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pharmacology sem 2 > brain conditions > Flashcards

brain conditions Flashcards

1
Q

what are the hypotheses for MDD?

A

monoamine hypothesis
glumatate (NMDA) hypothesis
GABAergic hypothesis
neurogenesis hypothesis
corticotrophic (glucocorticoid) hypothesis
HPA axis hypothesis

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2
Q

what are the hypotheses to explain SZ?

A

altered dopamine hypothesis
neurodevelopment hypothesis
NMDA-receptor hypothesis
diathesis-stress response axis

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3
Q

what is the 2-hit model for SZ?

A

it is a proposition that in neurodevelopment, there are 2 times in the patients life where the brain develops wrong, the first one is as early as the first or second trimester and the second is during puberty due to too much synapse elimination and loss of plasticity

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4
Q

what regions of the brain are affected with schizophrenia?

A

the mesolimbic dopamine neurons coming from the VTA and the prefrontal cortex (specifically the dorsolateral PFC)
the hippocampus is also affected (where learning and memory is)
amygdala where emotional stress and learning is

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5
Q

where does cell loss happen in SZ patients?

A

theres deficits in olgiodendrocytes in the PFC and limbic system inc anterior cingulate gyrus (ACC), and hippocampus

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6
Q

what is the modified dopamine hypothesis SZ?

A

its the hypothesis that theres significantly less dopaminergic neurons present in the PFC (hypodopaminergia) and too much dopaminergic activity in the mesolimbic regions (hyperdopaminergia)- negative and positive symptoms respectively

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7
Q

what can electroconvulsive therapy be used for?

A

parkinsons
treatment-resistant MDD
SZ
epilepsy

it works by non-focal and intense stimulation of the entire brain, usually causes a generalised seizure then shows greatly reduced symptoms for a long period of time, exact mechanism unknown

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8
Q

what parts of the brain are involved in MDD?

A

hyperactive anterior cingulate cortex
lower neural activity in PFC, hypothalamus, striatum and amygdala

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9
Q

explain the HPA axis

A

hypothalamus has neuroendocrine neurons which produce vassopressin and corticotrophin-releasing hormone which then act on the pituritary to release adrenocorticotrophic hormone which signals to the adrenal glands in the adrenal cortex to produce glucocorticoids inc cortisol (hypersecretion of which is thought to be a risk factor for depression)

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10
Q

what does clozapine target?

A

D1 and 2 receptors, M1 and 5-HT 2a + alpha-adrenoceptor (according to NICE) its 2nd gen

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11
Q

what is the first gen SZ med?

and what does it target?

A

cloropramazine- targets D2,3+5, H1 +M1 antagonist

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12
Q

what is the first choice SZ med and how does it work?

A

amisulpride- selective D2+3 receptor antagonist

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13
Q

how does olanzapine work?

A

it targtes the D1-5 receptors, 5-HT2, H1 and M1 receptors and antagonises them

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14
Q

what makes up the mesolimbic pathway?

A

the ventral-tegmental area (VTA) and the ventral striatum

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15
Q

what genes are involved in SZ?

A

DISK-1 - a truncated gene on chromosomes 1 and 11, need to associate with other genes and non-genetic factors to actually cause an effect
3q29 deletion- highest risk allele associated with SZ
22q11 deletion - associated with the immunodeficient DiGeorge syndrome, 25% of people with this also have SZ

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16
Q

where is there loss of grey matter in SZ?

A

superior temporal gyrus
the amygdala and hippocampus

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17
Q

why is the thalamus smaller in SZ patients?

A

becuase of loss of cell bodies in the mesodorsal neucleus of the thalamus and a loss of axonal terminals which contribute to the loss of cortical dendrites and the dendritic spines

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18
Q

what novel treatment targets both the positive and negative symptoms of SZ?

A

KarTX
trospium - peripheral muscarinic antagonist
xanomeline- M1/4 agonist crosses BBB to cause central effects whilst not being used up in the periphery - also means theres less side effects

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19
Q

what causes physiological anxiety?

A

the hypothalamus and the amygdala signal to the adrenal glands in the adrenal medulla to release adrenaline to cause the physiological symptoms of anxiety

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20
Q

what are the hypotheses explaining anxiety?

A

HPA axis- involved in the second part of the stress response
GABAergic altered sensitivity
5-HT implicated

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21
Q

what part of the brain is most affected in parkinsons and whats its role?

A

the substantia nigra which is responsible for much of the brains dopamine production leading to less positive motor control and more negative motor inhibition

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22
Q

what is the main treatment of parkinsons? and what is also given to help this?

A

levodopa - increases levels of dopamine in the brain
given with catechol-o-methyltransferase to stop peripheral breakdown of the drug

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23
Q

what are the effects of the inability to clear protein aggregates in parkinsons?

A

alpha-synuclein are associated with protein misaggregation and impaired protein cleavage to form lewy bodies which disrupt cell pathways leading to synaptic loss and glial damage and neuronal death

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24
Q
A
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25
how are misfolded proteins usually removed?
autophagy and the ubiqutin-proteasome system
26
why is the substantia nigra dark in colour?
dark neuromelanin which is stored as a waste product of dopamine oxidation
27
what does entacapone do?
it inhibits catachol-O-methyltransferase in the periphery to inhibit the breakdown of L-Dopa outside of the CNS
28
what are examples of dopamine agonists and what receptors do they targte and what condition do they treat?
parkinsons pramipexole (D2/D3), ropinirole (D2/D3), rotigotine (D3/D2/D1; patch
29
what are monoamine oxisase inhbitors used for? name some examples of MOAs?
MDD and parkinsons selegiline and rasagiline (irreverseible) safinamide (reversible)
30
what is the treatment for dynskineasa and what is it?
its a symptom of parkinsons where there is involantary movement of muscles glutamate antagonists like amantidine
31
what drugs stop peripheral breakdown of L-dopa?
benzerzide and carbidopa- inhibit DCC to stop breakdown into dopamine or entacapone which inhibits COMT to prevent breakdown into 3-OMD
32
what are potential future treatments of parkinsons?
gene therapy- glial-derived neurotrophic factor stem-cell derives dopamine progenitor cells into putamen inhibiting alpha-synuclein or stopping its aggregation
33
what is a hallmark of parkinsons?
accumulation and aggregation of alpha-syneuclin foming lewy bodies and neurites
34
what does alpha synuclein cause?
it causes lewy body formation and alpha-synuclin toxicty with ER dysfunction, autophagic/ lyosomal disruption, oxidative stress leading to aggregation, synaptic dysfunction and mitochondria dysfunction
35
what drugs treat alzheimers?
AChE inhibitors - donepzil, revastigmine and galantamine NMDA rceptor inhibitor- memantemine to stop excessive glutamate release (severe)
36
what future treatments could treat AD?
beta-secretase antagonists immunological clearance of beta-amyloid- antibodies clear the plaques or modulate immune system to clear them
37
how do beta-secretase antagonists work?
- inhibit beta-secretase-1 to reduce cleavage of APP to Abeta-1-42 - may be a drug class issue as none of them have been successful
38
what are examples of immunological removal drugs for beta-amyloid?
solanezumab aducanumab lecanemab + donaneumab (approved for use in UK) trontinemab
39
how does lecanumab work?
its a monoclonal IgG antibody which binds to Abeta-peptide protofibrils
40
how does donanumab work?
mAb which binds to Aβ(p3-42) and removes in through micro-glial mediated phagocytosis
41
how does trontinemab work?
A Fab fragment that binds the human transferrin receptor is attached to the effector (Fc) domain of the gantenerumab monoclonal antibody (an anti-amyloid mAb) transferrin allows it entry into the CNS where it binds to amyloid and stimulates plaque clearance
42
what are the downsides to donanumab?
high risk of brain oedema and bleeds and is also vvv expensive
43
what is the process of amyloid plaque formation?
amyloid precursor protein is cleaved by beta secretase, the proteins then mis-fold and clump together forming olgiomers> protofibrils> amyloid fibrils> amyloid plaques
44
what targets are there on microglial cells?
Trem2- activiting Ab promotes microglial survival CD33- major gene risk factor for AD- Abs targeting this may help
45
what is alchemab?
mAb targeting CD33 through competition with sioglycan (doesnt internalise CD33)
46
how do tau-tangles affect AD?
tau usually stabilises microtubules and hyperphosphorylation of with GSK-3beta and other kinases leads to hyper P-tau formation and microtubules falling apart misfolded tau clumps together (neurofibrillary tangles , causing synaptic and neuronal loss leading to inflammatory responses
47
what are genetic causes of AD?
APOE-risk gene involved in pathogenic pathways which lead to AD
48
what is the VEGF inhibitor treatment?
bevacizumab, binds to VEGF to prevent it from binding to VEGFR2 to regulate angiogenesis and endothelial cell proliferation
49
what does MGMT stand for?
0-6-methylguanine-DNA-methyltransferase
50
what are the side effects of vincristine?
theres the well known side effects of bone marrow depression and peripheral neuropathy and GI distress as well as cardiovascular miocardial infarctions and ischaemia
51
why is vincristine thought to have cardiotoxic side effects?
becuase of the coronary artery vasospasms due to vascular cell hypoxia however it hasnt been extensively studied
52
what are the mechanisms of action of procarbazide?
it alkylates DNA by reacting with the O6 position on guanine and autoxidation to form free radicals for DNA damage and inhibits the transmethylation of DNA inhibiting the conversion of methionine into transfer RNA
53
what is the stupp protocol?
it is the standardised protocol used for the treatment of glioblastomas to prolong the time lived with it it involves concominant treatment with radiotherapy and temozolomide then adjuavant treatment with temozolomide
54
what do IDH1/2 mutations cause?
they cause an alteration in the structure of the enzyme homodimer usually involved in the breakdown of isocitrate into alpha-ketoglutarate. instead, isocitrate is broken down into D2-HG which alters the activity of TETs and KDMs, these are involved with regulating gene expression and epigenetic changes. NAPDH is also broken down into NADP+ in both wt and mutated phenotypes the accumulation of D2-HG also leads to hypermethylation of DNA which is irreversible, leading to increased rates of recurrence and maligniant transformation however, IHD mutations are also associated with increased survival
55
what does the 1p19q co-del mean?
it is a whole-arm co-deletion almost always seen with the presence of IDH mutations, its associated with increased overall survival and progression-free survival
56
are IDH1/2 mutations somatic mutations or epigenetic changes?
their somatic mulations
57
what are the most important negative prognostic markers?
IDH1/2 mutations and MGMT promoter region methylation status
58
what are the mesolimbic dopamine neurons?
theyre a group of neurons which project from the VTA to the nucleus accumbens and the pathway plays a role in processing and motivation for rewards
59
what is the proposed role of brain derived neurotrophic factor in MDD?
theres been said that theres a negative correlation between the amount of BDNF and the amount of inflammation keller et al found that suicide victims were more likely to have DNA methylation in the BDNF promotor than healthy subjects
60
what gene is commonly associated with MDD as a risk factor for developing it?
val66met polymorphism associated with the BDNF gene and has been associated with aggressive behavior in SZ patients

pharmacology sem 2 (5 decks)

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