Pharmacology of CNS (psychosis, mood disorder, anxiety)

• Neurologic-psychiatric disorders


  • Psychosis
  • Mood disorder
  • Anxiety disorder
  • Seizures
  • Parkinsonian disorder
  • Anesthesia
• Neurotransmission


  Basic functioning of neurons in the CNS is similar to that of ANS. Involves release of neurotransmitters that diffuse across the synaptic space to bind to specific receptors on the postsynaptic neuron. Has more complex neurotransmission
• Excitatory pathways


  Stimulation of an excitatory neuron causes the release of excitatory neurontransmitter molecules which binds to receptors post synaptically causing Na+ influx (depolarization)
• Inhibitory pathways


  Stimulation of an inhibitory neuron causes the release of inihibitory neurontransmitter molecules which binds to receptors post synaptically causing Cl- influx and K+ efflux (hyperpolarization)
• Psychosis


  Altered perception of reality
• Positive symptoms of psychosis


  • Hallucinations
  • Delusion
  • Disorganized thinking
  • Disorganized behavior
• Negative symptoms of psychosis

  • Alogia
  • Anhedonia
  • Avolition
  • Asociality
• Biologic theory of psychosis

  Increased dopamine, norepinephrine, and serotonin
• Typical antipsychotics


  • Phenothiazines
  • Butyrophenones
  • Thioxanthenes
• Atypical antipsychotics


  • Clozapine
  • Olanzapine
  • Risperidone
  • Quetiapine
  • Ziprasidone
  • Aripiprazole
• First generation antipsychotics


  Decrease dopamine by competitively blocking D2 receptor, may decrease positive symptoms, associated with extrapyramidal symptoms
• Second generation antipsychotics


  Lower incidence of extrapyramidal symptoms, associated with higher risk of metabolic side effects, can block both dopamine and serotonin receptors, considered as first-line therapy
• Antipsychotic mechanism of action

  Dopamine (D2) antagonist in the brain and periphery, serotonin receptor-blocking activity (5HT2A receptors)
• Clozapine


  Only antipsychotic that decreases suicide risk, associated with agranulocytosis
• Risperidone


  For intractable hiccups, for young patients, associated with hyperprolactinemia
• Quetiapine


  Associated with sedation "Quiet Time"
• Ziprasidone


  Associated with ECG abnormalities and QT prolongation
• Aripiprazole


  Less sedating, partial agonist of D2 receptor
• Adverse effects of antipsychotics

  • Antimuscarinic effects
  • Extrapyramidal symptoms
  • Dystonia
  • Tardive dyskinesia
  • Akathisia
• Hyperprolactinemia


  Increased prolactin, associated with typical antipsychotics due to dopamine D2 antagonism
• Mood


  Internal pervasive feeling that influences a person's behavior and perception of the world
• Affect


  External expression of mood
• Spectrum of mood


  • Euthymia
  • Dysthymia
  • Major depressive disorder
  • Hypomania
  • Mania
• Major depressive disorder


  At least 5 symptoms for 2 weeks including sleep disturbances, decreased interest, guilt, decreased energy, decreased concentration, anhedonia, psychomotor disturbances, and suicidal ideation
• Selective serotonin reuptake inhibitors (SSRIs)

  • Fluoxetine
  • Citalopram
  • Escitalopram
  • Fluvoxamine
  • Paroxetine
  • Sertraline
• SSRI mechanism of action

  Inhibits serotonin reuptake, increases serotonin, takes at least 2 weeks to produce significant improvement in mood
• SSRI therapeutic uses


  Depression, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder, social anxiety disorder, bulimia nervosa
• SSRI pharmacokinetics


  Well absorbed orally, peak levels in 2-8 hours, little effect of food, metabolized by CYP450 enzymes, half-life 16-36 hours
• Serotonin withdrawal syndrome


  Headache, balance problems, nausea, vomiting (slow onset of action)
• Serotonin syndrome


  Fever, tachycardia, diaphoresis, hyperreflexia, agitation, palpitations (caused by SSRI + MAOIs or SSRI + tyramine, ephedrine, amphetamine)
• First generation antidepressants


  • Tricyclic antidepressants
  • Tetracyclic antidepressants
  • Non-selective MAO inhibitors
• Tricyclic antidepressants


  Inhibit reuptake of norepinephrine > serotonin, associated with coma, convulsions, and cardiotoxicity
• Tetracyclic antidepressants


  Antagonist at presynaptic alpha 2 receptor, inhibit reuptake of norepinephrine
• Non-selective MAO inhibitors


  Inhibit MAO A and MAO B, increase dopamine, norepinephrine, and serotonin
• Second generation antidepressants


  • Trazodone
  • Nefazodone
• Second generation antidepressants


  Inhibit reuptake of serotonin, block 5HT receptors, increase serotonin
• Other antidepressants


  • SNRIs (venlafaxine, duloxetine, desvenlafaxine, levomilnacipran)
  • Reversible inhibitor of MAO A (moclobemide)
  • 5HT1A partial agonist (buspirone)
• Bipolar disorder


  Mania - persistently elevated, irritable and expansile mood for 7 days, symptoms include distractibility, flight of ideas, irritability, agitation, grandiosity, sleep disturbances, talkativeness
• Bipolar disorder treatment


  Lithium salts - first line agent for mania, used acutely and prophylactically, effective in 60-80% of patients
• MAO Inhibitors


  Phenelzine, Isocarboxazid, Tranylcypromine