Pharmacology 25 - Alzheimers Disease Flashcards
Describe epidemiology of Alzheimers
- Age is the main risk factor
- Huge economic cost in the UK but low research investment
- Alzheimers disease and dementia are leading cause of death in UK
- Genetic mutations in amyloid precursor protein (APP), Presenilin-1 (PSEN gene), Apolipoprotein E (ApoE) increase risk of Alzheimers.
- Around 8% of cases hereditary.
List clinical symptoms of Alzheimers
- Memory loss (especially recently acquired information)
- 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)
Describe the amyloid hypothesis of Alzheimers
Physiological processing - Amyloid precursor protein (APP) cleaved by a-secretase - sAPPa released - C83 fragment remains - C83 -> digested by gamma-secretase - Products removed REMEMBER a-secretase and gamma-secretase
Pathophysiological
- APP cleaved by beta-secretase
- sAPPB released - C99 fragment remains
- C99 -> digested by gamma-secretase releasing beta-amyloid (Abeta) protein
- Abeta forms toxic aggregates (immune reaction destroying neurones? Plaques themselves release toxins?)
Describe the Tau hypothesis of Alzheimers
Physiology
- Tau is a soluble protein present in axons
- Important for assembly and stability of microtubules
Pathophysiology
- Hyperphosphorylated tau is insoluble, so tau self-aggregates to form neurofibrillary tangles
- These are neurotoxic
- This also results in microtubule instability
Describe the inflammation hypothesis of Alzheimers
Physiology
- Microglia are specialised CNS immune cells - similar to macrophages
Pathophysiology (may be a consequence of B-amyloid and Tau hypothesis)
- Microglia release inflammatory mediators and cytotoxic proteins
- Phagocytosis
- Levels of neuroprotective proteins
List anticholinesterases used in Alzeimers Disease
- Donepezil (Reversible cholinesterase inhibitor, long plasma half-life)
- Rivastigmine (pseudo-reversible anticholinesterase and butyrylcholinesterase inhibitor, 8 hour half-life, reformulated as transdermal patch)
- Galantamine (reversible cholinesterase inhibitor, 7-8 hour half-life, alpha7 nAChR agonist)
Give an example of a NMDA receptor blocker used in Alzheimers disease
- Memantine
- Use-dependent non-competitive NMDA receptor blocker with low channel affinity (blocking binding of glutamine, which is more effective when overstimulation by glutamine occurs)
- Only licensed for moderate-severe AD
- Long plasma half-life
List drugs used in Alzheimers pharmacology
- Anticholinesterases (dinapezil, rivastigmine, galantamine)
- NMDA receptor blocker (memantine)
List drugs that have failed use in Alzheimers
- Gamma secretase inhibitors (tarenlurbil and semagacestat)
- B-amyloid inhibition (bapineuzumab and solanezumab)
- Tau inhibitors (methyline blue)
Describe action of the gamma-secretase inhibitors
- Gamma secretase involved in both physiological and pathophysiological processing of amyloid precursor protein
- Tarenflurbil binds to amyloid precursor protein (APP) molecule
- Semagacestat is a small molecule gamma-secretase inhibitor (inhibited notch which increased risk of skin cancer)
Describe use of B-amyloids inhibitors in Alzheimers
- Bapineuzumab and Solanezumab are humanised monoclonal antibodies targetting beta amyloid
- Aducanumab in clinical trials (B-amyloid fibrils and B-amyloid monomers)
- Vaccines also in early stages of development (eg. target B-secretase)
What are Tau inhibitors licensed for?
Treatment of methaemoglobinaemia
List the hypotheses for Alzheimers
Most prominent
- Tau hyperphosphorylation hypothesis (may occur first)
- B-amyloid hypothesis (may occur following tau)
Also…
- Inflammation hypothesis (as individuals who take ibuprofen a lot have decreased risk of developing Alzhiemers in the future)
Why is rivastigmine given as a transdermal patch?
- Acts on both Acetylcholinesterase and butyrylcholinesterase enzyme
- Therefore, if taken orally it has increased side effects
How effective are anticholinesterases in Alzheimers?
- Very effective at initially treating the disease (mild-moderate alzhiemers disease)
- Domeprazil also licensed for severe Alzheimers
- However, effect on memory is lost after around 2 years of use, due to no effect on B amyloid or Tau (licensed drugs for Alzheimer’s do not affect the pathophysiology)
Which neurones are affected in Alzheimers disease?
- Degeneration of cholinergic nerves, reducing acetylcholine release.
- Glutaminergic nerves are damaged, and release excessive amounts of glutamate. Glutamate binds to NMDA receptors on postsynaptic nerves causing damage to the postsynaptic nerves (excitotoxicity).
