Before we get into Parkinson’s Disease, let’s review something. What are the side effects of antipsychotics?
Parkinson’s-Like Syndrome (aka EPS). And if you recall, Parkinson’s-Like Syndrome occurs because of an imbalance: The ACh receptors were being stimulated more than the dopamine receptors in the brain. That’s because the antipsychotics blocked the dopamine receptors creating an imbalance. The CNS likes balance between the two. So we talked about this imbalance and we had the solution of blocking the ACh receptors using anticholinergic drugs.
How come we didn’t talk about putting the dopamine side into balance? We couldn’t stimulate it because it was the excess dopamine/dopamine receptor stimulation that was making the person psychotic in the first place! So we couldn’t work on the dopamine side to treat psychosis.
This time we’re going to talk about the actual Parkinson’s Disease. To treat this disease, we want to work on the dopamine side. The drugs involved are called Dopa (not dopamine), a combination drug called Dopa/Carbidopa and Dopamine Receptor Stimulants (without having to be dopamine).
We will also talk about something that won’t make sense right now, but we could fix the anticholinergic-side by using antihistamines.
Parkinson’s is a progressive motor disorder.
Symptoms include rigidity, tremors at rest and it eventually leads to an advanced “frozen” state where the individual can’t initiate movement.
Historical therapy treated the person only for a few years before they got in the frozen state. Nowadays the therapy has changed so much that the person can go on for decades without hitting the frozen state. We found out that the lower the dose of medication we use, the longer it will take before they get into the frozen state. Historically we were using grams of medication and people were going to the frozen state quickly.
There were secondary symptoms to the disease such as slurred speech, stooped posture, shuffling gait (not picking up their feet), pill rolling motion with their hands and they could be depressed and apathetic.
While Parkinson’s-like syndrome was drug induced, the etiology of the actual Parkinson’s disease is unknown. We have some theories but nothing absolutely proved. We have a theory that a virus could be doing this. Another is that it’s cerebral hypoxia (atherosclerosis in the brain).
Physiologic Cause: Dysfunction of the basal ganglia of the brain that controls the EPS. There’s a reduction of the number of dopamine terminals in substantia nigra and as a result we have an imbalance of Dopamine neurotransmitters and ACh neurotransmitters. There is not enough dopamine to help control the muscle movement (and relatively too much ACh).
The anticholinergics are going to block the muscarinic receptors and cause a regain of control. We will use anticholinergics during adjunct therapy (meaning in addition to another drug) and it’s usually utilized when a person has minimal symptoms. This is also used when someone has EPS due to drug use.
Mechanism of action: blocks the acetylcholine receptors
Side effects: dry mouth, blurred vision, urinary retention, constipation
- Benztropine (Cogentin) – inj., p.o.
- Biperiden (Akineton) – inj., p.o.
- Trihexyphenidyl (Artane) – p.o.
Why do antihistamine’s fall into this therapy? They are often used specifically for allergies to block histamine receptors because we don’t want the histamine (produced by the immune system) to attach to the receptors. There’s a lot of things going on when someone is having an allergic reaction like runny nose, red eyes, welts on the skin, etc. You’ll also find antihistamines in non-allergy medications such as cough and cold syrups because some symptoms of a cold are the same as allergies.
But how do antihistamines do this? When a person is having a viral infection, are they having an allergic reaction that’s causing a histamine release? No. There’s no antigen/antibody reaction going on here, it’s just a viral infection that’s causing the person to be congested and have a runny nose, yet we have antihistamines in these cold and flu products. So it can’t be that they’re there to block the histamine receptors, so when we utilize these products for the cold/flu, it clears out the nose because it dries it out. Why is it doing that? Because antihistamine’s have mild anticholinergic properties.
So we could see how antihistamines could come into play here with Parkinson’s disease, because they will block the muscarinic receptor. Will it be a strong effect or mild effect? Mild!
We mentioned the side effects of anticholinergics above already, so if we use an antihistamine, and it’s milder, then the side effects will be milder too. This will be especially useful for elderly men who have urinary retention or constipation problems and don’t want to exacerbate the situation.
- Diphenhydramine (Benadryl) – p.o., inj. – Our strongest antihistamine. Drowsiness is the main complaint for this, especially in the elderly as they may fall and break something. Tylenol PM has Benadryl in it that causes you to fall asleep.
Dopamine and Dopamine Agonists
Now we turn to the dopamine side. We need to understand a couple concepts here and how the historical therapy started out. DOPA can cross the Blood-Brain-Barrier (BBB). Dopamine cannot cross the BBB. So if you gave someone dopamine, it couldn’t cross the BBB.
Which leads us to another problem: 95% of DOPA is metabolized to dopamine prior to crossing the BBB. So only 5% at best crosses into the brain. So we are talking about very high doses of DOPA which raises side effects and this high dosage accelerates the arrival of the frozen state. To make matters work, Vitamin B6 induces decarboxylase, the enzyme that converts DOPA to Dopamine, making even less DOPA available to cross into the BBB. Patients were given a special vitamin that didn’t include vitamin B6. This was our historical therapy.
Then a major breakthrough happened in the 1980’s: The discovery of cardidopa. It has nothing to do with DOPA or dopamine. It binds to the decarboxylase enzyme so that it doesn’t work and more of the DOPA could enter the brain without being converted to dopamine. This way almost all of the DOPA makes it into the brain. Now we are talking about milligrams instead of grams and the frozen state is delayed for decades.
Cardidopa was the potentiator. It did not get into the brain to treat the parkinson’s disease. What it did was make DOPA a stronger drug, so it was a potentiator.
The effect of having DOPA relieved rigidity, decreased tremors, enhanced mood but could not be used with treating EPS because you couldn’t raise the already-high levels of dopamine in an person with antipsychotics.
- Levodopa (Larodopa, L-Dopa) – p.o.
- Carbidopa/Levodopa (Sinemet) – p.o.
Note: We could take a mentally healthy patient and treat them for Parkinson’s and possibly induce psychosis. It does happen. And if this happens then we have to go a different direction in the therapy.
Side effects of Dopamine Agonists: Orthostatic hypotension (dizzy spell when standing), arrhythmogenic, nausea/vomiting, psychiatric disturbance (psychosis), on/off effect. Limiting the dose decreases the side effects.
Contraindications: We cannot use DOPA when someone has narrow angle glaucoma. The most common glaucoma is the wide angle one so this affects a small percentage of patients with glaucoma. Acute psychosis or history of psychosis. Melanoma (cancer of the skin).
These other drugs below are not dopamine but dopamine stimulants. They have nothing to do with dopamine chemically yet they will stimulate the dopamine receptor and can be used to correct the imbalance.
- Amantadine (Symmetrel) – p.o. – Amantadine stimulates the dopamine receptor but you’re going to find another use of dopamine over the next few months because during Flu season it’s prescribed for helping protect an individual from Influenza Type A. The influenza virus is categorized into Type A and Type B. Amantadine is only useful for the specific Type A. (Here in California a flu epidemic is usually type A).
Does the flu shot work? For most people it works but it is a guessing game. The government has to decide what we are going to vaccinate against this year. There’s 3 strains (one of which is still the swine flu and that’s type A). Typically when we are vaccinating, we are vaccinating against one type B and two type A’s. Back in February 2012 they were predicting what strain of flu will be coming out sometime in October and April. We don’t even know in September what it is. So the manufacturers had to guess. What is the guess based upon? On what was hit last year and on epidemiological studies. It’s still a guessing game. For 6 out of 7 years, the guess is right on. In 2011 the guess was correct but the epidemic hit in April, which was very late. People who got vaccinated in August and September were open to getting the flu. So it’s better to wait until the end of September and October just to be on the safe side.
People allergic to eggs can’t get the flu shot. So when do we use amantadine? When they can’t get the flu shot cause they’re allergic and they are at high risk for the flu. They have to be on it during the entire epidemic, though.
Side effects of Amantadine: Insomnia, depression, orthostatic hypotension. Some people might tell you, I rather have the flu.
Other Dopamine Agonists
- Bromocriptine (Parlodel) – p.o.
- Pramipexole (Mirapex) – p.o. – This drug as of September 2012 just got publicity that it is associated with heart failure. They are still investigating.
- Ropinirole (Requip) -p.o.
Inhibitor of MAO
- Selegiline (Eldepryl) – p.o.