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3153 Psychiatry > IC15 Pharmacology of PD and Alzheimer's Disease Drugs > Flashcards

IC15 Pharmacology of PD and Alzheimer's Disease Drugs Flashcards

1
Q

What is the characteristics of degenerative disease? (optional)

A

Neurodegenerative disease:

  • Progressive & incurable
  • ↑ with age
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2
Q

What are the possible targets for medications to treat neurodegenerative diseases?

A
  • Since it’s about losing functions, we want to agonise / ↑
  1. ↑amt of precursor
  2. Destroy degrading enzymes
  3. ↑release of NTM
  4. Block autoreceptors to ↑release
  5. Bind and activate post-synaptic receptors
  6. Block reuptake/degradation of NTM
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3
Q

What is the pathophsyiology of PD?

A
  • Progressive
  • ↑ with age
  • Young & juvenile onset PD (more genetically based)
  • Patho:
    o Lack of DA
    o Impaired cleaning of abnormal / damaged intracellular proteins by ubiquitin proteasomal system
     1) Failure to clear toxic proteins (accumulation of aggresomes)
     2) Lewy bodies
     Both present in the substantia nigra led to the degeneration of dopaminergic neurons
     loss of substantia nigra
    no release of inhibition
    *hypokinetic state (via direct and indirect pathways); all motor cortex is more inhibited than usual
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4
Q

What are the symptoms of PD?

A
  • Symptoms:
    o Tremors at rest (pill rolling)
    o Rigidity (cogwheel rigidity)
    o Bradykinesia
    o Postural instability and gait disturbances
    o Motor fluctuation, dyskinesia, non-motor symptoms (common at later stages)
    Top 3 are cardinal symptoms
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5
Q

What is the rationale behind the therapeutic appraoches of PD?

A

Breakdown Levodopa –> dopamine by:

  • Dopa-Decarboxylase

Levodopa/dopamine –> Inactive form:

  1. COMT
  2. MAO-B
  • Presence of excitatory D1 and inhibitory D2 receptors
  • Dopamine does NOT pass through the BBB
  • Levodopa PASSESS through the BBB
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6
Q

What are the possible meds used for PD?

A

1) levodopa + (carbidopa/benserazide/ entacapone/tolcapone)
2) MAO-Bi e.g. selegiline/rasagiline
3) Dopamine agonist e.g. pramipexole
4) Amantadine
5) anticholinergics e.g. trihexyphenidyl

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7
Q

What is the gold standard for PD treatment?

A

Levodopa

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8
Q

What are the ADRs of levodopa?
Which is the most serious?

A

1) N&V
2) Postural Hypotension
3) Motor fluctuation
4) Dyskinesia

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9
Q

What are carbidopa/benserazide?
What are their place in therapy?

A

Peripherally DOPA-decarboxylase inhibitor

  • used in adjunct with levodopa
  • helps to prevent systemic SE due to excess DA e.g. dyskinesia & ↑amt going into the brain by inhibiting peripheral conversion of levodopa into dopamine
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10
Q

What are some examples of COMT inhibitors?
What are their place in therapy?
What is the MOA?

A
  • entacapone, tolcapone
  • Adjunct to levodopa / levodopa+benserazide
  • blocks COMT conversion of dopamine/L-dopa to inactive form inside the neuron and peripherally
  • ↑duration of each levodopa dose
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11
Q

What are the ADRs of COMT inhibitors?

A

increase Levodopa SE:
1) Dyskinesia (much milder)
2) Liver dysfunction (tolcapone)
3) Nausea
4) Visual Hallucination
5) Daytime drowsiness, sleep disturbances

1) Diarrhea
2) Urinary discoloration (orange)

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12
Q

What are some examples of MAO-B inhibitors?
What is its place in therapy?

A
  • selegiline, rasagiline
  • Monotherapy in early stages (main diff from COMTi) / Adjunct
  • mild anti-parkinson activity
  • interferes with breakdown of DA
  • possibly delay nigral brain cell degeneration
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13
Q

What is the main difference between COMTi and MAO-Bi?

A

COMTi is adjunct while
MAO-Bi can be used as monotherapy

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14
Q

What is an example of dopamine agonist?
What is the place in therapy?

A
  • pramipexole
  • Monotherapy / adjunct
  • Bind to dopamine receptors
  • not as great as levodopa
  • prevent and delay onset of motor complications
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15
Q

What are the ADRs of dopamine agonist?

A

1) N&V
2) orthostatic hypotension
3) Headache
4) Dizziness
5) Arrhythmias
6) Hallucinations
8) leg edema

1) Ergot toxic (pergolide)
2) sedation, somnolence, daytime sleepiness (pramipexole)
3) compulsive disorder

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16
Q

Which is usually 1st line for younger patients with PD?

A

Start dopamine agonist eg. pramipexole as 1st line in younger patients to prevent the presence of dyskinesia with levodopa

17
Q

What is the place in therapy of amantadine? What is the MOA of amantadine?

A

Monotherapy / adjunct

  • mild anti-parkinsonian effect
  • ↑release of stored dopamine
  • inhibit presynaptic uptake of catehcholamine
  • dopamine receptor agonist
  • NMDA receptor antagonist (anti-glutamate)
  • antidyskinetic (reduce dyskinesia in patients with motor fluctuations)
18
Q

What is the ADR of amantadine?

A

1) Can’t concentrate
2) Hallucination
3) Insomnia
4) nightmares
5) Livedo reticularis (thromboses everywhere)

19
Q

What is an example of anticholinergic used for PD? What is the place in therapy?

A

Trihexyphenidyl
Monotherapy in early stage / adjunct

  • effective in controlling tremor
  • treat sialorrhea (excess saliva)
20
Q

What is the ADR of trihexyphenidyl?

A

1) Dry mouth, constipation, urinary retention, delirium, confusion
2) sedation
3) hallucinations

21
Q

What is the patho of Alzheimer’s Disease?

A
  • Progressive
  • Pathophysiology
    o 1) Senile plagues –> aggregates of beta-amyloid (Abeta) peptide
     Inflammatory, activates neurons to produce / release a lot of cytokines
    o 2) Neurofibrillary tangles
    Hyper-phosphorylated tau protein aggregates forming paired helical filaments (PHF)
     Tau – protein needed for microtubule stabilization and intracellular transport
    o These 2 leads to neurodegeneration –> brain atrophy (↓cognition)
    o NTM systems involved: cholinergic, serotonergic, glutamatergic
    o Degeneration of central cholinergic system –> cholinergic deficit
22
Q

What is the main difference between the cholinergic synapse and the monoaminergic (dopaminergic) synapse?*

A
  • Degrading enzymes (COMT, MAO-B) are in the pre-synaptic neuron for the latter –> drugs need to enter the neuron
  • While degrading enzymes (Acetylcholinesterase) are in the synaptic cleft –> drugs don’t need to enter the neuron
23
Q

What is the treatment goal of AD?

A
  1. Slow progression of cognitive decline and preserve function
  2. ↑QOL
24
Q

What are the possible medication options for AD?

A
  1. Acetylcholinesterase inhibitor (mild-mod)
  2. Memantine (mod-sev AD)
25
Q

What are some examples of acetylcholinesterases? What level of AD is used for?
How does it help?

A
  1. Acetylcholinesterase inhibitor (mild to mod)
    a. Examples: donepezil (for sev too), galantamine, rivastigmine
    b. MOA: ↑cognition, ADL, and behaviour
26
Q

What are the differences between rivastigmine and galantamine?

A

Formulation 1) Oral, Transdermal patch 2) Oral
T1/2 1) Shorter 2) Longer
Additional effect 1) - 2) Act on nicotinic receptor in the brain –> greater therapeutic effects
Metabolised 1)Kidneys 2)Liver (CYP450)

See page 38 of notes

27
Q

What are the ADRs of acetylcholinesterases?

A

ADRs:
i. Cholinergic hyperactivation: N&V, diarrhea
means too much rest, relaxation and digestion
ii. Less common: muscle cramp, bradycardia, loss of appetite, ↑gastric juice secretion

28
Q

Which actylcholinesterase can be used for severe AD?

A

Donepezil

29
Q

What is memantine’s MOA?
What level of AD is it used for?
What are the ADRs of memantine?

A
  1. Memantine (mod-sev AD)
    a. Non-competitive NMDA receptor antagonist (similar amantadine, anti-glutamate)
    b. ADRs: hallucination, confusion, dizziness, headache, constipation
30
Q

What is used for the behavioural and psychological symptoms of AD? (optional look at IC16 instead)

A

For behavioural and psychological symptoms of Dementia (below are off label use, SE can be severe)

  1. Antidepressants e.g. SSRI citalopram
  2. Anxiolytics e.g. BZD
  3. Neuroleptics e.g. SGA risperidone
  4. Sleep medications

3153 Psychiatry (10 decks)

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