Anticholinergic-type effects following a pediatric venlafaxine overdose

Anticholinergic-type effects following a pediatric venlafaxine overdose

To the Editor:

We describe the case of a 10-year-old male (weight: 43.7 kg) who presented to our hospital who developed anticholinergic-type symptoms secondary to ingestion of Effexor XR® (venlafaxine hydrochloride) following a medication error. At admission, his symptoms consisted of: a mildly tachycardic heart rate (132 beats per minute), pupils equal, reactive and dilated (8 mm), tremor, drowsiness, and auditory/visual hallucinations which began that morning and resolved in 24 hours. The patient also complained of needing to urinate, but was unable to do so. He was an otherwise healthy male with a history of chronic MRSA abscesses, for which he had been previously prescribed rifampin and trimethoprim/sulfamethoxazole (TMP/SMX). When he presented at a clinic in our healthcare facility, it was discovered that venlafaxine capsules were mistakenly in the bottle that should have contained TMP/SMX. The source of the venlafaxine was never definitively established in this medication error event. The family alleged the prescription had been misfilled at a pharmacy that was no longer in business at the time of this event, so the prescription could not be verified.

He had reportedly been taking the extended release venlafaxine 150 mg twice a day for the past two days, with a total ingested amount of 600 mg (6.86 mg/kg/day). On day one, he was normotensive (120/77 mmHg) and afebrile (35.8°C). Baseline ECG and chemistries were also taken upon admission, and results were within normal limits. No drug screen, urine analysis or cultures were preformed.

On day two, the patient's pupils were dilated to 6 mm, and his urinary retention persisted (total oral intake of 3170 mL and output of only 1900 mL). The patient also reported some abdominal pain and constipation. Docusate sodium 50 mg and one glycerin suppository were administered.

On day three, the patient was still having difficulty urinating (total oral intake of 1560 mL and output of 550 mL), some abdominal pain, and continued lack of bowel movement. The decision was made to initiate administration of a Fleet enema®, as well as one dose of MiraLax® with positive results. His pupillary size had decreased to 4 mm.

Four days following discontinuation of the venlafaxine, his urinary output was improved, and his pupillary size remained at 4 mm. The patient was discharged later that day due to improvement in his symptoms and resolution of urinary retention.

Venlafaxine is a phenethylamine antidepressant that can be converted to an equally active metabolite, O-desmethylvenlafaxine (ODV), by the CYP 2D6 isoenzymes within the liver. Both venlafaxine and ODV non-selectively inhibit the reuptake of serotonin, norepinephrine and dopamine within the CNS. At low doses, venlafaxine and ODV affect mainly the serotonin receptors. As doses increase, they begin to exert their actions at norepinephrine receptors, until high doses are reached at which time they begin to show some dopamine receptor affinity (1,2). Neither venlafaxine nor ODV have shown a high affinity for muscarinic receptors, meaning that the medication should have a lower incidence of anticholinergic effects when compared to other antidepressants (3,4).

In this case, the child presented with characteristic anticholinergic symptoms, and few of the symptoms normally related with serotonin or norepinephrine excess. The patient did experience tremors (one side effect associated with increased serotonin levels) but lacked other important indications to classify it as serotonin syndrome such as clonus, agitation, diaphoresis or hyperreflexia (5). In our research, we found little information regarding anticholinergic syndrome due to venlafaxine. Wyeth Pharmaceuticals Inc. (the manufacturer of Effexor XR®) reported patients in pre-marketing trials had experienced anticholinergic-type symptoms (dry mouth, constipation, abnormality of accommodation, urinary hesitancy/retention, etc.), but were not significantly different from that of placebo (1). The observed anticholinergic-type effects may have resulted from an adrenergic effect secondary to norepinephrine- reuptake blockade by venlafaxine rather than a cholinergic blockade (3). There have also been reports about the appearance of anticholinergic-type symptoms that occurred when venlafaxine was used in combination with other medications. Within these reports, it was proposed that the other medications inhibited the metabolism of venlafaxine, leading to increased concentration (6,7).

Venlafaxine (in the bottle labeled TMP/SMX) was apparently the only medication taken by this patient at the time the symptoms started to occur. The fact that the patient ingested the extended release formulation, which would extend the time required for his symptoms to resolve (apparent half-life of 15 ± 6 hours) (8), correlates well with the length of time that he exhibited anticholinergic-type symptoms. This increases the likelihood that the anticholinergic-type symptoms sustained by this patient were directly related to the ingested venlafaxine.

Venlafaxine is currently approved only for the treatment of major depressive disorder, generalized anxiety disorder and social anxiety disorder in adults; various off-labeled uses are being explored in the pediatric populations. Further investigation is crucial so that safety and efficacy can be more accurately determined in these patients given their unique reactions to medications.