Pharmacology of Parkinson's Disease

in StemSocial9 months ago

This week, I began a post on Parkinson's disease. I started with the Pathophysiology of Parkinson's disease, discussing the lentiform nucleus and Caudate Nucleus, and I explained the effect of GABA and Glutamate in Parkinson's disease. In the next post I created which was my previous post, I discussed the Hypothesis and theories around Parkinson's disease. If you missed both posts, you should check them out. You can read about the Pathophysiology of Parkinson's disease by clicking on Pathophysiology of Parkinson's Disease, and read on the hypothesis and theory surrounding Parkinson disease by clicking on Hypothesis, Theories, and Drugs for Treating Parkinson's Disease. In this post, I will be discussing the Pharmacology of Parkinson's disease. Before I continue, let me say a very big thank you to everyone who has been reading my post. Thanks a lot for reading, so let's continue.

Let me quickly do a little be o pathophysiology of Parkinson's disease. I will be starting with the Basal ganglia where the Caudate nucleus and the Lentiform nucleus are located. The Lentiform nucleus is made up of the Putamen, the Globus Pallidus internus and the Globus Pallidus externus. Close to each lentiform nucleus is the Thalamus on each side. Below the Thalamus is the subthalamic nucleus and in the midbrain, the substantia nigra is found. When a patient has Parkinson's disease, the substantial nigra is destroyed, causing a decrease in the release of dopamine to the Striatum (a combination of the caudate and the Putamen). There are two pathways involved with Parkinson's disease, these are the direct pathway and the Indirect pathway. The direct pathways deal with motor movement initiation, which allows one to modulate and perform actions, while the indirect pathway prevents unwanted motor movement from performing actions. You can read about how the pathway works in my post on the pathophysiology of Parkinson's disease. When it comes to the pathophysiology of Parkinson's, the substantial nigra is destroyed decreasing dopamine in the striatum, also since acetylcholine inhibits the direct pathway and stimulates the indirect pathway, it would lead to an imbalance in both the Dopamine and Acythocoline in the Striatum, leading to decreased movement, and an increase in acetylcholine would lead to tremors and rigidity. You can read more on this in my post. I will be going straight to Pharmacology ,,

The drug classes that can be used to treat Parkinson's disease are of two types, one would increase Dopamine, while the other would reduce acetylcholine. Drugs that increase dopamine include L-DOPA, Dopamine agonists, Catechol-o-methyltransferase inhibitors, monoamine oxidase-B in inhibitors, and Amantadine. Drugs that would reduce the acetylcholine effects for tremors and rigidity would be Anticholinergics.

In other to release dopamine, Tyrosine is taken up from the blood-brain barrier into the substantia nigra which is worked on by Tyrosine hydroxylase to become L-DOPA which will then be worked on by Dopa decarboxylase which will be converted into Dopamine. The dopamine attaches to the vesicles and triggers action potentials which will simulate the Voltage-gated Calcium channels allowing calcium to rush into the neuron stimulating the vesicle to the membrane and causing Dopamine to be released where it will bind to the D1 or D2 receptor. Some dopamine gets reuptake into the Neuron of the substantia nigra through the Dopamine reuptake transporter after which it get's recycled and used again, or it can combine with mono amine oxidase-B which breaks the dopamine into a non-active metabolite. The dopamine can also be broken down by the Catechol O-Methyltransferase and it inhibits it., ,. When the patient is given L-DOPA, it will bypass the tyrosine stage and become dopmine in the neuron, and increasing dopamine in the synapes but one challenge with taking L-DOPA as a medication is only a percentage of it can be taken up across the Blood-brain barrier as Dopa Decarboxylase converts majority of the peripheral L-DOPA into dopamine in the blood-brain barrier making it impossible to be taken up through the blood-brain barriers.,. Also, Catechol O-methyltransferase (COMT) in the peripheral region converts L-DOPA into 3-O-Methyldopa, which cannot be taken up across the blood brain barrier. To allow more L-DOPA go through the blood-brain Barrier, drugs can be given to inhibit the peripheral enzymes converting L-DOPA in the blood-brain barrier.,. It is important to know that L-DOPA is a first-line drug, and due to the difficulty of passing through the blood-brain barrier completely, it is given with Carbidopa which inhibits the Dopa Decarboxylase enzyme in the peripheral of the blood-brain barrier which prevent the conversion of L-DOPA into dopamine, allowing for more L-DOPA to pass through the Blood-Brain Barrier and reducing the amount of dopamine in the periphery. Excessive dopamine in the peripheral system can cause cardiac problems, and emotional imbalance such as anxiety, delirium, hallucinations, delusions, and psychosis. So Carbidopa helps reduce dopamine in the periphery. , .

Another drug that is used for Parkinson's disease is the Dopamine Agonist. The drugs contains ethanolamine moiety and bind directly to the dopaminergic receptors in the CNS acting as dopamine directly. It crosses the blood-brain barrier and gets to the dopaminergic receptors stimulating the activity of the dopamine system..

The COMT inhibitor inhibits the COMT enzyme in the CNS which converts dopamine into inactive metabolite, allowing more dopamine presence within the synapes.,,. Monoamine Oxidase B (MAO-B) inhibitors is another drug that inhibits the Monoamine Oxidase B (MAO-B) enzyme, preventing the reuptake of dopamine, as well as inhibit the braking down of dopamine into an inactive metabolite, thereby allowing dopamine to be present in the synaptic bulb.. Amantadine acts as a weak glutamate antagonist, and it fuses the synaptic with the membrane, increasing the dopamine release, and it will inhibit the intake of dopamine into the dopamine reuptake transporter, thereby allowing more dopamine to be available in the synapse and getting to the dopamine receptors.,,.

When Acytocholine gets released from the cholonergic neurons, they bind on the Muscuranic receptors, and Anticholinergics inhibits such interactions thereby increasing the dopaminergic activity in the striatum, which allows for an increase in movement. Agent such a Bentropines and Trihexyphenyl are Anticholinergics restoring the balance between dopamine and Acytocholine.

Image Reference

Image 1 || Wikimedia Commons || Parkinson disease symtpoms


an excellent explanation you have given here @eni-ola
I think the mechanism of action of drugs is quite clear. Particularly I have never treated a patient with this disease, if I have helped them with other ailments, but not with the disease itself.

This post has given me a better idea of ​​what treatment is, although in reality I prefer to leave it to the specialists.

Parkinson's can be a very disturbing progressive disorder of the nervous system. I really enjoyed this post, and I hope to read more of this type of posts in the future.

Fantastic post I am really impressed to read it. There is no cure for Parkinson's disease, but medications and surgery can help manage the symptoms.

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