Venlafaxine / Desvenlafaxine – bicyclic
Duloxetine – 3-ring
Milnacipran – cyclopropane ring
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
SERT / NET
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
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
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
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
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.