Welcome to this video tutorial on the pharmacology of Parkinson’s Disease. Parkinsons Disease is the second most common
neurodegenerative disease after Alzheimer’s Disease, affecting 1% of all people over 60
and 4% of all those over 80. When examining the pharmacological treatment
of Parkinson’s Disease there are four main drugs and drug classes we will be concerned
with: Levodopa, Dopamine antagonists, Monoamine oxidase-B inhibitors or MAO-B inhibitors and
Catechol-O-methyl transferase or COMT inhibitors – but more on that shortly.
Let's start of with a simple representation of the anatomy and physiology
relevant to Parkinson's Disease
Here we have a representation of the blood brain barrier, a nigrostriatal dopaminergic neuron
which produces the neurotransmitter dopamine, and a neuron in the corpus striatum – which
upon activation by dopamine exerts its modulating effect on movement pathways leading to smoother
more co-ordinated movement. There are also some very important enzymes
at work in these regions: Dopa decarboxylase which is present both peripherally outside
the blood brain barrier and centrally within nigrostriatial dopaminergic neurons MAO-B
which is present in nigrostriatal neurons, and COMT which is present centrally and peripherally
It is important to note that there are dopamine receptors present on neurons within the corpus
striatum. In Parkinson’s Disease nigostriatal dopaminergic
neurons are not able to produce enough dopamine, which stops the neurons in the corpus striatum
from exerting their control on movement pathways leading to the characteristic tremor and jerking
movements associated with Parkinson’s Disease. One way to counteract this is to give the
patient levodopa – the precursor to dopamine. Lets see what happens if we administer Levodopa.
As it will be given in tablet or capsule form, levodopa enters the systemic circulation outside
the blood brain barrier and so a certain amount will be metabolised by the enzyme Dopa decarboxylase
to dopamine. However, this dopamine outside the blood brain
barrier will give rise to peripheral side effects such as nausea,movement disorders
such as tics which are called dyskinesias, and joint stiffness.
Some levodopa will be metabolised by peripheral COMT to 3-O-Methyl-dopa or 3-OMD, further
reducing the amount of peripheral levodopa which is available to cross the blood brain
barrier. In the end only about 5 to 10% of administered
levodopa actually manages to cross the blood brain barrier. It is then taken up into nigrostriatal
dopaminergic neurons, where it is metabolised by dopa decarboxylase into dopamine.
Some of this dopamine will be metabolised by MAO-B into 3,4-Dihydroxyl phenyl acetic
acid or DOPAC for short, and some will be metabolised by central COMT to 3-methoxy tyramine.
The end result is less dopamine available to be transported to the dopamine receptor
on neurons in the corpus striatum. From this you can see that both peripheral and central
enzymes greatly reduce the efficacy of levodopa therapy. However, there are ways we can get
around this. Carbidopa and Benserazide are dopa decarboxylase
inhibitors and block the actions of peripheral dopa decarboxylase stopping it from breaking
down Levodopa into dopamine. This reduces the side effects of levodopa treatment as
well as making more levodopa available to cross the blood brain barrier.
COMT inhibitors such as Entacapone block peripheral COMT. Blocking the actions of these two peripheral
enzymes results in more levodopa crossing the blood brain barrier to be taken up by
nigrostriatal dopaminergic neurons, where it is metabolised by centrally-acting Dopa
decarboxylase to produce dopamine. To prevent this dopamine being broken down
by MAO-B, an MAO-B inhibitor such as selegiline can be used, and to prevent dopamine being
broken down by centrally acting COMT, a COMT inhibitor such as Tolcapone can be administered.
The overall effect of these medications is to increase the amount of dopamine available
to be transported to the dopamine receptors on the neurons in the corpus striatum, increasing
its influence on movement pathways and reducing the movement problems associated with Parkinson’s
Disease. In addition to these drug treatments, dopamine
agonists such as bromocriptine and pergolide can also be very beneficial. These act directly
on the dopamine receptors of the neurons in the corpus striatum stimulating the modulating
effect it has on movement pathways and reducing the characteristic tremor and other movement
disorders associated with Parkinson’s Disease.