Parkinson's Pharmacotherapy: Difference between revisions

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Understanding the impact of medication on both the movement and thought quality of people with Parkinson’s will help set goals and plans for [[Physical Therapy Implications for Parkinson's Drugs|physiotherapy intervention]].
Understanding the impact of medication on both the movement and thought quality of people with Parkinson’s will help set goals and plans for [[Physical Therapy Implications for Parkinson's Drugs|physiotherapy intervention]].


== Pharmacotherapy ==
PD is caused by decreased dopamine production in the basal ganglia due to degeneration of dopamine-secreting neurons. Dopaminergic drugs designed to replace the action of dopamine in the deplete basal ganglia form the mainstay of PD treatment at present. This may be achieved through drugs that are metabolized to dopamine, that activate the dopamine receptor, or that prevent the breakdown of endogenous dopamine. [https://www.epda.eu.com/living-well/therapies/surgical-treatments/deep-brain-stimulation-dbs/ Deep brain stimulation, stem cell therapy and gene therapy] are alternative approaches that aim to lower the need to medications. Understanding the impact of medication on both the movement and thought quality of people with Parkinson’s will help set goals and plans for [[Physical Therapy Implications for Parkinson's Drugs|physiotherapy intervention]].
PD is caused by decreased dopamine production in the basal ganglia due to degeneration of dopamine-secreting neurons. Dopaminergic drugs designed to replace the action of dopamine in the deplete basal ganglia form the mainstay of PD treatment at present. This may be achieved through drugs that are metabolized to dopamine, that activate the dopamine receptor, or that prevent the breakdown of endogenous dopamine. [https://www.epda.eu.com/living-well/therapies/surgical-treatments/deep-brain-stimulation-dbs/ Deep brain stimulation, stem cell therapy and gene therapy] are alternative approaches that aim to lower the need to medications. Understanding the impact of medication on both the movement and thought quality of people with Parkinson’s will help set goals and plans for [[Physical Therapy Implications for Parkinson's Drugs|physiotherapy intervention]].


The video below outlines briefly medication rational and major drug types{{#ev:youtube|https://www.youtube.com/watch?v=T8VojsSvv4E|width}}<ref>PD care New York Taking Control: Medications for Parkinson's Available from: https://www.youtube.com/watch?v=T8VojsSvv4E (last accessed 8.11.2019)</ref>
The video below outlines briefly medication rational and major drug types{{#ev:youtube|https://www.youtube.com/watch?v=T8VojsSvv4E|width}}<ref>PD care New York Taking Control: Medications for Parkinson's Available from: https://www.youtube.com/watch?v=T8VojsSvv4E (last accessed 8.11.2019)</ref>


Main Medications
== Main Medications ==
 
# Levodopa: The mainstay of current PD treatment are levodopa-based preparations, designed to replace the dopamine in the depleted striatum. See [[Levodopa in the treatment of Parkinson's|Levodopa in the Treatment of Parkinson's]]
# Levodopa: The mainstay of current PD treatment are levodopa-based preparations, designed to replace the dopamine in the depleted striatum. See [[Levodopa in the treatment of Parkinson's|Levodopa in the Treatment of Parkinson's]]
# Dopamine agonists: Stimulate the activity of the dopamine system by binding to the dopaminergic receptors. Dopamine agonists are often prescribed as an initial therapy for PD, particularly in younger patients. This approach allows for a delay in the use of levodopa, which may reduce the impact of the problematic motor complications
# Dopamine agonists: Stimulate the activity of the dopamine system by binding to the dopaminergic receptors. Dopamine agonists are often prescribed as an initial therapy for PD, particularly in younger patients. This approach allows for a delay in the use of levodopa, which may reduce the impact of the problematic motor complications
Line 18: Line 16:
# Anticholinergics: reduce the activity of the neurotransmitter acetylcholine, by acting as antagonists at cholinergic receptors. While their role is limited and they are now prescribed infrequently, they may offer some benefit in improving rigidity and tremor in PD
# Anticholinergics: reduce the activity of the neurotransmitter acetylcholine, by acting as antagonists at cholinergic receptors. While their role is limited and they are now prescribed infrequently, they may offer some benefit in improving rigidity and tremor in PD


==== Levodopa ====
== Levodopa ==
The mainstay of current PD treatment are [[Levodopa - Parkinson's|levodopa]]-based preparations, designed to replace the dopamine in the depleted striatum. Dopamine itself is unable to cross the [[Blood-Brain Barrier|blood brain barrier]] (BBB) and cannot be used to treat PD. In contrast, the dopamine precursor levodopa is able to cross the BBB and can be administered as a therapy. After absorption and transit across the BBB, it is converted into the neurotransmitter dopamine by DOPA decarboxylase
The mainstay of current PD treatment are [[Levodopa - Parkinson's|levodopa]]-based preparations, designed to replace the dopamine in the depleted striatum. Dopamine itself is unable to cross the [[Blood-Brain Barrier|blood brain barrier]] (BBB) and cannot be used to treat PD. In contrast, the dopamine precursor levodopa is able to cross the BBB and can be administered as a therapy. After absorption and transit across the BBB, it is converted into the neurotransmitter dopamine by DOPA decarboxylase


=== MAO-B Inhibitors ===
== Prevention of the Breakdown of Endogenous Dopamine ==
Monoamine Oxidase B Inhibitors, such as Selegiline and Rasagiline, are commonly used by patients with Parkinson's because of their potential disease modifying and neuroprotective effects <ref name=":3">Teo KC, Ho SL. [https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/2047-9158-2-19 Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease]. Translational neurodegeneration 2013 Dec;2(1):19.</ref>. This drug class is considered a potential disease modifier due to its ability to inhibit the monoamine oxidase type B (MAO-B) enzyme, which naturally breaks down dopamine in the brain<ref name=":3" />.By inhibiting the breakdown of the MAO-B enzyme, these drugs are able to extend the effects of dopamine at the CNS synapse <ref>Fabbrini G, Abbruzzese G, Marconi S, Zappia M. [https://journals.lww.com/clinicalneuropharm/Abstract/2012/05000/Selegiline___A_Reappraisal_of_Its_Role_in.7.aspx Selegiline: a reappraisal of its role in Parkinson disease.] Clinical neuropharmacology 2012 May 1;35(3):134-40.</ref><ref>Magyar K. [http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.670.7461&rep=rep1&type=pdf The pharmacology of selegiline.] In: International review of neurobiology. Academic Press, 2011 (Vol. 100, pp. 65-84).</ref>. However, more research needs to be done on the ability of MAO-B inhibitors to slow the progression of PD. MAO-B inhibitors exhibit neuroprotection by decreasing dopamine oxidation, therefore preventing excessive production of free radicals, while prolonging the effects of endogenous dopamine<ref>Weinreb O, Amit T, Bar-Am O, Youdim MB. [https://www.sciencedirect.com/science/article/pii/S0301008210001206 Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity.] Progress in neurobiology 2010;92(3):330-44.  </ref><ref>Aluf Y, Vaya J, Khatib S, Loboda Y, Finberg JP. [https://www.sciencedirect.com/science/article/pii/S0028390812004698 Selective inhibition of monoamine oxidase A or B reduces striatal oxidative stress in rats with partial depletion of the nigro-striatal dopaminergic pathway.] Neuropharmacology 2013;65:48-57.</ref> MAO-B inhibitors can be used as an initial drug in the treatment of Parkinson’s Disease or can be combined with Levodopa in order to reduce motor fluctuations<ref name=":3" />.
'''MAO-B Inhibitors''' work by inhibiting the enzymes involved in dopamine metabolism, which preserves the levels of endogenous dopamine eg Monoamine Oxidase B (MAO-B) inhibitors, Catechol-O-methyl transferase inhibitors. While they are sometimes sufficient for control of symptoms in early disease, most patients ultimately require levodopa-based treatment. MAO-B inhibitors may also be used in combination with levodopa-based preparations, to allow for a reduction in the levodopa dose. Commonly used MAO-B inhibitors include selegiline (Deprenyl, Eldepryl, Zelapar) and rasagiline (Azilect). More recently, the drug safinamide (Xadago) was also approved for use in PD, which appears to have multiple modes of action, one of which is thought to be inhibition of MAO-B <ref name=":0">Zahoor I, Shafi A, Haq E. Pharmacological treatment of Parkinson’s disease. Exon Publications. 2018 Dec 21:129-44. Available:https://www.ncbi.nlm.nih.gov/books/NBK536726/<nowiki/>(accessed 14.4.2022)</ref><ref name=":3">Teo KC, Ho SL. [https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/2047-9158-2-19 Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease]. Translational neurodegeneration 2013 Dec;2(1):19.</ref>. MAO-B inhibitors are generally well tolerated, with gastrointestinal side effects being the most common problem. Other adverse effects include aching joints, depression, fatigue, dry mouth, insomnia, dizziness, confusion, nightmares, hallucinations, flu-like symptoms, indigestion, and headache.<ref name=":0" />
 
The prototypical selective, irreversible MAO-B inhibitor, Selegiline, is absorbed in the GI tract and then distributed to tissues throughout the body, including the brain<ref name=":4">Heinonen EH, Myllylä V, Sotaniemi K, Lamintausta R, Salonen JS, Anttila M, Savijärvi M, Kotila M, Rinne UK. [https://europepmc.org/abstract/med/2515726 Pharmacokinetics and metabolism of selegiline.] Acta neurologica Scandinavica. Supplementum 1989;126:93-9.</ref>. Selegiline is metabolized to L-amphetamine-like metabolites which may promote insomnia <ref name=":3" />. This drug is primarily metabolized in the liver and then excreted by the kidneys <ref name=":4" />. Selegiline has an oral bioavailability of 10% and an oral clearance rate of 59 L/min <ref>Mahmood I. [https://link.springer.com/article/10.2165/00003088-199733020-00002 Clinical pharmacokinetics and pharmacodynamics of selegiline.] Clinical pharmacokinetics 1997;33(2):91-102.</ref>. This drug is given at a therapeutic dose of 10mg/day and has a half-life of 10 hours<ref name=":3" />. Selegiline is typically administered twice per day as a 5mg oral tablet <ref name=":5">UCSF School of Medicine. Parkinson's Clinic and Research Center. Available from: [http://pdcenter.neurology.ucsf.edu/patients-guide/parkinson%E2%80%99s-disease-medications/monoamine-oxidase-b-mao-b-inhibitors http://pdcenter.neurology.ucsf.edu/patients-guide/parkinson’s-disease-medications/monoamine-oxidase-b-mao-b-inhibitors](accessed 5 November 2018).</ref>. If this dose is increased Selegiline will lose it’s selective ability<ref name=":3" />.
 
Rasagiline, another selective, irreversible MAO-B inhibitor, is metabolized into aminoindan in the liver by cytochrome p450 type 1A2, which means it does not have the amphetamine-like effects that Selegiline displays and may be preferred<ref name=":6">Lecht S, Haroutiunian S, Hoffman A, Lazarovici P. Rasagiline–a novel MAO B inhibitor in Parkinson’s disease therapy. Therapeutics and clinical risk management 2007;3(3):467.</ref>. Its oral bioavailability is 35% and it reaches its therapeutic maximum after 0.5-1 hour <ref name=":6" />. The oral clearance rate of Rasagiline is 94.3 L/day<ref name=":6" />. This drug is given at a recommended dose of 0.5-1 mg/day and has a half-life or 1.5-3.5 hours <ref name=":6" />. It is typically administered once per day as a 0.5mg or 1mg oral tablet <ref name=":5" />.


When used in adjunct with Levodopa both Selegiline and Rasagiline have been known to decrease motor fluctuations in patients with Parkinson's <ref name=":3" />. These two drugs are relatively safe compared to other MAO inhibitors due to their selective ability<ref name=":7">Chen JJ, Wilkinson JR. [https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1177/0091270011406279 The monoamine oxidase type B inhibitor rasagiline in the treatment of Parkinson disease: is tyramine a challenge?] The Journal of Clinical Pharmacology 2012 May;52(5):620-8.</ref>. Common adverse effects of other MAO-B Inhibitors may include dizziness, headache, GI distress, and sedation<ref name=":7" />.
'''Catechol-O-methyl transferase inhibitors''': another enzyme that is involved in dopamine degradation is COMT. These drugs are predominantly used as adjunctive therapy to levodopa, prolonging its duration of action by increasing its half-life and its delivery to the brain. COMT inhibitors come in the form of tablets and are not generally prescribed as monotherapy, as on their own they offer only limited effect on PD symptoms. Examples of COMT inhibitors include entacapone (Comtan), tolcapone (Tasmar), and opicapone (Ongentys). <ref name=":0" />


=== Dopamine Agonist Medications   ===
== Dopamine Agonist Medications ==
Dopamine agonists are another commonly used class of drugs implemented during the treatment of PD<ref>Bonuccelli U, D. D. Role of dopamine receptor agonist in the treatment of early Parkinson's. Parkinsonism Related Disorders, 2009;(4): S44-53.doi: 10.1016/S1353-8020(09)70835-1.</ref><ref>Harris PE ,C. K. Prevalence of complementary and alternative medicine (CAM) used by the general population: a systematic review and update. Int J Clin Pract, 2012; 66(10): 924-939. doi: 10.1111/j.1742-1241.2012.02945.x.</ref>. Dopamine agonists work by actively influencing dopamine receptors in the brain to produce more in-vivo dopamine, thus making it the preferential treatment early on in the disease process. Apomorphine is considered the premier drug in this category, due to its powerful motor fluctuation modulating capabilities, such as those seen in end of dose dyskinesias generated by some anti-parkinsonian medications (i.e. LD)<ref name=":8">Regina Katzenschlager MD, W. P. Apomorphine subcutaneous infusion in patients with Parkinson's with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet Neurology, 2018;(9):749-759. doi: 10.1016/S1474-4422(18)30239-</ref>. Apomorphine is typically administered subcutaneously on a continuous cycle for an average of 16 hours per day at a rate of 3-6 mg/hr<ref name=":9">Auffret M, D. S. (2018) Pharmacological Insights into the Use of Apomorphine in Parkinson's: Clinical Relevance. Clinical Drug Investigation, 2018; 38(4) 287-312. doi: 10.1007/s40261-018-0619-3.</ref>. Further pharmacokinetics of apomorphine, include the drug taking approximately 15-20 minutes to reach its maximum bioavailability within the bloodstream<ref name=":10">Nomoto M, Kubo SI, Nagai M, Yamada T, Tamaoka A, Tsuboi Y, Hattori N, Parkinson's Study Group. A randomized controlled trial of subcutaneous apomorphine for Parkinson disease: a repeat dose and pharmacokinetic study. Clinical neuropharmacology. 2015 Nov 1;38(6):241-7.</ref><ref name=":11">Elisa Unti, R. C. Apomorphine hydrochloride for the treatment of Parkinson's . Expert Review of Neurotherapeutics, 2015; 15(7): 723-732. doi: 10.1586/14737175.2015.1051468.</ref>. Once in the blood, the drug takes about 30-40 minutes to reach its half life<ref name=":9" /><ref name=":10" /><ref name=":11" />. This is fairly quick and the reason for the drug being given on a constant basis throughout the day<ref name=":9" />. Apomorphine’s clearance in the system is close to 3-4 L/h/kg, meaning that it leaves the plasma at a rapid rate<ref>rgiolas A, H. H. (2001). The pharmacology and clinical pharmacokinetics of apomorphine. BJU international, 2001; 88(3): 18-21. <nowiki>https://doi.org/10.1046/j.1464-4096.2001.00124.x</nowiki></ref>. After the drug has been metabolized, it is then excreted through urine by the kidneys<ref name=":9" />.
Dopamine agonists are another commonly used class of drugs implemented during the treatment of PD<ref>Bonuccelli U, D. D. Role of dopamine receptor agonist in the treatment of early Parkinson's. Parkinsonism Related Disorders, 2009;(4): S44-53.doi: 10.1016/S1353-8020(09)70835-1.</ref><ref>Harris PE ,C. K. Prevalence of complementary and alternative medicine (CAM) used by the general population: a systematic review and update. Int J Clin Pract, 2012; 66(10): 924-939. doi: 10.1111/j.1742-1241.2012.02945.x.</ref>. Dopamine agonists work by actively influencing dopamine receptors in the brain to produce more in-vivo dopamine, thus making it the preferential treatment early on in the disease process. Apomorphine is considered the premier drug in this category, due to its powerful motor fluctuation modulating capabilities, such as those seen in end of dose dyskinesias generated by some anti-parkinsonian medications (i.e. LD)<ref name=":8">Regina Katzenschlager MD, W. P. Apomorphine subcutaneous infusion in patients with Parkinson's with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet Neurology, 2018;(9):749-759. doi: 10.1016/S1474-4422(18)30239-</ref>. Apomorphine is typically administered subcutaneously on a continuous cycle for an average of 16 hours per day at a rate of 3-6 mg/hr<ref name=":9">Auffret M, D. S. (2018) Pharmacological Insights into the Use of Apomorphine in Parkinson's: Clinical Relevance. Clinical Drug Investigation, 2018; 38(4) 287-312. doi: 10.1007/s40261-018-0619-3.</ref>. Further pharmacokinetics of apomorphine, include the drug taking approximately 15-20 minutes to reach its maximum bioavailability within the bloodstream<ref name=":10">Nomoto M, Kubo SI, Nagai M, Yamada T, Tamaoka A, Tsuboi Y, Hattori N, Parkinson's Study Group. A randomized controlled trial of subcutaneous apomorphine for Parkinson disease: a repeat dose and pharmacokinetic study. Clinical neuropharmacology. 2015 Nov 1;38(6):241-7.</ref><ref name=":11">Elisa Unti, R. C. Apomorphine hydrochloride for the treatment of Parkinson's . Expert Review of Neurotherapeutics, 2015; 15(7): 723-732. doi: 10.1586/14737175.2015.1051468.</ref>. Once in the blood, the drug takes about 30-40 minutes to reach its half life<ref name=":9" /><ref name=":10" /><ref name=":11" />. This is fairly quick and the reason for the drug being given on a constant basis throughout the day<ref name=":9" />. Apomorphine’s clearance in the system is close to 3-4 L/h/kg, meaning that it leaves the plasma at a rapid rate<ref>rgiolas A, H. H. (2001). The pharmacology and clinical pharmacokinetics of apomorphine. BJU international, 2001; 88(3): 18-21. <nowiki>https://doi.org/10.1046/j.1464-4096.2001.00124.x</nowiki></ref>. After the drug has been metabolized, it is then excreted through urine by the kidneys<ref name=":9" />.


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== Anticholinergic Medications  ==
== Anticholinergic Medications  ==
Anticholinergic drugs, including Benztropine mesylate, Biperiden, Diphenhydramine, and Trihexyphenidyl, are another important class of medications used to mitigate the motor symptoms of Parkinson’s disease. By using these drugs in the early progression of the disease, the need for Levodopa can be prolonged. While the exact mechanism of action is unknown, it is said that anticholinergic drugs are competitive antagonists of muscarinic receptors; thus, inhibiting disproportionate acetylcholine action from the basal ganglia, specifically involuntary muscle movement. These drugs are taken orally and range from 30-70% bioavailable. After taken, they are rapidly absorbed (with the exception of benztropine mesylate) into the brain and produce a high volume of distribution, then biotransforming via N-dealkylated and hydroxylated metabolites. The drug clearance appears to be low in comparison to hepatic blood flow, which reduces the chances of first pass effect. Excretion of the parent drug and metabolite are through the kidneys. With these things being said, there is very little information on the pharmacokinetic information for anticholinergic drugs.
The medications that have so far been discussed are all aim to increase dopaminergic activity in the striatum. These reduce the activity of the neurotransmitter acetylcholine, by acting as antagonists at cholinergic receptors. While their role is limited and they are now prescribed infrequently, they may offer some benefit in improving rigidity and tremor in PD. Loss of dopaminergic neurons results in disturbance of the normal balance between dopamine and acetylcholine in the brain, and anticholinergic drugs may lead to restoration and maintenance of the normal balance between these two neurotransmitters.<ref name=":0" />


As for dosage, the suggested amount of this class of drugs is between 6-20 mg daily; however, there is a specific anticholinergic phenothiazine compound that is to be taken from 50-600 mg daily. The half life of anticholinergic drugs is between 4 hours to 24 hours, with Diphenhydramine being on the shorter range and Biperiden being on the higher range.
The main role of these drugs is in young patients at early stages of the disease for the relief of mild movement symptoms, particularly tremors and muscle stiffness. They are generally avoided in elderly patients or those with cognitive problems, due to an increased risk of confusion with this class of drugs<ref name=":0" />.


Each medication has its own particular side effects; however common adverse effects of anticholinergic drugs include memory problems, drowsiness, constipation, sedation, urinary retention, blurred vision, tachycardia, and delirium. Increased side effects are typically seen in the elderly, when compared with younger adults. As a physical therapist, these are all things to consider, especially when treating your elderly patients. Future studies must be performed to get a better understanding of why elderly patients tolerate this drug less<ref>Brocks, D. R. Anticholinergic drugs used in Parkinson's: An overlooked class of drugs from a pharmacokinetic perspective. J Pharmaceut Sci.<nowiki>https://sites.ualberta.ca/~csps/JPPS2(2)/D.Brocks2/anticholinergic.htm</nowiki>. August 22, 1999. Accessed November 5, 2018</ref>.
Examples of anticholinergics include benztropine, orphenadrine, procyclidine, and trihexyphenidyl (Benzhexol). Common adverse effects of anticholinergic drugs include memory problems, drowsiness, constipation, sedation, urinary retention, blurred vision, tachycardia, and delirium. Increased side effects are typically seen in the elderly, when compared with younger adults. As a physical therapist, these are all things to consider, especially when treating your elderly patients<ref>Brocks, D. R. Anticholinergic drugs used in Parkinson's: An overlooked class of drugs from a pharmacokinetic perspective. J Pharmaceut Sci.<nowiki>https://sites.ualberta.ca/~csps/JPPS2(2)/D.Brocks2/anticholinergic.htm</nowiki>. August 22, 1999. Accessed November 5, 2018</ref>.


== Conclusion ==
== Conclusion ==

Revision as of 02:03, 15 April 2022

Original Editor - Andrew Bennett Lee Price Top Contributors - Lucinda hampton, Kim Jackson, Lauren Lopez, Mariam Hashem, Andrew Bennett Lee Price, Aminat Abolade, Tony Lowe and Nicole Bailey

Introduction[edit | edit source]

Dopamine .jpg

Parkinson’s disease (PD) is a gradually progressive neurodegenerative condition. The etiology and pathogenesis remain incompletely understood. There are currently no disease-modifying treatments for PD, with no neuroprotective agents currently available, treatment should only be initiated when quality of life is affected, and the potential benefits and side effects of these drug classes should be discussed with the patient[1]. The long-term duration of disease means that patients may take sophisticated medication regimes aimed at controlling the motor symptoms, with a likelihood of problematic side effects.

Understanding the impact of medication on both the movement and thought quality of people with Parkinson’s will help set goals and plans for physiotherapy intervention.

PD is caused by decreased dopamine production in the basal ganglia due to degeneration of dopamine-secreting neurons. Dopaminergic drugs designed to replace the action of dopamine in the deplete basal ganglia form the mainstay of PD treatment at present. This may be achieved through drugs that are metabolized to dopamine, that activate the dopamine receptor, or that prevent the breakdown of endogenous dopamine. Deep brain stimulation, stem cell therapy and gene therapy are alternative approaches that aim to lower the need to medications. Understanding the impact of medication on both the movement and thought quality of people with Parkinson’s will help set goals and plans for physiotherapy intervention.

The video below outlines briefly medication rational and major drug types

[2]

Main Medications[edit | edit source]

  1. Levodopa: The mainstay of current PD treatment are levodopa-based preparations, designed to replace the dopamine in the depleted striatum. See Levodopa in the Treatment of Parkinson's
  2. Dopamine agonists: Stimulate the activity of the dopamine system by binding to the dopaminergic receptors. Dopamine agonists are often prescribed as an initial therapy for PD, particularly in younger patients. This approach allows for a delay in the use of levodopa, which may reduce the impact of the problematic motor complications
  3. Drugs that prevent the breakdown of endogenous dopamine work by inhibiting the enzymes involved in dopamine metabolism, which preserves the levels of endogenous dopamine eg Monoamine Oxidase B (MAO-B) inhibitors, Catechol-O-methyl transferase inhibitors.
  4. Anticholinergics: reduce the activity of the neurotransmitter acetylcholine, by acting as antagonists at cholinergic receptors. While their role is limited and they are now prescribed infrequently, they may offer some benefit in improving rigidity and tremor in PD

Levodopa[edit | edit source]

The mainstay of current PD treatment are levodopa-based preparations, designed to replace the dopamine in the depleted striatum. Dopamine itself is unable to cross the blood brain barrier (BBB) and cannot be used to treat PD. In contrast, the dopamine precursor levodopa is able to cross the BBB and can be administered as a therapy. After absorption and transit across the BBB, it is converted into the neurotransmitter dopamine by DOPA decarboxylase

Prevention of the Breakdown of Endogenous Dopamine[edit | edit source]

MAO-B Inhibitors work by inhibiting the enzymes involved in dopamine metabolism, which preserves the levels of endogenous dopamine eg Monoamine Oxidase B (MAO-B) inhibitors, Catechol-O-methyl transferase inhibitors. While they are sometimes sufficient for control of symptoms in early disease, most patients ultimately require levodopa-based treatment. MAO-B inhibitors may also be used in combination with levodopa-based preparations, to allow for a reduction in the levodopa dose. Commonly used MAO-B inhibitors include selegiline (Deprenyl, Eldepryl, Zelapar) and rasagiline (Azilect). More recently, the drug safinamide (Xadago) was also approved for use in PD, which appears to have multiple modes of action, one of which is thought to be inhibition of MAO-B [3][4]. MAO-B inhibitors are generally well tolerated, with gastrointestinal side effects being the most common problem. Other adverse effects include aching joints, depression, fatigue, dry mouth, insomnia, dizziness, confusion, nightmares, hallucinations, flu-like symptoms, indigestion, and headache.[3]

Catechol-O-methyl transferase inhibitors: another enzyme that is involved in dopamine degradation is COMT. These drugs are predominantly used as adjunctive therapy to levodopa, prolonging its duration of action by increasing its half-life and its delivery to the brain. COMT inhibitors come in the form of tablets and are not generally prescribed as monotherapy, as on their own they offer only limited effect on PD symptoms. Examples of COMT inhibitors include entacapone (Comtan), tolcapone (Tasmar), and opicapone (Ongentys). [3]

Dopamine Agonist Medications[edit | edit source]

Dopamine agonists are another commonly used class of drugs implemented during the treatment of PD[5][6]. Dopamine agonists work by actively influencing dopamine receptors in the brain to produce more in-vivo dopamine, thus making it the preferential treatment early on in the disease process. Apomorphine is considered the premier drug in this category, due to its powerful motor fluctuation modulating capabilities, such as those seen in end of dose dyskinesias generated by some anti-parkinsonian medications (i.e. LD)[7]. Apomorphine is typically administered subcutaneously on a continuous cycle for an average of 16 hours per day at a rate of 3-6 mg/hr[8]. Further pharmacokinetics of apomorphine, include the drug taking approximately 15-20 minutes to reach its maximum bioavailability within the bloodstream[9][10]. Once in the blood, the drug takes about 30-40 minutes to reach its half life[8][9][10]. This is fairly quick and the reason for the drug being given on a constant basis throughout the day[8]. Apomorphine’s clearance in the system is close to 3-4 L/h/kg, meaning that it leaves the plasma at a rapid rate[11]. After the drug has been metabolized, it is then excreted through urine by the kidneys[8].

The main adverse effects seen after the intake of this medication include somnolence, withdrawal, and psychiatric disorders, such as confusion and hallucinations[7][8]. It is vital that the physical therapist is aware of such side effects to dictate the treatment.

Anticholinergic Medications[edit | edit source]

The medications that have so far been discussed are all aim to increase dopaminergic activity in the striatum. These reduce the activity of the neurotransmitter acetylcholine, by acting as antagonists at cholinergic receptors. While their role is limited and they are now prescribed infrequently, they may offer some benefit in improving rigidity and tremor in PD. Loss of dopaminergic neurons results in disturbance of the normal balance between dopamine and acetylcholine in the brain, and anticholinergic drugs may lead to restoration and maintenance of the normal balance between these two neurotransmitters.[3]

The main role of these drugs is in young patients at early stages of the disease for the relief of mild movement symptoms, particularly tremors and muscle stiffness. They are generally avoided in elderly patients or those with cognitive problems, due to an increased risk of confusion with this class of drugs[3].

Examples of anticholinergics include benztropine, orphenadrine, procyclidine, and trihexyphenidyl (Benzhexol). Common adverse effects of anticholinergic drugs include memory problems, drowsiness, constipation, sedation, urinary retention, blurred vision, tachycardia, and delirium. Increased side effects are typically seen in the elderly, when compared with younger adults. As a physical therapist, these are all things to consider, especially when treating your elderly patients[12].

Conclusion[edit | edit source]

Levodopa, MAO-B inhibitors, Dopamine agonist, and Anticholinergic drugs are the main medications used in the treatment of the neurodegenerative condition, Parkinson’s Disease. Understanding the importance and impact of antiparkinsonian medications on our patients living with this disease is imperative. Being able to recognize early warning signs of adverse symptoms of the medications such as: weakness, dizziness, confusion, and dyskinesias could greatly alter our plan of care and the patient’s safety. If left unaddressed, these adverse effects could substantially decrease our overall quality of care that we could administer. Furthermore, if we had a better grasp on how the drug worked within the body from the time it was given, to the point of excretion, a physical therapist may be able to plan their time of care accordingly to avoid these adverse issues.

References[edit | edit source]

  1. ↑ Pharmaceutical Journal Parkinson’s disease: management and guidance Available: https://pharmaceutical-journal.com/article/ld/parkinsons-disease-management-and-guidance(accessed 14.4.20220
  2. ↑ PD care New York Taking Control: Medications for Parkinson's Available from: https://www.youtube.com/watch?v=T8VojsSvv4E (last accessed 8.11.2019)
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Zahoor I, Shafi A, Haq E. Pharmacological treatment of Parkinson’s disease. Exon Publications. 2018 Dec 21:129-44. Available:https://www.ncbi.nlm.nih.gov/books/NBK536726/(accessed 14.4.2022)
  4. ↑ Teo KC, Ho SL. Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Translational neurodegeneration 2013 Dec;2(1):19.
  5. ↑ Bonuccelli U, D. D. Role of dopamine receptor agonist in the treatment of early Parkinson's. Parkinsonism Related Disorders, 2009;(4): S44-53.doi: 10.1016/S1353-8020(09)70835-1.
  6. ↑ Harris PE ,C. K. Prevalence of complementary and alternative medicine (CAM) used by the general population: a systematic review and update. Int J Clin Pract, 2012; 66(10): 924-939. doi: 10.1111/j.1742-1241.2012.02945.x.
  7. ↑ 7.0 7.1 Regina Katzenschlager MD, W. P. Apomorphine subcutaneous infusion in patients with Parkinson's with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet Neurology, 2018;(9):749-759. doi: 10.1016/S1474-4422(18)30239-
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Auffret M, D. S. (2018) Pharmacological Insights into the Use of Apomorphine in Parkinson's: Clinical Relevance. Clinical Drug Investigation, 2018; 38(4) 287-312. doi: 10.1007/s40261-018-0619-3.
  9. ↑ 9.0 9.1 Nomoto M, Kubo SI, Nagai M, Yamada T, Tamaoka A, Tsuboi Y, Hattori N, Parkinson's Study Group. A randomized controlled trial of subcutaneous apomorphine for Parkinson disease: a repeat dose and pharmacokinetic study. Clinical neuropharmacology. 2015 Nov 1;38(6):241-7.
  10. ↑ 10.0 10.1 Elisa Unti, R. C. Apomorphine hydrochloride for the treatment of Parkinson's . Expert Review of Neurotherapeutics, 2015; 15(7): 723-732. doi: 10.1586/14737175.2015.1051468.
  11. ↑ rgiolas A, H. H. (2001). The pharmacology and clinical pharmacokinetics of apomorphine. BJU international, 2001; 88(3): 18-21. https://doi.org/10.1046/j.1464-4096.2001.00124.x
  12. ↑ Brocks, D. R. Anticholinergic drugs used in Parkinson's: An overlooked class of drugs from a pharmacokinetic perspective. J Pharmaceut Sci.https://sites.ualberta.ca/~csps/JPPS2(2)/D.Brocks2/anticholinergic.htm. August 22, 1999. Accessed November 5, 2018
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