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2.1.11.9.3 Antipsychotics Teaching Resources
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Problems for Discussion
Antipsychotics (typical)
DRUGS INCLUDED
- Chlorpromazine
- Droperidol
- Fluphenazine
- Haloperidol
- Loxapine
- Perphenazine
- Pericyazine
- Pimozide
- Promazine
- Thioridazine
- Thiothixene
- Trifluoperazine
OVERVIEW
Neuroleptics are a common cause of poisoning (Buckley et al, 1995). Their toxicity in overdose varies widely between drugs but is similar to that observed with
tricyclic antidepressants (TCAs).
MECHANISM OF TOXIC EFFECTS
Antipsychotic effects are mainly due to dopamine blockade which, with the exception of dystonic reactions, is largely unimportant in overdose. However, the drugs are pharmacologically "dirty" and 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).
KINETICS IN OVERDOSE
Absorption
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.
Distribution
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).
Metabolism - Elimination
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.
CLINICAL EFFECTS
In neuroleptic overdose there are four possible toxic scenarios. These are
- Dopamine blocking effects
- Anticholinergic effects
- Cardiac toxicity
- CNS toxicity (sedation and seizures)
Death in neuroleptic overdose is usually due to CNS and cardiotoxic effects.
Dopamine blocking effects
These are usually minimal, perhaps due to competing anticholinergic effects. However, patients may develop dystonias, dyskinesia or akathisia.
Anticholinergic syndrome
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. This may be due to the lack of any other sedating drug effects in these poisonings. These other poisonings often have an agitated delirium with associated management problems. The pupils may be dilated, but are often found to be mid range or small. 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 and this may persist for some days (see also
serotonin toxicity). 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.
A severe delirium may make it difficult to communicate with the patient at all and may interfere with their psychiatric assessment. Anticholinergic symptoms or signs are a very sensitive indicator for ingestion of low potency neuroleptics but are a poor predictor for life threatening toxicity.
Cardiac effects
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 (exacerbated by osmotic faecuretics). Other possibilities include anxiety,
catecholamine excess and
drug withdrawal.
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
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
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 not advisable. These prolong the effective refractory period (as do neuroleptics) and thus may be proarrhythmic.
Central nervous system effects
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. Patients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activity. 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.
INVESTIGATIONS
The following investigations are usually performed
- Electrolytes
- Arterial blood gases (ABGs)
- ECG
Biochemistry
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 gases
All unconscious patients require arterial blood gas to access adequacy of ventilation and to ensure they are not acidotic.
ECG
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.
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
gastrointestinal decontamination is extremely unlikely to develop major complications.
Blood concentrations
These are unhelpful in aiding management.
DIFFERENTIAL DIAGNOSIS
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).
DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS
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).
DETERMINATION OF SEVERITY
A worse outcome is associated with any of the following
However the in-hospital mortality is low (<1% in most centers) and therefore patients even from these groups have a reasonable prognosis once they reach hospital.
TREATMENT
Supportive
All patients should have assessment of the adequacy of their airway protection and ventilation. Comatose patients require management in ICU and will need to be intubated in order to have gastrointestinal decontamination safely. All patients should have intravenous fluids (normal saline).
GI Decontamination
Gastric lavage should be considered in patients who require airway protection.
Activated charcoal in a standard dose should be given to patients following the lavage or to alert and co-operative patients presenting within 1-2 hours.
Treatment of specific complications
Seizures
Initially,
diazepam 5-20 mg IV followed by
phenobarbitone 15-18 mg/kg IV and elective intubation and ventilation. If neuromuscular blockade is required for management, EEG monitoring is mandatory.
Anticholinergic delirium
Mild delirium can often be managed with reassurance plus or minus oral benzodiazepines. Severe hallucinations may require large doses of parenteral benzodiazepines. Although physostigmine is effective, the short half life of this drug and its occasional life threatening adverse effects limit its application.
Arrhythmias
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.
Alkalinisation
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.
Hypotension
This usually responds to
volume expansion and pH correction. Refractory hypotension may require drugs with alpha agonist properties (e.g. adrenaline & noradrenaline) but these should be used cautiously, if at all, in this setting as they may precipitate ventricular tachycardia.
Elimination enhancement
Repeated doses of activated charcoal may increase the clearance of the drug, but there is no evidence of clinical benefit. If the patient is unconscious and develops increasing abdominal distension with absent
bowel sounds, repeated doses of charcoal should be stopped.
Haemoperfusion is of no benefit.
LATE COMPLICATIONS
Patients are medically fit for discharge if they have no symptoms or signs of toxicity and a normal ECG six hours following the overdose (especially if they have passed a charcoal stool). Patients who still have an isolated tachycardia generally would be kept in hospital and observed. As the usually cause is volume depletion, IV fluid to ensure adequate volume replacement should be given. Patients with a QRS complex of greater than 100 milliseconds should be monitored until this has returned to normal. Thioridazine has cardiotoxic metabolites with long half lives and there are occasional late cardiac arrests in this group.
REFERENCES
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.
Campbell TJ. Proarrhythmic actions of antiarrhythmic drugs: a review. Aust NZ J Med 1990; 20(3): 275-82.
Faber TS. Zehender M. Just H. Drug-induced torsade de pointes. Incidence, management and prevention. Drug Safety 1994;11(6):463-76.
Keren A, Tzivoni D. Torsades de pointes: prevention and therapy. Cardiovasc Drugs Ther 1991; 5(2): 509-13.
Parsons M, Buckley NA. Antipsychotic drugs in overdose: Practical Management Guidelines. CNS Drugs 1997;6(6):427-441
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