Trazodone's antidepressant mechanism of action in man is not fully understood, but is thought to be related to its potentiation of serotonergic activity in the CNS. It is also called a Serotonin 2A/2C Antagonist and Serotonin Reuptake Inhibitor (SARI).
Preclinical studies have shown that trazodone functions as an antagonist at 5-HT2A and 5-HT2C receptors and as a weak inhibitor of serotonin reuptake.
Trazodone's active metabolite, m-chlorophenylpiperazine (mCPP) functions as a potent 5-HT2C agonist and as a partial agonist at several of the other subtypes of serotonin receptors.
Trazodone is a potent α1-adrenergic receptor antagonist with relatively weak α2-adrenergic receptor activity and its main actions at adrenergic receptors are dominated by antagonism of α1-adrenergic receptor subtypes. Trazodone has weak action at a variety of other neurotransmitter receptors, ion channels and transporters.
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.
Comparative Bioavailability Studies: A single-dose comparative bioavailability study was conducted between two different formulations of trazodone hydrochloride. The study compared a 100 mg dose (2 x 50 mg tablets) of pms-TRAZODONE (trazodone hydrochloride tablets) manufactured by Pharmascience Inc. versus DESYREL (trazodone hydrochloride tablets) manufactured by Bristol Inc., administered to fourteen healthy volunteers. The pharmacokinetic parameters are summarized as follows: See Table 1.
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The pharmacological profile of trazodone differs significantly from that of other known psychopharmacological agents.
Trazodone impedes the membrane uptake of serotonin. Small doses of the drug impede the depletion of brain serotonin, by fenfluramine, but doses of 50 mg/kg do not affect the concentration of serotonin in the rat brain. In experimental studies, trazodone is a weak inhibitor of noradrenalin re-uptake but is practically inactive against 1-dopa, histamine and acetylcholine. It has no known monoamine oxidase inhibiting activity.
Trazodone exhibits CNS depressant properties, causing decreased motor activity in cats, rats and mice and increasing the hexobarbital-induced sleeping time in mice. It also inhibits conditioned avoidance responding in rats at doses which do not influence the unconditioned response (ED50
= 19.5 mg/kg p.o.). Trazodone has no anticonvulsant, anti-reserpine or cataleptogenic effects and its muscle relaxant activity is very weak.
In mice, responses to painful stimuli are suppressed by doses at which motor activity is unaffected (10 mg/kg p.o.), and oxotremorine-, clonidine- and nicotine-induced tremors are significantly inhibited by 12.5 mg/kg i.p. Trazodone protects grouped mice against amphetamine-induced toxicity, but does not inhibit the stereotyped behaviour due to amphetamine or apomorphine.
In rats, infusion of trazodone produces first a fall in mean blood pressure, followed by ECG changes only as a consequence of the hypotension produced. In anesthetized dogs, graded doses between 1 and 30 mg/kg i.v. demonstrated no effect on the bundle of His conduction and no evidence of heart block or rhythm disturbance other than the slowing of normal sinus rhythm, while 0.5 to 5 mg/kg imipramine slowed impulse conduction as well as atrial transmission. The effect of trazodone on the sleep-wakefulness cycle in rats was comparable to that of similar doses of imipramine: 10 mg/kg p.o. reduced and 160 mg/kg completely suppressed REM sleep.
Trazodone hydrochloride is well absorbed after oral administration with peak plasma levels obtained within one-half to two hours after ingestion. Absorption is somewhat delayed and enhanced by food.
Trazodone is 89-95% protein bound in vitro
at concentrations attained with therapeutic doses.
Metabolism: In vitro
studies in human liver microsomes show that trazodone is metabolized to an active metabolite, mCPP, by cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may be involved in 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 60-70% of 14
C-labelled trazodone was found to be excreted in the urine within two days and 9-29% in feces over 60-100 hours. In some patients trazodone may accumulate in the plasma.
Special Populations and Conditions:
Pediatrics (< 18 years of age): The safety and efficacy of trazodone in patients below the age of 18 years have not been evaluated.
Geriatrics (> 65 years of age): pms-TRAZODONE should be used with caution in geriatric patients (see Recommended Dose and Dosage Adjustment: Geriatrics (>65 years of age) under Dosage & Administration).
Hepatic Insufficiency: pms-TRAZODONE has not been studied in patients with hepatic impairment and should be used with caution in this population.
Renal Insufficiency: pms-TRAZODONE has not been studied in patients with renal insufficiency and should be used with caution in this population.
Toxicology: Acute Toxicity:
The acute toxicity of trazodone has been examined in the mouse, rat, rabbit and dog. Summarized LD50
values are presented in the following table. (See Table 2.)
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Signs of toxicity included dyspnea, salivation, ptosis, aggressivity, hypoactivity, prostration and clonic convulsions.
Subacute and Chronic Toxicity:
In several subacute studies in rats, 100 to 450 mg/kg/day p.o. for one to four months produced a decrease in body weight gain and slight liver enlargement in males as the main toxic effects. The highest dose also caused some deaths. In dogs, 50 and 100 mg/kg/day p.o. for one month produced tremors, vomiting and clonic convulsions.
One of two dogs receiving 100 mg/kg died after 3 weeks. In a 6-month rat study, administration of approximately 250 mg/kg/day in the diet resulted in significantly greater liver weights than in control rats and in slightly lower weight gain in males. Dogs receiving 5 and 25 mg/kg/day for 6 months showed no toxic effects.
An eighteen-month study was carried out in rats using doses of 0, 30, 100 and 300 mg/kg/day p.o. A decrease in body weight gain was seen in all treated groups and males at the highest dose level showed significantly reduced food intake. No behavioral or pathologic effects were observed at the lowest dose level, while rats at the 100 mg/kg dose exhibited some lethargy and salivation immediately following dosing. At the highest dose level, there was excessive salivation and the animals became inactive, assuming a prone position for approximately 3 hours after dosing. Occasional body tremors were also seen. Tolerance developed to all these reactions within 30 weeks.
Beagle dogs were given oral doses of 0, 10 and 40 mg/kg/day for one year; however, after 8 weeks the highest dose was reduced to 30 mg/kg/day following the death of 3/10 animals in the group. No abnormal signs were observed at the 10 mg/kg level. In the 20 mg/kg group, one animal was found prostrate and panting on one occasion and another was unexpectedly found dead near the end of the study. 40 mg/kg produced occasional transient ataxia, excessive salivation and convulsions. Following the three deaths and the reduction of dosage to 30 mg/kg, a fourth death occurred 16 weeks later, subsequent to convulsions. A fifth animal became hypersensitive to touch and aggressive during the final 6 months of the study. Hematological and biochemical analyses were normal apart from one case of transient anemia in the 20 mg/kg group and slightly elevated SGPT values in 2/6 high dose dogs during the final 3 months.
Groups of 6 rhesus monkeys received 0, 20, 40, and 80 mg/kg/day of trazodone by gavage for one year. The only effects noted were a slight dose-related decrease in activity and tremors in 3 high dose monkeys. Both effects decreased during the study.
A number of reproductive studies were performed. Fertility and general reproductive performance of male and female rats were not affected by doses of up to 250 mg/kg/day. At 300 mg/kg, the birth weight of pups was significantly reduced.
In one rat study, 100 and 210 mg/kg/day p.o. was given during days 10-15 and 6-15 of gestation respectively, and another study, 150 to 450 mg/kg/day p.o. during days 9-14 of gestation. At 100 mg/kg only a sedative effect on dams was noted. 150 mg/kg and higher doses produced increased sedation, decreased maternal and fetal weights, and retarded ossification. 300 and 450 mg/kg resulted in a significant increase in resorption and stillborn feti in addition to retarded fetal growth. Also noted were isolated cases of branched rib, separated thoracic arch, umbilical hernia, and exencephalia.
Peri-and postnatal effects of up to 300 mg/kg/day of trazodone were examined in rats. The only effects observed were reduced birth and weaning weights of offspring in the highest dosage group.
When doses approximately 30 - 50 times the proposed maximum human dose were administered to rats, trazodone was shown to cause increased fetal resorption and other adverse effects on the fetus. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15 - 50 times the maximum human dose.
A two-year carcinogenicity study was performed in rats at dose levels of 0, 40 and 80 mg/kg/day. Larger numbers of female rats in both treatment groups died sooner than controls and most deaths were related to the presence of pituitary tumors. The incidence of palpable masses (mammary tumors, cysts, etc.) also was increased in both treatment groups at 12, 13, and 14 months. The observations may be related to the effects of trazodone on prolactin secretion. (Acute administration caused an increase in prolactin blood levels; chronic administration did not; however, turnover was not studied. A neuroleptic, used as a positive control, produced similar results). The relative incidences of male rats with pituitary tumors were reversed; however, early deaths due to nephritis and other causes might have influenced these observations.