Pcol

• CNS drugs


  Drugs that act on the central nervous system
• CNS drugs


  • Most act by changing ion flow through transmembrane channels of nerve cells
  • Transmitter reuptake transporters constitute a second class of drug targets, especially for antidepressant agents
  • A few drugs appear to act by altering the function of neuroglia
• Neurons


  Electrically excitable cells that process and transmit information via an electrochemical process
• Parts of a neuron

  • Soma (Body)
  • Dendrites
  • Axon
  • Synapse
• Types of neuroglia


  • Astrocytes
  • Oligodendrocytes
  • Microglia
  • Ependymal cells
• Blood-Brain Barrier (BBB)


  Protective separation of the circulating blood from the extracellular fluid of the CNS that limits the penetration of substances
• Voltage-Gated Channels


  Responds to changes in the membrane potential
• Ligand-Gated Channels


  Neurotransmitter receptor, binding of ligand opens the channel
• Metabotropic Receptors


  Neurotransmitter receptor, GPCR, binding of neurotransmitter triggers the disassociation of a from beta-gamma subunit
• 2 Main Types of Receptors

  • Ionotropic Receptors
  • Metabotropic Receptors
• Synapse


  Specialized gap region between 2 apposing cell membranes, communication between neurons in the CNS occurs through chemical synapses in majority of cases
• Synaptic Transmission


  1. Action potentials propagating down the axon activates voltage-sensitive Ca2+ channels

  2. Increase in intracellular calcium promotes the fusion of synaptic vesicles with the presynaptic membrane

  3. Neurotransmitter (NTM) are released in the synaptic cleft and diffuses on the postsynaptic membrane

  4. NTM binds to a receptor and opens a channel (directly or indirectly) → postsynaptic event or response
• Excitatory (depolarizing) postsynaptic potentials (EPSP)


  Usually generated by the opening of Na+ or Ca2+ channels
• Inhibitory (hyperpolarizing) postsynaptic potentials (IPSP)

  Generated by opening of K+ or Cl- channels
• Site of Drug Action

  A small number of neuropharmacological drugs exert their effects in the axon, most therapeutically important CNS drugs acts mainly on the synapses (either presynaptically or postsynaptically)
• Cellular Organization of the Brain

  • Hierarchical Systems
  • Diffuse Neuronal System
• Types of Neurons in Hierarchical Systems

  • PROJECTION/RELAY NEURONS (Excitatory neurons)
  • LOCAL CIRCUIT NEURONS (Most are inhibitory neurons)
• Central Neurotransmitters


  • Acetylcholine
  • Monoamines (Da, NE, 5-HT)
  • Diamine (His)
  • Amino acid NTM (Excitatory: Glu, Asp; Inhibitory: GABA, Gly)
  • Peptides
  • Endocannabinoids
• Acetylcholine


  First compound to be identified pharmacologically as neurotransmitter in the CNS, most CNS responses to Ach are mediated by M1 receptors → Excitation
• Monoamines


  Include the catecholamines (Da & NE) and 5-HT
• Dopamine (Da)


  Dopaminergic pathways include the Nigrostriatal, Mesolimbic, Mesocortical, and Tuberoinfundibular, Nigrostriatal pathway is associated with the therapeutic action of antiparkinsonism drugs like levodopa
• Norepinephrine (NE)


  Excitatory effects are produced by α1 & β1 receptors, inhibitor effects are produced by α2 & β2 receptors
• Serotonin (5-HT)


  Can cause excitation or inhibition, most agents for major depressive disorders affect serotonergic pathways to some degree
• Histamine


  Modulate arousal, appetite, and memory, centrally acting antihistamines have significant sedative and anti-motion sickness effects
• Glutamate


  Major excitatory neurotransmitter in the brain, NMDA receptors play a role in synaptic plasticity related to learning and memory
• GABA & Glycine


  Major inhibitory neurotransmitters in the brain, GABA A receptors activation opens Cl- channels, GABA B receptors activation opens K+ channels, Glycine receptors are blocked by strychnine (Spinal convulsant)
• Peptides


  • Opioid peptides
  • Substance P
  • Orexins
• Endocannabinoids


  Primary psychoactive ingredient of cannabis (Δ9-tetrahydrocannabinol (Δ9-THC)) affects the brain by activating CB1 receptor, may affect memory, cognition, and perception