CPTP 3.19 Neuropharmacology 4 Drugs for neurodegenerative disorders

Question 1

Dementing disorders and Parkinson’s disease are examples of what?

Answer 1

Neurodegenerative disorders

Question 2

Describe the following pathologies of Alzheimer’s:

1) Macro
2) Micro
3) Chemical

Answer 2

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

Question 3

Where is atrophy seen in Alzheimer’s?

Answer 3

• Hippocampus
  
  • Entorhinal cortex
  • Temporal cortex

Question 4

How is acetylcholine generated in cholinergic neurones?

Answer 4

• Choline is taken up by cells

* Choline acetyltransferase creates acetyl choline, taking the acetate group from acetyl CoA

Question 5

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

Answer 5

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

Question 6

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

Answer 6

Acetylcholinesterase inhibitors
• Donepezil
• Rivastigmine
• Galantamine

Question 7

What other target is affected by some acetylcholinesterases?

Answer 7

Butyrylcholinesterase (pseudocholinesterase)

Question 8

What are the side effects of acetylcholinesterase?

Answer 8

• Bradycardia
  
  • GI complaints
  • Sleep disturbance

Question 9

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

Answer 9

It has severe liver toxicity

Question 10

Which acetylcholinesterase inhibitor has the longest half life?

Answer 10

Donepezil (70 hours)

Question 11

Which acetylcholinesterase inhibitor is given as a transdermal patch?

Answer 11

Rivastigmine

Question 12

Which acetylcholinesterase inhibitor also acts as a nicotinic receptor agonist?

Answer 12

Galantamine

Question 13

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

Answer 13

NMDA antagonists
• Memantine
• Prevents glutamate excitotoxicity

NB: not very effective on its own

Question 14

Outline the 𝛽-amyloid hypothesis of Alzheimer’s.

Answer 14

• 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

Question 15

How might Alzheimer’s be prevented in the future?

Answer 15

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

Question 16

Briefly recall the symptoms of Parkinson’s disease

Answer 16

• Bradykinesia
  
  • Muscular rigidity
  • Resting tremor
  • Stiff posture

Emotional and cognitive:
• Slower thought
• Depression

Question 17

What causes Parkinson’s symptoms

Answer 17

80% depletion of dopaminergic neurotransmission in the nigrostriatal pathway

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

Question 18

How can Parkinsonism be treated

Answer 18

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

Question 19

Describe the neuronal synthesis of dopamine and noradrenaline

Answer 19

• 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)

Question 20

How would tyrosine supplementation effect Parkinson’s and why?

Answer 20

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

Question 21

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

How is this worked around?

What is the resulting drug?

Answer 21

• 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

Question 22

Co-careldopa triple therapy may also include what?

Answer 22

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

Question 23

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

Answer 23

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