cns degenerative disorders ,their treatment with pharmacotherapy as well as newer modalities employed

1. PRESENTED BY
SHAHEEN BEGUM ,
M.PHARMACY (PHARMACOLOGY) ,
UCPSC,KAKATIYA UNIVERSITY ,
WARANGAL .

2. Overview
 Introduction
 Mechanism of neuronal cell death
 Selective vulnerability & Neuro-protective strategies
 Classification of disorders
 Details about each disorder
 Pharmacotherapy
 Recent advances

3. • Protein misfolding & Aggregation
• Excitotoxicity
• Necrosis
• Apoptosis
• Oxidative Stress
Mechanisms of Neuronal cell Death

4. Native
protein
Misfolded
protein
Oligomer
Insoluble
aggregates
Molecular
chaperones
Mutation,
External Factors
Cellular disposal
mechanisms
Cellular deposits
Neurotoxicity

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

8. Pathophysiology
Dopamine
⇓ MAO
DOPAC
⇓
H2O2
⇓ Fe++
Hydroxyl free radicals
⇓ Inadequate
protective mechanism
Degeneration of DA neurons
 Wilsons Disease
 Excitotoxicity
 MPTP
 Lewy bodies containing synuclein
 Exposure to pesticides
 Cigarette smoking
•Oxidative stress

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

10. Corpus
striatum
Glu
GABA
GABA
GABA
Glu
GABA
GluDA
D2 (-)
DA
PD
Ach Ach
D1 (+)
Glu
Direct pathway
Indirect pathway

11. Bradykinesia
TremorRigidity
Clinical features
Other motor features Non-motor features
Gait disturbance
‘Shuffling gait’
Anosmia
Masked face
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

12.  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
(e) COMT inhibitors:
- Entacapone, Tolcapone
(f) Dopamine facilitator: -
Amantadine
 Drugs affecting brain Cholinergic
system :
(a) Central anticholinergics: -
Trihexyphenidyl (Benzhexole),
-
Benztropine mesylate,
-
Procyclidine,
-
Biperiden
(b) Antihistaminics : -
Diphenhydramine
Pharmacotherapy

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

24. 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

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

35. Pharmacotherapy
 Untreatable
Riluzole :
 Recently approved
 MoA:- Diminishes glutamate
release & excitotoxicity
 ADRs:- Nausea, dizziness, weight
loss
 Dose: - 50 mg BD
Tizanidine :
 α – 2 agonist
 Prevents post synaptic
transmission
 So, inhibits excess spasticity
 ADRs: Dizziness, drowsiness
Beclofan
Gabapentin
Ceftriaxone

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
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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.