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Parkinson’s Disease and Antiparkinson Drugs Part 11

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Parkinson’s Disease is an incompletely understood neurodegenerative disease of the brain affecting primarily older individuals.

Okay so welcome back to this next video which we are discussing parkinson’s disease and the anti parkinson’s drugs okay right so we’re going to start off by discussing the first-line treatment for parkinson’s disease them okay which is levodopa okay which is also called l-dopa now this drug literally is the l-dopa that we saw earlier it’s the lardo rotatory enantiomer

Of this doper molecule the dihydroxy female alanine which is the precursor to dopamine okay right so how does this help them in parkinson’s disease well there are two theories as to why l-dopa helps okay or two theories as to how it works it’s pretty obvious how it might help okay but there are two theories as to how it works and we don’t know which of these is

Correct so warm option is that the l-dopa is up taken by the dopaminergic neurons of the sniper striatal pathway okay so it’s up taken by oops up taken by dopamine neurons okay and this is the remaining dopamine neuron so remember even in parkinson’s disease not quite all of the dopaminergic neurons of the substantia pars compacta are going to generate some of

Them will still be there okay so the idea is that the remaining ones are going to now take up the drug l-dopa okay and then in their axon terminals are draw the axon terminal here they’re going to convert the l-dopa into dopamine okay so they’re now going to have more dopamine okay they’re going to store this dopamine in their synaptic lisa cause so they draw the

Synaptic vesicles these selectively sequoias are going to end up full up of dopamine okay like so and then these remaining dopaminergic neurons will then release these synaptic vesicles full of dopamine and then they’re going to be releasing now more dopamine and therefore that’s going to make up for the dopaminergic neurons that have been lost that’s warm theory

Of how our doper works there is however another theory which i think is gaining popularity over this theory here okay and this other theory is that other cells of the brain besides the remaining dopaminergic neurons okay are going to take up the l-dopa and they’re going to convert it into dopamine and then this dopamine is going to be released into the extracellular

Fluid causing dopamine to go up in the extracellular fluid all over the brain basically and that includes in the dorsal striatum so this is also going to need to dopamine going up in the dorsal striatum okay and then we understand what happens after that dopamine going up in the dorsal striatum whether it’s because the dopaminergic neurons that are remaining and

Now releasing more dopamine or whether it’s because other cells of the brain and how producing and releasing dopamine whichever is the case the increased dopamine in the dorsal striatum is then going to activate the d1 and the d2 receptors on the medium spiny neurons of the direct and indirect pathways respectively okay and that’s going to be pro movement so d1

Receptors on the direct pathway medium spiny neurons are going to make them more excitable okay which will make the direct pathway more excitable okay and that means the going to find it easier to initiate movements and in addition the d2 receptors on the indirect medium spiny neurons are going to inactivate those ones they’re going to make it more difficult to

Excite those medium spiny neurons on the indirect pathway and that means are going to tone down the indirect pathway which remember is an t movement that’s stopping the permission signal going to the cerebral cortex okay so this then is going to make movement more easy again it really does when you take l-dopa it is fantastic it makes the hypokinesia which remember

Means the difficulty in initiating voluntary movements it makes that go away completely okay sorry if miss spouted hypokinesia so that hypokinesia will go down okay right now l-dopa is generally not given a low and instead it’s given in combination with other drugs okay now the common ones that are usually given alongside l-dopa are either carbidopa okay or and

Sarah’s id okay now what do these two drugs do well let me firstly explain the problem with giving l-dopa thirsty okay so the problem is that loads of other cells all around your body can convert l-dopa into dopamine okay so let me draw a little picture here so we’ll have a stickman okay so here’s the hare here are the legs okay so we want l-dopa to be going to

The brain and being converted into dopamine okay the problem is that all the other tissues of the body can also take up our dopa and they can also convert it into dopamine now we don’t want that now the tissues of the peripheral body they take out opa and they convert it to dopamine using the same enzyme as is used in axon terminals ie the dopa decarboxylase ends

Like more the el animatic amino acid decarboxylase okay so why don’t we inhibit this enzyme dopa decarboxylase well this is exactly what carbidopa and then sarah side do they inhibit dopa decarboxylase now you might be saying hang on a moment you can’t just do that because now the el dope is going to be totally useless because even if it gets into the brain it

Now can’t be converted to dopamine okay but this is the genius of this these drugs cannot cross the blood-brain barrier okay so not blood brain barrier permeable okay so they can’t get into the brain however they can go everywhere else in the body so everywhere else in the body the use drugs are going to block dopa decarboxylase and stop l-dopa being converted to

Dopamine in the peripheral tissues okay that means that cells are going to stop up taking l-dopa because that they’re just going to accumulate it and not be able to actually convert it into anything okay then we will have more l-dopa left over to go to the brain okay and now in the brain these drugs can’t get into the brain so we can now convert this into dopamine

And then we’ve got the dopamine that we need to remove the hyper can easier problems that result from having to though dopamine in the dorsal striatum okay right so that’s why carbidopa been sarah’s id are usually used with either dopa in addition you can also give the drug and tuck up owen as well which further helps to prevents the peripheral breakdown of levodopa

So and took her poem cup home okay right so and tuck up on what doesn’t uh capone do well and took a poem is an inhibitor of caracalla only file transfers okay so another problem with giving l-dopa is that the liver is capable breaking down their delta okay so her parasites i’ll draw one here have a lot r of catecholamine file transfers both forms of catecholamines

Are trans phrase so both the soluble catecholamine file transferase which will be floating around their cells okay and then also the membrane bound catecholamine file transfers which will be on their membranes okay and of course these two forms of catecholamine file transferase not only can they break down dopamine but they can also break down l-dopa okay so we don’t

Want these enzymes metabolizing the l-dopa before it’s actually been able to get to the brain okay so what aunt uh capone does is it blocks the catecholamine file transfers enzymes in the hepatocyte so now once again and took a pony is not capable of crossing the blood-brain barrier so it’s not going to block comt in the brain you might think that wouldn’t that be

A good idea of blocking comt in the brain because it breaks down dopamine it will break down the old duper presumably when you put that in okay but you you don’t need to basically okay what you want to do is block the liver ones okay and that’s what ain’t uh capone does so in took a bone does not cross the buff embarrass oh you might think that it would be a good

Idea to block comt in the brain as well but that’s not what this drug does it just blocks the peripheral at comt enzymes okay and hence prevents the breakdown of the drug by the liver or at least to some extent okay right so let’s talk a little bit more than about l-dopa therapy so l-dopa therapy is absolutely brilliant at first it works fantastically it reduces

The hypokinesia right down and these people who previously were having a horrendous time initiating movements suddenly they can walk again like they could previously okay so it is a fantastic drug when we first take it but problem is that generally it does stop working over the years as you continue to take it again this is believed to be because it doesn’t stop

The neuro degeneration it just replaces the dopamine okay and as the neuro degeneration continues on the disease is going to progress and get worse and levodopa is not going to stop that and eventually it seems that the neuro degeneration gets so bad that levodopa can’t get rid of the hypokinesia anymore okay in addition levodopa also has pharmacokinetic problems

As well okay so let me explain these pharmacokinetic problems okay so basically the pharmacokinetic problems with levodopa are that it is removed from your body far too quickly okay it’s half-life is far too short okay so basically if we plot one of these graphs where we plot drug concentration okay so let’s say that this is how much drug we’ve got in the blood

Versus time okay what you get is graphs that look like this when you take the drug the drug concentration goes right up so that sits right down initially okay when you take the drug it goes right up and then it falls right down and then you take another dose of the drug and it goes right up and then it falls right down so your drug levels are not very stable okay

Now when you have very high levels of the drug in your blood that correlates to having very high that was a dopamine within the dorsal strait and now what happens when you have very high dopamine levels within the dorsal striatum okay well it makes movement very very easily but the problem is if you get too much dopamine in the dorsal stratum it lets through all

Sorts of movements it gives permission to all sorts of motor plans that you don’t want to give permission to okay so that’s through modes of movements that you don’t actually want to that through okay and this is what’s known as dis kinase ii er so when you’re on one of these spikes of l-dopa it can cause dis kinase and that doesn’t cause this in everyone but in

Quite a few patients it causes dyskinesias now what do i mean by this far let me give you some examples you end up with riving movements okay involuntary riving movements okay particularly of the hands and the face okay hands and face and the neck okay so riving movements basically particularly of the face and there okay so that’s because you’re letting through

All sorts of motor plans which you have no voluntary intention of actually letting through motor plans that have just been made haphazard by the secondary motor cortex but we’re never actually supposed to be initiated but if dopamine is too high then you let through motor plans that weren’t supposed to be initiated so that’s the problem with levodopa because of

Its bad pharmacokinetics it peaks and troughs and peaks and troughs so when you’re on a peak you start getting dyskinesia so at these some people start getting dyskinesias okay and then you go into a trough that okay so you have a period where it’s brilliant okay and you’ve got normal voluntary movement initiation and then you go into a trough and then you get

Hypokinesia against you’ve got too little dopamine and now you’ve got your hypokinesia again where you just can’t initiate movements again okay so that’s the problem that’s one of the major problems with either dopa is peaking and troughing which is a pharmacokinetic problem fundamentally what we would like is if we could keep dopamine levels at or rather keep the

Drug levels steady like so okay but you can only do that with drugs that have very slow removal time basically a slow half-life okay right so that then is all i’m going to say about reaver dopa let’s now turn our attention onto other drugs that can be used to treat parkinson’s disease besides levodopa okay right so levodopa therapy focused on trying to increase

The amount of dopamine in the dorsal striatum however why do we need to watch the increase the dopamine in the dorsal striatum why don’t we just actually create a drug that activates the d1 and d2 receptors directly because that’s all that dopamine was actually doing it was activating those receptors why don’t we just create a drug that does that for us okay so

The next type of anti parkinson drug are the dopamine agonists okay which are drugs which are going to bind to the dopamine receptors and activate them okay so firstly we have the drugs which are both d warm agonists and d2 agonists that are going to both activate the sensitivity of the direct pathway and inactivate the sensitivity of the indirect pathway okay

So they’re going to do both for the things that dopamine does within the dorsal striatum okay right so the two example drugs that i have as dopamine warmth and dopamine – receptor agonists are thirsty bromocriptine okay which is an old drug used to treat parkinson’s disease okay and then also per glide okay so bromocriptine and per glide are both non selective

Dopamine agonists for both d1 and d2 receptors and this kind of cuts out the middle rubbish was duck trying to raise dopamine levels we can just do it directly now don’t mean agonists are not the first-line treatment for parkinson’s disease neither doper is okay but if either doper fails then you can go on to dopamine i can okay right now newer dopamine agonists

Just activate the d2 receptors rather than the d1 receptors which means that they just focus on this inactivation of the sensitivity of the indirect pathway rather than activating the direct pathway okay and these seem to be effective in helping the initiation of movement as well so it doesn’t seem that you actually do need that sensitization of the direct pathway

It’s enough to just inactivate the sensitivity of the indirect pathway that also has the pro movement effect okay so examples of d2 agonists used to treat parkinson’s disease are prime it persol okay ramit puzzled and also rip in a role okay so prim oppose all and rip in a role okay right so these just work by doing exactly what dopamine does without actually

Replacing the dopamine okay the final type of an t parkinson drug that i want to talk about them is mono aiming oxidase b inhibitors okay and these drugs are selected from all the way in oxidase b they own me and hibbott monoamine oxidase be rather than just inhibiting monoamine oxidase a and b okay so examples of monoamine oxidase b inhibitors and then i’ll tell

You the reasoning behind why these work okay so you’ve got sunny jeanine okay and then also r as a theme okay so both of these drugs selectively inhibits monoamine oxidase b now why is that helpful well this action truly is in the dopaminergic neurons that have managed to survive the parkinson’s zees okay so if we bring back our dopaminergic axon okay in the

Dopamine neurons that have survived the degeneration okay if you inhibit monoamine oxidase b then you’re going to get more dopamine actually making it into synaptic vesicles because the less that the dopamine that you’re synthesizing will be destroyed by the moneywe mean oxidase b okay therefore your synaptic vesicles are going to end up stuffed full of dopamine

Okay which means that when these dopaminergic neurons do release dopamine into the dorsal striatum they’re now going to release more dopamine okay so you’re going to increase dopaminergic transmission in the dorsal striatum and that’s going to help produce this pro movement effect okay so that initiating voluntary movements becomes easier okay right so all of

These anti parkinson drugs i will say it again are fantastic at treating the hypokinesia associated with parkinson’s disease okay because that truly does result from the lack of dopamine in the dorsal striatum but they are less good at treating the other symptoms of parkinson’s disease which results from wider neuro degeneration of the brain okay and they also do

Nothing to stop the degeneration that is occurring within the brain okay so that concludes now our discussion of parkinson’s disease and the anti parkinson drugs

Transcribed from video
Parkinson's Disease and Antiparkinson Drugs Part 11 By Elliot Nicholson