35 - Regulating Dopamine Levels Flashcards
Effect of dopamine in the extrapyramidal motor system
Dopamine (released from the substantia nigra) tonically inhibits acetylcholine (released from the corpus striatum).
How long has L-DOPA been prescribed for?
~50 years
Motor signs and symptoms of Parkinson’s disease
1 - 7
• Tremor • Rigidity of limbs • Bradykinesia • Impairment of postural reflexes • Facial – Impassive, no blinking • Speech – Monotonous, hypophonic • Movement – Decreased manual dexterity
Basic cause of Parkinson’s disease
Dopaminergic cell death (cause of death not known)
Non-motor features of Parkinson’s
1 - 9
- Cognitive deficiencies
- Depression
- Raised anxiety levels
- Olfactory deficiencies
- Sleep disturbances
- Fatigue
- Pain
- Bowel & bladder problems
- Sexual dysfunction
First sense often affected with Parkinson’s
Smell
Proportion of dopaminergic neurons that need to die before Parkinson’s symptoms manifest
~80%
Usual age of onset of Parkinson’s
~50 years of age
Why might dopaminergic neurons be susceptible to death in Parkinson’s
Dopamine production requires Fe2+ to Fe3+ oxidation generates ROS.
Doesn’t explain why not everyone gets Parkinson’s
Proteins shown to be involved in Parkinson’s
Alpha-synuclein (not broken down, accumulates, or misfolds)
Parkin
Management of Parkinson’s
1
2
3
1) Palliative, not curative
2) Restore dopamine deficiency
– Increase DA synthesis
– Increase DA release
– DA receptor agonists
– Reduce DA metabolism
3) Restore dopaminergic / cholinergic
balance in striatum.
– Cholinergic antagonists
Biosynthesis of dopamine
Tyrosine converted to L-DOPA by tyrosine hydroxylase.
L-DOPA to dopamine by L-DOPA decarboxylase.
Why can’t people with Parkinson’s be given dopamine?
Doesn’t cross blood brain barrier.
If ingest dopamine, vomit.
Which enzymes degrade dopamine?
MAO, COMT
Amount of L-DOPA (Levodopa) metabolised in the periphery
~90%
Formulation that can increase dopamine levels in Parkinson’s patients
L-DOPA + a peripheral dopamine decarboxylase inhibitor (EG carbidopa or benserazide).
Because over 90% of L-DOPA is metabolised in the periphery.
Issue with prescribing L-DOPA treatment
Reduces symptoms, but accelerates pathology with most people.
Common side-effect of L-DOPA treatment
Severe addictions.
Alterations to dopamine pathway (reward)
Levodopa
– Reduces rigidity, tremors and other symptoms
– Considered first line treatment
– Fluctuations in motor control
• “on-off” phenomenon
– Tremors, cramps, immobility
– Rapid absorption on empty stomach
• Competition with other neutral amino acids (Leu,
IsoLeu)
• Short half-life (1-2 hrs)
– variable plasma concentration
– Effectiveness declines with time
• Continued degeneration of dopaminergic nerves
• Increase dose or incorporate other drugs
Adverse effects of levodopa
• Peripheral
– Anorexia, nausea & vomiting
– Tachycardia & ventricular dysrhythmias
– Orthostatic hypotension
– Pupil dilation (avoid in patients with glaucoma)
• Central
– Visual & auditory hallucinations, abnormal motor
movements
– Mood changes, depression, anxiety
Dopamine agonists
Bromocriptine, carbergoline.
Drawbacks of dopamine agonists
L-DOPA only metabolised by neurons in substantia nigra.
Dopamine agonists stimulate dopamine receptors throughout brain.
Advantage of dopamine agonists
Don’t accelerate pathology like L-DOPA does
Side effects of dopamine agonists
– Similar to L-Dopa but hallucinations, confusion,
delirium, nausea and hypotension more common
– Dyskinesias less prominent
– Arrhythmias, myocardial infarction
Selegiline
MAOb inhibitor.
Reduces dopamine inactivation
COMT inhibitors
Reduce degradation of dopamine.
Used as an adjunct to L-DOPA
Why can muscarinic antagoinsts used for Parkinson’s?
Prevents ACh stimulation of GABAnergic neurons
