Setting: office
CC: “My walking is getting really slow.”
HPI: A 74-year-old man with progressive inability to walk over the past year comes to your office. He also has a hard time getting up from a seated position and he becomes lightheaded when he tries.
PMHX: ostearthritis
Medications: acetaminophen
PE:
General: immobile, seems very “grim-faced”
Neurological:
Tremor at rest at 3 cycles/second, cogwheeling present
Slow gait; significant retropulsion. He cannot easily turn.
Initial Orders:
MRI of head
CHEM-20
The patient’s diagnosis of Parkinson disease (PD) is obvious on examination. There is no test to specifically diagnose PD. An MRI of the head can be used to see if there are previous strokes that led to the PD. All of your Step 3 examination questions on PD will concern drug therapy, and the basic science fundamental questions will be on the mechanisms of these treatments.
Which should be tested for on examination?
a. Hyperreflexia
b. Orthostatic hypotension
c. Spasticity of muscles
d. Decreased papillary reflexes
Answer b. Orthostatic hypotension
Patients with PD frequently have orthostatic hypotension. This is why they cannot easily get up from a seated position. When rising, the autonomic nervous system is slow to respond. The normal increase in pulse rate and vasoconstriction is not occurring. When a normal person stands, the baroreceptors in the carotid sinus and atria sense the decrease in pressure or stretch. Because these are mechanoreceptors, firing is decreased. The medulla does not perceive the change in posture and there is no output to the sinoatrial (SA) node to increase firing or to the arterioles to contract. Hence, BP is abnormally low when standing and patients can experience syncope. This is like “cogwheel rigidity” of the autonomic nervous system.
Response to Standing
• Normal: vasoconstriction and tachycardia
• PD: inappropriately low pulse rate
In PD, phase 4 depolarization of the SA node stays abnormally flat.
The patient has orthostasis on examination as well as decreased facial movements (hypomimia). The main thing that bothers him is slow gait and general immobility. He is not as bothered by the tremor because it stops when he reaches for something.
Orders:
Anticholinergic agent (benztropine, trihexyphenidyl)
The mechanism by which anticholinergics improve PD is unknown.
Why does decreasing acetylcholine increase dopamine?
We do not know!
Instead of the previously scheduled 2-week follow-up appointment, the patient is brought back in 4 days by his wife. He has abdominal pain, dry mouth, and urine retention.
Which of the following should you also ask about or examine for?
a. Bradycardia
b. Memory difficulty
c. Diarrhea
d. Constricted pupils
Answer b. Memory difficulty
Acetylcholine helps with memory formation. Inhibition of acetylcholine (ACh) will provoke dementia. This is why anticholinergic medication like benztropine is hard to use in those older than 65 to 70 years old. It worsens Alzheimer disease. This is why we use drugs like donepezil, rivastigmine, and galantamine for Alzheimer disease. They increase ACh and improve memory. In addition, inhibiting ACh should cause tachycardia, constipation, and dilate pupils.
More ACh = More Memories
Less ACh = Less Memories
Anticholinergics worsen glaucoma.
Dilated Pupils = Blocked Canal of Schlemm
You stop the benztropine and start amantadine. When you see the patient again in 2 weeks, there is no significant improvement.
What is the next step to try?
a. Catechol-O-methyltransferase (COMT) inhibitor (tolcapone, entacapone)
b. Ropinirole or pramipexole
c. Bromocriptine
d. Selegiline
Answer b. Ropinirole or pramipexole
These medications are direct-acting dopamine receptor agonists. They have less efficacy than levodopa/carbidopa, but they have less adverse effects as well. The standard of care in most PD is to try a dopamine receptor agonist at the beginning of treatment.
Bromocriptine is a dopamine agonist but is a derivative of ergot, and thereby has more adverse effects, such as nausea and vomiting. In choosing treatment, if two medications have the same efficacy, use the one with less adverse effects.
Selegiline is a monamine oxidase (MAO) inhibitor. This class of drugs decreases the metabolism of dopamine, but the efficacy is unclear.
Amantadine efficacy is limited.
Amantadine may increase dopamine release from the substantia nigra.
You start ropinirole and see the patient again in 2 weeks. He has modest improvement in mobility and orthostasis. Over the next year, he is stable then begins to deteriorate again. You now add levodopa/carbidopa, and he markedly improves.
What is the mechanism of carbidopa?
a. Direct dopamine agonist
b. Inhibition of dopamine decarboxylase
c. Decreased urinary excretion of dopamine
d. Synergistic with dopamine at substantia nigra
Answer b. Inhibition of dopamine decarboxylase
Levodopa normally has a very short half-life. It, therefore, will decompose and not allow transfer across the blood brain barrier into the brain. Carbidopa is a peripheral dopamine decarboxylase inhibitor. This allows a greater level to enter the brain.
You see the patient at 2-week intervals and increase the dose of levodopa/carbidopa. Perform a neurological examination and check for orthostasis at each visit. The patient is not fully controlled after 2 months.
What should you do?
a. Nothing more can be done.
b. Add tolcapone or entacapone.
c. Order deep brain stimulation.
Answer b. Add tolcapone or entacapone.
Tolcapone and entacapone are COMT inhibitors. They block the metabolism of dopamine in the brain. They enhance activity of dopamine at the substantia nigra. They have definite efficacy but are exclusively an add-on therapy to levodopa/carbidopa. They will not work by themselves.
After a few days on the new medications, the good news is, the patient has much better mobility. The bad news is, he has started to develop visual hallucinations and sees “bugs coming out of the walls.”
What is the mechanism of the hallucinations?
a. It is the direct toxicity of the COMT inhibitor.
b. The patient has decreased serotonin levels.
c. Dopamine increases psychosis.
d. Decreased ACh increases psychosis.
Answer c. Dopamine increases psychosis.
The difficulty of medicating patients with PD is that the massive increase in dopamine can cause psychosis in some patients. The dose needed to control PD may mean that the only way to get the PD controlled is to give enough dopamine even though it may lead to the adverse effect of psychosis. The treatment is quetiapine, which is an antipsychotic medication with the lowest amount of parkinsonian adverse effects.
Anti-Parkinson disease (PD) medications cause psychosis.
Antipsychosis medications cause PD.
Anti-PD medications cause dementia.
Anti-dementia medications cause PD.