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Serotonin Norepinephrine Reuptake Inhibitors

Selective SNRIs


—  Venlafaxine / Desvenlafaxine – bicyclic

—  Duloxetine – 3-ring

—  Milnacipran – cyclopropane ring


Well absorbed after oral administration.

Desvenlafaxine (cyt P450 2D6)– lowest PPB (27-30%)

Excreted unchanged in urine, rest is directly conjugated and excreted urine

Duloxetine – extensive PPB / extensive oxidative metabolism

Mechanism of Action


Same as SSRI, not only inhibit serotonin but also norepinephrine transporters. Both serotonin and norepinephrine levels increase. Increased transcription of neurotrophic growth factors occurs.

Difference – TCAs

Tricyclic antidepressants acting along these transporters, also act on alpha, muscarinic and histamine receptors.

Tricyclic anti-depressants (TCAs)


Iminodibenzyl (tricyclic) ring


—  Absorption– well absorbed after oral administration

—  PPB –have extensive protein binding

—  Undergo extensive metabolism Demethylation / hydroxylation / glucuronide conjugation

—   Metabolized by CYP2D6, if polymorphism occurs, either slow or rapid metabolism

Mechanism of Action

SERT – clomipramine / imipramine

NET – desipramine / nortriptyline

As SNRI, act both at serotonin and norepinephrine transporter, inhibit uptake of monoamine, increasing levels at neuronal junctions. Some drugs have more affinity for serotonin, others for norepinephrine.

Apart also affect also receptors:

—  Antimuscrinic, anticholinergic effect

—  Antihistamine – Doxepin, block H1 effect, used in pruritis

—  α – Adrenergic blockade –orthostatic hypotension is adverse effect

Adverse effects

More than others because of action on multiple receptors.


a. hypertension due to norepinephrine release, due to alpha blockage, may cause postural hypotension

b. increased BP in dose dependent manner – venlafaxine

c. Cardiac rhythm, TCAs have antiarrhythmic effect, quinidine like property at higher doses may cause arrhythmias.

Venlafaxine is also cardio toxic.

CNS activation, stimulation, irritability, insomnia, agitation

Hepatic toxicity– duloxetine, not seen with other members of group

Anticholinergic effects – amitriptyline / imipramine –dry mouth, constipation, urinary retention, blurred vision

α – Adrenergic blockade 

Antihistamine – weight gain / sedation

Sexual function diminished, both genders

Discontinuation syndrome, when discontinued abruptly- dizziness, parasthesias

Cholinergic rebound / flu like symptoms

Drug interactions


—  Duloxetine – CYP2D6 inhibitor

—  TCAs – CYP2D6 substrate so increased levels are seen

—  CYP2D6 polymorphism – additive effects may be seen


Not combined with monoamine oxidase inhibitors , as increase levels

As have anticholinergic, antihistamine and alpha blocking effect so care is taken when given with anticholinergics / antihistamines /  antihypertensives

Over dosage

—  Venlafaxine – cardiac toxicity

—  TCAs are well known for toxic effects– CVS effects include hypertension, tachycardia, arrhythmias / CNS effects include irritation, irritability, seizures


Managed conservatively. Gastric lavage, vital signs, airways.

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Anti Depressant Agents

Selective Serotonin Reuptake Inhibitors

5HT2 Antagonists and Tetracyclic Unicyclic Antidepressants

Monoamine Oxidase Inhibitors

Clinical Uses of Antidepressants

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