1. Parkinson's disease is a progressive neurodegenerative disorder that causes movement abnormalities like tremors and rigidity due to the loss of dopamine-producing neurons in the substantia nigra. 2. Levodopa is the most effective treatment for motor symptoms but its effectiveness reduces over time and side effects like dyskinesia emerge. 3. Deep brain stimulation (DBS) is an alternative treatment that involves implanting electrodes in the brain to deliver electrical stimulation to areas affected by Parkinson's and help control motor symptoms.

1. 1

2. WHAT IS PARKINSON’S
DISEASE (PD)
2

3. 3
Parkinson’s disease is the second most common neurodegenerative disorder
The disease causes progressively more pronounced movement abnormalities, along with symptoms
including speech problems and cognitive abnormalities
Symptoms start gradually starting barely with noticeable tremor in just one hand. Tremors are common
but the disorder also causes stiffness or slowing of movement.
The muscles of PD persons become weaker and may assume unusual posture

4. 4
A progressive disease of the nervous system marked by tremor, muscular rigidity, and
slow imprecise movement, chiefly affecting middle-aged and elderly people.
It is associated with degeneration of the basal ganglia of the brain and a deficiency of
the neurotransmitter dopamine.
Parkinson’s disease (PD)
Dopamine
Dopamine is a neuromodulatory molecule , a type of monoamine neurotransmitter.
An organic chemical of the catecholamine and phenethyl-amine families. Acts as a chemical
messenger, communicating messages between nerve cells in the brain and the rest of the
body. Also acts as a hormone.

5. CAUSES OF PARKINSON’S
Dopamine acts as a messenger between two brain areas - the substantia nigra and the corpus
striatum - to produce smooth, controlled movements.
• PD  caused by a lack of dopamine due to the
loss of dopamine-producing cells in the
substantia nigra.
• When the amount of dopamine is too low 
communication between the substantia nigra and
corpus striatum becomes ineffective 
movement becomes impaired.
• The greater the loss of dopamine, the worse the
movement-related symptoms
5

6. PATHOLOGY
Neuro degenerative disease
Dopamine levels in Basal
Ganglia
6
Parkinson's disease is a
neurodegenerative
disorder, which leads to
progressive deterioration of
motor function due to loss
of dopamine-producing
brain cells.

7. 7
Motor pathways
A motor neuron (or Moto
neuron or efferent neuron is a
neuron whose cell body is
located in the motor cortex or
the brainstem and whose axon
(fiber) projects to the spinal
cord and outside of the spinal
cord to control effector organs,
mainly muscles and glands.
There are two types of motor
neuron – upper motor neurons
and lower motor neurons.
Axons from upper motor
neurons synapse in the spinal
cord and occasionally directly
onto lower motor neurons.
The axons from the lower
motor neurons are efferent
nerve fibers that carry signals
from the spinal cord to the
effectors.
Types of lower motor neurons
are alpha motor neurons, beta
motor neurons, and gamma
motor neurons.

8. A motor skill is a function that
involves specific movements of
the body's muscles to perform
a certain task. These tasks
could include walking, running,
or riding a bike.
In order to perform this skill,
the body's nervous system,
muscles, and brain have to all
work together
What part of the brain controls motor function?
The Cerebellum
This area of the brain is responsible for fine motor
movement with balance,.
What is the difference between motor and sensory nerves?
Sensory neurons carry signals from receptors to the spinal cord and brain
whereas motor neurons carry signals from the central nervous system to
effector organs.

9. 9
Basal ganglia (BG) —situated-- base of the
forebrain and top of the midbrain--
interconnected with-- cerebral cortex,
thalamus, and brainstem, as well as --other
brain areas. BG- functions-- control of
voluntary motor movements, procedural
learning, habit learning, conditional learning,
eye movements, cognition, and emotion.
Main components of BG – striatum,
consisting of (caudate nucleus and
putamen) -- Globus pallidus, , the
Substantia Nigra (NG) and the subthalamic
nucleus.
The substantia nigra is the source of the
input of neurotransmitter dopamine, which
plays an important role in basal ganglia
function.
The dysfunction of basal ganglia involves
degeneration of the dopamine-producing
cells in the SN which eventually damages
the SN.
Basal ganglia

10. 1. IMBALANCE BETWEEN DOPAMINE AND
ACETYLCHOLINE
• Parkinsonism is a disease of the nigrostriatal
pathway of the basal ganglia. Two neuro
transmitters in this pathway dopamine and
acetylcholine. Both Dp and AcT have opposite
action, due to which a balance is required between
these two NT for proper functioning of basal
ganglia.
• Imbalance between any of these two will cause
parkinsonism.
• Degeneration of neurons occurs in substantia
nigra of basal ganglion
• Dopamine is formed by nigrostriatal pathway
(Dopaminergic pathway)
• Nigrostriatal pathway or Dopaminergic pathway is
present in the substantia nigra
• Acetylcholine excitatory neurotransmitter
• Dopamine Inhibitory neurotransmitter
BASAL GANGLION CONSISTS OF
 Caudate nucleus
 Putamen
 Substantia nigra
 Sub thalamic nucleus
Corpus
Striatum
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11. 11

12. 2. PATHOLOGY IN DOPAMINERGIC NEURONS
• WHY IS THERE DECREASE IN THE DOPAMINERGIC NEURONS ?
• WHY IS THERE DEGENERATION OF DOPAMINERGIC NEURONS ?
• THIS OCCURS DUE TO THE DEPOSITION OF INCLUSION BODIES
CALLED AS LEWY BODIES.
• DEPOSITION OF THE LEWY BODIES WITHIN THE NIGROSTRIATAL
PATHWAY LEADS TO DECREASE IN THE DOPAMINE LEVELS THEREBY
THE ACETYLCHOLINE DOMINATES
• MAIN STRATEGY IN TREATMENT OF PARKINSON
• TO INCREASE DOPAMINE
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13. 13
Dopamine & BG

14. Cause of Parkinson’s disease
Environmental
Exposure to pesticides
History of head injury
Genetics
~15% of individuals with PD have a first-degree relative
who has the disease
~5–10% of people with PD  have mutation in one of
several specific genes.
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15. List of genes known to contribute to
Parkinson:
SNCA: SNCA makes the protein alpha- synuclein,this
protein gathers in clumps called Lewy bodies. Mutations
in the SNCA gene occur in early-onset Parkinson’s
disease.
PARK7:.
PINK1: PARK7 & PINK1 mutations occur in early-onset
Parkinson’s disease.
LRRK2: LRRK2 gene have been linked to late-onset
Parkinson’s disease.
SNCA is the gene responsible for
making the protein that “clumps” in the
brain and triggers symptoms,
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16. 16
Normal : Deep
tendon
reflexes,
sensation like
pain
temperature ,
muscle power
Symptoms of Parkinson
Symptoms of Parkinson

17. SYMPTOMS OF PARKINSON
• Motor symptoms are those that are
related to movement,
• Bradykinesia/ Hyperkinesia - slow
movement
• Rigidity - cogwheel rigidity mostly elicited
in wrist joints
• Tremor – resting tremors initially
unilateral afterwards bilateral , typically
pill rolling movement
• Non-motor symptoms are those that are not
related to movement
• Mask like face – expressionless
• Micrographia – Handwriting becomes short
• Orthostasis – Postural hypotension
• Dementia initially later memory loss
• Gait is festinating – patient bends forward with
no arm swing
• Reduced blinking
17

18. RISK OF Parkinson’s
Age is the largest risk factor for the development and progression of PD.
• Most people who develop PD
are older than 60 years of
age, but some can even get PD
at 40 or younger.
• Men are affected about 1.5 to
2 times more often than
women.
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19. Indian scenario
In India  few population-based studies determining the exact incidence and
prevalence of PD.
• Bangalore (2004) 
76 per 100,000.
• Kolkata (2006) 
45.82 per 100,000.
• Kashmir  134 per 100,000
• Parsi community in Mumbai 
192 per 100,000.
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20. 20

21. CURRENT TREATMENTS
FOR PD
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22. Levodopa — Levodopa is a precursor of dopamine
It works by being converted to dopamine in the brain
Levodopa — Carbidopa--decarboxylase inhibitors
Levodopa Carbidopa both are given combined .In addition to
helping prevent nausea, Carbidopa prevents levodopa from being
converted into dopamine prematurely in the bloodstream,
allowing more of it to cross the blood brain barrier.
Dopamine agonists -- Dopamine agonists don't change into
dopamine. Instead, they mimic dopamine effects in brain (the
brain is tricked into thinking it is receiving the dopamine ).
Dopamine agonists include Pramipexole, Ropinirole, Rotigotine &
Apomorphin an injectable dopamine agonist used for quick relief
Istradefylline -- Adenosine A2a antagonists
COMT Inhibitors -- Entacapone & Tolcapone
MAO-B Inhibitors -- Selegiline ,Rasagiline & Safinamide
COMT Inhibitors & MAO-B Inhibitors should not be given
combined
Deep Brain Stimulation : High frequency stimulation to Globus
pallidus or sub thalamic nucleus
Complementary
Therapies:
Antioxidants: Vitamin C ,
D, E, Coenzyme Q10,
Folate and Milk Thistle are
also used as supportive
therapies . i
Treatment
Treatment
Exercise guidelines
include aerobic activity,
strength training,
balance, agility and
stretching.
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23. 23
Pramipexole
Ropinirole
Pergolide
Apomorphine
Talcopone
Entacopone

24. LEVODOPA + CARDBIDOPA
MECHANISM OF ACTION
• Levodopa is converted to dopamine via the action of an enzyme called DOPA Decarboxylase
(DDC).
• Occurs in two places:
peripheral blood circulation
Central Nervous System (CNS) after crossing the Blood
Brain Barriers (BBB).
• Activation of dopamine receptors:
In peripheral  causes nausea and vomiting
In CNS  improves symptoms of PD.
• Carbidopa  inhibits DDC
• Carbidopa  does not cross BBB and does not enter
CNS  Prevents peripheral conversion of levodopa to
dopamine and prevents unwanted side effects.
Levodopa
Carbidopa
Levodopa

25. LEVODOPA + CARDBIDOPA
MECHANISM OF ACTION
• Initially LD is well tolerated and provides no Motor complications (MC).
• This is called the honeymoon period of LD therapy,
• Followed by the insidious onset of MC and associated
non motor features, when the drug efficacy vanes.
Levodopa
Carbidopa
Levodopa

26. Limitations of Levodopa therapy
26
Levodopa and other dopaminergic medications drastically improve the motor symptoms and
quality of life of patients with Parkinson's disease in the early stages of the disease.
However, once the “honeymoon” period has waned, usually after a few years of dopaminergic
therapy, patients become progressively more disabled despite an ever more complex
combination of available anti-parkinsonian treatments.
Sooner or later, they suffer from “Dopa-resistant” motor symptoms (speech impairment,
abnormal posture, gait and balance problems),
“Dopa-resistant” non-motor signs (autonomic dysfunction, mood and cognitive impairment,
sleep problems, pain)
And drug-related side effects (especially psychosis, motor fluctuations, and dyskinesias).
Therefore, the current anti-parkinsonian therapy cannot be considered as ideal with regard to
both efficacy and safety.
Ann Neurol 2003;53 (suppl 3):S3–S15

27. 27

28. DEEP BRAIN SURGERY (DBS)
28

29. Problems of oral therapy in PD patients
More than 80 % of patients with (PD) develop dysphagia during the course of their disease.
Dysfunction of the gastrointestinal tract leads to:
-Problems with absorption of oral PD medication.
-Erratic treatment response.
-Silent aspiration, which is one of the key risk factors in developing pneumonia.
The issue is further complicated by gut abnormalities, such as
-Small intestinal bacterial overgrowth (SIBO), altered gut microbiota.
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30. 30

31. Problems of oral therapy in PD patients
-Failure of an oral dose of levodopa to produce an effect and delay in the onset of action have been associated
with problems in absorption of oral medication in PD patients.
-Most patients continue to experience residual OFF time with Oral dopamine agonists, monoamine oxidase
(MAO) inhibitors, and (COMT) inhibitors, which causes,
• Delayed time-to-ON,
• Dose failures
• Suboptimal ON response.
Therefore, non-oral therapies that avoid the gastrointestinal system seem a rational option to overcome the
problems of oral therapies in PD. Hence, several non-oral strategies like the infusion therapies with Apomorphine,
Apomorphine Pump and Apomorphine pen strategy are currently been developed and used clinically.
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32. Indication
•Treatment of motor fluctuations (“on-off”
phenomena) in patients with Parkinson's
disease.
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33. 33

34. 34

35. 35

36. APOSAN – fast onset of action
Absorption
Apomorphine is rapidly and
completely absorbed from
subcutaneous tissue,
correlating with the rapid
onset of clinical effects (4-10
minutes).
36

37. BIOCHEMISTRY--DOPAMINE RECEPTORS
• Dopamine a hormone neurotransmitter binds to the dopamine
receptors present in the central nervous system.
• Five types of dopamine receptors, D1, D2, D3, D4, and D5
• D1 and D5 receptors group together, and D2, D3, D4 are
together.
• D1 and D5 receptors mainly in the striatum and substantia
nigra while D2, D3, and D4 receptors mainly in the striatum,
the external globus pallidus and cerebral cortex.
• Functions are memory, attention, impulse control, regulation of
renal function, locomotion, sleep and decision making.
• Dopamine agonists exert their anti parkinsonian effects by
acting directly on dopamine receptors and mimicking the
endogenous neuro transmitter
• Apomorphine, is a potent direct and broad spectrum dopamine
agonist ( D1 , D2,D3,D4 and D5) 37

38. Different PD treatments
38

39. Mechanism of action
APOSAN® contains apomorphine hydrochloride salt and is non-Ergoline dopamine agonist
with high selectivity for dopamine D2, D3, D4 and D5 receptors.
Due to stimulation of post-synaptic dopamine D2-type receptors within the brain,
apomorphine shows improvement in motor and non-motor functions in Parkinson's disease.
Ergot-derived dopamine agonists
(bromocriptine, cabergoline,
pergolide), are related to cardiac
and other fibrotic reactions (fibrotic
cardiac valvulopathy)
Non ergot-derived drugs
(apomorphine, pramipexole,
ropinirole, rotigotine) do not
produce cardiac and other fibrotic
reactions.
39

40. Apomorphine
40
Apomorphine does not actually contain morphine, nor does it bind to opioid receptors. The apo- prefix relates to it being a
morphine derivative
Apomorphine is an agonist of both D1 and D2 dopamine receptors, with higher activity at D2.( members of the D2
subfamily, consisting of D2, D3, and D4 receptors,) .
Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway,
It also increases blood flow to the supplementary motor area (stimulation of which has been found to reduce the
dyskinesia effects of L-DOPA).
Apomorphine also exerts neuroprotective effects by stimulation of NGF (nerve growth factor) and GDNF(glial cell-derived
neurotrophic factor) .
NGF promote the growth of neurons while GDNF supports the survival of many types of brain cells, including the cells lost
in Parkinson's.
Apomorphine has a similar chemical structure as the neurotransmitter dopamine
.Its lipophilic structure allows it to cross the blood–brain barrier.

41. 41

42. NON-MOTOR BENEFITS
OF APOSAN
42

43. NON-MOTOR BENEFITS
OF APOSAN
43

44. 44

45. APOSAN® INJECTION
PACKAGING DESIGN & MRP
2 ml N5
₹
5 ml N5
45

46. APOSAN kit
APOSAN
ampoules
• 25*2ml
Syringe
• 25
Needles
• 150
46

47. Use of APOSAN
APOSAN is licensed for
use in patients with
disabling motor
fluctuations in patients
with Parkinson‟s disease,
-Intermittent
subcutaneous injection
-Continuous
subcutaneous infusion
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48. What is needed to inject aposan
-One syringe and needle. 30g*0.5 Hypodermic needle
-APOSAN ampoules and syringes should be disposed safely in an appropriate
manner.
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49. Qualitative and quantitative composition
2 ml contains 20 mg apomorphine hydrochloride
5 ml contains 50 mg apomorphine hydrochloride
Solution for Injection or Infusion
Clear, colourless or almost colourless, practically
free from visible particles
pH 3.0-4.0
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50. Dose recommendations
•The recommended dose is in the range of 3 mg (0.3ml) to 30 mg (3ml) per
day, injected 1 to 10 times a day at the first sign of an unpredictable “off”
period.
•Do not exceed a total daily dose of 100 mg (10ml).
•Do not inject more than 10 mg at any one time, unless advised by the
doctor.
•30g*0.5 Hypodermic needle
50

51. APOSAN® INJECTION
DURATION OF TREATMENT
• Apomorphine therapy is a treatment for a chronic disease and
therefore course length can be many years.
• It is used in late-stage PD and some patients have received
apomorphine for >5 years.
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52. How to calculate daily dose and number of ampoule
required?
ART Rescue
dose
Number of off
episodes
Total daily
dose
Number of
ampoule
needed
Choice of
ampoule
0.1ml ,
0.3ml……0.5ml
0.5 ml
(5mg)
5 offs/day 25mg
(2.5ml)
1-2 ampoule 2ml*2
0.1ml , 0.3ml,0.5ml,
…0.7ml
0.7ml
(7mg)
9 offs/day 63mg(6.3mg) 3-4 ampoules 2ml*4
52

53. How to break the APOSAN Ampuole
1. Locate the color dot on the region above the neck
of the ampoule. This indicates breaking point of
the ampoule.
2. Hold the bottom of the ampoule in one hand.
3. Grasp the neck of the ampoule at the color dot.
4. Apply pressure in a backward direction. This will snap off
the top of the ampoule.
5. Carefully dispose of the top of the ampoule.
Caution: Take care not to spill APOSAN on clothing or household surfaces and textiles as spillages
may turn green.
53

54. Injection sites
-Intermittent subcutaneous injections should
be administered in the lower abdominal wall,
below the umbilicus, the upper outer aspects
of the thighs. The injection site should be
rotated for each injection.
-Injection site should be made clean and sterile
before injecting.
When choosing injection site
- It is at least 2.5 cm (1 inch) away from a
previous Injection site.
- It is at least 2.5 cm (1 inch) away from the
belly button. 54

55. APOSAN :IV route
APOSAN must not be
used via the
intravenous route.
Do not use if the
solution has turned
green. The solution
should be inspected
visually prior to use.
Only clear, colourless
and particle free
solution should be used.
55

56. Caution
Extra caution is recommended in -Renal, pulmonary or cardiovascular disease and
persons prone to nausea and vomiting, Elderly and/or debilitated patients,
patients with hypertension and taking treatment.
At high dose, may have the potential for QT prolongation,
An ECG should be performed:
- during the treatment initiation phase
- as clinically indicated thereafter
56

57. Contraindications to APOSAN
APOSAN is contraindicated in patients with
Respiratory depression, dementia, psychotic
diseases , Hypersensitivity to the active
substance or to any of the excipients.
APOSAN is contraindicated for children and
adolescents under 18 years of age.
57

58. Psychiatric disorders
Very common:
Hallucinations
Common:
Neuropsychiatric disturbances
(including transient mild confusion and
visual hallucinations) have occurred
during apomorphine HCl therapy.
• Nervous system disorders
• Common:
• Transient sedation with each
dose of apomorphine HCl at
the start of therapy may occur;
this usually resolves over the
first few weeks.
• Dizziness / light-headedness
have also been reported.
• Respiratory, thoracic and
mediastinal disorders
• Common:
• Yawning has been reported
during apomorphine
therapy.
Adverse effect
58

59. Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to
<1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
• General disorders and administration site
conditions
• Very common:
• Most patients experience injection site
reactions, particularly with continuous use.
These may include subcutaneous nodules.
Various other local reactions (such as irritation,
itching, bruising and pain) may also occur.
• Gastrointestinal disorders
• Common:
• Nausea and vomiting, particularly when
apomorphine treatment is first initiated, usually as
a result of the omission of domperidone
ADVERSE EFFECTS
59

60. storage
Do not store above 25°C. Protect from light.
APOSAN should be used immediately. Full
contents of ampoule should be drawn in the
syringe.
Use the required amount of dose, put the
needle protection cap on after use. Store the
filled syringe at the temperature below 25°C and
protect from light. Needle needs to be changed
every time you inject.
Do not freez.
Keep this medicine out of the sight and reach of
children.
60