Parkinson.pptx

MOMITUL AHMED
PARKINSON
S DISEASE

HISTORY
• In the early 19th century, James Parkinson described in detail the clinical
features of a new disease .
• A few decades later, Jean-Martin Charcot in Paris first proposed the term
Parkinson’s disease (PD) for this disorder, and added bradykinesia and
rigidity as key features of the disease
Doi: 10.3389/fneur.2018.00156. eCollection 2018.

INTRODUCTION
What is Parkinson disease ?
Parkinson disease (PD) is a degenerative condition of the brain associated with
motor symptoms (slow movement, tremor, rigidity and imbalance) and other
complications including cognitive impairment, mental health disorders, sleep
disorders and pain and sensory disturbances - WHO

Parkinsonism is a general term that refers to a group of neurological
disorders that cause movement problems similar to those seen in
Parkinson’s disease such as tremors, slow movement and stiffness.
What is Parkinsonism?

EPIDEMIOLOGY
• Global estimates in 2019 showed over 8.5 million individuals with PD.
• The prevalence of PD has doubled in the past 25 years - WHO

Gupta BM, Dhawan SM (2021) Parkinson’s Disease Research by India: A Scientometric Assessment of Publications Output for
the Period 1990-2019. J Brain Neursci 5: 017.
Parkinson disease research studies
(Global Vs India 1990 -2019)

Distribution of Parkinson’s Disease by Country of Publication 1990- 19
Gupta BM, Dhawan SM (2021) Parkinson’s Disease Research by India: A Scientometric Assessment of Publications Output for the Period 1990-201
9. J Brain Neursci 5: 017.

Brain areas affected by neurodegenerative diseases

Symptoms of Parkinsons disease

Pathophysiology
• The pathological hallmark of PD is the loss of the pigmented,
dopaminergic neurons of the substantia nigra pars compacta
(provide innervation to the striatum i.e. caudate and putamen),
with the appearance of intracellular inclusions known as
Lewy bodies.
• The principal component of the Lewy bodies is aggregated
α-synuclein .

Genetic Factors
 There are several genes that, when mutated, can increase the risk of
PD and one of these is called LRRK2
 It is particularly frequent in families of N.African /Ashkenazi Jewish
descent
 Mutations in the alpha-synuclein gene have also been found to
trigger PD (quite rare)
• Other genes that contribute to PD include the GBA gene, the parkin
gene , DJ-1 gene and PINK-1 gene).

Environmental Factors
• Certain environmental factors, such as significant exposure to pesticides
or solvents and repeated head injuries, can increase the risk of PD.
• Some environmental factors are associated with a lower risk of PD, such
as exposure to caffeine and exercise.

PATHOGENESIS
Fig : Involvement of different factors and signaling pathways for degeneration of
DA-neurons in PD

Causes of motor impairment in PD
(i) Role of dopamine
Inadequate DA levels cause less inhibition of the activity of striatal neurons,
allowing them to fire excessively.
This makes it difficult for PD patients to control their movements, leading to tremor,
rigidity, and bradykinesia, the hallmarks of PD-associated motor symptoms .
(ii) Role of serotonin
Other than DA, serotonin (5-HT) also plays an important role in PD development,
especially in several motor and non-motor symptoms, including tremor, cognition,
depression, and psychosis, as well as L-DOPA-induced dyskinesia .

DIAGNOSIS
PD can often be identified by a general neurologist, who is trained to
diagnose and treat neurologic disorders.
To avoid misdiagnosis, consultation with a movement disorder specialist
is recommended

DIAGNOSIS
Tools to Aid Diagnosis
 Use of imaging is most helpful when the diagnosis is uncertain.
 Imaging studies that may be used include :
Magnetic resonance imaging (MRI), which examines the structure of the
brain, and
DaTscan, an imaging test that measures dopamine function in the brain.

DIAGNOSIS
• However, researchers are actively trying to find a PD biomarker or
measurable characteristic in the body which indicates that disease is
present.

Wiring diagram of the basal ganglia in PD

CLASSIFICATION OF DRUGS
I. Drugs affecting brain dopaminergic system
(a) Dopamine precursor : Levodopa (l-dopa)
(b) Peripheral decarboxylase inhibitors : Carbidopa, Benserazide.
(c) Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole
(d) MAO-B inhibitor: Selegiline, Rasagiline
(e) COMT inhibitors: Entacapone, Tolcapone
(f) Glutamate (NMDA receptor) antagonist (Dopamine facilitator): Amantadine.

II. Drugs affecting brain cholinergic system
(a) Central anticholinergics: Trihexyphenidyl (Benzhexol),
Procyclidine,Biperiden.
(b) Antihistaminics : Orphenadrine, Promethazine.

Levodopa
• Levodopa (also called L-DOPA or L-3,4-dihydroxyphenylalanine),
the metabolic precursor of DA, is the single most effective agent in th
e treatment of PD .
• It enter the brain (via an L-amino acid transporter, LAT), where it is
decarboxylated to dopamine.
• In clinical practice, levodopa is almost always administered in
combination with a peripherally acting inhibitor of AADC, such as
carbidopa (used in the U.S.) or benserazide (available outside the U
.S.)

3.Cardiac arrhythmias
4..Alteration in taste sensation.
Due to β adrenergic action
of peripherally formed DA;
more in patients with pre existing
heart disease.
ADVERSE EFFECTS
At the initiation of therapy
1.Nausea and vomiting
The vomiting has been attributed to stimulation of the chemoreceptor trigger zone
located in the brainstem but outside the blood-brain barrier.
2.Postural hypotension- It occurs in about 1/3 of patients. It is more
common in patients receiving antihypertensives .
Tolerance develops with continued treatment and BP normalizes.

After prolonged therapy
• Abnormal movements (dyskinesias)
• “Wearing off” phenomenon :-
Each dose of levodopa effectively improves mobility for a period of time, perhaps
1–2 h, but rigidity and akinesia return rapidly at the end of the dosing interval.
(usually after 3-4 hours after a dose of levodopa)
Wearing off happens more frequently as Parkinson disease progresses

DRUG HOLIDAY Of LEVODOPA
• Drug Holiday of levodopa is given for a period of atleast one
weeks in severely unresponsive parkinson patients as it may
resensitizing the receptors.
Interactions of Levodopa
1. Pyridoxine : Abolishes the therapeutic effect of levodopa
(not combined with carbidopa) by enhancing its peripheral
decarboxylation so that less of it remains available to cross to
the brain .
2. Phenothiazines, butyrophenones, metoclopramide reverse
the therapeutic effect of levodopa by blocking DA receptors.

PERIPHERAL DECARBOXYLASE INHIBITORS
• Carbidopa and benserazide are extracerebral dopa decarboxylase inhi
bitors;
• They do not penetrate blood-brain barrier and do not inhibit
conversion of levodopa to DA in the brain.
• Administered along with levodopa
Benefits of the combination are—
• 1. The plasma t½ of levodopa is prolonged and its dose is reduced to
approximately 1/4th.
• 2. Systemic concentration of DA is reduced, nausea and vomiting are
not prominent
• 3. Cardiac complications are minimized.

DOPAMINERGIC AGONISTS
Bromocriptine
• It is an ergot derivative which acts as potent agonist on D2
but as partial agonist or antagonist on D1 receptors.
• Improvement in parkinsonian symptoms occurs within ½–1 hr
of an oral dose of bromocriptine .
• Bromocriptine has been largely replaced by the newer DA
agonist Ropinirole and Pramipexole. (Orally)
• Ropinirole and Pramipexole have selective activity at D2 class
sites (specifically at the D2 and D3 receptor).
• There is also a transdermal formulation of the DA agonist
Rotigotine available
The duration of action of the DA agonists (8–24 h) often is longer than that of
levodopa (6–8 h), and they are particularly effective in the treatment of patients
who have developed on/off phenomena .

Apomorphine
• Apomorphine is a dopaminergic agonist that can be administered by
subcutaneous injection.
• Apomorphine is FDA-approved as a “rescue therapy” for the acute
intermittent treatment of “off” episodes in patients with a fluctuating
response to dopaminergic therapy.
• Apomorphine is highly emetogenic and requires pre- and
posttreatment antiemetic therapy.(Oral Trimethobenzamide 300mg)
• Concomitant use of apomorphine with antiemetic drugs of the 5HT3
antagonist class is contraindicated.(causes hypotension & loss of consciousness)
• Other potentially serious side effects of apomorphine include QT
prolongation .
• Because of these potential adverse effects, use of apomorphine is
appropriate only when other measures, such as oral DA agonists or
COMT inhibitors, have failed to control the off episodes

MAO-B inhibitor
• MAO-B is the predominant form in the striatum (also blood platelets)
and is responsible for most of the oxidative metabolism of DA in the
brain.
• Selective MAO-B inhibitors are used for the treatment of PD:Selegiline
and Rasagiline.
• Selective MAO-B inhibitors do not substantially inhibit the peripheral
metabolism of catecholamines and can be taken safely with levodopa,
• These agents also do not exhibit the “cheese effect”
• Selegiline is partly metabolized by liver into amphetamine which some
times causes insomnia and agitation.
• Rasagiline is 5 times more potent, longer acting and not metabolized
to amphetamine .

Catechol-O-Methyltransferase Inhibitors
• Two selective, potent and reversible COMT inhibitors Entacapone and
Tolcapone have been introduced as adjuvants to levodopa-carbidopa
for advanced PD .
• The two drugs differ in their pharmacokinetic properties and adverse
effects .
• Tolcapone has a relatively long duration of action and appears to act
by inhibition of both central and peripheral COMT whereas
• Entacapone has a short duration of action (2 h) and principally
inhibits peripheral COMT
• An important adverse effect associated with tolcapone is hepatotoxicity
.

GLUTAMATE (NMDA receptor) ANTAGONIST
(Dopamine facilitator)
• Developed as an antiviral drug for prophylaxis of influenza A2
• Amantadine promotes presynaptic synthesis and release of DA in the
brain,decreases the reuptake and has anticholinergic properties, .
Toxicity
• Dermatologic reactions include livedo reticularis(skin).
• Amantadine is usually administered at a dose of 100 mg, twice per
day, and is well tolerated

II. Drugs affecting brain cholinergic system
(a) Central anticholinergics
The anticholinergics are the only class that can provide benefit in
the treatment of the drug-induced parkinsonism seen with
antipsychotic therapy.
Example are-Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden
(b) Antihistaminics
The antihistamine diphenhydramine (Benadryl), because it has
anticholinergic properties, is used for mild parkinsonism and with
the elderly, who may not be able to tolerate the more potent
anticholinergics, levodopa, or the dopamine agonists.
• Other Examples are- Orphenadrine, Promethazine.

Cell transplantation therapy
• Transplantation of neuronal stem cells into the brains of PD patients is
considered to be one of the most promising approaches for treating
this disease

Gene therapy for PD
(i) Viral vectors-mediated gene delivery –
Several viral vectors, such as lentivirus (LV), nonlentivirus,adeno-virus and
recombinant adenoassociated virus (rAAV), containing target genes, are
injected to the animal brain either by direct stereotaxic administration
or via systemic injections.
These viruses can integrate with the host cell and induce certain gene
expression, promote DA-cell survival, as well as prevent degeneration
of DA-neurons, which, ultimately, increases DA levels .

(ii)AADC-TH-GCH Gene Therapy
Chemical synthesis of DA from L-DOPA
requires three-enzyme systems,
- AADC, TH, and guanosine triphosphat
e cyclohydrolase(GTC).
The TH and GCH catalyze the dietary tyr
osine and convert it to L-DOPA, whereas
AADC turns the L-DOPA to DA.
Therefore, delivery of this triple gene the
rapy (AADC-TH-GCH) could
be helpful to in maintaining basal DA lev
els in advanced

(iii)RNA interference-based therapy
• Interference RNA (RNAi) is another powerful gene silencing approach,
which could be used to inhibit SNCA, PINK, or parkin genes in PD
(iv)CRISPR-Cas9 gene editing system
CRISPR/Cas-9 system is a powerful gene editing tool, including adding,
disrupting, or changing the sequence of specific genes , which may be
applied for PD-related gene therapy

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