naloxone and Hypotension--Orthostatic

We describe the first ziprasidone overdose with quantitative serum levels of a pediatric patient in coma and with pinpoint pupils. This case is an important contribution to the pediatric ziprasidone literature because it illustrates that ingestion of just 1 pill may result to profound mental status and respiratory depression in a child. H.C., a 30-month-old girl, presented to the emergency department approximately 30 minutes after an accidental ingestion of an adult family member's medication. The child was found on the floor surrounded by numerous pills and was witnessed to have ingested at least 1 tablet by a caregiver. After finding the child with the pills, the family observed the child for a brief period but transported her to the hospital after she became lethargic and unresponsive. The child received 2 doses of 0.4 mg of intravenous naloxone without change in her neurologic status. The child then underwent a rapid sequence intubation for airway protection and subsequently received gastrointestinal decontamination with 15 g of activated charcoal via the orogastric tube. Ziprasidone is an atypical antipsychotic drug that was approved by the Food and Drug Administration in February 2001 for the general treatment of schizophrenia in adults. Previously reported pediatric ziprasidone overdoses describe a syndrome of sedation, tachycardia, hypotonia, and coma consistent with that of the patient described in this paper. In pediatric ziprasidone overdose, QTc prolongation and hypotension have also been illustrated, but seizures have not been reported. An interesting aspect of this case is the development of pinpoint pupils unresponsive to naloxone. This phenomenon has been reported before with overdose of olanzapine, a similar atypical antipsychotic. The mechanism of miosis associated with overdose of atypical antipsychotics is unclear but is likely related to interference with central innervation of the pupil. Pupil size is maintained by a balance between sympathetic and parasympathetic neurohumeral tones. We propose that an overdose of an alpha-1 receptor blocking agent, such as ziprasidone, results in unopposed parasympathetic stimulation resulting in miosis.

Topics: Adrenergic alpha-1 Receptor Antagonists; Antidotes; Antipsychotic Agents; Charcoal; Child, Preschool; Coma; Drug Resistance; Emergencies; Female; Humans; Hypotension, Orthostatic; Intubation, Intratracheal; Miosis; Naloxone; Piperazines; Tachycardia; Thiazoles

The mechanism of vasovagal syncope during orthostasis in humans is unknown. Opioid receptors have been implicated in the vasovagal-like responses to hemorrhagic hypotension in conscious animals. We sought to determine if opioid receptor blockade with naloxone (mu receptor antagonist) would prevent or delay the onset of vasovagal syncope in humans. Three protocols were performed in which heart rate, arterial pressure, sympathetic nerve activity, thoracic impedance and forearm vascular resistance were measured during stepwise steady-state increments of lower body negative pressure (LBNP) in nine healthy volunteers. In protocol 1, duplicate trials of LBNP to syncope or -60 mmHg were performed with a 30-45 minute rest period separating the trials. No significant differences in any physiologic responses or cumulative stress tolerance were found. In protocol 2, graded LBNP was repeated after administration of saline or naloxone (0.1 mg/kg) in six subjects in which vasovagal syncope occurred prior to -60 mmHg LBNP. The peak increase of sympathetic nerve activity during LBNP was augmented after naloxone (P = 0.02), but the occurrence of vasovagal syncope was not prevented nor was the cumulative stress tolerated affected (P = 0.42). The heart rate and arterial pressure responses to LBNP were not affected by naloxone. Similarly, in protocol 3, naloxone given just prior to the onset of pre-syncopal symptoms did not alter the physiologic response or the occurrence of vasovagal syncope. These data show that naloxone does not prevent or delay the onset of vasovagal syncope in humans which suggests that mu opioid receptors do not mediate the vasovagal response.

Topics: Adult; Blood Pressure; Electrocardiography; Female; Heart Rate; Humans; Hypotension, Orthostatic; Injections, Intravenous; Lower Body Negative Pressure; Male; Naloxone; Regional Blood Flow; Sympathetic Nervous System; Syncope; Vagus Nerve; Vascular Resistance

We showed previously that patients with progressive autonomic failure with multiple system atrophy (MSA) failed to excrete a water load while they were standing, suggesting abnormal postural regulation of vasopressin release. The rise of plasma arginine vasopressin (AVP) with upright posture is modulated by central dopamine and opioid receptors. Patients with MSA may have depletion of brain dopamine and opioid peptides. We measured the plasma levels of AVP in patients with MSA and control subjects during postural stimulation by head-up tilt and the inhibition of this rise in AVP by L-DOPA (dopamine precursor) and naloxone (opiate antagonist). Since L-DOPA and naxolone can alleviate hypotension, we also studied the effects of these agents on orthostatic hypotension. Plasma AVP concentration of normal subjects rose progressively over 90 min of head-up tilt and this postural rise in AVP was abolished by L-DOPA and naloxone. Patients with MSA had similar levels of AVP while horizontal. However, they showed a severely blunted postural AVP response since their levels rose to only 10 per cent of the rise in the normal subjects despite the additional stimulus to AVP secretion of considerable postural hypotension. They also showed no inhibition of AVP secretion by L-DOPA or naloxone. Naloxone did not alter the blood pressure of either group. Although L-DOPA did not change the blood pressure of normal subjects, it lowered it in patients with MSA both while they were horizontal and tilted.. (1) the postural stimulation of AVP release is blunted in MSA; (2) this postural rise in AVP is not inhibited by a dopamine agonist or opioid antagonist in MSA suggesting loss of dopaminergic and opioid pathways involved in AVP release; (3) endogenous opioids do not contribute to orthostatic hypotension in MSA; (4) patients with MSA are supersensitive to the hypotensive effects of an acute L-DOPA infusion.

Topics: Aged; Arginine Vasopressin; Autonomic Nervous System Diseases; Female; Humans; Hypotension, Orthostatic; Levodopa; Male; Middle Aged; Naloxone; Physical Stimulation; Posture