Parkinson's: Therapies

I am going to start this with a table just showing what I am going to cover in the green column and I will probably mention what is in the blue column. The red column is just there for anyone who wants to help someone with PD as some hings that can be done to help keep the person moving and healthy.

As you might expect, there is a timeline for what drugs to use at what stage in the progression of PD. Levodopa used to just be the treatment for most of the disease, but now it usually begins with MAO-B inhibitors alone, once these begin to fail, Amantadine, then COMT inhibitors or MAO-B inhibitors are used in combination with Levodopa. In late stage PD, dopamine agonists are used, often still with L.DOPA even though this is much less effective at this point. Anticholinergics are used to reduce hand tremor for much of PD but they are used late stage also to aid the dopamine agonists.

Monoamine oxidase-B inhibitors (MAOIs):

There are two types of MAO, A and B, A are more effective at metabolising serotonin and B are more effective at metabolising dopamine and noradrenalin. Drugs such as selegiline are selective for MAO-B and inhibit its action in the neuron and astrocytes to prevent the metabolism of dopamine into homovanillinic acid by covalently binding to the MAO-B enzymes to stop them catalysing reactions in both pathways needed for homovanillinic acid production. Selegiline enters the active site of MAO-B where it is converted into its active form but this form covalently binds to the active site of the enzyme during the catalytic phase preventing dopamine entering the active site. This action is irreversible so new MAO-B must be synthesised to break down dopamine so more dopamine is available to act on receptors. Some evidence shows MAOIs as antioxidants thus making them neuroprotective too which means it should slow the loss of dopaminergic neurons. This drug is usually used as a monotherapy to begin with and then combined with levodopa.

COMT inhibitors (COMTIs): 

I am going to talk about these before L.DOPA because they act on the same two pathways of dopamine metabolism as MAOIs but they act on a different enzyme, catechol-O methyl transferase, which also converts dopamine to homovanillinic acid. These are newer drugs, the most common of which is entacapone. COMT catalyses the transfer of S-adenosyl-L-methionine residues methyl group to a phenyl group in catechol structured molecules, such as dopamine. Entacapone selectively and reversibly inhibits COMT to stop the metabolism of dopamine. This means more dopamine is available and active at the synapse and it is active for longer. The idea of COMTIs and MAOIs is to counter the loss of dopaminergic neurons by increasing the dopamine available in the neurons that are left. I just mentioned that COMT acts on any catechol structure so not only does it act on other catecholamines like adrenaline but L.DOPA (the drug and the chemical that already exists in the body) also has a catechol structure. This precursor to dopamine is either converted to dopamine by decarboxylase or converted to 3-O-methyl DOPA by COMT, stopping this pathway is an extra effect of COMTIs because it means that L.DOPA (and the drug) is converted to dopamine not methyl DOPA. This is an added advantage of this drug and explains why it is more effectively used in combination with levodopa.

This image shows what I am talking about when I say COMT and MAO-B is used in both pathways to convert dopamine to homovanillinic acid, they are just used at different stages.

Levodopa (L.DOPA):

This is the most common and well known drug used to treat PD. The reason the precursor drug is used and dopamine not just given to patients is for one simple reason. Dopamine is a large molecule and the blood in the brain is almost completely sealed off from the brain itself. It is a phenomenon known as the blood brain barrier and it stops all but essential molecules entering the brain. Its evolutionary function is to stop pathogens and toxins etc... entering the brain and killing us. As I said, dopamine is to large to enter by diffusion and it is not an essential molecule because the brain makes its own dopamine so it has no transporter. However, L.DOPA is an essential molecule because the brain needs it to make dopamine, therefore it does have a transporter in the blood brain barrier so can enter easily.

There are some problems and I am going to point some out before going into the mechanism of action. Levodopa enters through the intestine no problem so is orally bioavailable, however because it is a dopamine precursor it is a monoamine and MAOs are abundant in the intestine walls, so 90% of levodopa is metabolised by MAOs. So 10% of the dose has entered the blood and of that 10% only 10% enters the brain because the other 90% is either metabolised in the blood or enters peripheral cells because dopamine is used throughout the body. This poses a further problem, the peripheral cells using dopamine are fine, so there is now excess dopamine in the periphery acting on receptors which causes vomiting and anorexia as well as many other side effects. The good news is that most dopamine receptors in the periphery are D2 receptors and a drug called carbidopa inhibits D2 receptors but is incapable of crossing the blood brain barrier, therefore it limits the peripheral effects of levodopa without compromising the central effects.

The mechanism of action is basically to put the precursor in the dopaminergic neurons and let the cell use it in its normal functioning. Levodopa enters the dopaminergic neurons in the substantia nigra that remain and is converted to dopamine via dopa decarboxylase. The overall effect being the same as the other drugs mentioned, compensate for the loss of neurons by increasing the output of those neurons that remain. If used too early it can lead to excess dopamine which is the believed cause of schizophrenia, so levodopa can cause psychosis but clozapine is an antipsychotic that inhibits D4 receptors, reversing the psychosis without effecting the treatment because motor movement is controlled by D1 and D2 receptors.

In the first image, amantadine is mentioned, many of you will have herd of amantadine and not know why and some of you will know that amantadine is an antiviral drug used to treat flu. It is used in PD because it increases the release of dopamine from vesicles in the synaptic cleft, because well no-one really knows and it acts on M2 proteins in flu viruses so there is no link there either but it works because science. It is useful in early stages but can be combined with L.DOPA which amazingly has showed to increase the effectiveness of levodopa to 79% of people responding to treatment up to late moderate stages. Statistically, it is significant at 0.05.

Dopamine agonists: 

During late stage PD all of the above become in effective because there is only so much you can increase the output of one neuron and eventually the neuron loss is so extensive that those that are left cannot increase their levels to counter that loss. So a different approach to just increasing the output of neurons is needed.

That approach is to activate the dopamine receptors in the striatum largely independently of whether the post synaptic membrane is being innervated by a dopaminergic neuron from the substantia nigra or whether that neuron has been lost. To do this, dopamine receptor agonists are needed, preferably ones specific to either D1, D2 or both (to reduce the chance of psychosis and to limit the areas the drug is activating. Earlier I said that dopamine cannot be used because it is too large to cross the blood brain barrier, agonists are just molecules that activate the receptors, they do not have to be the same or even very similar to dopamine. The agonists used are Bromocriptine which is selective for D1 and D2 and crosses the BBB and pergolide which is D2 selective and crosses the BBB. As you might expect they have similar side effects to levodopa due to the periphery but carbidopa will also help here. Their mechanism of action is just to mimic the action of dopamine in its absence.

Anticholinergics:

These can be used throughout PD for those with a hand tremor, benzhexol is very effective at reducing the hand tremor and they work by inhibiting the muscarinic receptors at the neuromuscular junctions. This is because acetylcholine release to the muscle at the NMJ is what initiates muscle movement. The lack of dopamine acting on D2 receptors in the in the striatum reduces the inhibition of unwanted movement which translates to increased acetylcholine which is enough to cause a tremor in the hand. Antimuscarinics block the muscarinic cholinergic receptors on the muscle to reduce the unwanted movement.

In late stage PD anticholinergics are useful because they inhibit cholinergic neuron activation in the striatum which opposes some dopaminergic action. This means a lower dopamine concentration is needed to elicit the same effect as the usual concentration of dopamine due to the lack of opposing influence of cholinergic neurons.

This diagram shows simply the mechanisms of the drugs above to just give a visual idea of what I am talking about. for the most part it is accurate but it is worth noting that COMTIs also do what MAOIs do and that MAO-B is mostly a neuronal enzyme so should be inside the neuron not in the extracellular matrix.

Deep brain stimulation:

I am not going to go into too much detail on this but in essence it causes action potentials in groups of neurons in the area of the electrode to cause a response, or it can hyperpolarise so in PD it potentially hyperpolarises the striatum to reduce the tremor and other movements. But honestly, so far there is no one clear or believed theory of how DBS works so I am not going to reel off  bunch of equally refutable hypotheses that may or may not be correct. Although, the results show that fully understood or not, it certainly works.

This will the most amazing thing you will have seen all day, probably the most amazing thing for quite a while. This is an amazing scientific and medical achievement not only because of how well it works but also the simplicity of use and that it is not just someone lying there with wires coming out of their head, which is sometimes peoples view of DBS but it is allowing people to have a relatively normal life. The difference really is staggering. Link just in case: https://www.youtube.com/watch?v=mO3C6iTpSGo

That is it for Parkinson's disease.