SchizophreniaParkinsons Epileptics

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Schizophrenia/ParkinsonsEpileptics

• Jim Fawcett
• Departments of Pharmacology and Surgery
• jim.fawcett_at_dal.ca

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Disease of the synapse

• Antipsychotic drugs Chapter 7
• Depression and Bipolar Chapter 8
• Antiepileptic Drugs Chapter 9
• Parkinsons disease - Chapter 10

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Psychosis Schizophrenia Altered perception of
reality and disturbances of thought

• Social isolation
• Apathy
• Blunted emotion
• Personal neglect
• Lacking motivation

• Visual and auditory hallucinations
• Delusions
• Disorganized thinking
• agitation

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Schizophrenia

• Dopamine hypothesis
• Over activity of dopamine pathways in certain
  parts of the brain.
• L-dopa aggravate symptoms or produce symptoms de
  novo.
• Blocking dopamine receptors alleviates symptoms.

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D2 receptor and schizophrenia

• There is a direct linear relationship between the
  strength with which the compounds bind at the
  dopamine D2 receptor, and the clinical potency of
  the drug.

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Schizophrenia

• Since D2 receptors are affected motor pathways
  are also affected. Newer drugs more selective and
  less adverse affects on motor systems
• Antipsychotic interact with other receptor
  subtypes including serotonin receptors.

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Schizophrenia

• Extrapyramidal side effects
• Akathisia motor restlessness, insomnia
• Pseudoparkinsonism resting tremor, rigidity
• Dystonia/dyskinesia involuntary, uncoordinated
• (lower drug dose or change drug)
• Long term Tardive Dyskinesia
• (lower dose and time of antipsychotic)

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Concerns for Rehab

• Behavioural mood swings.
• Extrapyramidal side effects postural changes,
  balance and involuntary movements.
• Orthostatic hypotension.

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Depression and Bipolar

• Depression is most prevalent mental illness in
  North America
• 15 adults will experience major depression in
  lifetime
• Sadness and despair
• Lack of interest
• Eating issues, sleep disorders, fatigue
• Recurrent thoughts of death and suicide

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Depression and Bipolar

• Amine systems involved (serotonin,
  norepinephrine, dopamine)
• Serotonin is the likely candidate
• Disease of the synapse

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Pathology of Depression
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Depression and MAO

• MAO monoamine oxidase inhibitors
• - enzyme in synapse
• - removes released drug through enzymatic
  degradation
• - drugs that inhibit this enzyme allow for
  transmitter to remain effective
• Problems sympathetic activity, hypertension

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Depression and tricyclics

• tricyclics three-ring chemical structure
• - block transmitter re-uptake
• - amitriptyline and nortriptyline
• - newer second-generation drugs more common
• Problems sedative, fatigue, insomnia
• major anti-cholinergic effects, dry mouth,
  constipation, arrhythmias.

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Depression and SSRI

• New generation block re-uptake similar to
  tricyclics more selective
• - SSRI selective serotonin reuptake inhibitors
• Advantages of SSRI
• Fewer side effects
• Higher tolerance of drug over longer term

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Depression and Li

• Li monovalent cation
• Competes with Na, K and Ca
• Decreases sensitivity of postsynaptic receptors
  by uncoupling with intracellular signaling
• Problems
• Li not metabolized, collects in body
• Ataxia, respiratory complications, seizures

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Concerns for Rehab

• Blurred vision and anticholinergic effects.
• Dizziness, electrical shock, lethargy.
• Takes time to effect change after drug regime
  starts suicide and depression may worsen.
• Tricyclics lethargy and sedation and muscle
  weakness.

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Parkinsons disease

• Parkinsons disease is characterized by resting
  tremor, rigidity, akinesia (difficulty in
  initiation of movement) and bradykinesia
  (slowness in the execution of movement).

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Parkinsons Disease

• Parkinsons disease results from the degeneration
  of dopaminergic neurons in the substantia nigra
• These neurons project to other structures that
  together control movement

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Parkinsons disease Treatments

• Drugs that increase dopamine levels.
• Dopamine receptor agonists.
• Acetylcholine receptor antagonists.

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Parkinsons disease

• Cholinergic neurons also participate in the
  interconnections between nuclei of the basal
  ganglia
• Loss of dopaminergic neurons in the substantia
  nigra leads to excessive cholinergic activity in
  these pathways.

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Parkinsons disease Treatments

• Levodopa is the biosynthetic precursor of
  dopamine. L-dopa can cross the blood-brain
  barrier.
• Large first pass effect before L-dopa reaches
  target in CNS due to metabolism in peripheral
  tissues by LAAD and COMT

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L-dopa

• L-dopa is taken up by dopaminergic neurons in the
  substantia nigra and converted to dopamine by
  L-amino acid decarboxylase (LAAD)
• As the disease progresses, more dopaminergic
  neurons die and the effectiveness of L-dopa drops

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Adverse effects of L-dopa

• Nausea, orthostatic hypotension and cardiac
  arrhythmias can occur
• These effects are due to the formation of
  dopamine in peripheral tissues

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Adverse effects of L-dopa

• Long-term use of L-dopa can lead to the
  development of involuntary movement or dyskinesia
• Psychotic effects due to excess dopamine in
  mesolimbic and mesocortical pathways.

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Carbidopa

• Is a peripheral decarboxylase inhibitor
• Inhibits the conversion of L-dopa to dopamine by
  LAAD in peripheral tissues.
• Carbidopa does not cross the bbb.
• Combination therapies of L-dopa and carbidopa
  allow for a reduction in the amount of L-dopa
  needed.
• Carbidopa L-dopa (Sinemet)

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Dopamine receptor agonists

• Directly activate dopamine receptors in the
  striatum.
• Different dopamine receptor subunits i.e.. D2
  subunit
• Can be more selective and less side effects than
  L-dopa.

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Anticholinergic Drugs

• Benztropine and trihexphenidyl are
  anticholinergics drugs, block AchR.
• Used in combination with L-dopa to control
  tremors and rigidity.

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Anticholinergic Drugs

• Drowsiness, inattention, confusion, delusions,
  hallucinations.
• Peripheral adverse effects include dry mouth,
  blurred vision, constipation, urinary retention,
  cardiac arrhythmias.

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Treatments of PD

• Drugs that increase dopamine levels
• Dopamine receptor agonists
• Acetylcholine receptor antagonists.

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Concerns for Rehab

• Disease is progressive.
• Fluctuations in response to drug treatment.
• Behavioural concerns.
• Orthostatic hypotension.

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Antiepileptics

• Epilepsy is chronic neurological disorder
  characterized by recurrent seizure activity.
• Seizures are sudden, transient disturbances in
  neuronal excitation.
• Activity can remain localized or spread into
  motor cortex activating descending motor pathways
  convulsions
• Seizures are often self limiting but over time
  recurrent seizures lead to neuronal death

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Antiepileptics

• Drug therapy aimed at quieting the neuron.
• Increase the inhibitory drive
• Glutamate vs gama-aminobuyric acid (GABA).
• Alter movement of ions across membranes

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Antiepileptics - drugs

• GABA related
• Phenobarbital increase GABA effects
• Benzodiazepines (Valium)
• Problems sedation, skin rashes.

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Antiepileptics - drugs

• ion dynamics
• phenytion stabilizes membranes delaying Na
  entry
• Problems GI, dizziness, headache.

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Antiepileptics - drugs

• ion dynamics
• phenytion stabilizes membranes delaying Na
  entry
• Problems GI, dizziness, headache.