Antidepressant drugs in the tricyclic drug group (along with their actions as listed in MeSH) include:
|Name||Brand||Norepinephrine reuptake inhibitor||Serotonin reuptake inhibitor||Dopamine antagonist||Histamine antagonist|
|amitriptyline (& butriptyline)||Elavil, Endep, Tryptanol, Trepiline, Amyzol||yes||yes||yes|
|amoxapine||Asendin, Asendis, Defanyl, Demolox, Moxadil||yes||yes||metabolite||yes|
|dosulepin hydrochloride (dothiepin hydrochloride)||Prothiaden, Thaden||yes|
|imipramine (& dibenzepin)||Tofranil, Janimine||yes||yes||yes|
Note: Other sources suggest that most of the tricyclics combine adrenergic and serotonergic effects to some degree. This is often reported as selectivity ratios. Some of the above, in order from most selective for nor-epinephrine to most selective for serotonin: lofepramine, nortriptyline, amitriptyline, imipramine, clomipramine.
Tertiary amines include: amitriptyline, imipramine, trimipramine, doxepin, clomipramine, and lofepramine.
Secondary amines include: nortriptyline, desipramine, protriptyline, and amoxapine.
Many side effects are related to tricyclics antimuscarinic actions. The antimuscarinic side effects are relatively common and include:
Tolerance to these adverse effects often develops if treatment is continued, side effects may also be less troublesome if treatment is initiated with low dose and then gradually increased, although this may delay the clinical effect.
Other side effects may include drowsiness, anxiety, restlessness, cognitive and memory difficulties, confusion, dizziness, akathisia, hypersensitivity reactions, increased appetite with weight gain, sweating, decrease in sexual ability and desire, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs.
TCAs are highly metabolized by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, antipsychotics, and calcium channel blockers) may produce decreases in the tricyclic's metabolism leading to increases in tricyclic blood concentrations and accompanying toxicity. Drugs which prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs which have antimuscarinic properties.
Tricyclic antidepressant overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity and the availability of these in the home when prescribed for bed wetting and depression.
The central nervous system and heart are the two main systems that are affected. Initial or mild symptoms include drowsiness, a dry mouth, nausea, and vomiting. More severe complications include hypotension, cardiac rhythm disturbances, hallucinations, and seizures. Electrocardiogram (ECG) abnormalities are frequent and a wide variety of cardiac dysrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay (QRS prolongation). Seizures and cardiac dysrhythmias are the most important life threatening complications.
Tricyclics have a narrow therapeutic index, i.e. the therapeutic dose is close to the toxic dose. In the medical literature the lowest reported toxic dose is 6.7 mg per kg body weight, ingestions of 10 to 20 mg per kilogram of body weight are a risk for moderate to severe poisoning, although doses ranging from 1.5 to 5 mg/kg may even present a risk. Most poison control centers refer any case of TCA poisoning (especially in children) to a hospital for monitoring. Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs. However, serum drug levels are not useful for evaluating risk of arrhythmia or seizure in tricyclic overdose.
Most of the toxic effects of TCAs are caused by four major pharmacological effects. TCAs have anticholinergic effects, cause excessive blockade of norepinephrine reuptake at the postganglionic synapse, direct alpha adrenergic blockade, and importantly they block sodium membrane channels with slowing of membrane depolarization, thus having quinidine like effects on the myocardium.
Initial treatment of an acute overdose includes gastric decontamination of the patient. This is achieved by administering activated charcoal which adsorbs the drug in the gastrointestinal tract either orally or via a nasogastric tube. Other decontamination methods such as stomach pumps, ipecac induced emesis, or whole bowel irrigation are not recommended in TCA poisoning.
Symptomatic patients are usually monitored in an intensive care unit for a minimum of 12 hours, with close attention paid to maintenance of the airways, along with monitoring of blood pressure, arterial pH, and continuous ECG monitoring. Supportive therapy is given if necessary, including respiratory assistance, maintenance of body temperature, and administration of sodium bicarbonate as an antidote. Sodium bicarbonate is given intravenously and it has been shown to be an effective treatment for resolving the metabolic acidosis and cardiovascular complications of TCA poisoning. If sodium bicarbonate therapy fails to improve cardiac symptoms, conventional antidysrhythmic drugs such as phenytoin and magnesium can be used to reverse any cardiac abnormalities. However, no benefit has been shown from lidocaine or other class 1a and 1c antiarrhythmic drugs; it appears they worsen the sodium channel blockade, slow conduction velocity, and depress contractility and should be avoided in TCA poisoning. Hypotension is initially treated with fluids along with bicarbonate to reverse metabolic acidosis (if present), if the patient remains hypotensive despite fluids then further measures such as the administration of epinephrine, norepinephrine, or dopamine can be used to increase blood pressure. Another potentially severe symptom is seizures; often seizures resolve without treatment but administration of a benzodiazepine or other anticonvulsive may be required for persistent muscular overactivity. There is no role for physostigmine in the treatment of tricyclic toxicity as it may increase cardiac toxicity and cause seizures.
Tricyclic antidepressants are highly protein bound and have a large volume of distribution; therefore removal of these compounds from the blood with hemodialysis, hemoperfusion or other techniques are unlikely to be of any significant benefit.
Studies in the 1990s in Australia and the United Kingdom showed that between 8 and 12% of drug overdoses were following TCA ingestion. TCAs may be involved in up to 33% of all fatal poisonings, second only to analgesics.
Tricyclic antidepressants were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of Chlorpromazine in December 1950 by Rhône-Poulenc's chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely-used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Research chemists quickly began to explore other derivatives of chlorpromazine.
The first TCA reported for the treatment of depression was imipramine, an imino-dibenzyl analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a sedative inducing mania lead to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Ronald Kuhn in 1957. Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. Geigy later became Ciba-Geigy and eventually Novartis.
Many patents were filed in the 1950s and 1960s concerning variations on these three-ring structures with applications to psychiatric conditions.
Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.
These patents cover the structures of the compounds and their mode of chemical synthesis. Understanding of their mode of action as re-uptake inhibitors and development of the serotonin theory of depression came in the years to follow.