Antipsychotic Poisoning

Antipsychotic Poisoning

Michael J. Burns

Christopher H. Linden

Antipsychotic agents, sometimes termed neuroleptics and major tranquilizers, are primarily used to treat schizophrenia, the manic phase of bipolar disorder, and agitated behavior. They are also used as preanesthetics and to treat drug-associated delirium and hallucinations, nausea, vomiting, headaches, hiccups, pruritus, Tourette’s syndrome, and a variety of extrapyramidal movement disorders (e.g., chorea, dystonias, hemiballismus, spasms, tics, torticollis). Antipsychotics are a structurally diverse group of heterocyclic compounds; more than 50 different drugs are available for clinical use worldwide with numerous others in various stages of development. Classes include benzamide, benzepine, butyrophenone (phenylbutylpiperidine), dibenzo-oxepino pyrrole, diphenylbutylpiperidine, indole, phenothiazine, quinolinone, rauwolfia alkaloid, and thioxanthene derivatives (Table 124.1). The phenothiazine and thioxanthene classes are further subdivided into three groups (aliphatic, piperazine, and piperidine) based on central ring side-chain substitution.

Although traditionally classified by structure, antipsychotics are more ideally classified by pharmacologic profile. Each agent has a unique receptor-binding profile (Table 124.2), and this profile can be used to predict adverse effects in both therapeutic and overdose situations [1,2,3]. Clinical toxicity is the result of exaggerated pharmacologic activity. Antipsychotics are also classified as typical or atypical (Tables 124.1 and 124.2). Traditional or conventional antipsychotics, which readily produce extrapyramidal signs and symptoms (EPS) at antipsychotic doses, are considered typical. Newer agents that have minimal extrapyramidal side effects at clinically effective antipsychotic doses are effective for treating the negative symptoms (e.g., alogia, avolition, social withdrawal, flattened affect) of schizophrenia and have a low propensity to cause tardive dyskinesia with long-term treatment are considered atypical [1,2,3,4]. The characterization of antipsychotics as typical or atypical is ultimately determined by receptor binding. One or more of several different receptor-binding characteristics are associated with drug atypia, and each agent is atypical for different reasons [4,5]. Understanding how specific receptor-binding characteristics produce clinical effects has facilitated the development of antipsychotics that separate antipsychotic activity from other activity, thus minimizing adverse effects and maximizing patient compliance.

Antipsychotic toxicity may occur as an idiosyncratic reaction during therapeutic use or following accidental or intentional overdose. Central nervous system (CNS) and cardiovascular disturbances are the most common dose-related toxic manifestations, but other effects include the anticholinergic syndrome (see Chapter 121) and various extrapyramidal syndromes. Therapeutic use has been associated with agranulocytosis, aplastic anemia, diabetes mellitus, hepatotoxicity, hypertriglyceridemia, fatal myocardial infarction, myocarditis, neuroleptic malignant syndrome (see Chapter 66), pancreatitis, seizures, sleep apnea, sudden infant death syndrome, sudden adult death, venous thromboembolism, and vasculitis [21,22,23,24,25,26,27,28,29]. Most deaths are the consequence of suicidal overdose by psychotic or depressed adults and frequently involve mixed ingestions or ingestion of the agents chlorpromazine, loxapine, mesoridazine, quetiapine, or thioridazine [30,31]. Because of a large toxic to therapeutic ratio for most antipsychotics, fatalities rarely occur. In 2007, there were 46,239 antipsychotic exposures reported to United States poison centers, of which 41,607 (90%) were due to atypical agents and 4,632 (10%) were due to phenothiazines [32]. Major toxicity and death occurred in 1.1% and 0.02% of atypical agent exposures, and in 0.8% and 0.04% of phenothiazine exposures. From this data, death occurred in less than four patients for every 1,000 antipsychotic agent toxic exposures. Quetiapine was most commonly associated with fatality in both mixed and single substance ingestions but this may reflect usage pattern and not individual agent toxicity [32]. From another study, the most toxic antipsychotics result in death from poisoning for every 100 patient-years of use [30]. Dose-related effects are most pronounced in nonhabituated patients at the extremes of age.

Recent data has demonstrated that users of antipsychotic drugs have higher rates of sudden cardiac than do nonusers and former users of antipsychotic drugs [6]. The increased risk of sudden cardiac death is similar in magnitude for both typical and atypical agents, with adjusted incidence-rate ratios of 1.99 and 2.26, respectively, when compared with nonusers. For both classes of drugs, the risk of sudden cardiac death increases significantly with an increasing dose. Users of clozapine and thioridazine had the greatest increased of sudden cardiac death, with an adjusted incidence rate that was more than three times that for nonusers.


Antipsychotics bind to and antagonize presynaptic (autoreceptors) and postsynaptic type 2 dopamine (D2) receptors in the CNS and peripheral nervous system [7]. Initially, dopamine neurons increase the synthesis and release of dopamine in response to autoreceptor antagonism. With repeated dosing, however, depolarization inactivation of the neuron occurs, and decreased synthesis and release of dopamine occur despite ongoing postsynaptic receptor blockade [7,8].

All antipsychotics produce their therapeutic antipsychotic effect from mesolimbic D2-receptor antagonism. D2-receptor affinity (potency) in this region strongly correlates with the daily therapeutic dose (see Table 124.1) [1,4,9]. Simultaneous antagonism of other D2 receptors produces additional clinical effects, the majority of which are undesirable. Mesocortical receptor blockade appears to create cognitive impairment and further worsens the negative symptoms of schizophrenia [10]. Excessive D2-receptor blockade in mesocortical and mesolimbic areas, as occurs after neuroleptic overdose, may partly mediate CNS depression from these agents. Antagonism of nigrostriatal D2-receptors produces EPS (e.g., acute dystonia, akathisia, parkinsonism). D2-receptor potency in nigrostriatal relative to mesolimbic areas correlates with the likelihood of developing EPS [1,2,4,11,12]. Typical antipsychotics antagonize basal ganglia D2 receptors in the same dose range necessary for limbic D2-receptor blockade, thus creating high EPS liability [11,12]. The high-potency or typical agents (i.e., fluphenazine,

haloperidol, perphenazine, thiothixene, and trifluoperazine) are most commonly associated with EPS [1]. Atypical agents have low D2-receptor potency and occupancy (i.e., clozapine, olanzapine, quetiapine) at therapeutic doses, are partial D2-receptor agonists (e.g., aripiprazole), or are more site selective (i.e., sulpiride, raclopride) and preferentially antagonize limbic D2 receptors [2,3,4,8,13]. Thus, they are less likely to cause EPS or worsen negative symptoms of schizophrenia at therapeutic doses.

Table 124.1 Classification and Dosing of Neuroleptic Agents

Structural class Generic name (trade name) Affinity of neuroleptic agent for dopamine (D2) receptor (potency)a Daily dose range (mg)
Typical agents
   Butyrophenone (phenyl-butylpiperidine) Droperidol (Inapsine) 3+ 1.25–30
  Haloperidol (Haldol) Other: benperidol, bromperidol, melperone, pipamperone, trifluperidolc 2+ 1–30
   Diphenylbutylpiperidine Pimozide (Orap) Other: fluspirilene, penfluridolc 2+ 1–20
   Indole Molindone (Moban)
Other: oxypertinec
1+ 15–225
   Aliphatic Chlorpromazine (Thorazine) 2+ 25–2,000
  Promazine (Sparine)b 50–1,000
  Promethazine (Phenergan) 2+ 25–150
  Triflupromazine (Vesprin) 5–90
   Piperazine Acetophenazine (Tindal) 40–400
  Fluphenazine (Prolixin) 3+ 0.5–30
  Perphenazine (Trilafon) 3+ 4–64
  Prochlorperazine (Compazine) 2+ 10–150
Trifluoperazine (Stelazine) 3+ 2–40
  Thiethylperazine (Torecan) 10–30
   Piperidine Mesoridazine (Serentil) 2+ 30–400
  Thioridazine (Mellaril, Millazine) 2+ 20–800
  Other: diethazine, ethopropazine, levomepromazine, perazine, pipotiazine thiopropazate, thioproperazine, pericyazinec    
Thioxanthene Chlorprothixene (Taractan) 2+ 30–600
  Flupenthixolc 3+ 4
  Thiothixene (Navane) 3+ 6–60
  Zuclopenthixol (Cisordinol, Clopixol)c 3+ 10–50
Atypical agents
   Benzamides Amisulpridec 2+ 100–1,200
  Raclopridec 3+ 5–8
  Remoxipridec 1+ 150–600
  Sulpiridec 2+ 100–1,600
  Sultopridec 2+ 100–1,200
  Trimethobenzamide (Tigan)b 100–600
Other: epidepride, eticlopride levosulpiride, nemonapride, tiapridec    
   Dibenzodiazepine Clozapine (Clozaril, Leponex) 1+ 150–900
   Dibenzo-oxazepine Loxapine (Loxitane) 1+ 20–250
   Thienobenzodiazepine Olanzapine (Zyprexa) 2+ 5–20
   Dibenzothiazepine Quetiapine (Seroquel) 1+ 300–600
   Dibenzothiazepine Zotepinec 2+ 100–300
  Other: butaclamol, fluperlapine, clothiapine, metiapine, savoxepinec    
   Benzisoxazole Risperidone (Risperdal) 3+ 2–16
  Paliperidone (Invega) 3+ 3–12
   Imidazolidinone Sertindole (Serlect)c 3+ 12–24
   Benzisothiazole Ziprasidone (Zeldox) 3+ 40–160
  Other: iloperidonec    
Pyrrole Asenapine (Saphris) 3+ 10–20
Quinolinone Aripiprazole (Abilify, Abitat) Bifeprunoxc 3+ 10–30
aA higher numerical value indicates greater binding affinity (greater antagonism) at D2 receptor. Binding affinity (potency) at D2 receptor correlates with daily dose range.
bAntiemetic only.
cNot available for clinical use in the United States.
0, minimal to none; 1+, low; 2+, moderate; 3+, high to very high.

Table 124.2 Relative Neuroreceptor Affinities for Neurolepticsa

Neuroleptic agent H1 Histaminergic α1-Adrenergic α2-Adrenergic M1 muscarinic 5-HT2A serotonergic EPS riskb
Typical agents
   Chlorpromazine 2+ 3+ 0 1+ 3+ 1+
   Fluphenazine 0 0 0 0 0 3+
   Haloperidol 0 1+ 0 0 1+ 3+
   Loxapine 3+ 3+ 0 2+ 3+ 1+
   Mesoridazine 3+ 3+ 1+ 1+
   Molindone 0 0 1+ 0 0 3+
   Perphenazine 1+ 1+ 0 0 3+
   Pimozide 0 1+ 0 1+ 3+
   Prochlorperazine 1+ 1+ 0 0 0 3+
   Thioridazine 2+ 3+ 0 3+ 2+ 1+
   Thiothixene 0 0 0 0 0 3+
   Trifluoperazine 0 1+ 0 0 1+ 3+
Atypical agents
   (Ami)sulpiride 0 0 0 0 0 1+
   Asenapine 3+ 2+ 2+ 0 3+ 1+
   Aripiprazole 2+ 2+ 0 0 3+ 0
   Clozapine 3+ 3+ 3+ 3+ 3+ 0
   Olanzapine 2+ 2+ 0 3+ 3+ 0
   Paliperidone 1+ 2+ 1+ 0 3+ 1+ c
Quetiapine 3+ 3+ 0 3+ 1+ 0
Remoxipride 0 0 0 0 0 1+
Risperidone 1+ 2+ 1+ 0 3+ 1+c
   Sertindole 0 1+ 0 0 3+ 0
   Ziprasidone 0 3+ 0 0 3+ 1+
   Zotepine 2+ 0 2+ 0 3+ 1+
aRelative neuroreceptor affinity [neuroreceptor affinity at receptor X/dopamine (D2)-receptor affinity] indicates relative receptor antagonism at therapeutic (D2-blocking) antipsychotic doses.
bA higher M1 and 5-HT2 relative neuroreceptor affinity confers a lower EPS risk.
cDose-dependent incidence of extra EPS.
Adapted from references [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20].
0, minimal to none; 1+, low; 2+, moderate; 3+, high; 4+, very high; EPS, extrapyramidal side effects.

D2-receptor blockade in the anterior hypothalamus (preoptic area) may alter core temperature set point and block thermosensitive neuronal inputs and thermoregulatory responses [7]. Hypothermia or hyperthermia may result. D2-receptor blockade in the pituitary (tuberoinfundibular pathway) results in sustained elevated prolactin secretion, which may cause galactorrhea, gynecomastia, menstrual changes, and sexual dysfunction (impotence in men) [1,11]. The antiemetic activity of antipsychotics results from similar inhibition of dopaminergic receptors in the chemoreceptor trigger zone (area postrema) of the medulla oblongata [7]. Antagonism of dopamine receptors present on peripheral sympathetic nerve terminals and vascular smooth muscle cells may produce autonomic dysfunction (i.e., tachycardia, hypertension, diaphoresis, pallor) [7,33,34,35]. Simultaneous blockade of D2 receptors in the hypothalamus, striatum, mesocortical and mesolimbic areas, peripheral sympathetic nerve terminals, and vasculature mediate the neuroleptic malignant syndrome in susceptible individuals (see Chapter 66).

In addition to D2 receptors, antipsychotics are competitive antagonists at a wide range of neuroreceptors; varied binding affinities exist at α-adrenergic (α1,2), dopaminergic (D1 – 5), histaminergic (H1 – 3), muscarinic (M1 – 5), and serotonergic (5-HT1 – 7) receptors (see Table 124.2) [1,4,12]. The neuroreceptor-binding profile for each agent predicts clinical effects. The ratio of other neuroreceptor-binding affinities to D2-receptor–binding affinity (relative binding affinity) predicts the likelihood of producing those receptor-mediated effects at clinically effective antipsychotic (D2-blocking) doses and in overdose [1,12]. A ratio similar to or greater than 1 makes other receptor-mediated effects likely. High relative α1-adrenergic antagonism (i.e., aliphatic and piperidine phenothiazines, asenapine, clozapine, olanzapine, risperidone, ziprasidone) correlates with the incidence and severity of orthostatic hypotension, reflex tachycardia, nasal congestion, and miosis [11]. Significant relative α2-adrenergic blockade, as occurs with asenapine, clozapine, paliperidone, and risperidone, may result in sympathomimetic effects (e.g., tachycardia). High relative H1-receptor blockade (e.g., aliphatic and piperidine phenothiazines, asenapine, clozapine, olanzapine, quetiapine) produces sedation, appetite stimulation, and hypotension [1,11]. Relative potency at M1 receptors correlates directly with anticholinergic effects (i.e., tachycardia, hypertension, mydriasis, blurred vision, ileus, urinary retention, dry skin and mucous membranes, cutaneous flushing, sedation, memory dysfunction, hallucinations, agitation, delirium, and hyperthermia) and inversely with the incidence of extrapyramidal
reactions [1]. Olanzapine, clozapine, and aliphatic and piperidine phenothiazines are associated with clinically significant anticholinergic effects. The ability of clozapine to produce sialorrhea is likely mediated by its partial agonism at M1 and M4 receptors [1]. High relative antagonism at 5-HT1A and 5-HT2A receptors appears to predict a low EPS risk [1,7,36,37]. The clinical effects that occur with other neuroreceptor subtype binding are not well understood.

The advent of atypical agents, which provide an improved motor side effect profile, marks significant progress in neuroleptic development. Atypical agents may be subdivided into four functional groups: (a) the D2-, D3-receptor antagonists (i.e., amisulpride, raclopride, remoxipride, and sulpiride); (b) the D2-, 5HT2A-, and α1-receptor antagonists (i.e., paliperidone, risperidone and ziprasidone); (c) the broad-spectrum, multireceptor antagonists (i.e., asenapine, clozapine, olanzapine, quetiapine); and (d) the D2-, 5-HT1A-receptor partial agonists (i.e., aripiprazole, bifeprunox), also known as dopamine and serotonin system stabilizers [3] (see Table 124.2). One or more of several different pharmacologic mechanisms define drug atypia. Low D2-receptor potency (high-milligram dosing), low (less than 70%) D2-receptor occupancy in mesolimbic and nigrostriatal areas at therapeutic drug doses, partial agonist activity at D2 receptors, selective mesolimbic D2-receptor antagonism, and high D1-, D4-, M1-, 5HT1A-, 5HT2A-receptor potencies relative to D2-receptor–binding are pharmacologic characteristics that alone or in combination may be responsible for the atypical nature of these agents [1,2,3,7,13,36,37]. Conversely, typical antipsychotics are characterized by high D2-receptor potency (low-milligram dosing) and a narrow receptor profile in the brain [1]. Unlike typical agents, atypical agents also appear to have a minimal propensity to elevate serum prolactin concentrations.

Serotonin antagonism enhances antipsychotic efficacy and reduces the incidence of EPS [36,37]. 5HT2A-receptor antagonism in the striatum and prefrontal cortex offsets neuroleptic-induced D2-receptor blockade and reduces EPS and negative symptoms of schizophrenia, respectively [7,10,36,37,38]. 5HT2A-receptor antagonism also increases serotonin levels in the limbic system, which may have a direct antipsychotic effect [7,10]. Drugs with high relative 5HT2A-receptor antagonism as compared to D2-receptor antagonism (i.e., amperozide, asenapine, clozapine, olanzapine, paliperidone, risperidone, ziprasidone) can be given in smaller clinically effective antipsychotic doses and thus have a smaller risk of inducing EPS [1,11,38,39]. In addition, antipsychotics that stimulate 5HT1A autoreceptors in the striatum (i.e., aripiprazole, clozapine, ziprasidone) reduce striatal D2-receptor blockade, thereby decreasing the likelihood of EPS [8,36,37].

Aliphatic and piperidine phenothiazines (e.g., chlorpromazine, thioridazine, mesoridazine) have local anesthetic, quinidine-like (type Ia) antiarrhythmic, and myocardial depressant effects [7]. These agents block both fast-sodium channels responsible for myocardial membrane depolarization [40]. Sodium channel blockade is voltage and frequency dependent; blockade is augmented at less negative membrane potentials and faster heart rates [40]. Thus, the anticholinergic properties (e.g., tachycardia) and tissue acidemia-producing effects (e.g., seizures, hypotension) of these drugs potentiate their sodium channel blocking effects. Although specifically demonstrated for sertindole and thioridazine only, all neuroleptics appear to variably antagonize delayed-rectifier, voltage-gated, potassium channels responsible for myocardial membrane repolarization; antagonism occurs specifically at the potassium channel encoded by the human ether-a-go-go (hERG) gene [41,42]. Potassium-channel blockade is concentration-, voltage-, and reverse-frequency dependent; blockade is increased at higher tissue concentrations, less negative membrane potentials, and slower heart rates [41,42]. Potassium channel blockade may result in early after depolarizations and subsequent torsade de pointes (TdP)–type ventricular tachycardia. Haloperidol, mesoridazine, thioridazine, and pimozide share an added property of calcium channel blockade [43,44].

Electrophysiologic effects variably include a depressed rate of phase 0 depolarization, depressed amplitude and duration of phase 2, and prolongation of phase 3 repolarization. Ventricular repolarization abnormalities, such as T-wave changes (blunting, notching, inversion), increased U-wave amplitude, and prolongation of the QT interval, are the earliest and most consistent electrocardiographic changes produced by neuroleptics [45,46,47,48]. Dose-related prolongation of the QT interval has been described with droperidol, haloperidol, loxapine, phenothiazines, pimozide, quetiapine, risperidone, sertindole, and ziprasidone [31,41,42,45,46,47,48,49,50,51,52,53,54,55,56,57]. Conduction disturbances (i.e., bundle-branch, fascicular, intraventricular, and atrioventricular [AV] blocks) and supraventricular and ventricular tachyarrhythmias (i.e., monomorphic and polymorphic TdP ventricular tachycardia, ventricular fibrillation) have been reported [31,49,57,58,59,60,61]. Cardiac effects are dose and concentration dependent but can occur with therapeutic as well as toxic doses. Ventricular tachyarrhythmias and asphyxia (due to seizures, aspiration, or respiratory depression) have been postulated as etiologies of sudden death for patients taking therapeutic doses of antipsychotics, particularly phenothiazines [29,62].

Antipsychotics produce dose-related electroencephalographic changes, and some agents have been shown to lower the seizure threshold [26,27,63,64,65,66]. The risk of seizures is dose related, and thus, greatest after overdose [27,65,66]. Chlorpromazine, clozapine, and loxapine are the most likely agents to produce seizures [26,27,54,63,64,65,66]. Most other agents, however, are uncommonly associated with seizures, even after overdose. The mechanism by which antipsychotics produce seizures is not well understood but likely involves dose-related blockade of norepinephrine reuptake, antagonism of gamma-aminobutyric acid type A receptors, and altered neuronal transmembrane ionic currents.

Antipsychotics have a relatively flat dose-response curve. Effective therapeutic doses vary over a wide range (see Table 124.1). The optimal dose is determined by the clinical response, not by serum drug levels. Pharmacologic effects generally last 24 hours or more, allowing for once-daily dosing. Tablet, capsule, and liquid oral preparations, suppository, and injectable immediate-release and sustained-release (depot) solutions are available [7]. Oral preparations include both rapidly disintegrating (sublingual absorption) and sustained-release formulations. Paliperidone, the active metabolite of risperidone, is commercially available in an extended-release oral preparation (Invega®). Following a single dose, plasma concentrations gradually rise and do not peak until approximately 24 hours after dosing [67]. Slow-release, highly lipophilic depot formulations (i.e., fluphenazine enanthate and decanoate, haloperidol decanoate, paliperidone palmitate) for intramuscular injection are created by esterifying the hydroxyl group of an antipsychotic with a long-chain fatty acid and dissolving it in a sesame oil vehicle. A long-acting formulation of risperidone (Risperdal Consta®) is available that contains an aqueous suspension of risperidone mixed with a biodegradable carbohydrate copolymer.

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Sep 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Antipsychotic Poisoning
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