parkinson's disease

PARKINSON’S DISEASE

MERIN BABU

M.Pharm 1st Semester

Department of Pharmacology

Amrita School of Pharmacy, Kochi

SUBJECT: SYSTEMIC PHARMACOLGY

15-10-2014

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PARKINSON’S DISEASE

Parkinson’s disease is an idiopathic, slowly progressive

degenerative CNS disorder characterised by resting tremor,

muscular rigidity, slow and decreased movement and postural

instability.

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RISK FACTORS

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Age

Positive family history

Genetic constitution

Toxin- MPTP

KNOWN CAUSES

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PATHOLOGY

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A defect in dopamine pathway.

Parkinson’s disease affects extrapyramidal system ( corpus striatum,

Globus pallidus & substantia nigra) of brain.

In Parkinson’s disease, dopamine deficiency occurs in basal ganglia.

Major pathologic process- neuronal degeneration of pigmented substantia

nigra compacta (SNpc) a region of basal ganglia that produces dopamine, intrinsically involved in motor control.

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PATHOLOGY

Causes an imbalance of neurotransmitters:

Reduction of dopamine in corpus striatum affects the balance between 2

neurotransmitters- Acetyl choline and dopamine.

Excess of acetyl choline. The excessive excitation caused by cholinergic activity creates movement disorders.

CLINICAL SYMPTOMS

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MOTOR SYMPTOMS NON-MOTOR SYMPTOMS

DYSKINESIA

Bradykinesia

Hypokinesia

Resting tremor

Other : Pill rolling

Micrographia

Reduced blink rate

DYSTONIAS

Limb rigidity

Stooped posture

Inarticular speech

Painful cramps

CNS

Cognitive: Dementia

Psychiatric : depression, anxiety, psychosis

Sleep disorder: Somnolescence, Insomnia

Sensory : Taste, visual, olfactory disturbances

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CLINICAL SYMPTOMS

STAGING OF PD- HOEHN & YAHR SCALE

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Stage 1: Unilateral disease ( affects one side of the body).

Stage 2: Bilateral disease without balance impairment.

Stage 3: Mild to moderate bilateral disease. Some postural instability,

physically independent.

Stage 4: Severe disability: unable to live alone independently.

Stage 5: Unable to walk / stand without assistance.

DIAGNOSIS

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No lab tests are available.

Genetic testing not routinely helpful.

IMAGING TECHNIQUES:

• Positron emission tomography (PET)

• Single photon emission tomography ( SPECT)

• Normal CT scan• Normal MRI scan

MANAGEMENT

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PHARMACOLOGIC NON-PHARMACOLOGICAL SURGERY

Anti-cholinergic

DOPA decarboxylase

inhibitor

COMT inhibitor

MAO-B inhibitor

DA receptor agonist

Miscellaneous

Education

Nutrition

Psychiatric counselling

Exercise

Speech therapy

Occupational therapy

Neurorehabilitation

Deep brain stimulation

PHARMACOLOGICAL

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Anticholinergic – TRIHEXYPHENIDYL, PROCYCLIDINE, BENZTROPIN

ORPHENADRIN.

Dopamine precursor – LEVODOPA

DOPA decarboxylase inhibitor - CARBIDOPA

Levodopa treatment: Immediate release Levodopa: CARBIDOPA+ LEVODOPA

LEVODOPA+ BENSERAZIDE

Controlled release Levodopa

COMT inhibitors- ENTACAPONE, TOLCAPONE

MAO-B inhibitors – RASAGILINE, SELEGILINE

Dopamine receptor agonists- BROMOCRIPTINE, APOMORPHINE,

PRAMIPEXOLE, ROPIRINOLE.

Miscellaneous - AMANTADINE

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PHARMACOLOGICAL

CLASS DRUGS MOA USE ADVERSEEFFECTS

ANTICHOLINERGIC Trihexylphenidyl

Procyclidine

BenztropineOrphenadrin

Decreases

the

cholinergicactivity

Effective

against

tremor

Early stages

of PD

Control

siallorhea

Reduce

severity of

akinesia & rigidity

Anticholinergic

SE-

• Dry mouth

• Constipation

• Urinary

retention

• Agitation• Excitation

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PHARMACOLOGICAL

CLASS DRUG MOA USE ADVERSE EFFECTS

DOPAMINEPRECURSOR

Levodopa Crosses BBB,

dopaminergic

neurons convert Levodopa to DA

Improve

Hypokinesia &

rigidity

Resolve

symptoms of

posture,

Handwriting,

Speech,

Facial

expression,

Mood.

• Nausea

• Vomiting

• Posturalhypotension

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PHARMACOLOGICAL


PERIPHERAL

DECARBOXYLA-SE INHIBITORS

Carbidopa/

Benserazide

Given in

combination with L-DOPA.

Drugs prevent

the peripheral

metabolism of

L-DOPA.

Plasma half life

of L-DOPA

increased.

• Nausea• Vomiting

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PHARMACOLOGICAL

CLASS DRUG MOA USE ADVERSEEFFECTS

COMT INHIBITORS

TolcaponeEntacapone

Peripheral

decarboxyltion

by COMT–

blocked.

Entacapone-

acts only in

periphery. Short

duration of

action

Tolcapone –

central action.

Prolong &

enhance L-DOPA action

Combination of

L-DOPA in

patients with

wearing-off-effect.

• Nausea

• Vomiting

• Postural

hypotension

Tolcapone SE –

Diarrhoea.

Entacapone SE-

yellow orange urine.

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PHARMACOLOGICAL


MAO-B INHIBITORS

SelegilineRasagiline

Selegiline-

selective,

irreversible

MAO-B inhibitor

Combination

with L-DOPA –

prolong action,

prevent

wearing-off-

effect.

Rasagiline-

Selective MAO-

B inhibitor, long

acting

Prevent the

progression of

disease.

Selegiline

metabolised to

amphetamine

– cause

insomnia &

agitation.

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PHARMACOLOGICAL


DOPAMINE

RECEPTOR AGONIST

Bromocriptine

RopinirolePramipexole

Bromocriptine –

ergot derivative

Potent agonist

on D2.

Ropinirole &

Pramipexole –

non ergoline

derivatives

Selective D3 agonist

Improvement in

parkinsonism symptoms

• Nausea

• Dizziness

• Hallucination

• Postural hypotension

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PHARMACOLOGICAL


DOPAMINE FACILIATOR

Amantadine Promote

presynaptic

synthesis &

release of DA in brain

Provide

symptomatic

benefit

• Insomnia

• Dizziness

• Confusion

NON-PHARMACOLOGICAL

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• Helps to relieve some of the motor symptoms. • Aid in the management of postural instability and non- motor symptoms.

EDUCATION:

Provide patient & family information and control over the disorder.

NUTRITION:

Elderly patients with chronic illness are at risk of poor nutrition and weight.

A high fibre diet & adequate hydration therapy is beneficial. Protein restriction.

SUPPORT:

Exercise, Physiotherapy, Speech therapy & occupational therapy are essential

to help patients to cope up with their progressive disability.

To maintain muscle and tendon strength

Psychiatric help and medication : needed for depression.

SURGERY

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Plays a role in people who can’t achieve a satisfactory response to available medications.

DEEP BRAIN STIMULATION:

Brain pacemaker sends impulses to brain to stimulate sub thalamic nucleus.

STEM CELL TRANSPLANTATION:

Transplanting foetal dopaminergic neurons directly into dopamine depleted

regions of basal ganglia.

NEWER ADVANCES

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DRUG MOA USE STUDIES TRIAL SPONSOR

PARDOPRUNOX

Partial

agonist for DA receptor

Treat anxiety & depression

Double blind

study of

pardoprunox,

a new partial

DA agonist in early PD

Phase 3 Abbottlaboratories

APLINDORE Partial

agonist

selective for DA receptor

Treat PD &

restless leg syndrome

Aplindore (

DAB_452), a

high affirnity

selective D2

receptor

partial agonist

Phase 2 Neurogen

Pharmaceuticals

LISURIDE Affirnity for

D2,D3, D4.Agonist.

Treat PD Lisuride

patch to treat PD

Phase 2 National

Institute of

Neurological

Disorders & stroke

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NEWER ADVANCES


NEBICAPONE

Inhibit COMT enzyme

Treat PD A double

blinded,

randomised,

placebo & active

controlled study

of nebicapone

for the treatment

of motor

fluctuations in PD

Phase 2 BIAL- Portela& C

SAFINAMIDE Reversible &

selective

MAO-B inhibitor

For any stage of PD

Randomised trial

of safinamide

add on to

levodopa in PD

with motor fluctuations

Phase 3 Newron

pharmaceuticals

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NEWER ADVANCES


ISTRADEFYLLINE

Selective

antagonist at A2 A

Treat PD A 12-week

randomised

study to evaluate

oral

istradefylline in

subjects with

modertae to severe PD

Phase 3 Kyowa

Hakko Kirin Pharma

FIPAMEZOLE Selective α2

adrenergic

receptor

antagonist.

Enhances

signaling of

NTs – DA, NE.

Reduce

levodopa

induceddyskinesia

Randomised

clinical trial of

fipamezole for dyskinesia in PD

Phase 2b

Santhera

pharmaceuticals

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PRELADENANT Selective

antagonist –

adenosine

A2 A

receptor

Treat PD A placebo and

active controlled

study of

Preladenant in early PD

Phase 3 Merck Sharp

& DohmeCorp

GM1GANGLIOSIDE

Improve

symptoms,

delay

disease

progression

& partially

restore

damaged

brain cells in PD patients

Treat PD GM1 Ganglioside effects on PD

Phase 2 Thomas

Jefferson University

NEWER ADVANCES

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REFERENCE

• Roger Walker, Cate Whittlesea. Clinical pharmacy and therapeutics. 5th

edition. Sydney: Churchill Livingstone; 2012.

• KD Tripathi, Essentials of medical pharmacology. 6th edition. New Delhi :

Jaypee Brothers Medial Publishers; 2009.

• http://wikipedia.com

• www.clinicaltrials.org

http://wikipedia.com/

http://www.clinicaltrials.org/

parkinson's disease

Health & Medicine