Indication |
For the treatment of depression. |
Pharmacodynamics |
Trazodone is an antidepressant and hypnotic chemically unrelated
to tricyclic, tetracyclic, or other known antidepressant agents. The
mechanism of trazodone's antidepressant action in man is not fully
understood. In animals, trazodone selectively inhibits serotonin uptake
by brain synaptosomes and potentiates the behavioral changes induced by
the serotonin precursor, 5-hydroxytryptophan. Cardiac conduction effects
of trazodone in the anesthetized dog are qualitatively dissimilar and
quantitatively less pronounced than those seen with tricyclic
antidepressants. Trazodone is not a monoamine oxidase inhibitor and,
unlike amphetamine-type drugs, does not stimulate the central nervous
system. In man, trazodone is well absorbed after oral administration
without selective localization in any tissue. Since the clearance of
trazodone from the body is sufficiently variable, in some patients
trazodone may accumulate in the plasma. |
Mechanism of action |
Trazodone binds at 5-HT2 receptor, it acts as a serotonin agonist
at high doses and a serotonin antagonist at low doses. Like fluoxetine,
trazodone's antidepressant activity likely results from blockage of
serotonin reuptake by inhibiting serotonin reuptake pump at the
presynaptic neuronal membrane. If used for long time periods,
postsynaptic neuronal receptor binding sites may also be affected. The
sedative effect of trazodone is likely the result of alpha-adrenergic
blocking action and modest histamine blockade at H1 receptor. It weakly
blocks presynaptic alpha2-adrenergic receptors and strongly inhibits
postsynaptic alpha1 receptors. Trazodone does not affect the reuptake of
norepinephrine or dopamine within the CNS. |
Absorption |
Rapidly and almost completely absorbed following oral administration. Food may decrease the rate and extent of absorption. |
Volume of distribution |
Not Available |
Protein binding |
89-95% bound to plasma proteins in vitro |
Metabolism |
Undergoes extensive hepatic metabolism via hydroxylation,
N-dealkylation, N-oxidation and splitting of the pyridine ring.
Cytochrome P450 (CYP) 3A4 catalyzes the formation of the major active
metabolite, m-chlorophenylpiperazine (m-CPP). Metabolites may be further
conjugated to glucuonic acid or glutathione. CYP2D6 is responsible for
4'-hydroxylation of m-CPP and the formation of at least one glutathione
conjugates of m-CPP, a quinone imine-sulhydryl adduct.
Oxotriazolopyridinpropionic acid, an inactive metabolite, and its
conjugates account for about 20% of the total excreted oral dose. Less
than 1% of the oral dose is excreted unchanged. Approximately 70-75% of
the dose is eliminated in urine with the remainder being excreted in
feces via biliary elimination. |
Route of elimination |
Not Available |
Half life |
Undergoes biphasic elimination with an initial phase t1/2 α of 3-6 hours and a terminal phase t1/2 β of 5-9 hours. |
Clearance |
Not Available |
Toxicity |
LD50=96mg/kg (i.v. in mice) |