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Drugs that affect the NS > New Deck > Flashcards

New Deck Flashcards

1
Q

what are the functions of the 4 main players in the brain?

A

cerebral hemisphere

  • where sensory information is processed
  • controls voluntary movement
  • regulates conscious thought and activity

cerebellum: in charge of balance and coordination
brainstem: relays and recieved messages to and form the brain to other organs
hippocampus: short term memories converted to long term - affected in AD

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2
Q

what are β-amyloid plaquesand how do they form?

A
  • β-amyloid plaques = dense deposits of protein and cellular material that accumlate outside and around nerve terminals
  • amyloid precursor protein (APP) is the precursor to amyloid plaque:
    1. APP sticks through the neuron membrane
    2. enzymes cut the APP into fragments of protein, including β-amyloid
    3. β-amyloid fragments come together in clumps to form plaques
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3
Q

how do β-amyloid plaques –> AD?

A
  • β-amyloid generation –> 2o events –> death of neurons
  • plaques disrupt the work of neurons - affects hippo and other areas of cerebral cortex
  • accumulation due to failure to clearance mechanisms
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4
Q

describe the metabolism of APP.

A
  • cleaved at A/B domain at N-terminal
  • then cleaved at A/B domain at C-terminal end –> pathological part i.e. β-amyloid
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5
Q

what are the features of neurofibrillar tangles (NFTs)

A
  • twisted fibres that build up inside the nerve cells
  • neurons have internal support structure - partly made up of MTs, tau helps to stabilise them
  • NTFs:
    • hyperphosphorylation of tau disrupts its normal function –> aggregation of tau into NFTs
    • paired helical filaments of abnormally phosphorylated tau
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6
Q

what is the cholinergic hypothesis in AD?

A
  • AD caused by deficiency of ACh
  • not cause: anti-chlinesterases do not slow disease, just treat symptoms
  • loss of ACh correlates with AD cholinergic systems are important in learning, memory, cognition
  • atrophy of nucleus basalis of Meynert (source of acetyltransferase) –> actual deficieny
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7
Q

what are the aims of therapy?

A
  • improve cognitive function
    • treat decreases choline acetyltransferase in cortex and hippocampus
    • enhance cholingeric func may stabilise cog function
  • limit progression
  • symptom control
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8
Q

what are the feature of Donepezil?

A
  • AD treatment
  • non-competitive cholinesterase inhbitior
  • decreases breakdown
  • generally well tolerated
  • metabolised by Cyt P450
  • once daily dose
  • adverse effects:
    • nausea, vomiting, anorexia, depression, urinary incontinance
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9
Q

what are the features of Galantamine?

A
  • competitive chlinesterase inhibitor and allosteric modulator of nic R’s
  • AD drug
  • dual mechanism
  • lower levels of ACh required to sensitise NR’s
  • may increase release of ACh and have neuroprotective effect
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10
Q

what are Rivastigmine, Tacrin and Mamatine and their properties?

A

AD drugs

  • Rivastigmine: chloinesterase inhibitor
  • Tacrine: chloinesterase inhibitor (can –> liver toxicity)
  • mamatine: NMDAR antagonist
    • reduce glu-induced neuronal degradation
    • prevents mitochondrial dysfunction, inflammation
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11
Q

what role to seretases play in AD?

A
  • β secretase: membrane-tethered aspartyl protease, amyloid precursor protein amino terminus
  • γ secretase: cleaves APP within its TM segment
  • presenilin: affects APP processing, if mutation –> amyloid plaques
  • secretase inhibitors do NOT work in trials
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12
Q

describe the use of vaccinations in AD.

A

amyloid vaccine:

  • reduced plaque burden and memory loss in mice modes
  • trials halted due to deaths
  • vaccine showed less declune in neurons, slower cognition fall
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13
Q

describe how Zn-treatment and MAb’s can be used in AD treatment.

A

MAb’s

  • humanised MAb: bapineusumab (anti- Aβ)
  • given i.v.
  • slowed memory loss, conclusions undefined

Zn2+

  • Cu2+ and Zn2+ involved in sequestering Aβ –> clearance, degradation
  • decreased levels of Zn2+ in cleft
  • possible treatment?
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14
Q

describe the pathology of PD.

A
  • degeneration of DAergic neurons in the substantia nigra compacta
  • lewy bodies present
    • Parkin gene implicated in lewy bodies
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15
Q

what is the current treatment managing in PD?

A
  • drugs provide symptomatic relief (not curative)
  • restore DA deficiency
    • increase synthesis and release
    • DA agonists
    • decrease DA metabolism
  • restore DAergic /cholinergic balance in striatum
    • cholinergic antags
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16
Q

describe DA synthesis, metabolism etc in CNS.

A
  • Tyr –> L-DOPA by tyrosine hydroxylase
  • L-DOPA –> DA by Dopa decarboxylase\
    • inhibiting peripheral DDC>> more DA in CNS
  • neuronal uptake by DAT
  • MAO metabolism
  • extraneuronal uptake (as not many DATs), metabolism by COMT
17
Q

what are the properties of Levodopa as a drug?

A
  • 90% metabolised in periphery - large doses, peripheral inhibitors
    • peripheral conversion DA>>NA
    • carbidopa = DDC inhibitor
  • effectiveness decreases over time: continued degen of DAergic neurons so must increase doses
  • req some function of DAergic neurons
  • 1st line treatment
  • rapid half life
18
Q

what are the adverse effects of levodopa?

A
  • anoerxia, nausea, vomiting
  • tachcardia
  • pupil dilation
  • halluncinations
  • mood changes, depression
  • drug interactions - MAOIs
19
Q

what are the DA agonists used in PD and their properties?

A
  • bromocriptine and cabergoline
  • can be used as monotherapy - improves bradykinesia and rigidity
  • preferred in younger patients - gradual increase dose
  • pergolige - only as addition to L-dopa
  • side effects:
    • similar to L-dopa but hallucinations, nausea, hypotension more common
    • arrthymias, MCI
    • dyskinesias less prominent
20
Q

dicuss MAOB inhibitors as PD drug treatment.

A
  • selegiline
  • decrease metabolism of DA
  • no hypertensive crises like MAOA inhibsm - at recommended doses
  • early use may delay disease progression - decrase free radical prod
21
Q

dicuss amantadine as an anti-PD agent.

A
  • antiviral used in influenza - observed to decr rigidity and bradykinesia
  • enhances DA release
  • less efficacious than L-DOPA and more rapid tolerance
  • adverse effects:
    • restlessness, agitation, confusion, halluncinations
    • postural hypotension, urinary retention
    • dry mouth
  • less-anticholinergic act (not good)
22
Q

discuss DBS and COMT-inhibitors as PD treatments.

A

DBS

  • electrode in brain, adjust symptoms and mitigates side effect
  • MOA unclear

COMT inhibitors

  • Entacapone
  • decrease metabolism of L-dopa
  • adjunct to L-dopa - increase CNS levels
23
Q

dicuss how the DAergic/cholinergic balance is restore in PD patients.

A
  • muscarinic R antag’s - Bezhexol, benztropine, biperiden
  • adjunct to L-dopa ONLY
    • modest effect on tremor, rigidity
  • adverse effects: SLUD
    • dry mouth, blurred vision, constipations, vomiting
    • memory impairment, confusion
24
Q

what can we expect to see in the next 5, 10 and 20 years in PD drug development?

A

5 years

  • adenosine A2A receptor antagonists: interacts with D2 receptor in BG to increase sensitivity to DA
    • increase effects of L-DOPA
  • decrease glutamate levels with mGluR5 - allow L-DOPA to be given at higher levels

5-10 yrs

  • optogenetics- integrating light-sen proteins into partiuclar neurons in brain (similar to DBS)

10-20 yrs

  • genetics
  • cell replacement therapy: pluripotent stem cells, reprogrammed to DAergic neurons and put back in
25
Q

what are the links between alpha-synuclein and mitochondria to PD?

A

alpha-synuclein

  • mutations in this gene –> PD disease
  • found in large amounts in Lewy bodies
  • mutations –> mitochondrial fragmentation

mitochondria

  • mito dysfunction involved in PD pathogeneis
  • damage by toxins –> ROS prod, CytC release –> cell death
  • several mito-related genes are linked to PD pathogenesis when mutated
26
Q

describe the links to PD with smoking, drinking, pesticides and your gut and nose.

A

smoking and dranking

  • protective link? lower incidence

pesticides

  • farmers have high incidence: paraquat and rotenone exposure link

gut and nose

  • first signs of PD = loss of smell
  • suggests environmental exposure to toxin
27
Q

what is the link between PD and age?

A
  • bigger risk factor as you age
  • increase damaged mitochondria - more oxidative stress
  • decrease ability to dispose of harmful alpha-synuclein
    • less HSP, HSF1 chaperons to destroy abnormal proteins
28
Q

describe the significance of the MPTP toxin.

A
  • toxin affecting neuronal cell body
  • leads to PD symptoms
  • depletes DA at terminals
  • lipid soluble
  • enters astrocytes and is converted –> MPP+ by MAOB
  • MPP+accumulates in DAergic cells of substantia nigra via DAT reuptake system
  • MPP+ enters mito’s and blocks respiration –> neuronal cell death
  • PARP-1 KO mice have reduced sensitivity to MPTP - suggests PARP-1 inhibitors may be used to treat PD
29
Q
A

Drugs that affect the NS (3 decks)

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