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HNNS > HNS52 Drugs Used For Neurodegenerative Diseases > Flashcards

HNS52 Drugs Used For Neurodegenerative Diseases Flashcards

1
Q

Neurodegenerative diseases

A

Deterioration of neurons (cannot regenerate) —> Affect brain function

Common brain regions:

  1. Basal ganglia (movement, reward)
  2. Hippocampus (memory)
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2
Q

2 different groups of neurodegenerative diseases

A
  1. Movement problems (Parkinson’s disease)
  2. Memory problems / Dementia (Alzheimer’s disease)

Huntington’s disease: both categories

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3
Q

Parkinson’s disease

A
  • 2nd commonest neurodegenerative disease (after Alzheimer’s disease)
  • No cure

Movement disorder (四寶):

  1. ***Resting tremors in limbs (手震)
    - most common 1st symptom
    - asymmetric (one side of body first before the other)
    - evident in one hand with arm rested
  2. ***Muscle rigidity (僵硬)
    - ↑ muscle tone in flexor + extensor —> constant resistance to passive movements of joints
  3. ***Bradykinesia (慢動作)
    - difficulty with daily activities
    - decreased blinking, slowed chewing and swallowing (eventually lost)
  4. ***Abnormal posture and gait (姿勢不正確)
    - small steps

Pathophysiology:
Degeneration in Substantia nigra
—> Loss of Dopaminergic neurons in Nigrostriatal pathway
—> ↓ Dopamine release to Basal ganglia

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4
Q

Basal ganglia control + Treatment strategy

A

Dopamine: Stimulate Basal ganglia —> Stimulate movement
—> Balanced by ACh (from Striatum): ***Inhibition of Basal ganglia —> Inhibition of movement
—> Well-balanced controlled muscle activity

Lack of Dopamine + Inhibition by ACh
—> Lack of muscle control

∴ Treatment strategy: Re-establish balance between Dopamine and ACh in brain

  1. ↑ Dopamine activity in Nigrostriatal system
  2. ↓ Muscarinic cholinergic activity in Striatum
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5
Q

Causes of Parkinsonism

A
  1. Impaired release of Dopamine —> Idiopathic parkinsonism (Parkinson’s disease) (Majority)
  2. Drug-induced parkinsonism (Antipsychotics)
    - Reserpine (depleting dopamine store)
    - Haloperidol (dopaminergic blocker, Typical antipsychotic)
  3. Toxin damaging dopaminergic neurons
  4. Viral infection (Encephalitis)
  5. Trauma-repeated head injury
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6
Q

Levodopa (L-dopa)

A
  • Precursor of dopamine
  • ***High therapeutic index (drug of choice for symptom control esp. in elderly)
  • **Readily cross BBB (dopamine cannot) —> converted to Dopamine in brain by **DOPA decarboxylase (also present in periphery)
  • Large dose required when given alone —> broken down by ***DOPA decarboxylase in periphery
  • ***Well-absorbed in GI tract
  • Extremely short t1/2 —> “on/off” effect (***Apomorphine to counteract)
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7
Q

Drugs NOT to be given concurrently with L-dopa

A
  1. Non-selective MAOI (e.g. Phenelzine) —> **excess dopamine in periphery —> converted to NA, adrenaline —> **hypertensive crisis (life-threatening)
  2. Pyridoxine (vit B6) —> ***co-factor for DOPA decarboxylase —> ↑ peripheral breakdown of L-dopa
  3. Antipsychotics —> block dopamine receptors —> parkinsonism-like symptoms
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8
Q

Adverse effects of L-dopa

A

Overstimulation of central dopamine receptors:

  1. ***Dyskinesia (involuntary muscle movement)
  2. ***Hallucinations
  3. Restlessness
  4. Confusion

Conversion of L-dopa to Dopamine in periphery:

  1. ***N+V (∵ stimulate Dopamine receptor in CTZ)
  2. ***Postural hypotension (∵ vasodilation)
  3. Arrhythmia
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9
Q

Peripheral DOPA decarboxylase inhibitors

A
  1. Carbidopa
    - peripheral inhibitor —> do not cross BBB
    - combination with L-dopa (L-dopa:Carbidopa = 4:1) —> Sinemet
    —> ↓ breakdown of L-dopa in periphery
    —> ↑ availability of dopamine to CNS
  2. Benserazide
    - peripheral inhibitor
    - combination with L-dopa (L-dopa:Benserazide = 4:1) —> Madopar
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10
Q

Dopamine receptor agonist

A
  1. Bromocriptine
  2. Pergolide
  3. Pramipexole, Ropinirole
  4. Rotigotine
  5. Apomorphine
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11
Q
  1. Bromocriptine
A
  • Ergot derivative (from fungus)
  • act on D2-like receptors (D2, D3, D4)

Use:

  • useful to delay use of L-dopa in younger patients
  • ***minimal effects on bradykinesia
  • can be used in conjunction with Sinemet —> relieve rigidity and tremor

SE:

  • Hallucination, Delirium
  • N+V
  • Arrhythmia, Postural hypotension
  • ***Erythromelalgia: red, painful, swollen feet / hands (blood vessels blocked)
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12
Q
  1. Pergolide
A
  • Ergot derivative
  • act on D1-like + D2-like receptors (D1-D5)

Use:
- used in conjunction with Sinemet and Anticholinergics

SE:

  • Confusion
  • Hallucinations
  • Postural hypotension
  • Urinary tract infection
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13
Q
  1. Pramipexole, Ropinirole
A
  • Non-ergot derivative (Synthetic)
  • act on D2-like receptors

Use:

  • ***1st line in younger patients
  • Adjunct to Sinemet treatment in advanced PD
  • fewer GI SE

SE:

  • Dyskinesia
  • Insomnia / Somnolence
  • Dizziness
  • Postural hypotension
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14
Q
  1. Rotigotine
A
  • Non-ergot derivative
  • act on D2-like receptors

Use:
- ***Transdermal patches in PD for swallowing problems (NEUPRO patch)

SE:

  • Hypersensitivity reactions / skin problems (redness, rashes, irritation)
  • Dizziness
  • Headache
  • Nausea
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15
Q

Selegiline + Rasagiline - Selective MAO-B inhibitor

A

MOA:
Inhibit ***MAO-B
—> prevent metabolism of Dopamine in periphery + brain
—> ↑ Dopamine level

(Non-selective MAOI: Phenelzine, Tranylcypromine
Selective MAO-A inhibitor: Moclobemide)

Use:
- Adjuvant therapy: Enhance effects of Sinemet, Madopar

SE:
- Hypertensive crisis in high dosage (conversion to NA / adrenaline in periphery)

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16
Q

Entacapone + Tolcapone - COMT inhibitors

A 
MOA:
Block COMT (Catecholamine-O-methyl transferase) (NOT cross BBB)
  1. Prevent peripheral conversion of L-dopa —> ***3-O-methyldopa
    —> prevent 3-O-methyldopa competing with L-dopa for active carrier to transport across GI tract, BBB)
  2. Prevent conversion of Dopamine —> 3-methoxytyramine

Use:
- ONLY as adjuncts to Sinemet, Madopar

SE:

  • Diarrhoea
  • Postural hypotension
  • Dyskinesia
  • Sleep disorder
  • Hallucinations
  • Hepatic necrosis (Tolcapone only)
17
Q

Amantadine - Dopamine facilitator

A
  • Antiviral against influenza

MOA:

  • Unknown mechanism
    1. **↑ Dopamine release from surviving nigral neurons
    2. **    Inhibit reuptake of Dopamine in synapse

Use:

  • more effective than Anticholinergics in improving ***bradykinesia, rigidity when used along Sinemet, Madopar
  • Adjuvant in severe patients (NOT 1st line)

SE:

  • Restlessness, agitation, confusion
  • Postural hypotension
  • Peripheral edema
  • Skin rash
18
Q

***Summary of drugs acting on dopaminergic system

A
  1. Levodopa (+ Peripheral DOPA decarboxylase inhibitors)
    - Sinemet (Levodopa + Carbidopa)
    - Madopar (Levodopa + Benserazide)
  2. Dopamine agonist
    - Bromocriptine (D2-like)
    - Pergolide (D1+D2-like)
    - Pramipexole, Ropinirole (D2-like, 1st line)
    - Rotigotine (D2-like, patches)
    - Apomorphine
  3. Selective MAO-B inhibitor
    - Selegiline
    - Rasagiline
  4. COMT inhibitor
    - Entacapone (Stalevo: Levodopa + Carbidopa + Entacapone)
    - Tolcapone
  5. Amantadine
19
Q

Central anticholinergics

A

DO NOT confuse with AChE inhibitor!!!

  1. ***Benztropine
  2. Trihexyphenidyl (Benzhexol)
  3. Biperidine
  4. Procyclidine
  5. Orphenadrine

MOA:
↓ Cholinergic output from Striatum / Block Cholinergic receptor
—> ↓ Inhibition of Basal ganglia
—> ↓ Inhibition of movement

Use:

  • much less efficacious than Sinemet
  • ***Adjuvant in PD
  • Reduce primary symptoms (e.g. tremor, rigidity, akinesia) (***NOT bradykinesia) + secondary symptoms (drooling)

SE:

  • Sedation (CNS effect)
  • Urinary retention
  • Dry mouth
  • Constipation
  • Mental confusion
20
Q

Treatment for drug-induced parkinsonism (Antipsychotics)

A

(Too little Dopamine in body)

  1. Lower drug levels (antipsychotics)
  2. Change drug to less potent one
  3. Use an anticholinergic agent (↓ ACh) if have to maintain antipsychotic dose
21
Q

Treatment guideline to idiopathic PD

A 
Dopamine agonist / Sinemet
—> inadequate control —> add Sinemet
—> inadequate control / wearing off —> Sinemet dose more frequently / higher dose
—> + COMT inhibitor / MAO-B inhibitor
—> Surgery (DBS)

***Adjunct:
For tremor: Anticholinergic
For drug-induced dyskinesia: Amantadine
For “off” episodes: Apomorphine

22
Q

Huntington’s disease / chorea

A

Genetic disorder due to single defective “dominant” gene on ***chromosome 4

**Hyper-reactivity of dopaminergic pathways
—> due to **diminished GABA functions in Basal ganglia
—> ***inhibition of indirect pathway
—> promote movement

Symptoms:

  • Involuntary movements
  • Dementia
  • Depression
  • Cognitive decline
23
Q

Treatment for Huntington’s disease

A

Symptomatic and only partially successful

  1. Medication for movement symptoms:
    - **Tetrabenazine —> **deplete dopamine —> suppress chorea
    - ***Antipsychotic (Haloperidol, Risperidone) —> SE of suppressing movement
  2. Medication for psychiatric symptoms:
    - Antidepressant (Fluoxetine)
    - Mood-stabilising drugs (Carbamazepine) —> treat irritability
24
Q

Alzheimer’s disease

A
  • Neurodegenerative condition
  • Loss of cognitive function —> eventually mobility
  • Chronic, progressive dementia (no cure)
  • Female > Male

Clinical Features:

  1. β-amyloid accumulations
  2. Neurofibrillary tangles formation (numerous) (Tau protein)
  3. ***Loss of cortical cholinergic neurons

Affected regions:
1. **Cortical shrinkage
2. **Hippocampus shrinkage
—> enlarged Ventricles

Symptoms:

  • forgetfulness
  • getting lost in familiar setting
  • lose interest in family
  • deterioration of work performance
  • disorientation (time and place)
  • behavioural changes
  • slower walking / falls

Stages:

  1. Pre-dementia
    - mild cognitive impairment
  2. Mild (early)
    - difficulty remembering newly learned information
  3. Moderate
    - disorientation
    - mood and behavioural changes
    - deepening confusion about events, time and place
  4. Severe
    - difficulty speaking, swallowing and walking
25
Q

Treatment options of Alzheimer’s disease

A
  1. AChE inhibitors (↑ ACh)
    - Improve cholinergic transmission within CNS
    - **Donepezil —> all stages
    - **    Rivastigmine (patch) —> all stages
    - ***Galantamine —> mild-moderate (also Nicotinic receptor allosteric modulation)

SE:

  • N+V
  • Diarrhoea
  • Abdominal cramps
  • Anorexia —> appetite and weight loss
  • Agitation
  • Dizziness
  • Urine incontinence
  1. Memantine
    - **NMDA receptor antagonist (uncompetitive) —> moderate-severe
    - Protect CNS neurons from **    excitotoxicity actions of glutamate on NMDA glutamate receptors —> Improve cognitive ability
    - Add-on therapy

SE:

  • Headache
  • Dizziness
  • Confusion
  • Constipation
  • Diarrhoea

HNNS (58 decks)

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