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Sinemet and the Tablet Analysis Program
This was originally sent to the PARKINSN list. Comments to Brian Collins
On Tue 07 Jan, W.S. wrote:
> I am a new member to your group, I am looking
> for information on parkinsons for my mother, I am interested
> in the ups and downs of sinemet cr, could anyone tell me what
> the usual dose of sinemet cr is ? just for comparison, we are
> not changing it without the doctor's say so...
>
> I have gained a lot of helpfull information from this
> group in my first 24 hours, I thank you all,I am in the prosess
> of changing doctors, we need more info than " take 2 sinemet and
> see you in three months" It is good to see such an active group
> sharing information, and it is helpfull to know the symptoms that
> are parkinsons and not unusual. If I am actualy sending out this
> message, like I think I am, ( I'm new to computers and Internet)
> I wish you all well, and thank you for your help.
> Whitie@worldnet.att.net
>
>
Hello W.S. You are very sensible to try to find out the principles which
determine how and why we take Sinemet. I will try to give you the story
in a compact form, but it is quite complex, so I may have to do it in
installments.
1) What is Sinemet
Let's clear away one point; Sinemet is a brand name for a tablet
containing levodopa and carbidopa. In the USA there are no alternatives
so Sinemet has become the standard name. In many other parts of the
world there is an alternative, called Madopar, which is functionally
interchangeable with Sinemet. The key compound in both these tablets
is levodopa ( or L-dopa ), which is the pre-cursor of Dopamine, a
neuro-transmitter. (Pre-cursor means that it is only one chemical
reaction away from dopamine. The brain uses dopamine in the process of
sending messages from the brain to the muscles of the body. In the
Parkinson's sufferers brain, the part which is responsible for
production of Dopamine - the substantia nigra - for some unknown reason
progressively dies off, and when approximately 80% of the normal
complement of dopamine-producing cells have died off, the familiar
tremor and/or muscular rigidity begins to reveal itself, along with an
assorted bunch of other symptoms.
2) How do we get the levodopa to the brain?
It is not as simple as taking a tablet of levodopa, unfortunately.
When we take a tablet like this, it goes through a pretty wild ride
before it finally gets to the brain. First it has to survive until
it reaches the lower intestine, where it is absorbed through the
lining of the lower intestine (Providing the last meal is not blocking
the way). From there it has to hitch a ride in the blood stream,
until it finally arrives at the blood-brain barrier (The BBB). It
then has to cross this barrier, get to the substantia nigra, and
make up for the missing cells.
In the blood stream, there are many chemicals whose sole function
is to break down Large Amino Acids of which levodopa is one. If we
swallowed say 200 mg of levodopa, less than 1mg would survive the
journey to the brain. This is where the carbidopa comes in (In the
madopar tablet the other constituent is Benserazide, but it does just
the same job as carbidopa). The carbidopa protects the levodopa during
its journey to the BBB. Now comes the clever bit: the BBB is very
selective about what it will allow through to the brain. It will not
allow dopamine, or levadopa+carbidopa, or carbidopa for instance.
However, it will allow levodopa by itself, and in the process the
carbidopa is stripped away from the levodopa, and left behind.
So far so good, but the brain itself is full of chemicals just
waiting to pounce on the levodopa, break it down to its constituents
and cart it away. A small quantity makes it through to the substantia
nigra, where it performs its neuro transmitter role, before being
pounced on and etc, etc.
One last pitfall to be avoided: If we supply too much levodopa, the
effect is as if the dopamine overflows the assigned neural pathways, and
'floods' the system surrounding it. This causes muscles at virtually
any part of the body, depending where the spill occurs, to initiate
muscular movement which we did not command. These uncommanded movements
are called dyskinesias, and they can be as bad or worse than the PD
tremor.
3) You may begin to see that what we have to do, is by trial and error,
find a tablet which will deliver enough dopamine to supply the
brain's requirements, and allow for all the losses along the way.
What this boils down to is that we are trying to maintain a constant
RATE of FLOW of levodopa, through the day. If we let the flow rate fall
too low we get PD tremor etc, and if we get the rate too high, we get
Dyskinesias.
I have gone far enough for one day. In the next part, I will try to show
how a newcomer can tolerate rates of flow ranging from (Approximately)
10 mg/hour up to 100 mg/hour, while an old hand like me, after 17 years
of taking Sinemet/Madopar can only tolerate rates of flow ranging from
(about) 35 mg/hour to 40 mg/hour.
Here's the next part.
Hello W.S. Here goes with part 2 of my explanation of the ins and outs of
taking Sinemet. I have probably given you quite a shock at the complexity
of the subject, but if you save these notes I feel sure that the day will
come when you need to know some aspect which is covered in here. The
reason why I am going into this in such detail is that I have not seen
all the points pulled together in one article before.
4) Getting the best out of your Sinemet tablets
with almost any ordinary tablet, we are accustomed to a relaxed sort
of regime such as 'Take one before meals', or 'Take two per day',etc
It is obvious that it is not important that the tablets be taken at
a specific time or in a specific order. Sinemet is different, because
we are trying to maintain the rate of flow of levodopa reaching the
subsrantia nigra. A question which occurs to me at this point is :
If flow rate is so important, how do we manage with effectivly three
sizes of tablet: 50mg, 100mg, and 250mg ? True, you can break them
in half but the steps are still large.
The answer lies in the ability of the brain to regulate the
production of dopamine so that in a normal person, the dopamine is
produced and sent to the required site at the right time, and in the
right quantity. The normal brain has a substantial over-supply of
dopamine-producing cells, so that about 80% to 90% of the production
capability has to be lost before PD symptoms become visible.
I should say that the description of the system which follows is my
own, but aside from probably being rather over-simplified, I am
convinced that it accurately describes the levodopa system
It is reasonable to assume that even in a non-PD person, the normal
production rate of dopamine is just above 10% of the maximum.
(corresponding to the 90% of cell loss required before the PD
symptoms start.
It is also reasonable to assume that if the production rate should
rise above this normal level by a quite small amount, then we are
in dyskinesia country. Similarly if the flow rate falls below the
10% level, the PD 'Off' condition starts up : Tremor, rigidity etc.
When a lump of Sinemet appears in the brain, the automatic system
detects this intrusion, and makes room for it by throttling back the
natural dopamine production rate. When a person has just been
diagnosed as having PD, their production capability is of course 10%
of the maximum. The brain therefore has the capability to make room
for a quite large quantity of external levodopa, typically 300 mg
or more.
As PD proceeds, the quantity of dopamine-producing cells continues
to decrease, and inevitably so does the amount of Sinemet which can
be tolerated, so that as time goes by, it becomes more and more
difficult to achieve an exact match of the required dopamine, and
over- or under-dosing results. This aspect of the dopamine regulation
system is covered in a more understandable way, in 2 charts (A and B)
which I have distributed before. If any newcomers are interested,
they can email me, and I will send them a set.
For the newly-diagnosed PWP, when they are finally introduced to
levodopa, they are typically prescribed a large tablet, say 250mg,
which will last anything up to 5 or 6 hours. This is accepted by the
brain as described above, but in reality, we could also have achieved
an acceptable treatment by taking a tablet which released a mere
10 mg per hour. Unfortunately such a tablet does not exist.
5) Controlled Release tablets or Standard
The controlled release tablet is designed to release its load of
levodopa over a period of time, thus avoiding the chance of a sharp
increase in flow occuring shortly after the tablet enters the
bloodstream. Typically a standard tablet, such as Sinemet 25/100
(100mg of levodopa) will last 2 to 3 hours, thus giving a rate of
50mg/hr to 33mg/hr. The CR tablet contains 200 mg of levodopa and,
since it lasts about twice as long, gives the same nominal rate,
and of course is more convenient. I took the CR tablets when they
first became available, and for 2 or 3 years, they were ideal. If
newer users find that they can get a satisfactory response, then I
would recommend their use. In my case, my tolerance level fell
below 50mg/hr, and I could not tolerate the quantity of levodopa
released by the CR tablets. You should be very clear about this:
The continuing reduction in the tolerance level is Not due to the
way that you took the tablets; it is due to the continuing erosion
of the cells in the substantia nigra.
When you start on Sinemet, you have several years of virtual
freedom from the symptoms of PD. Enjoy it, its free. You are not
mortgaging the future, Not only that, nono of the other drugs can
give that degree of control. Eventually, you will need to resort
to combinations of these drugs, but that is another story.
I hope that some of you have managed to follow me through to the
end. If you have, I hope you feel that perhaps some of the mystery
has been drawn aside, and you know what you are dealing with.
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