Anti-parkinson medications

Definitions & Key takeaways

Parkinson's disease is a neurodegenerative disorder in which there is progressive depletion of dopaminergic neurons in the basal ganglia, especially in the substantia nigra. Anti-Parkinson medications are drugs used in the management of this disorder.

There are a few different classes of medications used to manage Parkinson's Disease. These include dopamine precursors such as levodopa (L-Dopa); dopaminergic drugs such as bromocriptine that increases the amount of dopamine in the brain; monoamine oxidase (MAO)-B inhibitors like rasagiline that blocks an enzyme that breaks down dopamine; and catechol-O-methyltransferase (COMT) inhibitors such as tolcapone which work by stopping an enzyme from breaking down levodopa.

Chapters:

Watch video only

Introduction0:00–0:23

Anti-parkinson medications are used to treat Parkinson’s disease, which is a movement disorder where the dopamine-producing neurons in the substantia nigra of the brain undergo degeneration.
It’s a progressive, adult-onset disease, and is more common with age, affecting about 1% of people over 60. The substantia nigra is a part of the basal ganglia, a collection of nuclei in the brain that control movement through their connections with the motor cortex.

Pathophysiology0:23–1:49

The substantia nigra actually can be split into two sub-regions. First, there’s the pars reticulata, which receives signals from another part of the basal ganglia called the striatum, and relays messages to the thalamus via neurons rich in the neurotransmitter GABA, also known as gamma-aminobutyric acid.
Second, there’s the pars compacta, and this is the part of the substantia nigra affected in Parkinson’s. The pars compacta sends messages to the striatum via neurons rich in the neurotransmitter dopamine, forming the nigrostriatal pathway, which helps to stimulate the cerebral cortex and initiate movement.
In Parkinson’s disease, the neurons in the substantia die, so the individual may experience hypokinesia, which is difficulty initiating movements, and bradykinesia, or slowed movements.
The substantia nigra also helps to calibrate and fine tune a person’s movements, which leads to the other clinical features of Parkinson’s, like “pill-rolling” tremor, which is the repetitive, involuntary rubbing of the thumb and index finger, as well as rigidity, stooped posture, and an expressionless, mask-like face.
As the neurodegeneration progresses, non-motor dysfunction can appear, including depression, dementia, sleep disturbances, and difficulty smelling.
Now, in order to treat Parkinson’s disease we can use medications that directly or indirectly increase the stimulation of the dopamine receptors in the brain.

Mechanism of Action1:49–2:29

Now within the brain, dopamine is found mainly in one of the four 4 dopamine pathways: the nigrostriatal pathway is responsible for movement coordination and is the intended target for anti-parkinson medications; the mesolimbic and mesocortical pathways control motivation, emotion, and desire; and lastly the tuberoinfundibular pathway inhibits the secretion of prolactin.
So besides alleviating the symptoms of Parkinson’s disease, these medications can sometimes affect these other regions, leading to a number of side effects.Okay, so the simplest treatment would be to just give more dopamine!

Levodopa2:29–4:38

But unfortunately, dopamine can’t cross the blood-brain barrier. So levodopa, or L-DOPA, is given instead, which is a precursor of dopamine that can cross the blood-brain barrier.
Once it crosses into the brain, levodopa is converted to dopamine by the enzyme DOPA decarboxylase. This extra boost of dopamine stimulates the remaining nigrostriatal neurons and relieves the symptoms of Parkinson’s disease, and it’s often used as a first line medication.
However, the dopamine is eventually broken down by different enzymes in the brain, which can lead to a “wearing off” phenomenon, where the patient’s symptoms of rigidity and hypokinesia improve when they take the medication, but the effects rapidly end after one or two hours.
People can also experience the “on/off” phenomenon, where one second the medication is working, and then it’s like a switch is flipped, and the symptoms return or get even worse.Another problem is with chronic use, levodopa can cause dyskinesias, which are uncontrolled, involuntary movements.
These motor complications apparently occur because, as the disease progresses, the nigrostriatal neurons lose their capacity to store and recycle dopamine.
So higher doses of levodopa are needed, which could lead to over-excitation. Besides motor complications, levodopa can also cause hallucinations and confusion; so it’s contraindicated in patients with psychosis.
Okay, so another thing to keep in mind is that DOPA decarboxylase exists outside the CNS as well, which can increase dopamine levels in the rest of the body.
This can cause unwanted side effects like nausea, vomiting, anorexia, and orthostatic hypotension. These problems can be lessened by taking lower doses more frequently throughout the day.
A more problematic side effect is that dopamine is enzymatically metabolized into other catecholamines, like epinephrine, which can cause tachycardia or even arrhythmias.
This is why levodopa is administered with carbidopa, a DOPA decarboxylase inhibitor that doesn’t cross the blood-brain barrier, so it prevents the conversion of Levodopa into dopamine outside the CNS.

Dopamine-receptor agonists4:38–5:24

Now, a different strategy is to use dopamine-receptor agonists, which are molecules that are not dopamine, but can bind to the dopamine receptors and stimulate them.
These include bromocriptine, pramipexole, and ropinirole. These medications have a short half-life and are used alone or together with levodopa when the patient no longer responds to levodopa alone, or when it starts causing motor complications.
Bromocriptine causes a number of side effects, like nausea, vomiting, somnolence, and pulmonary fibrosis. So pramipexole and ropinirole are prefered over bromocriptine because they cause fewer side effects, but they can still cause somnolence, which in rare cases can be so unpredictable that they lead to car crashes.

COMT Inhibitors5:24–6:39

Pramipexole and ropinirole can also cause hallucinations and confusion. Now, another way to increase the stimulation of dopamine receptors is by preventing the dopamine from being broken down.
The first group of medications that do this inhibit an enzyme within the dopaminergic neurons called catechol-o-methyltransferase, or COMT, which degrades dopamine to 3-methoxytyramine and levodopa to 3-O-methyldopa.
COMT inhibitors like entacapone, and tolcapone prevent the peripheral enzyme from degrading levodopa, and therefore allows more levodopa to get into the brain.
But only tolcapone can cross the blood brain barrier to enter the central nervous system, where it can prevent COMT from degrading dopamine.
COMT inhibitors are used together with levodopa when patients develop motor complications, in order to keep a stable concentration of levodopa in the blood for a longer period.
So, they improve response to levodopa and reduce the “wearing off” phenomenon. Both entacapone, and tolcapone have the same side effects as levodopa - like nausea, orthostatic hypotension, confusion and hallucinations.
In addition, tolcapone can cause liver injury. So it’s the last option for treatment, when no other medication works.

MAO-B Inhibitors6:39–7:54

When it is chosen, hepatic enzymes should be measured regularly to monitor liver function.The next group of medications are the MAO-B inhibitors, which block the enzyme monoamine oxidase B, or MAO-B.
This enzyme breaks down dopamine to 3, 4-dihydroxyphenylacetic acid, or DOPAC, in the central nervous system, but it can also break down other neurotransmitters like serotonin and norepinephrine.
Because of this, they can also be used as antidepressants. The main medications in this group include safinamide, selegiline, rasagiline.
Now, MAO-B inhibitors can be used alone as an initial treatment to reduce symptoms in early-stage or mild Parkinson's disease.
Rasagiline can also be given together with levodopa, to reduce motor complications; whilst selegiline does the opposite, it may increase motor complications of levodopa.
Selegiline is degraded to amphetamine, which can cause a number of unwanted side effects - like excitement, anxiety, and insomnia.
Rasagiline isn’t degraded to amphetamine; therefore, it doesn’t have this problem. In addition, rasagiline may have a neuroprotective effect and slow the progression of Parkinson’s disease.
A very important issue with MAO-B inhibitors are drug interactions. Side effects include CNS depression, dyskinesias, and hypertension.

Amantadine7:54–8:20

Interactions with SSRIs or SNRIs are pretty rare, so the use of these two classes of medications can be used together with caution.The last medication is amantadine, which is also an antiviral medication that’s thought to increase dopamine release and decrease its reuptake, but the mechanism is still not completely understood.
It isn’t very potent, and it’s used as initial treatment of mild Parkinson’s disease, or together with levodopa to reduce motor complications.

Deep-brain stimulation8:20–8:33

Side effects like lethargy, GI distress, and strange dreams are uncommon and usually mild when they’re present. Finally, a special treatment available to help treat Parkinson’s disease is deep-brain stimulation, which involves an implantable device that directly sends electrical signals to the basal ganglia to counteract the aberrant signaling in Parkinson’s.Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts!

Memory Palace8:33–11:19

Let’s use a large parking lot as the scene, since we’re talking about anti-parkinson medications. Now, the best spots are under a large doberman statue, and this is where we’ll put the medications that directly act on the dopamine receptors.
There are 2 spots here. One of them has a large pile of leaves with a playful doberman on top to represent levodopa.
The doberman helps you remember that this medication is converted directly into dopamine. This happy dog is wiggling and squirming with uncontrollable excitement to help you remember the side effects like dyskinesia.
There’s also a switch on it, to help you remember the “on/off” phenomenon. Okay, the dog’s owner who just started jogging couldn’t keep up with his energetic pet; his heart rate is going crazy to represent tachycardia; he’s feeling dizzy, representing orthostatic hypotension; and he also just threw up.
He’s thinking about getting a car so he can keep up with his dog.This will help you remember levodopa is taken with carbidopa, which can prevent the side effects the poor owner is experiencing.
In the next parking spot we have the dopamine agonists. So, let’s use an old crippled man who is sweeping the leaves with a broom for bromocriptine.
He’s babysitting his granddaughter who’s in a stroller, or pram, for pramipexole. To make sure the pram doesn’t roll away, he tied it to himself with a rope, representing ropinirole.
Now for side effects, all these medications can cause drowsiness so let’s have everyone dozing off. A spider built a web on the old man’s chest since bromocriptine causes pulmonary fibrosis.
The baby is dreaming about a diamond pacifier to represent CNS side effects like hallucination. Okay, let move on to the next group of drugs, which decrease the breakdown of dopamine.So let’s put these medications by the toll booth at the entrance of the parking lot.
In the toll booth, we have someone who looks like Al Capone for tolcapone. The fact that he’s inside will help you remember it could cross into the brain!
Another Al Capone look-alike is trying to enter the parking lot and he represents entacapone. He doesn’t have a car so they won’t let him pass, so entacapone can’t cross the blood brain barrier.
A comet is about to hit the toll booth to help you remember both are COMT inhibitors. For the MAO-B inhibitors, let’s have someone who looks a little like chairman Mao in a ghillie suit for selegiline and rasagiline, and he’s working as the security for this place.
The final medication is amantadine which is represented by a lethargic manate who came to the parking lot to look for dinner.
Human food doesn’t sit well with it, so it has GI distress. People who saw this strange sight had to question whether they were dreaming, so that should help you remember amantadine can cause strange dreams.

Review11:19–11:54

All right, as a quick recap—Parkinson’s disease is a progressive movement disorder caused by degeneration of dopaminergic neurons in the substantia nigra.
The treatment primarily focuses on increasing dopamine in the brain. This can be done using different medications, which include: a precursor of dopamine like levodopa, which then metabolizes into dopamine in the brain; a dopamine receptor agonist that stimulates dopamine receptors; medications that inhibit dopamine degradation by inhibiting the COMT and MAO enzymes; and other agents like amantadine.

Mind Map11:54–12:05

But wait, there's more: Here's a mind map with all of the mnemonics from the video.