CPTP 3.19 Neuropharmacology 4 Drugs for neurodegenerative disorders Flashcards Preview

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Flashcards in CPTP 3.19 Neuropharmacology 4 Drugs for neurodegenerative disorders Deck (23)
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Dementing disorders and Parkinson's disease are examples of what?

Neurodegenerative disorders


Describe the following pathologies of Alzheimer's:
1) Macro
2) Micro
3) Chemical

1) Atrophy of brain areas. Ventricular enlargement.
2) 𝛽-amyloid plaques. Neurofibrillary tau-protein tangles. Neuronal loss.
3) Synaptophysin loss. Cortical cholinergic, NA and 5-HT loss


Where is atrophy seen in Alzheimer's?

• Hippocampus
• Entorhinal cortex
• Temporal cortex


How is acetylcholine generated in cholinergic neurones?

• Choline is taken up by cells
• Choline acetyltransferase creates acetyl choline, taking the acetate group from acetyl CoA


Why is increasing the amount of available choline not a viable method of enhancing cholinergic neurotransmission?

Choline availability is not the rate-limiting step, as only 1% of plasma choline is synthesised into ACh


Which class of drugs is the main class used to treat dementia? Name the formulary examples

Acetylcholinesterase inhibitors
• Donepezil
• Rivastigmine
• Galantamine


What other target is affected by some acetylcholinesterases?

Butyrylcholinesterase (pseudocholinesterase)


What are the side effects of acetylcholinesterase?

• Bradycardia
• GI complaints
• Sleep disturbance


Why is tacrine (an acetylcholinesterase inhibitor) no longer on the market?

It has severe liver toxicity


Which acetylcholinesterase inhibitor has the longest half life?

Donepezil (70 hours)


Which acetylcholinesterase inhibitor is given as a transdermal patch?



Which acetylcholinesterase inhibitor also acts as a nicotinic receptor agonist?



What class of drug is effective as an adjunct to acetylcholinesterase inhibitors? Name an example and explain why it works.

NMDA antagonists
• Memantine
• Prevents glutamate excitotoxicity

NB: not very effective on its own


Outline the 𝛽-amyloid hypothesis of Alzheimer's.

• 𝛽 amyloid is synthesised from amyloid precursor protein (APP) by 𝛽-secretase (beta) and 𝛾-secretase (gamma) (the 'nasty' secretases which cause Alzheimer's, not the 'nice' 𝛼 (alpha) ones)

• 𝛽-amyloid plaques are layed down which leads to abnormal tau proteins, causing tangles

• This all leads to inflammation, neurodegeneration and cell death

• This cell death eventually leads to dementia


How might Alzheimer's be prevented in the future?

Prevention of the formation of plaques by using 𝛽-secretase or 𝛾-secretase inhibitors

𝛽-amyloid vaccines

Lithium blocks the hyperphosphorylation of Tau

Argenase inhibitors


Briefly recall the symptoms of Parkinson's disease

• Bradykinesia
• Muscular rigidity
• Resting tremor
• Stiff posture

Emotional and cognitive:
• Slower thought
• Depression


What causes Parkinson's symptoms

80% depletion of dopaminergic neurotransmission in the nigrostriatal pathway

This leads to an imbalance between dopamine and ACh in the striatum, causing motor dysfunction


How can Parkinsonism be treated

Reestablish good balance between ACh and dopamine levels in the striatum by:
• Increasing dopaminergic transmission
• Decreasing cholinergic transmission


Describe the neuronal synthesis of dopamine and noradrenaline

• Tyrosine is taken up by the cell
• This is converted into L-DOPA by tyrosine hydroxylase
• This is converted to Dopamine by DOPA decarboxylase

(NB: dopamine can then be converted into noradrenaline, another catecholamine, by dopamine-beta-hydroxylase)


How would tyrosine supplementation effect Parkinson's and why?

No effect because tyrosine hydroxylase is the rate limiting step of dopamine synthesis, and so is saturated with tyrosine already


Why is L-DOPA supplementation alone for Parkinson's treatment not effective?

How is this worked around?

What is the resulting drug?

• 70% of L-DOPA gets metabolised in the gut, 29% in the periphery
• The periphery uses L-DOPA to create more dopamine and Noradrenaline
• This means high doses must be given to have an effect on the nigrostriatal pathway
• This creates a lot of sympathetic side effects

To work around this, L-DOPA is combine with a peripheral DOPA decarboxylase inhibitor (which doesn't cross the BBB) which blocks gut and periphery metabolism so that a greater proportion of L-DOPA reaches the brain

Co-careldopa (levodopa and carbidopa combination)
• Carbidopa = peripheral DOPA decarboxylase inhibitor


Co-careldopa triple therapy may also include what?

catechol-O-methyltransferase inhibitors (this enzyme breaks down L-DOPA too)


What drugs are available for Parkinson's? Explain each.


D1 and D2 agonist
• Apomorphine
• Bromocriptine

L-DOPA supplementation
• Co-careldopa (carbidopa and levodopa combination)
• Carbidopa is a peripheral DOPA decarboxylase inhibitor

Catechol-O-methyltransferase inhibitors
• Entacapone
• Given with co-careldopa as a triple therapy

Monoamine oxidase B inhibitors
• Selegiline


Anticholinergic drugs