Regulating Dopamine Levels Flashcards by Srishti D

Describe the extrapyramidal motor system?

Dopaminergic neurons in substantia nigra give tonic inhibition to cholinergic neurons in corpus striatum
Cholinergic neurons in corpus striatum give excitatory input to inhibitory interneurons
Inhibitory interneurons give inhibitory input to spinal cord
Inhibition of output to skeletal muscle

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What happens in Parkinson’s disease (PD)?

Death of dopaminergic neurons in substantia nigra

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Describe the time course of PD

Chronic

Progressive

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What is PD a disorder of?

Muscle movement

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What are the motor signs and symptoms of PD?

Tremor
Rigidity of limbs
Bradykinesia
Impairment of postural reflexes
Facial
- Impassive
- No blinking
Speech
- Monotonous
- Hypophonic
Movement
- Decreased manual dexterity

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What are the non-motor signs and symptoms of PD?

Cognitive deficiencies
Depression
Raised anxiety levels
Olfactory deficiencies
Sleep disturbances
Fatigue
Pain
Bowel and bladder problems
Sexual dysfunction

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What is one of the first symptoms of PD?

Lack of smell

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How many dopaminergic neurons are destroyed by the time motor deficits emerge?

80%

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What is diagnostic of PD?

Reduced dopamine levels

Lewy bodies present at post-morten

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How many cases of PD are genetic?

10%

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When do genetic cases of PD tend to develop?

At younger age

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How many people have no known genetic mutations?

90%

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What is the biggest risk factor for developing PD?

Age

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What do drugs do in PD?

Provide symptomatic relief

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How can dopamine deficiency be restored?

Increase dopamine synthesis
Increase dopamine release
Dopamine receptor agonists
Reduce dopamine metabolism

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What is necessary to balance if you’re exogenously increasing dopamine levels?

Decrease ACh levels to keep balance

- Via cholinergic antagonists

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Does dopamine cross the BBB?

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What is L-DOPA converted to in the body?

Dopamine

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What is the effect of ingesting dopamine?

Emetic

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How is dopamine stored in the neuron?

Packaged into vesicles

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What is reserpine?

Depletes dopamine

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What is the gold standard therapy of PD?

L-DOPA

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How do you increase dopamine synthesis?

Give levodopa

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What is levodopa?

Amino acid isomer

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How much levodopa is metabolised in the periphery?

Over 90%

What is done to increase levodopa bioavailability?

Block dopadecarboxylases (DDC) in peripheral tissues

What are the peripheral effects of levodopa because of its conversion to dopamine and noradrenaline?

Nausea Vomiting Orthostatic hypotension Cardiac dysrhythmias

What is levodopa formulated with?

Peripheral DDC inhibitor - Carbidopa - Benserazide

What is needed for levodopa to work?

Some functional dopaminergic neurons

What are the beneficial effects of levodopa?

Reduces rigidity Reduces tremors Reduces other symptoms

When is levodopa given?

First line of treatment

When is levodopa rapidly absorbed from the stomach?

When it's empty

What does levodopa compete with for uptake?

Other neutral amino acids

What is the half life of levodopa?

1-2 hours

What is the plasma concentration of levodopa?

Variable

How does the effectiveness of levodopa change over time?

Declines

Why does the effectiveness of levodopa change over time?

Continued degeneration of dopaminergic nerves

What is done when levodopa starts to become ineffective?

Increase dose | Incorporate other drugs

What are the peripheral adverse effects of levodopa?

``` Anorexia Nausea Vomiting Tachycardia Ventricular dysrhythmias Orthostatic hypotension Pupil dilation ```

What are the central adverse effects of levodopa?

``` Visual and auditory hallucinations Abnormal motor movements Mood changes Depression Anxiety ```

What are the drug interactions of levodopa?

``` Vitamin B6 Monamine (MAO) type A inhibitors Inhalational anaesthetics Anticonvulsants Neuroleptics ```

What are bromocriptine and cabergoline?

Dopamine agonists

How are bromocriptine and cabergoline used?

Can be used as monotherapy

What are the beneficial effects of bromocriptine and cabergoline?

Improve bradykinesia and rigidity

Why may bromocriptine and cabergoline be preferred in young patients?

Some evidence suggests that giving L-DOPA accelerates progression of PD by increasing IC dopamine levels > causes oxidative stress in neuron > damage > death of dopaminergic neurons

What is pergolide?

Dopamine agonist

How is pergolide used?

Adjunct to levodopa

Why aren't dopamine agonists as good as levodopa?

Because they bind indiscriminately to dopamine receptors, whereas levodopa is taken up selectively by dopaminergic neurons for synthesis of dopamine, and subsequent release

What are the side effects of dopamine agonists?

``` Similar to levodopa, but some more common: - Hallucinations - Confusion - Delirium - Nausea - Hypotension Dyskinesias less prominent Arrhythmias Myocardial infarction ```

What does it mean for dosage of levodopa if there is a titration effect?

Different doses for morning and evening | Different doses for different people because don't know how many neurons degenerated with each person

What is selegiline?

MAO type B inhibitor

How do MAO type B inhibitors work?

Reduce metabolism of dopamine

What are the benefits of using MAO type B inhibitors?

No hypertensive crises like with MAO type A inhibitors Early use may delay disease progression - Reduced formation of free radicals

What is entacapone?

Catechol-O-methyltransferase (COMT) inhibitor

What do COMT inhibitors do?

Reduce metabolism of L-DOPA

How are COMT inhibitors used?

Adjunct to L-DOPA > increase CNS levels

What are MOA and COMT?

Enzymes involved in the metabolism of dopamine

What is amantadine?

Antiviral in influenza | Observed to reduce rigidity and bradykinesia

How does amantadine work?

Enhances release of dopamine

What are the drawbacks of amantadine?

Less efficacious than L-DOPA | More rapid tolerance

What are the adverse effects of amantadine?

``` Restlessness Agitation Confusion Hallucinations Orthostatic hypotension Urinary retention Dry mouth ```

What is the cholinergic activity of amantadine?

Anticholinergic > don't need to give extra anticholinergic

Why are muscarinic receptor antagonists used in the treatment of PD?

Restore dopaminergic-cholinergic imbalance

How are muscarinic receptor antagonists used?

Adjunct to L-DOPA

What are the effects of muscarinic receptor antagonists?

``` Modest effect on - Tremor Little effect on - Rigidity - Bradykinesia ```

What are some examples of muscarinic receptor antagonists?

Bezhexol Benztropine Biperiden Orphenadrine

What are the classic anti-muscarinic side effects?

``` Reduced - Salivation - Lacrimation - Urination - Defacation (SLUD) ```

What are the peripheral adverse effects of muscarinic receptor antagonists?

``` Dry mouth Dry skin Blurred vision Constipation Urinary hesitancy Nausea Vomiting ```

What are the central adverse effects of muscarinic receptor antagonists?

Memory impairment Confusion Worsening of dyskinesias

Does deep brain stimulation work in all patients with PD?

What is required for deep brain stimulation to work in PD?

Relatively high levels of dopaminergic neurons

What is alph-synuclein?

Protein monomer of Lewy bodies

What are Lewy bodies made of?

Alpha-synuclein fibrils

Where are Lewy bodies found?

Deposits inside neurons in affected brain areas in PD

What can cause PD?

Mutating/overproducing alpha-synuclein | Several mitochondria-related genes when mutated

What is believed to be the toxic drivers of PD?

Small oligomers of alpha-synuclein

Does smoking increase or decrease your risk of developing PD?

Decrease

Which pesticides have been linked to high incidence of PD?

Rotenone | Paraquat

Which areas are first affected in PD?

Loss of smell | Loss of gut motility

What does some evidence suggest stabilises alpha-synuclein oligomers?

Oxidised dopamine

What is the average age of onset of PD?

Regulating Dopamine Levels Flashcards

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