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)
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
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
4
Q
what does prolactin do
A
milk production
5
Q
what is LH and FSH responsible for
A
oestrogen and progesterone and testosterone
6
Q
what is TSH responsible for
A
triiodothyronine (T3)
thyroxine (T4)
7
Q
what is ACTH responsible for
A
cortisol production
8
Q
what is primary disease
A
an issue or failure with the gland itself eg thyroid gland, adrenal cortex or gonads
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?
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)
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
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)
13
Q
what is secondary hypoadrenalism
A
eg pituitary tumour damaging corticotrophs
cannot make ACTH > ACTH falls > cortisol falls
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)
15
Q
what is secondary hypogonadism
A
eg pituitary tumour damaging gonadotrophs
cannot make FSH/LH > LH/FSH falls > testosterone/oestrogen falls
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
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
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)
19
Q
what can also cause posterior pituitary dysfunction too
A
inflammation (hypophysitis)
surgery
20
Q
what is total loss of anterior and posterior pituitary function called
A
panhypopituitarism
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)
22
Q
what are the most sensitive to radiotherapy
A
GH and gonadotrophins
23
Q
what hormone can increase after radiotherapy
A
prolactin (loss of hypothalamic dopamine)
24
Q
for how long do risks persist after radiotherapy
A
10years
25
what are the presentations of hypopituitarism for FSH/LH
reduced libido
secondary amenhorrhoea
erectile dysfunction
reduced pubic hair
26
what are the presentations of hypopituitarism for ACTH
fatigue (not a salt losing crisis bc aldosterone exists)
27
what are the presentations of hypopituitarism for TSH
fatigue
28
what are the presentations of hypopituitarism for GH
reduced QoL
short stature only in children
29
what are the presentations of hypopituitarism for PRL
inability to breastfeed
30
what is Sheehan's syndrome and where is it most commmon
post partum hypopituitarism secondary to hypotension (post partum haemorrhage PPH)
most common in developing countries
31
what is normally seen in a pregnancy that is otherwise abnormal
anterior pituitary enlargement due to lactotroph hyperplasia
32
what does a post partum haemorrhage lead to
pituitary infarction
33
what are some common presentations of Sheehans syndrome
lethargy, anorexia and weight loss - due to TSH/ACTH/GH deficiency
failure of lactation - due to PRL deficiency
failure to resume menses post delivery
34
is the posterior pituitary affected in Sheehans
usually not affected
35
what is the best way to radiologically visualise the pituitary gland
MRI scan
36
what is pituitary apoplexy
intra-pituitary haemorrhage or less commonly infarction
often dramatic presentation in patients with pre-existing pituitary tumours (adenomas)
37
what are the symptoms of pituitary apoplexy
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
38
what may the cavernous sinus involvement lead to
diplopia (IV, VI), ptosis (III)
39
what are the biochemical diagnoses' of hypopituitarism (tests)
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
40
how do we test/diagnose hypopituitarism (specific test) and how does it work
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
41
why do we use MRI to visualise pituitary gland
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
42
what hormones can you treat for in hypopituitarism
GH
TSH
LH/FSH
ACTH
NOT PROLACTIN
43
what are the treatments for GH deficiency
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
44
what are the treatments for TSH deficiency
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
45
what are the treatments for ACTH deficiency
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
46
what is very important to tell patients who have ACTH deficiency
sick day rules
47
what are the sick day rules
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
48
what is the treatment for FSH/LH deficiency in men if no fertility is required
replace testosterone - topical or intramuscular (most pop)
measure plasma testosterone
replacing testosterone does not restore sperm production (dependent on FSH)
49
what is the treatment for FSH/LH deficiency in men if fertility is required
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
50
what is the treatment for FSH/LH deficiency in women if no fertility is required
replace oestrogen
oral or topical
will need additional progestogen if intact uterus to prevent endometrial hyperplasia - risk of endometrial cancer
51
what is the requirement for FSH/LH deficiency in women if fertility is required
can induce ovulation by carefully timed gonadotrophin injections (IVF)
52
what are the main 3 things you need to know about how a drug exerts its effect on the body
where is the effect produced
what is the target for the drug
what is the response that is produced after interaction with the target
53
are drugs limited to 1 effect
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
54
for eg where would the effect of cocaine be produced
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
55
what are the 4 drug target classes (proteins)
transport proteins
ion channels
receptors
enzymes
56
what is the drug target for aspirin and how does it work
enzyme (cyclooxygenase) and blocks production of prostaglandins
57
how do local anaesthetics work and what are their drug targets
ion channel (sodium) prevents nerve conduction
58
what is the drug target for prozac and how does it work
anti depressant - transport proteins (serotonin carrier proteins) prevents serotonin removal from the synapse
59
what is the drug target for nicotine
receptor (nicotinic acetylcholine receptor)
60
what does a drug need to show to be an effective therapeutic agent
it must show a high degree of selectivity for a particular drug target
61
example for selectivity
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
62
why is drug dose important
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
63
what are the 4 drug receptor interactions
electrostatic interactions
hydrophobic interactions
covalent bonds
stereospecific interactions
64
what are electrostatic interactions
most common mechanism and involves hydrogen bonds and Van der Waal forces
65
what are hydrophobic interactions
this is important for lipid soluble drugs
66
what are covalent bond interactions
these are the least common as the interactions tend to be irreversible
67
what are stereospecific interactions
many drugs exist as stereoisomers and interact stereospecifically with receptors
68
what is the equation for a drug + receptor
drug + receptor ←→ drug receptor complex
for a specific conc of the drug, a specific no. of drug receptor complexes are formed
69
what happens to the drug receptor complexes when you increase drugs
↑ 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
70
what happens to drug receptor complexes when you decrease drugs
↓↓ drug + receptor ←→ ↓ drug receptor complex
71
what 2 categories are drugs classed into
agonists and antagonists
72
what is the difference between agonist and antagonist action
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)
73
what determines strength of binding of the drug to the receptor
affinity
74
what is affinity linked to
receptor occupancy
75
fill in this blank
each individual drug receptor is --- with many interactions only lasting milliseconds
transient
76
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
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
77
what is efficacy
refers to the ability of an individual drug molecule to produce an effect once bound to a receptor
78
what happens after a drug occupies a receptor
it does not necessarily produce one standard unit of response
may produce a complete/no/partial response
79
what is A if Drug A - has affinity for the receptor but no efficacy
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
80
what is B if Drug B - has affinity for the receptor and sub-maximal efficacy
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
81
what is C if Drug C - has affinity for the receptor and maximal efficacy
therefore acts as a full agonist. When bound to the receptor, it can produce the maximal response expected from that receptor
82
what is potency
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
83
what is the standard measure of potency
is to determine the conc or dose of a drug required to produce a 50% tissue response
84
what is the standard nomenclature for potency
EC50 (half maximal effective conc) or the ED50 (half maximal effective dose)
85
what is the difference between EC50 and ED50
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
86
which is used to compare potencies, ED50 or EC50
ED50
87
what does a highly potent drug produce
large response at relatively low concs
88
what does a highly efficacious drug produce
a maximal response and this effect is not particularly related to drug conc
89
what is the diff between a partial and full agonist
diff in efficacy
90
is efficacy or potency related to dose
potency
91
which is more important, efficacy or potency
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
92
what is the posterior pituitary anatomically continuous with
hypothalamus
93
what do hypothalamic magnocellular neurons contain
AVP and oxytocin
94
where do hypothalamic magnocellular neurons originate
long, originate in supraoptic and paraventricular hypothalamic nuclei
nuclei → stalk → posterior pituitary
95
what is another name for vasopressin
ADH (antidiuretic hormone)
96
what does diuresis mean
production of urine
97
what is the main physiological action for ADH
stimulation of water reabsorption in the renal collecting duct > concentrates urine (smaller vol)
98
what does ADH act through
the V2 receptor in the kidney
also a vasoconstrictor (via V1 receptor)
stimulates ACTH release from anterior pituitary
99
what is the mechanism for ADH/AVP action
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
100
how can we visualise the posterior pituitary on MRI
sagittal MRI
posterior pituitary = bright spot on MRI
not visualised in all healthy individuals so absence may be normal variant
101
what are the physiological effects of vasopressin (3)
antidiuretic effect
vasoconstriction via V1 receptor
stimulation of reabsorption of water in collecting duct
(also stimulates ACTH)
102
what is the difference between osmotic and non osmotic stimuli for vasopressin release
osmotic (increase in conc)
rise in plasma osmolality sensed by osmoreceptors
non osmotic
decrease in atrial pressure sensed by atrial stretch receptors
103
where are osmoreceptors found
hypothalamic nuclei
organum vasculosum and subfornical organ
both nuclei which sit around the 3rd ventricle (circumventricular)
104
why is it beneficial for there being no blood brain barrier between the circumventricular nuclei
neurons can respond to changes in the systemic circulation
highly vascularised
neurons project to the supraoptic nucleus - site of vasopressinergic neurons
105
STEPS for how osmoreceptors regulate vasopressin
1) increase in extracellular NA+
2) H2O leaves osmoreceptor
3) osmoreceptor shrinks
4) increased osmoreceptor firing
5) AVP release from hypothalamic neurons
106
STEPS for non osmotic stimulation of vasopressin release
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
107
why is vasopressin released following a haemorrhage
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
108
what happens when you have increased plasma osmolality
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
109
what is diabetes insipidus
a problem with AVP
either insufficiency or resistance (cranial or nephrogenic)
110
what are the symptoms of diabetes insipidus
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
111
what are the 2 types of DI
cranial DI
nephrogenic DI
112
what is cranial DI
cranial (central) diabetes insipidus - problems with hypothalamus and or posterior pituitary - unable to make arginine vasopressin
113
what is nephrogenic DI
nephrogenic diabetes insipidus - can make arginine vasopressin (normal hypothalamus and posterior pituitary)
kidney (collecting duct) - unable to respond to it
114
what are the acquired (more common) causes of cranial DI
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
115
what are the congenital causes of nephrogenic diabetes I
rare (mutation in gene encoding V2 receptor, aquaporin 2 type water channel)
116
what are the acquired causes of nephrogenic DI
drugs eg lithium (damages the collecting duct - reduces ability to respond to AVP)
117
what is the presentation for DI
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
118
why do people with DI present with high serum sodium
passing large volumes of dilute urine
less water retained therefore salty blood
119
STEPS for how DI works/why these symptoms occur
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
120
what are the clinical features of DI (No PPE)
nocturia
polyuria
polydipsia
extreme thirst
121
what is psychogenic polydipsia
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
122
STEPS for psychogenic polydipsia and how it affects patients
increased drinking
plasma osmolality falls
less AVP secreted by posterior pituitary
large volumes of dilute (hypotonic) urine
plasma osmolality returns to normal
123
how do we distinguish between DI and PP
water deprivation test
124
what is the water deprivation test
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)
125
explain the water deprivation test
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
126
how do we distinguish between cranial and nephrogenic diabetes insipidus
give ddAVP
127
how does giving ddAVP help us distinguish between CDI and NDI
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
128
what is the treatment for cranial DI
want to replace vasopressin
desmopressin
selective for V2 receptor (V1 receptor activation would be unhelpful)
different preparations = tablet // intranasal
129
what is the treatment for nephrogenic DI
this is rare but difficult to treat successfully
thiazide diuretics eg bendrofluazide
paradoxical - mechanism unclear
130
what is SIADH
syndrome of inappropriate antidiuretic hormone
131
what happens when you have too much AVP
reduced urine output
water retention
high urine osmolality
low plasma osmolality
dilutional hyponatremia
132
what are some causes of SIADH
CNS
- head injury, stroke, tumour
pulmonary disease
- pneumonia, bronchiectasis
malignancy
- lung cancer (small cell)
drug related
- carbamazepine, serotonin reuptake inhibitors (SSSRIs)
idiopathic
133
other expensive treatments of SIADH
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
134
what happens at the kidney regarding sodium in SIADH
water reabsorption happens at the kidney so sodium will be low not high
135
what does thyroxine do to cells in the body
binds to cells
increases basal metabolic rate
speeds up processes in those cells
"warms" cells up
136
what is the control of thyroid activity
TRH released by thyrotrophs in the hypothalamus
stimulates pituitary to produce TSH
stimulates thymus to produce T3 and 4
negative feedback
137
what is the level of TSH in a patient with primary hypothyroidism and how do we treat this
high TSH
increase dose till TSH falls back to normal
137
what is the level of TSH in a patient with primary hypothyroidism and how do we treat this
high TSH
increase dose till TSH falls back to normal
138
what is Graves disease
autoimmune
antibodies bind to and stimulate the TSH receptor in thyroid
cause goitre (smooth) and hyperthyroidism
139
what are some symptoms of Graves disease
- perspiration
- facial flushing
- SoB
- loss of weight
- goiter
- exophthalmos
- diarrhoea
- tremor
- pretibial myxoedema
- increased appetite
140
what causes exophthalmos
other antibodies bind to muscle behind the eye and cause this
141
what causes pretibial myxoedema
other antibodies
(hypertrophy)
142
what is the swelling (non-pitting) that occurs on the shins of patients w/Graves disease
growth of soft tissue
143
what is Plummer's disease
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
what are the effects of thyroxine on the SNS
sensitises beta adrenoreceptors to ambient levels of adrenaline and noradrenaline
there is apparent sympathetic activation
tachycardia, palpitations, tremor in hands, lid lag
145
what are the features of hyperthyroidism
weight loss despite increased appetite
breathlessness
palpitations, tachycardia
sweating
heat intolerance
diarrhoea
lid lag and other sympathetic features
146
what is a thyroid storm/symptoms of a thyroid storm
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
what are treatment options for hyperthyroidism
surgery (thyroidectomy)
radioiodine
drugs (thionamides - antithyroid drugs)
148
symptoms of hyperthyroidism
weight loss despite increased appetite
SoB
palpitations, tachycardia
sweating
heat intolerance
diarrhoea
lid lag and other sympathetic features
fatigue/tiredness
149
what is the daily treatment of hyperthyroidism
thionamides
150
how do thionamides affect thyroid hormone synthesis
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
what are some unwanted actions of thionamides
agranulocytosis (usually reduction in neutrophils) - rare and reversible on withdrawal of drug
rashes (common)
152
what does the follow up of thionamides consist of
aim to stop antithyroid drug treatment after 18 months
review patient periodically including thyroid function tests for remission/relapse
153
what are the roles of beta blockers in thyrotoxicosis
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
describe the treatment of KI
(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
what is the mechanism action of KI
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
why does KI only work for about 10 days
eventually the iodide is taken up
activated and makes thyroxine
157
what are some problems with surgery
risk of voice change - recurrent laryngeal nerve
risk of also losing parathyroid glands
scar
anaesthetic
158
how does radioiodine work as a treatment
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
what are the drug treatment options
drugs
- beta blockade is v important
- propranolol
antithyroid drugs
- carbimazole
- propylthiouracil
160
what is the mechanism for Viral (de Quervains) thyroiditis
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
what are some symptoms for viral (de Quervains) thyroiditis
painful dysphagia
hyperthyroidism
pyrexia
thyroid inflammation
162
what is post partum thyroiditis
similar to viral thyroiditis but no pain and only occurs after pregnancy
immune system modulated during pregnancy
163
summary of viral thyroiditis
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
what do somatotrophs make
GH
somatotrophin
165
what do lactotrophs make
PRL
166
what do thyrotrophs make
TSH
thyrotrophin
167
what do gonadotrophs make
LH and FSH
168
what do corticotrophs make
ACTH
corticotrophin
169
what are functioning pituitary tumours of somatotrophs called
causes acromegaly
170
what are functioning pituitary tumours of lactotrophs called
prolactinomas
171
what are functioning pituitary tumours of thyrotrophs called
TSHoma
172
what are functioning pituitary tumours of gonadotrophs called
gonadotropinoma
173
what are functioning pituitary tumours of corticotrophs called
corticotroph adenoma
Cushing's disease
174
how do we classify pituitary tumours
radiologically (MRI)
function
benign
175
how do we describe the radiological classification of a pituitary tumour
microadenoma <1cm
macroadenoma >1cm
sellar or suprasellar
compressing optic chiasm or not
invading cavernous sinus or not
176
how do we describe classification of a pituitary tumour using function (of the tumour)
excess secretion of a specific pituitary hormone eg prolactinoma
no excess secretion of pituitary hormone eg non functioning adenoma
177
how do we describe the classification of a pituitary tumour using whether it is benign (not cancer)
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
how does hyperprolactinaemia inhibit kisspeptins
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
describe prolactinomas
commonest functioning pituitary adenoma
usually serum [prolactin] >5000mU/L
serum [PRL] proportional to tumour size
180
what is the presentation for patients with a prolactinoma
menstrual disturbance
erectile dysfunction
reduced libido
galactorrhoea (more common in women)
subfertility
181
what are the physiological causes of an elevated PRL
pregnancy/breastfeeding
stress : exercise, seizure, venepuncture (as it is a stress hormone)
nipple/chest wall stimulation
182
what are the pathological causes of an elevated PRL
primary hypothyroidism (high TSH = high PRL)
polycystic ovarian syndrome
chronic renal failure
183
what are iatrogenic causes of an elevated PRL
antipsychotics
selective serotonin reuptake inhibitors
anti-emetics
high dose oestrogen
opiates
184
why is it important to confirm TRUE elevation in serum PRL
(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
describe macroprolactin
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
describe how stress of venepuncture causes high PRL
exclude by cannulated PRL series
sequential serum [PRL] measurement 20 mins apart with an indwelling cannula to minimise venepuncture stress
187
what do you do when confirmed true pathological elevation of serum PRL
organise pituitary MRI
188
what are treatments of prolactinoma
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
how do dopamine receptor agonists reduce PRL and shrink prolactinomas
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
what do pituitary tumours secreting excess GH cause in adults and children
gigantism = children
acromegaly = adults
acromegaly
often insidious presentation - mean time to diagnose from onset of symptoms = 10y
191
what is menorrhagia a feature of
primary hypothyroidism
192
what are the symptoms of acromegaly
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
what are the mechanisms of growth hormone
released by AP
acts on liver which produces IGF-1 (somatomedin)
IGF-1 also causes increased metabolic actions > growth and development
194
how do we diagnose acromegaly
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
what do you do once you confirm GH excess
pituitary MRI to visualsies pituitary tumour
196
what are the treatments for acromegaly - increased CV risk in untreated acromegaly
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
what is Cushings syndrome
occurs due to an excess of cortisol or other glucocorticoid
excess cortisol
cushings disease is due to a corticotroph adenoma secreting ACTH
198
what are causes of Cushings syndrome
taking steroids by mouth (common)
pituitary depending Cushings disease (pituitary adenoma)
Ectopic ACTH (lung cancer)
adrenal adenoma or carcinoma
199
what are some symptoms of Cushings syndrome
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
what are ACTH dependent causes
cushings disease (corticotroph adenoma)
ectopic ACTH (lung cancer)
201
what are ACTH independent causes
taking steroids by mouth (common)
adrenal adenoma or carcinoma
202
what are some investigations for Cushing's disease
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
what do you do once you confirm hypercortisolism
measure ACTH
if ACTH high = pituitary MRI ACTH dependent
204
what are non functioning pituitary adenomas doing to vision
don't secrete any specific hormone
often present with visual disturbance (bitemporal hemianopia)
205
what are non functioning pituitary adenomas : hormones
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
what hormones are involved to increase levels of serum calcium and phosphate
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
what hormones are involved in decreasing the levels of serum calcium and phosphate
calcitonin (secreted by thyroid parafollicular cells)
reduces calcium acutely - no negative effect if parafollicular cells are removed via thyroidectomy
208
what is a good indicator for body vit D status
serum 25-OH vitamin D
209
what regulates its own synthesis by decreasing transcription of 1 alpha hydroxylase
1, 25 (OH)2 vitamin D (calcitriol)
210
we cannot measure calcitriol so instead we measure
25 hydroxycholecalciferol
211
what is the synthesis of vitamin D metabolism from UVB
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
what is the synthesis of vit D from vit D2 in diet
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
what are the 3 effects of calcitriol
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
what are the actions of PTH on calcium and phosphate
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
what is the regulaion of serum phosphate by fgf23
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
what are the signs and symptoms of hypocalcaemia
paraesthesia (hands, mouth, feet and lips)
convulsions
arrhythmias
tetany
CATs go numb
217
what is Chvosteks sign
facial paraesthesia
218
what is Trousseaus sign
carpopedal spasm
219
what are the causes of hypocalcaemia
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
what are the signs and symptoms for hypercalcaemia
“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
what are the causes of hypercalcaemia
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
how does the parathyroid gland respond when there is a decrease in calcium levels
increase PTH
223
how does the parathyroid gland respond when there is an increase in calcium levels
decrease PTH
(negative feedback)
224
what happens when there is a parathyroid adenoma producing too much PTH
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
what is the biochemistry for primary hyperparathyroidism
high calcium
low phosphate - increased renal phosphate excretion (inhibition of Na+/PO43- transporter in kidney)
high PTH (not suppressed by hypercalcaemia)
226
what is the treatment for primary hyperparathyroidism
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
what is secondary hyperparathyroidism
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
what are the causes of secondary hyperparathyroidism
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
what is the treatment for secondary hyperparathyroidism
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
what is tertiary hyperparathyroidism
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
summary of primary hyperparathyroidism
parathyroid adenoma
makes too much PTH
calcium increases
PTH stays high
no negative feedback
232
summary of secondary hyperparathyroidism
normal physiological response to low calcium
(commonly caused by low vit D)
calcium low/low normal
PTH high
233
summary of tertiary hyperparathyroidism
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
what is the diagnostic approach to hypercalcaemia
always look at PTH
normal PTH response = PTH to fall
235
if a patient has high calcium and high PTH what do they have
primary if renal function is normal eg parathyroid adenoma
tertiary (all 4 glands enlarged - hyperplastic) if chronic renal failure
236
if a patient has a malignancy or bony metastases what would their PTH look like
low
237
what is the diagnostic approach to vit D deficiency
calcium will be low or low normal
PTH will be high (hyperparathyroidism) secondary to low Ca
238
what is the adrenal cortex
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
what does the adrenal cortex produce
corticosteroids
mineralocorticoids (aldosterone)
glucocorticoids (cortisol)
sex steroids (androgens, oestrogens)
240
what is the secretions precursor
cholesterol
241
what enzymes does angiotensin 2 affect
activation of the following enzymes
side chain cleavage
3 hydroxysteroid dehydrogenase
21 hydroxylase
11 hydroxylase
18 hydroxylase
242
what does aldosterone do
controls blood pressure, sodium and lowers potassium
cholesterol → aldosterone
243
what does ACTH do to the adrenals
activation of the following enzymes
side chain cleavage
3 hydroxysteroid dehydrogenase
21 hydroxylase
11 hydroxylase
17 hydroxylase
244
what does 21 hydroxylase do
makes progesterone into 11 deoxycorticosterone
245
what is Addisons disease
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
what is the biochemistry of addisons
pituitary starts secreting lots of ACTH and hence MSH
increased pigmentation
autoimmune vitiligo may coexist
no cortisol or aldosterone, so low blood pressure
247
what is proopiomelanocortin (POMC)
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
what are the causes of adrenocortical failure
Adrenal glands destroyed
Enzymes in the steroid synthetic pathway not working
249
what are the consequences of adrenocortical failure
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
what are the tests for addisons
9 am cortisol = low
ACTH = high
Short synACTHen test
Give 250uh synacthen IM (injection of ACTH)
Measure cortisol response
251
what would the typical addisons patient display with the tests
Cortisol at 9am = 100 (270-900)
Administer injection IM of synacthen
Cortisol at 9:30 = 150 (>600)nM
low despite ACTH injection
252
why is aldosterone not suitable for once daily administration
half life too short for safe once daily administration
253
what is a better option than aldosterone
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
what is wrong with oral hydrocortisone
has short half life - too short for once daily administration
255
why do we use prednisolone
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
how much do we need of prednisolone
2-4mg once daily
More research needed to define correct dose for each patient
Equivalent dose of 15-25mg hydrocortisone daily
257
what are the treatments for adrenal failure
Hydrocortisone 3 times daily (10 + 5 + 2.5)
Prednisolone 3mg daily
Fludrocortisone 50-100 mcg daily
258
what is congenital adrenal hyperplasia
Commonest is caused by 21 hydroxylase deficiency
Can be complete or partial
259
what is complete 21 hydroxylase deficiency and their symptoms
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
what is partial 21 hydroxylase deficiency and its symptoms
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
what does 11 deoxycorticosterone behave like
behaves like aldosterone
In excess = can cause hypertension and hypokalaemia
262
what are the symptoms of 11 hydroxylase deficiency
Deficient hormones = cortisol and aldosterone
Excess hormones = sex steroids and testosterone and 11 deoxycorticosterone
Problems = virilisation, hypertension and low k
263
what are the symptoms of 17 hydroxylase deficiency
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
what do neuroendocrine or chromaffin cells in the adrenal medulla produce
Catecholamines
Adrenaline/epinephrine (80%)
Noradrenaline/norepinephrine (80%)
Dopamine
265
what are the clinical features of cushings
Hypercortisolemia
Moon face
Striae
Thin skin
Bruising - due to turned off protein synthesis
Centripetal obesity
Buffalo hump
Proximal myopathy
Hypertension
Hypokalaemia
Osteoporosis
Diabetes
266
what are the causes of cushings disease
Too many steroids
Pituitary dependent Cushings (secondary hypercortisolemia)
Adrenal adenoma secreting cortisol (primary hypercortisolemia)
Ectopic ACTH from lung cancer
267
what are the tests or investigations for cushings
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
what does a low dose dexamethasone suppression test do
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
what are the methods for pharmacological manipulation of steroids
enzyme inhibitors
receptor blocking drugs
hyperadrenal disorders
drugs used in the treatment of hyperadrenal disorders
270
what are the 2 inhibitors of steroids biosynthesis for cushings
inhibitors of steroid biosynthesis
metyrapone; ketoconazole
271
at are the mechanisms and actions of metyrapone
inhibition of 11b-hydroxylase
steroid synthesis in the zona fasciculata (and reticularis) is arrested at the 11 deoxycortisol stage
272
at are the uses of metyrapone
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
what are the unwanted actions of metyrapone
hypertension on long term administration (due to deoxycortisone accumulation - aldosterone like, increased retention of salt)
hirsutism
274
what is the mechanism of action for ketoconazole
mainly blocks 17 hydroxylase mainly inhibiting cortisol production
275
what are the uses of ketoconazole
Cushing’s syndrome
treatment and control of symptoms prior to surgery
orally active
276
what are the unwanted actions of ketoconazole
liver damage - possibly fatal - monitor liver function weekly, clinically and biochemically
277
what are the treatments for cushings disease
depends on cause
pituitary surgery (transsphenoidal hypophysectomy)
bilateral adrenalectomy
unilateral adrenalectomy for adrenal mass
metyrapone
ketoconazole
278
what is conns syndrome
benign adrenal cortical tumour (zona glomerulosa)
aldosterone in excess
hypertension and hypokalaemia
primary hyperaldosteronism
renin - angiotensin system should be suppressed (exclude secondary hyperaldosteronism)
279
what is the treatment for conns syndrome
XS aldosterone
MR antagonist : spironolactone, eplerenone
280
what are the uses and mechanisms of action for spironolactone
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
what are some unwanted actions from spironolactone
menstrual irregularities (+progesterone receptor)
gynaecomastia (-androgen receptor)
282
what is eplerenone
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
what is a phaeochromocytoma
tumours of the adrenal medulla which secrete catecholamines
(adrenaline and noradrenaline)
284
what are clinical features of a phaeo
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
what is the management for a phaeo
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
what does our body do to a drug
absorption
distribution
metabolism
excretion
287
what is absorption of a drug
the passage of a drug from the site of administration into the plasma (the process for drug transfer into the systemic circulation)
288
what is bioavailability
the fraction of the initial dose that gains access to the systemic circulation (outcome of drug transfer into the systemic circulation - how much)
289
what is a determinant of absorption and bioavailability
site of administration
290
what are some examples of drug administration
oral
inhalational
dermal (percutaneous)
intra nasal
injections
many more
291
how do drugs move around the body
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
what is pinocytosis
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
what is diffusion across aq pores
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
how do most drugs move across membranes
diffusing across lipid membranes
295
for drugs to diffuse across lipid membranes what do they need to be or what is another method for transportation
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
do drugs tend to be more lipid soluble or water soluble and why
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
how do drugs exist
as weak acids or weak bases
therefore exist as ionised or unionised
298
describe aspirin
weak acid = in ionised state - donates protons eg H+
299
describe morphine
weak base = in ionised state - accepts protons
300
which form of the drug retains more lipid solubility, ionised or unionised
unionised
more likely to diffuse across plasma membranes
301
what determines whether the drug is ionised or not
dissociation constant (pKa) for that drug and
the pH in that particular part of the body
302
explain the split of unionised and ionised forms in terms of aspirin (a weak acid)
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
explain the split of ionised and unionised in terms of morphine (a weak base)
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
would weak bases be trapped in the stomach
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
could weak acids become trapped in the blood
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
where are the most important carrier systems relating to drug action found
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
what are factors that affect/influence drug distribution
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
what is regional blood flow
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
what is plasma protein binding
once drugs reach systemic circulation = common to bind to plasma proteins
most important = albumin - good at binding acidic drugs
310
what does the amount of drug bound depend on
the free drug concentration
the affinity for the protein binding sites
the plasma protein conc
311
why is the plasma conc required for clinical effect for nearly all drugs less than 1.2mmol/l
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
when can drugs leave/diffuse out to blood
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
what is capillary permeability and how does that affect drugs
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
what happens to drugs when there is a discontinuous structure
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
what happens when there is a fenestrated structure for drugs
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
what is tissue localisation
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
why do we need to eliminate drugs
to eliminate drugs = pathways for excretion
without this = continuous circulation and effects of drugs
318
what is the controversy with drugs being effective and their excretion
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
what is the major metabolic tissue
liver
320
what enzymes are mainly responsible for drug metabolism
cytochrome P450 enzymes
321
what is phase 1 for drug metabolism
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
what is a pro drug
parent drug has no own activity and only produces an effect once metabolised to respective metabolite (metabolism required for pharmacological effect)
323
what is phase 2 for drug metabolism
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
what is first pass presystemic metabolism
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
what are some routes of excretion for drugs
lungs (basis of alcohol breath test)
breast milk (careful it does not affect baby)
kidney (urine)
liver (bile)
326
what are the 3 major excretion routes via the kidney
glomerular filtration
active tubular secretion (or reabsorption)
passive diffusion across tubular epithelium
327
describe excretion by glomerular filtration
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
describe excretion by active tubular secretion
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
describe excretion by passive diffusion
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
what are factors that affect extent of reabsorption
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
what is biliary excretion
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
what is enterohepatic recycling - prolongs drug effect
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
what are the therapeutic objectives for diabetes
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
describe metformin
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
where is the organic cation transporter 1 expressed (OCT1)
hepatocytes (liver)
enterocytes (small bowel)
proximal tubules (kidney)
336
what happens at the small bowel OCT1
small bowel OCT-1 allows it to be absorbed (intestine can get the drug from the gut to the blood)
337
what happens at the hepatocyte OCT1
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
what is the primary mechanism of action for metformin
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
what is the drug target for metformin
5' AMP activated protein kinase (AMPK)
hepatocyte mitochondria
340
what are the main side effects of metformin
GI side effects
eg abdominal pain, decreased appetite, diarrhoea, vomiting
esp high doses - slow increase might improve tolerability
341
what does metformin need to access tissues and why
as it is highly polar - it needs OCT-1
342
what is an example of DPP-4 inhibitors (and what does it stand for)
dipeptidyl-peptidase 4 (DPP) inhibitors
example = sitagliptin
343
what is the primary mechanism of action for DPP-4 inhibitors
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
what is the drug target for DPP-4 inhibitors
DPP-4
the primary site of DPP-4 inhibitor action = vascular endothelium
345
what are the main side effects of DPP-4 inhibitor
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
what is an example of sulphonylurea
gliclazide
347
what is the primary mechanism of action of sulphonylurea
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
what is the drug target for sulphonylurea
ATP - sensitive potassium channel
primary site of SUs inhibitor action is the pancreatic beta cell
349
what are the side effects of sulphonylurea
weight gain
hypoglycaemia
350
what is an example of a sodium glucose cotransporter (SGLT2) inhibitors
dapagliflozin
351
what is the primary mechanism of drug action for SGLT2 inhibitors
reversibly inhibit sodium glucose cotransporter 2 in renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
352
what is the drug target for SGLT2 inhibitors
SGLT2 = primary site of SGLT2 inhibitor action = proximal convoluted tubule
353
what are the side effects of SGLT2 inhibitors
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
