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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
Q

What are the benefits of co-careldopa (L-DOPA + carbidopa ) over L-Dopa only?

A

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

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26
Q

What is the alternative drug to carbidopa used with L-DOPA?

A

Benserazide

Benserazide + L-DOPA = co-beneldopa

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27
Q

In practice tou get prescriptions of L-DOPA on its own, true or false?

A

False

It only comes with carbidopa (ca-careldopa) or benserazide(co-beneldopa)

28
Q

What is the primary treatment for PD?

A

Co-careldopa / co-beneldopa

29
Q

What is the limitation of Co-careldopa / co-beneldopa to treat PD? Why does this happen ?

A

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
Q

Why may patients be given other drugs in very early mild PD ?

A

It delays the point that they will be given L-DOPA (Co-careldopa / co-beneldopa) > delays the point L-DOPA will become ineffective

31
Q

What are the side effectd of L-DOPA (Co-careldopa / co-beneldopa)?

A

Involuntary movements, confusion - schizophrenia-like effects, postural hypotension, “on-off” effects: rapid fluctuations in clinical state

32
Q

What is the dosage of Co-careldopa / co-beneldopa?

A

3-4 times daily

33
Q

How can we block the breakdown of dopamine?

A

Blocking Monoamine oxidase B (MAO-B) and Catechol-O-methyltransferase (COMT), which both breakdown dopamine in the synaptic cleft

34
Q

What drugs are used to block MAO-B to stop breakdown of Dopamine in the synaptic cleft?

A

Selective MAO-B inhibitors

35
Q

How are selective MAO-B inhibitors administered?

A

individually or co-administered with L-DOPA (reduce L-DOPA dose!)

36
Q

What are the drugs used as selective MAO-B inhibitors?

A
  • 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
Q

Why does Selegiline cause amphetamine side effects ?

A

Weaklu selective for MOA-B + selective for MOA-A > increases noradernaline activity > amphetamine side effects

38
Q

What are thr side effects of selective MAO-B inhibitors?

A

Nausea & abdominal pain, hypotension, headache, dry mouth, confusion / dizziness
Selegiline: amphetamine-like effects
Rasagiline: joint pain

39
Q

What are used to block COMT to orevent breakdown of domaoine in the synaptic cleft?

A

L-DOPA + COMT inhibitors

40
Q

What happens to L-DOPA in the periphery, when administerd with COMT inhibitors ?

A

Brokedown into 3-OMD

41
Q

What drugs are used as COMT inhibitors with L-DOPA?

A

Entacapone
Tolcapone
Opicapone

42
Q

What are the benefist of COMT inhibitors?

A

Counteract “end-of-dose” fluctuations in plasma L-DOPA concentrations;

Reduce L-DOPA dose dyskinesias (“on-off” syndrome, hyperkinesia)

43
Q

Which drug between entacapomr and tolcapone bring more benefit?

A

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
Q

What are used to mimick dopamine in the treatment of PD?

A

Dopamine receptor agonists (Older drugs are marginally selective for D2 / D3 over D1. Newer drugs are more D2 / D3 selective)

45
Q

What is the advantage of dopamine receptor agonist to mimick dopamine, over L-DOPA?

A

No “on-off” effect

46
Q

What drugs are used as dopamine recotor agonists ti mimick dopamine in PD?

A

Pramipexole
Ropinorole
Rotigotine (transdermal patch)

47
Q

What are the side effects of dopamine receptor agonjsts drugs (Pramipexole, ropinirole; rotigotine)?

A

Hypotension, nausea, drowsiness, dizziness,

hallucinations, impulse control disorders

48
Q

What older dopamine receptor agnists are jot used anymore and why?

A

bromocriptine, pergolide, cabergoline, apomorphine

Can cause cardiac & pulmonarh fibrosis

49
Q

What is restless legs syndrome and how can it be treated?

A

Urge to move legs

Dopamine receptor agonists

50
Q

What can dopamine receptor agonists be used to treat outside of PD?

A

Restless leg syndrome

51
Q

What drugs are useful for people on antipsychotics to control Parkinsonian symptoms, as they can’t receive drugs that enhance dopaminergic syndrome?

A

Antimuscarinics : suppress Gi/o receptor proteins> inhibition of dopamine release

52
Q

Which drugs can PD drugs interact with?

A

Antidepressants
Monoamine signalling
CNS drugs

53
Q

Which other drug do patients with early PD receive to delay L-DOPA treatment and the development of on-off effects?

A

MAOI-B (monoamine oxidase B inhibitor) or dopamine antagonists

54
Q

What is the most common dementia neurodegenerative condition which accounts for 60- 70%?

A

Alzheimer’s disease

55
Q

What causes Alzheimer’s disease?

A

Widespread cell death; characteristic intracellular neurofibrillary tangles and extracellular amyloid beta (Aβ) plaques

56
Q

What is the lofe expectancy of Alzheimer’s disease?

A

3-9 years

57
Q

Alzheimer’s diease is Progressive, irreversible, curable, true or false

A

False

It is Progressive, irreversible, incurable

58
Q

What is the firl line treatment for Alzheimer’s disease?

A

Anticholinesterases

59
Q

Why are anticholinesterases the first line treatment for Alzheimer’s disease?

A

Cholinergic cells amongst first to die> loss of excitatory modulation via nAChRs.

These reduce breakdown of of ACh

60
Q

The use of anticholinesterases in Alzheimer’s disease is useful when?

A

During early stages mild-moderste Alzheimer’s disease

61
Q

Which drugs are used as Cholinesterase inhibitors reduce breakdown of ACh im Alzheimer’s disease?

A

Rivastigmine
Donepezil
Galantamine (also enhances nAChR activity)?

62
Q

What are the side effects of cholinesterase inhibitors drugs?

A

Nausea, GI dysfunction, arrhythmias, hypertension, hallucinations. Liver toxicity.

63
Q

What drug is used in later stages of Alzheimer’s disease (AD)? How does it work?

A

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
Q

What are the side effects of memantine used in late stages of AD?

A

dizziness, drowsiness, constipation, headache

65
Q

Memanrine is a drug used to improve cognitive function in AD. WHAT IS ITS MECHANISM of action?

A

NMDA receptor antagonist

UM2010 Pharmacology (7 decks)

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