hikma midterms

• Types of Neurotransmitters (NTM)


  • Acetylcholine
  • Monoamines
  • Diamine
  • Amino acid NTM
  • Peptides
  • Endocannabinoids

  
• Acetylcholine (Ach)


  First compound to be identified pharmacologically as NTM in the CNS, Most CNS responses - M1 receptors → Excitation
• Monoamines


  • Dopamine
  • Norepinephrine
  • Serotonin
• Dopamine (DA)


  • 4 pathways: Nigrostriatal, Mesolimbic, Mesocortical, Tuberoinfundibular, Has 5 receptor subtypes (D1-D5), D2 is the main receptor subtype (Dominant)

  
• Norepinephrine (NE)


  • Located in the locus coeruleus (brain stem) or lateral tegmental area of pons, Excitatory effects → α1 & β1 receptors, Inhibitory effects → α2 & β2 receptors
• Serotonin (5-HT)


  • Originates in the midline raphe nuclei of pons and upper brain stem, All are metabotropic receptors except for 5-HT3 receptor (Ionotropic), Can cause excitation or inhibition
• Diamine


  Related to monoamines and is present in very small amounts in CNS, Histamine originates in the tuberomammillary nucleus in the posterior hypothalamus, modulates arousal, appetite, and memory

  
• Amino acid NTM


  • Excitatory: Aspartate, Glutamate
  • Inhibitory: GABA, Glycine

  
• Glutamate


  • Major excitatory NTM in the brain, 3 Receptors for binding: NMDA, AMPA, Kainate

  
• NMDA receptor


  Involved in synaptic plasticity related to learning and memory, Blocked by Phencyclidine (PCP, aka Angel Dust) and Ketamine, Memantine (NMDA Antagonist) is approved for Alzheimer's Dementia
• GABA


  • Major inhibitory NTM in the brain, 2 Receptors: GABA A (activation → opening of Cl- channels), GABA B (activation → opening of K+ channels)
• Glycine


  Inhibitory NTM, Blocked by Strychnine (Spinal Convulsant)
• Peptides


  • Packaged in large, dense cores and synthesized in cell/neuron body, others synthesize in axon, No reuptake mechanisms, Opioid peptides, Substance P, Orexins
• Endocannabinoids


  Primary psychoactive ingredient of cannabis (Δ9-tetrahydrocannabinol (Δ9-THC)), affects the brain by activating CB1 receptor, Ligands are not stored but are rapidly synthesized, May affect memory, cognition, and perception
• Sedation


  Calming effect
• Hypnosis


  Produce drowsiness
• Benzodiazepines (BZD)


  • 1,4-benzodiazepines, Must contain carboxamide group, Substituent at C7 should be Halogen or Nitro group for sedative-hypnotic effect, Most are lipid-soluble and well absorbed in the GI, α1 subunit → sleep; α2/3 subunit → anxiety, GABA binds between α1 & β2 subunits, BZD binds between α1 & γ2 subunits, Barbiturates binds at a different site from BZD

  
• Zolpidem, Zaleplon, Eszopiclone


  Not BZDs but exerts CNS effects by binding with certain BZD receptors (BZ1 or ω1 subtypes)
• Buspirone


  Partial agonist at 5-HT1A, Precise MOA for anxiolysis is unknown
• Melatonin Receptor Agonist (Ramelteon, Tasimelteon)


  Activates Melatonin receptors (MT1 & MT2) → decreases latency of sleep onset, MT1 promotes sleep, MT2 shifts the circadian rhythm
• Flumazenil


  Competitive antagonist at BZD receptor, Reverses the CNS effects of BZD
• Benzodiazepines


  • Short-Acting: Midazolam, Triazolam
  • Intermediate-Acting: Alprazolam, Clonazepam, Estazolam, Lorazepam, Oxazepam, Temazepam
  • Long-Acting: Chlordiazepoxide, Clorazepate, Diazepam, Flurazepam, Prazepam, Quazepam
• Barbiturates


  • Ultra Short-Acting: Thiopental
  • Intermediate-Acting: Pentobarbital, Amobarbital, Secobarbital
  • Long-Acting: Phenobarbital
• Alcohols


  • Ethanol
  • Methanol
  • Ethylene Glycol

  
• Fomepizole


  Treatment for acute methanol or ethyl glycol (EG) poisoning

  
• Ethanol is hydrophilic, absorbed rapidly from the GIT, has 2 major metabolic pathways: Alcohol Dehydrogenase (90%) and Microsomal Ethanol-Oxidizing System (MEOS) (10%), Acetaldehyde is the metabolite responsible for the hangover effect, Acetaldehyde is oxidized to Acetate by Aldehyde dehydrogenase (ALDH), ALDH2 Polymorphism → Asian Flush
• Uses of sedatives


  • Phenobarbital
  • Insomnia
  • Seizure Disorders (Phenobarbital)
  • Status Epilepticus (Phenobarbital)
  • Muscle spasticity (Phenobarbital)
  • Hyperbilirubinemias (Gilbert's syndrome)
• Other names for alcohol withdrawal treatment

  • Ethanol
  • Ethyl Alcohol
  • Grain Alcohol
  • Drinking Alcohol
• Uses of alcohol withdrawal treatment

  • Treatment of Drug Dependence
  • Acute Methanol or Ethyl Glycol (EG) Poisoning

  
• Thiamine (Vitamin B1)


  Used in alcohol withdrawal treatment in ethanol
• Disulfiram (Antabuse)


  Used in drug dependence treatment in ethanol
• Methanol


  Wood Alcohol
• Acamprosate


  Used in drug dependence treatment in EG
• Ethanol pharmacokinetics


  • Hydrophilic
  • Absorbed rapidly from the GIT
  • 2 Major Metabolic Pathways: Alcohol Dehydrogenase (90%) and Microsomal Ethanol-Oxidizing System (MEOS) (10%)
• Acetaldehyde


  Metabolite responsible for the hangover effect
• Ethanol metabolism


  1. Acetaldehyde is oxidized to Acetate by Aldehyde dehydrogenase (ALDH)

  2. ALDH2 Polymorphism → Asian Flush

  3. Both Alcohol and Aldehyde Dehydrogenase requires a cofactor (NAD+)

  
• Substances that inhibit Aldehyde dehydrogenase

  • Disulfiram
  • Metronidazole
  • OHA
  • Some Cephalosphorins

  
• Glycolysis


  Ethanol metabolism increases the NADH/NAD+ ratio, leading to lactic acidosis, fasting hypoglycemia, ketoacidosis, and hepatosteatosis

  
• Ethanol metabolism via CYP2E1


  Limits the availability of NADPH for the generation of reduced glutathione → enhance oxidative stress

  
• Management for alcohol intoxication

  1. Prevention of severe respiratory depression & aspiration vomitous: Left Lateral Decubitus Position

  2. Correction of electrolyte imbalance, hypoglycemia and ketoacidosis: Glucose

  3. Thiamine to protect against wernicke-korsakoff syndrome