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UM2010 Pharmacology > Drugs In Neurodegenerative Disorders > Flashcards

Drugs In Neurodegenerative Disorders Flashcards

1
Q

What are the symptoms of Parkinson’s disease?

A

Ataxia-rigidity, bradykinesia
Resting tremor (3-7 Hz)
Cognitive (memory, attention, loss of inhibition)
Postural instability - higher risk of falling
Eventually dementia

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2
Q

What is the second most common neurodegenerative disease. Incurable, progressive, not directly lethal

A

Parkinson’s disease (PD)

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3
Q

Life expectancy of PD

A

10-15 years

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4
Q

What are the biological causes of PD ?

A

Loss of dopaminergic neurones of the substantia nigra projecting to the stratium

PD onset after ~ 20-40% dopamine loss

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5
Q

What causes cells to die in PD?

A

Unclear

May be due to:

  • “Lewy bodies” in neurones – insoluble protein clumps
  • Excitotoxic damage (oxidative stress)
  • Infection; chemical; brain damage
  • Genetic (rare)
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6
Q

What is the part of the brain majorly affected by PD?

A

Basal ganglia - great amount substantia nigra

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7
Q

Explain the Basal ganglia pathways through the direct pathway

A

movement intitiated by +ive feedback corticobasal ganglia thalamic loop

  • thalamus sends excitatory glutametergic signals to the motor cortex
  • DIRECT pathway: motor cortex send excitatory glutamatergiv signals to Striatium (putamen)
  • striatium sends inhibitory GABAergic signals to inhibit Globus Pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr)
  • GPi + Snr together inhibit thalamus which INCREASES its activity

Conclusion: 2 inhibitory pathways = excitatory

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8
Q

Explain the Basal ganglia pathways through the indirect pathway

A
  • motor cortex sends excitatory glutamatergic signals to Striatium (putamen)
  • striatium send inhibitory gabaergic signals to Globus pallidus external segment (GPe) and decreases its activity
  • GPe sends inhibitory gabaergic signals to the Subthalamic nucleus (STN) and decreases its activity
  • Activity of STN increases due to disinhibition
  • Increase in activity of output stations in the Globus pallidus internal segment (GPi) and Substantia nigra pars reticulata (SNr)
  • GPi+ SNr = inhibit thalamus
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9
Q

Which pathway increases the output going from the thalamus to the motor cortex? (Disinhibition of thalamus)

A

Direct pathway

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10
Q

Which pathway decreases the output going from the thalamus to the motor cortex? (Inhibition of thalamus)

A

Indirect pathway

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11
Q

Explain dopaminergic pathway between Substantia nigra pars compacta amd Striatum ?

A
  • cells from Substantia nigra pars compacta release dopamine to the gabanergic medium spiny neurons (cells in the striatum)
  • Gabanergic medium spiny neurons are two types: one set goes to the output stations, the other set inmervate the GPe
  • The first set has D1 receptors > Gs linked > increase activity of neurons
  • The second set has D2 receptors > Gi/o linked > decrease activity of neurons
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12
Q

What happens when dopamine is released in the striatum?

A

D1 containing medium spiny neurons which head to the output stations have a larger activity than the D2 contaning medium spiny neurons to the GPe, which are less active

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13
Q

In summary, what happens in the Basal Ganglia + dopamine pathway at rest?

A

There is no dopaminergic activity

No signalling from motor cortex > no motor commands> lots of inhibition from output stations to the thalamus > very little feedback to the cortex

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14
Q

In summary, what happens in the Basal Ganglia + dopamine pathway in movement?

A

Now the dopaminergic activity is added

Dopamine enhances direct pathways from striatum to output stations (in basal ganglia) > decreasing the influenceof the indirect pathway > decrease output of tonically active cells in the output stations> less inhibition of thalamus > thalamus excites motor cortex more> +ive feedback loop > movement

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15
Q

What happens to the basal ganglia + dopamine pathway, when we loose dopamine?

A

Problems initiating movement - PD

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16
Q

PD is irreversible and incurable, true or false?

A

True

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17
Q

What is the treatment management of symptoms of PD?

A

Increass dopamine production
Decrease dopamine breakdown
Mimic dopamine

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18
Q

What are the limitations of pharmacological use of domapine to manage PD?

A

Pharmacological treatment becomes ineffective im time > use of surgical techniques: Deep brain stimulation (DBS) > can lead to lesion of parts of basal ganglia

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19
Q

Which drug is used to increase dopamin production?

A

L-Dopa

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20
Q

Why cant we administer dopamine directly to patients?

What type is then given?

A

Dopamine does not cross the blood/brain barrier (BBB) > more side effects

L-Dopa aka levodopa (metabolic precursor for dopamine) crosses BBB

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21
Q

What happens to L-Dopa once crossed the BBB?

A

Diffuse around the brain > taken up by neurons > converted to dopamine

More L-dopa > More dopamine produced by nerve terminals

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22
Q

What is the gold standard treatment for PD?

A

L-DOPA (levodopa)

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23
Q

Complications with L-DOPA

A

More than 90% of L-DOPA won’t reach the central nervous system and will be metabolised to dopamine in the periphery

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24
Q

How is L-DOPA administered to avoid complications by administering it alone?

A

Co-administer L-DOPA with Carbidopa (DOPA decarboxylase inhibitor)

L-DOPA+ Carbidopa= co-careldopa

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25
What are the benefits of co-careldopa (L-DOPA + carbidopa ) over L-Dopa only?
Carbidopa does not cross BBB Blocks more than 90% of conversion of L-DOPA to dopamine in the periphery > more to CNS > we can lower dose > lower side effects
26
What is the alternative drug to carbidopa used with L-DOPA?
Benserazide Benserazide + L-DOPA = co-beneldopa
27
In practice tou get prescriptions of L-DOPA on its own, true or false?
False It only comes with carbidopa (ca-careldopa) or benserazide(co-beneldopa)
28
What is the primary treatment for PD?
Co-careldopa / co-beneldopa
29
What is the limitation of Co-careldopa / co-beneldopa to treat PD? Why does this happen ?
Highly effective in ~80% of patients initially, but drops to about ~30-40% effective by 5 years. Due to the point people start taking the drug and not progression of disease
30
Why may patients be given other drugs in very early mild PD ?
It delays the point that they will be given L-DOPA (Co-careldopa / co-beneldopa) > delays the point L-DOPA will become ineffective
31
What are the side effectd of L-DOPA (Co-careldopa / co-beneldopa)?
Involuntary movements, confusion - schizophrenia-like effects, postural hypotension, “on-off” effects: rapid fluctuations in clinical state
32
What is the dosage of Co-careldopa / co-beneldopa?
3-4 times daily
33
How can we block the breakdown of dopamine?
Blocking Monoamine oxidase B (MAO-B) and Catechol-O-methyltransferase (COMT), which both breakdown dopamine in the synaptic cleft
34
What drugs are used to block MAO-B to stop breakdown of Dopamine in the synaptic cleft?
Selective MAO-B inhibitors
35
How are selective MAO-B inhibitors administered?
individually or co-administered with L-DOPA (reduce L-DOPA dose!)
36
What are the drugs used as selective MAO-B inhibitors?
* Selegiline: weakly MOA-B selective + MOA-A selective > increase amount of noradrenaline activity > amphetamine side effects * Rasagiline: MOA-B selective * Safinamide (new; reversible; also DA reuptake inhibitor)
37
Why does Selegiline cause amphetamine side effects ?
Weaklu selective for MOA-B + selective for MOA-A > increases noradernaline activity > amphetamine side effects
38
What are thr side effects of selective MAO-B inhibitors?
Nausea & abdominal pain, hypotension, headache, dry mouth, confusion / dizziness Selegiline: amphetamine-like effects Rasagiline: joint pain
39
What are used to block COMT to orevent breakdown of domaoine in the synaptic cleft?
L-DOPA + COMT inhibitors
40
What happens to L-DOPA in the periphery, when administerd with COMT inhibitors ?
Brokedown into 3-OMD
41
What drugs are used as COMT inhibitors with L-DOPA?
Entacapone Tolcapone Opicapone
42
What are the benefist of COMT inhibitors?
Counteract “end-of-dose” fluctuations in plasma L-DOPA concentrations; Reduce L-DOPA dose dyskinesias (“on-off” syndrome, hyperkinesia)
43
Which drug between entacapomr and tolcapone bring more benefit?
Tolacapone: crosses BBB > less L-DOPA breakdown to 3-OMD in the periphery > peripheral & CNS specific > more L-DOPA can be converted to dopamine Entacapone: does not cross BBB > peripheral specific
44
What are used to mimick dopamine in the treatment of PD?
Dopamine receptor agonists (Older drugs are marginally selective for D2 / D3 over D1. Newer drugs are more D2 / D3 selective)
45
What is the advantage of dopamine receptor agonist to mimick dopamine, over L-DOPA?
No “on-off” effect
46
What drugs are used as dopamine recotor agonists ti mimick dopamine in PD?
Pramipexole Ropinorole Rotigotine (transdermal patch)
47
What are the side effects of dopamine receptor agonjsts drugs (Pramipexole, ropinirole; rotigotine)?
Hypotension, nausea, drowsiness, dizziness, | hallucinations, impulse control disorders
48
What older dopamine receptor agnists are jot used anymore and why?
bromocriptine, pergolide, cabergoline, apomorphine Can cause cardiac & pulmonarh fibrosis
49
What is restless legs syndrome and how can it be treated?
Urge to move legs Dopamine receptor agonists
50
What can dopamine receptor agonists be used to treat outside of PD?
Restless leg syndrome
51
What drugs are useful for people on antipsychotics to control Parkinsonian symptoms, as they can’t receive drugs that enhance dopaminergic syndrome?
Antimuscarinics : suppress Gi/o receptor proteins> inhibition of dopamine release
52
Which drugs can PD drugs interact with?
Antidepressants Monoamine signalling CNS drugs
53
Which other drug do patients with early PD receive to delay L-DOPA treatment and the development of on-off effects?
MAOI-B (monoamine oxidase B inhibitor) or dopamine antagonists
54
What is the most common dementia neurodegenerative condition which accounts for 60- 70%?
Alzheimer’s disease
55
What causes Alzheimer’s disease?
Widespread cell death; characteristic intracellular neurofibrillary tangles and extracellular amyloid beta (Aβ) plaques
56
What is the lofe expectancy of Alzheimer’s disease?
3-9 years
57
Alzheimer’s diease is Progressive, irreversible, curable, true or false
False | It is Progressive, irreversible, incurable
58
What is the firl line treatment for Alzheimer’s disease?
Anticholinesterases
59
Why are anticholinesterases the first line treatment for Alzheimer’s disease?
Cholinergic cells amongst first to die> loss of excitatory modulation via nAChRs. These reduce breakdown of of ACh
60
The use of anticholinesterases in Alzheimer’s disease is useful when?
During early stages mild-moderste Alzheimer’s disease
61
Which drugs are used as Cholinesterase inhibitors reduce breakdown of ACh im Alzheimer’s disease?
Rivastigmine Donepezil Galantamine (also enhances nAChR activity)?
62
What are the side effects of cholinesterase inhibitors drugs?
Nausea, GI dysfunction, arrhythmias, hypertension, hallucinations. Liver toxicity.
63
What drug is used in later stages of Alzheimer’s disease (AD)? How does it work?
Memantine Weak NMDA receptor antagonist * Improves cognitive function, but does not appear to delay AD progression * Effective in moderate-severe AD improving cognitive function
64
What are the side effects of memantine used in late stages of AD?
dizziness, drowsiness, constipation, headache
65
Memanrine is a drug used to improve cognitive function in AD. WHAT IS ITS MECHANISM of action?
NMDA receptor antagonist

UM2010 Pharmacology (7 decks)

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