NEURODEGENERATIVE DISORDERS

JAYARAM.R Assistant professor, Department of Pharmacology, K.M.C.H College of Pharmacy, Kovai Estate,Coimbatore

Neurodegenerative disease
Neurodegenerative disease is a condition in which cells of the brain and

spinal cord are lost. [Nuro- "nerval" and Dgenerre -"to decline" or "to worsen]
The brain and spinal cord are composed of neurons that perform different

functions

such

as

controlling

movements,

processing

sensory

information, and making decisions.

Cells of the brain and spinal cord do not readily regenerate en masse, so

excessive damage can be devastating.

Neurodegenerative diseases result from deterioration of neurons or their

myelin sheaths, which may eventually lead to CNS-related dysfunction.

MECHANISMS OF NEURONAL DEATH

Excitotoxicity
Apoptosis

Oxidative stress

MAJOR NEURODEGENERATIVE DISORDERS

Parkinsons diseases Alzheimer's disease Huntington's disease Multiple sclerosis

Amyotrophic lateral sclerosis

Parkinsons Disease
A degenerative and progressive disorder characterized by tremor, hypokinesia, rigidity, and postural instability. causes are numerous, and diagnosis can be complex. Associated with neurological consequences of decreased dopamine

levels in basal ganglia (substantia nigra)

Neurotransmitter Imbalance
Basal ganglia normally contains balanced levels of dopamine

(inhibitory) and acetylcholine (excitatory).

Balance necessary to regulate posture, muscle tone and voluntary

movement
In Parkinsons, lack inhibitory dopamine and thus an increase in

excitatory acetylcholine

Parkinson Disease Neurochemistry

Loss of Dopaminergic (DA) Cells Located in Basal Ganglia; most

symptoms do not appear until striata DA levels decline by at least 70-

80%.

 Imbalance primarily between the excitatory neurotransmitter

Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia

DA

ACh

Etiology/Pathogenesis:
Idiopathic Cerebral atherosclerosis Viral encephalitis Side effects of several antipsychotic drugs (i.e., phenothiazides,

butyrophenones, reserpine)
Exposure to Environmental factors and neurotoxins

Consequences of dopamine reductions- Motor Symptoms:

Tremors hands and head develop involuntary movements when at

rest; pin-rolling sign (finger and thumb)

Muscle rigidity arthritis-like stiffness, difficulty in bending or

moving limbs; poker face

Brandykinesia problems chewing, swallowing or speaking; difficulty

in initiating movements and controlling fine movements; walking becomes difficult (shuffle feet)
Postural instability humped over appearance, prone to falls

Additional symptomology- Nonmotor Symptoms:

Anxiety Depression Sleep disturbance Dementia

Disturbance of ANS (difficulty in urinating)

Anti-Parkinson drugs

GOALS OF TREATMENT:
drugs used should

Increase the levels of dopamine in the brain or To inhibit the actions of Ach in the brain

A. Dopaminergic drugs

Dopamine precursor P. Decorboxylase inhibitors Dopamine receptor agonists Dopamine facilitator MAO-B inhibitors

: Levodopa : Carbidopa : Bromocriptine : Amantadine : Selegiline

COMT Inhibitors

: Entacapone, Tolcapone

B. Drugs affecting the brain cholinergic system

Central anticholinergics Antihistamines

:Benzhexol,Procyclidine :Promethazine

Site of action of Antiparkinson drugs

LEVODOPA
It is inactive by itself but is the immediate metabolic

precursor of dopamine
95% of an oral dose is decarboxylated in perihral tissues. Dopamine Decarboxylase Converts L Dopa to Dopamine That Gets

Stored into Secretory Vesicles and Gets Released from Basal Gangla.

1. Effects of L Dopa on the Symptoms of PD

L Dopa Fairly Effective in Eliminating Most of the Symptoms of Disease Bradykinesia and Rigidity Quickly Respond to L Dopa Reduction in Tremor Effect with Continued Therapy Parkinson

2. Effects of L Dopa on Behavior

L Dopa Partially Changes Mood by Elevating Mood, and of Well Being. Increases Patient Sense

3. Effects on Cardiovascular System

Tachycardia Due to Stimulation of Beta Adrenergic Effect on HeartIn Some Individuals, L Dopa produces Orthostatic Hypotension Tolerance Will Develop Within Few Weeks 4.Effects on GIT Nausea, Vomiting, and Anorexia due to Stimulation of Chemoreceptor Trigger Zone (CTZ) in Medulla

5. Effects on Endocrine System

Causes decrease in Prolactin & increases GH release

Pharmacokinetics
Absorbed by the small intestine by an active transport system Decarboxylation occurs in peripheral tissues (gut wall, liver and kidney

decrease amount available for distribution 1% of an oral dose Extracerebral dopamine amounts causing unwanted effects (benserazide)

Short half-life

Adverse effects

Nausea, vomiting Postural hypotension

Dyskinetic involuntary movements (face & neck)

Hallucinations and confusion

CLINICAL USE: Early use lowers mortality rate Combined with Carbidopa & Benseraside 30 -60 minutes before meals DRUG INTERACTIONS: Vitamin B6 enhance extracerebral metabolism of levodopa MAO A inhibitors CONTRAINDICATIONS: Psychoses Angle closure glaucoma Cardiac dysrhythmia Melanoma or suspicious undiagnosed skin lesions

Periphral Decarboxylase inhibitors-CARBIDOPA

It prevents the periphral conversion of levodopa into dopamine Does not crosses BBB

MOA
Blocks the activity of peripheral dopa decarboxylase exzymes which is

responsible for metabolism of dopamine

Combination of levodopa with carbidopa

Dose of levodopa can be reduced by 75 % Side effects like nausea,vomiting and cardiac effecs can be

prevented.
Tolerance can be delayed Improvement is faster

Dopamine receptor agonists

DA agonists can act on striatal DA receptors thereby increases the

dopamine levels. Can combine with levodopa to smooth out control when PD is getting progressive (especially young) ERGOT ALKALOIDS BROMOCRIPTINE D2 agonists Endocrinologic disorders

Pharmacokinetics
Incompletely abosrbed need extensive first-pass metabolism

(biotransformed in liver) Pergolide & Ropinirole have higher bioavailability (distribution) Short to medium half life (Potency)

Adverse effects:
Dyskinesia,Hallucinations and confusion Peripheral vasospasm ,Respiratory depression

MONOAMINE OXIDASE INHIBITORS

MAO A: metabolizes NE & serotonin

MAO B: metabolizes dopamine

monoamine oxidase B inhibitors-SELEGILINE

Selective inhibitor of MAO-B Retards breakdown of dopamine Adjunct in fluctuating response to levodopa 5 mg with breakfast & lunch Cause insomnia when taken during the day

Not to be taken with meperidine, TCAs, SSRIs

Increase adverse effects of levodopa

monoamine oxidase B inhibitors

MoA: Blocks the action of monoamine oxidase B .

Pharmacokinetics: completely absorption, short half-

life
Adverse effects: N, V, Dia, Constipation; dry mouth,

sore throat; transient dizziness; insomnia, confusion

and hallucinations

RASAGILINE
MAO-B inhibitor
Potent than selegiline CI with levodopa HPN crisis

COMT Inhibitors
MoA: inhibits the breakdown of dopamine Pharmacokinetics: variability of absorption, extensive first-pass

metabolism, short half-life

Adverse effects: dyskinesias, hallucinations; N, V, Dia and

abdominal pain
New combination Levodopa/carbidopa/entacapone (Stalevo) as

1 tablet (50, 100, 150mg)

DOPAMINE FACILITATOR-Amantadine
Originally an antiviral drug, now used as conjucntive therapy for dyskinesis

effects produced by Levodopa

MoA:
stimulates/promotes the release of dopamine stored in the synaptic

terminals
Reduces reuptake of released dopamine by pre-synaptic neuron

Pharmacokinetics:
Well absorbed, long half-life, excreted unchanged by the kidney

Adverse effects:
Ankle oedema, postural hypotension, nervousness, insomnia,

hallucinations (high dose)

Antimuscarinic/Anticholinergic Drugs:

Less common drugs but they affect Ach based interactions MoA: blocking cholingeric (Ach) receptors to restore balance Pharmacokinetics: fairly well absorbed, extensive hepatic

metabolism, intermediate to long half-lifes

Adverse effects: dry mouth and confusion

Video Sites
HealingWell.com

Birmingham Teaching Tutorials (hopefully)

The Neuron Connection

www.bio.davidson.edu/projects/neuron/video.asp

Useful Websites:
Parkinsons Disease Society

http://www.parkinsons.org.uk/

Nursing Standard (CPD)

http://www.nursing-standard.co.uk/

Textbook References
Karch AM (2006) Focus on Nursing Pharmacology, 3rd Edition. Lippincott

Williams & Wilkins

Rang et al (2003) Pharmacology, 5th Edition. Churchill Livingstone. Lilley et al (2005) Pharmacology and the Nursing Process, 4th Edition.

Mosby
Page et al (2002) Integrated Pharmacology, 2nd Edition. Mosby. Martini (2005) Principles of Anatomy and Physiology, Pearson Education

Publishers