Parkinson's disease results from the loss of dopamine-producing neurons in the substantia nigra. The document discusses the etiology, symptoms, and treatment strategies for Parkinson's disease including pharmacotherapies like levodopa and dopamine agonists. Adverse effects associated with long-term levodopa use include fluctuations in response and dyskinesias. Combining levodopa with carbidopa or COMT inhibitors can help minimize some of these adverse effects. Other treatment options mentioned include deep brain stimulation surgery and supportive therapies.

1. NEURO-DEGENERATIVE
DISORDERS-1
By Dr Chintan

2. Selective Vulnerability & Neuroprotective Strategies
PD : - DA neurons of SN affected - disabling
motor impairments- loss of nigrostrial dopaminergic
neuron

3. Parkinson’s
disease

4. ETIOLOGY

5. GENETIC FACTORS
• Mutation / over-expression of α-synuclein
protein - autosomal dominant parkinsonism
⇓
• Protein misfolding and Aggregation

6. Oxidative stress
Dopamine
⇓ MAO
DOPAC
⇓
H2O2
⇓ Fe++
Hydroxyl free radicals
⇓ Inadequate protective mechanism
Degeneration of DA neurons

7. Energy metabolism & Aging
• Increasing age ⇒ mutation in mitochondrial genome ⇒
↓ed capacity of neurons for oxidative metabolism
• PD ⇒ several defects in energy metabolism, more than
expected with age
• Most commonly, ↓ed function of complex-1 in ETC
Excitotoxicity
• Glutamate excess

8. Bradykines
ia
Tremor
Rigidity
Cardinal features
Other motor features Non-motor features
Gait disturbance
‘Shuffling gait’
Anosmia
Masked facies
Sensory disturbances
(e.g., pain)
Reduced eye blink
Mood disorders (e.g.,
depression)
Soft voice (hypophonia) Sleep disturbances
Dysphagia Autonomic disturbances
Freezing Cognitive
impairment/Dementia
Micrographia

9. PHARMACOTHERAPY

10. INTRO….
• Does not slow or prevent disease progression
• Improves quality of life
• 5-10% respond poorly to all medications
• AIM - Trying to stimulate the dopaminergic system
and control the resulting excitation in cholinergic
pathways

11. CLASSIFICATION
 Drugs affecting brain DA system :
(a) Dopamine precursor :- Levodopa (l-dopa)
(b)Peripheral decarboxylation inhibitors:-
Carbidopa, Benserazide
(c) Dopaminergic agonists:- Bromocriptine,
Ropinirole, Pramipexole
(d) MAO-B inhibitor: - Selegiline,Rasagiline
(e) COMT inhibitors:- Entacapone, Tolcapone
(f) Dopamine facilitator:- Amantadine

12. Conti…
 Drugs affecting brain Cholinergic system :
(a) Central anticholinergics:- Trihexyphenidyl
(Benzhexole), -
Benztropine mesylate,
- Procyclidine,
- Biperiden
(b) Antihistaminics : - Diphenhydramine

13. Levodopa (L-dopa)
• DA itself -Not cross BBB- no effect in PD
• Precursor of dopamine – cross BBB –peripherally
decarboxylated to DA – 1 to 3% enter in brain.
• 97-98% metabolised in GIT & peripheral tissue by dopa-
decarboxylase enzyme
• Both therapeutic and adverse effects result from the
decarboxylation of levodopa to dopamine
• 6-18 months to see improvement

14. Adverse Drug Reactions
Fluctuations in response :
 “ Wearing-off effect ”-Long term therapy-shorten the benefit
• Duration of benefit is reduced as therapy progresses
 “ On – Off Phenomenon ”- unpredictable fluctuation between
both of these -↓
• ‘On’ state : Normal mobility
• ‘Off’ state : decreased mobility- unable to rise from chair – sat
down few minutes.
 Reason : Very short plasma T1/2 (1 – 2 hours)
so rapid fluctuations in plasma concentration

16. Dyskinesias :
• Excessive abnormal choreiform movements of limbs,
trunk, face, tongue
• Occurs in high dosage long-term therapy
Other CNS side effects :
• Vivid dreams
• Hallucinations
• Sleep disturbances
• Confusion

17. Cardiovascular side effects :
• Postural hypotension (release of DA in circulation)
• Cardiac arrhythmia (cardiac α1 β1 receptors)
Peripheral side effects :
• Anorexia, nausea, vomiting (CTZ stimulation by DA)
Miscellaneous :
• Mydriasis (may precipitate glaucoma attck)
• Abnormalities of taste, smell; hot flushes; precipitates
gout

18. LEVODOPA CARBIDOPA COMBINATION
 Dosage :
 Carbidopa : Levodopa = 1 : 4 ration = 25 mg : 100 mg
3 times a day to be taken 30 min before meals
Gradually increased to 1 : 10 proportion thrice a day

19. LEVODOPACARBIDOPA COMBINATION
Advantages
• The plasma T1/2 of levodopa
is prolonged
• Better improvement
• Nausea and vomiting are
not prominent
• Cardiac complications are
minimized
• “On-off” effect is minimized
• Pyridoxine reversal of levo
dopa does not occur
Problems Not Solved
• involuntary movements
• Behavioral abnormality
• Postural hypotension

20. Dopamine Agonists
• Bromocriptine - Potent D2 receptor agonist
- Weak D1 antagonist
• Cabergoline - Same as bromocriptine
- Longer acting (T1/2 > 80 hrs)
• Ropinirole- D2 > D3, D4 Agonist
• Pramipexole - Same as ropinirole

21. Advantages
 Do not require their conversion to DA
 Do not depend on functional integrity of nigrostriatal
neurons
 Longer duration of action, lesser dyskinesia & ‘on-off’
phenomenon
 More selective than levodopa on specific receptors
 Less likely to generate damaging free radicals

22. Adverse Drug reactions
• Anorexia, nausea, vomiting
• Postural hypotension
• Peripheral oedema
• Digital / peripheral vasospasm
• Vertigo
• Erythromelalgia (red, tender, swollen joints of feet &
hands)
 Less frequent & less severe with pramipexole,
ropinirole

24. COMT inhibitors
• Dopamine 3-o-methyldopa (inactive)
⇓
Inhibition of COMT causes more DA available
More plasma half life
Diminish peripheral metabolism of Levodopa
• Drugs are:
COMT
Entacapone Tolcapone
Peripheral action Central & peripheral actions
T1/2 2 hours T1/2 2 hours
Less potent More potent
Short duration of action Longer action
200 mg TID or QID 100 mg TDS

25. Reasons to combine Levodopa + COMT inhibitor
 Blockade of dopa decarboxylase by carbidopa
⇓
Activates COMT mediated degradation of levodopa
Increased level of 3-o-methyldopa
 3-o-methyldopa competes with levodopa to cross
BBB ⇓
Decreased therapeutic effect of levodopa

26. MAO – B inhibitor
• MAO –B is principal enzyme responsible for metabolism of
DA
• Selegiline : Irreversible inhibitor of MAO-B
• Early stages : - used alone
• Later - with levodopa + carbidopa
- To reduce the need of levodopa
• Neuroprotective role : Reduces the oxidative damage by free
radicals

27. • Desmethyl selegiline (metabolite) is responsible for
neuroprotection & antiapoptotic effect
• ADR : - Insomnia

28. Central Anticholinergic drugs
• Block muscarinic receptors in striatum
• Reduces striatal cholinergic activity
• Most commonly used for –
 Early stage of disease
 Late stage – as adjunct to levodopa + carbidopa
therapy
 Neuroleptic-induced extrapyramidal side effects

29. • Interestingly, they correct tremors & rigidity
more efficiently than other symptoms
• ADRs : dry mouth, urinary retention, blurred
vision

30. Amantadine
• Anti-viral drug
• Dopamine facilitator
 Mechanism :
 Prevents DA uptake
 Facilitates presynaptic DA release
 Weak antimuscarinic effects
 Blocks glutamate NMDA receptors
Treats PD symptoms
Reduces
excitotoxicity

31. Uses :
• Alone to treat early stage PD or for patients who
do not respond to levodopa
• In combination with levodopa + carbidopa when
more beneficial response is required
ADRs:
• Nausea, hallucination, insomnia, confusion,
dizziness
• Livedo reticularis (discolored area on skin due to
passive congestion)

33. Blood
Brain
Barrier
L-dopa
DDC
MAO-B
Dopamine
DOPAC
D
A
D2
3-o-methyl dopa
Levodopa
3-o-methyl dopa
(Competes with l-dopa
for uptake)
Entacapone
Tolcapone
COMT
DDC Carbidopa
Dopamine
Does not cross BBB
Peripheral degradation
ADRs
Brain
Peripheral tissue, Gut
Selegiline
Tolcapone
Bromocriptine
Amantadine

34. Other supportive drugs
• Depression- Citalopram (or Amitriptyline)
• Dementia in ~30% with late disease
– Treat as per dementia guideline
• Psychosis-low dose Clozapine or Quetiapine

35. Surgery
DEEP BRAIN STIMULATION
• 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

36. Other Surgical Procedures
ABLATIVE
• Thalamotomy,
• Pallidotomy
RESTORATIVE –
• Embryonic dopaminergic tissue transplantation

37. MCQ
• Anti-Parkinsonism drug that is a selective
COMT inhibitor:
(a) Entacapone
(b) Ropinirole
(c) Pergolide
(d) Pramipexole

38. • Which of the following drug should not be
given along with levodopa
(a) Carbidopa
(b) MAO inhibitors
(c) Vitamin B complex
(d) Benserazide

39. • Drug of choice in drug induced parkinsonism
is:
(a) Levodopa
(b) Benzhexol
(c) Amantidine
(d) Carbidopa

40. • A 72-year-old patient with Parkinsonism
presents with swollen feet. They are red, tender
and very painful. You could clear up these
symptoms within a few days if you tell the
patient to stop taking:
(a) Amantadine
(b) Benztropine
(c) Bromocriptine
(d) Levodopa

41. Contd.
• True statement about drugs used in
Parkinsonism is:
(a) Amantadine is a cholinergic drug
(b) Vitamin B6 enhances the L-Dopa action
(c) COMT inhibitors prolong the action of L-dopa
(d) None

42. • Ropinirole is most useful for the treatment
of:
(a) Parkinson’s disease
(b) Wilson’s disease
(c) Hoffmann syndrome
(d) Carpal tunnel syndrome

43. • Which of the following adverse effects of
levodopa is not minimized even after
combining it with carbidopa?
(a) Involuntary movements
(b) Nausea and vomiting
(c) Cardiac arrhythmia
(d) ‘On-off’ effect

44. Overview
• Alzheimer’s disease (AD)
• Huntington’s disease (HD)
• Amyotrophic Lateral Sclerosis (ALS)

45. INTRODUCTION
• 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

46. 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

47. Neuropathology
• Loss of neurons & synapses in the cerebral
cortex and certain subcortical regions.

48.  Beta-amyloid plaques:
• Dense deposits of protein and
cellular material
• Accumulate outside and
around nerve cells
 Neurofibrillary tangles:
• Twisted fibers that build up
inside the nerve cells

49. Donepezil Rivastigmine Galantamine Tacrine
Enzymes
inhibited AChE AChE, BuChE AChE AChE, BuChE
Mechanism Noncompetitive Noncompetitive Competitive Noncompetitive
Typical
maintenance
dose
10 mg once
daily
9.5 mg/24h
(transdermal)
8-12 mg twice
daily
(immediate-
release)
20 mg, four
times daily
3-6 mg twice
daily (oral)
16-24 mg/day
(extended-
release)
FDA-approved
indications
Mild–severe AD
Mild–moderate
AD,
Mild–moderate
AD
Mild–moderate
AD
Metabolism CYP2D6, CYP3A4 Esterases CYP2D6, CYP3A4 CYP1A2

50. Huntington’s
Disease

51. Introduction
• Autosomal Dominant disorder
• Characterized by –
 Choreic hyperkinesia
(dance-like movements of limbs & rhythmic
movements of face & tongue)
 Dementia with progressive brain degeneration
• Prevalence rate = 1 : 10,000

53. 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

54. Drugs
Drug Mechanism Dose ADRs
Chlorpromazine Antipsychotic
1 mg orally
BD
DA
receptor
antagonist
Behavioral
changes,
Tolerance &
dependenc
e
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

55. Amyotrophic
Lateral
Sclerosis
(ALS)
Lou Gehrig
disease

56. INTRODUCTION
• 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

57. Etiology
 Defect in functioning of SOD (Superoxide dismutase)
 ↓ed uptake of glutamate by glutamate transporters
⇓
Overactivity of glutamate at NMDA receptors
⇓
Excitotoxicity

58. Treatment
• Untreatable
Riluzole :
• Recently approved
• MoA: - Diminishes glutamate release &
excitotoxicity
• ADRs: - Nausea, dizziness, weight loss
• Dose: - 50 mg BD

59. Baclofen
• GABA-B agonist
• Indication: Muscle spasticity
• Dose: 5 – 10 mg orally OD
• Intrathecal catheter also available
• ADRs: Life-threatening depression
• Advantage: No / minimal sedation

60. Tizanidine
• α – 2 agonist
• Prevents post synaptic transmission
• So, inhibits excess spasticity
• ADRs: Dizziness, drowsiness

61. Other drugs
Gabapentin:
• Slows decline in muscle strength
Ceftriaxone:
• 3rd generation cephalosporin
• ↑es glutamate uptake
• Anti excitotoxic

62. “Ice-Bucket Challenge”
 Raising awareness about ALS
 Accept the challenge or Donate or do both

63. Thank You

64. Conti…
HD :- Mutant gene expressed throughout brain,
other organs- GABAergic striato-nigral pathway
impaired.
- Pathological changes only in neostriatum
ALS :- degeneration of spinal, bulbar & cortical
neuron
Multiple sclerosis – autonomic disease –
impairment of nerve conduction – demyelination
of neuron.

65. 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 diseaseHuntingtin 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
Neurodegenerative Diseases Associated With Protein Misfolding And Aggregation