See also Atypical Antipsychotics
Chlorpromazine, Droperidol, Fluphenazine, Haloperidol, Loxapine, Perphenazine, Pericyazine, Pimozide, Promazine, Thioridazine, Thiothixene, Trifluoperazine
Antipsychotics are a relatively common cause of poisoning as a group. However the atypical antipsychotics are seen more commonly in overdose than typical or older neuroleptics. Thioridazine is no longer available in Australia and use had declined significantly following concerns regarding cardiac toxicity. Thus the drugs covered in this monograph are seen much less commonly now in overdose.
Antipsychotic effects are mainly due to dopamine blockade which, with the exception of dystonic reactions, are largely unimportant in overdose. There is a significant variation in the effects of individual drugs. Haloperidol, a butyrophenone, is a potent dopamine blocker with relatively little affinity for other receptors. Other drugs such as chlorpromazine , a phenothiazine, may bind to many other receptors including histamine (H1 & H2), alpha 1 & 2, GABA-A and muscarinic receptors.
Blockade of histamine receptors leads to sedation, alpha receptor blockade leads to vasodilatation, GABA-A blockade may contribute to seizures and anticholinergic effects result from muscarinic receptor blockade. In addition, some neuroleptic drugs have what is termed a quinidine-like action on cell membranes. Importantly, they appear to block sodium and other membrane ion channels and have the antiarrhythmic and proarrhythmic effects of a class Ia antiarrhythmic drug. In overdose proarrhythmic effects are dominant.
The influx of sodium is the major event responsible for the zero phase of depolarisation in cardiac muscle and Purkinje fibres. This initiates cardiac muscle contraction (systole). The duration of phase 0 in the heart as a whole is measured indirectly as the duration of the QRS complex on the ECG. Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width. Prolongation of QRS width is a reflection of the extent of Na+ channel blockade and is predictive of cardiac arrhythmias. Neuroleptics block voltage-gated Na+ channels in a use dependent manner (i.e. block increases with heart rate). As the degree of Na+ channel block increases with use, the QRS width will increase with increasing heart rates. However, the Na+ channel blockade also slows the heart rate. The presence of a very wide QRS complex without tachycardia is a sign of severe cardiotoxicity. The affinity of different neuroleptics for these different binding sites varies widely (see differences in toxicity within this drug class).
Some neuroleptics may block the inward K+ channel rectifier currents. This is important for phase 3 of the cardiac action potential, may lead to prolongation of the QT interval and a possible risk of Torsades de Pointes (TdP)
These drugs are highly lipid soluble and therefore rapidly absorbed. Peak drug concentrations occur early and this is the reason why most deaths from poisoning occur outside of hospital. However, the anticholinergic side effects associated with low potency neuroleptics may sometimes cause delayed emptying of unabsorbed tablets from the stomach and delayed peak concentrations leading to deterioration after some hours.
The large volume of distribution reflects high intracellular concentrations in the brain, heart and other tissues. To some extent their effects in overdose may be more pronounced due to the initial high concentrations they achieve in plasma before they redistribute extensively into the tissues. These drugs are highly bound to protein. It is not known whether this protein binding is sensitive to changes in the pH (c.f. TCAs).
Neuroleptics are generally metabolised by the hepatic microsomal enzyme system. In overdose, this system is normally overwhelmed and so the half-life of the drug becomes prolonged. Many neuroleptics have active metabolites. Both the parent drug and the active metabolites may undergo enterohepatic circulation. Renal excretion of the parent drugs is low (3% - 10%). The half life of thioridazine is 5-10 hours. However thioridazine has a cardiotoxic metabolite and peak blood concentrations of this ring sulphoxide metabolite occur 4.5-7 hours after a single dose. In overdose, it would be expected that the half-life of thioridazine would be much longer and the peak concentrations of metabolites would occur later, particularly as thioridazine has dose-dependent kinetics.
In neuroleptic overdose there are four possible toxic scenarios. These are:
Death in neuroleptic overdose is usually due to cardiotoxic effects.
These are usually minimal, perhaps due to competing anticholinergic effects. However, patients may develop dystonias, dyskinesia or akathisia. It should be noted however that single tablet or small ingestions of potent dopamine blockers such as haloperidol can cause dystonic type reactions in children up to 24 hours after ingestion.
The anticholinergic syndrome seen in tricyclic antidepressant, neuroleptic and antihistamine poisonings is often less florid than that seen in the classic anticholinergic syndromes from antimuscarinic plants (Datura) and anticholinergic drugs such as benztropine. The delirium associated with anticholinergic toxicity is usually absent due to the overriding sedative effects initially. The pupils may however be dilated, but are often found to be mid range or small as coexisting alpha receptor blocking leads to a small pupil. Paralysis of accommodation may lead to some blurring of vision. The pupils react relatively poorly to light. The other anticholinergic effects will lead to a dry mouth, dry skin and a tachycardia, occasionally urinary retention. Bowel sounds may be absent; this may be associated with an ileus.
Severely poisoned patients (who are generally unconscious on presentation) very commonly develop an anticholinergic delirium late in the course of their illness as the sedative effects wear off. The patient may have visual and auditory hallucinations or patients with relatively mild delirium may just appear to be hypervigilant and suspicious. Thus, it is often useful to ask patients when they regain consciousness whether they're hearing or seeing anything strange and reassure them that this is a drug effect.
For more mechanistic detail and clinical evaluation see Cardiotoxic Drugs.
There is a wide spectrum of toxic effects ranging from trivial to life threatening.
Minor ECG changes
There may be an increase in the PR interval and dimpling of the T-waves.
Narrow complex tachycardia
Many patients with significant neuroleptic poisonings have a sinus tachycardia which is due to the anticholinergic effects of these drugs. Persistent tachycardia after regaining consciousness is most frequently due to persisting anticholinergic effect or volume depletion.
Broad complex tachycardia
It is difficult to distinguish between the types of broad complex tachycardias in neuroleptic poisoning. They may be due to a sinus tachycardia (anticholinergic effect) or supraventricular tachycardia with a prolonged QRS due to rate dependent Na+ channel blockade. They may also develop ventricular tachycardias. In any case, it is not uncommon for the blood pressure to be reasonably well maintained.
Bradycardia can occur in neuroleptic poisoning and is a marker of severe toxicity, if associated with an abnormal QRS width, as it indicates severe conduction block.
Hypotension may be due to a number of causes. Some neuroleptics can cause direct myocardial depression. However, in practice, the hypotension usually relates to relative volume depletion and alpha receptor blockade induced vasodilatation. Thus it usually responds rapidly to intravenous fluids. The use of inotropes, in particular those with alpha agonist effects, is rarely required as most of these cases will respond to supportive care and intravenous fluids.
Many patients with significant ingestions of neuroleptics are likely to also have seizures or a significantly impaired level of consciousness. Patients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drug. Some patients who are likely to have seizures may be noted to have relatively brisk reflexes compared to the normal hyporeflexia seen with coma from other causes. This can be a marker of high seizure risk.
Loxapine, in particular, causes seizures more frequently as it is a GABA antagonist. Seizures themselves are associated with an increased mortality. The acidosis produced by the seizures may cause a subsequent minor increase in the free drug concentrations by reducing protein binding. The increased concentrations may then lead to cardiac arrhythmias. In addition, and more importantly, acidosis affects the partitioning of basic drugs between the cell membrane and the Na+ channel binding site and increases Na+ channel blockade.
The following investigations are usually performed:
Electrolytes are normally assessed but are rarely of much assistance with the exception of patients who are on other medications that may effect electrolytes and thus their risk for arrhythmia.
Blood gas analysis may provide some useful additional information with regard to ventilation and may give some insight into tissue perfusion if the blood gas sample measures serum lactate.
An ECG should be performed on admission and also at 6 hours after the self poisoning. The ECG is probably the most accurate predictor of toxicity for neuroleptic poisonings based on the similarity to TCA poisonings. Patients with abnormal ECGs require further monitoring. Reliance on ECG findings on presentation as the sole predictor of subsequent problems cannot be recommended.
Any concern with regard to QT prolongation should be assessed by referring to the QT nomogram. However the likelihood hood of TdP developing is low in patients with heart rates greater than 90 bpm thus this is unlikely to be an issue in drugs with anticholinergic properties which cause a sinus tachycardia in overdose.
The majority of complications occur within the first six hours and in patients who are sedated. An alert patient with a normal ECG six hours after overdose who has had is extremely unlikely to develop major complications.
These are unhelpful in aiding management.
Neuroleptics should be considered, along with other drugs with membrane blocking effects, in patients with seizures, QRS prolongation and/or ventricular arrhythmias. A presentation with coma in the presence of anticholinergic signs make neuroleptics the second most likely drug class ingested (after TCAs).
There is some variation in the toxic dose between the drugs in this class. The number of deaths per million prescriptions in the UK (a fatal toxicity index) varies from similar to the most toxic TCAs for loxapine, to some high potency neuroleptics that have no recorded deaths (Buckley & McManus, 1998). The majority of these deaths occurred outside of hospital. Large differences in the likelihood of producing major complications have also been noted in clinical studies with thioridazine having significantly higher rates of arrhythmias and chlorpromazine having significantly greater sedation when taken in overdose (Buckley et al, 1995).
A worse outcome is associated with any of the following:
However the in-hospital mortality is low and therefore patients even from these groups have a reasonable prognosis once they reach hospital.
All patients should have assessment of the adequacy of their airway protection and ventilation. Cases who cannot protect their airway adequately eg tolerance of a guedel airway, should be intubated, ventilated and receive generous IV fluid replacement.
A single dose of activated charcoal should be considered for patient's who present early to hospital - within the first hour - and who are alert and cooperative enough to ingest.
Initially, titrated benzodiazepines eg midazolam 2.5-10 mg IV followed by phenobarbitone if seizures are refractory,15-18 mg/kg IV.
Mild delirium can often be managed with reassurance plus or minus oral benzodiazepines. Severe hallucinations may require large doses of parenteral sedation. Although physostigmine is effective, the short half life of this drug and its occasional life threatening adverse effects limit its application.
It is often very difficult to distinguish whether the patient is having a supraventricular arrhythmia with aberrant conduction or primary ventricular tachycardia. Most arrhythmias, especially if they are associated with low output are treated in a standard cardiac arrest protocol manner. The main difference is the expected benefit from early and large doses of NaHCO3.
Treatment with plasma alkalinisation to a pH of 7.5 using sodium bicarbonate (to alter both pH and sodium) or hyperventilation may be effective for neuroleptic induced arrhythmias (extrapolating from TCAs). Initial treatment is normally with sufficient IV NaHCO3 to produce a pH of 7.5 to 7.55. Following the rapid correction of pH to 7.5 by IV NaHCO3, the patient is usually maintained at this pH by mild hyperventilation. Alkalosis may affect the partitioning of neuroleptics between the cell membrane and the Na+ channel binding site and thus decrease Na+ channel blockade.
Further drug treatment of arrhythmias
All other treatments are of questionable efficacy and safety and therefore controversial. All class 1a antiarrhythmic drugs are contraindicated and lignocaine and phenytoin (class 1b drugs), while they may be used, may exacerbate Na+ channel blockade and potentially exacerbate arrhythmias (e.g. convert VT into asystole). Magnesium is normally the drug of choice for treating torsade de pointes and is used for refractory arrhythmias in other settings. However, its calcium channel blocking activity may aggravate the hypotension and heart block that can also complicate neuroleptic poisoning. Second or third degree heart block should be treated with bicarbonate and isoprenaline followed by a pacemaker.
This usually responds to volume expansion and pH correction.
Patients are medically fit for discharge if they have no symptoms or signs of toxicity and a normal ECG six hours following the overdose. Thioridazine has cardiotoxic metabolites with long half lives and there are occasional late cardiac arrests in this group. However thioridazine has practically disappeared as an entity in poisoning within Australia thus one is unlikely to encounter it in this situation.
Le Blaye I, Donatini B, Hall M, Krupp P. Acute overdosage with thioridazine: a review of the available clinical exposure. Vet Hum Toxicol 1993; 35:147-150.
Buckley NA, Whyte IM, Dawson AH. Thioridazine has greater cardiotoxicity in overdose than other neuroleptics. Journal of Toxicology - Clinical Toxicology 1995;33(3):199-204.
Buckley NA, Dawson AH, Whyte IM, McManus P & Ferguson N. Six years of self-poisoning in Newcastle: 1987-1992. Med J Aust 1995;162:190-193.
Buckley NA, McManus P. Fatal toxicity of drugs used in the treatment of psychotic illnesses. Br J Psychiatry. 1998 Jun;172:461-4.
Levine M, Burns MJ. Antipsychotic Agents. Fourth Edi. Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. Elsevier Inc.; 2004. p. 703–20.
Isbister GK, Page CB. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice. British journal of clinical pharmacology. 2013 Jul;76(1):48–57.
Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug safety : an international journal of medical toxicology and drug experience. 2005 Jan;28(11):1029–44.