35 - Regulating Dopamine Levels Flashcards
(27 cards)
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
