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CM2001 > PED2006 brief 2 > Flashcards

PED2006 brief 2 Flashcards

1
Q

what are barbiturates

A

used as sedative/hypnotic/anaesthesia inducing agents
they are positive allosteric modulators of GABA A receptors

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2
Q

examples of commonly used barbiturates

A

pentobarbital
butobarbital
phenobarbital
sodium thiopental

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3
Q

which barbiturates are used in the induction of general anaesthesia

A

pentobarbital
sodium thiopental

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4
Q

which barbiturates are used in some cases of epilepsy

A

phenobarbital
pentobarbital

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5
Q

what are ultra short acting barbiturates used for

A

the induction of general anaesthesia because of their short durations allows for control

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6
Q

what are short/intermediating acting barbiturates used for

A

anaesthetic purposes such as insomnia and anxiolytics

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7
Q

what are long acting barbiturates used for

A

e.g. phenobarbital
used as an anticonvulsant
this is due to its low lipid solubility and low plasma binding properties

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8
Q

what is thiopental

A

example of a fasting acting barbiturate as it is highly lipid soluble so absorbed quickly into the bloodstream

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9
Q

what is bicuculline

A

a competitive antagonist
can be used for low barbiturate dose

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10
Q

what is picrotoxin

A

a non-competitive antagonist can can be used for high barbiturate doses

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11
Q

what are benzodiazepine

A

used as a sedative/ hypnotic/anticonvulsasnt/muscle relaxant
positive allosteric modulators of GABA A receptors

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12
Q

what benzodiazepines are used for sedation and anxiety

A

diazepam
alprazolam

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13
Q

what is temazepam used for

A

sleep aid

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14
Q

what is midazlolam used for

A

a pre-treatment for procedures

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15
Q

how were the effects of benzodiazepines shown

A

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

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16
Q

where is the benzodiazepine binding site

A

located at the interface of an alpha and gamma subunit

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17
Q

what are typ1 benzodiazepines

A

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

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18
Q

what are type 2 benzodiazepines receptors

A

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

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19
Q

what are the drawbacks from the use of benzodiazepines

A

tolerance to hypnotics and my-relaxant effect
anticonvulsant and anxiolytic effects
withdrawal symptoms sich as depression, psychosis, seizures and delirium tremens

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20
Q

what is flumazenil

A

a competitive inhibitor of benzodiazepine binding to GABA-A receptor

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21
Q

what are Z drugs

A

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

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22
Q

what is zolpidem

A

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

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23
Q

what is zopiclone

A

used in sedation as shows preferential agonist activity at the a1 subunit of the GABA A receptor and has the longest duration of action

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24
Q

what is zaleplon

A

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

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25
Q

what causes excitatory signalling in the brain

A

depolarisation
action potential generated
neurotransmitter release and postsynaptic activation

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26
Q

how can excitatory signalling be controlled

A

by inhibitor neutrons which involves suppressing neuronal firing through which allows cl- to enter

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27
Q

what is used to treat focal seizures

A

first choice - lamotrigine and levetiracetam
second - carbamazepine, sodium valproate and zonisamide

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28
Q

what is used to treat tonic-clonic seizures

A

first - sodium valproate
second - lamotrigine

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29
Q

what is used to treat absence seizures

A

ethosuximide
sodium valproate

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30
Q

what is used to treat myoclonic seizures

A

first - sodium valproate
second - lèvetiracetam

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31
Q

what is used to treat atonic and tonic seizures

A

sodium valproate with lamotrigine

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32
Q

which types of drugs are contraindicated in myoclonic seizures

A

anticonvulsants such as carbamazepine, oxcarbazepine and phenytoin

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33
Q

which types of drugs are contraindicated in myoclonic epilepsy

A

gabapentin
pregabalin
tiagabine
vigabatrin

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34
Q

how do anticonvulsants work

A

reduce firing by blocking sodium channels
seen by; phenytoin, carbamazepine, valproic acid, lacosamide, lamotrigine, zonisamide and topiramate

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35
Q

action of phenytoin

A

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

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36
Q

side effects of phenytoin

A

neurologic effect
hirsutism
gingival hyperplasia
impaired insulin secretion
mild neuropathy
rash

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37
Q

what is carbamazepine used for

A

generalised and focal seizures
works by limiting the repetitive firing of action potentials

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38
Q

adverse effe its of carbamazepine

A

drowsiness
vertigo
ataxia
diplopia
blurred vision

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39
Q

action of lamotrigine

A

acts on both VGSCs and VGCCs
works by slowing rapid firing of neurons
used to treat focal epilepsy
used to treat bipolar

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40
Q

adverse effects of lamotrigine

A

rash
stevens-johnsons syndrome
toxic epidermal necrolysis

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41
Q

how does valproate work

A

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

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42
Q

adverse effects of valproate

A

sedation
ataxia
tremor
GI effects
hepatotoxicity
prolong the durations of barbiturates, BZDs and narcotics

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43
Q

action of lacosamide

A

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

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44
Q

what is the difference between Z drugs and barbiturates on inhibitory transmission

A

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

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45
Q

action of gabapentin and pregabalin

A

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

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46
Q

how does perampanel work

A

targeting AMPA-Rs
decrease excitation

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47
Q

how does felabamte work

A

targets GABA. plus NMDA-Rs
decrease excitation

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48
Q

how does topiramate work

A

targets VGSCs, GABA plus AMPA-Rs

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49
Q

action of levetiracetam

A

targets presynaptic sodium channels and used as an anti epileptic drug

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50
Q

action of levetiracetam and brivaracetam

A

reducing short term plasticity at glutamatergic synapses and may alter protein-protein interaction at the synapse

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51
Q

action of ethosuximide

A

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

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52
Q

what is GAD

A

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

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53
Q

what causes anxiety

A

changes in dopaminergic and 5HT they impact anxiety disorders

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54
Q

what causes depression

A

by depleted monoamines, tryptophan depletion

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55
Q

what is iproniazid

A

first antidepressant drug that works by promoting monoamine signalling

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56
Q

drugs classes for anxiety

A

SSRI
SNRI
TCA
MAOI
atypical antidepressants
pregabalin
BZDs
beta blockers

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57
Q

drug classes for depression

A

TCA
SSRI
SNRI
NRI
NaSSA/tetracyclines
MAOIs
atypical antidepressants
melatonergic antidepressants

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58
Q

action of MAO-A

A

degrades amine neurotransmitters (dopamines, norepinephrines, serotonin

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59
Q

action of MAO B

A

metabolises dopamines

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60
Q

main treatment for anxiety

A

was barbiturates (phenobarbital)
now benzodiazepines

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61
Q

examples of SSRIs

A

selective serotonin reuptake inhibitors
citalpram
escitalopram
fluoxetine
paroxetine
sertraline

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62
Q

adverse effects of SSRIs

A

nausea
sexual dysfunction
agitations
weight gain
insomnia

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63
Q

action of SSRIs

A

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

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64
Q

action of tricyclic antidepressants

A

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

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65
Q

side effects of TCAs

A

blurred vision
dry mouth
constipation
orthostatic hypotension
urinary retnetion
rash
hives
tachycardia
increased risk of seizures

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66
Q

what happens during TCAs overdose

A

can be hypotension due to inhibition of alpha-adrenergic receptors
slowed cardiac conduction due to inhibition of cardiac VGSCs

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67
Q

examples of SNRIs

A

venlafaxine
duloxetine

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68
Q

action of SNRIs

A

higher affinity for SERT than NET, opposite of TCAs.
They have minimal actions at adrenergic, histamine, muscarinic, dopamine or postsynaptic serotonin receptors

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69
Q

action of venlafaxine

A

potent inhibitors of neuronal serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake

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70
Q

examples of atypical antidepressants

A

buspirone
mirtazapine
trazodone

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71
Q

action of bus-irons

A

5-HT1A receptor partial agonista nad a dopaminę antagonist. so it depresses 5HT and enhances DA release
used for anxiety

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72
Q

action of mirtazapine

A

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

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73
Q

action of trazodone

A

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

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74
Q

effects of antidepressants on weight

A

mirtazapine and citalopram - greatest weight gain
bupropion, nortriptyllin and amitriptyline show less weight gain

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75
Q

drugs with rapid antidepressant effect

A

psylocybine - has 5HT2A psychedelic action
ketamine - a dissociative open channel NMDA receptor blocker
ECT

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76
Q

what is psychosis

A

a disorder that is a disturbance of reality and perception. it denotes main mental disorders

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77
Q

what is schizophrenia

A

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

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78
Q

which drugs can induce psychosis

A

levodopa
CNS stimulants - cocaine, amphetamines, Khat, apomorphine and phencyclidine

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79
Q

what type of drugs are antipsychotics

A

D2 receptor antagonists

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80
Q

what is the dopamine hypothesis for schizophrenia

A

the mesolimbic pathway - positive symptoms
the mesocortiyal pathway - negative symptoms
the nigrostriatal pathway - side effects
the tuberoinfundibular pathway - side effects

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81
Q

what are the positive symptoms of schizophrenia

A

distortion and disorganisation in thought
feelings and behaviour
hallucinations
delusions
grossly disorganised speeches
catatonia

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82
Q

what are the negative symptoms of schizophrenia

A

diminished ability or absence of feelings
motivation and reactivity
alogia
affective flattening
abolition
anhedonia
asociality

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83
Q

what are the cognitive symptoms of schizophrenia

A

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

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84
Q

what is the dopamine hypothesis for schizophrenia

A

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

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85
Q

what are D1 like DA receptors

A

include D1 and D5
they are g-coupled, stimulate adenylyl cyclase and are postsynaptic

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86
Q

what are D2 like DA receptors

A

include D2, D3 and D4
they are G protein coupled, inhibit adenylyl cyclase and are pre and postsynaptic

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87
Q

where are D1 receptors found

A

in substantia nigra
nucleus accumbent
olfactory bulb
cerebellum
hippocampus
thalamus
kidney

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88
Q

where are D5 receptors found

A

substantia nigra
hypothalamus
kidney
heart
sympathetic ganglia

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89
Q

where are D2 receptors found

A

substantia nigra
nucleus accumbent
ventral tenemental area
heart
blood vessels
adrenal gland
sympthatetic ganglia

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90
Q

where are D3 receptors found

A

olfactory bulb and nucleus accumbent

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91
Q

where are D4 receptors found

A

heart
blood vessels
substantia nigra
hippocampus
amygdala and gastrointestinal tract

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92
Q

what is chlorpromazine

A

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

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93
Q

side effects of chlorpromazine

A

muscle spasms due to antimuscarinic effects
restlessness
agitations

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94
Q

examples of typical antipsychotics

A

benperidol
flupentixol
haloperidol

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95
Q

action of typical antipsychotics

A

reducing dopaminergic neurotransmission by blocking D2 receptors in limbic and cortical areas
the affinity for antipsychotics correlates with therapeutic efficacy

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96
Q

examples of atypical antipsychotics

A

amisulpride
olanzapine
risperidone
clozapine

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97
Q

action of atypical antipsychotics

A

dopamine-serotonin receptor antagonists (5HT1A agonist)
more effective and greater amount of side effects

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98
Q

examples of SDA type antipsychotics

A

risperidone
perospirone
luraspirone

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99
Q

examples of MARTA-type antipsychotics

A

clozapine
olanzapine
quetiapine

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100
Q

example of the D2 partial agonists

A

aripiprazole

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101
Q

what does disruption in the dopamine pathway lead to

A

disruptions in the mesocortical pathway, nigrostriatal pathway, hypothalamic and mesolimbic pathway

102
Q

what does disruption in mesocortical pathway

A

negative symptoms
cognitive symptoms
depression

103
Q

what does disruption of the nigrostriatal pathway lead to

A

dystonia
akinesia
rigidity
tremor
dyskinesia

104
Q

what does disruption of the hypothalamic system lead to

A

prolactin elevation
amenorrhea
galactorrhea
sexual dysfunction

105
Q

what does disruption of the mesolimbi pathway lead to

A

agitations
psychosis
Maria
disorganisation
thrill/drug seeking

106
Q

what are phenothiazines

A

antipsychotic that can be classified based on their side effect profile

107
Q

what are the classes of phenothiazines

A

group 1 - chlorpromazine
group 2 - thiordazine
grup 3 - fluphenazine

108
Q

what are the group 1 side effects

A

sedation
H1 receptors

109
Q

what are group 2 side effects

A

anticholinergic

110
Q

what are group 3 side effects

A

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

111
Q

what is parkinsons disease

A

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

112
Q

what causes drug induced Parkinsonism

A

antipsychotics/antiemetics can reduce dopamine transmission

113
Q

what are some of the symptomatic medical treatment for parkinsons

A

levodopa - dopamine precursor
dopamine receptor agonists - apomorphine, pergolide, bromocriptin, carbegoline, ropinirole, pramipexole
MAO B inhibitor - selegeline
COMT inhibitor - entacantone

114
Q

what is amatadine

A

a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release and blocks dopamine reuptake

115
Q

what is carbidopa

A

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

116
Q

side effects of levodopa

A

nausea
anorexia
orthostasis
sleepiness
hallucinations
dyskinesia

117
Q

side effects of dopamine agonists

A

nausea
sleep attacks
hypotensions
compulsive behaviours
edema

118
Q

what is Alzheimers disease

A

a chronic neurogenerative disease of the brain resulting in progressive loss of cognitive function

119
Q

what are the 2 types of Alzheimers disease

A

familial - autosomal dominant, ApoE4
sporadic - general population, SNPs with small effect size, GWAS

120
Q

what is familial Alzheimers

A

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

121
Q

what is amyloid-beta peptide

A

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

122
Q

what is gamma secretase

A

a complex of 4 protein including PSEN1, nicastrin, APH-1 PEN2

123
Q

what is Abeta

A

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

124
Q

what is V717I mutation in APP

A

valine –> isoleucin close to the gamma-secretase cleavage site
this increases Abeta42 production

125
Q

what is A673T APP mutation

A

alanine –> threonine close to the beta-secretase cleavage site. less Abeta42 production so Alzheimers disease productions

126
Q

what are the 2 major pathological hallmarks of Alzheimers disease

A

extracellular amyloid plaques
intracellular neurofibrillary tangles
mutations in the tau gene is linked to other forms of dementia

127
Q

what is microtubule associated protein tau (MAPT)

A

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

128
Q

what are the 2 components of pain perception

A

nociceptive
affective

129
Q

what is nociceptive

A

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

130
Q

what are the different nociceptors

A

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

131
Q

what are opioid analgesics

A

bind to opioid receptor which are found principally in the CNS and gastrointestinal tract

132
Q

what is morphine

A

one of the alkaloids found in opium
poor oral bioavailability

133
Q

what are the different classes of opioids

A

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

134
Q

what is the difference between classes of opioids

A

different opioids have different therapeutic range and relative potency of analgesic action and the duration of action adverse effects

135
Q

what is opioid chemistry

A

phenathrenes - morphine and codeine
phenylheptylamines - methadone
phenylpiperidine - fentanyl
morphinans - butorphanol

136
Q

what are opioid classification

A

full agonists - morphine
partial agonist - buprenorphine
antagonists - naloxone

137
Q

what happens during opioid metabolism

A

opioids are metabolised by the conversion to polar metabolites

138
Q

metabolisation of morphine

A

morphine is metabolised to morpine-3-glucuronide (neuroexcitatory), morphine-6-glucuronide (high potency)

139
Q

which opioids undergo hepatic oxidative metabolism

A

merperidine
fentanyl
alfentanil
sufentanil
these are phenypeperidine opioids

140
Q

side effects of opioid analgesics that act on the mug receptors

A

analgesia
euphoria
respiratory depression
physical dependence

141
Q

why is analgesia caused by opioids

A

decreased neuronal transmitter release and decreased nociceptive impulse propagation. it works by elevating the pain threshold, thus decreasing the brains awareness to pain

142
Q

how do opioids work in the pre synaptic membrane

A

close voltage gates calcium channels on presynaptic nerve terminals
this inhibits the release of glutamate, acetylcholine, norepinephrine, serotonin and substance p

143
Q

side effects of opioids

A

depression of the respiratory system
constipation
excitation
euphoria
nausea
pupil constriction
tolerance and dependence
bradycardia

144
Q

opioids tolerance

A

methadone tolerance develops slowly
mophrine and heroin develops quickly

145
Q

what are the female sex hormones

A

oestrogen and progesterone

146
Q

what are the male sex hormones

A

androgen

147
Q

where is oestrogen used

A

in fertility as it increases growth of ovarian follicles, endometrial growth and increase in tubal motility and uterine contractions

148
Q

how does oestrogen play a role in fertility

A

stimulates duct growth and inhibits milk let down (prolactin)

149
Q

what are the secondary sexual characteristics of oestrogen

A

breast development
female habitus
development of external genitalia

150
Q

what is the role of progesterone in fertility

A

endometrial receptivity
decrease in fallopian tube motility
decrease in uterine contractions

151
Q

what is the role of progesterone in lactations

A

stimulates lobuloalveolar development
inhibits milk let down

152
Q

what is PMS

A

progesterone withdrawal

153
Q

what is the hypothalamic-pituitary-ovarian axis

A

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

154
Q

what is oestrogen in charge of

A

follicular maturations
proliferation of endometrium
inhibits FSH so regulates cycle

155
Q

role of progesterone in reproductive cycle

A

renders the endometrium suitable for implanting of a fertilised ovum. it inhibits further release of GnRH, FSH and LH so regulates cycle and ovulation

156
Q

stages of the ovarian cycle

A

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

157
Q

what happens if there is no fertilisation after ovulation

A

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

158
Q

what happens if there is fertilisation and implantation

A

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

159
Q

what is required to induce follicle formation and ovulation

A

GnRH, FSH, LH
they are ER and PR agonists

160
Q

how is feedback involved in ovary cycle

A

oesterogen and progesterone are required to feedback on hypothalamus and pituitary and so inhibits further follicle being forms
they are ER and PR agonists

161
Q

which hormone is required to maintain pregnancy

A

progesterone
PR antaonist

162
Q

action of oral contraceptives

A

target the negative feedback system clamping secretion of GRH, FH and LH
oral contraceptives are exogenous oestrogen/progesterone (ER/PR agonist)

163
Q

what is the combination pill

A

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

164
Q

how is the combination pill taken

A

for 21 days then a 7 day pill free period causes withdrawal bleeding

165
Q

action of progesterone only pill

A

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

166
Q

how is progesterone only pill taken

A

continuously and can cause irregular periods

167
Q

examples of emergency contraception

A

contragestation
mifepristone

168
Q

action of emergency contraception

A

terminates pregnancy at the level of the endometrium.
progesterone antagonist as progesterone is responsible for maintaining pregnancy

169
Q

what are the clinical targets for female sex hormones

A

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

170
Q

Which hormone sensitive tissues can tumours arise

A

breast
endometrial
ovarian
prostate

171
Q

how can we inhibit the growth of tumours in hormone sensitive tissue

A

by oestrogen/progesterone/androgens receptor antagonists
these antagonists inhibit the synthesis of these hormones

172
Q

which drugs are involved in breast cancer treatments

A

tamoxifen is a selective estrogen receptor modulator
anastrozole is an aromatase inhibits

173
Q

action of tamoxifen

A

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

174
Q

action of anastrozole

A

growth and survival signal is switched off, so reduce cell proliferation and cell survival

175
Q

how does breast cancer develop

A

ER is positive and ER drives cancer growth and survival

176
Q

which hormone plays a role in prostate cancer

A

androgen

177
Q

what is androgen deprivation therapy

A

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

178
Q

what is ezalutamide

A

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

179
Q

side effects of ADT

A

erectile dysfunction
mood changes
hot flushes
memory problems
brain fog
bone loss
fatigue

180
Q

what is incurable prostate cancer

A

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

181
Q

mechanism of castration resistant prostate cancer

A

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

182
Q

what is KMT5A

A

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

183
Q

what is AR-V8 in castrate resistant prostate cancer

A

AR splice variant
AR constitutively active without the need for androgens

184
Q

what is IKBKE

A

IKBKE activity enhances AR levels through modulating the hippo pathways

185
Q

what are the steps in targeting the hippo pathway in prostate cancer

A

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

186
Q

what causes androgenic alopecia

A

excessive follicular sensitivity to androgens. it causes shrinkage of hair follicles, replacing terminal hairs with vellus hairs

187
Q

treatment for androgenic alopecia

A

finasteride which is a 5-alpha-reductase inhibitor. this blocks the conversion of testosterone to its active for dihydrotestosterone lowering DHT levels

188
Q

what are the new treatments for prostate cancer

A

PARP inhibitors
ADT
IKBKE inhibitors
ADT

189
Q

what is the pituitary

A

master endocrine gland

190
Q

what is the hypothalamus

A

the supreme commander

191
Q

what are the two main parts of the pituitary gland

A

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)

192
Q

what is the posterior pituitary

A

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

193
Q

action of ADH

A

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

194
Q

where does water absorption occur

A

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

195
Q

examples of ADH hormone level stimulants

A

opioids
anti-depressants
nicotine
MDMA

196
Q

examples of ADH hormone level depressant

A

alcohol

197
Q

what is syndrome of inappropriate ADH secretion

A

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

198
Q

how does SIADH

A

tolvaptan can be used which is an ADH V2 agonist

199
Q

action of SIADH

A

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

200
Q

what is diabetes insipidus

A

non functional ADH system - resulting in excessive water loss. polyuria, polydipsia, hypernatremia and hypotension

201
Q

what is neurogenic DI

A

failure of ADH secretion - lesion of hypothalamus or pituitary. desmopressin is a treatment for this

202
Q

what is nephrogenic DI

A

failure of principal cells to respond to ADH due to V2 receptor mutation. a treatment for this is a sodium ion restricted diet

203
Q

how to treat disorders with low ADH

A

V2 agonists - lyspressin and desmopressin

204
Q

how to treat disorders which high ADH

A

v2 antagonists - demeclocycline tolvaptan

205
Q

what makes up the adrenal cortex

A

zonal glomerulosa - produces mineralocorticoid (aldosterone)
zona faasiculata - produces glucocorticoid (cortisol)
zona reticularis - produces androgens (DHEA)

206
Q

wha is adrenal steroid genesis

A

cholesterol –> pregnolone –> progesterone –> deoxycortisterone –> corticosterone –. 18OH corticosterone –. aldosterone

207
Q

stages in steroid hormone receptor signalling

A

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

208
Q

role of aldosterone

A

regulates sodium and potassium ion balance. it acts on distal tubule principal cells to increase sodium reabsorption and increased potassium ion secretion

209
Q

how is aldosterone regulated

A

stimulated by low plasma sodium ion or high potassium ions.
it can be indirectly regulated by stimulation by angiotensin 2

210
Q

causes of hyperaldosteronism

A

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

211
Q

treatments of hyperaldosteronism

A

spironolacterone or eplereonone which is an MR antagonists

212
Q

what causes hypoaldosteronism

A

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

213
Q

how to treater hypoaldosteronism

A

fludrocortisone which is a MR agonist

214
Q

distribution of cortisol and aldosterone at basal conditions

A

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

215
Q

distribution of MR

A

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

216
Q

MR in the kidney

A

in a kidney cell aldosterone is free to act on the MR

217
Q

what is carbenoxolone

A

used in the treatment of oral and gastric ulcer
inhibits cortisol metabolism

218
Q

what is type 1 diabetes

A

where the body does not produce enough insulin, insulin hypo secretion

219
Q

what is type 2 diabetes

A

where the body produces insulin but can’t use it well, insulin receptor hyposensitivity

220
Q

different types of insulin

A

animal - extracted by pancreas of pigs and cows
human
- short duration - act rapid, humulin S
- intermediate - insulatard, humulin I

221
Q

treatments for type 2 diabetes

A

education
diet
lifestyles
blood glucose management and medication

222
Q

what is blood glucose management

A

involves intensification of HbA1c more than 58 mmol/mol. this medication is called metformin

223
Q

action of metformin

A

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

224
Q

what are the 2 pathways metformin lower blood glucose

A

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

225
Q

other blood glucose management medications

A

sulphonylureas
pioglitazone
dipeptyl peptidase-4 inhibitors
glucagon like polypeptide 1
sodium glucose like transporter 2 inhibitors

226
Q

what are thiazolidinediones

A

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

227
Q

what does activation of PPAR-y lead to

A

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

228
Q

action of glucagon like polypeptide 1

A

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

229
Q

what is dipeptyl peptidase -4 inhibitors

A

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

230
Q

action of SGLT-2 inhibitors

A

reduce glucose reabsorption in the kidneys, resulting in increased urinary glucose excretion, and lower plasma glucose

231
Q

what is the thyroid gland

A

used for brain development, bone maintenance and metabolic controls (muscle control, heart function, digestive function)

232
Q

how does the thyroid control hormones

A

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

233
Q

what are the thyroid hormones

A

thyroxine (T4) most abundant
triiodothyronine (T3) most active
calcitonin is involved with calcium homeostasis in the blood in conjunction with parathyroid gland

234
Q

how are T3/T4 produced

A

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

235
Q

what is iodination

A

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)

236
Q

what is the binding affinity if TR

A

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

237
Q

what is the metabolic importance of thyroid hormones

A

increased basal metabolic rate
glycolysis
oxygen consumption
thermogenesis
protein turnover

238
Q

what is the growth and development importance of thyroid hormones

A

fetal neural development
post natal - bone growth, tooth development

239
Q

what is the neurological importance of thyroid hormones

A

maintains emotion tone
increased alterness, memory, reflexes and wakefulness

240
Q

what is the cardiovascular importance of thyroid hormones

A

increased cardiac output and systolic pressure
enhances catecholamine actions

241
Q

what is the reproduction importance of thyroid hormones

A

permissive role in males and females

242
Q

what is hypothyroidism

A

weight gain
decreased metabolic rate
depressed central NS function
decreased sympathetic NS
bradycardia
low GI tract movement and constipation
decreased catecholamine sensitivity

243
Q

treatment for hyothyroidism

A

synthetic thyroid hormones are used such as levothyroxine (T4) liothryonine sodium (T3)

244
Q

adverse effects of synthetic thyroid hormones

A

precipitation of cardiac arrhythmias, angina pectoris and cardiac failure

245
Q

what happen in hyperthyroidism

A

weight loos
increased metabolic rate
increased central NS function
increased sympathetic NS
tachycardia
high GI tract motility
increased catecholamine sensitivity

246
Q

what is graves disease

A

type of hyperthyroidism
an autoimmune disease targeting and activating TSH receptors causing increased thyroxine secretion

247
Q

how to treat hyperthyrodism

A

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

248
Q

how can hyperthyroidism be treated with iodine

A

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

249
Q

how to treat thyrotoxicosis

A

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

250
Q

when is propranolol hydrochloride used

A

it treats the symptoms of hyperthyroidism such as tachycardia, arrhythmias, tremor and can be used alongside radioactive iodine

251
Q

what is thyrotoxicosis

A

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

252
Q
A

CM2001 (13 decks)

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