Dopaminergic Enhancers
This group of drugs boost dopaminergic (and cholinergic transmission) within the brain. They are classically used to treat Parkinson’s disease (PD), characterised by dopaminergic neurone loss in the substantia nigra.
Treatment for PD motor symptoms is started once they are problematic; the watch-and-wait strategy is rarely practiced, although it may be given to patients as an option.
All three of the following drug classes can be used as first-line treatment for Parkinson’s.
L-DOPA gives the best improvements in motor symptoms, but has the highest rate of motor complications. It also gives reduced effectiveness with time (on-off periods).
DA-agonists are associated with less symptom improvement, but this is offset by fewer motor complications. They have a higher rate of hallucinations and impulsivity.
MAO-B inhibitors, like DA-agonists, show less improvement in symptoms but fewer motor complications. They are less likely to cause impulsivity.
Levodopa
This is a dopamine precursor that is uptaken by the CNS and converted to dopamine.
It is given with carbidopa, a peripheral DOPA decarboxylase inhibitor, which reduces the peripheral conversion of levodopa to dopamine, enhancing CNS uptake.
Peripheral dopamine causes side effects and cannot cross the blood-brain barrier.
It provides 2–5 years of clinical improvement in most patients and can give motor on-off periods, particularly after a few years.
Side effects
Tardive dyskinesia (involuntary movements)
Confusion and symptoms of psychosis (e.g., hallucinations, paranoia)
Cardiovascular – palpitations, orthostatic hypotension (consider midodrine, an a1-agonist which increases peripheral arterial resistance to increase blood pressure)
Daytime sleepiness
Nausea and vomiting – due to D2 activation in the chemoreceptive trigger zone
If stopped acutely, patients can develop neuroleptic malignant syndrome
DA receptor agonists – Pramipexole, ropinirole, bromocriptine
These are selective dopaminergic agonists that act on dopamine receptors.
They are given as alternative first line drugs or in combination to reduce the dose of levodopa needed, and may also have an antidepressant effect.
Side effects
Similar to levodopa – orthostatic hypotension, nausea, hallucinations, impulse control disorders, daytime somnolence
Ergot-derived agonists such as bromocriptine and cabergoline can cause fibrosis (e.g., pleuropulmonary and valvular fibrosis) and so are rarely used
MAO-B inhibitors – Selegilline
Selective monoamine oxidase-B (MAO-B) inhibitors prevent dopamine breakdown.
They can theoretically precipitate serotonin syndrome if taken with SSRIs/TCAs, but safety has been shown in trials.
COMT inhibitors – Entecapone, tolcapone
These reduce the peripheral metabolism of levodopa, increasing CNS bioavailability.
They are used to augment the effect of carbidopa in a combined treatment for Parkinson’s disease to prevent the effects from wearing off.
Amantadine
This has multiple mechanisms of action in the CNS, the net result of which is to increase dopamine release.
It is used in early Parkinson’s disease, usually as an add-on therapy.
Side effects
Confusion
Dizziness
Hallucinations
Peripheral oedema
CNS Muscarinic antagonists – Benztropine, procyclidine
They block muscarinic receptors in the CNS and suppress overactivity in the striatum.
They are typically used in managing drug induced side effects (e.g., extra-pyramidal side effects secondary to antipsychotics).
Side effects
Anticholinergic effects (dry mouth, tachycardia, dilation)
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