ic14 pharmacology of parkinsons, dementia Flashcards by Nathaniel Chan

What are the cardinal signs of Parkinsons disease

TRA
1) Tremors at rest (pill rolling)
2) Rigidity
Cogwheel rigidity
3) Akinesia / Bradykinesia
Slowness of movement

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What is the difference between the cause of Parkinsons disease and EPSE

Parkinsons disease: dopamine deficiency due to neuronal degeneration

EPSE: dopamine deficiency due to dopamine blockade

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Pathology of parkinsons disease

Impaired clearing of abnormal / damaged intracellular proteins by ubiquitin-proteosomal system

Misfolded alpha-synuclein proteins aggregate to form fibrils, fibrils aggregate to form Lewy body

Results in accumulations of aggresomes or Lewy bodies in the basal ganglia, causing:

Decrease in Dopamine neurotransmission
Mitochondrial failure

Degeneration of dopaminergic neurons with Lewy body inclusions in substantia nigra

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Function of basal ganglia

Contains substantia nigra

Involved in action selection
AKA brain is telling body to move in many different directions but Substantia Nigra sends a dopamine signal to only select one action and inhibits the rest

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What are the dopamine subtypes in the nigrostriatum? What is the nature of the neuronal pathway?

Excitatory D1 and inhibitory D2

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What happens when the substantia nigra is damaged

Loss of Substantia Nigra → no release of inhibition → hypokinetic state

Usually Substantia Nigra will release inhibition of one action and hence can carry out one action, but now all actions are inhibited and patient becomes hypokinetic, moves slowly

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How is dopamine produced?

L-tyrosine → L-dopa
By tyrosine hydroxylase

L-dopa → Dopamine
By DOPA decarboxylase

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How is dopamine broken down?

By COMT and MAO

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Between L-dopa and Dopamine, which one pass through BBB?

L-dopa passes through BBB
So that L-dopa can be synthesised into Dopamine

Dopamine does not pass through BBB
Hence no point making Dopamine elsewhere apart from the brain

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What are the drugs to treat parkinsons and their MOA? (6 points)

1) Levodopa benserazide + carbidopa
2) COMTi (Entacapone, Tocapone)
3) MAOi
4) Dopamine receptor agonist (Pramipexole, Pergolide, Ropinirole)
5) Amantadine (NMDA antagonist)
6) Benzhexol / Trihexyphenidyl (anticholinergic)

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What is Levodopa paired with? What is the MOA?

Carbidopa / Benserazide

Peripherally DOPA-decarboxylase inhibitor
Prevent L-dopa from converting to Dopamine in other parts of the body other than the brain and causing side effects

“Since DOPA-decarboxylase blocks conversion of L-dopa to Dopamine, if i block DOPA-decarboxylase in other sites, more L-dopa retained and not converted to Dopamine, more L-dopa can pass through BBB and enter brain + lesser peripheral Dopamine causing side effects”

Allows for lower dose of L-dopa also

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What is the bioavailability of Levodopa? What is absorption affected by?

Bioavailability
33% for Levodopa, 75% with benserazide or cabidopa

Absorption decreased with high fat or protein meals

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Side effects of Levodopa, short term (4 points) and long term (3 points)

Short term:
nausea, vomiting
postural hypotension
Sudden sleep onset
Hallucination, psychosis

Long term:
Wearing off
Peak dose dyskinesia
On off phenomenon

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How to resolve motor complications of Levodopa

Wearing off
Between 8am to 2pm dose, effect of Levodopa wears off before the next dose
Can reduce dosing interval eg. TDS → QDS
Replace with modified release preparations eg. Madopar HBS

Peak dose dyskinesia
Can occur at the peak dose, 1-2hrs after taking dose
Increase dosing frequency but maintain total dose → Peak will be lower

On Off” phenomenon
Unpredictable, not related to dosing interval
Late stage of disease, taking Levodopa for very long already
Can offer Amantadine which may help with dyskinesia

General: Offer adjunctive treatment eg. Dopamine agonist, MAOi, COMTi, Amantadine

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Counselling points of Levodopa

Take with empty stomach or snacks, do not take with high protein or fat meal

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MOA and example of COMT inhibitors

Entacapone, Tolcapone

MOA
Block Dopamine and L-DOPA breakdown by inhibiting COMT
More Levodopa available to enter brain

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Which drug should be administered with Levodopa

COMTi, should not be monotherapy

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Formulations of COMTi and benefits

Exist in combination with Levodopa + Carbidopa

Good for patients with swallowing difficulties but cannot be titrated individually

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Side effects of COMTi (6 points)

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Increase dyskinesia (abnormal movement) upon initiation
Liver dysfunction (Tolcapone)
Nausea, diarrhea
Urinary discoloration
Visual hallucination
Drowsiness, sleep disturbances

Drug food / drug interactions with COMTi (2 points)

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Iron, Calcium

MAO-A inhibitors eg. Moclobemide

What drugs interact with iron

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Levodopa, COMTi (Entacapone)

Examples of MAOi used for parkinsons

What is the indication?

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MAO-B selective
Selegiline, Rasagiline

For mild parkinsons
Can try before Levodopa
Can be used as monotherapy

What is a side effect of Selegiline? How does it occur?

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Insomnia, Selegiline hepatically metabolised to amphetamines, very stimulating
BD second dose should be taken earlier, so patient can fall asleep
Not for Rasagiline as it is not metabolised to amphetamines

Drug food interaction with Selegiline, Rasagiline

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Tyramine rich food eg. cheese

Ergot dopamine agonists (3 points) Non-ergot dopamine agonists (4 points)

Ergot derivatives Pergolide Cabergoline Bromocriptine Non-ergot derivatives Ropinirole Pramipexole Rotigotine (transdermal) Apomorphine (SC)

Indication of dopamine agonists

Adjunct or monotherapy Can reduce dose or delay use of Levodopa Young patients If start young patients on Levodopa, they will eventually get dyskinesia

What medications should be started for mild parkinsons or young parkinsons patients?

1) MAO B inhibitors eg. Selegiline 2) Dopamine receptor agonist eg. Pramipexole, Pergolide, Ropinirole Levodopa not suitable cos patients will get dyskinesia eventually, want to delay use COMT need to use with Levodopa Amantadine is more for reducing dyskinesia Anticholinergics used to control tremors

What are some side effects of ergot derivatives

Peritoneal fibrosis, cardiac valve regurgitation

Peripheral dopaminergic side effects Central dopaminergic side effects

Peripheral = legs, head Nausea, vomiting Orthostatic hypotension Leg oedema Central = brain Hallucinations Drowsiness Compulsive behaviors Must counsel for newly started patients Gambling, shopping, eating

Important counselling point for Dopamine agonist

Compulsive behavior eg. Gambling, shopping, eating

Which has longer bioavailability, ergot or non ergot DA

ergot has lower bioF

Which dopamine agonist need dose adjustment in renal impairment

Pramipexole

MOA of Amantadine (6 points)

1) NMDA receptor antagonist Glutamate bind to NMDA receptors, cause excitation Higher glutamatergic activity → lead to Levodopa induced dyskinesia 2) Dopamine reuptake inhibitor 3) Release stored dopamine 4) Dopamine receptor agonist 5) Upregulate D2 receptors 6) Anticholinergic

How is Amantadine excreted When should second dose be taken

Renally In the afternoon, very stimulating (like Bupropion and Selegiline)

What drugs are stimulating, and what to do?

Bupropion, Selegiline, Amantadine Bupropion and selegiline metabolised to amphetamine like molecules Dose in afternoon

Side effect of Amantadine

Livedo reticularis Net-like pattern, reddish blue discoloration

Why are anticholinergics used in Parkinsons?

controlling tremors in PD Treat sialorrhea (hypersalivation)

What is dementia caused by?

1) Senile plaques Amyloid Precursor Protein (APP) cleaved by secretase to form Beta - amyloid peptides Senile plaques are aggregates of Beta-amyloid (AB) peptide 2) Neurofibrillary tangles 1) Tau protein is needed for intracellular transport in neurons 2) When Tau protein phosphorylate by kinases, they aggregate to form PHF (paired helical filaments) 3) No intracellular transport in the neuronal cell, causing neurons to degenerate Result in degeneration of the central cholinergic system and hippocampus

Drugs to treat dementia

1) Acetylcholinesterase inhibitors aka Cholinergics Donepezil, Galantamine, Rivastigmine 2) Memantine (NMDA antagonist)

Indication and Examples of AChEi (3 points)

For mild to moderate dementia Slow titration dosing regimen over 4-8 weeks Donepezil (also for severe) Galantamine Rivastigmine

Similarity and differences between Galantamine and Rivastigmine (4 points)

Dosage form Rivastigmine: oral and transdermal Galantamine: oral only Half life Rivastigmine has shorter half life (hence need transdermal patch) Additional MOA Galantamine act on nicotinic receptors in brain, contributing to therapeutic effect Metabolism Galantamine: liver CYP450 Rivastigmine: kidneys

Side effects of AChEi

Cholinergic activation (opposite of anticholinergic) Nausea, vomiting Diarrhea (opposite of constipation) Muscle cramp Bradycardia (opposite of tachycardia in anticholinergics) Loss of appetite Increased gastric juice secretion

Who are contraindicated with AChEi caution in use

CI: Patients on beta blockers, bradycardia Caution: Patients with PUD, respiratory disease, seizures, urinary tract obstruction

Indication of Memantine

For moderate to severe disease

MOA of memantine

Non-competitive NMDA receptor antagonist NMDA is a Glutamate receptor, Glutamate is the main excitatory neurotransmitter Glutamate binds to NMDA, causing overstimulating various glutamate receptors and leading to excitotoxicity and neuronal cell death, contributing to AD → hence need to block NMDA receptor

Side effects of Memantine

Hallucination Confusion Dizziness Headache

ic14 pharmacology of parkinsons, dementia Flashcards

(46 cards)