Review of Pharmacology - 9E (2015)

Review of Pharmacology
Parkinsonism
It is a neurodegenerative disease characterized by rigidity, bradykinesia, dyskinesia, tremor,
mask like facies and unstable gait. Idiopathic Parkinsonism is known as Parkinson’s disease.
In basal ganglia, the output neurons are controlled by dopamine and acetylcholine. Due to
their opposite action, a balance is required between these two neurotransmitters for proper
functioning of basal ganglia.
Major pathology in Parkinsonism is decrease in nigrostriatal dopaminergic neurons, (with
appearance of Lewy bodies) consequently cholinergic activity becomes dominant. Thus, two
major strategies for the treatment of Parkinsonism are to increase brain dopaminergic activity
or to decrease central cholinergic activity.
Drugs Increasing Brain Dopaminergic Activity
Brain dopaminergic activity can be increased by precursors of dopamine, inhibitors of
dopamine metabolism, dopamine receptor agonists and drugs increasing presynaptic release
of dopamine.
Central Nervous System
A. Dopamine Precursors
Dopamine itself cannot cross blood brain barrier (BBB) but its precursor levo-dopa can cross
BBB. Levo-dopa is metabolized by dopa decarboxylase (contains pyridoxine as co-factor)
to dopamine. This conversion occurs both in periphery as well as in the brain. Peripheral
conversion is undesirable due to two reasons:
• It forms dopamine peripherally that cannot cross BBB, therefore only about 1-3% of
l-dopa can reach its target site (brain).
• Peripherally formed dopamine will result in adverse effects like postural hypotension.
Therefore levo-dopa is always given in combination with peripheral dopa decarboxylase
inhibitors like carbidopa or benserazide. This combination has beneficial effects on all symptoms
of Parkinsonism, although tremors respond less well than rigidity or bradykinesia.
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Addition of carbi-dopa to
I-dopa therapy
• Increase entry of L-dopa in
brain.
• Decrease adverse effects due
to peripherally formed dopamine
Adverse Effects
• Peripherally formed dopamine can lead to postural hypotension and arrhythmias.
Nausea and vomiting occurs commonly due to CTZ stimulation by dopamine
(Domperidone but not metoclopramide can be used for the treatment of this vomiting). On
long term use “wearing off” effect and on-off phenomenon can result. ‘On’ means
patient is having no symptoms of Parkinsonism (but abnormal move ments are
present) and ‘off’ means patient has full blown symptoms of Parkinsonism (like
no treatment is given). This effect is due to short half life (1-2hrs) of l-dopa and
is reduced by carbidopa. Long acting dopamine agonists show little tendency to
cause on-off phenomenon.
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