Antipsychotics and Neuroleptic Malignant Syndrome

review of the brand new anti-psychotics · Phenothiazines-chlorpromazine, promethazine, thioridazine, mesoridazine, fluphenazine · Butyrophenones-Haldol · Dibenzodiazapines-clozapine · Dibenzoxapines-Loxapine · Indoles-molindone · Thioxathines-thiothixene   Most hit D2 Clozapine hits D1 and serotonin, associated c agranulocytosis Phenothiazines-rarely NMS, mostly EPS, Thioridizine can give cardiac dysrhythmias IV Haldol can cause V. Tach, TDP CNS depression, miosis or mydriasis, ACh effects, reduced seizure threshold, Orthostatic hypotension Dystonia Observe for 6 hours  

Geodon

Ziprasidone is a second generation anti-psychotic currently marketed under the brand name Geodon®. Ziprasidoneis available in 20, 40, 60 and 80 mg capsules as well as a reconstitutable injectable form of 20 mg/1.2 mL. Theoral capsule form, or ziprasidone hydrochloride, is indicated for bipolar I disorder and schizophrenia, and the intramuscularinjectable form, or ziprasidone mesylate, is indicated for acute agitation in schizophrenia. Ziprasidone isa serotonin (5HT)-2A/dopamine (D2) antagonist as well as a 5HT-1A agonist. It also antagonizes alpha-1 adrenergicand histamine receptors and inhibits norepinephrine reuptake.Ziprasidone overdoses rarely result in severe toxicity. Patients under the age of 12 can be observed at home if theingested dose is 80 mg or less. The toxic dose in adults is at least 100 mg, or five times the patient’s current singledose. Signs and symptoms of toxicity can range from mild sedation, vomiting, diarrhea, and miosis to hypotension,hypertension, tachycardia, dysrhythmias and coma. Ziprasidone is associated with dose-related QTc prolongation.Among all atypical antipsychotics ziprasidone is associated with the greatest degree of QTc prolongation. Ventricularfibrillation and Torsades de Points (TdP) are known risks when QTc prolongation occurs; however, there is noevidence that ziprasidone is associated with TdP. Most reported cases of ziprasidone overdose describe an onsetof symptoms occurring within a few hours of ingestion, but QTc prolongation may not be evident until 12 hours afterwards.Based on adverse effects reported following therapeutic use, the patient should also be observed forincreased liver enzymes (AST, ALT) and extrapyramidal symptoms. Should an acute overdose of ziprasidone occur, activated charcoal may be administered if the ingestion is recent.IV fluids and vasopressors (e.g. norepinephrine, phenylephrine) should be used to correct hypotension resulting from alpha-blockade; sympathomimetics with beta agonist activity such as epinephrine and dopamine should notbe used because of hypotension potentiation. Dystonic reactions are treated with benztropine or diphenhydramine.Although unlikely to occur, patients with QTc prolongation should be monitored for progression to TdP, especially ifother QTc-prolonging drugs are co-ingested. Cardioversion, repeat infusions of magnesium sulfate, overdrive pacingand treatment of electrolyte abnormalities should be considered if TdP occurs. Hemodialysis is not effective in ziprasidoneoverdoses due to its high level of protein binding and large volume of distribution. from toxtidbits  

Olanzapine overdose

May produce drowsiness and anticholinergic delirium. However, like other atypical antipsychotic drugs (quetiapine, clozapine), olanzapine causes paradoxically small pupils (due to peripheral alpha blockade) rather than the dilated pupils seen in this case.

Quetiapine Poisoning

CNS depression with sinus tachycardia Atypical antipsychotic similar to clozapine occasionally presents with hypotension and seizures   best review (Ann Emerg Med 2008;52(5):543) QT prolongation hypotension is common  

Paliperidone

long acting risperdal can cause tachycardia long after initial ingestion time (Ann Emerg Med 2011;58:80)

Neuroleptic Malignant Syndrome (NMS)

excellent review 1% of pts given neuroleptics Excessive blockade of dopaminergic receptors Altered mental status, hyperthermia, muscle rigidity (lead pipe) and autonomic dysfunction. patients are often sweaty, drooling, and in rhabdo as well   Can happen anytime while taking the meds. Can also be seen c TCAs, Reglan, Reserpine, MAOI, Valium, Ativan, Dilantin and Tegratol   Discontinue agents, Active Cooling Benzos Bromocryptine 5 mg PO then 2.5-10 mg po TID Dantrolene 2-3 mg/kg IV Q6 Amantidine 100 mg PO Bid Fluids   The differentiation between NMS and SS is important, as treatment is quite different; cyproheptadine should not be used if NMS has not been excluded because of its dopaminergic-blocking effects. To help distinguish the two, recall:   · NMS usually develops over 3 to 9 days (may be as quick as 24-72 hours) while SS develops much more rapidly (hours) · NMS is associated with neuroleptic drugs whereas SS is associated with serotonergic drugs · NMS patients develop “lead-pipe” rigidity, whereas the rigidity in SS is much less severe · NMS patients to do not exhibit clonus or nystagmus     fhfh Table 1. Comparison of the Levenson5and the Nierenberg and colleagues4 diagnostic criteria for neuroleptic malignant syndrome Level of diagnostic criteria Levenson criteria Nierenberg and colleagues criteriaEssential Recent use of antipsychotic Recent use of antipsychotic OR Recent use of other dopaminergic agent OR Recent discontinuation of dopamine agonist Major Fever

Fever (>38°C) without other cause Muscle rigidity Muscular lead-pipe rigidity Elevated CK (>1000 IU/L) Elevated serum CK (>3 times normal) Autonomic instability (2 or more of sweating, tachycardia, elevated or decreased blood pressure) Altered consciousness Minor Tachycardia Autonomic instability (incontinence, arrhythmias or 1 of the features under Major criteria not already accounted for) Diaphoresis Abnormal BP Tachypnea Respiratory distress (dyspnea, tachypnea, hypoxia or respiratory failure) Leukocytosis Leukocytosis (>12.0 × 109/L) Altered consciousness EPS (tremor, cogwheeling, dystonia or choreiform movements) No. of criterion required 3 Major 4 Major OR OR 2 Major + 4 Minor 3 Major + 3 Minor BP = blood pressure; CK = creatine kinase; EPS = extrapyramidal symptoms       Table 2. Differential diagnosis of neuroleptic malignant syndrome (NMS)1,2,7,9,19 Neurologic *Parkinson’s disease *Meningitis *Encephalitis Multiple system atrophy (Shy-Drager syndrome) Epilepsy Stroke Space-occupying lesions Cerebral vasculitis Metabolic Hyperthyroidism Hypocalcemia Hypomagnesemia Pheochromocytoma Psychiatric *Delirium *Depression / mania with catatonic features *Catatonic schizophrenia / psychosis Substance-induced catatonia Medication-induced *Serotonin syndrome *Extrapyramidal drug reactions Benign medication side-effects associated with atypical antipsychotics Rapid withdrawal of dopaminergic medications (e.g., levodopa) Dopamine depleting medications (e.g., reserpine, tetrabenazine) Lithium toxicity Allergic drug reactions Substance-induced / toxic *Anticholinergic poisoning Cocaine intoxication Phencyclidine intoxication Alcohol / benzodiazepine withdrawal Strychnine poisoning Other conditions *Heat stroke Malignant hyperthermia Acute intermittent porphyria Systemic lupus erythematosus Tetanus Botulism *Common causes of NMS-like symptoms