Neurodegenerative Disorders

Neurodegenerative Disorders

• Brain experiences of higher quantum of • oxidative stress• Excitotoxicity• protein deposition (amyloidosis) • apoptosis

• All event cause damage to the brain cells and neurons Neurodegenerative diseases

• Brain cells not replicable, damage would remain for rest of life

OXIDATIVE STRESS Cell metabolism H2O2 + oxy-radicals OH + H2O2 DNA damage Lipid peroxidation

CELL DEATH

• EXCITOTOXICITY Due to excess of glutamate in brain. Mainly through NMDA Receptors Activated NMDA receptor Influx of Ca

Free radicals Ca overload DNA damage Protein damage Lipid peroxidation

(N- Methyl D-asparate)

Neurodegenerative diseases

• Alzhemiers Hippocampus and cortex

• Parkinson’s loss of nigrostriatal Dopa

• Huntington’s GABA nigrostriatal pathway impairment

• Amyotrophic sclerosis Degen. of spinal and cortical • Multiple sclerosis Impair in conduction due

demyelination of neurons

History of Parkinson´s disease (PD)

First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.”

The famous French neurologist, Charcot, further described the syndrome in the late 1800s.

Epidemiology of PD

The second most common neuro degenerative disorder after Alzheimer´s disease (AD).

The most common movement disorder affecting 1-2 % of the general population over the age of 65 years.

Parkinsonism :• It is an extrapyramidal motor disorder characterised by

rigidity, tremor and hypokinesia.• Secondary manifestations like defective posture & gait,

mask like face, sialorrhoea and dementia.

• Chronic progressive degenerative disorder of the CNS, mostly affecting older people.

TYPES OF PARKINSONISM

IDIOPATHIC or Primary- Multi factorial

PATHOPHYSIOLOGY FACTORS CONTRIBUTING TO DEGENERATION: AGEING of brain FREE RADICAL GENETIC PREDISPOSITION MPTP (Methylphenyl tetra puridinium) MPP by MAO-B

IATROGENIC PARKINSONISM

Drugs which induce parkinsonismReserpine, Haloperidol, Phenothiazine group of antipsychotics, Chlorazepam

TREATMENT• Benzhexol:2-10mg/day Trihexyphenidyl• Procyclidine:5-20mg/day• Biperidine:2-10mg/day• Promethazine:25-75mg/day

Stages of PD

• Stage I: unilateral symptoms of disease• Stage II: bilateral symptoms of disease• Stage III: all of above, plus postural instability• Stage IV: all of above, plus patient need assistance • Stage V: patient cannot function independently

Clinical features of PD

• Three cardinal symptoms:resting tremor bradykinesia (generalized

slowness of movements) muscle rigidity

Clinical features of PD• P Pill rolling tremors • A Akathisia (Inability to sit)• R Rigidity• K Kinesias (Akinesia,dyskinesia) Defect in movement

• I Instable posture(Stooped)• N No arm swinging in rhythm with legs• S Sialorrhea (Excessive flow of saliva)

• O Oculogyric crisis (deviation and fixation of eyeball)

• N Nervous depression• I Involuntary tremors• S Seborrhea (Fun. Disease of sebaceous glands)

• M Masked facial expressions

Parkinson’s dec. DA in basal ganglia

Scizopherenia Over activity of DA in Mesolimbic Mesocortical Mesofrontal

There are four major pathways for the dopaminergic system in the brain:I. The Nigro-Stiatal Pathway: Voluntary movementsII. The Mesolimbic Pathway.: BehaviourIII. The Mesocortical Pathway: Behaviour IV. The Tuberoinfundibular Pathway: Prolactin release

Dopamine pathways in human brain

Gross pathology

• Degeneration of pigmented Dopa neurons in SN• Loss of Dopa in neostriatum • Presence of intra cellualr inclusion bodies( Lewy bodies)

Neurotransmitter role in PDBasal ganglion

Pathophysiology Of Parkinsonism..

• primary defect--- loss of neurons in the substantia nigra pars compacta & nigrostriatal tract……

• as a result imbalance between dopaminergic and cholinergic system in the striatum occurs …

• which is responsible for parkinsonism signs and symptoms

Neurotransmitter levels in PD

AIM

Dopamine metabolism in striatum• Dopa synthesized

from tyrosine

• Rate-limiting step: tyrosine hydroxylase

• Metabolized by COMT, then MAO

• Re-uptake

3,4 dihydroxyphenylacetic acid

Homovanilic acid

Drug treatment

1.Drugs affecting brain dopaminergic system-

a)Dopamine precurssor- Levodopa

b)Peripheral decarboxylase inhibitors- Carbidopa, Benserazide

c)Dopaminergic agonist- Bromocriptine, pergolide, Lisuride, Ropinirole, pramipexole

d)MAO-B inhibitor- Selegiline

e)COMT inhibitors- Entacapone, tolcapone

f)Dopamine facilitators- Amantadine

• 2.Drugs affecting brain cholinergic system-

a) Central anticholinergics- Trihexyphenidyl, benzotropine

b) Antihistaminics- Orphenadrine, promethazine

Dopaminergic Agents• Dopamine does not cross BBB• Levodopa metabolic precursor to dopamine

– crosses blood brain barrier– converted into dopamine

Actions

Resolves hypokinesia, rigidity and tremors of parkinsonism No effect on normal individual

Levodopa / carbidopa

• Gold standard of treatment• Helps with slowness, rigidity, gait• Patient response changes over time• Depends on surviving nigrostriatal neurons to

convert levodopa to dopamine• Two formulations 1:4, 1:10• Carbidopa 25mg + levodopa 100mg• Carbidopa 25mg + levodopa 250mg

Peripheral decarboxylase inhibitors:• carbidopa, benserazide are peripheral decarboxylase

inhibitors • does not cross BBB. • Benefits of the combinations are:Plasma t1/2 of levodopa is prolonged & its dose is

reduced to approximately 1/4 thNausea and vomiting are not prominent.Cardiac complications are minimized.On-off effect is minimized since cerebral DA levels is

more sustained. Degree of improvement may be higherPyridoxine reversal levodopa effect can not occur.

• Problems not resolved or accentuated.. 1. involuntary movements. 2. behavioral abnormalities. 3. postural hypotension.• Dose .

Levodopa / carbidopa • Absorbed from small bowel with peak

plasma levels in 0.5-2.0 hours• Absorption dependent on gastric emptying• Dietary amino acids compete with l-dopa

for transport.• In the brain, l-dopa converted to dopa via

amino acid decarboxylase

• Dose :• start with 0.25 gm BD …taken

after meal.

increase the dose till adequate response is obtained

usual dose is 2to3 gram/day

Long-term Levodopa complications

• “Long-duration response” seen in early PD – lasts days

• Duration of response shortens; patients develop “on-off” symptoms

• Dyskinesia develops: involuntary, hyperkinetic movements

Relationship between plasma dopamine levels, dyskinesia, and “off / on”

Adverse effectsThese are frequent and troublesome which limits the therapy Nausea,vomiting Cardiac (Postural hypotension, Arrhythmias) Hypotension Abnormal movements like choria, facial tics develop.

CIPsychosesNarrow angle glaucoma (mydriasis)

DI

• Pyridoxine (vit B6) metabolism of levodopa• MAO-A inhibitors toxicity• Tri cyclic antidepressants absorption of

levodopa

Structure of dopamine agonists

DOPAMINERGIC AGONIST Alternative to use of levodopa No enzymatic conversion required Do not depend on functional integrity nigrostriatal More selective in action, lesser dyskinesias, no on off phenomen

DRUGS USED IN THIS CATEGORY Bromocriptine (D2 agonist)

Pergolide (D1,2,3 agonist) PiribidelRopinorole (D2,3,4 agonist but D2 more action )Pramiprexole

Dopamine agonistsAdvantages:• Directly stimulate DA receptors, metabolic conversion to dopamine is not

required.• Not depend on functional integrity of nigrostriatal dopaminergic neurons.• Food doesn’t interfere with absorption• Have longer duration of action with lesser on-off effect.• More selective action• Less likely to generate damaging free radicals• Neuroprotective action Disadvantages:

– Motor effect not quite as good as LD– Difficult titration schedules– Cost

Side effects of agonists

• Same as for levodopa: nausea, light headedness, visual hallucinations, dyskinesia

• Excessive daytime sleepiness: may affect safe driving

• Bromocriptine :• Potent D2 agonist and partial agonist or

antagonist of D1.• Adverse effect:

peripheral vasospasm peripheral oedema pleural fibrosis erythromelalgia first dose hypotension

• Pergolide is withdrawn from the market due its adverse effect on cardiac valves

Dopamine agonist dosing

• Start with very low TID dose, slowly titrate upward over 8-12 weeks

• Dose: -Ropinirole: starting dose 0.25mg, max. 4 to 8 g TDS -Pramipexole: starting dose 0.125mg tds … max. 0.5-1.5 g tds

How else can we reduce the complications of levodopa therapy?

• COMT inhibitors:–Tolcalpone –Entacapone

COMT inhibitors

• 3-O-Methyldopa levels so inc levodopa Bioavai• Tolcapone has both central and peripheral • Entacapone is peripheral inhibitor• T ½ 2 hours• Tolcapone occasionally produce hepatotoxicity • Tolcapone 100-200 mg p.o. TID• Entacapone: 200 mg with each dose of

levodopa/carbidopa

Side effects of COMT inhibitors

• Enhancement of levodopa effects may cause dopaminergic side effects

• Diarrhea 10-20%; mechanism unknown• Tolcapone: Patients must have bi-weekly liver

function tests.

Amantadine

• Anti viral drug with anti PD• Old drug with mild efficacy for PD symptoms;

mechanism unclear• Ulters dopamine release & / reuptake, has

anticholinergic effect.• Recent data: amantadine blocks

glutamatergic pathway from STN to GPi• Reduces dyskinesia by up to 60%

Centrally acting anti cholinergic

• Block M receptor in striatum• Adjunct to levodopa+ carbidopa therapy• Benzotropine, procyclidine, biperiden,

benzhexolAdverse effects Doses

Trihexyphenidyl – 2 to 10 mg/day

Developing therapies

• Rasagaline: MAO-B inhibitor with good clinical efficacy

• Dopamine agonists transdermal patches

Summary:

• Early PD– Dopamine agonists, amantadine, levodopa

• Mid-stage PD– Dopamine agonist with levodopa, COMT inhibitor

• Advanced PD– Frequent small doses levodopa, dopamine

agonists, COMT inhibitor, amantadine, apomorphine

Alzheimer’s disease

• 5% of population at the age 65-80• 10% in 80-95% & 90% in above 95y• Progressive loss of memory and disorder to

cognitive functions, loss of short term memory• Loss of cholinergic activity • Anti cholinesterase , Tacrine

• Tacarine also inhibits MAO cause inc NE, DA, 5HT from nerve endings.

• Hepatotoxicity• Donepezil, Rivastigmine and galantamine

newer anticholinesterases. • Recent stduies 2000 IU per day + Antioxidants

Vit C, Vit A, Zinc, Selenium dec. progression of AD

Thank you

Huntington’s chorea

• Genetic error Huntington’s gene (1:10,000)• Contain several repeats of poly glutamine • Loss GABA mediated inhibition of basal ganglia • Administration of choline chloride • DA antagonist• DA depleting drug terabenazine also use

• A reduction in gastric acidity produced by agents such as proton pump inhibitors and H2 antagonists may increase the incidence of infectious gastroenteritis and ventilation associated pneumonia.4 In addition, as indicated in several reports, proton pump inhibitors2 5 and H2 antagonists6 7 may impair some aspects of neutrophil function such as production of oxygen free radicals. Several authors2 3 have concluded that this impairment may increase the risk of infectious complications. In contrast, others5 8 suggest that this impairment represents an anti inflammatory response, which may be ‐beneficial for suppression of systemic inflammation and healing of gastric ulceration. Therefore, we feel that these agents should be given to ICU patients only following careful consideration of the potential adverse and beneficial effects.