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Year 2 - LCRS - Pharmacology > Alzheimer's disease (04.03.2020) > Flashcards

Alzheimer's disease (04.03.2020) Flashcards

1
Q

Epidemiology of AD (incl. RFs)

A
  • Main risk factor – Age
  • Huge economic cost in the UK BUT low research investment
  • Nov 2016 – ONS announces AD & dementia are leading cause of death in UK
  • Genetics - APP, PSEN, ApoE (hereditary ~ 8%) -> these increase the risk of getting early onset AD, not seen in the majority of patients so this is not the age related AD. (2 different types of AD - we are not sure what causes the late onset one)
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2
Q

What are the symptoms of AD?

A
  • Memory loss – especially recently acquired information

The following ones are may be present at different levels:

  • Disorientation/ confusion – forgetting where they are
  • Language problems – stopping in the middle of a conversation
  • Personality changes – becoming confused, fearful, anxious
  • Poor judgement – such as when dealing with money
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3
Q

Name the theories that are established to explain the pathophysiology of AD

A
  • Amyloid Hypothesis
  • Tau Hypothesis
  • Inflammation Hypothesis

=> there are 2 main hypotheses and many smaller ones.

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4
Q

Physiological processing of APP

A
  1. Amyloid precursor protein (APP) cleaved by alpha-secretase
  2. sAPP alpha released - C83 fragment remains
  3. C83 -> digested by gamma-secretase
  4. Products removed

The three components (APP, alpha and gamma-sec) are found on the cell membrane in normal conditions (primarily in the CNS).

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5
Q

Pathophysiological processing of APP

A
  1. APP cleaved by beta-secretase (cleaves at a slightly different site)
  2. sAPPbeta released - C99 fragment remains
  3. C99 -> digested by gamma-secretase releasing beta-amyloid (A-beta) protein
  4. A-beta forms toxic aggregates

-> not removed (congregate within or outside neurones and form clumps) primarily form outside the neurones

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6
Q

Why would the beta-amyloid plaques cause AD?

A

Not known but the thought is that they cause neurodegeneraation in some way.

Ideas:

a) immune reaction -> inflammation which causes neuronal destruction -> neurodegenerative disorder
b) the plaques release toxic compounds themselves that are destroying the neurones.

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7
Q

Physiology and pathophysiology of Tau proteins

A

Phys:

  • Soluble protein present in axons
  • Important for assembly, integrity & stability of microtubules

Pathophysiology:

  • Hyperphosphorylated tau is insoluble -> self-aggregates to form neurofibrillary tangles (intracellular)
  • These are neurotoxic
  • This also results in microtubule instability (because of redistribution of tau from the microtubules to aggregates)
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8
Q

Do the beta-amyloid and tau hypotheses exclude one another?

A

No, they could be occurring simultaneously.

Generally Tau first and then beta-amyloid.

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9
Q

Inflammation hypothesis

A

Not mutually exclusive to amyloid or tau

Physiology - Microglia
- Specialised CNS immune cells - similar to macrophages

Pathophysiology - Microglia

  • increase release of inflammatory mediators & cytotoxic proteins
  • increase phagocytosis
  • decreased levels of neuroprotective proteins

Why this theory?
people taking NSAIDs (e.g. Ibuprofen) for years have less incidence 0f AD; however giving people with AD ibuprofen does not help.

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10
Q

Why do pharmaceutical companies not want to put too much money into AD drug research?

A
  • there have been numerous fails.
  • therefore high risk
  • however AD is a big financial burden, both of the patients themselves as well as because of people having to stay eat home and help them.
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11
Q

Pharmacology of AD

A

-> not relaxed to pathophysiology

  • Anticholinesterases
  • NMDA receptor blockers
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12
Q

Anticholinesterases in AD

A

-> for mild and moderate AD

  1. Donepezil
    - Reversible cholinesterase inhibitor.
    - Long plasma half-life (admin 1x/d)
  2. Rivastigmine
    - Pseudo-reversible AChE & BChE inhibitor (the BChEi is bad and there are some SE; lessened as a td patch)
    - 8 hour half-life
    - Reformulated as transdermal patch
  3. Galantamine
    - Reversible cholinesterase inhibitor
    - 7-8 hour half-life
    - alpha7 nAChR agonist (also acts as an agonist which has a beneficial effect)

=> the effects are almost immediate and these drugs are really good at reversing memory; however these effects only last for about 2 years.

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13
Q

NMDA receptor

A
  • N-methyl-D-aspartate receptor
  • activated by ACh
  • found at NMJ and in the brain (slightly different subtypes)
  • prevents Glu binding to NMDA R
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14
Q

What are the names of the 3 anticholinesterases used in AD?

A

Donepezil
Rivastigmine
Galantamine

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15
Q

First line treatment for AD

A

Donepezil

also for severe AD

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16
Q

NMDA receptor blockage in AD

A

Drug: Memantine

  • Use-dependent non-competitive NMDA receptor blocker with low channel affinity (only works if there is excessive activity of the NMDAR which is quite common in neurodegeneration)
  • Only licensed for moderate-severe AD
  • Long plasma half-life
17
Q

Treatment failures in AD

A
  1. gamma-secretase inhibitors
    - Tarenflurbil & Semagacestat
    - Tarenflurbil binds to amyloid precursor protein (APP) molecule (it is an enantiomer of flurbiprofen; it is not a NSAID; did not work in praactice)
    - Semagacestat is a small molecule gamma-secretase inhibitor (made people worse and increased the risk of skin cancer)
  2. beta-amyloid
    - Bapineuzumab & Solanezumab
    - Humanised monoclonal antibodies
    - Aducanumab? (currently phase 3)
    - Vaccines also in early stages of development
  3. Tau inhibitors
    - Methylene blue
    - Licensed for the treatment of methaemoglobinaemia
    - there is evidence that it is effective at reducing Tau
    - not running clinical trials because not much money in it
    - also: makes the skin blue
18
Q

LO1: Alzheimer’s disease: identify the underlying pathology, the clinical symptoms and risk factors

A
  • beta- amyloid plaques due to incorrect processing of APP
  • Tau hyperphophorylation leading to the formation of neurofibrillary tangles
  • Inappropriate activation of microglia
  • Main risk factor – Age
  • Memory loss, disorientation/ confusion, language problems, personality changes, poor judgement
19
Q

LO2: Alzheimer’s medication: summarise and compare the mechanisms of action of drugs used to treat Alzheimer’s disease

A
  • Donepezil is a cholinesterase inhibitor with a long duration of action
  • Rivastigmine also inhibits BChE and is available in patch formulation Galantamine has additional nAChR agonist properties
  • Memantine is a NMDA receptor antagonist licensed for moderate-severe AD
20
Q

Different cholinesterases

A

Acetylcholinesterase found primarily in the CNS

Butyrylcholinesterase is found e.g. in the liver, some in the CNS bit lower levels

21
Q

Targets in AAD treatment

A
  • anticholinesterases
  • NMDA R blockers
  • gamma-secretase
  • tau
  • beta-amyloid

Year 2 - LCRS - Pharmacology (34 decks)

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