NEURODEGENERATIVE DISORDERS

JAYARAM.RAssistant professor,

Department of Pharmacology,K.M.C.H College of Pharmacy,

Kovai Estate,Coimbatore

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

spinal cord are lost.

[Néuro- "nerval" and Dēgenerāre -"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

Parkinson’s diseases

Alzheimer's disease

Huntington's disease

Multiple sclerosis

Amyotrophic lateral sclerosis

Parkinson’s DiseaseA 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 ImbalanceBasal ganglia normally contains balanced levels of

dopamine (inhibitory) and acetylcholine (excitatory).

Balance necessary to regulate posture, muscle tone and

voluntary movement

In Parkinson’s, 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

AChDA

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

brainor

To inhibit the actions of Ach in

the brain

A.Dopaminergic drugs

Dopamine precursor : Levodopa

P. Decorboxylase inhibitors : Carbidopa

Dopamine receptor agonists : Bromocriptine

Dopamine facilitator : Amantadine

MAO-B inhibitors : Selegiline

COMT Inhibitors : Entacapone, Tolcapone

B.Drugs affecting the brain cholinergic system

Central anticholinergics

:Benzhexol,Procyclidine

Antihistamines :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

Parkinson DiseaseBradykinesia and Rigidity Quickly Respond to L DopaReduction in Tremor Effect with Continued Therapy

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

3. Effects on Cardiovascular SystemTachycardia Due to Stimulation of Beta Adrenergic Effect on HeartIn Some Individuals, L Dopa produces Orthostatic HypotensionTolerance Will Develop Within Few Weeks

4.Effects on GITNausea, 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 agonistsDA 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 confusionPeripheral 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

RASAGILINEMAO-B inhibitor

Potent than selegiline

CI with levodopa – HPN crisis

COMT InhibitorsMoA: 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 SitesHealingWell.com

Birmingham Teaching Tutorials (hopefully)

The Neuron Connection www.bio.davidson.edu/projects/neuron/video.asp

Useful Websites:

Parkinson’s 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