CPTP 3.19 Neuropharmacology 4 Drugs for neurodegenerative disorders Flashcards
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?
Rivastigmine
Which acetylcholinesterase inhibitor also acts as a nicotinic receptor agonist?
Galantamine
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.
INCREASING DOPAMINE FUNCTION:
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
DECREASING ACH FUNCTION:
Anticholinergic drugs
