A model to describe the effect of Levodopa on a person with Parkinson's Disease

2. Assumptions.

2.1 The whole process - of taking a tablet of levodopa - waiting for it to take effect, possibly having to endure the effects of having taken too large or too small a dose - returning to the Off condition as the Dopamine, (produced from the levodopa tablet) loses its effectiveness and is carted away by the ever-present debris collection system - represents a striving to achieve a constant rate of input of Dopamine into the brain, to make up for the missing quantity of Dopamine-producing cells in the Substantial nigra. This concept of a flowing system, and changes in rates of flow is at the heart of my model, and I am convinced that in this aspect it mirrors the operation of the real brain.

2.2 It is generally accepted that the first symptoms of PD only manifest themselves when between 80% to 90%. of the Dopamine-producing cells have died for some unknown reason. This "first symptoms" point is important, because it forms a reference-point for the diagram of the model.

2.3 The healthy dopamine-producing cells also feature Dopamine Receptors. These receptors give the cell the ability to regulate the output of Dopamine in response to the local environment, and possibly on a much more widespread basis. this clearly represents a powerful 'feedback control system'. The efficacy of this control can be demonstrated by feeding a large dose of Levodopa (250 mg for instance by the usual oral method) to a person who does not have PD: The result is : Nothing! The brain simply shuts down the appropriate number of cells to cancel out the amount of Dopamine produced by the tablet, which is thus absorbed with no effect.

2.4 The control elements described above represent a system dedicated to controlling the level of Dopamine, and in particular to controlling so that it never exceeds a pre-determined level. So effective is this control, that I believe that the brain has no system for coping with a situation where the Dopamine level exceeds this hypothetical nominal flow rate. Indeed, it is only a PWP who is mis-guided into taking a large tablet of levodopa who will find themselves in a situation where the actual flow rate exceeds the 'control' level. The results are unpleasant and best avoided. Similarly, only a PWP will experience the symptoms of insufficient Dopamine, and the tremor, stiffness etc which can result.

3.0 Progress of PD & Sensitivity to Levadopa

(Click the graphic for a larger version of chart A)

The following section shows how the diagram labelled 'New Chart A' was built-up.

3.1 The X-axis represents the years following the discovery of PD, so the zero point is where the first symptoms become noticeable. Not only that, but if we sketch a line representing the Dopamine production capacity of the PWP, (The Red dotted line), the point at which it crosses the 'zero years from onset' line defines for us the required flow which must be maintained at all times. This is shown as the thin green horizontal line. At this point, I slip in a new Y-Axis definition: That of flow rate of levodopa in some arbitrary units

3.2 Consider the case where a PWP has had PD for 10 years. Referring to the red dashed line, we see that the fading Dopamine system in the brain can only supply about 7 units of flow (See the line marked 'X' )

Suppose now we introduce a tablet of levodopa (Or what's left of it by the time it gets to the brain.) As the flow rate builds up, the line 'Y' extends until it reaches the Target line (Horizontal, thin green). If the tablet continues to express levodopa, the brain's control system cuts in (All 7% of it)) and progressively shuts down sufficient Dopamine producing cells to maintain the flow rate at the desired level

3.3 Just as thered dotted line represents the maximum output of naturally -produced Dopamine, so its inverse, (shown as the thick green curve) defines the minimum quantity of Dopamine which must be supplied by tablet to boost the fading output of the brain back up to the minimum 20% line.

3.4 One more line is needed to complete the picture - the yellow line represents the maximum allowable rate of flow which may be caused by taking excess tablets : That is, the maximum input of tablet Dopamine which can successfully be controlled by the remaining naturally-produced Dopamine.

3.5 To Summarise, the Green and yellow curves, derived quite simply from the red dotted curve, show a quite rapid decline in Dopamine output by about 5 to 8 years after first symptoms. (Note that this line is quite consistent with a continuous loss since birth.

4.0 Observations and Conclusions

4.1 It is a sad fact that the system is capable of absorbing enormous quantities of levodopa in the early years, when the PWP has no need of such large doses. I often encounter newly-diagnosed PWPs who are taking tablets such as Sinemet 250 (200 mg levodopa): The most common reason given is that it takes a long time ( maybe 6 or even 8 hours before a new tablet is required. While this may be true, I am convinced that it is not a good strategy: The brain is forced to take extreme measures to cope with the onslaught of 200 mg of levodopa, when probably 20mg would have been adequate (but would need frequent doses.)

4.2 In the early years of my experience with levodopa I was prescribed large doses as mentioned above, but for the last 10 years or thereabouts I have made it my objective to take the minimum quantity of levodopa, consistent with adequate mobility. In fact, I find that the minimum flow rate, in my experience, is the one most likely to achieve that elusive concept of "How I used to feel before PD". To enable me to analyse the large number of factors involved with trying to understand what was going on, I wrote a computer program, and with the aid of that program, I defined a required steady-flow rate of 37.5 mg/hr of levodopa. Bycomparing this rate against my computer analysis, I concluded that I could achieve that by taking 1.5 tablets of Madopar Dispersible (50mg levodopa per tablet) every 2 hours. My analysis at that time showed the Madopar tablet to have a roughly flat-topped delivery characteristic and its duration was about 2 hours. Hence 72 mg of levodopa delivered in 2 hours =36mg/hr. The flat-topped characteristic of most of the tablets which I analysed struck me at the time as remarkably fortuitous, and I am now sure that in fact it is just another illustration of the Dopamine control system at work. See paragraph 4.4 .

4.3 "Unpredictable Fluctuations" ;a phrase beloved of Pharmaceutical Copywriters, particularly when hyping the latest and greatest Dopamine Agonist. Their story seems to go along the lines that 'Levodopa is OK for the first 7 or 8 years, but then it gets uunpredictable, and the patient starts to get severe Offs and Ons. Many doctors interpret this as some unknown mechanism which is going to happen eventually according to some unpredictable timetable. So: if we delay the introduction of levodopa for as long as possible, it may be more effective in later years. I can only find one suitable reply : Rubbish!

It may be that the worry is connected with experiments 'in vitro' which claim to show that free radicals can be generated in a levodopa/Dopamine cell mixture, but as far as I know this has never been found in the living body.

I am a great believer in the theory that if a simple, logical explanation can be found, it is more likely to be correct than the elaborate ungainly alternative. My explanation is as follows:

The only thing which degenerates is the number of properly-functioning Dopamine-producing cells in the brain. That never stops, and I suspect that the exponential shape of the curve which I have used in my diagrams fits quite nicely with this theory. As the available cells decrease, a greater proportion of the flow must be made up by the tablet-produced Dopamine. This can clearly be seen in 'New Chart A' where the green and yellow lines almost converge on zero. This leads us to the final factor; the touching belief that PWPs come calibrated in in whole numbers of tablets, and if you shuffle them around enough things will turn out alright. To illustrate the enormous gaps in this logic, I have only to quote my own case: I have found by experiment that the tolerance band on my levodopa intake are plus or minus 1/4 of a Madopar Dispersible (62.5) or to put it into numbers, I take 75 mg of levodopa plus or minus 12mg, every 2 hours. If I stray outside these limits I get uncontrollable shaking on the low side, and bad Diskinesias on the high side. Try matching that without breaking a tablet It is easy to see how someone trying to hit the required band with whole tablets might describe the results as unpredictable!

4.4 I mentioned earlier that my analysis showed a flat-topped response curve for several of the commonly-used tablets, and that this seemed too good to be true. This latest model supports my suspicions and provides a more acceptable explanation. [ Note that the measure which I use to measure my response to the tablets is an arbitrary scale calibrated from -2 (No levodopa) through 0 (Ideal 'Just like it used to be before PD') to +2 (Overdosed with Diskinesias) ]. Values like +1.3 can be identified repeatably with practice.

(Click the graphic for a larger version of chart B)

4.5 Diphasic Diskinesias.

I have not heard of a convincing explanation of this phenomenon, ( the second part of which I occasionally encounter) so I looked at my model for an explanaton. It is by such means that I believe such a model can be validated.

Peak Dose diskinesia appears to be the result of a race to be first between the digestive system/ transport mechanism, and the Dopamine-producing cells, when faced with a large tablet of Dopamine. Some people insist on taking more than the minimum dose first thing in the morning to 'kick-start' the system. The result is that the brain goes shooting through the thick green line (Chart A) at high speed. The Dopamine system wakes up, and starts trimming off its own output which had been running flat out, to absorb the new tablet. Depending on how fast the rate of introduction is, compared with the Dopamine Controller's speed, there may be an overshoot of Dopamine above the thin green line: Result - Short term dyskinesias. occuring at the peak of the tablet's output. My system of following the minimum required line means that I never experience this .

I do however encounter the diskinesias which occur in the late evening, often well after the latest tablet has been taken. Consider what has been happening during the day: The systam has been trimming off flow, witholding Dopamine in response to the tablets, and then releasing that Dopamine as the tablet wears off. Of course, the natural breakdown of the Dopamine having done its job, is equally important, and represents the other end of the flowing system

If, during the day, the tablet input has been a little high - not much, and still within the capability of the system to absorb, we are going to reach a point where the system has been 'inhaling' more than it has 'exhaled', and it just runs out of capacity. The only way that normal operation can be restored is by getting rid of the trapped Dopamine, and if the normal wastage is not enough, then a burst of Dopamine must ensue, and the diskinesia is inevitable.

The usual objective of minimum flow all through the day certainly seems to avoid the diskinesias, but inevitably, I sometimes find that I have run a little on the high side,and that is all it takes to provoke the mechanism. I can on some occasions get sufficient warning, and can create the time needed by leaving say 1 hour without any tablets. This seems to work well, and I can resume normal doses as usual , right up to bedtime (which is my normal practice)

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