Poisoning with 2nd generation antidepressants (atypical)

Post by Doctor CCII Tran Ngoc Thuy Hang - Resuscitation - Emergency Doctor - Emergency Department - Vinmec Central Park International General Hospital

The second generation of antipsychotics, often referred to as "atypical antipsychotics", was introduced in 1998. The term "atypical" refers to the less potent antipsychotic class. Extrapyramidal side effects (EPS) are clinically effective at low doses, have little tendency to cause tardive dyskinesia (TD) with long-term treatment, and treat both signs and symptoms. positive and negative signs and symptoms of schizophrenia.

Currently available atypical antipsychotics include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify) and paliperidone (Invega), metabolites active chemical of risperidone. Some of the newer atypical antipsychotics include asenapine (Saphris), iloperidone (Fanapt), and lurasidone (Latuda).
Atypical antipsychotics have largely replaced traditional drugs as first-line therapy in the treatment of schizophrenia. Toxic exposures and deaths associated with these agents pose a persistent problem in the United States and elsewhere.

1. Pharmacodynamics and cytotoxicity of atypical antipsychotics

The pharmacology of atypical antipsychotics is complex. As a general rule, all exhibit dopamine (D2) receptor blockade, similar to first-generation antipsychotics, but with lower binding affinity. In addition to lower potency and occupancy of D2 receptors at therapeutic doses, atypical agents selectively antagonize mesolimbic cortical D2 receptors more than nigrostriatum and cortical D2 receptors. front forehead. As a result, adverse events due to nigrostriatal D2 blockade (eg, extrapyramidal symptoms, such as acute dystonia, parkinsonism, akathisia, and tardive dyskinesia) are less likely to occur. more frequently, as well as side effects due to central (ie, prefrontal) D2 blockade (eg, neurocognitive impairment and negative symptoms).
Atypical antipsychotics are also serotonin (5-HT) antagonists at the 5-HT2A receptor type. This pharmacological effect alleviates the negative signs and symptoms of schizophrenia by de-inhibiting the dopamine system in the nigrostriatum and prefrontal cortex.
The serotonin-dopamine antagonism is why atypical antipsychotics can be administered in smaller doses, producing fewer extrapyramidal side effects, while maintaining clinical efficacy
Beyond Given the general mechanisms outlined above, each atypical agent has a unique pharmacodynamic profile that can be used to predict adverse events in both therapeutic use and overdose. Although each agent has different affinities for specific receptors, most drugs fall into one of two classes. The first group includes clozapine, olanzapine, and quetiapine, all of which exhibit multiple receptor (alpha-1, histamine-1, and muscarinic-1) antagonism. The second group includes risperidone, paliperidone and ziprasidone, which exhibit alpha-1 adrenergic and histamine-1 receptor antagonism
The atypical antipsychotic aripiprazole possesses distinct mechanisms. Partial postsynaptic dopamine binding attenuates positive symptoms, while basal D2 receptor activation produces less dyskinesia than with other nonspecific dopamine antagonists. Aripiprazole also binds to presynaptic dopamine auto-receptors, reducing dopamine release and synthesis. These pre- and post-synaptic actions lead to a stabilizing effect on neurotransmitter levels, reducing excess activity and enhancing deficient activity. Aripiprazole also has low affinity for serotonin, alpha-1 adrenergic and histamine-1 receptors.
Newer antipsychotics also have some distinctive features:
Iloperidone has low antimuscarinic and antihistamine receptor activity, so it is less likely to cause tachycardia and sedation.
Asenapine is administered sublingually. If swallowed, its bioavailability is significantly reduced from 35 to 2%. It has high affinity and antagonism for serotonin, alpha adrenergic, dopamine and histamine receptors but not muscarinic receptors. Therefore, hypotension and sedation are more likely to occur and there is no tachycardia or agitation.
Lurasidone possesses strong alpha-2C adrenoreceptor antagonism and low alpha-1 adrenergic antagonism. This can lower blood pressure. Adrenoreceptor alpha-2C is located presynaptically and functions as an inhibitory autoreceptor similar to adrenoreceptor alpha-2A, preventing the release of norepinephrine.
1.1 Pharmacodynamics Atypical antipsychotics are completely and rapidly absorbed after oral administration, but a significant part undergoes first pass metabolism. The time to reach peak plasma concentration ranges from 1 to 10 hours. Atypical antipsychotics have a large volume of distribution. They are lipophilic, highly protein bound, and accumulate in the brain, lungs and other tissues. Plasma drug concentrations with therapeutic doses are quite low (nanograms per milliliter). These agents pass into breast milk and the fetal circulation.
The liver metabolizes atypical antipsychotics primarily through cytochrome P450 enzymes (isoenzymes 1A2, 2D6 and 3A4). Therefore, serum concentrations may be affected by other drugs that stimulate or inhibit the cytochrome P450 system.
Some atypical agents have active metabolites. The extended half-life and active metabolites allow for once or twice daily therapeutic dosing. The correlation between dose, serum concentrations and clinical effects is quite variable. Fetuses, neonates, and the elderly are less able to metabolize these agents because of reduced cytochrome p450 activity, whereas children metabolize them more rapidly. While risperidone is subject to drug interactions affecting the CYP2D6 enzyme, in vivo studies have shown that this isozyme plays a limited role in the clearance of paliperidone, the major active metabolite of risperidone. This property of paliperidone makes dose adjustment unnecessary in patients with mild to moderate hepatic impairment.
1.2 Clinical Features of Overdose Overview: In acute overdose, atypical antipsychotics cause only mild to moderate toxicity in the majority of patients, and may be asymptomatic. Although the number of reported exposures has increased significantly, the mortality rate remains low. The toxic effects that occur after an overdose are largely an extension of the physiological effects of the drug.

The toxic and lethal doses of atypical antipsychotics are highly variable and depend largely on the specific drug, the presence of the substance, the age and whether the patient is taking the drug for the first time. or not. Children and adults are more sensitive to the toxic effects of these agents
Atypical antipsychotic toxicity usually begins within one to two hours and peaks four to six hours after ingestion , and the effect was similar for both adults and children. Toxicolysis usually occurs 12 to 48 hours after ingestion but has been reported to take up to six days.
History and physical examination:
The diagnosis of an atypical antipsychotic overdose is primarily based on the medication history and clinical findings. Central nervous system (CNS) effects occur most frequently. Extrapyramidal side effects (EPS) and neuroleptic malignant syndrome (NMS) are infrequent, but are more common in children.
The most common clinical manifestations include:
Coma and sedation (due to histamine block) Arrhythmia, tachycardia, and orthostatic hypotension (due to alpha adrenergic blockade) Anticholinergic toxicity, including including confusion (due to muscarinic blockade – in case of anticholinergic poisoning) Certain effects may be more common for specific agents. A large retrospective case series has shown that quetiapine overdose is more likely to cause respiratory depression, mental depression, and hypotension than other antipsychotics. Multiple case reports have described a rapid fluctuation between sedation and agitation in olanzapine overdose, which is considered "agitated despite sedation." The seizure rate for clozapine (10 percent) is higher than for most atypical agents (less than 1 percent).
Possible functional symptoms:
Central nervous system - CNS: Fatigue / coma / sedation / agitation, confusion, dizziness, slurred speech, convulsions, delirium, coma Cardiopulmonary: Shortness of breath, chest pain, palpitations Anticholinergic manifestations - Blurred vision, dry mouth, constipation, urinary retention Gastrointestinal (rare) - Nausea, vomiting, abdominal pain Clinical findings:
CNS – pupillary constriction (sometimes mydriasis), cardiac arrhythmias, dystonia, hypotonia, extrapyramidal side effects (eg, acute dystonia, parkinsonism, dyskinesias) developmental delay), rapidly fluctuating mental states (depression and agitation), hypersecretion, myoclonus, convulsions, coma Cardiopulmonary - Tachycardia, orthostatic hypotension / mild hypertension, respiratory failure Anticholinergic - Flushing of the face, dry mucous membranes, decreased sweating, mild hyperthermia Gastrointestinal - Abdominal pain, usually localized to the right lower quadrant, decreased intestinal sound. Laboratory evaluation:
Routine laboratory evaluation of patients with poisoning includes the following:
Capillary blood sugar: to rule out hypoglycemia as a common cause of any changes mental status Measure acetaminophen and salicylate, to rule out toxicity with these with an Electrocardiogram (ECG), to rule out drug conduction toxicity affecting the QRS or QTc interval Pregnancy test in women of reproductive age There are no specific clinical tests for atypical antipsychotic toxicity. It should be noted that atypical antipsychotics, particularly quetiapine, can produce false-positive results for tricyclic antidepressants.
Sinus tachycardia is the most common abnormal ECG finding, but other aberrations can occur. These include dose-related repolarization abnormalities (QTc prolongation, ST depression, flattened T waves) and supraventricular/ventricular arrhythmias. Such ECG findings are usually clinically insignificant, although in some cases QTc prolongation.
Of the atypical antipsychotics that increase the QTc interval, ziprasidone, quetiapine, and risperidone have all been associated with this ECG finding, but only quetiapine and risperidone have been associated with an increased risk of developing torsades de pointes. Aripiprazole did not induce QTc prolongation or cardiotoxicity in preclinical trials or in rare cases of published toxicity reports.

Although not associated with overdose, some atypical agents have been shown to increase serum prolactin levels (risperidone), hyperglycemia (clozapine and olanzapine), and hepatic transaminases (clozapine, olanzapine). , quetiapine, risperidone, and ziprasidone), and cause agranulocytosis or leukopenia/neutropenia (clozapine and olanzapine)
Additional testing may be needed depending on the clinical situation, such as creatine phosphokinase and myoglobin in urine in patients with impaired and at risk of rhabdomyolysis, analysis of cerebrospinal fluid in patients with unexplained altered mental status, or liver transaminases in patients with significant abdominal pain.
Quantification of drug levels is generally not used, as these tests are not readily available and do not predict toxicity or guide treatment.

2. Diagnosis of poisoning with second-generation antipsychotics

The diagnosis of second-generation (atypical) antipsychotic poisoning is made clinically based on the drug history and suggestive clinical findings. The most common clinical findings associated with atypical antipsychotic toxicity include coma and sedation; arrhythmia , tachycardia and orthostatic hypotension; and, anticholinergic toxicity.
It is important to note the problem of poisoning with other substances that accompany poisoning in patients with 2nd generation antidepressant drugs such as 1st generation antidepressants, tranquilizers, analgesics, muscle relaxants.....

3. Treatment of poisoning with second-generation antipsychotics

General management : Treatment of atypical antipsychotic drug overdose is mainly supportive. The general approach for any poisoned patient begins with stabilizing the airway, respiration, and circulation.
Detailed treatment of second-generation antipsychotic drug toxicity includes:
All patients require continuous cardiac monitoring, establishment of intravenous access, electrocardiogram (ECG), and ongoing re-evaluation. continuously to recognize mental status changes. Altered mental status may range from depression to signs of extrapyramidal side effects (EPS), tardive dyskinesia (TD), neuroleptic malignant syndrome (NMS), or psychomotor agitation. terrible. Hypotension secondary to alpha adrenergic (alpha) blocking is treated initially with intravenous infusion of isotonic crystalloid solutions. Infusion-responsive hypotension, due to atypical antipsychotics that block peripheral alpha, can often be treated with a vasoconstrictor alpha-agonist such as norepinephrine or phenylephrine. Drugs with beta 2 agonist effects (eg, epinephrine) should be avoided as they may aggravate the vasodilator effects of alpha blockers. Arrhythmias (suppressive and ventricular) are treated according to arrhythmia treatment guidelines. Antiarrhythmic drugs that prolong the QTc interval, such as class IA (quinidine, procainamide), IC (flecainide, propafenone) and class III drugs (amiodarone, sotalol, ibutilide) should be avoided. conduction abnormalities. Class IB antiarrhythmic drugs (eg, lidocaine) may be used. Wide QRS can be treated with intravenous sodium bicarbonate, as well as with tricyclic antidepressants and other Na+ channel blockers. Seizures secondary to atypical antipsychotic intoxication are usually self-limited, and rarely require anticonvulsant treatment. If treatment is needed, a benzodiazepine (such as lorazepam) is first-line therapy. Acute extrapyramidal side effects (eg, dystonia) from second-generation antipsychotic toxicity can be treated with anticholinergics, such as diphenhydramine or benztropine. Patients with neuroleptic malignant syndrome require supportive treatment, which may include intensive cooling, benzodiazepines, bromocriptine, or neuromuscular blockade, depending on the severity of symptoms. Treatment of tardive dyskinesia including benzodiazepines and supportive care The anticholinergic effects of atypical antipsychotics may contribute to severe agitation and altered levels of consciousness in acute poisoning. Benzodiazepines are usually sufficient to control these symptoms. Physostigmine, a short-acting acetylcholinesterase inhibitor, has been used successfully to reverse anticholinergic syndrome with clozapine and olanzapine. Physostigmine has potential side effects (bradycardia, bronchospasm, tachypnea) and its use as an antidote to atypical antipsychotic overdose remains poorly defined. Physostigmine is recommended for use only in the treatment of atypical antipsychotic poisoning in consultation with a medical toxicologist or poison control center. Patients with tricyclic antidepressants toxicity should not take physostigmine. Resistant Poisoning - In rare cases of severe poisoning due to second-generation antipsychotics that do not improve with the standard treatments described above, lipid emulsion therapy may be helpful. However, support for this intervention includes only case reports and routine treatment is not recommended. Detoxification and Enhanced Elimination:
Whenever feasible, a single dose of activated charcoal (AC) with or without a catalyst (eg, sorbitol) should be administered immediately after an anti-inflammatory drug toxicity patient. stabilized second-generation psychosis. Gastric lavage is not recommended as these drugs are associated with low mortality in overdose. AC should be discontinued in patients who are sedated and who may not be able to protect their airway, unless prior intubation is performed. However, intubation should not be performed solely for the purpose of AC infusion.
Due to high protein binding, large volume of distribution, and low plasma concentrations of atypical antipsychotics, elimination from the body, by hemodialysis or hemodialysis, is not beneficial. So any measures are not recommended.
Monitoring and management:
Second-generation antipsychotics are associated with a rapid onset of symptoms following an overdose, so the decision to discharge or to be hospitalized is often determined in within six hours of ingestion. Asymptomatic patients after the six-hour observation period did not require further medical evaluation, assuming no cardiac conduction abnormalities developed during the observation period and no clinically significant problems other. Psychiatric consultation is required for patients who wish to commit suicide. Patients with moderate to severe toxicity (CNS/respiratory depression, hypotension, agitation/delirium, arrhythmias) should be hospitalized for observation in the intensive care unit or ward. clinical, depending on the severity of symptoms.

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Reference source: Second-generation (atypical) antipsychotic medication poisoning - Update

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