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5HT2 Antagonists and Tetracyclic Unicyclic Antidepressants

5-HT2 antagonists

Chemically triazole moiety, having antidepressant effect.

Pharmacokinetics

Well absorbed after oral administration.

Extensive plasma protein binding

Extensively metabolized in liver

Both drugs are converted into active metabolites, having potent antidepressant activity.

Trazodone is converted to MCPP (m-chloro phenyl piperazine)

Nefazodone is converted into hydroxyl nefazodone and MCPP.

Mechanism of action

Antagonist at 5HT2A  receptors so have antianxiety, antipsychotic and antidepressant effects.

Agonists to %HT2A receptors produce hallucinations and psychotic behavior.

Weak inhibitor of serotonin and norepinephrine transporter raising amine levels.

Trazodone effects alpha adrenergic receptors inhibiting antihistamines in addition.

Adverse effects

Sedation –Trazodone antihistamine

GIT upset

Nefazodone is known for hepatotoxicity

Orthostatic hypotension

Drug interactions

—  Trazodone cyp 3 A4 substrate

—  Nefazodone cyp 3 A4 inhibitor

Tetracyclic Unicyclic Antidepressants

Chemically versatile group.

Bupropion is unicyclic aminoketone

Chemically resemble amphetamines

Rest of the drugs are tetracyclic in structure

Amoxapine is a metabolite of old antipsychotic loxapine.

Pharmacokinetics

Well absorbed after oral administration.

Extensive PPB.

Extensively metabolized in liver

Bupropion has three active metabolites:

Hydroxyl bupropion-typical biphasic elimination

1st phase 1 hour, 2nd phase 14 hours

Amoxapine forms active metabolite hydroxyl amoxapine, which is well known for D2 receptor blocking activity.

Mirtazapine undergoes metabolism. Various P450 enzymes and pathways are involved.

Mechanism of action

Slightly variable among drugs.

Bupropion inhibits reuptake of norepinephrine and dopamine but has prominent effect on presynaptic release, which is enhanced. Has both effects.

Mirtazapine mainly acts on

  1. norepinephrine and serotonin levels and increase their release and inhibitory receptors alpha 2, 5HT2 and 5HT3 leading to increased presynaptic release of these amines.
  2. Anti-histaminic effect

Amoxapine and Maprotiline block NET and SERT, increasing levels of norepinephrine and serotonin, also has anticholinergic effect.

Amoxapine has D2 blocking effect.

Adverse effects

Sedation –Bupropion –antihistaminic effect

Parkinsonism –Amoxapine –D2 antagonist

Maprotiline –tricyclic antidepressant like effects

Bupropion –causes stimulation, leading to agitation, insomnia, anorexia.

Drug interactions

Hydroxy bupropion is 2D6 inhibitor, if combined with drugs acting here, have to monitor, like TCAs

Avoided in patients taking monoamine inhibitors.

Mirtazapine as metabolized by several cyp, is affected by inducers and inhibitors

Has sedating, CNS depressing effect, caution needs to be taken when given with other sedatives, benzodiazepines, alcohols

Amoxapine and maprotiline, as anticholinergic and histaminergic, caution needs to be taken when taking with anticholinergics and antihistaminics.

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