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Chemistry
Different chemical structure.
Fluoxetine / sertraline / citalopram have enantiomers R and S, formulated as racemic products
Escitalopram S enantiomer is available as separate formulation.
Pharmacokinetics
Well absorbed after oral administration
PPB –in between 80-90%
Undergo hepatic metabolism, some form active metabolites
Notably fluoxetine forms Norfluoxetine which is an active metabolite
T1/2 7 days, once weekly dose
Potent enzyme inhibitor –especially inhibits CYP 2D6 / 3A4, drug interaction occurs with the drugs metabolized here as given for longer duration
Mechanism of Action
SERT – 80%
In serotonergic neuronal endings there are serotonergic transporters labeled as SERT, which are glycoprotein in nature. They are responsible for reuptake of serotonin from synaptic cleft. Normally when binds this SERT, brings about conformational change in transporter protein. Due to this serotonin and sodium and chloride are passed inside and from inside potassium ions bind and bring back transporter to original shape leading to release of serotonin inside.
In this way, serotonin is taken up by synaptic cleft and brought inside.
SSRI bind transporter SERT, site is different from where serotonin binds. They inhibit uptake of serotonin by these transporters, leading to increased levels of serotonin in synaptic cleft. Activity of transporter is inhibited up to 80% to bring about clinical effectiveness.
This serotonin is in turn responsible for enhanced transcription of genes for neurotrophic factors, which are responsible for antidepressant effect.
Polymorphism
Polymorphism exists is these genes responsible for variability in mood, some are more vulnerable and some resistant.
Other sites
SSRI do not effect other receptors, as seen with other groups.
Adverse effects
As serotonergic neurons are not only present in CNS, but also on many other body parts, responsible for adverse effects.
GIT
Most abundant in GIT.
a. nausea
b. gastrointestinal upset
c. diarrhea
settles down in about a week or so.
Sexual function
Decreased sexual functions
Decreased libido, both males and females
Changes in pattern of sleep
Either loss of sleep, insomnia or leads to increased sleep or hypersomnia
Headache
Weight gain esp. with Paroxetine when discontinued abruptly
Discontinuation syndrome
Dizziness, paresthesias
Suicidal tendency
Not used in patients less than 25 years of age as noted that patients have increased suicidal tendency.
Drug interactions
Pharmacokinetic – CYP 2D6 / 3A4 inhibitor
When given with drugs metabolized by these enzymes, toxicity of those drugs is enhanced.
Pharmacodynamic
When monoamine oxidase inhibitors inhibit monoamine enzyme responsible for degradation, increased serotonin occurs at neuronal endings occurs, which is not degraded, and levels reach toxic levels.
Serotonin syndrome
Esp. in central grey nuclei and medulla
Cognitive effect, delirium, coma
Autonomic, hypertension and tachycardia
Somatic effects myoclonus, hyperreflexia, tremors
To avoid this interaction, gap of 2 weeks between administration of these drugs either SSRI or MAO inhibitors, for fluoxetine it is 4-5 weeks as active metabolites with longer half life are formed.
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Serotonin Norepinephrine Reuptake Inhibitors
