Trazodone
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Collated from TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.
A novel antidepressant of the SARI class, a serotonin antagonist and reuptake inhibitor. Often used to treat depression and anxiety. It has anxiolytic and hypnotic effects.TS
Oral
Route dataTripSit
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| — | 25–50 mg | 50–100 mg | 100–150 mg | —+ |
| Onset | 20–40 minutes |
|---|---|
| Total | 6–10 hours |
🧬 Receptor activityDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| 5-hydroxytryptamine receptor 2A (HTR2A) | Antagonist | 7.35 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2A (HTR2A) ActionAntagonist Affinity7.35 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2C (HTR2C) | Antagonist | 6.65 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2C (HTR2C) ActionAntagonist Affinity6.65 Ki SourceDRUGCENTRAL |
| Sodium-dependent serotonin transporter (SLC6A4) | Inhibitor | 6.8 Kd | DRUGCENTRAL | TargetSodium-dependent serotonin transporter (SLC6A4) ActionInhibitor Affinity6.8 Kd SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 1A (HTR1A) | — | 7.018 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 1A (HTR1A) Action— Affinity7.018 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 1B (Htr1b) | — | 6.081 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 1B (Htr1b) Action— Affinity6.081 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 1D (HTR1D) | — | 6.975 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 1D (HTR1D) Action— Affinity6.975 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2A (Htr2a) | — | 7.77 IC50 | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2A (Htr2a) Action— Affinity7.77 IC50 SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2B (HTR2B) | — | 7.08 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2B (HTR2B) Action— Affinity7.08 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 7 (HTR7) | — | 5.749 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 7 (HTR7) Action— Affinity5.749 Ki SourceDRUGCENTRAL |
| Alpha-1A adrenergic receptor (ADRA1A) | — | 9.551 IC50 | DRUGCENTRAL | TargetAlpha-1A adrenergic receptor (ADRA1A) Action— Affinity9.551 IC50 SourceDRUGCENTRAL |
| Alpha-1B adrenergic receptor (Adra1b) | — | 7.215 Ki | DRUGCENTRAL | TargetAlpha-1B adrenergic receptor (Adra1b) Action— Affinity7.215 Ki SourceDRUGCENTRAL |
| Alpha-1D adrenergic receptor (ADRA1D) | — | 7.328 Ki | DRUGCENTRAL | TargetAlpha-1D adrenergic receptor (ADRA1D) Action— Affinity7.328 Ki SourceDRUGCENTRAL |
| Alpha-2A adrenergic receptor (ADRA2A) | — | 6.58 Ki | DRUGCENTRAL | TargetAlpha-2A adrenergic receptor (ADRA2A) Action— Affinity6.58 Ki SourceDRUGCENTRAL |
| Alpha-2B adrenergic receptor (ADRA2B) | — | 6.75 Ki | DRUGCENTRAL | TargetAlpha-2B adrenergic receptor (ADRA2B) Action— Affinity6.75 Ki SourceDRUGCENTRAL |
| Alpha-2C adrenergic receptor (ADRA2C) | — | 6.81 Ki | DRUGCENTRAL | TargetAlpha-2C adrenergic receptor (ADRA2C) Action— Affinity6.81 Ki SourceDRUGCENTRAL |
| D(1A) dopamine receptor (DRD1) | — | 5.428 Ki | DRUGCENTRAL | TargetD(1A) dopamine receptor (DRD1) Action— Affinity5.428 Ki SourceDRUGCENTRAL |
| D(2) dopamine receptor (DRD2) | — | 5.456 Ki | DRUGCENTRAL | TargetD(2) dopamine receptor (DRD2) Action— Affinity5.456 Ki SourceDRUGCENTRAL |
| D(3) dopamine receptor (DRD3) | — | 5.896 Ki | DRUGCENTRAL | TargetD(3) dopamine receptor (DRD3) Action— Affinity5.896 Ki SourceDRUGCENTRAL |
| D(4) dopamine receptor (DRD4) | — | 6.153 Ki | DRUGCENTRAL | TargetD(4) dopamine receptor (DRD4) Action— Affinity6.153 Ki SourceDRUGCENTRAL |
| HLA class I histocompatibility antigen, A-3 alpha chain (HLA-A) | — | 5.6 Kd | DRUGCENTRAL | TargetHLA class I histocompatibility antigen, A-3 alpha chain (HLA-A) Action— Affinity5.6 Kd SourceDRUGCENTRAL |
| Histamine H1 receptor (HRH1) | — | 6.21 Ki | DRUGCENTRAL | TargetHistamine H1 receptor (HRH1) Action— Affinity6.21 Ki SourceDRUGCENTRAL |
| Histamine H2 receptor (HRH2) | — | 5.483 Ki | DRUGCENTRAL | TargetHistamine H2 receptor (HRH2) Action— Affinity5.483 Ki SourceDRUGCENTRAL |
| Membrane-associated progesterone receptor component 1 (Pgrmc1) | — | 6.083 Ki | DRUGCENTRAL | TargetMembrane-associated progesterone receptor component 1 (Pgrmc1) Action— Affinity6.083 Ki SourceDRUGCENTRAL |
| Potassium voltage-gated channel subfamily H member 2 (KCNH2) | — | 5.54 IC50 | DRUGCENTRAL | TargetPotassium voltage-gated channel subfamily H member 2 (KCNH2) Action— Affinity5.54 IC50 SourceDRUGCENTRAL |
| Sigma non-opioid intracellular receptor 1 (SIGMAR1) | — | 6.033 Ki | DRUGCENTRAL | TargetSigma non-opioid intracellular receptor 1 (SIGMAR1) Action— Affinity6.033 Ki SourceDRUGCENTRAL |
| Sodium-dependent dopamine transporter (SLC6A3) | — | 5.13 Kd | DRUGCENTRAL | TargetSodium-dependent dopamine transporter (SLC6A3) Action— Affinity5.13 Kd SourceDRUGCENTRAL |
| Sodium-dependent noradrenaline transporter (SLC6A2) | — | 5.07 Kd | DRUGCENTRAL | TargetSodium-dependent noradrenaline transporter (SLC6A2) Action— Affinity5.07 Kd SourceDRUGCENTRAL |
Mechanism of actionPH
The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms.
The precise mechanism of antidepressant action of trazodone is unclear, but the drug has been shown to selectively block the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. The effects of serotonin may thus be potentiated. Unlike other antidepressant agents (e.g., tricyclic antidepressants), trazodone may have a dual effect on the central serotonergic system. Animal studies indicate that trazodone acts as a serotonin agonist at high doses (6-8 mg/kg), while at low doses (0.05-1 mg/kg), it antagonizes the actions of serotonin. Trazodone does not appear to influence the reuptake of dopamine or norepinephrine within the CNS; however, animal studies indicate that trazodone may enhance release of norepinephrine from neuronal tissue. Trazodone does not cause serotonin release in vitro.
PharmacodynamicsPH
Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected.
Pharmacokinetics
Half-lifePH
The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours.
The half-life of trazodone in the initial phase is about 3-6 hours and the half-life in the terminal phase is about 5-9 hours.
... Following IV administration /of trazodone HCl to beagle dogs/, the mean +/- SD elimination half-life /was/ 169 +/- 53 minutes ... . Following oral administration, the mean +/- SD elimination half-life /was/ 166 +/- 47 minutes ... .
In dogs after 8 mg/kg IV, volume of distribution was (all value are means ) 2.53 L/kg, elimination half life 169 minutes, and plasma total body clearance was 11.15 mL/min/kg. After 8 mg/kg PO, bioavailability was 85%, and elimination half life was 166 minutes, peak plasma levels occurred at 445 minutes (mean), but there was wider inter-subject variation (+ or - 271 minutes).
AbsorptionPH
Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%.
Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug.
A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg.
A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone.
Following oral administration of single doses of 25, 50, or 100 mg of trazodone to healthy, fasted adults in another study, mean peak plasma trazodone concentrations were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curves (AUCs) were 3.44, 5.95, and 11.19 ug-hr/mL, for the 25-, 50-, and 100-mg doses, respectively. Limited crossover data are available comparing AUCs in fasted and nonfasted patients; however, it appears that the presence of food slightly increases the AUC for trazodone.
Following oral administration of a single 25-mg dose of radiolabeled trazodone to healthy adults in one study, mean peak plasma drug concentrations of 650 and 480 ng/mL occurred at 1.5 and 2.5 hours after ingestion, in the fasted and nonfasted state, respectively.
MetabolismPH
Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid.
Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring. A hydroxylated metabolite and oxotriazolopyridinpropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. Results of in vitro studies indicate that metabolism of trazodone to an active metabolite, m-chlorophenylpiperazine, is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme. The manufacturers state that other metabolic pathways involved in metabolism of trazodone have not been well characterized. Results from animal studies indicate that trazodone does not induce its own metabolism.
In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.
Approximately 70-75% of an oral dose of trazodone is excreted in urine within 72 hours of administration, principally as metabolites. About 20% of an oral dose of trazodone is excreted in urine as oxotriazolopyridinpropionic acid and its conjugates, and about 10% as a dihydrodiol metabolite; less than 1% of a dose is excreted unchanged. The remainder of an oral dose of the drug is excreted in feces via biliary elimination, principally as metabolites.
Trazodone has known human metabolites that include 1-(3-Chlorophenyl)piperazine, p-Hydroxytrazodone, and Trazodone epoxide.
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.
Half Life: Undergoes biphasic elimination with an initial phase t<sub>1/2 α</sub> of 3-6 hours and a terminal phase t<sub>1/2 β</sub> of 5-9 hours.
Protein bindingPH
The plasma protein binding of trazodone is 89-95% according to in vitro studies.
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