CHAP 8

• Excitatory Pathways

  Stimulation of excitatory neurons causes movement of ions that results in a depolarization of the postsynaptic membrane
• EPSP generation


  1. Stimulation causes release of neurotransmitters (glutamate, ACh)

  2. Transient increase of Na+ ion permeability

  3. Influx of Na+ causes weak depolarization

  4. Increased stimulated excitatory neurons causes increase in excitatory neurotransmitter release (action potential)
• Inhibitory Pathways


  Stimulation of inhibitory neurons causes movement of ions that results in a hyperpolarization of the postsynaptic membrane
• IPSP generation


  1. Stimulation of inhibitory neurons causes the release of inhibitory neurotransmitters (GABA, glycine)

  2. Influx of ions (K+ and Cl-) causes weak hyperpolarization causing diminished action potential
• Combined Effects of EPSP and IPSP


  Overall action is the summation of the individual actions of the various neurotransmitters on the neuron
• Neurodegenerative Diseases


  Characterized by the progressive loss of of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both
• Examples of Neurodegenerative Diseases


  • Parkinson's Disease
  • Alzheimer's Disease
  • MS
  • ALS
• Parkinsonism


  A progressive neurological disorder of muscle movement, characterized by tremors, muscle rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities
• Most cases of Parkinsonism involve people over 65 above (incidence is 1 in 100 individuals)
• Etiology of Parkinson's Disease

  The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum (neostriatum), parts of the basal ganglia system that are involved in motor control
• Secondary Parkinsonism (Pseudoparkinsonism)


  Caused by drugs that block dopamine receptors in the brain (Ex. Phenothiazine, Haloperidol)
• Drugs used in Parkinson's Disease only offer temporary relief from the symptoms of disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease
• Levodopa


  A metabolic precursor of dopamine that restores dopaminergic neurotransmission in the neostriatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra (20%)
• Carbidopa


  A dopamine decarboxylase inhibitor that diminishes the metabolism of levodopa in the periphery, thereby increasing the availability of levodopa in the CNS
• Without carbidopa, levodopa will be decarboxylated to dopamine in the periphery, resulting in N&V, cardiac arrhythmias and hypotension
• Absorption of Levodopa


  Should be taken with an empty stomach, typically 30 minutes before a meal as protein interferes with the transport of levodopa in the CNS
• Half-life of Levodopa


  1. 2 hours (on-off phenomenon)
• Adverse Effects of Levodopa


  • Anorexia
  • N&V (due to stimulation of chemoreceptor trigger zone)
  • Tachycardia, ventricular extrasystoles, hypotension (dopaminergic effects in the heart)
  • Adrenergic actions (mydriasis)
  • Blood dyscrasias, positive Coombs test
  • Brownish saliva and urine (from melanin pigment produced from catecholamine oxidation)
• Interactions of Levodopa


  • Vitamin B6 (increases peripheral breakdown of levodopa)
  • Non-selective MAO Inhibitors
  • Antipsychotic Agents
• Levodopa should not be given to psychotic patients and should be used with caution in cardiac patients
• MAO Type A


  Metabolizes norepinephrine and serotonin
• MAO Type B


  Metabolizes dopamine
• Selegiline (Deprenyl)


  Inhibits MAO type B at low to moderate doses consequently increasing the dopamine level in the brain, but is metabolized to amphetamine and methamphetamine
• Rasagiline


  An irreversible and selective inhibitor of brain MAO type B, with 5x the potency of selegiline, and is not metabolized to methamphetamine and amphetamine
• COMT Inhibitors


  Cathechol-O-methyltransferase inhibitors that selectively inhibit the enzyme that metabolizes levodopa to 3-O-methyldopa, which competes with levodopa for active transport into the CNS
• Entacapone and Tolcapone


  Selective COMT inhibitors, with Tolcapone having a longer duration of action but can cause fulminating hepatic necrosis
• Dopamine Receptor Agonists


  Have longer duration of action than levodopa and are associated with less risk of developing dyskinesia and motor fluctuations, but are ineffective for patients who have not responded to levodopa
• Bromocriptine


  An ergot derivative with actions similar to levodopa, but can cause hallucinations, confusion, delirium, nausea and orthostatic hypotension
• Nonergot Dopamine Agonists


  • Pramipexole (orally active)
  • Ropinirole (orally active)
  • Apomorphine (used for acute management of the hypomobility "off" phenomenon in advanced Parkinson's disease)
  • Rotigotine (administered as a once daily transdermal patch that provides even drug levels over 24 hours)
• Actions of Dopamine Receptor Agonists


  Alleviate the motor deficits in patients who have not taken levodopa and in patients with advanced Parkinson's disease who are treated with levodopa
• Adverse Effects of Dopamine Receptor Agonists

  • Nausea
  • Hallucinations
  • Insomnia
  • Constipation
  • Orthostatic hypotension
• Amantadine


  An antiviral drug used for influenza that increases the release of dopamine, blocks cholinergic receptors, and inhibits N-methyl-D-aspartate (NMDA) type of glutamate receptors
• Adverse Effects of Amantadine


  • Restlessness
  • Agitation
  • Confusion
  • Hallucinations
  • Acute toxic psychosis
  • Orthostatic hypotension
  • Urinary retention
  • Peripheral edema
• Amantadine is less efficacious than levodopa but has fewer side effects
• Antimuscarinic Agents


  • Benztropine
  • Trihexyphenidyl
  • Procyclidine
  • Biperidin
• Antimuscarinic Agents


  Used as adjuvant treatment, with mechanism of action being blockage of cholinergic transmission, and adverse effects including mood changes, xerostomia, constipation, visual problems
• Alzheimer's Disease


  The most common form of dementia, characterized by difficulty in remembering newly learned information, accumulation of senile plaques (β-amyloid accumulations), formation of neurofibrillary tangles, and loss of cortical neurons, particularly cholinergic neurons
• Acetylcholinesterase Inhibitors


  Donepezil, Galantamine (may augment action of ACh at nicotinic receptors in CNS), Rivastigmine (the only agent approved for the management of dementia associated with Parkinson's disease, administered transdermally)
• NMDA Receptor Antagonist


  NMDA receptors (Glutamate) - overstimulation can cause excitotoxic effects on neurons and is suggested as a mechanism for neurodegenerative or apoptopic processes
• Memantine


  Blocks the NMDA receptor and limits Ca2+ influx into the neuron, such that toxic intracellular levels are not achieved, often given in combination with an AChE inhibitor