CNS _ lippen

• Neurotransmission


  The process of transmitting information between neurons in the central nervous system (CNS)
• Neurons in the CNS

  • Transmit information via the release of neurotransmitters that diffuse across the synaptic cleft to bind to specific receptors on the postsynaptic neuron
  • Contain networks of inhibitory neurons that modulate the rate of neuronal transmission
  • Communicate through the use of multiple neurotransmitters, unlike the peripheral autonomic nervous system which uses primarily acetylcholine and norepinephrine
• Excitatory postsynaptic potential (EPSP)

  A depolarization of the postsynaptic membrane caused by the binding of excitatory neurotransmitters like glutamate or acetylcholine, which increases the permeability of sodium ions
• Inhibitory postsynaptic potential (IPSP)


  A hyperpolarization of the postsynaptic membrane caused by the binding of inhibitory neurotransmitters like GABA or glycine, which increases the permeability of chloride and potassium ions
• Most neurons in the CNS receive both EPSP and IPSP input, and the overall action is the summation of the individual actions of the various neurotransmitters on the neuron
• Neurodegenerative diseases


  Devastating illnesses characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both
• Parkinson disease


  • A progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia, and postural and gait abnormalities
  • Most cases involve people over the age of 65, with an incidence of about 1 in 100 individuals
• Substantia nigra


  Part of the extrapyramidal system that is the source of dopaminergic neurons which terminate in the neostriatum and modulate motor activity
• Neostriatum


  Connected to the substantia nigra by neurons that secrete the inhibitory transmitter GABA, and receives inhibitory dopaminergic projections from the substantia nigra
• In Parkinson disease


  Destruction of cells in the substantia nigra results in degeneration of the nerve terminals that secrete dopamine in the neostriatum, leading to overproduction of acetylcholine and loss of control of muscle movements
• 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
• Carbidopa


  A dopamine decarboxylase inhibitor that diminishes the metabolism of levodopa in the periphery, thereby increasing the availability of levodopa to the CNS
• Levodopa administered with carbidopa


  Decreases the dose of levodopa needed and reduces the severity of adverse effects arising from peripherally formed dopamine
• Levodopa in combination with carbidopa is an efficacious drug regimen for the treatment of Parkinson disease, decreasing rigidity, tremors, and other symptoms
• Levodopa


  Synthesized to dopamine in the absence and presence of carbidopa, an inhibitor of dopamine decarboxylase in the peripheral tissues
• In approximately two-thirds of patients with Parkinson disease, levodopa-carbidopa substantially reduces the severity of symptoms for the first few years of treatment. Patients typically experience a decline in response during the 3rd to 5th year of therapy. Withdrawal from the drug must be gradual.
• Absorption and metabolism of levodopa

  Rapidly absorbed from the small intestine (when empty of food), has an extremely short half-life (1 to 2 hours) causing fluctuations in plasma concentration, ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS
• Adverse effects of levodopa

  • Anorexia
  • Nausea
  • Tachycardia
  • Hypotension
  • Psychiatric problems
• Diminished effect of levodopa

  Due to increased peripheral metabolism
• Hypertensive crisis


  Due to increased catecholamines from concomitant administration of levodopa and non-selective monoamine oxidase inhibitors (MAOIs)
• Selegiline (deprenyl)


  Selectively inhibits monoamine oxidase (MAO) type B, the enzyme that metabolizes dopamine, increasing dopamine levels in the brain
• Rasagiline


  An irreversible and selective inhibitor of brain MAO type B, with five times the potency of selegiline
• Safinamide


  A selective inhibitor of MAO type B indicated for use as an adjunct to levodopa-carbidopa
• Catechol-O-methyltransferase (COMT) inhibitors


  Entacapone and tolcapone selectively and reversibly inhibit COMT, leading to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine
• Entacapone


  • Does not exhibit the hepatic toxicity associated with tolcapone, and has largely replaced tolcapone in clinical practice
• Dopamine receptor agonists


  • Bromocriptine
  • Ropinirole
  • Pramipexole
  • Rotigotine
  • Apomorphine
• Dopamine agonists


  Have a longer duration of action than levodopa, are effective in patients exhibiting fluctuations in response to levodopa, and are associated with less risk of developing dyskinesias and motor fluctuations compared to patients started on levodopa
• Dopamine agonists may delay the need to use levodopa in early Parkinson disease and may decrease the dose of levodopa in advanced Parkinson disease
• Adverse effects of dopamine agonists

  • Sedation
  • Hallucinations
  • Confusion
  • Nausea
  • Hypotension
• Amantadine


  Has several effects on neurotransmitters implicated in parkinsonism, including increasing the release of dopamine, blocking cholinergic receptors, and inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors
• Antimuscarinic agents (e.g. benztropine, trihexyphenidyl)


  Play an adjuvant role in antiparkinsonism therapy, blocking cholinergic transmission to help correct the imbalance in dopamine/acetylcholine activity
• Dementia of the Alzheimer type has three distinguishing features: 1) accumulation of senile plaques (β-amyloid accumulations), 2) formation of numerous neurofibrillary tangles, and 3) loss of cortical neurons, particularly cholinergic neurons
• Current therapies for Alzheimer's disease aim to either improve cholinergic transmission within the CNS or prevent excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors
• Cholinergic transmission


  Blockade produces effects similar to augmentation of dopaminergic transmission, since it helps to correct the imbalance in the dopamine/acetylcholine activity
• Cholinergic blockers can induce mood changes and confusion, and produce xerostomia, constipation, and visual problems typical of muscarinic blockers
• Cholinergic blockers interfere with gastrointestinal peristalsis and are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis
• Dementia of the Alzheimer type


  • Accumulation of senile plaques (β-amyloid accumulations)
  • Formation of numerous neurofibrillary tangles
  • Loss of cortical neurons, particularly cholinergic neurons
• Current therapies for Alzheimer disease aim to either improve cholinergic transmission within the CNS or prevent excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors in selected areas of the brain
• Pharmacologic intervention for Alzheimer disease is only palliative and provides modest short-term benefit. None of the available therapeutic agents alter the underlying neurodegenerative process
• Acetylcholinesterase (AChE) inhibitors


  Improve cholinergic transmission by inhibiting the enzyme that breaks down acetylcholine