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<div class="editorbox"> '''Original Editor '''- [[User:User Name|Andrew Bennett Lee Price]] '''Top Contributors''' - {{Special:Contributors/{{FULLPAGENAME}}}}</div>
== Introduction ==
== Introduction ==
Parkinson’s Disease  is a progressive neurodegenerative disorder that affects motor function. This disease has become an epidemic, affecting approximately 1 percent of individuals over the age of 65 years old <ref>Harris PE ,C. K. Prevalence of complementary and alternative medicine (CAM) used by the general population: a systematic review and update. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/22994327</nowiki>. October, 2012. Accessed November 5, 2018.</ref>. It is caused by decreased dopamine production in the basal ganglia due to degeneration of dopamine-secreting neurons <ref name=":0">Chen JJ, Nelson MV, Swope DM. Parkinson’s disease. DiPiro JT, Et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: Mcgraw-Hill. 2011. </ref>,<ref>Parent M, Parent A. Substantia nigra and Parkinson's: a brief history of their long and intimate relationship. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/20481265</nowiki>. May, 2010. Accessed November 5, 2018.</ref>.
[[File:Parkinson disease representation.jpeg|thumb|Parkinson's Disease]]
 
[[Parkinson's|Parkinson’s]] disease (PD) is a gradually progressive [[Neurodegenerative Disease|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<ref>Pharmaceutical Journal Parkinson’s disease: management and guidance Available: https://pharmaceutical-journal.com/article/ld/parkinsons-disease-management-and-guidance<nowiki/>(accessed 14.4.20220</ref>.
Initially, PD sufferers may be asymptomatic with the first clinical symptoms appearing after 60% of the dopaminergic neurons have degenerated in the substantia nigra <ref>Lecht, S., Haroutiunian, S., Hoffman, A., & Lazarovici, P. Rasagiline – A Novel MAO B Inhibitor in Parkinson’s Disease Therapy. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386362/</nowiki>. June, 2007. Accessed November 5, 2018.</ref>. Cardinal symptoms of Parkinson disease include bradykinesia, akinesia, rigidity, and resting tremors <ref name=":0" />,<ref>Garcia Ruiz PJ, Catalan MJ, Fernandez Carril JM. Initial motor symptoms of Parkinson disease. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/22045320</nowiki>. November 17, 2011. Accessed November 5, 2018.</ref>. The exact cause of PD is unknown; however, contributing factors to may include trauma, infection, cortical degeneration, antipsychotic drugs and cerebrovascular disease <ref>Gelabert-Gonzalez M, Serramito-Garcia R, Aran-Echabe E. Parkinsonism secondary to subdural haematoma. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/22527627</nowiki>. July, 2012. Accessed November 5, 2018. </ref><ref>Gupta D Kuruvilla. Vascular parkinsonism: what makes it different? NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/22121251</nowiki>. December, 2011. Accessed November 5, 2018. </ref><ref>Lopez-Sedon JL, Mena MA, de Yebenes JG. Drug-induced parkinsonism in the elderly: incidence, management and prevention. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/22250585</nowiki>. February, 2012. Accessed November 5, 2018.</ref><ref>Mazokopakis EE, Koutras A, Starakis I, Panos G. Pathogens and chronic or long-term neurologic disorders. NCBI. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/21446901</nowiki>. March, 2011. Accessed November 5, 2018.</ref>. If PD goes untreated, total incapacitation will occur due to uncontrolled motor problems. This is why it is extremely important for PD patients to be prescribed the proper drug regimen.
 
The inter-dependency of healthcare professionals is significant in the management of Parkinson's. Specialists are encouraged to have the knowledge and understanding of the condition and its impact on the quality of life. Communication is a key and it should aim to empower individuals who suffer Parkinson's to develop effective self-management strategies with an optimistic and realistic approach.
 
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. Individual Parkinson’s Associations provide country-specific information about medications prescribed. E.g. In the UK, where physiotherapists can train to prescribe medication, a good summary of drug therapies can be found on the [http://www.parkinsons.org.uk/content/drug-treatments Parkinson’s UK] site&nbsp;and in the US, the [http://www.parkinson.org/Parkinson-s-Disease/Treatment/Medications-for-Motor-Symptoms-of-PD National Parkinson’s Foundation] provides advice. 


Parkinson's medications are most commonly administrated orally. Injections and subcutaneous medications are available but expensive.  
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>


Medication help in controlling motor and non-motor symptoms, however, fluctuations in the responsiveness are experienced as the condition is progressed. Wearing off and motor fluctuations occur as the body develops dependency and the threshold to medications is altered. [https://www.epda.eu.com/about-parkinsons/symptoms/motor-symptoms/wearing-off-and-motor-fluctuations/ Refer to the EPDA website to learn more on wearing off.] 
PD is caused by decreased [[dopamine]] production. Dopaminergic drugs are designed to replace the action of dopamine and form the mainstay of PD treatment at present. This may be achieved through drugs that are metabolised 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.  
[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.  


== Dopaminergic 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 [[Parkinson's Drugs Physiotherapy Implications|physiotherapy intervention]].


=== 1-Levodopa ===
== Main Medications ==
Levodopa (L-dopa) is a common drug administered during the progressive stages of PD. L-dopa is considered a prodrug, meaning it is not activated until after it crosses the blood brain barrier via active transport<ref>Standaert DG, Roberson ED. Chapter 22: Treatment of Central Nervous System Degenerative Disorders. In: Goodman & Gilman's: The Pharmacological Basis of Therapeutics. Vol 1. 12th ed. New York, NY: The McGraw-Hill Companies, Inc. ; 2011.1.</ref>. The primary use of Levodopa is to restore depleted levels of dopamine at the presynaptic terminal of the substantia nigra, which restores functional movement<ref name=":1">Lewitt MD, PA. Levodopa therapy for Parkinsons disease: Pharmacokinetics and pharmacodynamics. Movement Disorders. 2014;30(1):65-67. doi:10.1002/mds.26082.</ref>. This replacement can relieve symptoms of PD, such as freezing and rigidity<ref name=":2">Connolly MD, BS, Lang MD, AE. Pharmacological Treatment of Parkinson Disease. Jama. 2014;311(16):1670. doi:10.1001/jama.2014.3654.</ref>. If a tolerance is built up to L-dopa, or adverse motor effects become present with this drug alone, partner drugs Benserazide and Carbidopa (LD-CD) can be supplemented to prevent the further premature breakdown in the periphery<ref>del Amo EM, Urtti A, Yliperttula M. Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. European Journal of Pharmaceutical Sciences. 2008;35(3):161-174. doi:10.1016/j.ejps.2008.06.015</ref>.
# Levodopa: The mainstay of current PD treatment are levodopa-based preparations, designed to replace the dopamine in the depleted striatum. See [[Levodopa - 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
# 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.
# Anticholinergics: reduce the activity of the [[Neurotransmitters|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


Optimal oral dosing of LD-CD is typically between 97.5 mg-390 mg for a single dose, and 25mg-100mg bi-daily/tri-daily for either sustained release or immediate release<ref>Hsu A, Yao HM, Gupta S, Modi NB. Comparison of the pharmacokinetics of an oral extended‐release capsule formulation of carbidopa‐levodopa (IPX066) with immediate‐release carbidopa‐levodopa (Sinemet®), sustained‐release carbidopa‐levodopa (Sinemet® CR), and carbidopa‐levodopa‐entacapone (Stalevo®). The Journal of Clinical Pharmacology. 2015 Sep 1;55(9):995-1003.</ref>. The volume of distribution is typically around 28.5 L and the plasma half-life clearance is 1.8 hours. Therefore, frequent dosage is required. The renal clearance of L-dopa is approximately 72 ml/min<ref name=":1" />.
== 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


Many of the adverse effects that are present with Levodopa are due to the fact that it is not combined with a partner drug. Some of the most common adverse effects to be aware of during a physical therapy visit include gastrointestinal distress due to the enteral administration, cardiac difficulties, gait disturbances due to dyskinesias, end of dose akinesia, and a tolerance after around 3-4 years. Administering physical therapy treatment during the peak time of this drug helps to avoid these end of dose side effects<ref name=":2" />.
== Prevention of the Breakdown of Endogenous Dopamine Medications ==
'''MAO-B Inhibitors''' work by inhibiting the [[enzymes]] involved in dopamine metabolism, which preserves the levels of endogenous dopamine. 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" />


== 2-MAO-B Inhibitors ==
'''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" />
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" />.


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" />.
== Dopamine Agonist Medications ==
Dopamine receptor agonists came into the market for the treatment of PD in 1978. 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. <ref name=":8">Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, Henriksen T, Van Laar T, Spivey K, Vel S, Staines H. [https://www.sciencedirect.com/science/article/pii/S1474442218302394 Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial]. The Lancet Neurology. 2018 Sep 1;17(9):749-59.</ref> 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<ref name=":0" />. In general, dopamine agonists are not as potent as carbidopa/levodopa and may be less likely to cause dyskinesias.  


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" />.
* Examples include: Pramipexole (Mirapex®), Pramipexole Dihydrochloride Extended-Release (Mirapex ER®), Ropinirole (Requip®), Ropinirole Extended-Release Tablets (Requip® XL™).
* The main adverse effects seen after the intake of this medication include somnolence, withdrawal, and psychiatric disorders, such as confusion and hallucinations<ref name=":8" /><ref name=":9">Auffret M, Drapier S, Vérin M. [https://link.springer.com/article/10.1007/s40261-018-0619-3 Pharmacological insights into the use of apomorphine in Parkinson’s disease: clinical relevance]. Clinical Drug Investigation. 2018 Apr;38:287-312.</ref>. It is vital that the physical therapist is aware of such side effects to dictate the treatment.


When used in adjunct with Levodopa both Selegiline and Rasagiline have been known to decrease motor fluctuations in patients with PD <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" />.
== Anticholinergic Medications ==
The medications that have so far been discussed are all aim to increase dopaminergic activity in the striatum. These reduce the activity of the [[Neurotransmitters|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" />


== 3-Dopamine Agonist Medications  ==
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" />.
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, PD 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" />.


The main adverse effects seen after the intake of this medication include somnolence, withdrawal, and psychiatric disorders, such as confusion and hallucinations<ref name=":8" /><ref name=":9" />. It is vital that the physical therapist is aware of such side effects to dictate the treatment.
* 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<ref>Brocks DR. [https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=0277b08c308424821218ac2f0aa7092cb816f07c Anticholinergic drugs used in Parkinson's disease: An overlooked class of drugs from a pharmacokinetic perspective]. J Pharm Pharm Sci. 1999 May 1;2(2):39-46.</ref>.


== Anticholinergic Medications  ==
== Amantadine ==
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.
Amantadine was initially developed as an antiviral medication to treat influenza in the 1960s; later it was realized that it can be used as a treatment for PD, and this use was confirmed in clinical trials. It acts as a nicotinic antagonist, dopamine agonist, and noncompetitive NMDA antagonist.


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.
Immediate-release amantadine is a mild agent that is used in early and advanced PD to help tremor. In recent years, amantadine has also been found useful in reducing dyskinesia that occur with dopamine medication. In 2017, an extended-release form of amantadine (Gocovri) was the first drug approved by the FDA specifically to treat dyskinesia in Parkinson's.<ref>PD org Amantadine Available;https://www.parkinson.org/Understanding-Parkinsons/Treatment/Prescription-Medications/Amantadine-Symmetrel (accessed 15.4.2022)</ref>


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>. 
== Physiotherapy Implications  ==
See [[Parkinson's Drugs Physiotherapy Implications]]


==References==
== References ==
<references />
<references />
[[Category:Parkinson's]]
[[Category:Parkinson's - Interventions]]
[[Category:Pharmacology for Older People]]
[[Category:Pharmacology]]

Latest revision as of 19:55, 27 January 2023

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]

Parkinson's Disease

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 video below outlines briefly medication rational and major drug types

[2]

PD is caused by decreased dopamine production. Dopaminergic drugs are designed to replace the action of dopamine and form the mainstay of PD treatment at present. This may be achieved through drugs that are metabolised 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.

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 Medications[edit | edit source]

MAO-B Inhibitors work by inhibiting the enzymes involved in dopamine metabolism, which preserves the levels of endogenous dopamine. 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 receptor agonists came into the market for the treatment of PD in 1978. 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. [5] 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]. In general, dopamine agonists are not as potent as carbidopa/levodopa and may be less likely to cause dyskinesias.

  • Examples include: Pramipexole (Mirapex®), Pramipexole Dihydrochloride Extended-Release (Mirapex ER®), Ropinirole (Requip®), Ropinirole Extended-Release Tablets (Requip® XL™).
  • The main adverse effects seen after the intake of this medication include somnolence, withdrawal, and psychiatric disorders, such as confusion and hallucinations[5][6]. 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[7].

Amantadine[edit | edit source]

Amantadine was initially developed as an antiviral medication to treat influenza in the 1960s; later it was realized that it can be used as a treatment for PD, and this use was confirmed in clinical trials. It acts as a nicotinic antagonist, dopamine agonist, and noncompetitive NMDA antagonist.

Immediate-release amantadine is a mild agent that is used in early and advanced PD to help tremor. In recent years, amantadine has also been found useful in reducing dyskinesia that occur with dopamine medication. In 2017, an extended-release form of amantadine (Gocovri) was the first drug approved by the FDA specifically to treat dyskinesia in Parkinson's.[8]

Physiotherapy Implications[edit | edit source]

See Parkinson's Drugs Physiotherapy Implications

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 3.5 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. ↑ 5.0 5.1 Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, Henriksen T, Van Laar T, Spivey K, Vel S, Staines H. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet Neurology. 2018 Sep 1;17(9):749-59.
  6. ↑ Auffret M, Drapier S, Vérin M. Pharmacological insights into the use of apomorphine in Parkinson’s disease: clinical relevance. Clinical Drug Investigation. 2018 Apr;38:287-312.
  7. ↑ Brocks DR. Anticholinergic drugs used in Parkinson's disease: An overlooked class of drugs from a pharmacokinetic perspective. J Pharm Pharm Sci. 1999 May 1;2(2):39-46.
  8. ↑ PD org Amantadine Available;https://www.parkinson.org/Understanding-Parkinsons/Treatment/Prescription-Medications/Amantadine-Symmetrel (accessed 15.4.2022)
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