PED2006 brief 2 Flashcards
what are barbiturates
used as sedative/hypnotic/anaesthesia inducing agents
they are positive allosteric modulators of GABA A receptors
examples of commonly used barbiturates
pentobarbital
butobarbital
phenobarbital
sodium thiopental
which barbiturates are used in the induction of general anaesthesia
pentobarbital
sodium thiopental
which barbiturates are used in some cases of epilepsy
phenobarbital
pentobarbital
what are ultra short acting barbiturates used for
the induction of general anaesthesia because of their short durations allows for control
what are short/intermediating acting barbiturates used for
anaesthetic purposes such as insomnia and anxiolytics
what are long acting barbiturates used for
e.g. phenobarbital
used as an anticonvulsant
this is due to its low lipid solubility and low plasma binding properties
what is thiopental
example of a fasting acting barbiturate as it is highly lipid soluble so absorbed quickly into the bloodstream
what is bicuculline
a competitive antagonist
can be used for low barbiturate dose
what is picrotoxin
a non-competitive antagonist can can be used for high barbiturate doses
what are benzodiazepine
used as a sedative/ hypnotic/anticonvulsasnt/muscle relaxant
positive allosteric modulators of GABA A receptors
what benzodiazepines are used for sedation and anxiety
diazepam
alprazolam
what is temazepam used for
sleep aid
what is midazlolam used for
a pre-treatment for procedures
how were the effects of benzodiazepines shown
through mouse knock in strategies, where they were modulated by different GABA receptor subtypes. the results showed that mice were resistant to sedation, amnestic and anticonvulsant effects but not the anxiolytics, motor impairing and ethanol potentiating effects
where is the benzodiazepine binding site
located at the interface of an alpha and gamma subunit
what are typ1 benzodiazepines
contain alpha 1 isoforms
this BZ1 receptor is found highly concentrated in the cortex, thalamus and cerebellum
BZ1 is responsible for sedative and anticonvulsant effects
what are type 2 benzodiazepines receptors
contain he alpha 2/3/5 isoform and mediate the anxiolytic effects
these receptors are found in high concentrations in the limbic system, motor neurones and the spinal cord
what are the drawbacks from the use of benzodiazepines
tolerance to hypnotics and my-relaxant effect
anticonvulsant and anxiolytic effects
withdrawal symptoms sich as depression, psychosis, seizures and delirium tremens
what is flumazenil
a competitive inhibitor of benzodiazepine binding to GABA-A receptor
what are Z drugs
zolpidem, zopiclone and zaleprone
these are positive allosteric modulators of GABA A receptors.
they show preference for the alpha 1 contains receptor subunits so don’t have myorelaxant and anticonvulsant effects
what is zolpidem
a potent sedative and hypnotic with minimal anxiolytic effects
this is because it mediates its action through the activation of the alpha1 containing GABA A receptor
what is zopiclone
used in sedation as shows preferential agonist activity at the a1 subunit of the GABA A receptor and has the longest duration of action
what is zaleplon
used to reduce sleep latency so taken if stuggling to fall asleep and if waking at night is common
has selective binding at BZ1 receptors and low affinity and potency at a2 and a3 subunits
what causes excitatory signalling in the brain
depolarisation
action potential generated
neurotransmitter release and postsynaptic activation
how can excitatory signalling be controlled
by inhibitor neutrons which involves suppressing neuronal firing through which allows cl- to enter
what is used to treat focal seizures
first choice - lamotrigine and levetiracetam
second - carbamazepine, sodium valproate and zonisamide
what is used to treat tonic-clonic seizures
first - sodium valproate
second - lamotrigine
what is used to treat absence seizures
ethosuximide
sodium valproate
what is used to treat myoclonic seizures
first - sodium valproate
second - lèvetiracetam
what is used to treat atonic and tonic seizures
sodium valproate with lamotrigine
which types of drugs are contraindicated in myoclonic seizures
anticonvulsants such as carbamazepine, oxcarbazepine and phenytoin
which types of drugs are contraindicated in myoclonic epilepsy
gabapentin
pregabalin
tiagabine
vigabatrin
how do anticonvulsants work
reduce firing by blocking sodium channels
seen by; phenytoin, carbamazepine, valproic acid, lacosamide, lamotrigine, zonisamide and topiramate
action of phenytoin
blocks fast voltage dependent sodium channels by prolonging the inactive state, this prevents repetitive firing
it is licensed for tonic-clonic and focal seizures but may exacerbate absence or myoclonic seizures
side effects of phenytoin
neurologic effect
hirsutism
gingival hyperplasia
impaired insulin secretion
mild neuropathy
rash
what is carbamazepine used for
generalised and focal seizures
works by limiting the repetitive firing of action potentials
adverse effe its of carbamazepine
drowsiness
vertigo
ataxia
diplopia
blurred vision
action of lamotrigine
acts on both VGSCs and VGCCs
works by slowing rapid firing of neurons
used to treat focal epilepsy
used to treat bipolar
adverse effects of lamotrigine
rash
stevens-johnsons syndrome
toxic epidermal necrolysis
how does valproate work
prolonging inactivated states of VGSCs and inhibits low threshold T types VGCCs
increases GABA through inhibits of GABA transaminase and up-regulating glutamate decarboxylase.,
used as an antiseizure and used in bipolar disorder as it inhibits histamine deacetylase
adverse effects of valproate
sedation
ataxia
tremor
GI effects
hepatotoxicity
prolong the durations of barbiturates, BZDs and narcotics
action of lacosamide
selectively enhances sodium channel, slowing inactivation which sustains depolarisation
this results in stabilisation of hyper excitable neuronal membranes, inhibition of neuronal firing, and reducing in long term channel avaliability without affecting physiological function
what is the difference between Z drugs and barbiturates on inhibitory transmission
due to additional actions of barbiturates on excitability and glutamate release. so BZDs are first choice for status epileptics and phenobarbital is used as a convulsant
action of gabapentin and pregabalin
an indirect effect on inhibitory transmission
gabapentin works by elevating GABA synthesis via glutamate decarboxylase and brain chain aminotransferase
decreases calcium ion entry as inhibits binding to alpha2delta subunit of voltage gated Types ca2+ channels
pregabalin is used as an adjunctive for partial seizures
how does perampanel work
targeting AMPA-Rs
decrease excitation
how does felabamte work
targets GABA. plus NMDA-Rs
decrease excitation
how does topiramate work
targets VGSCs, GABA plus AMPA-Rs
action of levetiracetam
targets presynaptic sodium channels and used as an anti epileptic drug
action of levetiracetam and brivaracetam
reducing short term plasticity at glutamatergic synapses and may alter protein-protein interaction at the synapse
action of ethosuximide
used for absence seizures
works by targeting T-type currents that underlie bursts of action potentials without modifying the voltage dependence of steady state inactivation or the time course of recovery from inactivation
doesn’t inhibit repetitive firing or enhance GABA response
what is GAD
the hypo functions of serotonergic neurone and GABAergic neurones plus overactivity of noradrenergic neurone arising from the locus coeruleus may produce excessive excitation in the brain areas implicated in GAD
what causes anxiety
changes in dopaminergic and 5HT they impact anxiety disorders
what causes depression
by depleted monoamines, tryptophan depletion
what is iproniazid
first antidepressant drug that works by promoting monoamine signalling
drugs classes for anxiety
SSRI
SNRI
TCA
MAOI
atypical antidepressants
pregabalin
BZDs
beta blockers
drug classes for depression
TCA
SSRI
SNRI
NRI
NaSSA/tetracyclines
MAOIs
atypical antidepressants
melatonergic antidepressants
action of MAO-A
degrades amine neurotransmitters (dopamines, norepinephrines, serotonin
action of MAO B
metabolises dopamines
main treatment for anxiety
was barbiturates (phenobarbital)
now benzodiazepines
examples of SSRIs
selective serotonin reuptake inhibitors
citalpram
escitalopram
fluoxetine
paroxetine
sertraline
adverse effects of SSRIs
nausea
sexual dysfunction
agitations
weight gain
insomnia
action of SSRIs
inhibiting tomato-dendritic auto receptors on 5HT neurone. leading to elevated 5HT with raphe nuclei, this reduces expression of inhibitory 5HT1A receptors, so 5HT output is enhances
action of tricyclic antidepressants
e.g. imipramine
acts as serotonin-norepinephrine reuptake inhibitors by blocking serotonin inhibitors and the norepinephrine transporter, resulting in elevation of the synaptic concentrations of these neurotransmission
side effects of TCAs
blurred vision
dry mouth
constipation
orthostatic hypotension
urinary retnetion
rash
hives
tachycardia
increased risk of seizures
what happens during TCAs overdose
can be hypotension due to inhibition of alpha-adrenergic receptors
slowed cardiac conduction due to inhibition of cardiac VGSCs
examples of SNRIs
venlafaxine
duloxetine
action of SNRIs
higher affinity for SERT than NET, opposite of TCAs.
They have minimal actions at adrenergic, histamine, muscarinic, dopamine or postsynaptic serotonin receptors
action of venlafaxine
potent inhibitors of neuronal serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake
examples of atypical antidepressants
buspirone
mirtazapine
trazodone
action of bus-irons
5-HT1A receptor partial agonista nad a dopaminę antagonist. so it depresses 5HT and enhances DA release
used for anxiety
action of mirtazapine
a tetracyclic antidepressant
potential antagonist of central alpha2-adrenergic receptors which leads to a blockade of presynaptic auto receptors and thus enhances noradrenaline release
an antagonist of the 5ht receptor which results in a blockage of 5ht neurotransmission
action of trazodone
a monoamine oxidase
has hypnotic actions due to blockade of 5HT2A receptors, as well as H1 histamine receptors and alpha1 adrenergic receptors
used in elderly ad causes orthostatic hypotension
effects of antidepressants on weight
mirtazapine and citalopram - greatest weight gain
bupropion, nortriptyllin and amitriptyline show less weight gain
drugs with rapid antidepressant effect
psylocybine - has 5HT2A psychedelic action
ketamine - a dissociative open channel NMDA receptor blocker
ECT
what is psychosis
a disorder that is a disturbance of reality and perception. it denotes main mental disorders
what is schizophrenia
a kind of psychosis characterises mainly be a clear sensorium but a marked thinking disturbance. it usually has an onset in adolescence but develops quickly. main treatment is neuroleptics and episodic
which drugs can induce psychosis
levodopa
CNS stimulants - cocaine, amphetamines, Khat, apomorphine and phencyclidine
what type of drugs are antipsychotics
D2 receptor antagonists
what is the dopamine hypothesis for schizophrenia
the mesolimbic pathway - positive symptoms
the mesocortiyal pathway - negative symptoms
the nigrostriatal pathway - side effects
the tuberoinfundibular pathway - side effects
what are the positive symptoms of schizophrenia
distortion and disorganisation in thought
feelings and behaviour
hallucinations
delusions
grossly disorganised speeches
catatonia
what are the negative symptoms of schizophrenia
diminished ability or absence of feelings
motivation and reactivity
alogia
affective flattening
abolition
anhedonia
asociality
what are the cognitive symptoms of schizophrenia
lack of ability to understand and process information in inadequate way
poor memory
difficulty in decision making
poor judgement and insight
poor concentration and attention
impaired sensory perception
what is the dopamine hypothesis for schizophrenia
caused by an overactive dopamine system in the brain
positive symptoms are due to dopamine, acetylcholine and inflammatory
the negative symptoms include serotonin, glutamate and GABA
the cognitive symptoms include acetylcholine, glutamate and serotonin
what are D1 like DA receptors
include D1 and D5
they are g-coupled, stimulate adenylyl cyclase and are postsynaptic
what are D2 like DA receptors
include D2, D3 and D4
they are G protein coupled, inhibit adenylyl cyclase and are pre and postsynaptic
where are D1 receptors found
in substantia nigra
nucleus accumbent
olfactory bulb
cerebellum
hippocampus
thalamus
kidney
where are D5 receptors found
substantia nigra
hypothalamus
kidney
heart
sympathetic ganglia
where are D2 receptors found
substantia nigra
nucleus accumbent
ventral tenemental area
heart
blood vessels
adrenal gland
sympthatetic ganglia
where are D3 receptors found
olfactory bulb and nucleus accumbent
where are D4 receptors found
heart
blood vessels
substantia nigra
hippocampus
amygdala and gastrointestinal tract
what is chlorpromazine
a D2 receptor antagonists
first antipsychotic to be discovered
mainly used now for managing schizophrenia, psychoses, mania, severe anxiety and nausea/vomiting in terminal illness
side effects of chlorpromazine
muscle spasms due to antimuscarinic effects
restlessness
agitations
examples of typical antipsychotics
benperidol
flupentixol
haloperidol
action of typical antipsychotics
reducing dopaminergic neurotransmission by blocking D2 receptors in limbic and cortical areas
the affinity for antipsychotics correlates with therapeutic efficacy
examples of atypical antipsychotics
amisulpride
olanzapine
risperidone
clozapine
action of atypical antipsychotics
dopamine-serotonin receptor antagonists (5HT1A agonist)
more effective and greater amount of side effects
examples of SDA type antipsychotics
risperidone
perospirone
luraspirone
examples of MARTA-type antipsychotics
clozapine
olanzapine
quetiapine
example of the D2 partial agonists
aripiprazole
what does disruption in the dopamine pathway lead to
disruptions in the mesocortical pathway, nigrostriatal pathway, hypothalamic and mesolimbic pathway
what does disruption in mesocortical pathway
negative symptoms
cognitive symptoms
depression
what does disruption of the nigrostriatal pathway lead to
dystonia
akinesia
rigidity
tremor
dyskinesia
what does disruption of the hypothalamic system lead to
prolactin elevation
amenorrhea
galactorrhea
sexual dysfunction
what does disruption of the mesolimbi pathway lead to
agitations
psychosis
Maria
disorganisation
thrill/drug seeking
what are phenothiazines
antipsychotic that can be classified based on their side effect profile
what are the classes of phenothiazines
group 1 - chlorpromazine
group 2 - thiordazine
grup 3 - fluphenazine
what are the group 1 side effects
sedation
H1 receptors
what are group 2 side effects
anticholinergic
what are group 3 side effects
extrapyramidal side effects - a group of symptoms associated with the extrapyramidal system in the brains cerebral cortex such as Parkinsonism and dystonia, tardive dyskinesia, akathisia and neuroleptic malignant syndrome
what is parkinsons disease
a chronic and progressive movement disorder. it initially causes tremor, stiffness or slowing of movement which gets worse over time, this is due to progressive loss of dopaminergic neurone in the substantial nigra
what causes drug induced Parkinsonism
antipsychotics/antiemetics can reduce dopamine transmission
what are some of the symptomatic medical treatment for parkinsons
levodopa - dopamine precursor
dopamine receptor agonists - apomorphine, pergolide, bromocriptin, carbegoline, ropinirole, pramipexole
MAO B inhibitor - selegeline
COMT inhibitor - entacantone
what is amatadine
a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release and blocks dopamine reuptake
what is carbidopa
given in co-administration of levodopa and it doesn’t cross the BBB so reduces the peripheral conversion of levodopa to dopamine so decreases the dosage of levodopa and the side effects
side effects of levodopa
nausea
anorexia
orthostasis
sleepiness
hallucinations
dyskinesia
side effects of dopamine agonists
nausea
sleep attacks
hypotensions
compulsive behaviours
edema
what is Alzheimers disease
a chronic neurogenerative disease of the brain resulting in progressive loss of cognitive function
what are the 2 types of Alzheimers disease
familial - autosomal dominant, ApoE4
sporadic - general population, SNPs with small effect size, GWAS
what is familial Alzheimers
an unimodal progeroid disease
two major genes are amyloid precursor protein and presenilin. these genes are involved in the production of amyloid-beta from APP
what is amyloid-beta peptide
a small fragment of APP
the APP protein have a structure like some cell surface receptor involved in a variety of cell signalling pathways
the function is not really known but is involved in neuronal stem cell development, intracellular signalling promoting growth of axonal and dendritic process, regulating lipid homeostasis
what is gamma secretase
a complex of 4 protein including PSEN1, nicastrin, APH-1 PEN2
what is Abeta
produced by gamma secretase
the secretase cut at very specific sites in target proteins, however gamma secretase exception. the cleavage of gamma-secretase generates slightly different sizes of Abeta peptide
EO-FAD mutations in PSEN or APP which increases the Abeta40:42 ration, Abeta42 is more toxic.
aggregation/oligomerisation increases, cell death increases causing dementia
what is V717I mutation in APP
valine –> isoleucin close to the gamma-secretase cleavage site
this increases Abeta42 production
what is A673T APP mutation
alanine –> threonine close to the beta-secretase cleavage site. less Abeta42 production so Alzheimers disease productions
what are the 2 major pathological hallmarks of Alzheimers disease
extracellular amyloid plaques
intracellular neurofibrillary tangles
mutations in the tau gene is linked to other forms of dementia
what is microtubule associated protein tau (MAPT)
found in the nucleus in the soma
protein, organelles transported from cell body to synapse. microtubules play an essential role in active transport of axonal proteins, vesicles and organelles throughout the axon. this is essential for synaptogenesis and activity induced synaptic plasticity. tau stabilises microtubules
what are the 2 components of pain perception
nociceptive
affective
what is nociceptive
the sensory nervous system process of encoding potentially harmful stimuli. signal are sent from nociceptors to the central nervous systems. sensory neurone detect stimuli through nociceptors
what are the different nociceptors
Alpha/beta fibres are myelinated, large diameter, proprioception and light touch
Adelta fibres are lightly myelinated, medium diameter and nociception
C fibre is unmyelinated, small diameter, innocuous temperature, nociception
what are opioid analgesics
bind to opioid receptor which are found principally in the CNS and gastrointestinal tract
what is morphine
one of the alkaloids found in opium
poor oral bioavailability
what are the different classes of opioids
natural opiates - alkaloids contained in the resin of the opium poppy including morphine, codeine and thebaine
semi-synthetic opiates - created from the natural opioids such as hydromorphone, oxycodone and diacetylmorphine
full synthetic opiates - fentanyl, methadone and tramadol
endogenous opioid peptides - produced naturally in the body, such as endorphins, enkephalins, dynorphins and endomorphies
what is the difference between classes of opioids
different opioids have different therapeutic range and relative potency of analgesic action and the duration of action adverse effects
what is opioid chemistry
phenathrenes - morphine and codeine
phenylheptylamines - methadone
phenylpiperidine - fentanyl
morphinans - butorphanol
what are opioid classification
full agonists - morphine
partial agonist - buprenorphine
antagonists - naloxone
what happens during opioid metabolism
opioids are metabolised by the conversion to polar metabolites
metabolisation of morphine
morphine is metabolised to morpine-3-glucuronide (neuroexcitatory), morphine-6-glucuronide (high potency)
which opioids undergo hepatic oxidative metabolism
merperidine
fentanyl
alfentanil
sufentanil
these are phenypeperidine opioids
side effects of opioid analgesics that act on the mug receptors
analgesia
euphoria
respiratory depression
physical dependence
why is analgesia caused by opioids
decreased neuronal transmitter release and decreased nociceptive impulse propagation. it works by elevating the pain threshold, thus decreasing the brains awareness to pain
how do opioids work in the pre synaptic membrane
close voltage gates calcium channels on presynaptic nerve terminals
this inhibits the release of glutamate, acetylcholine, norepinephrine, serotonin and substance p
side effects of opioids
depression of the respiratory system
constipation
excitation
euphoria
nausea
pupil constriction
tolerance and dependence
bradycardia
opioids tolerance
methadone tolerance develops slowly
mophrine and heroin develops quickly
what are the female sex hormones
oestrogen and progesterone
what are the male sex hormones
androgen
where is oestrogen used
in fertility as it increases growth of ovarian follicles, endometrial growth and increase in tubal motility and uterine contractions
how does oestrogen play a role in fertility
stimulates duct growth and inhibits milk let down (prolactin)
what are the secondary sexual characteristics of oestrogen
breast development
female habitus
development of external genitalia
what is the role of progesterone in fertility
endometrial receptivity
decrease in fallopian tube motility
decrease in uterine contractions
what is the role of progesterone in lactations
stimulates lobuloalveolar development
inhibits milk let down
what is PMS
progesterone withdrawal
what is the hypothalamic-pituitary-ovarian axis
GnRH pulsatile generator is in the accurate nucleus of the hypothalamus. GnRH is released into bloodstream and travels to anterior pituitary gland. the anterior pituitary releases FSH and LH. these hormones bind to receptors on different target cells in the ovary to release either oestrogen or progesterone
what is oestrogen in charge of
follicular maturations
proliferation of endometrium
inhibits FSH so regulates cycle
role of progesterone in reproductive cycle
renders the endometrium suitable for implanting of a fertilised ovum. it inhibits further release of GnRH, FSH and LH so regulates cycle and ovulation
stages of the ovarian cycle
FSH is increased due to low ovarian hormone production
FSH aids follicular development
follicles produce oestrogen
high concentrations of oestrogen
positive feedback from increased oestrogen initiates the LH surge
the LH surge induces ovulations
the remainder of the ovulatory follicle becomes lutienised
it secretes progesterone and oestrogen
if not pregnancy then CL regresses and there is a decrease in oestrogen and progesterone
what happens if there is no fertilisation after ovulation
progesterone and oestrogen decrease
corpus luteum regression, progesteron and oestrogen levels drop so the endometrium cannot be maintained and menstruation occurs
lack of progesterone also means the clamp on GRH, FSH and LH secretion is released. these hormones are secreted against so the cycle starts again
what happens if there is fertilisation and implantation
there is an increase in HCG, progesterone and oestrogen
the ovum secretes human chorionic gonadotrophin, this stimulates corpus luteum to continue secreting progesterone. this helps to maintain endometrium and pregnancy thickens cervical mucus and inhibits further secretion of GRH, FSH and LH to prevent further follicle being developed
what is required to induce follicle formation and ovulation
GnRH, FSH, LH
they are ER and PR agonists
how is feedback involved in ovary cycle
oesterogen and progesterone are required to feedback on hypothalamus and pituitary and so inhibits further follicle being forms
they are ER and PR agonists
which hormone is required to maintain pregnancy
progesterone
PR antaonist
action of oral contraceptives
target the negative feedback system clamping secretion of GRH, FH and LH
oral contraceptives are exogenous oestrogen/progesterone (ER/PR agonist)
what is the combination pill
ER and PR agonist
contain oestrogen which inhibits secretion of FSH via negative feedback, this prevents development of ovarian follicles and blocks ovulation by blocking the FSH peak
contains progesterone which inhibits secretion of LH by negative feedback which prevents ovulation by blocking the LH surge and makes cervial mucus less suitable for passage of sperm
how is the combination pill taken
for 21 days then a 7 day pill free period causes withdrawal bleeding
action of progesterone only pill
works by inhibits LH thickening the mucus in the cervix to stop sperm reaching an egg. this pill blocks ovulation although not consistently as FSH peak can still occur
how is progesterone only pill taken
continuously and can cause irregular periods
examples of emergency contraception
contragestation
mifepristone
action of emergency contraception
terminates pregnancy at the level of the endometrium.
progesterone antagonist as progesterone is responsible for maintaining pregnancy
what are the clinical targets for female sex hormones
oral contraceptives/fertility control - ER and PR agonist
replacement therapy in menopause - ER and PR agonists
ovulation induction - mainly FSH and LH, also partial ER agonist, clomiphene citrate
cancer chemotherapy - ER antagonists or SERMS
Which hormone sensitive tissues can tumours arise
breast
endometrial
ovarian
prostate
how can we inhibit the growth of tumours in hormone sensitive tissue
by oestrogen/progesterone/androgens receptor antagonists
these antagonists inhibit the synthesis of these hormones
which drugs are involved in breast cancer treatments
tamoxifen is a selective estrogen receptor modulator
anastrozole is an aromatase inhibits
action of tamoxifen
a competitive inhibits of estradiol binding to the oestrogen receptors.
it binds to the ER to form a dimer, which is then transported from the cytosol to the nucleus where it binds to DNA to form an unstable complex. hormonal growth signal is switched off = reduced cell proliferation
action of anastrozole
growth and survival signal is switched off, so reduce cell proliferation and cell survival
how does breast cancer develop
ER is positive and ER drives cancer growth and survival
which hormone plays a role in prostate cancer
androgen
what is androgen deprivation therapy
reduces or interferes with androgens blocking receptor activation. androgen fuels the growth of prostate cancer so ADT slows the growth of prostate cancer. this can include surgical and chemical castrations
what is ezalutamide
an androgen receptor antagonist that competitively binds to the ligand binding domain of the androgen receptors preventing the binding of androgen ligand. this inhibits translocation of the androgen receptor into the nucleus. this prevents the binding of AR to DNA to inhibits transcription of AR target genes
side effects of ADT
erectile dysfunction
mood changes
hot flushes
memory problems
brain fog
bone loss
fatigue
what is incurable prostate cancer
GnRH and androgen receptor antagonists parents 100% successful, there can be incurable castrate resistant prostate cancer
this is where AR remains active in resistant disease
mechanism of castration resistant prostate cancer
intratumoural and adrenal steroid hormone synthesis - increased intratumoral androgen
AR gene amplification - increased AR expression and hypersensitivity to low T levels
AR mutations, gain of function - point mutations T877A, W741C, F876L, T878A. increased promiscuity activation by AR inhibitors (flutamised, bicalutamide, enzalutamide and progesterone)
AR splice variants - trunctated AR, LBD deficient. constrictive active AR without ligands
AR coregulatory - increased AR co activators, decreased AR co-repressorys
alternative splicing - up regulation of anti-apoptotic pathways such as AKT, loss of tumour suppressor PTEN which inhibits AKT
Up regulation of the glucocorticoid receptors
what is KMT5A
Is an AR coregulatory, it is a lysine methyltransferase. it interacts with the AR which is required for AR transcriptional activity. it also regulate oncogenic pathways such as CD20 in CRPC
what is AR-V8 in castrate resistant prostate cancer
AR splice variant
AR constitutively active without the need for androgens
what is IKBKE
IKBKE activity enhances AR levels through modulating the hippo pathways
what are the steps in targeting the hippo pathway in prostate cancer
activation of hippo pathway switches off transcriptional programmes that promote cell growth
through cascade of kinase signalling leading to phosphorylation and proteasome mediated degradation of downstream effector, YAP, which is a transcription factor
YAP associated with the AR
YAP stibailisation causes up regulation of YAP target genes including c-Myc
higher levels of c-Myc in turn up-regulates transcriptions of c-Myc target genes such as AR
IKBKE leads to YAP stabilisation, and ultimately increased AR signalling
IKBKE and YAP are often over expressed in many cancers including PC
what causes androgenic alopecia
excessive follicular sensitivity to androgens. it causes shrinkage of hair follicles, replacing terminal hairs with vellus hairs
treatment for androgenic alopecia
finasteride which is a 5-alpha-reductase inhibitor. this blocks the conversion of testosterone to its active for dihydrotestosterone lowering DHT levels
what are the new treatments for prostate cancer
PARP inhibitors
ADT
IKBKE inhibitors
ADT
what is the pituitary
master endocrine gland
what is the hypothalamus
the supreme commander
what are the two main parts of the pituitary gland
posterior - stores and secretes hormone synthesised in hypothalamus (oxytocin and ADH)
anterior - synthesises and secretes hormones in response to hypothalamic regulations (TSH, ACTH, FSH, LH, GH, PL)
what is the posterior pituitary
consists mainly of neuronal projections extending from the supraoptic and paraventricular nuclei of the hypothalamus. these axons release peptide hormones into the capillaries of the hypophyseal circulation
action of ADH
when blood pressure is low it is detected by the posterior pituitary gland which produces ADH
ADHa binds to V2 receptors on the basolateral of principal cells which promotes conversion of ATP to cAMP via adenylate cyclase. this activated protein kinase A which promotes fusion of aquaporin2 into the apical luminal membrane enhancing permeability to h2o. this increases water permeability in distal convoluted and collecting duct resulting in concentration urine
where does water absorption occur
the ascending limb of loop of henle, DCT and collecting duct are impermeable to water. so water absorption can occur in later DCT and collecting duct in the presence of ADH. ADH promotes membrane fusion of AQP2
examples of ADH hormone level stimulants
opioids
anti-depressants
nicotine
MDMA
examples of ADH hormone level depressant
alcohol
what is syndrome of inappropriate ADH secretion
ADH disorder where excessive ADH secretion leads to high urine osmolatiry, increased total body water - hyponatremia, hypo osmotic blood plasma and hypervolemia. this can be cause post operative, head trauma, ectopic ADH production and drugs
how does SIADH
tolvaptan can be used which is an ADH V2 agonist
action of SIADH
ADH increases which increase blood volume, which dilutes sodium in the blood. this causes a compensatory mechanism in the kidney which leads to decreased renin, decreased angiotensin 2, decreased mineralocorticoid, decreased sodium absorption in the blood. this causes high sodium in urine which makes hyponatremia worse
what is diabetes insipidus
non functional ADH system - resulting in excessive water loss. polyuria, polydipsia, hypernatremia and hypotension
what is neurogenic DI
failure of ADH secretion - lesion of hypothalamus or pituitary. desmopressin is a treatment for this
what is nephrogenic DI
failure of principal cells to respond to ADH due to V2 receptor mutation. a treatment for this is a sodium ion restricted diet
how to treat disorders with low ADH
V2 agonists - lyspressin and desmopressin
how to treat disorders which high ADH
v2 antagonists - demeclocycline tolvaptan
what makes up the adrenal cortex
zonal glomerulosa - produces mineralocorticoid (aldosterone)
zona faasiculata - produces glucocorticoid (cortisol)
zona reticularis - produces androgens (DHEA)
wha is adrenal steroid genesis
cholesterol –> pregnolone –> progesterone –> deoxycortisterone –> corticosterone –. 18OH corticosterone –. aldosterone
stages in steroid hormone receptor signalling
steroids diffuse across the cell membrane into the cell
binding to intracellular receptors induces translocation to nucleus
activated receptors bind to specific target gene response elements in DNA
modulate transcription of specific genes (synthesis of mRNA)
mRNA is translated to protein
protein exerts its effect on the cell, altering cellular activity
role of aldosterone
regulates sodium and potassium ion balance. it acts on distal tubule principal cells to increase sodium reabsorption and increased potassium ion secretion
how is aldosterone regulated
stimulated by low plasma sodium ion or high potassium ions.
it can be indirectly regulated by stimulation by angiotensin 2
causes of hyperaldosteronism
adrenal glands - conn’s syndrome is adrenal hyperplasia/tumour of zona glomerulosa
pathology outside of the adrenal - chronic low blood pressure which causes congestive heart failure = high renin = excess aldosterone
treatments of hyperaldosteronism
spironolacterone or eplereonone which is an MR antagonists
what causes hypoaldosteronism
adrenal gland - Addisons disease is an autoimmune disorder where there is destruction of zona glomerulus cells
pathology outside the adrenal - renin deficiency is genetic predisposition
how to treater hypoaldosteronism
fludrocortisone which is a MR agonist
distribution of cortisol and aldosterone at basal conditions
concentration of cortisol is higher than the concentration of aldosterone. MR is fully saturated by cortisol. MR will not respond to a change in aldosterone
distribution of MR
in specialised tissues such as kidney, colon and bladder
in these areas MR associated with high levels of an enzyme 11 beta-hydroxysteroid dehydrogenase. 11beta-GSD metabolises/removes cortisol
MR in the kidney
in a kidney cell aldosterone is free to act on the MR
what is carbenoxolone
used in the treatment of oral and gastric ulcer
inhibits cortisol metabolism
what is type 1 diabetes
where the body does not produce enough insulin, insulin hypo secretion
what is type 2 diabetes
where the body produces insulin but can’t use it well, insulin receptor hyposensitivity
different types of insulin
animal - extracted by pancreas of pigs and cows
human
- short duration - act rapid, humulin S
- intermediate - insulatard, humulin I
treatments for type 2 diabetes
education
diet
lifestyles
blood glucose management and medication
what is blood glucose management
involves intensification of HbA1c more than 58 mmol/mol. this medication is called metformin
action of metformin
acts to suppress glucose production in the liver
inside the hepatocyte metformin inhibits mitochondrial respiratory chain complex 1, resulting in reduced ATP levels and increased AMP
increased AMP levels activate adenosine monophosphate-activated protein kinase, which contributes to lowering of glucose production by 2 pathways
what are the 2 pathways metformin lower blood glucose
increased AMPK phosphorylates CBP and CRTC2 transcription factors, which inhibits genes involved in the production of glucose
increased AMPK also inhibits mitochondrial glycerol-3-phosphate dehydrogenase, leading to an increased cytosolic NADH, which both stimulates the conversion of pyruvate to lactate, and simultaneously decreases gluconeogenesis
other blood glucose management medications
sulphonylureas
pioglitazone
dipeptyl peptidase-4 inhibitors
glucagon like polypeptide 1
sodium glucose like transporter 2 inhibitors
what are thiazolidinediones
type of monooxygenase amine
improves insulin sensitivity
they activate peroxisome proliferator-activated receptors gamma. this activation of PPAR-y increases the expression of several insulin-responsive genes that enhance the production of proteins involved in glucose and lipid metabolism
what does activation of PPAR-y lead to
improved differentiation and function of adipocytes, which enhances their stability to store fats and reduces the release of free fatty acids
increased glucose uptake in muscle cells and adipose tissue, helping to lower blood glucose levels
reduced hepatic gluconeogensis, similar to metformin, although through different regulatory mechanisms
action of glucagon like polypeptide 1
potentiation of glucose-mediated insulin secretion believed to be related to an increase in beta cells
suppression of post prandial glucagon release by a mechanism that is currently unclear
CNS mediated loss of appetite
slowed gastric emptying this effect is mediated by reduced parasympathetic tone
what is dipeptyl peptidase -4 inhibitors
a protease that degraded the incretin GLP1
incretins are hormones released from the GI tract in response to nutrient ingestion
incretins potentiate glucose-stimulated insulin secretion from beta cells in the pancreases
as a result of inhibits DPP-4, increased or prolonged GLP-1 levels are able to potentiate the secretion of insulin by the pancreas
action of SGLT-2 inhibitors
reduce glucose reabsorption in the kidneys, resulting in increased urinary glucose excretion, and lower plasma glucose
what is the thyroid gland
used for brain development, bone maintenance and metabolic controls (muscle control, heart function, digestive function)
how does the thyroid control hormones
hypothalamus released TSH-releasing hormone to the pituitary gland. the pituitary gland released thyroid stimulating hormone to the thyroid gland. the thyroid gland released thyroxine/triiodothyronine to the body
what are the thyroid hormones
thyroxine (T4) most abundant
triiodothyronine (T3) most active
calcitonin is involved with calcium homeostasis in the blood in conjunction with parathyroid gland
how are T3/T4 produced
by iodination and coupling of tyrosine in the colloid
tyrosine residues are on the thyroglobulin synthesised by follicular cells and released in colloid
iodide from blood is transported through follicle cells into colloid
iodination occurs whereby iodine molecules attach to tyrosine and coupling occurs when tyrosine molecules bind together
when process is completed T3 and T4 enter the blood stream
what is iodination
the addition of an iodine molecule to the tyrosine residue. T3 is created by MIT (T1) and DIT (T2) bind toegther
T4 is created by DIT (T2) binds to another DIT (T2)
what is the binding affinity if TR
TR alpha 2 doesn’t bind T3 where other have higher affinity for T3 than T4. receptor bound hormone response element and represses transcription. key target is increased transcription of genes encoding mitochondrial uncoupling proteins
what is the metabolic importance of thyroid hormones
increased basal metabolic rate
glycolysis
oxygen consumption
thermogenesis
protein turnover
what is the growth and development importance of thyroid hormones
fetal neural development
post natal - bone growth, tooth development
what is the neurological importance of thyroid hormones
maintains emotion tone
increased alterness, memory, reflexes and wakefulness
what is the cardiovascular importance of thyroid hormones
increased cardiac output and systolic pressure
enhances catecholamine actions
what is the reproduction importance of thyroid hormones
permissive role in males and females
what is hypothyroidism
weight gain
decreased metabolic rate
depressed central NS function
decreased sympathetic NS
bradycardia
low GI tract movement and constipation
decreased catecholamine sensitivity
treatment for hyothyroidism
synthetic thyroid hormones are used such as levothyroxine (T4) liothryonine sodium (T3)
adverse effects of synthetic thyroid hormones
precipitation of cardiac arrhythmias, angina pectoris and cardiac failure
what happen in hyperthyroidism
weight loos
increased metabolic rate
increased central NS function
increased sympathetic NS
tachycardia
high GI tract motility
increased catecholamine sensitivity
what is graves disease
type of hyperthyroidism
an autoimmune disease targeting and activating TSH receptors causing increased thyroxine secretion
how to treat hyperthyrodism
thioureyelens can be used e.g. carbimazole
works by decreasing output of thyroid hormones leading yo gradual reduction in signs and symptoms of hyperthyroidism
propylthiouracil can also be used which blocks T4/T3 in peripheral tissue
how can hyperthyroidism be treated with iodine
iodine is converted in-vivo to iodide. high doses of iodine inhibits secretion of thyroid hormones over 2 weeks. it works by reducing blood supply to thyroid
how to treat thyrotoxicosis
radioactive sodium iodide if drugs not tolerated
it emits beta and gamma radiation which causes destruction of thyroid tissue so it is likely that patients will require T4 replacement therapy
when is propranolol hydrochloride used
it treats the symptoms of hyperthyroidism such as tachycardia, arrhythmias, tremor and can be used alongside radioactive iodine
what is thyrotoxicosis
is a rare and life threatening excessive release of thyroid hormones. emergency treatments include IV fluid, propranolol hydrochloride, hydrocortisone, oral iodine solution and carbimazole or propylthiouracile. symptoms of this conditions include hyperthermia, tachycardia, heart failure, dehydration, abdominal symptoms, tremors and confusion
