Neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's disease are caused by oxidative stress, excitotoxicity, protein deposition, apoptosis, and damage to brain cells and neurons. This damage occurs due to higher levels of oxidative stress, excitotoxicity from excess glutamate, and the deposition of amyloid proteins and inclusion bodies in the brain. While drugs can help treat symptoms, the damage to non-replicating brain cells is permanent.

1. Neurodegenerative
Disorders

2. Neurodegenerative Disorders
• Brain experiences of higher quantum of
• oxidative stress
• Excitotoxicity
• protein deposition (amyloidosis)
• apoptosis
• All event cause damage to the brain cells and
neurons Neurodegenerative diseases
• Brain cells not replicable, damage would
remain for rest of life

3. OXIDATIVE STRESS
Cell metabolism  H2O2 + oxy-radicals
OH + H2O2  DNA damage
Lipid peroxidation
CELL DEATH

4. • EXCITOTOXICITY
Due to excess of glutamate in brain.
Mainly through NMDA Receptors
Activated NMDA receptor
Influx of Ca
Free radicals
Ca overload DNA damage
Protein damage
Lipid peroxidation
(N- Methyl D-asparate)

5. Neurodegenerative diseases
• Alzhemiers  Hippocampus and cortex
• Parkinson’s  loss of nigrostriatal Dopa
• Huntington’s  GABA nigrostriatal pathway
impairment
• Amyotrophic sclerosis  Degen. of spinal and cortical
• Multiple sclerosis  Impair in conduction due
demyelination of neurons

6. History of Parkinson´s disease (PD)
 First described in 1817 by an English physician,
James Parkinson, in “An Essay on the Shaking
Palsy.”
 The famous French neurologist, Charcot, further
described the syndrome in the late 1800s.

7. Epidemiology of PD
 The second most common neuro
degenerative disorder after Alzheimer´s
disease (AD).
 The most common movement disorder
affecting 1-2 % of the general population
over the age of 65 years.

8. Parkinsonism :
• It is an extrapyramidal motor disorder characterised by
rigidity, tremor and hypokinesia.
• Secondary manifestations like defective posture & gait,
mask like face, sialorrhoea and dementia.
• Chronic progressive degenerative disorder of the CNS,
mostly affecting older people.

9. TYPES OF PARKINSONISM
IDIOPATHIC or Primary
- Multi factorial
PATHOPHYSIOLOGY
FACTORS CONTRIBUTING TO DEGENERATION:
 AGEING of brain
 FREE RADICAL
 GENETIC PREDISPOSITION
 MPTP (Methylphenyl tetra puridinium) MPP by
MAO-B

10. IATROGENIC PARKINSONISM
Drugs which induce parkinsonism
Reserpine, Haloperidol,
Phenothiazine group of antipsychotics, Chlorazepam
 TREATMENT
• Benzhexol:2-10mg/day Trihexyphenidyl
• Procyclidine:5-20mg/day
• Biperidine:2-10mg/day
• Promethazine:25-75mg/day

11. Stages of PD
• Stage I: unilateral symptoms of disease
• Stage II: bilateral symptoms of disease
• Stage III: all of above, plus postural instability
• Stage IV: all of above, plus patient need assistance
• Stage V: patient cannot function independently

12. Clinical features of PD
• Three cardinal symptoms:
resting tremor
bradykinesia (generalized
slowness of movements)
 muscle rigidity

13. Clinical features of PD
• P Pill rolling tremors
• A Akathisia (Inability to sit)
• R Rigidity
• K Kinesias (Akinesia,dyskinesia) Defect in movement
• I Instable posture(Stooped)
• N No arm swinging in rhythm with legs
• S Sialorrhea (Excessive flow of saliva)
• O Oculogyric crisis (deviation and fixation of eyeball)
• N Nervous depression
• I Involuntary tremors
• S Seborrhea (Fun. Disease of sebaceous glands)
• M Masked facial expressions

14. Parkinson’s  dec. DA in
basal ganglia
Scizopherenia  Over activity
of DA in Mesolimbic
Mesocortical Mesofrontal
There are four major pathways for the dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway: Voluntary movements
II. The Mesolimbic Pathway.: Behaviour
III. The Mesocortical Pathway: Behaviour
IV. The Tuberoinfundibular Pathway: Prolactin release

15. Dopamine pathways in human brain

16. Gross pathology
• Degeneration of pigmented Dopa neurons in SN
• Loss of Dopa in neostriatum
• Presence of intra cellualr inclusion bodies( Lewy bodies)

18. Neurotransmitter role in PD
Basal ganglion

19. Pathophysiology Of Parkinsonism..
• primary defect--- loss of neurons in
the substantia nigra pars compacta &
nigrostriatal tract……
• as a result imbalance between
dopaminergic and cholinergic system
in the striatum occurs …
• which is responsible for parkinsonism
signs and symptoms

20. Neurotransmitter levels in PD

21. AIM

22. Dopamine metabolism in striatum
• Dopa synthesized
from tyrosine
• Rate-limiting step:
tyrosine hydroxylase
• Metabolized by COMT,
then MAO
• Re-uptake
3,4 dihydroxyphenyl
acetic acid
Homovanilic acid

23. Drug treatment
1.Drugs affecting brain dopaminergic system-
a)Dopamine precurssor- Levodopa
b)Peripheral decarboxylase inhibitors- Carbidopa,
Benserazide
c)Dopaminergic agonist- Bromocriptine, pergolide,
Lisuride, Ropinirole, pramipexole
d)MAO-B inhibitor- Selegiline
e)COMT inhibitors- Entacapone, tolcapone
f)Dopamine facilitators- Amantadine

24. • 2.Drugs affecting brain cholinergic system-
a) Central anticholinergics-
Trihexyphenidyl, benzotropine
b) Antihistaminics- Orphenadrine,
promethazine

25. Dopaminergic Agents
• Dopamine does not cross BBB
• Levodopa metabolic precursor to dopamine
– crosses blood brain barrier
– converted into dopamine
 Actions
 Resolves hypokinesia, rigidity and tremors of parkinsonism
 No effect on normal individual

27. Levodopa / carbidopa
• Gold standard of treatment
• Helps with slowness, rigidity, gait
• Patient response changes over time
• Depends on surviving nigrostriatal neurons to
convert levodopa to dopamine
• Two formulations 1:4, 1:10
• Carbidopa 25mg + levodopa 100mg
• Carbidopa 25mg + levodopa 250mg

28. Peripheral decarboxylase inhibitors:
• carbidopa, benserazide are peripheral
decarboxylase inhibitors
• does not cross BBB.
• Benefits of the combinations are:
Plasma t1/2 of levodopa is prolonged & its dose is
reduced to approximately 1/4 th
Nausea and vomiting are not prominent.
Cardiac complications are minimized.
On-off effect is minimized since cerebral DA
levels is more sustained.
 Degree of improvement may be higher
Pyridoxine reversal levodopa effect can not occur.

29. .
• Problems not resolved or accentuated..
1. involuntary movements.
2. behavioral abnormalities.
3. postural hypotension.
• Dose .

30. Levodopa / carbidopa
• Absorbed from small bowel with peak
plasma levels in 0.5-2.0 hours
• Absorption dependent on gastric emptying
• Dietary amino acids compete with l-dopa
for transport.
• In the brain, l-dopa converted to dopa via
amino acid decarboxylase

31. • Dose :
• start with 0.25 gm BD …taken after
meal.
increase the dose till adequate
response is obtained
usual dose is 2to3 gram/day

32. Long-term Levodopa complications
• “Long-duration response” seen in early PD –
lasts days
• Duration of response shortens; patients
develop “on-off” symptoms
• Dyskinesia develops: involuntary, hyperkinetic
movements

33. Relationship between plasma dopamine
levels, dyskinesia, and “off / on”

34. Adverse effects
These are frequent and troublesome which limits the
therapy
 Nausea,vomiting
 Cardiac (Postural hypotension, Arrhythmias)
 Hypotension
 Abnormal movements like choria, facial tics develop.
CI
Psychoses
Narrow angle glaucoma (mydriasis)

35. DI
• Pyridoxine (vit B6) metabolism of levodopa
• MAO-A inhibitors toxicity
• Tri cyclic antidepressants absorption of
levodopa

36. Structure of dopamine agonists

37. DOPAMINERGIC AGONIST
 Alternative to use of levodopa
 No enzymatic conversion required
 Do not depend on functional integrity nigrostriatal
More selective in action, lesser dyskinesias, no on off phenomen
DRUGS USED IN THIS CATEGORY
 Bromocriptine (D2 agonist)
 Pergolide (D1,2,3 agonist)
 Piribidel
Ropinorole (D2,3,4 agonist but D2 more action )
Pramiprexole

38. Dopamine agonists
Advantages:
• Directly stimulate DA receptors, metabolic conversion to dopamine is not
required.
• Not depend on functional integrity of nigrostriatal dopaminergic neurons.
• Food doesn’t interfere with absorption
• Have longer duration of action with lesser on-off effect.
• More selective action
• Less likely to generate damaging free radicals
• Neuroprotective action
Disadvantages:
– Motor effect not quite as good as LD
– Difficult titration schedules
– Cost

39. Side effects of agonists
• Same as for levodopa: nausea, light
headedness, visual hallucinations, dyskinesia
• Excessive daytime sleepiness: may affect safe
driving

40. • Bromocriptine :
• Potent D2 agonist and partial agonist or
antagonist of D1.
• Adverse effect:
 peripheral vasospasm
 peripheral oedema
 pleural fibrosis
 erythromelalgia
 first dose hypotension
• Pergolide is withdrawn from the market
due its adverse effect on cardiac valves

41. Dopamine agonist dosing
• Start with very low TID dose, slowly titrate
upward over 8-12 weeks
• Dose:
-Ropinirole: starting dose 0.25mg,
max. 4 to 8 g TDS
-Pramipexole: starting dose 0.125mg tds …
max. 0.5-1.5 g tds

42. How else can we reduce the
complications of levodopa therapy?
• COMT inhibitors:
–Tolcalpone
–Entacapone

43. COMT inhibitors

44. • 3-O-Methyldopa levels so inc levodopa Bioavai
• Tolcapone has both central and peripheral
• Entacapone is peripheral inhibitor
• T ½ 2 hours
• Tolcapone occasionally produce hepatotoxicity
• Tolcapone 100-200 mg p.o. TID
• Entacapone: 200 mg with each dose of
levodopa/carbidopa

45. Side effects of COMT inhibitors
• Enhancement of levodopa effects may cause
dopaminergic side effects
• Diarrhea 10-20%; mechanism unknown
• Tolcapone: Patients must have bi-weekly liver
function tests.

46. Amantadine
• Anti viral drug with anti PD
• Old drug with mild efficacy for PD symptoms;
mechanism unclear
• Ulters dopamine release & / reuptake, has
anticholinergic effect.
• Recent data: amantadine blocks
glutamatergic pathway from STN to GPi
• Reduces dyskinesia by up to 60%

47. Centrally acting anti cholinergic
• Block M receptor in striatum
• Adjunct to levodopa+ carbidopa therapy
• Benzotropine, procyclidine, biperiden,
benzhexol
Adverse effects
 Doses
Trihexyphenidyl – 2 to 10 mg/day

48. Developing therapies
• Rasagaline: MAO-B inhibitor with good clinical
efficacy
• Dopamine agonists transdermal patches

49. Summary:
• Early PD
– Dopamine agonists, amantadine, levodopa
• Mid-stage PD
– Dopamine agonist with levodopa, COMT inhibitor
• Advanced PD
– Frequent small doses levodopa, dopamine
agonists, COMT inhibitor, amantadine,
apomorphine

50. Alzheimer’s disease
• 5% of population at the age 65-80
• 10% in 80-95% & 90% in above 95y
• Progressive loss of memory and disorder to
cognitive functions, loss of short term
memory
• Loss of cholinergic activity
• Anti cholinesterase , Tacrine

51. • Tacarine also inhibits MAO cause inc NE, DA,
5HT from nerve endings.
• Hepatotoxicity
• Donepezil, Rivastigmine and galantamine
newer anticholinesterases.
• Recent stduies 2000 IU per day + Antioxidants
Vit C, Vit A, Zinc, Selenium dec. progression of
AD

53. Huntington’s chorea
• Genetic error Huntington’s gene (1:10,000)
• Contain several repeats of poly glutamine
• Loss GABA mediated inhibition of basal
ganglia
• Administration of choline chloride
• DA antagonist
• DA depleting drug terabenazine also use

54. • A reduction in gastric acidity produced by agents such as proton
pump inhibitors and H2 antagonists may increase the incidence of
infectious gastroenteritis and ventilation associated pneumonia.4 In
addition, as indicated in several reports, proton pump
inhibitors2 5 and H2 antagonists6 7 may impair some aspects of
neutrophil function such as production of oxygen free radicals.
Several authors2 3 have concluded that this impairment may
increase the risk of infectious complications. In contrast,
others5 8 suggest that this impairment represents an
anti‐inflammatory response, which may be beneficial for
suppression of systemic inflammation and healing of gastric
ulceration. Therefore, we feel that these agents should be given to
ICU patients only following careful consideration of the potential
adverse and beneficial effects.