Module: Pharmacotherapy III Module Coordinator: Dr. Arwa M. Amin Mostafa Academic Level: Postgraduate, Master of Pharmacy in Clinical Pharmacy School: Dubai Pharmacy College Year of first presented in Class: 2018 This presentation is for Educational purpose. It has no commercial value associated with it.

1. Parkinson’s
Disease
Arwa M. Amin Mostafa
PhD, M.Pharm Clinical Pharm, Dip Mangt, B.Pharm.

2. Outlines
What we will discuss today?
• What is Parkinson’s Disease (PD)?
• What is the etiology of PD?
• What are the Risk Factors of PD?
• What is the Pathophysiology of PD?
• Parkinson’s Disease Vs Parkinsonism
• How to Diagnose PD?
• What are the Goals of PD Therapy?
• What are the Non-Pharmacological Treatment of PD?
• What are the Pharmacological Treatment of PD?
• How to evaluate PD Therapy?

3. Parkinson’s Disease
Parkinson’s Disease is a Neurodegenerative
Disease which involves motor deficits, as well as
other non-motor effect.
• PD is slowly progress over-time
and may severely affects patient’s
quality of life.
• PD is One of the most common
Brain diseases; second to
Alzheimer.

4. PD Etiology
• Primary PD: Unknown cause
• Secondary PD
– Genetic and Epigenetic factors
• PD related genes (Monogenic,
polygenic)
– Chronic Exposure to Toxins
• Herbicides and Pesticides
– Gut Microbiota Disturbances
• Recent literature suggest that alteration
of gut-microbiota is associated with
Motor Phenotype of PD (postural
instability and gait difficulty)*.
*Filip Scheperjans (2014). Gut Microbiota Are Related to Parkinson’s Disease and Clinical Phenotype

5. Risk Factors of PD
• Age: Risk ↑↑ with ↑↑ age
– Usually > 60 years old
– Early onset PD present but rare
• Sex: Men > Women
– Men 1.5 times women
• Family History
– Genetic predispositions
• Free Radicles
• Head Injury
• Gut Microbiota Disturbances

6. Risk Factors of PD
• Environmental Factors
– Chronic Exposure to Toxins
• Agriculture, Farmers
– Exposure to Herbicides, Pesticides
• Industrial Plants
• Air pollution
• Manganese dust
• Carbon monoxide (CO) poison
– Use of certain illicit neurotoxic
drugs such as MPTP (1-methyl-4-
phenyl-1,2,3,6-
tetrahydropyridine) → destroy
dopaminergic neurons in SN

7. Pathophysiology of PD
• PD is characterized by the presence of lesions in the
Substentia Nigra (SN) which is responsible of
dopamine production.
• When the SN gets affected, a substantial loss in
dopaminergic cell happens.
• PD involves high presence of Lewy bodies in
dopaminergic cells.
Genetic factors
Environmental Factors:
Pesticides, Neurotoxins
Age

8. Pathophysiology of PD
Reduced activation of dopamine1 and dopamine2
receptors results in:
• Greater inhibition of the Thalamus.
• Reduced activation of the Motor Cortex.

9. Pathophysiology of PD
Gut Microbiota Dysbiosis link with PD*
– Recent research showed that
• Phylum Firmicutes were ↓↓ in PD patients compared to
controls (Faecalibacterium prausnitzii, Lactobacillaceae
and Enterococcaceae).
• Phylum Proteobacteria were ↑↑ in individuals with PD
compared to controls (Enterobacteriaceae and
Bifidobacterium).
*Figure source: New insights into the role of gut microbiota in Parkinson’s disease,
http://www.gutmicrobiotaforhealth.com/en/new-insights-role-gut-microbiota-parkinsons-disease/
Marcus M. Unger et al (2016) Short chain fatty acids and gut microbiota differ between patients with
Parkinson's disease and age-matched controls http://www.prd-journal.com/article/S1353-8020(16)30323-
6/abstract

10. Pathophysiology of PD
Pathophysiology of PD:
https://www.youtube.com/watch?v=jyBakRkzswU
https://www.youtube.com/watch?v=NAfQoviLFR8

11. Clinical Presentation – Motor symptoms of PD
• Resting Tremors
– Hands tremors (begins unilateral)
• Muscular Rigidity or Stiffness
– Upper and lower extremities
– Facial muscle (Masklike face)
– Accompanied with Pain
• Bradykinesia (slowness of
movement)
• Akinesia (loss of movement)
• Balance Problem
• Gait Disorder
• Postural impairment (Falls)

12. Clinical Presentation- Motor symptoms of PD
Other Motor Symptoms (MS)
• Dystonia (Abnormal muscle
contraction)
• Akathisia (inability to stay still)
• Micrographia
Micrographia*
*Figure source: Micrographia secondary to lenticular lesions. https://www.ncbi.nlm.nih.gov/pubmed/12210889

13. *Figure source: http://neucrad.com/2018/01/15/risk-factors-symptoms-
and-complications-in-parkinsons-disease-an-awareness/
Autonomic Dysfunction:
• GI dysfunction (Constipation)
• 80% of PD patients
• Dysphagia (Difficulty to swallow)
• Sweating abnormalities
• Heart rate
• Sextual Dysfunction
• Drooling
• Dysphagia
• Decreased sense of smell
• Speech problems
• Urinary urgency, frequency and
incontinence
Clinical Presentation Non-Motor Symptoms of PD

14. Clinical Presentation Non-Motor Symptoms of PD
*Figure source: http://neucrad.com/2018/01/15/risk-factors-symptoms-and-
complications-in-parkinsons-disease-an-awareness/
• Pain
• Fatigue
• Central:
– Depression
– Irritability
– Dementia
– Anxiety
– Cognitive impairment
– Hallucination/delusion
– Sleep Disturbances

15. PD Diagnosis
• PD Diagnosis mainly is
CLINICAL
– Based on Clinical History and
Examination
• PD Clinical Diagnosis requires
2 of 3 cardinal signs:
– Resting Tremors
– Rigidity
– Bradykinesia
• MRI & CT
– Findings are unremarkable
MRI: Magnetic Resonance Imaging, CT: Computed Tomography

16. Laboratory Data
• No reliable Laboratory biomarker that can
distinguish PD from other conditions that have
a similar clinical presentation.
• Uric acid
• Serum Uric acid was significantly Low in
Male PD patients compared to controls*.
*Sakuta H, Suzuki K, Miyamoto T, et al. Serum uric acid levels in Parkinson’s disease and related disorders. Brain and Behavior. 2017;7(1):e00598. doi:10.1002/brb3.598.

17. PD Diagnosis: Parkinson’s Disease Vs Parkinsonism
• Parkinsonism “looks like Parkinson’s disease”
• It describes symptoms of Parkinson’s which may
be due to PD or other conditions.
• Parkinsonism Signs and Symptoms:
– Rest tremors (shaking)
– Bradykinesia (slow movements)
– Rigidity
– Postural instability (loss of balance).

18. • Parkinsonism symptoms may present due to PD
or other causes such as:
– Side effect of some drugs
• Antipsychotics drugs (Phenothiazine).
• Antiemetics drugs (Metoclopramide).
– Essential Tremors
– Vascular disease (Vascular Parkinsonism)
– Progressive Supranuclear Palsy
– Multiple System Atrophy (MSA)
• In PD diagnosis, other Parkinsonism conditions
must be excluded.
PD Diagnosis: Parkinson’s Disease Vs Parkinsonism

19. Stages of PD

20. Case Discussion
Mr. JK, a 75-year-old man is brought
into hospital suffering from
dehydration, which appears to be the
result of prolonged nausea and
vomiting (>24 hours). He is shaking,
confused, incoherent and unable to
provide lucid history. He had an IV
NaCl 0.9% w/v infusion. He continued
to vomit.

21. Case Discussion
Mr. JK was administered I.V.
Metoclopramide 10 mg and promptly
suffers an Oculogyric crisis. This is
reversed by the administration of I.V.
Procyclidine. After 12 hours, Mr. JK
is conscious and lucid but now has a
pronounced tremor, characteristic of
Parkinson’s disease.
Oculogyric Crisis
https://www.youtube.com/watch?v=nK5Si762KXA

22. Case Discussion
He reports he was initially was diagnosed about a
year ago by his GP. His GP has prescribed for him
Sinemet-110 (Carbidopa-Levodopa) tablets, (the
initial dose was titrated) but Mr. JK did not take any
as the tremor did not really bother him until earlier
this week. He decided to start taking the Sinemet but
as the tremor was troublesome he started at the dose
of 1 tablet t.d.s.

23. Case Discussion
Mr. JK was a farmer and currently he is retired and
lives alone. He said he likes to farm his house
garden. However, he is no longer able to do so as
before because he feels muscle stiffness and it takes
him more efforts to get movement started.

24. Case Discussion
Basic laboratory values:
• Na+ 152 mmol/L (137–145 mmol/L)
• K+ 3.1 mmol/L (3.6–5.0 mmol/L)
• Bicarbonate 29 mmol/L (22–30 mmol/L)
• Urea 7.3 mmol/L (2.5–7.5 mmol/L)
• Creatinine 115 micromol/L (62–133 micromol/L)
• White blood count 8.4 × 109 /L (4–11 × 109 /L)

25. Case Discussion
What are the risk factors that may have lead to PD
in Mr. JK?
• Age: 75 years
• Male
• He was a farmer
• He had been chronically
exposed to herbicides and
pesticides

26. Case Discussion
What are the PD signs and symptoms of Mr. JK?
• Tremors
• Rigidity (muscle stiffness)
• Bradykinesia (Slowness)
• Severe adverse effect response to
Metoclopramide (Oculogyric crisis)

27. PD Therapeutic Targets
What are the Therapeutic Goals of PD
Treatment?
• Prevention of clinical progression.
• Delaying motor complications.
• Improvement of motor and non-
motor symptoms.
• Minimize drugs side effects

28. Case Discussion
• What are the Non-Pharmacological Treatment
options of PD that you can discuss with Mr.
JK?

29. • Educating patient about PD
• Psychiatric Counseling
• Exercise
• Physiotherapy
• Occupational Therapy
• Speech Therapy
• Following a Well balanced diet
• Diet should contain fibers and
sufficient water to reduce
constipation
• Stopping exposure to Toxins
• Industrial plants
• Pesticides exposure
Non-Pharmacological Treatment of PD

30. Case Discussion
What are the Pharmacological Treatment options
of PD? What is the suitable PD pharmacological
Treatment for Mr. JK?

31. Pharmacological Therapy of PD
DDC: Dopa-Decarboxylase Enzyme, MAO-B: Mono-amin-oxidase-B enzyme, COMT : catechol-o-methyl-transferase enzyme
Anticholinergic
Benztropine
Trihexyphenidyl

32. Source: Parkinson Disease, Pharmacotherapy: A Pathophysiologic Approach, 10e, Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A
Pathophysiologic Approach, 10e; 2017 Available at: http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=134127873 Accessed: March 14, 2018,
Copyright © 2018 McGraw-Hill Education. All rights reserved
General approach to the management of early to advanced Parkinson disease. *Age is not the sole determinant for drug choice. Other factors such as
cognitive function and overall tolerability of drug (especially in the elderly) should be considered.
General approach to the
management of early to
advanced Parkinson’s
disease

33. Source: Parkinson Disease, Pharmacotherapy Handbook: A Pathophysiologic Approach, 9e, Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2015

34. Let’s go back to Mr. JK
• Since Mr. JK is ≥ 65 years, the suitable
treatment for him is Carbidopa-Levodopa.
However, the dose should be titrated.
– Starting Dose: 100 – 300 mg/day
– Maintenance Dose: 300 – 1000 mg/day
What is the suitable PD pharmacological
Treatment for Mr. JK?

35. Let’s go back to Mr. JK
PD Drugs Adverse effects
• What may have caused severe vomiting for
Mr. JK when he was admitted?
• Why did he suffer the adverse effect of
Oculogyric crisis after taking
Metoclopramide?

36. Case Discussion
What may have caused severe vomiting for Mr.
JK? Why?
• Mr. JK didn’t titrate Senemit-110
(Carbidopa-Levodopa). Although it is
combined with carbidopa, levodopa is
peripherally metabolized to dopamine and
high peripheral levels of dopamine cause
nausea and vomiting.
• Levodopa causes nausea and vomiting due
to irritation of the GI.

37. Case Discussion
• Why did he suffer the adverse effect of
Oculogyric crisis after taking
Metoclopramide?
• Metoclopramide is a centrally acting dopamine
antagonist. In patients with Parkinson’s disease
it antagonizes the already depleted dopamine in
the brain so causing deterioration in
parkinsonism symptoms. An oculogyric crisis is
an extreme form of extrapyramidal adverse
effect.

38. Source: Parkinson Disease, Pharmacotherapy Handbook: A Pathophysiologic Approach, 9e, Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2015

39. Source: Parkinson Disease, Pharmacotherapy Handbook: A Pathophysiologic Approach, 9e, Citation: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2015

40. Case Discussion
Mr. JK was re-titrated on Sinemet-110 but at 3 times a
day dosage his symptoms were still not controlled.
The dose was increased to five times a day. He was
discharged on the following prescription:
• Sinemet-110 tablets five times a day
• Senna tablets 2 p.r.n.
• Lactulose liquid 15 mL b.d. p.r.n.
• Domperidone 10 mg tablets t.d.s. p.r.n.

41. Case Discussion
Why Domperidone is better option to treat
Nausea and Vomiting of Mr. JK? What other
options you can suggest to treat N & V of Mr.
JK?

42. Case Discussion
Why Domperidone is better option to treat Nausea
and Vomiting of Mr. JK? What other options you
can suggest to treat N & V of Mr. JK?
• Domperidone is peripherally selective dopamine
antagonist (D2 & D3 receptors), it does not pass
the blood–brain barrier (it will not interact with
D1 receptor). It will treat non-central dopamine-
induced nausea and vomiting.
• Other options to treat N & V due to Carbidopa-L-
dopa are taking it with food or (reducing the
dose + adding Amantadine).

43. Case Discussion
Why was the dosage interval of Sinemet-110
tablets reduced rather than increasing the
dose?

44. Case Discussion
Why was the dosage interval of Sinemet-110
tablets reduced rather than increasing the
dose?
• Frequent dosing is preferred to long intervals
between higher doses because they help in
achieving adequate dopamine levels while
avoiding excessive fluctuation in those levels
which produces better control of symptoms.

45. “End-of-Dose-Wear-Off” & Peak-dose Dyskinesia”
• “End-of-Dose-Wearing-off” is a fading of L-Dopa
effect (Tolerance).
• It happens over years and usually seen towards
the end of the dose period.

46. “End-of-Dose-Wear-Off” & Peak-dose Dyskinesia”

47. “End-of-Dose-Wear-Off” & Peak-dose Dyskinesia”
• End-of-Dose-Wearing-off” is related to the
increasing loss of neuronal dopamine storage
capability and the short half-life of L-dopa.
• Bedtime administration of a dopamine agonist or
a sustained-release formulation product may help
reduce nighttime off episodes and improve
morning functioning.

48. Evaluation of PD Therapy
• Educate patients and caregivers about
recording medication doses and administration
times and duration of “on” and “off ” periods.
• Monitor symptoms, side effects, and activities of
daily living, and individualize therapy.
• Concomitant medications that may worsen
motor symptoms, memory, falls, or behavioral
symptoms should be discontinued if possible.

49. Knowledge Increases By Sharing