Parkinson Disease 2 Flashcards
Dopamine
Agonists
- Directly stimulate dopamine receptor
- Used in early disease to minimize use of LD
- Used in late disease as adjunct to LD
- Older Agents
- Less receptor specificity
- Low cost
- High ADR
- Adjunct
- Newer Agents
- Receptor specific (D2-4)
- High cost
- Lower ADR
- Adjunct or monotherapy]
- Selective agents mainstay of therapy
I would expect you if I give a case study that you would recognize on a practice case or an exam that oh, yes. That’s an a dopamine agonist, but I’m not going to expect you to do a lot of categorization. I don’t expect you to know the doses.
But in general, are older therapies are less receptors specific, and the newer therapies that are coming out are much more receptors specific, so more focused on the dopamine tracks that are related to movement and less that are related to psych complications
Dopamine Agonists Dosing
- Titrate slowly – q1-2 weeks
- Decrease dose of LD up to 25%
- Newer formulations –
- ER for some products in other countries(e.g. pramipexole in US for early PD)
- Patches (some shortages)
Patients find pretty mild response to MEOs and then really quite a dramatic response with dopamine agonists. So always the smallest dose and then slower titration. If the patient is already on levodopa. Recognize someone may have started on levodopa for some reasons, then we would decrease levodopa a little bit when we start this.
even with insurance coverage, patients should be on one of the selective therapies. So you can see there’s quite a few,
Not every single drug is labeled for movement disorders such as cupboard saline is used more for prolactin disorders
There’s a few that had been taken off the market related to some complications
Rotigatine - patch shortage with mfr
dopamine agonists Adverse Effects
GI:
*N/V (25-30%)
Cardiac:
*orthostasis (approx 50% - advanced disease)
Psychiatric:
*Double that of LD (4-5% vs 8-9%)
*Hallucinations (10-20%)
Neuro:
*syncope (12%) – associated with increase in dosage
*excessive daytime sleepiness
*insomnia
*dyskinesias
*addiction disorders
So pretty much every dopaminergic therapy has the same side effects. It’s more just some have more, more of the side effects versus less of the side effects.
These are drugs that are taken, their systemic distribution. And so we also see other side effects like nausea and vomiting are most common. In fact, it’s so common this might be a reason why patients stop there dopamine agonist,
cardiac complications, so lowers blood pressure can cause ortho stasis.
complications are generally. About double what we see with levodopa. So even though we use these drugs generally earlier than when we would start levodopa. Levodopa is actually better tolerated.
Debates with DA Agonists
Not neuroprotective
* Duration of benefit
* Usually clinically significant for 1 year
* Cost vs LD
* More expensive than LD
* Response to different agents
* Variety of products, formulations
* Mood effects
* Increased dopamine can elevate mood
Levodopa
- Gold Standard
- L-form used
- Dosing
- Start 100/25 TID
- Max 1500 mg LD/day
- Usually dose ceiling 800 mg LD/day
- Minimum dose of carbidopa = 75 mg/day
- Sin emet
- Titration every few weeks
KNOW DOSING
. We could try another dopamine agonist. Sometimes it takes a few months to get the dose correctly titrated with the other product. That’s one option. We can also, after about a year, we’re not going to have as good a response. This is when patients often start levodopa. It’s considered the gold standard
Sinemet means? You’ve covered that already. It means no vomit, right?
we need a minimum of a peripheral dopa decarboxylase inhibitor to get into the patient’s brain. If we have less than that, the patient does not get enough medication centrally. So I do want you to know there’s a minimum for the peripheral dopa decarboxylase inhibitor.
this is one example where we are looking at two compartments and we can’t really measure what’s happening. We do take our time with titration, so that’s why you see a fairly slow titration if the patient is going to have any change in dose.
Product
Selection
Sinemet: (LD/carbidopa)
* IR: 50/12.5, 100/25, 200/50
Prolopa: (LD/benserazide)
* LD/carbidopa/entacapone
* 50/12.5/200
* 75/18.75/200
* 100/25/200
* 125/31.25/200
* 150/37.5/200
Stalevo (all IR products):
* 1 mL = 20 mg LD/5 mg carbidopa
Duodopa: LD/carbidopa intestinal gel (by NG or PEG)
Sinemet Formulations
Property Immediate Release (IR) Controlled Release (CR)
Onset 30 min. 2 h
Duration 2 h 4-6 h
Bioavailability 95% 70%
Dosing interval 3 times/day (early ds)
>4 times/day (late ds)
3-4 times/day
Cost/month $$ $$$
Pro
Rapid, immediate effect
Can be crushed, chewed
Lower cost
Control late stage complications
Lower peaks
Can be split (scored)
Con
Multiple doses/day
Dependence on “burst”
Peak related dyskinesias
More fluctuations in symptoms
Expensive
Higher dose required
Not chewed or crushed
Does not provide “burst”
. The immediate release product is onset within, within 30 min. And so patients might use this product, you’ll see a combination. It’s a bit like insulin, where people are using long and short acting to control things through the day. Patients might use combinations of immediate and controlled release. They might take immediate release first thing in the morning to get started. And then controlled release is there in a way basal amount to sustain them through the day? Some patients might take just immediate release, they get a better response.
important note for pharmacists is that these are not interchangeable. So 100/25 of the CR is not equivalent to the 100/25 of IR because the CR does not have the same availability only about 70% of the drug from CR.
- Which dose of LD do you recommend to start?
a) Sinemet 100/10 daily
b) Sinemet 100/25 daily
c) Sinemet 100/25 TID
d) Sinemet CR 100/25 TID
e) Stalevo 50/12.5/200
Question - When starting LD how should the DA be managed?
a) Abrupt discontinuation
b) Gradual taper
c) Keep the same dose
d) Reduce the dose
e) Switch to cabergoline (long t1/2) then tap
t 100/10, I’m the patient doesn’t have enough carbidopa and so they have a lot of complications like nausea. They tend to be vomiting. And so it might seem counter-intuitive, but they have less side effects by giving them this higher dose, this higher strength.
Anytime we add something on, you can see the principle is reduce the doses of the other meds you have. It tends to create an overshoot effect and the patient has dopaminergic toxicity for days. I’m to the point that they’re psychotic. They have to be hospitalized because they are delirious. They have extreme nausea and hyperemesis. So we don’t want to overshoot, we’d rather undershoot a little bit.
The general principle is most patients have reliable response to the immediate release products later in the disease. Sometimes we get patients on to see our products because they need so many doses throughout the day. But generally the principle is most patients respond best to IR, so that’s probably a good starting point.
d) Sinemet CR 100/25 TID
d) Reduce the dose
Dopamine Metabolism
Levodopa Therapy in Early PD
Levodopa Therapy in Advanced PD
just to highlight that we end up with sometimes free radical production because of the way levodopa is metabolized. So this is partly why this is a medication that is used later in the disease. Even though it’s really effective, tolerated pretty well. We have so many different strengths and formulations available. Because of this toxicity patients, once they start levodopa, they are more likely to develop other motor complications.
Levodopa Therapy in Early PD
Target Response
◼ Smooth, extended duration of target clinical response
◼ Low incidence of dyskinesias
Levodopa Therapy in Advanced PD
◼ Short duration of target clinical response
◼ “On” time is associated with dyskinesias
honeymoon phase before those complications occur. So we give a dose. This would be a typical profile for controlled release products. So it works after about 2 h, they get the dose, they have a nice response. There’s no toxicity associated with it.
As the disease progresses, we have more neuron loss. Things are becoming more sensitized and we’re having more damage as we’re exposing the patient to more levodopa. So we give a dose. I realize the yellow is not showing up fantastically here on a white background, but I hope you can see on your slide in order to get a response now we have a narrow therapeutic window.
we end up having such a close window that almost to get a response where at the same level where we’re causing dyskinesia, so we’re causing toxicity. So this is the reason why we tend to hold back on giving Levodopa. delay as much as possible
COMT Inhibitors
- COMT present in:
- bowel (conversion before absorption)
- liver (first pass)
- brain
- erythrocytes
- Tolcapone - emergency release
- Entacapone
- peripheral enzyme inhibitor
- dosed with each LD dose (max 8/day)
- Average reduction in LD = 25%
Entacapone is our drug of choice. Tolcapone can be used. It’s only available emergency release through Health Canada,
- Suggest early use with LD to decrease oxidative stress
by lowering LD dose - Side effects – excessive LD
- Drug interactions
- Antidepressants
- medication metabolized by COMT
- Dobutamine, epinephrine, methyldopa, isoprotereno
guidelines don’t say that we should be using this upfront, the combination. But there are some neurologists that like to use it right from the very start.
It really seems to increase their dopamine levels upfront. So that’s why there’s some hesitation, but it’s not, it’s not necessarily a wrong choice, but just prepare the patient. There might be more side effects.
it is nice to use more in the mid and later stages of disease because it allows us a little bit more time between the dosing intervals
On its own. It has no effect, but it could cause interactions even taken on its own. So keep in mind COMT it metabolizes more than just dopamine
Catechol-O-methyl transferase (COMT) is a body enzyme. When a person takes levodopa, COMT can deactivate levodopa before it enters the brain and central nervous system; COMT inhibitors prevent this from happening.
COMT inhibitors are most effective when used in combination with levodopa to extend “on” time.
COMT-I
Adverse
effects
Neuro:
* confusion (10.5%), hallucinations (8%)
GI
* nausea (28%), diarrhea (13%), hepatotoxicity (tolcapone)
Cardiac
* orthostasis (13%)
Intx:
* catecholamine reuptake inhibitors (antidepressants)
* methyldopa
* isoproterenol
* dobutamine
* epinephrine (increase risk of arrhythmias)
We can advise the patient to address which of the following dietary
interactions?
a) Avoid protein
b) Reduce protein
c) Shift protein to a different time of day
d) Do not take LD with protein
e) None of the abov
patients should speak with a dietitian.
none of the above would be a secondary response, but the correct answer would be just don’t take this at the exact same time. So still try to have protein in your diet and then just shifting the dosing of levodopa around that.
Interactions w/ levodopa
- Drug – Food
- Protein in diet
- Drug – Drug
- Additive AE (e.g. nausea)
- Dopamine blocking agents
- Anticholinergics (e.g. gastric emptying)
- Iron
- NOT B vitamins
- Drug - Disease
if patients are consuming a lot of protein, will try to adjust the levodopa around that versus having them eliminate protein because then they become very hectic and deconditioned
this is partly why dietitian should be involved. Patients tend to restrict their diet so they have more effect from their levodop
Adverse Effects
GI
* N/V * monitor carbidopa, entacapone dose * use peripheral motility agent * Domperidone 10 mg po ac
Neurologic
* Dyskinesia, hallucinations, confusion
Cardiac
* hypotension
Debate with Levodopa
– delayed start
- LD showed no disease modifying
effect - There is no reason to delay
treatment
higher scores
indicating more
severe disease
higher scores
indicating a
lower
diseaserelated
quality of life
So we could maybe start it in some patients early and give them the best quality of life and movement early on. And then try to manage the complications. And others generally believed like let’s restrict this until we really need it.
particular study published in New England Journal, that patients do tend to do a little bit better. And then over time in this particular sample, the quality of life was okay. So
perhaps in some patients it would be okay to start a little bit earlier.
contrasting research from just a few years ago that generally patients stopped treatment more with things like MAO inhibitors. So that’s the red line at the bottom. That’s the green line at the top. Patients don’t tolerate those as well. Then dopamine agonists are somewhere in the middle. So after seven years, half of patients have stopped those, and then only 7%
