Neurodegenerative disorders

Dr.Rathnakar U.P.
MD.DIH.PGDHM

MBBS. 5th Sem 8th and 18th July 2013

Neurodegenerative disorders
Dementia

Alzheimer's disease
Extrapyramidal and movement disorders

Parkinson's disease Huntington's disease

Motor neuron disease

Amyotrophic lateral sclerosis

PD
[Poverty of movements, tremors and rigidity]

PD
[Poverty of movements, tremors and rigidity]
Motor area Thought Of movement PFCortex

Inhibition of information PD
Inhibition of information

Pull out a programme

Cortex-Purposeful movement

Glu+ Glu+

GP-IntGABA[-] GABA[-]

Ex ACh
D1+

C.Striatum

GABA[-]

Thalamus

D2-

Glu+
CS tractPurposeful movement
GABA[-]

DA

STN

SNigraPC

Pathophysiology of PD
Normal
Thalamus Movement Tone M.Cortex

S.Cord

Degenaration of dopaminergic nigrostriatal pathway

PD
Movement Tone

Thalamus

M.Cortex

1.Increased inhibition of thalamus 2.Reduced excitation of cortex

S.Cord

Cortex-Purposeful movement

Glu+
1.Excitaion
2.More GABA 3.Less GABA

Glu+

4. Inhibition
5.Less GABA
6.GABA&Inhi

GP-Int3
GABA[-]

Ex
1

C.Striatum

2
GABA[-]

7.Less stim.
8. GABA & Inhi.

7
5

ACh
GABA[-]

D1+

4
D2-

9. Excitation
10. Movement

Thalamus

10

Glu+
6
GABA[-]

DA

CS tractPurposeful movement

STN
Dopaminergic system intact

SNigraPC

Cortex-Purposeful movement

Glu+
1.No stim.
2.No GABA
3.More GABA

Glu+

4.No Inhib.
5.More GABA
6.No GABA&Inhi

GP-Int3
GABA[-]

Ex
1

C.Striatum

2
GABA[-]

7.More stim.
8.More GABA&Inhi.

7
5

ACh
GABA[-]

D1+

4
D2-

9.No Stim. 10. No Mov.

Thalamus

10

Glu+
6
GABA[-]

DA

CS tractPurposeful movement

STN
PD

SNigraPC

Clinical features of PD
Parkinson's disease (PD) is the second commonest neurodegenerative disease, exceeded only by Alzheimer's disease (AD). 5 million persons in the world suffer from this disorder.

Pathophysiology of PD
"Dopaminergic" pathology Degeneration of dopaminergic neurons in SNc
Non-dopaminergic" pathology Over activity cholinergic neurones, Lewy bodies

The Substantia Nigra in Parkinsons Disease

Pathophysiology of PD
Normal
Thalamus Movement Tone M.Cortex

S.Cord

PD
Movement Tone

Thalamus

M.Cortex

1.Increased inhibition of thalamus 2.Reduced excitation of cortex

S.Cord

DA and Ach in PD
DA

Antichlonergics

Ach

DA Ach

DA Ach

DA

Normal DA=Ach

PD Deficiency of DA Relative excess of Ach

Treatment PD Dopaminergics Anticholinergics

Sites of action of drugs used to treat Parkinson's disease

Carbidopa Benserazide

Entacapone Tolcapone

0
Stupid

1 Dopamine DDC Levodopa COMT 3-MDOPA

BBB
3 Selegiline Rasagiline Levodopa Tolcapone 3

BBB

DOPAC
MAOB

Dopamine COMT 6

3MT 5
Anticholinergics Trihexyphenidyl Procyclidine Biperiden Antihistaminics

DA agonists

D1 & D2 Receptors

DA facilitator Amantadine

Drugs for PD
I.Drugs affecting brain dopaminergic system II.Drugs affecting brain cholinergic system

1. DA precursor- Levodopa 2. DDC inhibitors-Carbidopa 3. DA agonistsBromocriptine 4. MAO-B inhibitorsSelegiline 5. COMT inhibitorsEntacapone 6. DA facilitator-Amantadine

1. Central anticholinergics Trihexyphenydyl, procyclidine, biperiden 2. Antihistaminics Orphenadrine, promethazine

Levodopa

Levodopa - PK

Levodopa Pharmacological actions

CNS 1. Normal persons-no effect 2. PD: Excellent clinical improvement initiallyrigidity, hypokinesia, Tremors other nonmotor symptoms later 3. Psychosis 4. Sexual activity CVS 1. Tachycardia 2. Postural hypotension[central action] 3. Tolerance develops Endocrine Prolactin

Levodopa ADEs
At initiation of therapy Nausea & vomiting Postural hypotension Cardiac arrhythmias Exacerbation of angina Alteration of taste Prolonged therapy Abnormal movements [dyskinesia]-chorea, grimacing. Worsen with time Dose limiting Behavioral-Anxietydepression-psychosis End of dose effect On-off phenomenon
[worsening and improvement in a few minutes-progressive degeneration]

Levodopa DIs
Pyridoxine abolishes the effectnot with carbidopa] Antipsychotics abolish the effect Domperidone prevents vomiting without loss of th.effect Anti HTNves-Postural hypotension Atropine-enhance therapeutic effect at low doses of levodopa. May retard absorption

PERIPHERAL DECARBOXYLASE INHIBITORS [Carbidopa & Benserazide]

Benefits
Do not cross BBB t1/2 Dose of l.dopa reduced Side effects less No pyridoxine reversal On-off effect is less Respond better

Carbidopa Benserazide

Unchanged/worsened Involuntary movements Behavior Sleepy Postural hypotension Co-Careldopa

Carbidopa:levodopa=10:100mg

Dopamine DDC

Levodopa

Dopamine agonists [Bromocriptine, Ropinirole, Pramipexole]

Ropinirole, Pramipexole D2/D3 agonists Supplementary Monotherapy-early PD

Neuroprotective???? Oral Also in restless leg syndrome Has replaced bromocriptine

MAO-B inhibitors
[Selegiline, Rasagiline]
Selegiline
No hypertensive reactions[low doses] Early cases alone Adjuant to L.dopa Reduces the dose Metabolized amphetamine CI in epileptics, insomnia[ADE] DI-pethidine

Rasagiline Five times potent No amphetamine Longer acting Neuroprotective?????

COMT Inhibitors
[Entacapone, Tolcapone]

Entacapone Only peripheral action Prolongs action-l.dopa Used to smoothen the effect of L.dopa in onoff Not in early PD Yellow orange-urine Not hepatotoxic Tolcapone Similar to entacapone Crosses BBB Central action not v.imp Hepatotoxic

Amantadine
Antiviral Increases synthesis & release of DA Anticholinergic Glutamate antagonist DA facilitator Mild cases alone Combined with L.dopa Bluish discolration around ankle[livid reticularis]

Centrally acting anticholinergics

Restore Ach/ DA balance in striatum Tremor is benefitted more than rigidity Less effective than L.dopa Cheap, less side effects Atropine like side effects Trihexyphenidil Procyclidine Biperiden Orphenadrine Promethazine

Treatment strategies in PD
Pharmacotherapy only when disease interferes with daily life Selegiline/+anticholinergics Younger pt with severe diseaseLevodopa/+anticholinergics/+Amantadine More than 70-L.dopa Anticholinergics avoided in older pts and with dementia

PD-Other measures
1. Surgical Measures Thalamotomy or pallidotomy 2. Brain Stimulation High-frequency stimulation of the subthalamic nuclei or globus pallidus internus 3. Gene Therapy

HD

Underactivity of neurons containing GABA and acetylcholine Overactivity of DA

Huntington's disease
There is no cure for Huntington disease Progression cannot be halted Treatment is purely symptomatic Relative underactivity of neurons containing GABA and acetylcholine Tetrabenazine, a drug that interferes with the vesicular storage of
biogenic amines

Motor neuron disease

[Amyotrophic lateral sclerosis]
Spasticity Excessive stimulation of glutamate receptors [excitotoxicity] Riluzole - Blocks the release of glutamate Retards progression Other muscle relaxants - Baclofen, Tizanidine

Drug induced extrapyramidal reaction

Antipsychotics - Phenothiazines Antiemetic - Metoclopramide Reserpine Tt of acute reactions - Promethazine 25 mg.i.v

Alzheimers disease
Progressive cognitive deficit Cholinergic deficit due to atrophy and degeneration of subcortical cholinergic neurons Tt-Anticholinesterases Galantamine, rivastigmine, donepezil Memantine NMDA receptor antagonist

Multiple sclerosis
Demyelination Disease modifying drugs Natalizumab Fingolimod Carbamazepine-symptomatic

Other drugs

CNS stimulants Cognitive enhancers (Cerebroactive drugs)

CNS stimulants
Convulsants: Strychnine, Picrotoxin, Bicuculline, Pentylenetetrazol (PTZ) Analeptics: Doxapram Psychostimulants: Amphetamines, Methylphenidate, Atomoxetine, Modafinil, Cocaine, Caffeine

CNS stimulants *Amphetamines

Dextroamphetamine, Metamphetamine Higher central:peripheral activity Release NA from adrenergic neurons in the brain Attention Deficit Hyperkinetic Disorder improve attention span and behaviour Methylphenidate, Atomoxetine

*CNS stimulants
Modafinil: Narcolepsy, sleep apnoea Caffeine: Apnoea in premature infants

Cognitive enhancers (Cerebroactive drugs)

Heterogenous group of drugs developed for use in dementia and other cerebral disorders. Cholinergic activators-Rivastigmine Piracetam, Pyritinol (Pyrithioxine), Dihydroergotoxine (Codergocrine), Piribedil, Ginkgo biloba

Cognition enhancers Piracetam

Nootropic- a drug that selectively improves efficiency of higher telencephalic integrative activities [Learning and memory] May reduce blood viscosity Promoted for cognitive impairment and dementia in the elderly mental retardation in children

Cognition enhancers
Pyretinol - claimed to activate cerebral metabolism, improve regional blood flow Dihydroergotoxine - semisynthetic ergot alkaloid having adrenergic blocking property Ginkgo biloba - have PAF antagonistic action prevent cerebral impairment in MID.