Selective Serotonin Reuptake Inhibitors (SSRIs)Contents:

IntroductionList of drugsMechanism of actionAdvantage over TCAs1 and MAOIs2

IndicationsPharmacokineticsAdverse Drug Reactions (ADRs) / Side-effectsDiscontinuation SyndromeSerotonin Syndrome 1TCAs = Tri-cyclic Anti-depressants

2MAOIs = Monoamine Oxidase Inhibitors

IntroductionSSRIs are the ‘drugs of choice’ for treating

depression.Highly selective for serotonin transporter

gives them advantage over other drugs of this class.

Fluoxetine is the prototype drug.

Drugs include:

Can = CitalopramEffectively = EscitalopramForm = FluoxetineFavorable = FluvoxaminePotentials of = ParoxetineSerotonin = Sertraline

Mechanism of ActionPrimary aim in treatment of depression balance

levels of neurotransmitters to boost mood.SSRIs act on serotonin transporter block

reuptake of serotonin in pre-synaptic neuron more serotonin persists in the synaptic cleft more post-synaptic neuronal activities.

Balancing of serotonin seems to help brain cells send and receive chemical messages, which in turn boosts mood.

Very selective for serotonin transporter 300- to 3000-fold more selective for serotonin than for nor-epinephrine transporter.

Advantage over TCAs and MAOIsTCAs and MAOIs affect re-uptake of serotonin as

well as nor-epinephrine.Also have blocking activity at muscarinic, α-

adrenergic, histaminic H1 receptors.SSRIs very selective for serotonin don’t exhibit

antagonist activity at any other receptors.Hence side effects associated with TCAs and

MAOIs like orthostatic hypotension, sedation, dry mouth, blurred vision not seen with SSRIs

Fewer side effects, relatively safer in overdose and equally effective as TCAs

Acquired status of first line treatment for depression.

IndicationsPrimary indication: DepressionOthers:

Panic Disorder Generalized Anxiety Disorder Post-traumatic Stress Disorder Social Anxiety Disorder Bulimia Nervosa (only Fluoxetine) Obsessive – compulsive disorder

How? imbalance in the level of

neurotransmitters activates the ‘alarm-system’ of brain anxiety, obsessive-compulsive disorder etc SSRIs balance the amount of neurotransmitter.

Pharmacokinetics Well-absorbed after oral administration Fluoxetine

also available as sustained-release preparation. Max. bioavailability in 2-8 hours and average half-lives

of 16-36 hours. Fluoxetine longest half-life 50 hours, it’s metabolite

(nor-fluoxetine) 10 days half-life. Metabolized by cytochrome P450 enzyme system. Enzyme-drug interactions: Inhibit various iso-enzymes

of CYP450 system (e.g. CYP2D6) hence, decreases metabolism of drugs like TCAs, neuroleptic drugs, antiarrhythmic, beta-adrenergic antagonist drugs.

Excretion: Urine. Sertaline and Paroxetine Also fecal excretion.

Side-effectsSleep disturbances: Paroxetine and Fluvoxamine

sedating.

Fluoxetine and Sertraline more activating.Suicidal tendencies in children and teenagers.Headache, sweating, anxiety, agitation, weakness,

fatigue, changes in weight.GIT disturbances: nausea, vomiting, diarrheaOverdose: Tendency to cause Seizures

How? by reducing seizure threshold.

Discontinuation SyndromeOccurs on abrupt withdrawal of SSRIs.Symptoms include: headache, malaise,

agitation, irritability, flu-like symptoms, nervousness, changes in sleep pattern.

Agents with short half-lives, inactive metabolites abrupt washout higher risk.

So, Fluoxetine lowest risk for discontinuation syndrome.

Serotonin Syndrome“Excess of everything is harmful”Administration of an SSRI in presence of

another highly serotonergic drug such as MAOI life-threatening ‘serotonin syndrome’

Excess of serotonin changes in mental status and vital signs, hyperthermia, muscle rigidity, muscle twitching.

Washout period of 2 weeks before administration of an MAOI (6 weeks for Fluoxetine)