PRESENTED BY

SHAHEEN BEGUM ,

M.PHARMACY (PHARMACOLOGY) ,

UCPSC,KAKATIYA UNIVERSITY ,

WARANGAL .

Overview Introduction

Mechanism of neuronal cell death

Selective vulnerability & Neuro-protective strategies

Classification of disorders

Details about each disorder

Pharmacotherapy

Recent advances

• Protein misfolding & Aggregation

• Excitotoxicity

• Necrosis

• Apoptosis

• Oxidative Stress

Mechanisms of Neuronal cell Death

Native protein

Misfoldedprotein

OligomerInsoluble

aggregates

Molecularchaperones

Mutation,External Factors

Cellular disposalmechanisms

Cellular deposits

Neurotoxicity

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

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, ManganeseMercury

• Decreased DA content • Normal DA content• Decreased DA Activity• Blockade of postsynaptic D2

receptors

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 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

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

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

Corpusstriatum

Glu

GABA

GABA

GABA

Glu

GABA

GluDA

D2 (-)

DA

PD

Ach Ach

D1 (+)

Glu

Direct pathway

Indirect pathway

Bradykinesia

TremorRigidity

Clinical features

Other motor features Non-motor features

Gait disturbance‘Shuffling gait’

Anosmia

Masked faceSensory disturbances (e.g., pain)

Reduced eye blinkMood disorders (e.g., depression)

Soft voice (hypophonia) Sleep disturbances

Dysphagia Autonomic disturbances

Freezing Cognitive impairment/Dementia

Micrographia

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

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

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

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

CardiacarrhythmiasOccurs 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

Recent advance in therapyRotigotine

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

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

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

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.

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

The Stages of Alzheimer’s Disease

Mild Moderate Severe

Memory Loss

LanguageProblems

Mood andPersonalityChanges

DiminishedJudgement

Behavioral, Personality Changes

Unable to Learn orRecall New

Information

Long-Term MemoryAffected

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

Neuropathology Loss of neurons and synapses in the cerebral cortex and certain

subcortical regions.

Beta-amyloid plaque

Neurofibrillary tangles

Donepezil Rivastigmine Galantamine Tacrine

Enzymes inhibitedAChE 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

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 metalshypothesis

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

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

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 timesG: guanine (CAGCAGCAGCAG)

Known as TRINUCLEOTIDE REPEAT

This repeated part of gene is known as POLY Q region

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

EtiopathogenesisGenetic error in HUNTINGTIN GENE

⇓

Abnormal synthesis of Huntingtin protein

(Several repeats of polyglutamine)

⇓

Neuronal loss in striatum & cortex

⇓

Involuntary jerky movements

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

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

Drugs in pharmacotherapyDrug Mechanism Dose ADRs

Chlorpromazine Antipsychotic 1 mg orally BD

DA receptor antagonist

Behavioralchanges,Tolerance & dependence

Haloperidol Antipsychotic 1 mg orally BD

OlanzepineAtypical neuroleptic

10 mg orally OD

Tetrabenazine DA depletory12.5 – 25 mg orally TDS

Depression,Suicidal thoughts

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”

Etiology Defect in functioning of SOD (Superoxide dismutase)

↓ed uptake of glutamate by glutamate transporters

⇓

Overactivity of glutamate at NMDA receptors

⇓

Excitotoxicity

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

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 tanglesImplicated 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 lesionsOne 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

References Standaert DG & Roberson E. Treatment of central nervous system

degenerative disorders.In : Bruton LL, editor. Goodman & Gilman’s – The Pharmacological basis of therapeutics. 12th edition. New York : Mc Graw Hill Publication; 2011. p. 609- 28.

Tripathi KD. Essentials of Medical Pharmacology. 6th ed. New Delhi : Jaypee brothers medical publishers; 2009. p. 425-34.

Leon shargel,Parkinsons disease.5th ed.Lippincot williams and wilkins.p.907-923.

Rang and Dale,Neurodegenerative disorders.5th ed.Elsevier.p.490-501.

Bertram G.katzung.Basic and clinical pharmacology.11th ed.TATA McGRAW-HILL.p.469-486.