Beruflich Dokumente
Kultur Dokumente
Dr.Rathnakar U.P.
MD.DIH.PGDHM
Neurodegenerative disorders
Dementia
Alzheimer's disease
Extrapyramidal and movement disorders
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
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
PD
Movement Tone
Thalamus
M.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-
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
Pathophysiology of PD
Normal
Thalamus Movement Tone M.Cortex
S.Cord
PD
Movement Tone
Thalamus
M.Cortex
S.Cord
DA and Ach in PD
DA
Antichlonergics
Ach
DA Ach
DA Ach
DA
Normal DA=Ach
Carbidopa Benserazide
Entacapone Tolcapone
0
Stupid
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
Levodopa
Levodopa - PK
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
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
Dopamine DDC
Levodopa
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
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]
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
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
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
Convulsants: Strychnine, Picrotoxin, Bicuculline, Pentylenetetrazol (PTZ) Analeptics: Doxapram Psychostimulants: Amphetamines, Methylphenidate, Atomoxetine, Modafinil, Cocaine, Caffeine
*CNS stimulants
Modafinil: Narcolepsy, sleep apnoea Caffeine: Apnoea in premature infants
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.