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Parkinson’s Disease (PD): Parkinson’s Disease (PD): Levodopa Drug TreatmentLevodopa Drug Treatment

Presenter:Presenter: Pedro Da Pedro Da Silva Silva

Date:Date: February 27, February 27, 2007.2007.

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Celebrities with PDCelebrities with PD

Michael J. FoxMichael J. Fox Muhammad Ali Muhammad Ali

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History of PDHistory of PD

• James Parkinson was the first to collect James Parkinson was the first to collect certain symptoms such as ataxia, certain symptoms such as ataxia, paralysis, and tremor into a common paralysis, and tremor into a common syndrome which formed a distinctive syndrome which formed a distinctive condition. He published a treatise called condition. He published a treatise called “An Essay on the Shaking Palsy” in 1817 “An Essay on the Shaking Palsy” in 1817 which contained different sections which contained different sections outlining the symptoms, diagnoses, outlining the symptoms, diagnoses, causality, and possible treatments. causality, and possible treatments.

• These speculations were made by These speculations were made by watching the movements of six elderly watching the movements of six elderly males along the streets of London. males along the streets of London.

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History Continued…..History Continued…..

• It was not until 1861 that Jean-Martin Charcot It was not until 1861 that Jean-Martin Charcot added more symptoms to James Parkinson’s clinical added more symptoms to James Parkinson’s clinical description and attached the name Parkinson’s description and attached the name Parkinson’s Disease to the syndrome. Charcot added to the list Disease to the syndrome. Charcot added to the list of symptoms the mask face, various forms of of symptoms the mask face, various forms of contractions of hands and feet, and rigidity. contractions of hands and feet, and rigidity.

• The drug used in the emmergence stage of this The drug used in the emmergence stage of this syndrome was the alkaloid drug hyoscine (or syndrome was the alkaloid drug hyoscine (or scopolamine) derived from the Datura plant. A scopolamine) derived from the Datura plant. A century later, a new drug was prescribed to sustain century later, a new drug was prescribed to sustain some of the symptoms, one known by the name some of the symptoms, one known by the name levodopa, more commonly known as L-Dopa. levodopa, more commonly known as L-Dopa.

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Structure of L-DopaStructure of L-Dopa

• Levodopa (L-Dopa)Levodopa (L-Dopa)

Formula: C9H11NO4Formula: C9H11NO4Molecular Weight: 197.19 g/molMolecular Weight: 197.19 g/molMetabolism: Aromatic-L-amino acid decarboxylaseMetabolism: Aromatic-L-amino acid decarboxylaseHalf-life: 0.75-1.5 hoursHalf-life: 0.75-1.5 hoursAdministration: OralAdministration: OralLegal Status: Prescription onlyLegal Status: Prescription only

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Treatment with L-DopaTreatment with L-Dopa

• The drug Levodopa has been the most The drug Levodopa has been the most effective drug treatment for PD and remains effective drug treatment for PD and remains the gold standard treatment for those the gold standard treatment for those afflicted with this syndrome.afflicted with this syndrome.

• L-(Dopa) was first isolated from legumes in L-(Dopa) was first isolated from legumes in 1913 but declared biologically inactive. 1913 but declared biologically inactive. However, in 1938, it was found that an However, in 1938, it was found that an enzyme L-Dopa decarboxylase was able to enzyme L-Dopa decarboxylase was able to convert human body L-Dopa into dopamine convert human body L-Dopa into dopamine (DA). (DA).

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L-Dopa continued…..L-Dopa continued…..

• These conclusions set the bar for the beginning These conclusions set the bar for the beginning of DA studies in the brain of patients with of DA studies in the brain of patients with Parkinson’s Disease. Parkinson’s Disease.

• In 1960, the severe DA deficit in the brain, the In 1960, the severe DA deficit in the brain, the major etiology of this syndrome, was major etiology of this syndrome, was discovered and a year later, L-Dopa was shown discovered and a year later, L-Dopa was shown to have a strong therapeutic effect in these to have a strong therapeutic effect in these patients. patients.

• Now it is recognized as a classic example of a Now it is recognized as a classic example of a brain neurotransmitter replacement therapy. brain neurotransmitter replacement therapy.

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How does L-Dopa work?How does L-Dopa work?

• Levodopa is the precursor of dopamine and its use Levodopa is the precursor of dopamine and its use replaces the deficient neurotransmitter.replaces the deficient neurotransmitter.

• Levodopa is absorbed from the duodenum and Levodopa is absorbed from the duodenum and penetrates to a certain degree the brain through the penetrates to a certain degree the brain through the blood-brain barrier. In the brain, it is converted to blood-brain barrier. In the brain, it is converted to dopamine by the enzyme L-Dopa decarboxylase dopamine by the enzyme L-Dopa decarboxylase located in neuronal compartments. located in neuronal compartments.

• To prevent episodes of nausea or vomitting, levodopa To prevent episodes of nausea or vomitting, levodopa is combined with the peripheral dopa decarboxylase is combined with the peripheral dopa decarboxylase inhibitors such as carbidopa. This inhibits the inhibitors such as carbidopa. This inhibits the conversion of levodopa to dopamine at a peripheral conversion of levodopa to dopamine at a peripheral level which is responsible for vomitting episodes. level which is responsible for vomitting episodes.

• Levodopa has a short half-life of about 60 to 90 Levodopa has a short half-life of about 60 to 90 minutes.minutes.

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How does L-Dopa work How does L-Dopa work continued…..continued…..

• Failure to respond to L-Dopa Failure to respond to L-Dopa ultimately suggests that the disease ultimately suggests that the disease may not be Parkinson’s Disease and may not be Parkinson’s Disease and could just be a Parkinson-like could just be a Parkinson-like disorder.disorder.

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Chemical reaction in the Chemical reaction in the brainbrain

• Conversion of L-Conversion of L-Dopa to dopamineDopa to dopamine

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Neurobiology of Neurobiology of Parkinson’s diseaseParkinson’s disease• The main symptoms from Parkinson’s disease arise from The main symptoms from Parkinson’s disease arise from

the deterioration of the part of the brain that monitors the deterioration of the part of the brain that monitors motor functioning. This region is called the substantia nigra motor functioning. This region is called the substantia nigra which is found deep within the brain stem and contains which is found deep within the brain stem and contains neuronomelanin, pigment cells, which synapse to cells of neuronomelanin, pigment cells, which synapse to cells of the striatum. The striatum deals with balance, control of the striatum. The striatum deals with balance, control of movements, and walking. Dopamine which is produced in movements, and walking. Dopamine which is produced in the substantia nigra, passes messages between the the substantia nigra, passes messages between the striatum and the substantia nigra. In Parkinson’s disease, striatum and the substantia nigra. In Parkinson’s disease, the cells of the substantia nigra actually deteriorate causing the cells of the substantia nigra actually deteriorate causing there to be a decrease in the amount of dopamine there to be a decrease in the amount of dopamine produced between the cells. This decrease in the levels of produced between the cells. This decrease in the levels of dopamine causes the neurons of the striatum to fire dopamine causes the neurons of the striatum to fire excessively, leading the patient to refrain from proper excessively, leading the patient to refrain from proper movement. movement.

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Neurobiology Neurobiology continued…continued…• These alterations in the neural circuit within the basal These alterations in the neural circuit within the basal

ganglia causes irregular movements by ganglia causes irregular movements by inhibitinginhibiting the direct the direct pathway and pathway and excitingexciting the indirect pathway. the indirect pathway.

• The direct pathway is responsible for movement and the The direct pathway is responsible for movement and the indirect pathway inhibits movement. This ultimately leads indirect pathway inhibits movement. This ultimately leads to movements related to hypokinesia.to movements related to hypokinesia.

• There are four major dopamine pathways in the brain: 1.) There are four major dopamine pathways in the brain: 1.) The nigrostriatal pathway which mediates movement 2.) The nigrostriatal pathway which mediates movement 2.) Mesocortical pathway which deals with emotional Mesocortical pathway which deals with emotional responsiveness 3.) Mesolimbic pathway which is responsiveness 3.) Mesolimbic pathway which is responsible for desire and initiative and 4.) responsible for desire and initiative and 4.) Tuberoinfundibular pathway which is involved with sensory Tuberoinfundibular pathway which is involved with sensory processes. processes.

• As a result, disruption of dopamine along these pathways As a result, disruption of dopamine along these pathways explains much of the symptomology associated with this explains much of the symptomology associated with this disease.disease.

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Parkinson’s DiseaseParkinson’s Disease

SUBSTANTIA NIGRASUBSTANTIA NIGRA

Decrease Decrease DopamineDopamine

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PET SCANPET SCAN

A PET scan will A PET scan will automatically tell a automatically tell a physician if a patient is physician if a patient is diagnosed with Parkinson’s diagnosed with Parkinson’s Disease. Here, a Disease. Here, a radiolabelled amino acid radiolabelled amino acid called F-DOPA (analogue of called F-DOPA (analogue of L-DOPA) is used with PET to L-DOPA) is used with PET to see if there is a deficiency in see if there is a deficiency in dopamine synthesis. Note dopamine synthesis. Note the reduced uptake of DOPA the reduced uptake of DOPA in the basal ganglia. in the basal ganglia. Following treatment Following treatment involving transplanting involving transplanting dopamine synthesizing cells dopamine synthesizing cells into the striatum, there is into the striatum, there is more uptake of DOPA in the more uptake of DOPA in the patient. patient.

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Neurobiology Neurobiology Continued...Continued...• In order to compensate for the loss of dopamine and In order to compensate for the loss of dopamine and

the destroyed cells of the substantia nigra, the brain the destroyed cells of the substantia nigra, the brain may boost the level of activity in the pigment cells, or may boost the level of activity in the pigment cells, or increase the sensitivity of the cells of the striatum. In increase the sensitivity of the cells of the striatum. In the normal process of aging, these mechanisms can the normal process of aging, these mechanisms can compensate for neuronal degeneration in the compensate for neuronal degeneration in the substantia nigra. However, in Parkinson’s disease, substantia nigra. However, in Parkinson’s disease, this mechanism can only account for 75% of the loss this mechanism can only account for 75% of the loss of DA. This is where the treatment of L-Dopa comes of DA. This is where the treatment of L-Dopa comes into the picture.into the picture.

• L-Dopa crosses the blood-brain barrier, gets L-Dopa crosses the blood-brain barrier, gets converted to dopamine, and increases the overall converted to dopamine, and increases the overall levels of DA. Due to the large deficiencies of levels of DA. Due to the large deficiencies of dopamine though, large doses are required which dopamine though, large doses are required which can cause many side effects. can cause many side effects.

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Side Effects Side Effects (Disadvantages)(Disadvantages)• Levodopa causes what is known as Levodopa causes what is known as

“dopaminergic” side effects, which basically “dopaminergic” side effects, which basically means that they derive from mimicking the action means that they derive from mimicking the action of dopamine.of dopamine.

• These effects include the following:These effects include the following:• Nausea and vomittingNausea and vomitting• Orthostatic hypotensionOrthostatic hypotension• Excessive sleepinessExcessive sleepiness• HallucinationsHallucinations• DyskinesiasDyskinesias• Short half-lifeShort half-life

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Advantages of using L-Advantages of using L-DopaDopa• L-Dopa alleviates bradykinesia, rigidity, and tremor.L-Dopa alleviates bradykinesia, rigidity, and tremor.• Allows patients to improve in activities in daily life. Allows patients to improve in activities in daily life. • L-Dopa is readily combined with carbidopa which reduces L-Dopa is readily combined with carbidopa which reduces

the side effects experienced.the side effects experienced.• L-Dopa preparations are available in pill form as well as L-Dopa preparations are available in pill form as well as

liquid form allowing for patients to have options in selecting liquid form allowing for patients to have options in selecting the form of administration.the form of administration.

• L-Dopa is also good for the proper diagnosis of PD. If a L-Dopa is also good for the proper diagnosis of PD. If a patient takes levopoda and shows a significant patient takes levopoda and shows a significant improvement in the symptoms experienced, then that improvement in the symptoms experienced, then that concluded that the individual has Parkinson’s Disease. If concluded that the individual has Parkinson’s Disease. If the contrary happens and the individual feels no difference, the contrary happens and the individual feels no difference, then he/she does not have PD.then he/she does not have PD.

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Case Study #1Case Study #1

• One hundred patients (63 men and 37 One hundred patients (63 men and 37 women with an age ranging between 40 to women with an age ranging between 40 to 78) with Parkinson’s Disease were treated 78) with Parkinson’s Disease were treated with Levodopa for more than a year at UCLA with Levodopa for more than a year at UCLA Medical Centre.Medical Centre.

• They were examined at given intervals and They were examined at given intervals and their improvement was graded.their improvement was graded.

• At the end of the first year, 60 percent of At the end of the first year, 60 percent of the patients improved 50 percent or better, the patients improved 50 percent or better, and 10 percent were symptom-free. and 10 percent were symptom-free. (symptoms in this study analyzed were (symptoms in this study analyzed were rigidity, akinesia, and tremors.)rigidity, akinesia, and tremors.)

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Case Study #1 Case Study #1 continued…continued…

• More than one-fourth of the patients had improved 50 More than one-fourth of the patients had improved 50 percent or more by the end of the first trimester. At percent or more by the end of the first trimester. At the end of six months, more than half had improved the end of six months, more than half had improved 50 percent or better, and by end of the first year, 62 50 percent or better, and by end of the first year, 62 percent of patients had attained this improvement.percent of patients had attained this improvement.

• At the end of all this, 10 percent were symptom-free.At the end of all this, 10 percent were symptom-free.

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Case Study #1 Case Study #1 Continued…Continued…

• Table illustrating the symptoms experienced by patients with Parkinson’s Table illustrating the symptoms experienced by patients with Parkinson’s disease and the overall improvement.disease and the overall improvement.

• Limitations: Average Levodopa dose for group which responded poorly was Limitations: Average Levodopa dose for group which responded poorly was much greater than for the entire study group or select symptom-free group. much greater than for the entire study group or select symptom-free group. Since all the patients had the levodopa dosage pushed to a high level, this Since all the patients had the levodopa dosage pushed to a high level, this indicates that these individuals were able to tolerate larger than usual indicates that these individuals were able to tolerate larger than usual amounts of the drug.amounts of the drug.

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Case Study #2Case Study #2

• In this study, 32 patients (18 men and 14 women with an In this study, 32 patients (18 men and 14 women with an average age of 61 years) with Parkinson’s Disease were average age of 61 years) with Parkinson’s Disease were treated with L-Dopa.treated with L-Dopa.

• There was no selection of patients because of age or There was no selection of patients because of age or severity of affection, but those who showed forms of severity of affection, but those who showed forms of dementia were excluded from the trial.dementia were excluded from the trial.

• Features such as tremor, rigidity, and hypokinesis were Features such as tremor, rigidity, and hypokinesis were graded respectively in each patient as “marked,” graded respectively in each patient as “marked,” “moderate,” “slight,” or “absent.” All of the patients were “moderate,” “slight,” or “absent.” All of the patients were assessed clinically before treatment as well as during the assessed clinically before treatment as well as during the assessment.assessment.

• Other features associated with Parkinson’s Disease were Other features associated with Parkinson’s Disease were also measured such as postural defects, impassivity of the also measured such as postural defects, impassivity of the face, salivation, and mood.face, salivation, and mood.

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Case Study #2 Case Study #2 Continued…Continued…

• Table illustrating how Levodopa significantly helped the patients to perform Table illustrating how Levodopa significantly helped the patients to perform an activity with a much faster response.an activity with a much faster response.

• After the study was complete, 9 were markedly and 14 moderately improved. After the study was complete, 9 were markedly and 14 moderately improved. Such marked improvement does not imply restoration to normality but Such marked improvement does not imply restoration to normality but rather a restoration of function to a socially and economically acceptable rather a restoration of function to a socially and economically acceptable level. Two patients though achieved virtual normality after treatment for six level. Two patients though achieved virtual normality after treatment for six months. The rest of the patients still showed amelioration.months. The rest of the patients still showed amelioration.

• Limitations: Some individuals responded to levodopa with more side effects Limitations: Some individuals responded to levodopa with more side effects and could have discontinued the use of the drug treatment as a result.and could have discontinued the use of the drug treatment as a result.

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Evaluation/ConclusionEvaluation/Conclusion• Overall, Levodopa Therapy has revolutionized the treatment of Overall, Levodopa Therapy has revolutionized the treatment of

Parkinson’s Disease and remains the “gold standard” after so many Parkinson’s Disease and remains the “gold standard” after so many years.years.

• It definitely provides dramatic benefits in terms of alleviating many It definitely provides dramatic benefits in terms of alleviating many symptoms thus allowing patients afflicted with this disease to enjoy symptoms thus allowing patients afflicted with this disease to enjoy their routine activities as well as prolong their life span. their routine activities as well as prolong their life span.

• In the early stages of PD, levodopa is excellent in responding to the In the early stages of PD, levodopa is excellent in responding to the disease and even if a dose is missed, the benefits persist. Not disease and even if a dose is missed, the benefits persist. Not effective on every patient. Usually more successful in patients with effective on every patient. Usually more successful in patients with an early onset of the disease. an early onset of the disease.

• On the other hand, with progression of this disease, the benefit of the On the other hand, with progression of this disease, the benefit of the drug begins to wear off. Over time, the duration of the motor drug begins to wear off. Over time, the duration of the motor response to a given dose of L-Dopa becomes shorter and begins to response to a given dose of L-Dopa becomes shorter and begins to reflect the half-life of the drug itself (60-90 minutes). As a result, reflect the half-life of the drug itself (60-90 minutes). As a result, more research needs to be conducted to find a longer-lasting more research needs to be conducted to find a longer-lasting effective drug.effective drug.

• In the end, above the side effects experienced, I think it is an excellent In the end, above the side effects experienced, I think it is an excellent treatment with many benefits since it extinguishes many of the pains both treatment with many benefits since it extinguishes many of the pains both psychological and physical when dealing with such a debilitating disease.psychological and physical when dealing with such a debilitating disease.

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THE ENDTHE END