The pharmacology of drugs for Parkinson’s disease

Parkinson’s disease is a neurological disorder that results in a progressive loss of coordination and movement. Now, the neurons responsible for coordinating movement are located in a part of the brain called the striatum, which receives information from two major sources — the neocortex and a region known as the substantia nigra.

The cortex relays sensory information as well as plans for future action, while the substantia nigra sends dopamine that helps to coordinate all of the inputs. Now, Parkinson’s disease develops when the neurons connecting the substantia nigra to the striatum progressively degenerate.

Since dopaminergic neurons that originate in the substantia nigra normally exert inhibitory effects on GABA neurons located in the striatum, too little dopamine results in more GABA causing increased inhibition of the thalamus, as well as reduced excitatory input to the motor cortex. In addition to that, these same dopaminergic neurons also exert inhibitory effects on the excitatory cholinergic neurons in the striatum. And again, without sufficient levels of dopamine the production of acetylcholine is increased, which triggers a chain of abnormal signaling leading to impaired mobility. Ultimately this imbalance between inhibitory and excitatory activities leads to the manifestation of typical clinical symptoms that include resting tremor, rigidity, postural instability, and slowed movement.

The pharmacological therapy for Parkinson’s disease

This is aimed at replenishing dopamine levels, mimicking dopamine’s action, or antagonizing the excitatory effects of cholinergic neurons. Now, in order to get a better understanding of the pharmacology of antiparkinson agents, first we need to take a closer look at the dopamine producing neuron. So, here, inside this dopaminergic neuron, dopamine is synthesized in a two-step process starting with the amino acid tyrosine. First, with the help of enzyme tyrosine hydroxylase (TH), tyrosine gets converted to L-dopa, also known as levodopa. In the second step, the L-dopa formed by tyrosine hydroxylation is quickly decarboxylated by another enzyme called aromatic L-amino acid decarboxylase (AADC), to the neurotransmitter dopamine. Dopamine is then loaded into synaptic vesicles and released by physiological stimuli into the extracellular space where it can bind to dopamine receptors that are expressed on the postsynaptic neuron.

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Finally, excess dopamine in the synapse is reuptaken back into the neuron, or into glial cells where it gets metabolized by Monoamine Oxidase (abbreviated MAO) and Catechol-O-methyltransferase (abbreviated COMT). It’s important to note that while the MAO enzyme exists in two forms, known as type A and type B, the type that is predominantly found in the glial cells is the MAO type B. Now, let’s move on to discussing drugs used in treatment of Parkinson’s disease starting with one of the most commonly used drugs that is Levodopa. But first things first, you may wonder, well why would you use the precursor of Dopamine instead of Dopamine itself. And the answer is, it’s because of the blood-brain barrier. Blood-brain barrier is a tightly packed layer of endothelial cells that restricts free access of molecules between the blood and the brain. Dopamine happens to be one of those molecules that cannot freely pass through this barrier, however, Levodopa can, with a little bit of help.

One of the biggest problems Levodopa faces on it’s own is peripheral metabolism. There are two major enzymes in periphery, which cause breakdown of levodopa before it can reach the brain, that is; peripheral dopa- decarboxylase (DDC), which converts levodopa to dopamine, and catechol- O- methyltransferase (COMT), which converts levodopa to 3-O-methyldopa (3-OMD). Because of this, Levodopa must be administered with another agent called Carbidopa, which inhibits dopamine decarboxylase and thus reduces metabolism of Levodopa in the periphery. Another agent that is used in combination with Levodopa and Carbidopa is Entacapone, which inhibits peripheral COMT and thus just like Carbidopa, it prolongs the time that Levodopa is available to the brain. Now, Levodopa is carried across blood-brain barrier by amino acid transporter. Once inside the brain, Levodopa is efficiently converted to dopamine thus supplementing depleted dopamine levels in the midbrain.

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However, lets not forget that dopamine is also susceptible to breakdown by COMT as well as MAO-B, which convert dopamine to 3-methoxytyramine (3-MT) and 3,4dihydroxyphenylacetic acid (DOPAC) respectively. So, here another useful drugs come into play, namely Selegiline and Rasagiline, which selectively inhibit MAO-B, and Tolcapone, which inhibits COMT. As a side note here, in comparison to Entacapone, Tolcapone can better penetrate the blood–brain barrier, and thus can act both in the central nervous system and in the periphery. So, again, as you can see, by decreasing the metabolism of dopamine, these drugs help to increase dopamine levels in the brain.

Unfortunately, because Parkinson’s is a progressive disease, with time, the number of dopamine producing neurons decreases, and fewer cells are capable of making dopamine. Taking that into consideration, some drugs have been developed to mimic dopamine and directly stimulate dopamine receptors in the brain. Drugs that belong to this class include; Bromocriptine, Ropinirole, Pramipexole, Rotigotine, and Apomorphine. Now, as I mentioned at the beginning of this lecture, in Parkinson’s disease, dopamine depletion leads to increased acetylcholine release, which then activates muscarinic receptors located on the neurons responsible for smooth motor control.

The overstimulation of these neurons by acetylcholine then causes tremors and rigidity. This is where Antimuscarinic agents come into play by blocking the muscarinic acetylcholine receptors and cholinergic nerve activity. As a result, these anticholinergic agents restore the balance between acetylcholine and dopamine, which may improve the symptoms of Parkinson’s disease. Drugs that belong to this class include; Benztropine, Biperiden, Procyclidine, and Trihexyphenidyl.

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Now, before we move on, I wanted to briefly mention here one more drug used in the treatment of Parkinson’s disease, that is Amantadine. Amantadine doesn’t exactly fit into any of the classes that we discussed so far. Its mechanism of action is poorly understood, however, some of the speculated ones are that it prevents dopamine reuptake, facilitates presynaptic dopamine release, and blocks glutamate NMDA receptors.

Now, when it comes to side effects, Levodopa in combination with Carbidopa may cause nausea, loss of appetite, hypotension, mental disturbances, and discoloration of urine, sweat or saliva. Selegiline and Rasagiline may cause nausea, insomnia, dyskinesia, and visual hallucinations. Entacapone and Tolcapone may cause discoloration of urine, sweat or saliva, and diarrhea, which can get severe particularly with the use of Tolcapone.

In addition to that Tolcapone has been associated with liver toxicity. All dopamine agonists may cause nausea, orthostatic hypotension, mental disturbances, and daytime sleepiness. In addition to that, Bromocriptine has been associated with pulmonary and cardiac fibrosis. Lastly, drugs that block muscarinic receptors generally produce anticholinergic side effects such as constipation, urinary retention, dry mouth, and blurred vision. And with that, I wanted to thank you for watching, I hope you found this post useful, and as always, stay tuned for more.

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