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CNS Pharmacology


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CNS Pharmacology

  2. 2. CNS Pharmacology 2 Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. These agents are invaluable therapeutically, e.g., without general anesthetics, modern surgery would be impossible. Drugs that affect the CNS can: • selectively relieve pain, reduce fever, • suppress disordered movement, • induce sleep or arousal, reduce appetite, and allay the tendency to vomit. • treat anxiety, depression, mania, or schizophrenia
  3. 3. CNS Pharmacology 3 • In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one's sense of well-being. • However, the excessive use of such drugs can affect lives adversely?! when their uncontrolled, compulsive use leads to: 1. physical dependence on the drug 2. toxic side effects, including lethal overdosage.
  4. 4. Ion channels in the brain 4 are of two major types: Voltage & Ligand gated 1. Voltage gated: regulated by changes in membrane potential. i) axonal Na+ channels involved in propagation of action potentials ii) Presynaptic Ca+2 channels that play a critical role in the release of neurotransmitters from synaptic vesicles.
  5. 5. Ion channels in the brain II. Ligand (transmitter) gated: Such receptors may be: 1. directly linked to ion channels 2. Indirectly by change ion channel function via second messenger system.  Membrane delimited metabotropic ion channel Gprotein  & diffusible 2nd messenger metabotropic ion channel cAMP, IP3, DAG 5
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  7. 7. Molecular Targets for CNS Drugs 7
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  9. 9. Molecular Targets (sites) for CNS Drugs 9 I. Ion channels on axons: A SMALL no. of CNS drugs exert their effects through direct interactions with molecular components of ion channels on axons; examples i) certain anticonvulsant e.g., carbamazepine and phenytoin, ii) Local anesthesia (LA) and some general anesthesia (GA).
  10. 10. Molecular Targets (sites) for CNS Drugs 10 II. Synapse: The effects of MOST therapeutically important CNS drugs are exerted mainly at synapse; possible mechanisms are: A. Presynaptically: drugs act presynaptically to alter the synthesis, storage, release, reuptake, or metabolism of transmitter chemicals. B. Pre-post synaptic receptors: Other drugsactivate or block of pre-post synaptic receptors
  11. 11. Molecular Targets (sites) for CNS Drugs 11
  12. 12. Ion channels: 12 Role of the ion current carried by the channel • ↑Na+ or ↑ Ca+2 influx or ↓K+ efflux → excitation via membrane depolarization (EPSP) • ↑Cl- or ↓ Ca+2 influx or ↑ K+ efflux → inhibition via membrane hyperpolarization (IPSP)
  13. 13. ion current carried by potential; EPSP & IPSP I. 13 Excitatory postsynaptic potential (EPSP): a depolarizing potential change, i) are usually generated by the opening of Na+ or Ca+2. ii) In some synapses similar depolarizing potentials result from the closing of K+ channels
  14. 14. ion current carried by potential: 14 II. Inhibitory postsynaptic potential (IPSP): a hyperpolarizing potential change, i) are usually generated by the opening of K+, or Cl- channels; e.g., Activation of postsynaptic metabotropic receptor ↑ the efflux of K+. ii) Presynaptic inhibition can occur via a ↓ Ca+2 influx elicited by activation of metabotropic receptors.
  15. 15. Neurotransmitters • Ach • Monoamines: Dopamine, NE, 5-HT • 15 Amino acid neurotransmitters 1. Excitatory: Glutamate, Aspartate (learning and memory) 2. Inhibitory: GABA, Glycine • Peptides: opioids (enkephalins, endorphins), substance-P, nociception; hunger, metabolism • Endocanabinoids: the drug Anandamide CB1 ligand; memory, cognition and pain perception
  16. 16. Drugs and molecular targets in the CNS 16
  17. 17. CNS Transmitters and receptors Ach: • M1 excitatory (↓K+ efflux, via DAG), • M2 inhibitory (↑K+ efflux, via cAMP) • N excitatory (Na+ influx, direct coupling); activities of above receptors modified by: 1. nicotine, 2. AchE inhibitors (tacrine) in Alzheimer’s, 3. M blockers (benzotropine) in Parkinson’s. 17
  18. 18. Dopamine   1. 2. 18 Inhibitory, via GPCR activation of K+ channel, multiple subtypes (D1, D2, D3, D4, D5)G-protein linked to cAMP; activities ↑ by CNS stimulants (e.g., amphetamine) and antiparkinson drugs (e.g., levodopa), activities ↓ by antipsychotics (e.g., chlorpromazine).
  19. 19. Dopamine 19 D2 receptor is the main dopamine subtype in basal ganglia neurons and its widely distributed at the supraspinal level.  Dopaminergic pathways: 1. Nigrostriatal, 2. mesolimbic, 3. tuberoinfundibular tracts
  20. 20. Norepinephrine Excitatory or inhibitory, depending on receptor subtype (second messenger coupling): 1. Excitatory effects: α1 and β1 receptors 2. Inhibitory effects: α2 and β2 receptors Activities enhanced by: • CNS stimulants, • antidepressants, • MAO inhibitors • and some anxiolytics 20
  21. 21. Serotonin (5-HT): 21 Serotonin is inhibitory at MANY CNS site but can cause excitation of SOME neurons depending on the receptor subtype activity. All are metabotropic except 5-HT3 subtype (ionotropic), Activities modified by:  CNS stimulants,  antidepressants,  some anxiolytics.
  22. 22. Glutamate 22 Most neurons in the brain are excited by glutamic acid via influx of cations (direct coupling and Gprotein linked). NMDA (N-methyl D-aspartate)  AMPA: α-amino-3-hydroxy-5-methylisoxazole-4propionic acid  Kainate  ACPD: Metabotropic receptor Ionotropic 
  23. 23. Glutaminergic pathway 23
  24. 24. Glutamate 24 • NMDA mediate slow excitatory responses and also play a role in synaptic plasticity related to learning and memory. • NMDA is blocked by phencyclidine and ketamine (dissociative anesthesia). • Memantine is an NMDA antagonist RX Alzheimer, dementia. • AMPA and Kinate are involved in Fast excitatory transmission
  25. 25. GABA and Glycine 25 GABA is the primary neurotransmitter mediating fast IPSP in neurons in brains, it is also important in spinal cord.  GABAA activation opens chloride channel drugs: sedative hypnotics; barbiturates and benzodiazepine, some anticonvulsants; gabapentin, vigabatrin)
  26. 26. GABA & GLYCINE  GABAB; 26 GPCR either open K+ channel or close Ca+2 channel Slow IPSP (Drug: Baclofen)  Glycine: More numerous in the cord than in the brain. Blocked by strychnine, a spinal convulsant
  27. 27. GABAA Receptor Complex BZD binding GABA 27
  28. 28. Peptide transmitters 28 Many peptide have been identified in the CNS and some meet most or all of the criteria for acceptance as neurotransmitter: 1. present in higher concentration in the synaptic, 2. Released by electrical or chemical stimulation via Ca+2 dependent mechanism, 3. produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse.
  29. 29. Peptide transmitters Opioid Peptides & Substance-P 29 The best defined peptides are:  opioid peptides; β-endorphin, met-& leo-enkephalin &dynorphin Drugs: Opioid analgesics (morphine)  Substance-P mediator of slow EPSPs-nociceptive sensory pathways in the spinal cord and brain stem
  30. 30. Endocannabinoids  These are brain lipid derivatives (e.g., 2arachidonyl glycerol) Bind to cannabinoids** receptors  They are synthesized and release post synaptically after membrane depolarization  But travel backward acting presynaptically (retrograde) to decrease transmitter release **cannabinoids found in marijuana 30