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Slaves Of The Clock: Living With Levodopa 16 Apr 2k Page 1 of 3 Parkinson's disease is a progressive, neurodegenerative disease of the extrapyramidal nervous system, affecting the mobility and control of the skeletal muscular system. Its main features are resting tremor, rigidity, and bradykinesia. Symptomatic treatment such as levodopa medication may usually improve mobility. Symptoms of PD are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective because it doesn't cross the blood-brain barrier. However, dopamine's metabolic precursor levodopa does cross that barrier into the brain, where presumably it is converted to dopamine. Levodopa alone, taken orally, is rapidly decarboxylated outside the central nervous system to dopamine, so that only a very small proportion of a given dose survives to enter the brain. Hence, adequate control of motor symptoms requires large doses, and the corresponding amount of dopamine formed outside the CNS very often causes nausea and vomiting. Moreover, levodopa competes with other amino acids for the limited transport pathways through the gut wall, so a high-protein intake may further impair absorption. The enzyme decarboxylase is inhibited by carbidopa, which doesn't cross the blood-brain barrier, and therefore doesn't affect metabolism of levodopa to dopamine within the brain. Thus, more levodopa enters the brain if it is taken combined with carbidopa. The addition reduces levodopa required for a given therapeutic response by about 75%, and increases its plasma half-life from about 50 minutes to about 90 minutes. And as a bonus, nausea from superfluous peripheral dopamine is avoided. "Sinemet" is a Latin neologism for "no vomit". The optimum effective amount of carbidopa, to suppress completely the action of decarboxylase, is 75 to 100mg/day. Sinemet is a combination of carbidopa/levodopa, supplied as tablets in several formulations, of which the most commonly used is Sinemet 25/100. The recommended starting dose for new patients is 3 of these per day, increasing gradually if needed, up to 8 per day. After several years of dopaminergic therapy, PD patients notice that the effect of each medication dose is perceptible, not only in relief of motor symptoms but also in elevation of mood and energy. Conversely, at the end of each dose interval the patient may notice the return of PD tremor, fatigue, depression, and rigidity or painful muscle cramps from dystonia,. The rapidity of these changes has led to the term "On-Off" for the phases. Another effect that appears after several years of levodopa use is dyskinesia, involuntary writhing or oscillatory motion that seems due to temporary excess of dopamine from the most recent dose of medication. In comparison with the symptoms above being called "end-of-dose" effect, this is called the "peak-dose" effect. Slaves Of The Clock: Living With Levodopa Page 2 of 3 No doubt, dopamine may not be the only factor in PD, but it's probably the most important and easiest to deal with. In my view, the level of available dopamine has two components: a baseline level that declines gradually as neurons of the substantia nigra are lost with the progression of PD (clinical motor symptoms of PD appear when about 4/5 of the SN dopamine neurons are lost), and the transient added amount from medication which, as mentioned above, has a half-life measured in minutes. The aim of each succeeding dose of Sinemet is to add temporarily enough dopamine in the brain to relieve the PD symptoms; but there is also a kind of storage effect, where the successive intermittent doses tend to restore the normal baseline level, that may take several days or weeks to be felt. And a more rational goal of medication is somehow to raise the baseline of dopamine availability to a level above the threshold where PD motor symptoms appear. But replenishing the long-term supply of dopamine usually is done by the same intermittent dosing of Sinemet. The individual dose amount is limited by the appearance of dyskinesia as a "peak-dose" effect, so the net result is a kind of sawtooth pattern where dopamine concentration goes up and down with each dose. Ideally, one would like the baseline to be as smooth in time as it is in the absence of PD. While trying to maintain a condition between too much and too little, the excursion of dopamine level can be reduced by taking smaller doses of Sinemet at more frequent intervals, but here a "quality of life" factor enters, namely the resulting frequent interruptions of sleep at night and activities of waking hours. The dose interval may at first be 8 hours, but as the natural baseline declines with disease progression, the upper limit or dyskinesia threshold declines even faster, leaving the "window" of tolerable dose amount smaller and smaller. So PD patients respond by dosing more frequently; every 6 hours, then 4, 3, 2 and so on, until some reach the point where continuous infusion by means of a shunt and pump is the best remaining choice. When a scheduled dose is omitted because the patient forgets or oversleeps, the lost baseline level cannot be restored by increasing the next following dose amount, because of the dyskinesia limit. Instead therefore the alternative is cautiously to shorten the next few dose intervals until the assigned schedule is regained. Slaves Of The Clock: Living With Levodopa Page 3 of 3 All this sounds complicated enough, but there is more: First, in absence of PD the natural dopamine level and production rate probably varies during each day, I suspect it is less during sleep, and greater during any demanding activity, either mental or physical. So it would seem that the patient should not only follow a set dose schedule, but also learn to anticipate and prevent "off" periods by judicious temporary adjustments of the schedule. Second, growing evidence suggests that the onset of dyskinesia is accelerated by separation of medication into intermittent doses, so that the constant variation in dopamine level causes lasting changes in the way that dopamine receptors respond. Ideally, there should be a simple means for the patient to know if and how much medication is needed at any given time, to mimic the non-PD state. As a final note of caution, Sinemet is one of several drugs whose abrupt reduction or withdrawal after prolonged chronic use has (very rarely) caused a life-threatening syndrome first associated with neuroleptic drugs, therefore named Neuroleptic Malignant Syndrome. NMS features may include sudden onset, high fever, altered mental state, autonomic dysfunction, and signs of rhabdomyolysis. Therefore any reduction or withdrawal of Sinemet should be gradual if possible, carefully monitored otherwise. Because of dyskinesia, and possibly other suspicions that chronic levodopa medication may be harmful, some neurologists prefer to start their patients on other medication, such as one of the dopamine agonists, until the greater effectiveness of levodopa is needed. But the pulsed stimulation of dopamine receptors by an agonist for several years may also cause the onset of dyskinesia, and other neurologists feel it is better to start with levodopa. Several long-term studies seem to show that the eventual outcomes are similar, and have failed so far to resolve the dispute to everyone's satisfaction. Until the day that a cure for PD is found, dopaminergic drugs will continue as the mainstay of treatment. Generally, for the first 5 to 10 years after diagnosis, on-off fluctuations are not noticeable and peak-dose dyskinesia may appear as no more than a slight tremor. That period is known as the "levodopa honeymoon". From then on, though, the patient will be constantly aware of symptoms that change during each interval between doses, and should learn to adjust the dose schedule to achieve the best quality of life under the circumstances, without risking a future penalty such as faster progression of the disease. And, always keeping track of the time. Cheers, Joe -- J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks, CA 91403-5013