ANTI-Depressants

Question 1

Where are the drug sites of action?

Answer 1

NE, 5-HT, alpha2

Question 2

Classification of ANTI-depressant Drugs

Answer 2

• MAOI’s: Monoamine Oxidase Inhibitors
• TCAs: Tricyclic Antidepressants
• SSRI’s: Selective Serotonin Reuptake Inhibitors
• SNRI’s: Serotonin & Norepinephrine Reuptake inhibitors
• Mixed Action (Atypical) Antidepressants
  
  • Noradrenergic & Serotonergic alpha2 adrenergic antagonist
  • Serotonin re‐uptake blockade & serotonin 1A partial agonist
  • NDRI: Norepinephrine & Dopamine Reuptake Inhibitor
  • Serotonin/norepinephrine reuptake inhibitor & serotonin 2A antagonist

Question 3

MAOI General

Answer 3

• principle enzyme in monoamine NT metabolism
• MAO-A: metabolizes catecholamines (NE, E), 5-HT
  
  • ​must be inhibited for the ANTI-depressant effect
• MAO-B: metabolizes trace amines (phenethylamine)
  
  • 5HT (when 5-HT at high concentrations)
• MAO-A & B: both metabolize tyramine and DA
• Distributions:
  
  • A:B
  • Brain=25:75
  • Liver= 50:50
  • Intestine=80:20
  • NE & DA neurons=50:50
  • 5HT neurons= 0:100
  • peripheral adrenergic neurons= 90:10
• both A & B bind reversibly (no chemical bond) or irreversibly (forms covalent bond) to the mitochondrial enzyme, MAO
  
  • once an irreversible MAOI binds to MAO, the inactivated enzyme must be replaced by the the cells; this synthesis takes 10-14 days
  • Inhibition of MAO (irreversibly or reversibly) leads to an increase in NE and 5-HT that is available to be released when the neuron depolarizes (“fires”)

Question 4

Irreversible MAOIs

Answer 4

• Phenelzine (Nardil) ‐ inhibits both A & B
• Tranylcypromine (Parnate) ‐ inhibits both A & B
• Isocarboxazid (Marplan) ‐ inhibits both A & B
• Selegiline (l‐deprenyl; Eldepryl)
  
  • at low doses preferentially inhibits B
  • at high doses loses its selectivity and also inhibits A
• Selegiline (Emsam) transdermal patch, at the lowest dose (6 mg/24 hrs), DOES NOT require a modified diet like the other irreversible MAOIs

Question 5

Reversible Inhibitors of MAO (RIMAs)

Answer 5

• Meclobemide (Aurorix)-used abroad, not FDA approved in US
• shorter duration of action vs irreversible MAOIs

Question 6

MAOIs PK

Answer 6

• Half‐life is brief: 2‐4 hours
• MAOIs bind to the enzyme
  
  • if irreversible: once its bound, thats it
  • if reversible: the drug and enzyme can uncouple in certain conditions

Question 7

MAOI SE (Minor)

Answer 7

• GI‐nausea, constipation, appetite change
• Orthostatic hypotension/dizziness
• Sexual dysfunction
• Sleep disturbance‐insomnia & day/night shifting‐sleeping during the day, awake at night
• Sedation (from day/night shifting?)
• Weight gain

Question 8

MAOI SE (severe)

Answer 8

• DDI between MAOI and dietary tyramine –or– between MAOI and other drugs may result in Hypertensive crisis or SS-potentially lethal
• Hypertensive Crisis
  
  • may be brought on by ingestion of food with high amounts of TYRAMINE (aged cheeses, wines, cured meats)
    
    • Tyramine normally metabolized by MAOs in the intestinal wall and liver
    • nml persn can digest 200-800 mg tyramine before any increase in bp
      
      • on MAOI, 6-10 mg ty=mild rx, 10-25 mg=severe rxn
  • with MAO-I, unmetabolized tyramine enters the bloodstream, goes to NE sympathetic neurons, displaces NE from synaptic vesicles= INCREASE in cytosolic NE (NE not metabolized by the MAO-A in the neuron)
    
    • next: reversal of NE reuptake transporter and INCREASE in NE postsynaptic receptor stim=INCREASED BP->risk of ruptured brain aneurysm and possible hemorrhagic stroke
  • Tx with the Selegiline (Emsam): transdermal patch; at lowest dose no dietary risk or limitations
    
    • At doses high enough to block MAO‐A, transdermal-Emsam hits the brain SANS a 1st pass through the liver.
    • When it recirculates to the intestines its also doing a “1st pass” through the liver resulting in DECREASED drug levels and mostly only the intestine’s MAO‐B is inhibited
• Serotonin Syndrome