroph adenoma)
ectopic ACTH (lung cancer)

201
Q

what are ACTH independent causes

A

taking steroids by mouth (common)
adrenal adenoma or carcinoma

202
Q

what are some investigations for Cushing’s disease

A

elevation of 24h urine free cortisol - increased cortisol secretion
elevation of late night cortisol - salivary or blood test - loss of diurnal rhythm
failure to suppress cortisol after oral dexamethasone (exogenous glucocorticoid) - increased cortisol secretion

203
Q

what do you do once you confirm hypercortisolism

A

measure ACTH
if ACTH high = pituitary MRI ACTH dependent

204
Q

what are non functioning pituitary adenomas doing to vision

A

don’t secrete any specific hormone
often present with visual disturbance (bitemporal hemianopia)

205
Q

what are non functioning pituitary adenomas : hormones

A

can present with hypopituitarism
serum PRL can be raised (dopamine cannot travel down pituitary stalk from hypothalamus)
trans-spehnoidal surgery needed for larger tumours - esp if visual disturbance

206
Q

what hormones are involved to increase levels of serum calcium and phosphate

A

vitamin D (calcitriol//1,25 (OH)2 cholecalciferol
synthesised in the skin or intake via diet
PTH secreted by parathyroid glands

both have actions on the kidney, bone and gut

207
Q

what hormones are involved in decreasing the levels of serum calcium and phosphate

A

calcitonin (secreted by thyroid parafollicular cells)
reduces calcium acutely - no negative effect if parafollicular cells are removed via thyroidectomy

208
Q

what is a good indicator for body vit D status

A

serum 25-OH vitamin D

209
Q

what regulates its own synthesis by decreasing transcription of 1 alpha hydroxylase

A

1, 25 (OH)2 vitamin D (calcitriol)

210
Q

we cannot measure calcitriol so instead we measure

A

25 hydroxycholecalciferol

211
Q

what is the synthesis of vitamin D metabolism from UVB

A

UVB > 7 dehydrocholesterol > previtD3 > vitD3 > 25 hydroxylase in the liver = 25(OH) cholecalciferol > 1 alpha hydroxylase in the kidney = 1,25 (OH)2 cholecalciferol

212
Q

what is the synthesis of vit D from vit D2 in diet

A

vit D2 from diet > vit D3 > 25 hydroxylase in the liver = 25(OH) cholecalciferol > 1 alpha hydroxylase in the kidney = 1,25 (OH)2 cholecalciferol

213
Q

what are the 3 effects of calcitriol

A

1,25 (OH)2 D3
in kidney (increases calcium and phosphate reabsorption)
in gut (increases absorption of calcium and phosphate)
in bone (increases osteoblast activity (bone building))

214
Q

what are the actions of PTH on calcium and phosphate

A

stimulates vit D synthesis
in bone (increases osteoclast activity, bone consumption, increased calcium reabsorption from bone)
in kidney (increases calcium reabsorption, increases phosphate excretion, increases 1 alpha hydroxylase activity which therefore increases 1,25 (OH)2D3 synthesis)
increased vit D synthesis has effects on the gut (increases calcium and phosphate absorption)

215
Q

what is the regulaion of serum phosphate by fgf23

A

lower phosphate by increased secretion into urine
decreased calcitriol production
PTH and FGF23 both inhibit the transporter Na+/PO43- which promotes phosphate loss by urine (FGF 23 also inhibits calcitriol formation)

216
Q

what are the signs and symptoms of hypocalcaemia

A

paraesthesia (hands, mouth, feet and lips)
convulsions
arrhythmias
tetany
CATs go numb

217
Q

what is Chvosteks sign

A

facial paraesthesia

218
Q

what is Trousseaus sign

A

carpopedal spasm

219
Q

what are the causes of hypocalcaemia

A

low PTH levels = hypoparathyroidism
surgical - neck surgery
auto immune
magnesium deficiency
congenital (agenesis, rare)

low vitamin D levels
deficiency - diet, UV light, malabsorption, impaired production (renal failure)

220
Q

what are the signs and symptoms for hypercalcaemia

A

“stones, abdominal moans and psychic groans”
reduced neuronal excitability - atonal muscles
stones - renal effects
nephrocalcinosis - kidney stones, renal colic
abdominal moans - GI effects
anorexia, nausea, dyspepsia, constipation, pancreatitis
psychic groans - CNS effects
fatigue, depression, impaired concentration, altered mentation, coma (usually >3 mmol/L)

221
Q

what are the causes of hypercalcaemia

A

primary hyperparathyroidism
too much PTH
usually due to a parathyroid gland adenoma
no negative feedback - high PTH, but high calcium
malignancy
bony metastases produce local factors to activate osteoclasts
certain cancers (eg squamous cell carcinomas) secrete PTH related peptide that acts at PTH receptors
vitamin D excess (rare)

222
Q

how does the parathyroid gland respond when there is a decrease in calcium levels

A

increase PTH

223
Q

how does the parathyroid gland respond when there is an increase in calcium levels

A

decrease PTH
(negative feedback)

224
Q

what happens when there is a parathyroid adenoma producing too much PTH

A

parathyroid adenoma producing too much PTH
calcium increases but there is no negative feedback to PTH due to autonomous PTH secretion from parathyroid adenoma
primary hyperpararthyroidism

225
Q

what is the biochemistry for primary hyperparathyroidism

A

high calcium
low phosphate - increased renal phosphate excretion (inhibition of Na+/PO43- transporter in kidney)
high PTH (not suppressed by hypercalcaemia)

226
Q

what is the treatment for primary hyperparathyroidism

A

parathyroidectomy is treatment of choice for primary hyperparathyroidism
untreated, hyperparathyroidism has risks of
osteoporosis
renal calculi (stones)
psychological impact of hypercalcaemia - mental function and mood

227
Q

what is secondary hyperparathyroidism

A

a normal physiological response to hypocalcaemia
calcium will be low or low/normal
PTH will be high (hyperparathyroidism) secondary to the low calcium
different from primary hyperparathyroidism where calcium is high

228
Q

what are the causes of secondary hyperparathyroidism

A

vit D deficiency
commonly - diet, reduced sunlight
less common but important - cannot make calcitriol in renal failure (decreased vit D which is important for calcium reabsorption)

229
Q

what is the treatment for secondary hyperparathyroidism

A

vit D replacement
in patients with normal renal function
give 25 hydroxy vitamin D
patient converts this to 1,25 dihydroxy vitamin D via 1 α hydroxylase
ergocalciferol 25 hydroxy vitamin D2
cholecalciferol 25 hydroxy vitamin D3
in patients with renal failure - inadequate 1 α hydroxylation - cannot activate 25 hydroxy vitamin D preparations
give alfacalcidol - 1 α hydroxycholecalciferol

230
Q

what is tertiary hyperparathyroidism

A

rare
occurs in chronic renal failure
cannot make calcitriol
PTH increases (hyperparathyroidism)
parathyroid glands enlarge
(hyperplasia)
autonomous PTH secretion causes hypercalcaemia
treatment is parathyroidectomy

231
Q

summary of primary hyperparathyroidism

A

parathyroid adenoma
makes too much PTH
calcium increases
PTH stays high
no negative feedback

232
Q

summary of secondary hyperparathyroidism

A

normal physiological response to low calcium
(commonly caused by low vit D)
calcium low/low normal
PTH high

233
Q

summary of tertiary hyperparathyroidism

A

complication of chronic renal failure and prolonged calcitriol deficiency
initially calcium falls and PTH rises (2ndary) but over time high PTH drive by enlarged parathyroid glands increase calcium

234
Q

what is the diagnostic approach to hypercalcaemia

A

always look at PTH
normal PTH response = PTH to fall

235
Q

if a patient has high calcium and high PTH what do they have

A

primary if renal function is normal eg parathyroid adenoma
tertiary (all 4 glands enlarged - hyperplastic) if chronic renal failure

236
Q

if a patient has a malignancy or bony metastases what would their PTH look like

A

low

237
Q

what is the diagnostic approach to vit D deficiency

A

calcium will be low or low normal
PTH will be high (hyperparathyroidism) secondary to low Ca

238
Q

what is the adrenal cortex

A

the adrenal cortex is the outer region and also the largest part of an adrenal gland
It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis
Each zone is responsible for producing specific hormones

239
Q

what does the adrenal cortex produce

A

corticosteroids
mineralocorticoids (aldosterone)
glucocorticoids (cortisol)
sex steroids (androgens, oestrogens)

240
Q

what is the secretions precursor

A

cholesterol

241
Q

what enzymes does angiotensin 2 affect

A

activation of the following enzymes
side chain cleavage
3 hydroxysteroid dehydrogenase
21 hydroxylase
11 hydroxylase
18 hydroxylase

242
Q

what does aldosterone do

A

controls blood pressure, sodium and lowers potassium
cholesterol → aldosterone

243
Q

what does ACTH do to the adrenals

A

activation of the following enzymes
side chain cleavage
3 hydroxysteroid dehydrogenase
21 hydroxylase
11 hydroxylase
17 hydroxylase

244
Q

what does 21 hydroxylase do

A

makes progesterone into 11 deoxycorticosterone

245
Q

what is Addisons disease

A

primary adrenal failure
autoimmune disease where the immune system decides to destroy the adrenal cortex (UK)
tuberculosis of the adrenal glands (commonest cause worldwide)

246
Q

what is the biochemistry of addisons

A

pituitary starts secreting lots of ACTH and hence MSH
increased pigmentation
autoimmune vitiligo may coexist
no cortisol or aldosterone, so low blood pressure

247
Q

what is proopiomelanocortin (POMC)

A

POMC is a large precursor protein that is cleaved to form a number of smaller peptides, including ACTH, MSH and endorphins
may become tanned

248
Q

what are the causes of adrenocortical failure

A

Adrenal glands destroyed
Enzymes in the steroid synthetic pathway not working

249
Q

what are the consequences of adrenocortical failure

A

Fall in BP
Loss of salt in urine
Increased plasma potassium
Fall in glucose due to glucocorticoid deficiency
High ACTH resulting in increased pigmentation

(tirednesss is a common symptom so low sodium and high potassium is a giveaway)

250
Q

what are the tests for addisons

A

9 am cortisol = low
ACTH = high
Short synACTHen test
Give 250uh synacthen IM (injection of ACTH)
Measure cortisol response

251
Q

what would the typical addisons patient display with the tests

A

Cortisol at 9am = 100 (270-900)
Administer injection IM of synacthen
Cortisol at 9:30 = 150 (>600)nM
low despite ACTH injection

252
Q

why is aldosterone not suitable for once daily administration

A

half life too short for safe once daily administration

253
Q

what is a better option than aldosterone

A

fludrocortisone - fluorine does not exist in natural steroids - presence slows metabolism
binds to both MR and GR, with half life 3.5h and effects seen for 18h

254
Q

what is wrong with oral hydrocortisone

A

has short half life - too short for once daily administration

255
Q

why do we use prednisolone

A

1-2 dehydro hydrocortisone
longer half life and is more potent than cortisol
2.3x binding affinity than cortisol aka prednisolone
NOT enteric coated which slows absorption

256
Q

how much do we need of prednisolone

A

2-4mg once daily
More research needed to define correct dose for each patient
Equivalent dose of 15-25mg hydrocortisone daily

257
Q

what are the treatments for adrenal failure

A

Hydrocortisone 3 times daily (10 + 5 + 2.5)
Prednisolone 3mg daily
Fludrocortisone 50-100 mcg daily

258
Q

what is congenital adrenal hyperplasia

A

Commonest is caused by 21 hydroxylase deficiency
Can be complete or partial

259
Q

what is complete 21 hydroxylase deficiency and their symptoms

A

Totally absent hormones = aldosterone and cortisol
Survival = less than 24 hrs
Excess hormones = sex steroids and testosterone
Girls may have ambiguous genitalia (virulised by adrenal testosterone)
As a neonate with a salt losing addisonian crisis
Before birth (while in utero) foetus gets steroids across placenta

260
Q

what is partial 21 hydroxylase deficiency and its symptoms

A

Cortisol and aldosterone are deficient
Excess hormones = sex steroids and testosterone
Will present at any age as they survive
Main problem later in life = hirsutism and virilisation in girls and precocious puberty in boys due to adrenal testosterone

261
Q

what does 11 deoxycorticosterone behave like

A

behaves like aldosterone
In excess = can cause hypertension and hypokalaemia

262
Q

what are the symptoms of 11 hydroxylase deficiency

A

Deficient hormones = cortisol and aldosterone
Excess hormones = sex steroids and testosterone and 11 deoxycorticosterone
Problems = virilisation, hypertension and low k

263
Q

what are the symptoms of 17 hydroxylase deficiency

A

Deficient hormones = cortisol and sex steroids
Excess hormones = 11 deoxycorticosterone and aldosterone (mineralocorticoids)
Problems = hypertension, low K, sex steroid deficiency and glucocorticoid deficiency (low gluc)

264
Q

what do neuroendocrine or chromaffin cells in the adrenal medulla produce

A

Catecholamines
Adrenaline/epinephrine (80%)
Noradrenaline/norepinephrine (80%)
Dopamine

265
Q

what are the clinical features of cushings

A

Hypercortisolemia
Moon face
Striae
Thin skin
Bruising - due to turned off protein synthesis
Centripetal obesity
Buffalo hump
Proximal myopathy
Hypertension
Hypokalaemia
Osteoporosis
Diabetes

266
Q

what are the causes of cushings disease

A

Too many steroids
Pituitary dependent Cushings (secondary hypercortisolemia)
Adrenal adenoma secreting cortisol (primary hypercortisolemia)
Ectopic ACTH from lung cancer

267
Q

what are the tests or investigations for cushings

A

24h urine for urinary free control
Blood diurnal cortisol levels (normally highest at 9)
Cushings = basal (9am) cortisol = 800nM, end of LDDST 680 nM (low dose dexamethasone suppression test)

268
Q

what does a low dose dexamethasone suppression test do

A

0.5mg 6 hourly for 48 hours
dexamethasone is an artificial steroid
normal = suppress cortisol to 0
ANY cause of Cushing’s will fail to suppress

269
Q

what are the methods for pharmacological manipulation of steroids

A

enzyme inhibitors
receptor blocking drugs
hyperadrenal disorders
drugs used in the treatment of hyperadrenal disorders

270
Q

what are the 2 inhibitors of steroids biosynthesis for cushings

A

inhibitors of steroid biosynthesis
metyrapone; ketoconazole

271
Q

at are the mechanisms and actions of metyrapone

A

inhibition of 11b-hydroxylase
steroid synthesis in the zona fasciculata (and reticularis) is arrested at the 11 deoxycortisol stage

272
Q

at are the uses of metyrapone

A

control of Cushing’s syndrome prior to surgery
adjust dose (oral) according to cortisol (aim for mean serum cortisol 150-300nmol/L)
improves patient’s symptoms and promotes better post op recovery (better wound healing, less infection etc)
control of Cushing’s symptoms after radiotherapy (usually slow to take effect)

273
Q

what are the unwanted actions of metyrapone

A

hypertension on long term administration (due to deoxycortisone accumulation - aldosterone like, increased retention of salt)
hirsutism

274
Q

what is the mechanism of action for ketoconazole

A

mainly blocks 17 hydroxylase mainly inhibiting cortisol production

275
Q

what are the uses of ketoconazole

A

Cushing’s syndrome
treatment and control of symptoms prior to surgery
orally active

276
Q

what are the unwanted actions of ketoconazole

A

liver damage - possibly fatal - monitor liver function weekly, clinically and biochemically

277
Q

what are the treatments for cushings disease

A

depends on cause
pituitary surgery (transsphenoidal hypophysectomy)
bilateral adrenalectomy
unilateral adrenalectomy for adrenal mass
metyrapone
ketoconazole

278
Q

what is conns syndrome

A

benign adrenal cortical tumour (zona glomerulosa)
aldosterone in excess
hypertension and hypokalaemia
primary hyperaldosteronism
renin - angiotensin system should be suppressed (exclude secondary hyperaldosteronism)

279
Q

what is the treatment for conns syndrome

A

XS aldosterone
MR antagonist : spironolactone, eplerenone

280
Q

what are the uses and mechanisms of action for spironolactone

A

primary hyperaldosteronism (Conn’s syndrome)
converted to several active metabolites, including canrenone, a competitive antagonist of mineralocorticoid receptor (MR)
blocks Na+ resorption and K+ excretion in the kidney tubules (potassium sparing diuretic)

281
Q

what are some unwanted actions from spironolactone

A

menstrual irregularities (+progesterone receptor)
gynaecomastia (-androgen receptor)

282
Q

what is eplerenone

A

also a mineralocorticoid receptor (MR) antagonist
similar affinity to MR compared to spironolactone
less binding to androgen and progesterone receptors compared to spironolactone - better tolerated

283
Q

what is a phaeochromocytoma

A

tumours of the adrenal medulla which secrete catecholamines
(adrenaline and noradrenaline)

284
Q

what are clinical features of a phaeo

A

hypertension in young people
episodic severe hypertension (after abdominal palpation)
more common in certain inherited conditions
severe hypertension can cause myocardial infarction or stroke
high adrenaline can cause ventricular fibrillation and death
medical emergency

285
Q

what is the management for a phaeo

A

eventually will need surgery but patient needs careful prep as anaesthetic can precipitate a hypertensive crisis
α blockade is the 1st therapeutic step
patients may need IV fluid as α blockade commences
beta blockade added to prevent tachycardia
10% extra adrenal (sympathetic chain)
10% malignant
10% bilateral
Phaeo = extremely rare

286
Q

what does our body do to a drug

A

absorption
distribution
metabolism
excretion

287
Q

what is absorption of a drug

A

the passage of a drug from the site of administration into the plasma (the process for drug transfer into the systemic circulation)

288
Q

what is bioavailability

A

the fraction of the initial dose that gains access to the systemic circulation (outcome of drug transfer into the systemic circulation - how much)

289
Q

what is a determinant of absorption and bioavailability

A

site of administration

290
Q

what are some examples of drug administration

A

oral
inhalational
dermal (percutaneous)
intra nasal
injections
many more

291
Q

how do drugs move around the body

A

1) bulk flow transfer (ie in bloodstream)
2) diffusional transfer (ie molecule by molecule across short distances)
(if IV - the drug is injected straight into the bloodstream > bulk flow transfer will then deliver the drug to its intended site of action
with other routes of administration - the drug needs to diffuse across at least 1 lipid membrane)

292
Q

what is pinocytosis

A

small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug, the vesicle can then release the chemical on the other side of the membrane, while this is relevant for some molecules eg insulin access to the brain it is rarely used to transport drugs

293
Q

what is diffusion across aq pores

A

ie. the gaps between epithelial/endothelial cells that make up the membrane is also not a major route for movement of drugs across membranes, most pores are less than 0.5nm in diameter and since there are very few drugs this small, there is little movement of drugs across this aqueous route

294
Q

how do most drugs move across membranes

A

diffusing across lipid membranes

295
Q

for drugs to diffuse across lipid membranes what do they need to be or what is another method for transportation

A

suitably lipid soluble
or
by carrier mediated transport (involves a transmembrane protein) - can bind drug molecules on one side of the membrane and then transfer them across to the other side of the membrane

296
Q

do drugs tend to be more lipid soluble or water soluble and why

A

water soluble
because most are oral and need to be water soluble to dissolve in aq environment of GI tract and be available for absorption

297
Q

how do drugs exist

A

as weak acids or weak bases
therefore exist as ionised or unionised

298
Q

describe aspirin

A

weak acid = in ionised state - donates protons eg H+

299
Q

describe morphine

A

weak base = in ionised state - accepts protons

300
Q

which form of the drug retains more lipid solubility, ionised or unionised

A

unionised
more likely to diffuse across plasma membranes

301
Q

what determines whether the drug is ionised or not

A

dissociation constant (pKa) for that drug and
the pH in that particular part of the body

302
Q

explain the split of unionised and ionised forms in terms of aspirin (a weak acid)

A

aspirin = weak acid, pKa = 3.5 (most weak = 3-5), when pH is 3.5 then it will be equally dissociated between the 2 forms - for weak acids - as pH decreases the unionised form starts to dominate - as pH increases the ionised form starts to dominate
(as pH goes towards alkaline for acids = ionised form dominates)

303
Q

explain the split of ionised and unionised in terms of morphine (a weak base)

A

morphine = weak base, pKa = 8 (most weak bases = 8-10) - when pH is 8 there are equal dissociations, for weak bases as pH decreases the ionised form starts to dominate and as pH starts to increase, the unionised form starts to dominate
(when pH increases towards alkaline for weak bases = unionsied form starts to dominate)

304
Q

would weak bases be trapped in the stomach

A

a weak base = poorly absorbed from the stomach due to the low pH leading to high drug ionisation
but once the drug reaches the small intestine, it will be able to access a huge number of transport proteins that will allow absorption from the gastrointestinal tract

305
Q

could weak acids become trapped in the blood

A

weak acid could potentially be absorbed from the stomach in its unionised state but would become more ionised at physiological pH and potentially trapped in the blood
most tissues possess transport proteins that could potentially move the ionised drug from the blood into the tissue

306
Q

where are the most important carrier systems relating to drug action found

A

renal tubule
biliary tract
blood brain barrier
GI tract
these particular carrier systems are therefore responsible for drug access to the bloodstream (absorption from the gastrointestinal tract) - for drug access to certain tissues (absorption across the blood brain barrier) and excretion of drugs from the body (excretion from the kidney of the GI tract)

307
Q

what are factors that affect/influence drug distribution

A

different tissues will be exposed to different amounts of the drug depending on these factors
regional blood flow
plasma protein binding
capillary permeability
tissue localisation

308
Q

what is regional blood flow

A

different tissues receive differing amounts of cardiac output
more drug = distributed to those that receive most blood flow
distribution of blood to tissues can increase or decrease depending on circumstances

309
Q

what is plasma protein binding

A

once drugs reach systemic circulation = common to bind to plasma proteins
most important = albumin - good at binding acidic drugs

310
Q

what does the amount of drug bound depend on

A

the free drug concentration
the affinity for the protein binding sites
the plasma protein conc

311
Q

why is the plasma conc required for clinical effect for nearly all drugs less than 1.2mmol/l

A

only consider albumin (though there are other plasma proteins) the conc of albumin in the blood = approx 0.6 mmol/l
each albumin protein has 2 binding sites
binding capacity of albumin alone = 1.2 mmol/l

312
Q

when can drugs leave/diffuse out to blood

A

only free drug is available to diffuse out of the blood and access tissues - any drug bound to plasma proteins CANNOT leave the blood until it dissociates from the protein

313
Q

what is capillary permeability and how does that affect drugs

A

if drugs are lipid soluble then they can diffuse across the endothelial cell and access the tissue
if drugs are less lipid soluble then (unless v small and can pass through gap junctions) they need to be transported into the tissue via carrier proteins

314
Q

what happens to drugs when there is a discontinuous structure

A

eg liver, a discontinuous capillary structure (big gaps between capillary endothelial cells) allows for drugs to easily diffuse out of the bloodstream and access the liver tissue

315
Q

what happens when there is a fenestrated structure for drugs

A

eg glomerulus of the kidney, circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs, allows for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs

316
Q

what is tissue localisation

A

water soluble drug, the equilibrium = more heavily weighted towards retention in the plasma
equilibrium is established between blood and brain usually
imagine water soluble drug accessing brain
will diffuse from high to low conc from blood to brain and establishes equilibrium
brain has higher fat content whereas blood has higher water content

317
Q

why do we need to eliminate drugs

A

to eliminate drugs = pathways for excretion
without this = continuous circulation and effects of drugs

318
Q

what is the controversy with drugs being effective and their excretion

A

ideal to excrete if they are not particularly lipid soluble (more effectively retained in the blood > not diffused into tissues > delivered to excretion sites)
but for drugs to be effective they need to be at least partially lipid soluble - to easily access tissues and produce effects

319
Q

what is the major metabolic tissue

A

liver

320
Q

what enzymes are mainly responsible for drug metabolism

A

cytochrome P450 enzymes

321
Q

what is phase 1 for drug metabolism

A

main aim = introduce reactive group to drug//production of metabolites with a functional group (attack point for conjugation in phase 2) - often makes pharmalogically active drugs
- introduce polar groups into substrates
- by oxidation, reduction and hydrolysis (most common - oxidation)
all oxidations start with hydroxylation using cytochrome P450 to incorporate O2 into non activated HCs

322
Q

what is a pro drug

A

parent drug has no own activity and only produces an effect once metabolised to respective metabolite (metabolism required for pharmacological effect)

323
Q

what is phase 2 for drug metabolism

A

attachment of a substituent group = resulting metabolite = nearly always inactive and far less lipid soluble than phase 1 metabolite
facilitates excretion in urine or bile

phase 2 enzymes are predominantly transferases to transfer the substituent group onto phase 1 metabolite

324
Q

what is first pass presystemic metabolism

A

problem for orally administered drugs
absorbed from small intestine > enter hepatic portal blood supply > pass through liver before systemic circ > at this point = rug is heavily metabolised > little drug actually reaches systemic circ
solution = administer larger drug dose to ensure enough drug reaches systemic circ
problem = extent of first pass metabolism varies amongst individuals > drug reaching systemic circ also varies > drug effects and side effects are hard to predict

325
Q

what are some routes of excretion for drugs

A

lungs (basis of alcohol breath test)
breast milk (careful it does not affect baby)
kidney (urine)
liver (bile)

326
Q

what are the 3 major excretion routes via the kidney

A

glomerular filtration
active tubular secretion (or reabsorption)
passive diffusion across tubular epithelium

327
Q

describe excretion by glomerular filtration

A

allows drug molecules of molecular weight <20,000 to diffuse into glomerular filtrate
= those with this weight have an extra route for excretion (glomerular filtration) compared to larger drugs > quicker rate of excretion

328
Q

describe excretion by active tubular secretion

A

most important method for excretion in kidney
only 20% of renal plasma filtered at glomerulus, 80% of renal plasma passes onto blood supply to the proximal tubule
more drug delivered to proximal tubule than glomerulus
within proximal tubule capillary endothelial cells are 2 AT carrier systems
one is good at transporting acidic drugs and the other for basic drugs
both good at transporting against gradient

329
Q

describe excretion by passive diffusion

A

generally leads to reabsorption from kidney tubule
as glomerular filtrate moves through kidney - most water is reabsorbed
if drugs are particularly lipid soluble then they will also be reabsorbed - passively diffuse across tubule back into blood

330
Q

what are factors that affect extent of reabsorption

A

drug metabolism (phase 2 metabolites tend to be more water soluble than parent drugs > less well reabsorbed)
urine pH (can vary from 4.5-8, based on before acidic drugs = better reabsorbed at lower pH and basic drugs at higher pH)

331
Q

what is biliary excretion

A

less major than kidney
liver cells transport some drugs from plasma to bile (primarily via transporters similar to those in kidney)
effective at removing phase 2 glucuronide metabolites
drugs transported to bile > excreted into intestines > eliminated in faeces

332
Q

what is enterohepatic recycling - prolongs drug effect

A

1) glucuronide metabolite = transported into bile
2) metabolite is excreted into small intestine where it is hydrolysed by gut bacteria releasing glucuronide conjugate
3) loss of this conjugate increases lipid solubility of molecule
4) increased lipid solubility = greater reabsorption from small intestine back into hepatic portal blood system for return to liver
5) molecule returns to liver where a proportion is remetabolised - some may escape into systemic circulation to continue to have effects on the body

333
Q

what are the therapeutic objectives for diabetes

A

1) always start with lifestyle changes
2) add medication if needed - in this case metformin (never start with a mixture of 2 drugs - try 1 first and prescribe later accordingly)

334
Q

describe metformin

A

too polar
uses another mechanism to get across membrane into tissue
more likely to be water soluble than lipid (ability to cross plasma membrane is restricted)
pKa = very high (12.4) - almost always ionised - cannot diffuse across membranes even in most alkaline solutions , metformin is charged

335
Q

where is the organic cation transporter 1 expressed (OCT1)

A

hepatocytes (liver)
enterocytes (small bowel)
proximal tubules (kidney)

336
Q

what happens at the small bowel OCT1

A

small bowel OCT-1 allows it to be absorbed (intestine can get the drug from the gut to the blood)

337
Q

what happens at the hepatocyte OCT1

A

hepatocyte OCT-1 allows it to be distributed to the site of action (liver metabolises a lipid soluble drug and makes it water soluble - easier to excrete

338
Q

what is the primary mechanism of action for metformin

A

activates AMPK in hepatocyte mitochondria
inhibits ATP production
blocks gluconeogenesis and subsequent glucose output
also blocks adenylate cyclase (promotes fat oxidation)
restore insulin sensitivity

339
Q

what is the drug target for metformin

A

5’ AMP activated protein kinase (AMPK)
hepatocyte mitochondria

340
Q

what are the main side effects of metformin

A

GI side effects
eg abdominal pain, decreased appetite, diarrhoea, vomiting
esp high doses - slow increase might improve tolerability

341
Q

what does metformin need to access tissues and why

A

as it is highly polar - it needs OCT-1

342
Q

what is an example of DPP-4 inhibitors (and what does it stand for)

A

dipeptidyl-peptidase 4 (DPP) inhibitors
example = sitagliptin

343
Q

what is the primary mechanism of action for DPP-4 inhibitors

A

works by inhibiting action of DPP-4
DPP-4 = present in vascular endothelium - metabolise incretins in plasma (which are secreted by enteroendocrine cells and help stimulate insulin production when needed and reduce proportion of glucagon by liver when not needed)
incretins also slow down digestion and decrease appetite

344
Q

what is the drug target for DPP-4 inhibitors

A

DPP-4
the primary site of DPP-4 inhibitor action = vascular endothelium

345
Q

what are the main side effects of DPP-4 inhibitor

A

upper resp tract infection (5% of patients)
flu like symptoms eg headache, runny nose, sore throat less common but serious
serious allergic reactions - avoid in patients with pancreatitis
do not appear to cause weight gain

346
Q

what is an example of sulphonylurea

A

gliclazide

347
Q

what is the primary mechanism of action of sulphonylurea

A

inhibit the ATP sensitive potassium channel (KATP) channel on the pancreatic beta cell
the channel controls beta cell membrane potential inhibition - causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis

348
Q

what is the drug target for sulphonylurea

A

ATP - sensitive potassium channel
primary site of SUs inhibitor action is the pancreatic beta cell

349
Q

what are the side effects of sulphonylurea

A

weight gain
hypoglycaemia

350
Q

what is an example of a sodium glucose cotransporter (SGLT2) inhibitors

A

dapagliflozin

351
Q

what is the primary mechanism of drug action for SGLT2 inhibitors

A

reversibly inhibit sodium glucose cotransporter 2 in renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion

352
Q

what is the drug target for SGLT2 inhibitors

A

SGLT2 = primary site of SGLT2 inhibitor action = proximal convoluted tubule

353
Q

what are the side effects of SGLT2 inhibitors

A

urogenital infections due to increased glucose load
slight decrease in bone formation can worsen diabetic ketoacidosis (stop immediately)
maybe weight loss and decrease in BP

bioregulatory systems y2 (6 decks)

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