5. It is slowly progressing, extrapyramidal motor disorder
Second most common neurodegenerative disorder in the world
5 million persons in the world
Prevalence rates in men are slightly higher than in women, reason
unknown, though a role for estrogen has been debated.
Mean age of onset is about 60 years
Can be seen in 20’s and even younger.
Parkinson’s disease
6. Parkinsonism
Primary parkinsonism /
Parkinson’s disease /
Paralysis agitans /
Idiopathic parkinsonism
Secondary parkinsonism
• Group of various clinical
features.
e.g. akathasia,
unstable posture,
Sialorrhea,
Mask-like face, etc.
• Most patients suffer from
primary parkinsonism
• Occurs from any known cause
• curable
• Genetic predisposition,
• Aging of brain & free radical
injury
• Antipsychotic drugs e.g. D2
receptor antagonists
• Toxic - MPTP, CO, Manganese
Mercury
• Decreased DA content • Normal DA content
• Decreased DA Activity
• Blockade of postsynaptic D2
receptors
7. History
Year Milestone
1817 J. Parkinson first described “An essay on the shaking palsy”
1841 Term ‘Paralysis agitans’ used for the first time by Marshall Hall
1888 Charcot referred the disease as Parkinson’s disease (PD)
1919 Recognized Parkinsons having cell loss in substantia nigra
1939 Surgery at basal ganglia by Meyers
1957 Carlsson and colleagues discovered dopamine
1960 Ehringer and Hornykiewicz identified reduced dopamine in striatum
1961 Levodopa used for the first time in injectable form and a year later in oral form
1987 Deep-brain stimulation (DBS) was first developed in France
9. Pathophysiology
Degeneration of darkly
pigmented dopaminergic
neurons in SN
Loss of Dopamine in
nigrostriatal tract
Lewy bodies
(Intracellular
inclusion bodies)
Imbalance between
inhibitory and
excitatory system
13. Levo - dopa ( L - dopa )
Precursor of dopamine
Both therapeutic and adverse effects result from the decarboxylation of
levodopa to dopamine
6-18 months to see improvement
CNS-No effect in normal individuals. Symptomatic improvement in patients
CVS-Tachycardia, Hypotension
CTZ-Activates, elicits nausea and vomiting
Endocrine-Inhibits prolactin release to increse GH release
Pharmacological Actions
14. Pharmacokinetics
Rapidly absorbed from the small
intestines
Undergoes first pass metabolism
in GIT and liver
About 1% of administered
levodopa enters brain
Plasma t1/2 is 1 to 2 hrs
Metabolites are excreted in urine
Bioavailability is effected by
gastric emptying and presence of
amino acids
15. Adverse effects
Frequent and trouble some
Dose related and reversible
Nausea and vomiting
Occurs in almost every patient
Hypotension
1/3 patient experience. Dizziness, fainting
attacks occurs
Cardiacarrhythmias
Occurs due to beta adrenergic action of DA
Alteration in taste sensations
Dyskinesias
Behavioural effects
Fluctuation in motor performance
Other CNS side effects :
Vivid dreams
Hallucinations
Sleep disturbances
Confusion
Miscellaneous :
Mydriasis (may precipitate glaucoma attck)
Abnormalities of taste, smell; hot flushes;
precipitates gout
Increased blood urea, transaminases, ALP,
bilirubin
16. Recent advance in therapy
Rotigotine
Non-ergot DA agonist
D2, D3 receptor agonists
Transdermal patch formulation
Action : slows neurodegenerative process by D2 receptor action
ADR : somnolence
Other DOPAMINE AGONIST :
Sumanirole – also neuroprotective
17. Surgery
DEEP BRAIN STIMULATION
Often helpful in treatment of
motor fluctuations
Most common type is deep brain
stimulus of STN.
Acts like “electronic levodopa”.
Reduces tremor, rigidity and
bradykinesia,
Allows reduction of l-dopa dose,
but anti parkinsonism effect no
better than l-dopa except in
tremors
ABLATIVE
Thalamotomy,
Pallidotomy
RESTORATIVE –
Embryonic dopaminergic tissue
transplantation
18. Other newer modalities
Istradephylline
Adenosine 2a receptor antagonist – anti parkinsonism effect without
dyskinesias.
Ns2330 –
Triple monoamine reuptake inhibitor, i.e. dopamine, 5HT, NE to help
motor , cognition and depression
Botulinum toxin
In patients with dystonias it is very beneficial and the results last for 3 to 4
months.Blepharospasm has always responded
19. NEUROTROPHIC FACTORS (NTF'S)
• Substances that in and around our brain cells like glial derived
neurotrophic factor (GDNF) keep the cells functioning and healthy.
• Parkinson’s and other neurodegenerative diseases are a failure of
endogenous neuroprotection.
• Practical way to increase GDNF is to exercise.
• One who exercise regularly and aggressively have always seemed to have
done better.
Neuroprotection is perhaps best exemplified by strategies
designed to prevent cells undergoing apoptosis.
Cyclosporin A inhibits opening of the mitochondrial megapore, associated
with loss of membrane potential and the start of apoptotic cell death.
20. Alzheimer’s Disease
Dr. Alois Alzheimer in 1906
An irreversible, progressive neurodegenerative disease that slowly
destroys memory and thinking skills.
Most common form of dementia.
Risk increases with age
In Most people symptoms first appear after age 60
21. The Stages of Alzheimer’s Disease
Mild Moderate Severe
Memory
Loss
Language
Problems
Mood and
Personality
Changes
Diminished
Judgement
Behavioral, Personality
Changes
Unable to Learn or
Recall New
Information
Long-Term Memory
Affected
Wandering, Agitation,
Aggression, Confusion
Require Assistance
with ADLs
Unstable Gait
Incontinence
Motor Disturbances
Bedridden
Dysphagia
Mute
Poor/No ADLs
Vacant
LTC Placement
Common
Stage
Symptoms
ADL = activities of daily living
LTC = long-term care
22. Neuropathology
Loss of neurons and synapses in the cerebral cortex and certain
subcortical regions.
Beta-amyloid
plaque
Neurofibrillary tangles
25. Recent advancements in AD
(Drugs under investigation)
Aβ-aggregation inhibitors
Aβ-degrading enzymes
Drugs influencing Aβ BBB transport
β-secretase inhibitors
γ-secretase inhibitors/modulators
α-secretase activators/modulators
M1 muscarinic agonists
Apolipoprotein E (ApoE)
Immunotherapy
Drug development based on the metals
hypothesis
HMG-CoA reductase inhibitors
MAO inhibitors
Treatments based on tau pathology
N-methyl-D-aspartate receptor (NMDA)
antagonist
Non-steroidal antiinflammatory drugs
(NSAIDs)
Estrogens, Nicotine, Melatonin
Cell transplantation and gene therapy
Docosahexaenoic acid (DHA),
Clioquinol, Resveratrol
26. Huntington’s disease
Autosomal Dominant disorder
Characterized by –Choreic hyperkinesia
(dance-like movements of limbs & rhythmic movements of face & tongue)
Dementia with progressive
brain degeneration
27. GENETICS:
All human have 2 copies of huntingtin gene (HTT) which codes for
protein called huntingtin (htt).
Also called HD gene and IT15 (interesting transcript 15)
HUNTINGTIN GENE:
Located on short arm of chromosome 4
It contains a sequence of 3 DNA base:
C: cytosine
A: adenine Repeated multiple times
G: guanine (CAGCAGCAGCAG)
Known as TRINUCLEOTIDE REPEAT
This repeated part of gene is known as POLY Q region
28. CAG: It provides genetic code for amino acid GLUTAMINE.
So repetition of this gene cause production of chain of
glutamine
Known as POLYGLUTAMIC TRACT
Generally people have < 36 repeated glutamine in
poly Q region
29. Etiopathogenesis
Genetic error in HUNTINGTIN GENE
⇓
Abnormal synthesis of Huntingtin protein
(Several repeats of polyglutamine)
⇓
Neuronal loss in striatum & cortex
⇓
Involuntary jerky movements
30. Neuropharmacological changes in HD
Degeneration of GABAergic neurons
in striatum
⇓
75% reduction in activity of
Glutamate decarboxylase
(enzyme responsible for GABA
synthesis)
⇓
Loss of GABA mediated inhibition in
basal ganglia
⇓
Hyperactivity of DA neurons
Decreased concentration of
Choline acetyl transferase
(Enzyme responsible for synthesis of
ACh)
⇓
Decreased Cholinergic activity
31. Clinical Features
Impaired intellectual functioning
Interfere with normal activities
Less ability to solve the problems
Agitation and sleeping
disturbance.
Progressive mental deterioration
Patient eventually become totally dependent
loss of musculoskeletal control.
Tongue smacking
Dysarthia: indistinct speech
Bradykinesia: slow movement
Dysphagia: mostly occur in advanced stage.
It is difficulty in swallowing or feeling that
food is sticking in your throat or chest. This
lead to weight loss following malnutrition
32. Drugs in pharmacotherapy
Drug Mechanism Dose ADRs
Chlorpromazine Antipsychotic 1 mg orally BD
DA receptor
antagonist
Behavioral
changes,
Tolerance &
dependence
Haloperidol Antipsychotic 1 mg orally BD
Olanzepine
Atypical
neuroleptic
10 mg orally OD
Tetrabenazine DA depletory
12.5 – 25 mg orally
TDS
Depression,
Suicidal
thoughts
33. Progressive neurodegenerative
disorder of motor neurons
Muscle wasting & Atrophy (∴
Amyotrophic)
Clinically,
Starts with spontaneous twitching of
motor units,
Difficulty in chewing & swallowing
Respiratory failure leads to death
within 2 – 5 years
Amyotrophic Lateral Sclerosis (ALS)
“Ice-Bucket Challenge”
34. Etiology
Defect in functioning of SOD (Superoxide dismutase)
↓ed uptake of glutamate by glutamate transporters
⇓
Overactivity of glutamate at NMDA receptors
⇓
Excitotoxicity
36. Disease Protein Characteristic pathology Notes
Alzheimer's disease β-Amyloid (Aβ) Amyloid plaques
Aβ mutations occur in rare
familial forms of Alzheimer's
disease
Tau Neurofibrillary tangles
Implicated in other
pathologies ('tauopathies') as
well as Alzheimer's disease
Parkinson's disease α-Synuclein Lewy bodies
α-Synuclein mutations occur
in some types of familial
Parkinson's disease
Huntington's disease Huntingtin No gross lesions
One of several genetic
'polyglutamine repeat'
disorders
Amyotrophic lateral
sclerosis (motor neuron
disease)
Superoxide dismutase
(SOD)
Loss of motor neurons
Mutated superoxide
dismutase tends to form
aggregates; loss of enzyme
function increases
susceptibility to oxidative
stress
37. References
Standaert DG & Roberson E. Treatment of central nervous system
degenerative disorders.In : Bruton LL, editor. Goodman & Gilman’s
– The Pharmacological basis of therapeutics. 12th edition. New York
: Mc Graw Hill Publication; 2011. p. 609- 28.
Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi
: Jaypee brothers medical publishers; 2009. p. 425-34.
Leon shargel,Parkinsons disease.5th ed.Lippincot williams and
wilkins.p.907-923.
Rang and Dale,Neurodegenerative disorders.5th ed.Elsevier.p.490-
501.
Bertram G.katzung.Basic and clinical pharmacology.11th ed.TATA
McGRAW-HILL.p.469-486.