pharmacotherapy of neurodegenerative disorders
TRANSCRIPT
![Page 1: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/1.jpg)
PHARMACOTHERAPY OF
NEURODEGENERATIVE DISORDERS
Dr. Jayesh Vaghela
![Page 2: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/2.jpg)
Overview• Introduction• Mechanism of neuronal cell death• Selective vulnerability & Neuro-protective strategies• Classification of disorders• Details about each disorder• Pharmacotherapy• Recent advances
![Page 3: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/3.jpg)
Mechanisms of Neuronal cell death
• Protein misfolding &Aggregation
• Excitotoxicity
![Page 4: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/4.jpg)
Protein misfolding & Aggregation• Misfolding : Abnormal conformations of normally expressed
proteins ⇒ large insoluble aggregates
Linear AA chain
(Ribosomes)Functional
ProteinFolding correctly with specific AA located correctly
Conversion Requires
If goes wrong
Misfolded variantsCan’t find way to its
‘native’ conformation
Nonfunctional,Mischief in
cells
![Page 5: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/5.jpg)
Native protein
Misfolded protein Oligomer Insoluble
aggregates
Molecularchaperones
Mutation,External Factors
Cellular disposal
mechanismsCellular deposits
Neurotoxicity
![Page 6: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/6.jpg)
Excit
otox
icity
![Page 7: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/7.jpg)
Selective Vulnerability & Neuroprotective Strategies
PD : - DA neurons of SN affected- Cortical neurons unaffected
AD : - Hippocampus & neocortex most affected- Even not uniform in cortex
HD : - Mutant gene expressed throughout brain, other organs- Pathological changes only in neostriatum
ALS : - Loss of spinal motor neurons & cortical neurons
![Page 8: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/8.jpg)
Disorder Gene Mutations IncidenceHuntington’s disease • Huntingtin Autosomal
DominantAlzheimer’s disease • APP
• Presenilins
SporadicParkinson’s disease• Dominant –
α-synuclein, LRRK2• Recessive –
Parkin, PINK1, DJ-1ALS • SOD
Genetics & Environment
![Page 9: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/9.jpg)
Disease Protein Characteristic pathology Notes
Alzheimer's disease β-Amyloid (Aβ) Amyloid plaquesAβ 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 bodiesα-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
Neurodegenerative Diseases Associated With Protein Misfolding And Aggregation
![Page 10: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/10.jpg)
Parkinson’s disease
![Page 11: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/11.jpg)
Introduction• 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.
![Page 12: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/12.jpg)
ParkinsonismPrimary 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, Mn• ↓ed DA content • Normal DA content
• ↓ed DA Activity• Blockade of postsynaptic
D2 receptors
![Page 13: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/13.jpg)
HistoryYear 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 nigra1939 Surgery at basal ganglia by Meyers1957 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
![Page 14: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/14.jpg)
Etiology
![Page 15: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/15.jpg)
Genetic factors• Mutation / over-expression of α-synuclein protein - autosomal
dominant parkinsonism⇓
• Protein misfolding and Aggregation
![Page 16: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/16.jpg)
Oxidative stressDopamine
⇓ MAODOPAC
⇓ H2O2
⇓ Fe++
Hydroxyl free radicals ⇓ Inadequate protective mechanism
Degeneration of DA neurons
![Page 17: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/17.jpg)
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
![Page 18: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/18.jpg)
Environmental factors MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine),
a byproduct of manufacture of pethidine ⇓
Transported to CNS ⇓ MAO
MPP+ (methyle phenyle pyridine)⇓
Damage to DA neurons
Exposure to pesticides, rural living, drinking well-water
Cigarette smoking, caffeine ⇒ ↓ed incidence
![Page 19: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/19.jpg)
Neurotransmitter Role
![Page 20: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/20.jpg)
Cerebral cortex
Thalamus
STNSN-PR
GP-M
SN-PC
GPL
Corpusstriatum
Glu
GABA
GABA
GABA
Glu
GABA
GluDAD2 (-)
DAPD
Ach Ach
D1 (+)
Glu
Direct pathwayIndirect pathway
![Page 21: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/21.jpg)
![Page 22: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/22.jpg)
PathophysiologyDegeneration of
darkly pigmented dopaminergic neurons in SN
Loss of Dopamine in neostriatum
Lewy bodies(Intracellular
inclusion bodies)
![Page 23: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/23.jpg)
Clinical Manifestations
![Page 24: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/24.jpg)
Bradykinesia
TremorRigidity
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
![Page 25: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/25.jpg)
Pharmacotherapy
![Page 26: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/26.jpg)
• 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
![Page 27: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/27.jpg)
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(e) COMT inhibitors: - Entacapone, Tolcapone(f) Dopamine facilitator: - Amantadine
![Page 28: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/28.jpg)
Drugs affecting brain Cholinergic system :(a) Central anticholinergics: - Trihexyphenidyl (Benzhexole),
- Benztropine mesylate,- Procyclidine,- Biperiden
(b) Antihistaminics : - Diphenhydramine
![Page 29: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/29.jpg)
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
![Page 30: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/30.jpg)
Adverse Drug Reactions Fluctuations in response : “ Wearing-off effect ”• Duration of benefit is reduced as therapy progresses
“ On – Off Phenomenon ”• ‘On’ state : Normal mobility• ‘Off’ state : decreased mobility
Reason : Very short plasma T1/2 (1 – 2 hours)so rapid fluctuations in plasma concentration
![Page 31: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/31.jpg)
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
![Page 32: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/32.jpg)
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• Increased blood urea, transaminases, ALP, bilirubin
![Page 33: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/33.jpg)
Contraindications • Psychoses
• Narrow angle glaucoma
• Cardiac arrhythmias
• Melanoma (∵ levodopa is precursor of skin melanin)
![Page 34: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/34.jpg)
Drug interactions• Pyridoxine (vit B6) - Increases metabolism of levodopa
- Decreases therapeutic effects• MAO-A inhibitors - Potentiate toxicity of levodopa
- Hypertensive crisis• Proteins in meals - Compete with transport
- ∴ Given 30 min before meals• TCA Antidepressant - Decreases absorption of levodopa
![Page 35: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/35.jpg)
Blood Brain Barrier
L-dopa
DDC
MAO-B Dopamine
DOPAC
DA
D2
3-o-methyl dopa
Levodopa
3-o-methyl dopa
(Competes with l-dopafor uptake)
DDC Carbidopa
Dopamine
Does not cross BBBPeripheral degradationADRs
Brain
Peripheral tissue, Gut
COMT
![Page 36: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/36.jpg)
LEVODOPA CARBIDOPA COMBINATION Advantages• The plasma T1/2 of levodopa is prolonged• Nausea and vomiting are not prominent• Cardiac complications are minimized.• “On-off” effect is minimized
Dosage : Carbidopa : Levodopa = 1 : 4 ration = 25 mg : 100 mg
3 times a day to be taken 30 min before mealsGradually increased to 1 : 10 proportion thrice a day
![Page 37: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/37.jpg)
LEVODOPA CARBIDOPA COMBINATIONAdvantages
• The plasma T1/2 of levodopa is prolonged
• Nausea and vomiting are not prominent
• Cardiac complications are minimized
• “On-off” effect is minimized
Problems Not Solved
• lnvoluntary movements • Behavioral abnormality• Postural hypotension
![Page 38: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/38.jpg)
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
![Page 39: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/39.jpg)
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
![Page 40: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/40.jpg)
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
![Page 41: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/41.jpg)
COMT inhibitors• Dopamine 3-o-methyldopa (inactive)
⇓Inhibition of COMT causes more DA available
More plasma half life• Drugs are:
COMT
Entacapone TolcaponePeripheral action Central & peripheral actionsT1/2 2 hours T1/2 2 hoursLess potent More potentShort duration of action Longer action200 mg TID or QID 100 mg TDS
![Page 42: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/42.jpg)
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
![Page 43: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/43.jpg)
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
![Page 44: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/44.jpg)
• Desmethyl selegiline (metabolite) is responsible for neuroprotection & antiapoptotic effect
• ADR : - Insomnia
• Dose : - 5 mg with breakfast- 5 mg with lunch
![Page 45: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/45.jpg)
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
![Page 46: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/46.jpg)
• Interestingly, they correct tremors & rigidity more efficiently than other symptoms
• ADRs : dry mouth, urinary retention, blurred vision
Trihexyphenidyl :• Abuse potential• Patients display ‘fake’ signs to obtain the drug
![Page 47: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/47.jpg)
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
![Page 48: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/48.jpg)
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)
![Page 49: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/49.jpg)
Blood Brain Barrier
L-dopa
DDC
MAO-B Dopamine
DOPAC
DA
D2
3-o-methyl dopa
Levodopa
3-o-methyl dopa
(Competes with l-dopafor uptake)
EntacaponeTolcaponeCOMT
DDC Carbidopa
Dopamine
Does not cross BBBPeripheral degradationADRs
Brain
Peripheral tissue, Gut
Selegiline
TolcaponeBromocriptine
Amantadine
![Page 50: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/50.jpg)
Other supportive drugs• Depression- Citalopram (or Amitriptyline)
• Dementia in ~30% with late disease• Treat as per dementia guideline
• Psychosis-low dose Clozapine or Quetiapine
![Page 51: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/51.jpg)
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
![Page 52: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/52.jpg)
Other DOPAMINE AGONIST :• Sumanirole – also neuroprotective
![Page 53: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/53.jpg)
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
![Page 54: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/54.jpg)
OTHER SURGICAL PROCEDURES ABLATIVE • Thalamotomy, • Pallidotomy
RESTORATIVE –• Embryonic dopaminergic tissue transplantation
![Page 55: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/55.jpg)
ADVERSE EFFECTS• Hemorrhage,
• Infection,
• Wire breakage,
• Speech impairment,
• Dystonia
![Page 56: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/56.jpg)
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
![Page 57: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/57.jpg)
BOTULINUM TOXIN• In patients dystonias it is very beneficial and the results last
for 3 to 4 months. • Blepharospasm has always responded
![Page 58: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/58.jpg)
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.
• Ones who exercise regularly and aggressively have always seemed to have done better.
![Page 59: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/59.jpg)
NEUROPROTECTION• Neuroprotection is perhaps best exemplified by strategies
designed to prevent cells undergoing apoptosis.• Role of the mitochondria in the apoptotic pathway is also
receiving attention
• Cyclosporin A inhibits opening of the mitochondrial megapore, associated with loss of membrane potential and the start of apoptotic cell death.
![Page 60: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/60.jpg)
• There is also evidence that selegiline have anti-apoptotic properties.
• A recent trial has begun with patients using ubiquinone as a means both to increase mitochondrial energy production and decrease free radical release
![Page 61: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/61.jpg)
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.
• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras publication; 2012. p. 532-42.
• Olanow CW, Schapira AH. Parkinson’s disease and other movement disorder. In: LongoDL, editor :Harrisons’s principles of internal medicine.18th edition. New york:Mc Grew hill;2012. P.3317-35.
![Page 62: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/62.jpg)
![Page 63: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/63.jpg)
PHARMACOTHERAPY OF NEURODEGENERATIVE
DISORDERSPart – 2
Dr. Jayesh Vaghela
![Page 64: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/64.jpg)
Overview• Alzheimer’s disease (AD)
• Huntington’s disease (HD)
• Amyotrophic Lateral Sclerosis (ALS)
![Page 65: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/65.jpg)
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
![Page 66: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/66.jpg)
The Stages of Alzheimer’s Disease
Mild Moderate Severe
Memory LossLanguage ProblemsMood and Personality ChangesDiminished Judgement
Behavioral, Personality ChangesUnable to Learn or Recall New InformationLong-Term Memory AffectedWandering, Agitation, Aggression, ConfusionRequire Assistance with ADLs
Unstable GaitIncontinenceMotor DisturbancesBedriddenDysphagiaMutePoor/No ADLsVacantLTC Placement Common
Stage
Symptoms
ADL = activities of daily living LTC = long-term care
![Page 67: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/67.jpg)
STAGES OF AD
![Page 68: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/68.jpg)
Neuropathology • Loss of neurons and synapses in the cerebral cortex and
certain subcortical regions.
![Page 69: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/69.jpg)
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
![Page 70: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/70.jpg)
Hypothesis regarding NeuropathologyBAPtists
• Accumulation of fragments of the amyloid precursor protein (APP)
⇓• Formation of plaques that
kill neurons
TAUists• Abnormal phosphorylation
of tau proteins makes them “sticky”
⇓• Break up of microtubules
⇓• Loss of axonal transport
causes cell death
![Page 71: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/71.jpg)
Amyloid Hypothesis
![Page 72: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/72.jpg)
![Page 73: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/73.jpg)
![Page 74: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/74.jpg)
![Page 75: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/75.jpg)
‘Tau’ Hypothesis
![Page 76: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/76.jpg)
t (tau) protein is a microtubule-associated protein that is responsible for stabilization of neurons
Phosphorylation ⇓“Paired Helical Filaments” or PHFs
(like two ropes twisted around each other)⇓
Accumulation &Formation of Neurofibrillary Tangles
⇓Impaired axonal transport
(probable cause of cell death)
![Page 77: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/77.jpg)
![Page 78: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/78.jpg)
Pharmacotherapy
![Page 79: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/79.jpg)
Donepezil Rivastigmine Galantamine TacrineEnzymes inhibited
AChE AChE, BuChE AChE AChE, BuChE
Mechanism Noncompetitive Noncompetitive Competitive NoncompetitiveTypical 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
![Page 80: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/80.jpg)
Recent Advances in treatment of AD
![Page 81: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/81.jpg)
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
![Page 82: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/82.jpg)
• 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
![Page 83: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/83.jpg)
β-secretase inhibitors(β-site APP cleaving enzyme, BACE1)
GSK188909 non-peptidic BACE1 inhibitor oral
Significant reduction in thelevel of Aβ40 and Aβ42 in the brain
PMS777Cholinesteraseinhibitor with anti-PAF activity
Decrease sAPPα secretion and Aβ42 release
![Page 84: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/84.jpg)
γ-secretase inhibitors/modulatorsDAPT,
BMS-299897
MRK-560
AD mice/rats Decreased Aβ levels in plasma and CSF
LY450139 dihydrate
randomized, controlled trial of 70 patients with mild to moderate AD
decreased 38% plasma and CSF Aβ40,
well tolerated
Tarenflurbil double blind placebo controlledPhase III study
no benefit on cognitive or functional outcomes, discontinued
![Page 85: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/85.jpg)
α-secretase activators/modulators• α-secretase and β-secretase compete for the same substrate
of APP• Upregulation of α-secretase activity may decrease the
amount of APP available for β-secretase• Decrease Aβ secretion
![Page 86: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/86.jpg)
α-secretase activators/modulatorsADAM 10
ADAM 17
ADAM 9
Adamalysinfamily of proteins
Overexpression of ADAM10 in transgenic mice showed less amyloid deposition in the hippocampus and lower Aβ levels in brain homogenate
Improved neurological function
TPPB Protein kinase C (PKC) activator
increases α-secretase activity and decreases Aβ secretion
SIRT1 Activates the gene code for α secretase ADAM10
suppress Aβ production in AD transgenic mice
DeprenylIncreases α-secretase activity bypromoting ADAM10 and PKCα/ε translocation
Neuroprotective agent
![Page 87: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/87.jpg)
M1 muscarinic agonistsDecrease γ-secretase
Increase α-secretase activities⇓
Decrease Aβ secretionDecreased tau phosphorylation
• Inhibition of Aβ- and/or oxidative stress-induced cell death
![Page 88: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/88.jpg)
M1 muscarinic agonists
TalsaclidineSelective muscarinic M1agonist
Stimulates non-amyloidogenic α-secretaseprocessing in vitro
Decreased CSF Aβ by about 20%
AF102B M1 agonist Decreased CSF Aβof AD patients
AF267B In clinical trials
![Page 89: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/89.jpg)
Aβ-aggregation inhibitors
iAβ5p β-sheet breaker
Intrahippocampal injection improved spatial memory and decreased amyloid plaque deposits
![Page 90: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/90.jpg)
Immunotherapy
New modified vaccines
Novel peptide-carrier protein using an amino terminal fragment of Aβ are under developmentto avoid potentially harmful T-cell responses
Maintain a similar antibody response to that ofAN1792
![Page 91: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/91.jpg)
LY2062430IVIG
against Aβ peptide
Phase II trials
Decreased cognitiveDecline
Slight improvement in functional scores
Bapineuzumab
Monoclonal Ab
Phase II, multicenter, randomized, double blind, placebo controlled clinical trials
Decreased tau levels in CSF without affecting Aβ level
![Page 92: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/92.jpg)
Aβ Monoclonal Antibody Programs
Bapineuzumab Targets AA 1-
5; IgG1
Solanezumab Targets AA 16-24; IgG1
Ponezumab Targets AA 33-40; IgG2Da
N-Terminus C-Terminus
Ganteneruzumab targets Aβ aggregates
![Page 93: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/93.jpg)
Drugs influencing Aβ BBB transport• Receptor for advanced glycation end products (RAGE)
• Resides in the blood vessel wall cells• Transports Aβ across the blood brain barrier from systemic
circulation to facilitate their accumulation in brain ⇒ Dangerous
• Low density lipoprotein receptor related protein 1 (LRP-1)• Mediates transport of Aβ peptide out of brain• ⇒ Protective
![Page 94: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/94.jpg)
Alzheimer’s Disease⇓
↑ RAGE and ↓ LRP-1⇓
Inhibition of RAGE &Activation of LRP-1
⇓Therapeutic Targets
![Page 95: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/95.jpg)
Drug development based on the metals hypothesis
ClioquinolInhibits zinc and copper ions from binding to Aβ
Phase II clinical trial
Improved cognitive function
Decreased plasma Aβ42 level and zinc concentration
XH1, DP-109, PBT2 Metal chelators
Improved cognitive function and decreasedCSF Aβ42 compared with placebo
But not plasma Aβ
![Page 96: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/96.jpg)
HMG-CoA reductase inhibitors• Statins ⇒ ↓ed Incidence of AD• CH-rich diet⇒ ↑ β-secretase processing of APP• CH less diet⇒ ↓ Aβ production
• Atorvastatin and lovastatin: clinical benefit in AD patients
![Page 97: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/97.jpg)
Monoamine oxidase inhibitors
Rasagiline MAO-B inhibitorRegulation of APP processing,
Inhibition of cell death markers andupregulation of neurotrophic factors
LadostigilDual AchE & BuChEAndBrain selectiveMAO-A and -B inhibitor
Regulate APP processing
![Page 98: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/98.jpg)
Treatments based on tau pathologyLithium,AF267B,Propentofylline (PPF),SRN-003 & 556
Prevented thehyperphosphorylation of tau
PhenothiazinesAnthraquinonesPolyphenolsThiocarbocyanine dyesN-Phenylamines,Thiazolyl-hydrazides,Rhodanines,Quinoxalines,Aminothienopyridazines
Prevent tau protein aggregation
![Page 99: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/99.jpg)
Targeting tauchaperones
Prevent themisfolding of tau
Phosphorylated tau antigens
Reduction in soluble and insoluble phosphorylated tau
Significant attenuation of cognitiveimpairment
![Page 100: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/100.jpg)
N-methyl-D-aspartate receptor(NMDA) antagonist
Memantine-
• Low to moderate affinity noncompetitive NMDA receptor antagonist for the treatment of moderate to severe AD
• Restores the function of damaged nerve cells and reduce abnormal excitatory signals by the modulation of the NMDA receptor activity
• Improvement in cognitive, functional, and global outcomes
![Page 101: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/101.jpg)
Non-steroidal Anti-inflammatory Drugs (NSAIDS)
• Association between NSAID use and a lower incidence of AD
• Adverse effect in later stages of AD pathogenesis
• Asymptomatic individuals treated with naproxen experience reduced AD incidence, but only after 2 to 3 years
![Page 102: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/102.jpg)
Estrogens• Neuroprotective against oxidative stress, excitatory
neurotoxicity, and ischemia in the brain• Antioxidant, antiapoptotic, neurotrophic and
antiamyloidogenic activities• Activate matrix metalloproteinases-2 and −9 to increase beta
amyloid degradation• Withdrawal of estrogen in postmenopausal women-
predisposition to AD• Use of estrogen during HRT- neuroprotective• Premarin, raloxifen- in phase II
![Page 103: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/103.jpg)
Nicotine• Cholinergic agonist- acts both post and pre-synaptically to
release ACh
• AD: ↓ed Nicotinic receptor density
• Nicotine- ↑es neurone survival in neurotoxic insults
• Improvements in cognitive tasks such as recall, visual attention and perception and mood
![Page 104: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/104.jpg)
Melatonin• Tryptophan metabolite, synthesized by pineal gland
• Regulates circadian rhythms, clears free radicals, improves immunity, and inhibits the oxidation of biomolecules
• Important in mechanisms of learning and memory
• Melatonin deficit- related to aging and age related diseases
![Page 105: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/105.jpg)
• Prevents neuronal death caused by exposure to the amyloid beta protein
• Inhibits the aggregation of the amyloid beta protein
• Prevents the hyperphosphorylation of the tau protein
• Melatonin supplementation has been suggested to improve circadian rhythmicity, and to produce beneficial effects on memory
![Page 106: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/106.jpg)
Cell transplantation and gene therapy• Degeneration of the cholinergic neurons in the nucleus
basalis of Meynert- reduction in the cholinergic innervation in the cortical and subcortical regions
• In AD rat model, transplantation of cholinergic rich tissue or peripheral cholinergic neurons ameliorates abnormal behaviour and cognitive function
• No clinical trials have been initiated• Nerve growth factor (NGF)- rescues neurons from cell damage
and leads to memory improvements
![Page 107: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/107.jpg)
Docosa hexaenoic acid (DHA)• Increased intake of the DHA is associated with a reduced risk
for AD• Antiamyloid, antioxidant, and neuroprotective mechanisms• Positive effect in patients with very mild AD
![Page 108: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/108.jpg)
Resveratrol• Red wine polyphenol
• Protects against CVD, cancers
• Promotes antiaging effects
• Inhibits Aβ aggregation, by scavenging oxidants and exerting anti-inflammatory activities
• Slows down AD development
![Page 109: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/109.jpg)
Marijuana Compound a Novel Treatment for Alzheimer's ?
• Extremely low levels of delta-9-tetrahydrocannabinol (THC), the active compound in marijuana
⇓• may offer a novel and viable treatment for Alzheimer's
disease (AD)
• Under research
![Page 110: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/110.jpg)
Huntington’s
Disease
![Page 111: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/111.jpg)
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
![Page 112: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/112.jpg)
![Page 113: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/113.jpg)
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
![Page 114: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/114.jpg)
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
![Page 115: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/115.jpg)
![Page 116: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/116.jpg)
HUNTINGTIN PROTEIN• It regulates gene expression• Functional role in cytoskeleton anchoring and transport of
mitochondria• Interacts with protein HIP1 (A clathrin binding protein to mediate
endocytosis)• Major role in shaping rounded vesicles• Protects neurons• High conc. brain• Moderate conc. liver, heart and lung
![Page 117: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/117.jpg)
Etiopathogenesis Genetic error in HUNTINGTIN GENE
⇓Abnormal synthesis of Huntingtin protein
(Several repeats of polyglutamine)⇓
Neuronal loss in striatum & cortex⇓
Involuntary jerky movements
![Page 118: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/118.jpg)
Cerebral cortex
Thalamus
STNSN-PR
GP-M
SN-PC
GPL
Corpusstriatum
Glu
GABA
GABA
GABA
Glu
GABA
GluDAD2 (-)
DAPD
Ach Ach
D1 (+)
Glu
Direct pathwayIndirect pathway
HD
![Page 119: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/119.jpg)
Neuropharmacological changes in HDDegeneration 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 ofCholine acetyl transferase
(Enzyme responsible for synthesis of ACh)
⇓Decreased Cholinergic activity
![Page 120: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/120.jpg)
Clinical Features
• Impaired intellectual functioning
• Interfere with normal activities
• Less ability to solve the problems
• Agitation and sleeping disturbance.
• Progressive mental deterioration
![Page 121: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/121.jpg)
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
![Page 122: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/122.jpg)
Treatment Strategy: Replacing the missing neurotransmitter• GABA receptor agonists, or All are• GABA degradation inhibitors Not effective• Choline chloride therapy
Surprisingly, Adjusting DA / ACh balance has proved
more effective Done by antagonizing DA overactivity
![Page 123: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/123.jpg)
Drugs Drug Mechanism Dose ADRsChlorpromazine 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
![Page 124: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/124.jpg)
AmyotrophicLateralSclerosis (ALS)Lou Gehrig disease
![Page 125: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/125.jpg)
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
![Page 126: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/126.jpg)
Etiology Defect in functioning of SOD (Superoxide dismutase)
↓ed uptake of glutamate by glutamate transporters⇓
Overactivity of glutamate at NMDA receptors⇓
Excitotoxicity
![Page 127: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/127.jpg)
Treatment • Untreatable
Riluzole :• Recently approved• MoA: - Diminishes glutamate release & excitotoxicity• ADRs: - Nausea, dizziness, weight loss• Dose: - 50 mg BD
![Page 128: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/128.jpg)
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
![Page 129: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/129.jpg)
Tizanidine • α – 2 agonist • Prevents post synaptic transmission• So, inhibits excess spasticity• ADRs: Dizziness, drowsiness
![Page 130: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/130.jpg)
Other drugs Gabapentin:• Slows decline in muscle strength
Ceftriaxone:• 3rd generation cephalosporin• ↑es glutamate uptake• Anti excitotoxic
![Page 131: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/131.jpg)
“Ice-Bucket Challenge” Raising awareness
about ALS Accept the
challenge or Donate or do both
![Page 132: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/132.jpg)
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.
• Sharma HL & Sharma KK. Principles of Pharmacology. 2nd ed. New Delhi: Paras publication; 2012. p. 532-42.
• Olanow CW, Schapira AH. Parkinson’s disease and other movement disorder. In: LongoDL, editor :Harrisons’s principles of internal medicine.18th edition. New york:Mc Grew hill;2012. P.3317-35.
![Page 133: Pharmacotherapy of NeuroDegenerative Disorders](https://reader031.vdocument.in/reader031/viewer/2022022200/58aae2421a28ab27178b6531/html5/thumbnails/133.jpg)
Thank You