Pcol of CNS (Parkinsonian)

• Psychosis


  Neurologic-psychiatric disorder
• Mood disorder


  Neurologic-psychiatric disorder
• Anxiety disorder


  Neurologic-psychiatric disorder
• Parkinsonian disorder


  Neurologic-psychiatric disorder
• Seizures


  Neurologic-psychiatric disorder
• Anesthesia


  Neurologic-psychiatric disorder
• Parkinson's disease


  Neurodegenerative disease
• Alzheimer's disease


  Neurodegenerative disease
• Amytrophic sclerosis


  Neurodegenerative disease
• Pathophysiology of Parkinsonism


  • Degeneration of dopaminergic neurons in substantia nigra
  • ↓↓ DOPAMINE
• Substantia nigra - Dopamine, Raphe nuclei - 5HT, Locus Ceruleus - NE
• Parkinson's disease


  A progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia and postural gait abnormalities
• Parkinson's disease is correlated with the destruction of dopaminergic neurons in the substantia nigra
• Parkinson's disease is associated with the development of intracellular protein aggregates known as LEWY BODIES
• Symptoms of Parkinsonism


  • Tremors
  • Rigidity - Inability to bent
  • Akinesia - Loss of movement
  • Postural instability
  • Shuffling gait - Slowness of movement
• Parkinson's disease


  • Afflicts ~ 1 million of individuals in the US
  • Peak age of onset: early 60's (35-85 years)
  • Risk factors: Positive family history, Male gender, Head injury, Exposure to pesticides, Consumption of well water, Rural living
• Options for Parkinson's disease therapy

  • ↑ Dopamine
  • ↓ MAO, COMT
  • ↓Acetylcholine
• Classification of drugs for Parkinson's disease


  • Dopamine Precursors
  • Direct Dopamine Receptor Agonists
  • Enzyme inhibitors
  • Anticholinergic
  • Miscellaneous
• Levodopa


  Metabolic precursor of dopamine, restores dopaminergic neurotransmission in the neostriatum by enhancing synthesis of dopamine in the surviving neurons in the substantia nigra, offers symptomatic relief only
• Carbidopa


  Dopamine decarboxylase inhibitor, diminishes the metabolism of levodopa in the periphery, increases the availability of Levodopa to CNS
• Levodopa-carbidopa is the first line therapy for Parkinson's disease
• Levodopa-carbidopa


  • Absorbed rapidly from the small intestine (when empty of food)
  • Short half-life (1 to 2 hours)
  • Can cause fluctuations in plasma concentration
  • On-off phenomenon
  • Wearing off phenomenon
  • Ingestion of meals (protein) interferes with the transport of levodopa to CNS
• Adverse effects of Levodopa-carbidopa

  • Peripheral effects: Anorexia, nausea, and vomiting, Tachycardia and ventricular extrasystoles from dopaminergic action on the heart, Hypotension, Mydriasis, Positive Coomb's test, blood dyscrasias, Brownish discoloration of saliva and urine
  • CNS effects: Visual and auditory hallucinations, Abnormal involuntary movement (dyskinesias), Mood changes, depression, psychosis and anxiety
• Vitamin B6 (Pyridoxine)


  Increases the peripheral conversion of levodopa
• Concomitant administration of Levodopa-carbidopa with Non-Selective MAOI

  Hypertensive crisis
• Antipsychotic drugs


  Block dopamine receptors, contraindicated with Levodopa-carbidopa
• Dopamine receptor agonists


  Ergot derivative: Bromocriptine and Pergolide, Similar action as levodopa, Can cause hallucination, confusion, delirium, nausea, and orthostatic hypotension (more common), Dyskinesias (less common)

  Non-ergot derivative: Ropinirole, Pramipexole, Rotigotine, Apomorphine, Pramipexole and Ropinirole: oral, Apomorphine: IV, Used for acute management of the hypomobility "off" phenomenon in advanced Parkinson's disease, Rotigotine: transdermal
• Pramipexole


  • Excreted unchanged in the urine, Dose adjustment with renal dysfunction, ↑↑ Cimetidine increase the half-life of pramipexole
• Ropinirole


  • Fluoroquinolones and other inhibitors of CYP450 1A2 isoenzyme (Fluoxetine) inhibit its metabolism, Do not give with antidepressants, ↑↑↑↑↑ Dopamine
• Adverse effects of non-ergot dopamine receptor agonists

  • Nausea, hallucination, insomnia, dizziness, constipation, orthostatic hypotension, Dyskinesias (less)
• MAO B inhibitors


  Selegiline (Deprenyl): Selectively inhibits MAO B, Decrease metabolism of Dopamine, Increase level of dopamine in the brain, Enhance the action of Levodopa, Have little potential for causing hypertensive crisis, Metabolized to methamphetamine/amphetamine

  Rasagiline: Irreversible and selective inhibitor of brain MAO type B, 5x potency of selegiline, Not metabolized to an amphetamine-like substance
• Catechol-o-methyltransferase (COMT) inhibitors


  ENTACAPONE and TOLCAPONE: Selectively and reversibly inhibit COMT, Cause decreased plasma concentrations of 3-O-methyldopa, Increased central uptake of levodopa (increase level in the brain), Good oral absorption; not influenced by food, Extensively bound to albumin, Limited VD

  Tolcapone: long duration of action compared to Entacapone, Inhibits both central and peripheral inhibition of COMT

  Entacapone: Inhibits peripheral conversion of COMT, Extensively metabolized; eliminated in feces and urine, Dose adjustment for patient with moderate or severe cirrhosis
• Adverse effects of COMT inhibitors


  • Exhibit same adverse effects as with levodopa, Diarrhea,nausea, anorexia, Postural hypotension, dyskinesias, hallucinations, and sleep disorders, Fulminating hepatic necrosis: Tolcapone, Decrease the symptoms of wearing-off phenomena, Orange Urine
• Amantadine


  Antiviral, used to treat influenza, Has antiparkinsonian action, Increase the release of dopamine, Block cholinergic receptors, Inhibit the N-methyl-D-aspartate (NMDA) type of glutamate receptors
• Adverse effects of Amantadine

  • Restlessness, agitation, confusion, hallucinations, Induce toxic psychosis (high doses), Orthostatic hypotension, Urinary retention, Peripheral edema, Dry mouth, Tolerance may develop
• Anticholinergic agents


  Less efficacious, Adjuvant only in antiparkinsonism therapy, Can induce mood changes, produce xerostamia, constipation, and visual problems, Examples: Benztropine, Trihexyphenidyl, Biperiden
• Alzheimer's disease


  Approximately 10% of all persons over the age of 70 have significant memory, Most important risk factors: Old age, Positive family history, Cognitive changes follow a characteristic pattern: Beginning with Memory impairment, then language and visuospatial deficits, Anosognosia "denial", Aphasia, Apraxia
• Alzheimer's disease


  • Three distinguishing features: Accumulation of senile plaques (β-amyloid accumulations), Formation of numerous neurofibrillary tangles, Loss of cortical neurons, particularly cholinergic neurons, Most severe pathology is found at: Hippocampus, Temporal cortex, Nucleus basalis of Meynert
• Alzheimer's disease: Management


  • Acetylcholinesterase inhibitors: Donepezil, Galantamine, Rivastigmine (transdermal), Selective to AchE in the CNS than in periphery, Provide modest reduction in the rate of loss of cognitive function of Alzheimer's patients

  NMDA receptor antagonist: Memantine, Indicated for moderate to severe Alzheimer's disease, Block NMDA receptor and limit Ca2+ influx into the neuron, Given together with AChE inhibitors
• Rivastigmine


  Only agent approved for the management of dementia associated with AD, Hydrolyzed by AchE to carbamylate metabolites