Parkinson disease with The Pharmacotherapy

By Sara Sami Supervisor: Oruc Allahverdiyev

We can define PD as a slowly progressive of neurodegenerative disorder of the production neurotransmitter dopamine and with no identifiable cause.  

While Dopamine is a chemical messenger that transmits signals between two regions of the brain.

Any deficiency in the dopamine in the striatum will leaves the person unable to control movements and will then initial symptoms of Parkinson’s.[12]

Parkinson Disease

Striatum – Caudate Nucleus and Putamen

Substancia nigra pars compacta provide DA innervation to striatum

Golbus pallidus intra Substantia

Nigra

Golbus pallidus extera

Thalamus Subthalamu

s neuclia

Cortex

Basic gangilaStriatum

output

input

Cortex

Skeleton muscles

GABA receptor

GABA

GABA receptor

Glut

DA

D1 D2Excretory

Inhibitory

GABA receptor

Excessive inhibition Through the

spinal cord

Degeneration of neurones in the substantia nigra pars compacta

Degeneration of nigrostriatal (dopaminergic) tract

Results in deficiency of Dopamine in Striatum - >80%

The pathologic of Dopamine deficiency

Parkinson's disease has been known to mankind since ancient times. It is referred to in the ancient Indian medical system of Ayurveda under the name Kampavata (where “kampa” means tremor in Sanskrit).

In Western medicine it was described by the physician Galen as "shaking palsy" in AD 175.

Ancient Chinese sources also provide descriptions that suggest Parkinson's disease.[5]

Ancient references to Parkinson’s

James Parkinson: Whom was named Parkinson’s disease after him. In 1817 He detailed medical essay called “An Essay on the Shaking Palsy”[5]

Jean Martin Charcot: A French neurologist which found two types of  clinical spectrum – the tremor stage and the rigidity stage[5]

William Gowers: In his “Manual of Diseases of the Nervous System,” described his personal experience with 80 patients in the 1880s. He correctly identified the men were more prone to the disease and also detailed the joint deformities typical of the disease.[5]

In the 1960s chemical differences in the brains of Parkinson's patients were identified.

The researchers found that there were low levels of dopamine and degeneration of nerve cells in part of the brain called the substantia nigra  This made effective treatment of Parkinson’s disease with dopamine agonist.[5]

History of pathogenesis on Parkinson’s disease

◦ In the 1960s, Levodopa was first administered to treat the symptoms PD [6]

◦ Using of Belladonna alkaloids in treatment of the disease which active anticholinergic drugs was wildly used however the production of Hyoscyamine as anticholinergic agent had better results .[6]

◦ Dopamine was synthesized first in 1910 by G. Barger and J. Ewens. P. Holtz and discovered the enzyme, dopa decarboxylase that documented broken down levodopa to dopamine through its action.[6] 

◦ In1961 levodopa injected intravenously for the first time to PD [6]

History development of treatments for Parkinson’s

.

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease. The prevalence rate of PD varies

between 15 and 657/100.000 among different populations worldwide.[43]

.

Turkey: in a small area in the eastern part

Baskale with a population of 26.991 inhabitants in 2011 prevalence of PD in

Turkey was 202/100.000 that is slightly lower than those of European

countries, which may be caused by ethnical

differences or environmental factors

[43]

•It’s has been reported that 4% elderly over 60 years of the population over 80 with PD[21] however young onset begin between the ages of 20 and 50 is common .[22] •It’s less prevalent in African and Asian ancestry.•More common in men than women•Coffee and tea drinking,cigarette smoking anti-inflammatory drug ,high serum uric acid, physical activities [9][24] issued to lower the risk of PD however vitamin D deficiency index for higher risk of PD [9][24].

It has been reported to vary from 15 (per 100,000 population) in China to 657 in

Argentina [10,11].  However

the number of new cases per year  of

PD is between 8 and 18 per 100,000

Epidemiology incidence

Pathophsyology incidences The exact cause is unknown, however seems to relate to a combination of impaired degradation of proteins intracellular or protein accumulation or oxidative stress or mitochondrial damage or inflammatory cascades or and apoptosis. [24]

Enviromental facrors from : pesticide exposure, head injuries, and living in the country or farming places.[13][14] And the drinking of un well water exposure to pesticides.[15][16]

Gentitc : occurs in patients under age 50 [24]. Mutations in the parkin, LRRK2, and glucocerebrosidase genes are commonly found in multiethnic populations with familial early PD [17–19]

Lewy bodies (intracellular inclusion bodies containing αsynuclein) in fetal dopaminergic cells transplante into the brain of parkinsonian patients some years previously has provided some support for suggestions that Parkinson’s disease may represent a prion disease.[24]

Ageing : affects over 1% of the population over the age of 60while in individuals over the age of 85 this prevalence reaches 5%, [5]

Lysosomes :The most important functions of the lysosome is to store iron in a place in the cell where it is not accessible to participate in toxic oxidative stress-producing reactions," Mutation in a lysosomal gene results in the toxic release of iron into the cell, that resulting in neuronal cell death.

The solution : By tying up excess iron with a metal chelator that

protect mice from the ravaging effects of the well-known Parkinson's. It pulls iron from the cells indiscriminately and iron is needed throughout the body for many biological functions,“ [35]

New studies on pathological factor Excess iron in Parkinson's disease

Although There is no “one way” to diagnose Parkinson’s disease there must be two of the four main symptoms present over a period of time for a neurologist to consider a PD diagnosis, however new studies have found that the oxygen consumption  in the mitochondria, which leads to a build up of toxic byproducts that cause damage to brain cells and cause of the Parkinson’s disease.

Australia’s La Trobe University a blood test was developed of abnormal metabolism of blood cells in people with Parkinson. they said “We were able to show the mitochondria were perfectly normal but, were working four times as hard, which also leads to increased production of poisonous byproducts to occur.” [23]

New Diagnosis Blood test for parkinson disease

The test involves inserting a needle into the submandibular gland under the jaw and withdrawing the needle to obtain the core of gland tissue within. The researchers looked for a protein in the cells from patients who have early Parkinson's disease and compared this to subjects without the disease.[36]

New Diagnosis Submandibular gland biopsies

Lewy bodies : A proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated α-synuclein, also known as Lewy bodies, are the hallmark of Parkinson’s disease.

Genetic factors ,ageing or trauma in the head, has produce extra soluble protein that interacted with alpha-synuclein protein to produce toxic effects of Lewy bodies.

Solution :- The researchers used different forms of α-

synuclein and added to alpha-synuclein fibrils of the neurons, they interacted and no toxic

effects were present.[38]

New Diagnosis Optical ‘super-resolution’ techniques looking into

live neurons without damaging the tissue

Figure 30

Video

Video 39

◦Dopamine precursor: Levodopa◦Peripheral decarboxylase inhibitor: Carbidopa, Benserazide

(out the blood brain barrier )◦Dopaminergic agonists:

1) Ergot derivatives: as Bromocriptine or Pergolide

2) Non ergot derivatives as Ropinirole, Pramipexole ,Rotigotine◦MAO-B inhibitor: Selegiline , Arsagiline◦COMT inhibitors: Entacapone, Tolcapone◦Dopamine facilitator: Amantadine

Classification of Parkinsonian drugs

Fig 31

Drugs affecting brain cholinergic system

◦Central anticholinergics: Trihexyphenidyl, Procyclidine, Biperiden that are not used in turkey

◦Antihistaminics: Orphenadrine, Promethazine, Benztropine

dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) .

Figure [38]

Dopamine itself does not cross the blood-brain barrier and therefore has no CNS effects. However, levodopa, as an amino acid, is transported into the brain by amino acid transport systems, where It is converted to dopamine by the enzyme L-aromatic amino acid decarboxylase.[24]

Dopamine

levodopa can pass freely through the brain barrier reaching the CNS, however it administered with COMT inhibitor such as carbidopa that do not penetrate into the CNS[38] The most commonly prescribed form of carbidopa/levodopa is the 25/100. [26] and its limited by the development of dyskinesias

Figure 40

Levodopa

Nasal mucosal grafting is a technique regularly used in the ENT field to reconstruct the barrier around the brain after surgery to the skull base. ENT surgeons commonly use endoscopic approaches to remove brain tumors through the nose by making a window through the blood-brain barrier and access the brain. Once they have finished the treatment, they use adjacent nasal lining to rebuild the hole in a permanent and safe way. The safety and efficacy of these methods have been well established through long-term clinical outcomes studies in the field, with the nasal lining protecting the brain from infection just as the blood brain barrier has done.[32]

New surgical techniques to deliver drugs across the naturally impenetrable blood-brain barrier. 

1) Gastrointestinal effect: nausea and vomiting

2) Cardiovascular Effects: tachycardia , hypotention

3)Mental effects : Depression, anxiety.3) Dyskinesias as chorea and tremor4) Miscellaneous: acute glaucoma, blood

dyscrasias,

Levodopa Adverse effects

Contraindications[27]1. Psychotic patients2. Angle-closure glaucoma 3. Cardiac disease4. Peptic ulcer 5. Melanoma

Drugs Contraindications Levodopa

Four orally administered dopamine-receptor agonists are available for treatment of PD [27]

1) Ergot derivatives: as Bromocriptine or Pergolide old drugs are not wildly used these days.

2) Non ergot derivatives as Ropinirole, pramipexole

Dopamine receptor agonists

Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea. 

Pramipexole: agonist of D3,monotherapy for mild to advance PD, starting with the dose of 0.125mg , 0.5 and 1.5 mg 3 times s day for a week then doubled after the next week.

Ropinirole: agonst for D2, monotherapy smoothing the response to levodopa in patients with more advanced disease and response fluctuations. Starting with 0.25 mg three times daily and gradually increase reaching 1.5mg.

Rotigotine: available in skin patches

Gastrointestinal Cardiovascular Effects Dyskinesias Mental Disturbances Miscellaneous

Adverse effect of Dopamine agonist

1. Psychotic patients2. Angle-closure glaucoma 3. Cardiac disease4. Peptic ulcer 5. Peripheral vascular disease (ergot

derivatives).

Dopamine agonists Contraindications[43]

Monoamine oxidase (B) metabolizes dopamine.[28] Selegiline:Mechanism of action:• Selective inhibitor of monoamine oxidase B (retards the

breakdown of dopamine). Given alone, it has a weak action. It is therefore used as adjunctive therapy for patients with a declining response to levodopa of the stander dose 5mg.

Side effects:• May cause insomnia when taken later during the day. Drug interactions:• It should not be taken by patients receiving tricyclic

antidepressants, or serotonin reuptake inhibitors because of the risk of acute toxic interactions.

Drugs Monoamine oxidase B inhibitors

Meperidine: one of it’s contaminated manufacture product is MPP+ that selectively taken up by cells in the substantia nigra to inhibits mitochondrial complex oxidative phosphorylation that cause cell death and dopamine depletion and parkinsonism accrue.

Exposuring to toxin environmental that is similarly selective in MPP+ target, may lead to cell death by the same pathway However, no such toxin has been identified yet.

Pretreatment with a monoamine oxidase B inhibitor such as selegiline/ Arsagilin prevents the conversion of MPTP to MPP+ and thus protects against the occurrence of parkinsonism.[37]

It was sugguested that Selegiline or Rasagiline may retard the progression of Parkinson’s disease in humans and a first line in neuro prodation !!

Fig 42

Tolcapone

• Mechanism of action:1. Inhibit catechol O methyl transferase (COMT) which is

responsible for the conversion of dopa into 3 – O methyl dopa. Elevated levels of methyldopa decreases the response to levodopa, because methyldopa competes with levodopa for an active carrier mechanism that governs its transport across the blood-brain barrier.

• These agents may be helpful in patients receiving levodopa to reduce dose and decrease fluctuations in response

• Side effects are similar to levodopa

Catechol O methyl transferase inhibitors

Fig 41

Amantadine, an antiviral agent. Its mode of action in parkinsonism is unclear but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine

Clinical Use• Amantadine is less potent than levodopa and its effects

disappear after only a few weeks of treatmentAdverse Effects

1. Central nervous system effects 2. Peripheral edema3. headache 4. Heart failure5. postural hypotension 6. urinary retention 7. gastrointestinalContraindications• Amantadine should be used with caution in patients with a

history of seizures or heart failure.

Amantadine

Benztropine Clinical Use Antimuscarinic drugs may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia.

Acetylcholine blocking drugs

Adverse Effects 1) Central nervous system2) Atropine – like actions: dryness of the mouth,

blurring of vision.

withdrawal should be gradual in order to prevent acute exacerbation of parkinsonism.

Contraindications1. Prostatic hyperplasia, 2. Obstructive gastrointestinal disease (eg, paralytic

ileus)3. Angle-closure glaucoma.

None of the above drugs alter the basic pathology of PD – the disease continues to progress. Drugs only provide symptomatic relief and give most patients an additional 3-10 years of happier and productive life.

Important Note

A neurosurgical procedure: Is a neurostimulator delivers electrical signals to specific areas of the brain to help regulate abnormal signals, Stimulation of the subthalamic nucleus or globus pallidus by an implanted electrode and stimulator has yielded good results for the management of the clinical fluctuations occurring in advanced

parkinsonism.[37] However it’s benefit occurred inyounger (less than 60 years old)

New group of treatment

Rivastigmine: It’s already know that Rivastigmine works to treat dementia by preventing the breakdown of acetylcholine, however our study shows for the first time that it can also improve regularity of walking, speed, and balance. This is a real breakthrough in reducing the risk of falls for people with Parkinson's.“[34]

Howevre other thinking agents like of Memantine or Donepezil or placebo drug use in Alzheimer may be useful in nonmotor manifestation of PD.[37]

New group of treatment

GM1 Ganglioside: Is normally made by nerve cells in the brain, but the substance is made at much lower levels in patients with Parkinson's. It was extract from cow brains to improve earlier symptoms and progression of PD However new reseacher suggested instead of putting more GM1 into the brain, why not try to get the brain to make more of it. They he found an enzyme called sialidase was capable of converting other naturally occurring ganglioside molecules in the brain into GM1 ganglioside.  .[33]

New group of treatment

Reserpine and the related drug Tetrabenazine deplete Haloperidol, Metoclopramide, and the Phenothiazines block dopamine receptors and meperidine all those induce PD usually within 3 months after introduction .

DRUG-INDUCED PARKINSONISM

Life is easier with the right

Pharmaceutical Drugs

Thank you for your attention

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Schrag A (December 2012). "Meta-analysis of early nonmotor features and risk factors for Parkinson disease". Annals of Neurology 72 (6): 893–901. doi:10.1002/ana.23687.PMC: 3556649. PMID 23071076

14- 32 Van Maele-Fabry G, Hoet P, Vilain F, Lison D (October 2012). "Occupational exposure to pesticides and Parkinson's disease: a systematic review and meta-analysis of cohort studies". Environ Int 46: 30–43. doi:10.1016/j.envint.2012.05.004. PMID 22698719.

15- 33 de Lau LM, Breteler MM (June 2006). "Epidemiology of Parkinson's disease". Lancet Neurol. 5 (6): 525 35. doi:10.1016/S1474-4422(06)70471-9. PMID 16713924.

16- 34  IOM (Institute of Medicine), ed. (2009). "Neurologic disorders". Veterans and Agent Orange: Update 2008. Washington D.C.: The National Academies press. pp. 510–45.ISBN 0-309-13884-1.

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18 23. Punia S, Behari M, Govindappa ST, et al. Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson’s disease patients. Neurosci Lett 2006;409:83–8.

19- 24. Madegowda RH, Kishore A, Anand A. Mutational screening of the parkin gene among South Indians with early onset Parkinson’s disease. J Neurol Neurosurg Psychiatry 2005; 76:1588–90.

20- 5 (de Lau and Breteler, 2006,Nussbaum and Ellis, 2003 and Wood-Kaczmar et al., 2006) 21-  de Lau LM, Breteler MM (June 2006). "Epidemiology of Parkinson's disease". Lancet Neurol. 5 (6): 525–35. 

doi:10.1016/S1474-4422(06)70471-9. PMID 16713924. 22-  Samii A, Nutt JG, Ransom BR (29 May 2004). "Parkinson's disease". Lancet 363 (9423): 1783–1193. doi:

10.1016/S0140-6736(04)16305-8.PMID 15172778. 23- 40

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24- 39 katzung book bag484 25- 38 katzung book bag485 26- 41 katzung book bag486 27- 42 katzung book bag488 28- 43katzung book bag490 29- 44katzung book bag488 30- Figure http://www.biotechnologyforums.com/thread-6958.html 31 – figure https://www.youtube.com/watch?v=E8AJylo4-To

32- 50 - Massachusetts Eye and Ear Infirmary. "Researchers develop drug delivery technique to bypass blood-brain barrier: Breakthrough could help countless patients with neurological conditions that are currently hard to treat." ScienceDaily. ScienceDaily, 20 October 2015. <www.sciencedaily.com/releases/2015/10/151020145221.htm>.

33- 51- Jay S. Schneider, Thomas N. Seyfried, Hyo-S. Choi, Sarah K. Kidd.Intraventricular Sialidase Administration Enhances GM1 Ganglioside Expression and Is Partially Neuroprotective in a Mouse Model of Parkinson’s Disease. PLOS ONE, 2015; 10 (12): e0143351 DOI: 10.1371/journal.pone.0143351

34- 52- Henderson E J et al. Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurology, January 2016 DOI: 10.1016/S1474-4422(15)00389-0

35- 53 S. Rajagopalan, A. Rane, S. J. Chinta, J. K. Andersen. Regulation of ATP13A2 via PHD2-HIF1  Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease. Journal of Neuroscience, 2016; 36 (4): 1086 DOI: 10.1523/JNEUROSCI.3117-15.2016

36- 54- Charles H. Adler, Brittany N. Dugger, Joseph G. Hentz, Michael L. Hinni, David G. Lott, Erika Driver-Dunckley, Shyamal Mehta, Geidy Serrano, Lucia I. Sue, Amy Duffy, Anthony Intorcia, Jessica Filon, Joel Pullen, Douglas G. Walker, Thomas G. Beach. Peripheral Synucleinopathy in Early Parkinson's Disease: Submandibular Gland Needle Biopsy Findings. Movement

Disorders, 2016; DOI: 10.1002/mds.26476 37- 55 – book of katzung bag 492 38- 56 Dorothea Pinotsi et. al. Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in

neurons.Proceedings of the National Academy of Sciences, 2016 DOI:10.1073/pnas.1516546113 38- http://parkinsonsed.com/pd-dialogues/mao-b-in-parkinsons 39 - https://www.youtube.com/watch?v=j86omOwx0Hk 40- Figure https://www.studyblue.com/notes/note/n/parkinson-s-disease-/deck/7642706?blurry=e&ads=true 41 – figure http://tmedweb.tulane.edu/pharmwiki/doku.php/pd_pathways_targets 42 - figure http://bmsia.blogspot.com.tr/2012/10/mptp-and-mpp-toxicity-neuronal-and.html 43- Hacer Durmus • Mehmet A. Gokalp • Hasmet A. Hanagasi from Prevalence of Parkinson’s disease in Baskale, Turkey: a population based study