Trazodone is an oral antidepressant that is structurally related to tricyclic and tetracyclic antidepressants. However, its effects are similar to those of other antidepressants and antianxiety also has a certain effect. Trazodone is used in the treatment of depression, anxiety and insomnia.
Mechanism of action
Trazodone is an inhibitor of serotonin reuptake, although less potent than fluoxetine. At high doses (6 to 8 mg / kg), trazodone is a serotonin agonist, while at low doses (0.05 to 1 mg / kg) acts as an antagonist. It is believed that the antidepressant activity is produced by blocking the reuptake of serotonin in the presynaptic neuronal membrane. Long-term therapy can also affect the binding sites of postsynaptic neuronal receptors. Trazodone has no influence on the reuptake of norepinephrine or dopamine in the CNS. There is some evidence in animals that the release of norepinephrine is enhanced by trazodone. Trazodone does not inhibit monoamine oxidase. The anticholinergic activity is lower with trazodone than with tricyclic antidepressants. It has a sedative effect, which is believed to be produced by an alpha-adrenergic receptor blocker and a modest blockade of histamine. Trazodone increases total sleep time, but unlike the tricyclics, does not affect the stage 4 sleep.
Trazodone has a weak skeletal muscle relaxant activity and no anticonvulsant activity. Unlike tricyclic antidepressants trazodone is not similar to quinidine action on the cardiovascular system. Hypotension may be a consequence of decreased arterial blood pressure caused by the blockade of the pressor response to norepinephrine. Trazodone may affect the endocrine system, but the results are inconclusive.
Trazodone is administered orally and is well absorbed in the intestine. Food affects the absorption; when it administered with or shortly after a meal, a 20% increase in the amount of drug absorbed, a decrease in the maximum plasma concentration and delayed time to peak concentration is observed. Peak levels are achieved 1 hour after dosing in the fasted and 2 hours after dosing with food. Individual responses vary widely. Most patients respond to treatment with trazodone do end of the second week of treatment. The drug is extensively bound to plasma proteins.
Studies of the distribution of humans are incomplete, but the animals, the drug is distributed mainly in the liver, kidney, small intestine, lungs, adrenal glands and pancreas, and is able to cross the blood-brain barrier. Trazodone is excreted in breast milk. The metabolism in the liver is extensive but none of the metabolites is pharmacologically active.
There is a large individual variation in clearance of trazodone, which takes place in a biphasic manner. The duration of the first phase is 3-6 hours and the second phase of 5-9 hours. It may occur in some patients drug accumulation in the plasma. Elimination is mainly via urine excreted about 75% of the dose, mainly as metabolites, within 72 hours. About 20% is excreted via the bile into the feces.
Lethal dose of trazodone is 610 mg / kg in mice, 486 mg / kg in rats and 560 mg / kg in rabbits.
Indications and dosing
Treatment of major depression or generalized anxiety (including patients with schizophrenia or psychosis)
- Initially, 150 mg / day in divided doses, increasing the dose by 50 mg / day every 3-4 days as needed, but is preferably a slower escalation may be better tolerated. The maximum daily dose is 400 mg / day for outpatients and 600 mg / day for hospitalized patients. Maintenance therapy should be the lowest effective dose.
Elderly and weakened patients:
- In general, older patients may require a lower starting dose and slower titration compared with younger adults.
Adolescents and children of 6-18 years old:
- Initially 1.5-2 mg / kg / day in divided doses, gradually increasing at intervals of three or four days as tolerated or need, up to 6 mg / kg / day in divided doses not exceeding 400 mg / day.
Children <6 years of age:
- The safe and effective use of trazodone have not been established.
Treatment of insomnia
- 50 mg before bedtime
Adjunctive treatment of alcoholism
- Doses of 50-100 mg once daily decreased the desire to alcohol, depression and anxiety symptoms in patients with alcoholism.
Treatment of panic disorder or agoraphobia
- Initially, 150 mg / day in divided doses, increasing in 50 mg / day every 3-4 days as tolerated and need. Trazodone in divided doses of 300 mg / day decreases the symptoms of panic, phobia and anxiety in patients with panic disorder and agoraphobia. Compared with imipramine and alprazolam, trazodone is not as effective in the treatment of panic attacks.
- 400 mg / day for outpatient, 600 mg / day for inpatients
- 400 mg / day for outpatients, 600 mg / day for inpatients
- 6 mg / kg / day not exceeding 400 mg / day
children of 6-18 years old:
- 6 mg / kg / day not exceeding 400 mg / day
Children <6 years of age:
- The safe and effective use has not been established
Patients with hepatic dysfunction may require dose adjustment of trazodone according to the severity of liver failure; however, no quantitative guidelines available
Patients with renal insufficiency: creatinine clearance >50 ml / min: It is not necessary to adjust the dose; creatinine clearance <50 ml / min: value according to the patient's response and tolerance. No guidelines.
Contraindications and Precautions
Trazodone is contraindicated in patients with sesnibilidad to trazodone or any component formulation.
Trazodone should be used with caution in patients with heart disease and arrhythmias because trazodone could induce arrhythmias despite showing a limited arrhythmogenic potential. Trazodone should not be used during the recovery period after an acute myocardial infarction.
Trazodone should be used with caution in patients with liver disease because the drug could accumulate and could increase side effects.
Trazodone and its metabolites are primarily excreted in the urine and should be used with caution in patients with renal failure due to the possible reduction of excretion and increased the drug's effects.
All effective antidepressants can transform depression mania in predisposed individuals (for example patients with bipolar disorder). The usual presentation of this effect is the sudden onset of insomnia. The antidepressant should be maintained and should start appropriate therapy for treatment of manic symptoms. Therapeutic doses of lithium (and possibly carbamazepine or valproate) are effective in suppressing this process.
All antidepressants should be used with caution in patients with depression due to the possibility of suicidal ideation. Close monitoring of the patient is essential during the initial stages of therapy and trazodone should be prescribed in the smallest amount consistent with good management. Older people generally require a lower dosage scheme and are more susceptible to adverse reactions. If an elderly patient is unable to take an antidepressant from the group of selective inhibitors of serotonin reuptake inhibitors (SSRI), trazodone may be preferable to a tricyclic antidepressant because of the lower incidence of cardiac effects.
Patients should be advised to be cautious when driving or operating machinery until they know how it will affect them trazodone
There is limited experience with the use of trazodone with electroconvulsive therapy (ECT). You should avoid the concomitant use of these therapies.
Trazodone is classified under the category C in pregnancy risk. There are no adequate studies in humans and the benefits against the risks should be considered.
Trazodone is excreted in breast milk. Although no problems have been documented during lactation, the benefits and risks should be taken into account.
Concurrent use of trazodone and non-selective monoamine oxidase inhibitors (MAOIs, including linezolid), may result in a higher incidence of side effects associated with serotonin. The concurrent use of monoamine oxidase inhibitors and trazodone should be done with caution and should be avoided high doses of either agent. Patients should be closely monitored for adverse effects.
Tricyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction to wait between trazodone and trazodone or guanabenz and guanfacine.
Several interactions may occur between trazodone and anticonvulsants. Barbiturates and carbamazepine induce hepatic microsomal enzymes and may increase the metabolism of trazodone. Trazodone, in turn, can lower the seizure threshold of anticonvulsants. Patients may require higher doses of anticonvulsants to achieve equivalent effects when trazodone is added. Additionally, drowsiness may be additive when trazodone is administered concomitantly with barbiturates, phenytoin or other anticonvulsants.
CNS depressants should be used with caution in patients receiving trazodone due to additive effects, including possible respiratory depression or hypotension. These agents include benzodiazepines, barbiturates, entacapone, ethanol, general anesthetics, some H1 blockers (eg, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, methdilazine, promethazine, trimeprazine), opioid agonists, phenothiazines, skeletal muscle relaxants , anxiolytics, sedatives and hypnotics. A reduction in the dose of one or both drugs may be necessary.
Because of hypotensive additive effects, patients receiving antihypertensive drugs while trazodone can mostar excessive hypotension: decreased antihypertensive doses may be necessary.
Trazodone has been associated with reduced anticoagulant response to warfarin. They should monitor coagulation parameters and adjust the warfarin dose as needed.
Trazodone inhibits serotonin reuptake, although less potent than fluoxetine and other selective inhibitors of serotonin reuptake. Because of this similarity in the mechanism of action, patients treated with buspirone, SSRIs, St. John's wort, Hypericum perforatum, tricyclic antidepressants, or other agents that increase serotonin levels concomitantly with trazodone should be closely monitored by adverse effects associated with excessive serotonin stimulation. A case of serotonin or a trazodone treated after addition of paroxetine reported syndrome patient. They have also been cases of myoclonus, which respond to a serotonin antagonist, in patients treated with trazodone to which was added buspirone and haloperidol.
It described a case of a patient with Alzheimer treated with low doses of trazodone, wherein the addition of Ginko biloba caused a coma. Coma was reversed flumazelil by administering an antagonist of benzodiazepine receptors although trazodone is not active against this type of receptors.
There have been reports of priapism (including clitoral priapism) in patients treated with trazodone. Priapism sometimes results in permanent impairment of erectile function or impotence. Patients should be advised accordingly and discontinue the drug immediately and consult your doctor if this reaction occurs. Other abnormalities include sexual dysfunction ejaculation (retrograde ejaculation or not), dysfunction of orgasm (anorgasmia), and increased libido.
Hypotension (7%) may occur, including orthostatic hypotension and syncope (2-4%) during therapy with trazodone and dose related. Patients taking antihypertensive medications may require dose reduction.
They have been reported cardiac arrhythmias and palpitations while not as common during treatment with trazodone as tricyclic antidepressants. Hn occurred in patients with or without pre-existing heart disease isolated premature ventricular contractions, s short episodes (3-4 beats) ventricular tachycardia. Several other ECG changes have been observed during treatment with trazodone
Drowsiness (up 40%) is the most common side effect of trazodone. Other CNS effects include confusion (5%), dizziness (25%), nervousness (up 15%), fatigue (9%), and headache (15%). Many of these CNS side effects occur during the first weeks of therapy, and develop tolerance after 1 or 2 weeks. The administration of trazodone fasting can increase the incidence of these effects.
Muscle tremor has been reported (5%) and musculoskeletal pain (5%) during treatment with trazodone, probably due to the weaker muscle relaxant activity of the drug.
Xerostomia (up to 30%) is a common side effect during treatment with trazodone and is due to blockade of alpha-1 adrenergic effects resulting in anticholinergic action.
Trazodone administration with food, thus reducing the absorption rate, reduce the incidence of nausea / vomiting (10%), along with other manifestations of gastrointestinal discomfort. Constipation occurs in 7% of patients
Blurred vision (15%) during therapy with trazodone may be an anticholinergic effect. Patients who experience ocular changes must undergo an eye examination.
Photosensitivity has been reported in some patients during treatment with trazodone. The mechanism of this reaction is not known.
Similarly, there have been occasional allergic reactions including rash (unspecified) and pruritus.
Described overdose deaths in patients ingesting trazodone simultaneously with cocktails and other substances (alcohol, diazepam + alcohol + chloral hydrate, amobarbital spirit + spirit + meprobamate).
The adverse reactions reported with overdose of trazodone alone have been priapism, respiratory failure, convulsioes and abnormal electrocardiogram.
There is no specific antidote for trazodone. The overdose treatment should be supportive to control hypotension and excessive sedation. To proceed to lavage. Forced diuresis may be useful to facilitate removal of the drug.