Tricyclic Antidepressants: Intoxication in Man

2015

Effects of Acute Overdose

Most of the numerous publications on acute intoxication with tricyclic antidepressants deal with attempted suicide in adults or with accidental selfpoisoning in children. Taking into account the difficulty in establishing the dose ingested – particularly in the case of children and of successful suicides – it is not surprising that it is difficult to predict the severity of an acute intoxication from the dose apparently taken. In children, fatalities have occurred with doses below 500 mg and survival with doses as high as approximately 1,700 mg. In adults, doses below 1,000 mg may already prove fatal but survival has been reported with doses up to 4,000 mg or higher (). In children, the critical dose level for imipramine seems to lie around 500 mg. Of a survey comprising 34 cases, only two children who had ingested less died whereas only three with larger doses survived (). Adults, who have ingested 1,000 – 2,000 mg still have a good chance of recovery whereas the risk of a fatality becomes far greater at levels of over 2,000 mg (). In relation to body weight, an LD50 value for imipramine has been determined for children at 40 – 50 mg/kg and for adults at 30 – 50 mg/ kg ().

The symptoms from poisoning with these tricyclic antidepressants may be characterized as follows: After a lag period of 1 -12 h, patients may show motor disturbance, dryness of the mouth, sometimes mydriasis, then go through a phase of agitation with visual or auditory hallucination. While awake, they may complain of blurred vision photophobia, and difficulty with speech. After a few hours and depending on the dose ingested, coma usually sets in, the progress from a state of alertness to unconsciousness sometimes occurs over a short period of time. A striking feature in children is extreme agitation alternating with periods of drowsiness. At the height of the clinical picture, the patient is in coma with shock, respiratory depression, temporary agitation, and diminished or absent pupillary or corneal reflexes, hyperreflexive tendons, and positive Babinski’s sign. Generalized twitching and clonic movements may progress to seizures, particularly following external stimuli such as examination of pain reflexes or endotracheal intubation. Mucous membranes may be dry, bowel and bladder function depressed or paralyzed. Hyperpyrexia is a common finding and disturbances of cardiac function such as tachycardia, atrial fibrillation, ventricular flutters, atrioventricular or intraventricular block have to be expected. Coma is usually not protracted over 24 h though prolonged coma has been reported and death from cardiac arrhythmias may occur even after several days. In the presence of an increased QRS-complex, normal vital signs and level of consciousness do not ensure that the patient is not a medical risk (). Besides measuring plasma levels, the following symptoms appear to offer a guide to the dose ingested: onset and depth of coma, occurrence of grand mal seizures, abnormal deep tendon reflexes and, despite somewhat conflicting evidence (), a positive Babinski sign, presence of respiratory and cardiovascular disorders especially prolongation of the QRS-duration () – the duration over 100 ms having proven to be the most reliable clinical sign for evaluating the seriousness of tricyclic drug overdosage ().

The main toxic effects of tricyclic antidepressants are related to the anticholinergic action of these drugs, which is apparent at relatively low concentrations. The symptoms of the toxic confusional state are not unlike those seen in poisoning with other anticholinergic drugs. The hyperreflexia, twitching, and seizure activity are also thought to result from the anticholinergic properties leading to competitive inhibition of acetylcholine in the central nervous system and an excess of dopamine influence ().

Since the re-uptake of noradrenaline is blocked, the levels of circulating catechol-amines rise. At high concentrations, these drugs depress myocardial contractility, heart rate and coronary flow. Further cardiovascular changes suggest that, in toxic doses, they may also exert a quinidine-like action (). Further cardiovascular effects may be produced by inducing metabolic or respiratory acidosis and by interference with intracellular sodium and potassium exchange. Acidosis has been shown to reduce plasma protein binding and, as it is the unbound fraction of the drug that is pharmacologically active, acidosis will worsen the toxicity. In addition, acidosis will directly increase the hazard of a depression of myocardial contractility (). These factors should be born in mind when taking supportive measurements in the treatment and may explain the rapid deterioration in the clinical picture which is frequently seen in patients.

One of the most dangerous consequences of tricyclic drug poisoning is circulatory collapse. Profound hypotension may occur with a variety of ECG changes, most of which are indicative of disturbances affecting impulse formation and proximal and distal cardiac conduction (). While ECG changes invariably occurred in small children who had taken 200 mg of a tricyclic antidepressant or more, in the majority of adults 1000 mg were found to be necessary to provoke changes. Still higher doses are generally a prerequisite for the development of serious arrhythmias ().

The usual sequential electrocardiographic findings in patients who die from over-dosage of tricyclic drugs are sinus tachycardia, conduction defects, supraventricular tachycardia, ST and T-wave abnormalities, ventricular arrhythmias, profound bradycardia, and finally asystole (). Cardiac arrest arose within the first 24 h after TCA ingestion (). A QRS-prolongation (in the characteristic case over 100 ms) is always present in patients with a major overdose. Unlike the prolonged QT-time it is not correlated to heart rate ().

A direct toxic effect of the drug in reducing the contractility of the myocardium, combined with an increased adrenergic strain possibly accounts for the serious arrhythmias. These often take the form of a nodal rhythm with aberrant intraventricular conduction. This effect may become enhanced by the acidosis and hypokalemia which may occur. The direct effect has been postulated to be an inhibition of the ATP phosphohydralase which is thought to be the enzyme involved in the maintenance of sodium and potassium balance across the myocardial cell membrane ().

Tricyclic drugs may have a direct toxic effect on the respiratory system in addition to the ability to centrally depress respiration. Amitriptyline has been reported to cause a respiratory distress syndrome, bronchiolitis and interstitial pneumonitis resulting in death ().

In the electroencephalogram, the changes provoked by imipramine poisoning are atypical and relatively mild, i.e., they bear no relationship to the severity of the poisoning nor do they provide any guide to the prognosis (). Comparatively little has been published concerning findings obtained at autopsy, or the results of histological examinations. In cases of death due to imipramine poisoning, no specific changes were apparent in organs or tissues ().

In many cases of attempted suicide, several drugs are taken simultaneously. From the literature it would seem that, where a tricyclic drug is consumed together with other drugs in an attempt to commit suicide, these latter drugs usually consist of barbiturates or other psychopharmaceuticals. In the patients with mixed overdoses, it is as a rule the tricyclic drug which determines both the symptomatology of the poisoning and the clinical course which it assumes (). An increased rate of respiratory distress and a higher incidence of ventricular tachycardia has been reported under these circumstances ().

Treatment of Tricyclic Antidepressant Overdose

Treatment should always be performed in an intensive care unit. Vital signs and ECG should be monitored continuously for at least 72 h and preparation made for support of respiratory and cardio-vascular function. Plasma electrolytes should be examined as well as blood gas analysis performed to judge the degree of existing acidosis (). Since the drug is rapidly absorbed, rapid removal from the stomach is important, either by inducing vomiting or by gastric lavage. To prevent re-absorption of the parent drug and active metabolites secreted via the bile, activated charcoal should be administered and the reduced bowel movements should be stimulated with a saline laxative (). Forced diuresis and peritoneal dialysis are not effective owing to the firm protein binding of the drug ().

The further treatment depends on the particular signs exhibited:

a) For counteracting the central and peripheral anticholinergic effects, a vast amount of evidence speaks in favour of using physostigmine () which has been said to approach a specific antidote () and to be the drug of choice when treating life-threatening symptoms caused by tricyclic antidepressants (). Because it is a tertiary amine, physostigmine readily crosses the blood-brain barrier and thus is at present the only parasympathomimetic drug (neostigmine, for example, is a quaternary amine) capable of reversing both the central and peripheral manifestations of the antichohnergic syndrome. Physostigmine acts rapidly, dramatically reversing the toxic effects. Despite some controversy, the side effects are said to be minimal, provided a rapid i.v. injection is avoided. The drug is quickly degraded, allowing recurrence of symptoms of intoxication and may have to be readministered every 30 – 60 min ().

b) Seizures can be controlled with i.v. diazepam if they are not already counteracted by physostigmine. Barbiturates should be avoided even if they have previously been reported to be useful because their CNS depressant effect may be increased in the presence of a tricyclic drug overdosage. External stimulation should be minimized).

c) Ventricular tachycardia is best treated with procainamide or lignocaine and sodium lactate or bicarbonate. Physostigmine is also effective (). Propranolol may be helpful but should be used with care ().

d) Hypotension is counteracted with i.v. fluids, if necessary with a vasopressor such as phenylephrine that does not increase the heart rate ().

e) Hyperpyrexia is relieved by physical cooling, e.g., with ice packs ().

The basic approach has been summarized by Wood et al. () and involved:

(1) Administering physostigmine to treat life threatening symptoms

(2) Removing the drug from the stomach by emesis or gastric lavage

(3) Administering activated charcoal for at least 24 h

(4) Taking general supportive measures

(5) Monitoring the patient’s cardiovascular and respiratory system for an adequate time period

In view of the serious intoxication and the still-limited possibilities of treatment, Bickel () recommends preventive measures, e.g., that the products be stored safely out of the reach of children and that so-called child resistant containers are used. He relates that the use of these drug containers on a limited scale have reduced childhood poisoning by about 90%.