Antidepressant drugs

Pharmacology

The tertiary amine structure of TCAs nonselectively interacts with multiple receptors throughout the body, most of which are not implicated in positive antidepressant effects. Pharmacodynamic interactions include:

• Inhibition of central nervous system (CNS) serotonin and noradrenaline reuptake and modulation of genetic expression of serotonin, β-adrenergic and other CNS receptors contribute to antidepressant effects. This pharmacodynamic property does not contribute significantly to classical TCA toxicity, but is likely responsible for TCA-related serotonin toxicity (described later in this chapter).

• Binding to inactivated cardiac sodium channels producing rate-dependent inhibition of sodium conductance leading to membrane stabilizing effects, QRS prolongation and potentially lethal arrhythmias and impaired myocardial contractility. The effects of this on an ECG can be seen in Fig. 25.4.1 .

  

• Stimulation of central postsynaptic histamine receptors producing CNS depression, sedation and coma.

• Antagonism of muscarinic acetylcholine receptors producing anticholinergic effects including tachycardia, agitation and urinary retention.

• Antagonism of peripheral α ₁ -adrenergic receptors producing peripheral vasodilatation.

• Varying degrees of antagonism at potassium, chloride and γ-aminobutyric acid (GABA) receptors.

TCAs are well absorbed following ingestion, undergo extensive first-pass metabolism, are hepatically metabolized (often producing active metabolites), are highly protein bound and are lipophilic and therefore widely distributed throughout the body. Half-lives are relatively long (10 to 81 hours) and often observed to be longer following OD.

Clinical features

The most common clinical features of significant TCA OD are CNS depression (varying from agitated delirium to coma) and sinus tachycardia; these manifest rapidly within 1 to 2 hours of exposure. Risk assessment based on dose ingested and associated anticholinergic, CNS and cardiovascular clinical effects are described in Table 25.4.1 . Agitated delirium secondary to anticholinergic receptor agonism is not always evident in more severe cases as coma predominates. Sodium channel blockade and α-receptor mediated peripheral vasodilatation lead to supraventricular and ventricular arrhythmias, hypotension and asystole in a dose-dependent manner. Generalized seizures can lead to systemic acidosis and worsening cardiovascular toxicity. Anticholinergic features may become more apparent during the recovery phase as histamine receptor-induced sedation resolves. In severe cases anticholinergic delirium can last for up to 48 hours.

Clinical investigations

A 12-lead ECG is the most valuable prognostic investigation following TCA OD. A terminal 40 ms axis between 120 and 270 degrees is a sensitive indicator of TCA presence but this is difficult to measure at the bedside. Measurement of maximal limb lead QRS duration is a useful predictor of toxicity. Prolongation of >100 ms is associated with an increased incidence of coma, need for intubation, seizures, hypotension and arrhythmias. One study demonstrated no seizures or arrhythmias in patients with a QRS duration that remained <100 ms. Ventricular arrhythmias were predicted in one study by a QRS duration >160 ms. The finding of a positive R wave of >3 mm in amplitude in lead aVR or a ratio of >0.7 between the amplitude of R and S waves in aVR are sensitive markers for seizures and arrhythmias. A rightward frontal plane QRS vector (indicated by an S wave in lead I and an R wave in aVR) is associated with TCA toxicity. Although QT prolongation is observed in TCA therapy and toxicity, this finding is not predictive of clinical toxicity.

TCA plasma concentrations can be measured, but are poorly correlated with degree of clinical toxicity.

Treatment

Patients with significant clinical toxicity or those with a recent (previous 3 to 4 hours) reported ingestion of a potentially toxic amount of a TCA receive aggressive supportive care in a resuscitation area. Early securing of the airway via endotracheal intubation is indicated when there is any decrease in conscious state. Poor respiratory function and secondary hypoxia potentially worsen TCA toxicity.

Administration of activated charcoal should be considered within 1 hour of ingestion, provided facilities exist to protect the airway if decreased consciousness or seizures occur. Activated charcoal should be administered to patients requiring intubation via a nasogastric tube within 4 hours of ingestion, and should be considered in intubated patients with severe clinical toxicity at >4 hours post-ingestion.

Early aggressive use of sodium bicarbonate in conjunction with hyperventilation is indicated where there is any cardiovascular dysfunction in conjunction with QRS prolongation (>100 ms), hypotension unresponsive to initial intravenous fluid (see further discussion later) or in the presence of any arrhythmia. Intravenous bicarbonate 8.4% (1 mL = 1 mmol) 1 to 2 mmol/kg boluses should be administered to obtain an arterial pH of 7.50 to 7.55; pH should then be maintained in this range using hyperventilation. Sodium bicarbonate provides hypertonic sodium, competitively overcoming sodium channel blockade. Alkalization improves sodium channel function and reduces the free concentration of TCA available to produce toxicity. Acid–base manipulation using sodium bicarbonate is more effective than hyperventilation alone in TCA toxicity. Sodium bicarbonate may be prophylactically beneficial in cases where there is a significant history of TCA ingestion and an isolated finding of QRS duration of >100 ms.

Other therapies, including concentrated hypertonic saline (3% sodium chloride) and lignocaine, may be beneficial in treating resistant arrhythmias. Antiarrhythmics, including class 1a, 1c, III, β-blockers and calcium channel antagonists are contraindicated.

Hypotension is treated with intravenous crystalloid (up to 20 to 30 mL/kg). Administration of sodium bicarbonate to obtain an arterial pH of 7.50 to 7.55 is indicated if hypotension persists. Inotropes are indicated for resistant hypotension despite intravenous fluid administration and serum alkalinization. Noradrenaline is used first line, to treat negative cardiac inotropy and α-receptor–mediated peripheral vasodilatation.

Disposition

Patients who are well with no CNS depression and a normal ECG 6 hours post-reported TCA ingestion are safe for medical discharge. Those with any signs of significant toxicity require admission to a critical care environment.

Pharmacology

Monoamine oxidase inhibitors (MAOIs) either reversibly or irreversibly inhibit function of the enzymes monoamine oxidase A and B (MAO-A, MAO-B), leading to increased CNS concentrations of adrenaline, noradrenaline, serotonin and dopamine. The pharmacodynamic effects of nonselective irreversible MAOIs (including phenelzine and tranylcypromine) are not overcome until MAO is resynthesized, resulting in dose-dependent toxicity that may last for days. Moclobemide, a selective reversible inhibitor of MAO-A, is more benign in OD, but may cause severe serotonin toxicity when combined with other serotonergic agents.

The MAOIs are well absorbed orally, undergo extensive first-pass metabolism, readily cross the blood–brain barrier and have moderate volumes of distribution. Peak concentrations occur within 2 or 3 hours of ingestion. Metabolites are renally eliminated.

Clinical features

OD of irreversible MAOIs is characterized initially by peripheral sympathomimetic stimulation and CNS excitation. Symptoms do not usually manifest until 6 to 12 hours post-OD, but may be delayed up to 24 hours. Initial symptoms include nausea, headache, palpitations, agitation and restlessness. Initial signs include tachycardia, hyperreflexia, mydriasis, fasciculations and nystagmus. As toxicity progresses, there is progressive muscle rigidity, respiratory failure, decreasing conscious state, hyperthermia, rhabdomyolysis, coma and cardiovascular collapse. Clinical toxicity may last for days.

Lone OD of the reversible selective MAOI moclobemide generally produces only mild symptoms including tachycardia, nausea and anxiety. OD of moclobemide with another serotonergic agent may lead to significant serotonin toxicity.

MAOI adverse effects in therapeutic doses include the development of serotonin toxicity when combined with other serotonergic agents. The tyramine reaction may occur following ingestion of tyramine-containing foods. Tyramine is an indirect-acting sympathomimetic. MAOI inhibition of tyramine metabolism can lead to a hyperadrenergic crisis with severe hypertension, intracranial haemorrhage, renal failure, disseminated intravascular coagulopathy (DIC) and rhabdomyolysis.