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Antidepressants

Depresssion

Depression is characterized by symptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetite and/or sleep, melancholia, suicidal thoughts, etc.

 

Pathophysiology: Several hypothesis have been proposed and widely accepted is the integration of following:

 

Neurotrophic Hypothesis

Brain Derived Neurotrophic Factor (BDNF) are critical in the regulation of neural plasticity, resilience, and neurogenesis. The evidence suggests that depression is associated with the loss of neurotrophic support and that effective antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus.

Monoamine Hypothesis

The monoamine hypothesis of depression suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA).

Neuroendocrine Hypothesis

Depression is known to be associated with a number of hormonal abnormalities. Among the most replicated of these findings are abnormalities in the HPA axis in patients with M DD.

MDD is associated with elevated cortisol levels

Thyroid dysregulation has also been reported in depressed  

Estrogen deficiency states, which occur in the postpartum and postmenopausal periods, are thought to play a role in the etiology of depression in some women.

Severe testosterone deficiency in men is sometimes associated with depressive symptoms.

 

Classification:

Selective Serotonin Reuptake Inhibitors (SSRI)

Fluoxetine, Fluoxemine, Paroxetine, Sertraline, Citalopram, Escitalopram

Selective Nor-Epinephrine Reuptake Inhibitors (SNRI)

Duloxetine, Milnacipran, Venlafaxine, Desvenlafaxine

Tricyclic Antidepressants (TCA)

Amitriptyline, Imipramine, Clomipramine, Doxepin, Trimipramine

5-HT2 Antagonist

Trazodone, Nefazodone

Tetracyclic/Unicyclic Antidepressants

Amoxapine, Bupropion, Maprotiline,Dothiepene, Desipramine, Nortriptyline

Mao-A Inhibitors (RIMA)

Moclobemide, Clorgyline, Tranylcipromone

Mao-B Inhibitor

Selegiline

Selective Serotonin Reuptake Enhancer (SSRE)

Amineptine, Tineptine

Noradrenergic Specific Serotonergic (NSSA)

Mirtazapine

 

Classification Of Antidepressants

  • Two types
  1. Older            
  2. Newer
  1. Older
    1. MAO-Inhibitors
      1. MAO-A I
        i. Trynylcipromine            
        ii. Isocarboxazid              
        iii. Moclobamide   
        iv. Phenlezine          
        v. Clorglyine
      2. MAO-B I
        Selegiline
    2. Tricyclic ADs
      i. Amytrptaline         
      ii. Doxepine             
      iii. Trimipramine           
      iv. Imipramine
    3. Tetracyclics AD’S
      i. Clomipramine               
      ii. Dothiepene          
      iii. Nortryptaline              
      iv. Desipramine
  1. NEWER
    1. SSRIs
      i. Fluoxetine                 
      ii. Fluoxamine          
      iii. Citalopram            
      iv. Ecitalopram              
      v. Sertraline            
      vi. Paroxetine
    2. SNRIs
      i. Venlafaxine           
      ii. Desvenlafaxine
    3. SSRI/SNRI
      Duloxetine
    4. SDRI
      Bupropion
    5. Selective serotonin reuptake enhancers (SSREs)
       
      i. Tineptine                      
       
      ii. Amineptine
  1. MISCELLANEOUS
    i. Amoxapine           
    ii. Trazadone            
    iii. Nefazadone
    iv. Maprotiline  
    v. Mianserine           
    vi. Mirtazepine

 

General mechanism of action of antidepressants

  • Antidepressants act by increasing the synaptic concentrations of monoamines like serotonin, nor-epinephrine and dopamine.
  • Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition), and the TCAs respectively.
  • Inhibition of their enzymatic degradation (the MAOIs).
  • Binding presynaptic auto-receptors (mirtazapine) or specific postsynaptic receptors (5-HT2 antagonists and mirtazapine).

Older Anti-Depressant

  1. Tricyclic Antidepressants
    1. Inhibit reuptake of NE/5-HT
    2. Initial effects causes decrease in firing in locus cerulus (NE) and nucleus raphe magnus (5-HT)
    3. On long term causes desensitization and increase transmission of above receptors.
    4. Some drugs can inhibit uptake of one or more monoamine
      1. 5-HT reuptake is inhibited by clomipramine
      2. NE reuptake-desipramine, nortryptaline-brain activating property 

P/K

  1. Well absorbed; high first pass metabolism
  2. Lipid soluble (Large Vd=>20 L/kg)
  3. Low safety margin

Mechanism

Adverse effects seen

Antihistaminic

Sedation, Antipruritus

Antimuscarinic

Tachycardia, flushing, hyperthermia, paralytic ileus/urinary retention

Alpha-1 adrenergic blockage

Postural hypotension

NE reuptake inhibition

Insomnia, agitation, tremors

Cardiac sodium channels

Arrhythmia, hypotension, heart block

 

Uses

  1. DOC-diabetic neuropathy
    1. Also in non diabetic neuropathic pain
  2. Imipramine – nocturnal enuresis (Newer and better drug now a days is: Desmopressin)
  3. Amitryptaline: Prophylaxis of migraine
  4. Amoxapine also blocks D-2 receptors (Antipychotic property)
  5. Nortryptaline/desipramine
    1. Depression with hypersomnia   
    2. Depression with psychomotor retardation

Desmopressin

  1. Synthetic vasopressin analogue
  2. Nano peptide
  3. Acts upon V1, V2 receptors
  4. Poor oral absorption
  5. Given intra-nasally
  6. V1 receptors, contribute to side effects, V2-therapeutic
  7. V1 vascular (IP3/DAG)
  8. V2 present in collecting duct (Increase in cAMP)
  9. Both are GPCRs
  10. Despmoressin (DOC)
    1. Nocturnal enuresis
    2. Central/Craniogenic Diabetes Insipidus
    3. Other uses: Christmas disease (Liver), Von-Willebrand disease (Endothelium)
    4. S/e-HTN

 

Toxicity-3Cs

  1. Cardiac toxicity              
  2. Coma                        
  3. Convulsions
    1. No antidote          
    2. Rx-bicarbonate                    
    3. Anion gap is seen

2. MAOIs (Hit & Run drugs)

 

MAO-A

MAO-B

Metabolize NE, 5-HT, DOPAMINE in periphery

Metabolize Dopamine in CNS, platelets and liver

Tranylcypromine, Isocarboxazid, Phenelzine, Selegiline (high dose)

Selegiline (low dose)

S/E: Cheese reaction, Serotonin syndrome, Epileptogenic

 

 

  • Above drugs Inhibit the enzyme Irreversibly
    • Used in moderate to severe depression
  1. Dietary restrictions are major drawbacks
  2. Traynlcipromine is least potent. Shortest
  3. Isocarboxazid is safest 

RIMA (reversible inhibitor of MAO-A): Moclobemide, Clorgyline

a) Do not exhibit Cheese reaction, serotonin syndrome, etc

b) Alternative to TCA

  1. SSRI
  • Fluoxetine is the prototype: LONGEST ACTING
  • Fluvoxamine: SHORTEST ACTING
  • Escitalopram: most specific SSRI
  • Sertraline: safest

S/E: a) Nausea (MC)

        b) Anxiety (2nd MC)

        c) Impotency (hence DOC for Premature Ejaculation)

        d) Serotonin syndrome, abnormal bleeding (platelet serotonin receptors), diarrhea.

 

USES: (first choice of drugs)

  1. Premenstrual dysphoria                                 
  2. Premature ejaculation (MC male sexual dysfuntion)
  3. Bullemia                              
  4. Cyclothymia
  5. Dysthymia                           
  6. Kleptomania       
  7. Remitting & relapsing depression                    
  8. Panic disorders
  9. Depression                                                         
  10. PTSD

Fluoxamine (DOC)

  1. OCD; considered to be most specific              
  2. Clomipramine is gold standard
  1. Atypical Antidepressants

Bupropion

NA and DA uptake inhibitor

ANTISMOKING drug but can ppt. SEIZURES ANTIDEPRESSANT effect takes 2 weeks to develop

Trazodone

PRESYNAPTIC ALPHA-2 BLOCKER, 5-HT2 ANTAGONIST

i. DEPRESSION WITH PSYCHOMOTOR RETARDATION

II. DEPRESSION WITH IMPOTENCE (DOC)

S/E Priapism, Postural Hypotension

Nefazodone

SSRI AND 5-HT2 ANTAGONIST

HEPATOTOXIC

Venlafaxine

SNRI

Fast Onset, Min. Interactions

Mirtazapine

PRESYNAPTIC ALPHA-2 BLOCKER,

5-HT2/5-HT3 ANTAGONIST

Min. Sexual Side Effects

Atomoxetine

NA reuptake inhibitor

Used In ADHD

Duloxetine

NA and 5-HT uptake inhibitor

FIBROMYALGIA, NEUROPATHIC PAIN

 

Summary of Side effects:

  1. Sedation
    i. Mitazepine                    
    ii. Amitryptaline               
    iii. Trazadone
    iv. Desipramine, nortryptaline-least sedation                   

    v. SSRIs -insomnia
  2. Autonomic side effects
    i. Tricyclics, tetracyclics antidepressants           
    ii. Not seen with SSRIs
  3. Weight gain
    i. SSRIS, in beginning cause weight loss           
    ii. Weight again is maximum with mirtazepine
  4. Seizures (Maximum with bupropion-antismoking, also wiith maprotiline)
  5. Hypertension-venlafaxine
  6. Trazadone-priapism-Rx-local adrenaline
  7. Serotonin syndrome-develops when SSRIs are given with MAO Is
    1. Rx-cyproheptadine (5HT 2 antagonist)
  8. Cheese reaction
    1. Occurs with MAO-A I
    2. When patients consume, tyramine containing food e.g. beer, cheese, wine, meat etc
  • Hypertension
  • Rx-phentolamine
  • Selegiline does not cause cheese reaction

 





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