End of Dose Phenomenon
Parkinson’s
disease is a progressive neuro-degenerative disease where the dopaminergic neurons
in the substantia niagra and the nigro-striatal pathway degenerate gradually and
irreversibly over a period of time.
Under
normal physiology, dopamine is stored in vesicles in the pre-synaptic vesicle
and released in the synaptic cleft upon arrival of an action potential. This
event is highly “regulated” and exocytosis of neurotransmitter is “demand” based,
occurring as and when required for the smooth execution of muscle action.
In early
stages of Parkinson’s disease, exogenously administered dopamine as replacement
therapy tend to get stored in the pre-synaptic vesicle and is released on “demand”,
thus mimicking the normal physiology. The physiology of storage, release and
re-uptake is still intact and dopamine replacement provides immense symptomatic
relief to the patient.
As the
diseases progresses, the number of dopaminergic neurons decreases due to
degeneration. The capacity of the dopaminergic pathway to store the
neurotransmitter and release on “demand” is impaired. Relief of symptoms becomes
short lasting. Increase in amount and frequency of dose provide only limited
benefit. Patient is alternately “well” and “not well”. This is known as the “on-off” effect or “switch”
phenomenon or “end of dose” phenomenon or the “all or none” response. In the
terminal phase, when the majority of the neurons are destroyed, abnormal
movements (dyskinesia) occurs with administration of dopamine and as soon as
the effect of dopamine wanes, severe hypokinesia and rigidity returns.
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