wikitox:2.1.11.9.2.4.4_venlafaxine
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+ | ====== Venlafaxine ====== | ||
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+ | ===== OVERVIEW ===== | ||
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+ | Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI) structurally unrelated to the [[: | ||
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+ | The FTI (fatal toxicity index, deaths per million prescriptions) for venlafaxine is significantly higher than the FTI of SSRIs, other atypical antidepressants (data not available for bupropion or St John’s Wort) and in the range of some of the less toxic TCAs at 13.2 (CI 9.2 to 18.5). | ||
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+ | Co-ingestions of venlafaxine & [[: | ||
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+ | ===== MECHANISM OF TOXIC EFFECTS ===== | ||
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+ | Venlafaxine is a bicyclic antidepressant structurally and pharmacologically related to the non-opioid analgesic tramadol, but not to any conventional anti-depressant medications. Both venlafaxine and its major metabolite, o-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake (serotonin > noradrenaline >> dopamine). Venlafaxine has no notable monoamine oxidase inhibitor activity and minimal affinity for muscarinic, cholinergic, | ||
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+ | The mechanism of seizure activity is unclear. Animal models suggest the cardiotoxicity and QRS widening are due to Na+ channel blockade which is dose dependent. | ||
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+ | Most other adverse effects are due to excessive concentrations of serotonin, particularly in the central nervous system. The receptor that appears to be most important in toxicity symptoms is 5-HT2a. As other aspects of serotonin production and metabolism are unaltered, toxicity is minor unless there is increased production of serotonin or inhibition of serotonin metabolism. See [[: | ||
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+ | ===== KINETICS IN OVERDOSE ===== | ||
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+ | ==== Absorption ==== | ||
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+ | Venlafaxine is only available as an extended release preparation in Australia. Absorption from the gastrointestinal tract is good (more than 90% of an oral dose is absorbed rapidly) but bioavailability at therapeutic doses is relatively low at 42% due to high first pass liver metabolism. Bioavailability can potentially be reduced by a factor of 29% with the use of a single dose of [[: | ||
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+ | ==== Distribution ==== | ||
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+ | Plasma protein binding is low for venlafaxine (27%) and for ODV (30%). Volumes of distribution are large (7.5 L/kg (V) and 5.7 L/kg (ODV)). | ||
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+ | ==== Metabolism - Elimination ==== | ||
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+ | Venlafaxine is metabolised to ODV by CYP2D6 with both parent and metabolites excreted in urine. | ||
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+ | A study based on 76 ingestions to a regional toxicology service found the half life in overdose to be 12.9 hours and also showed a 35% increase in clearance with the use of SDAC. | ||
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+ | ===== CLINICAL EFFECTS ===== | ||
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+ | The highest recommended dose for venlafaxine is 225 mg/day. Plasma concentrations during therapeutic use are approximately 30 to 70 microg/L. Adverse effects in therapeutic use are predominantly those attributable to serotonergic effects such as nausea, nervousness, | ||
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+ | A detailed prospective clinical study of 51 sequential venlafaxine poisonings from a single centre found the common findings were seizures, serotonergic toxicity, and minor ECG changes with little or no anticholinergic or sedative effect. | ||
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+ | ==== Central nervous system effects ==== | ||
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+ | In overdose, venlafaxine has minimal CNS depression but can cause agitation as part of the spectrum of [[: | ||
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+ | The occurrence of serotonin toxicity is not necessarily an indication for specific treatment although it does identify a group of patients who require close observation as serotonin toxicity can be life threatening. | ||
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+ | The occurrence of fever & respiratory failure (associated with muscle rigidity) are poor prognostic features. Fortunately they occur relatively rarely and usually with large ingestions. | ||
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+ | Complications of serotonin toxicity include: | ||
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+ | * Severe hyperthermia | ||
+ | * Dehydration | ||
+ | * Seizures from serotonin toxicity alone are rare (note: if the patient is conscious repeated muscle activity is more commonly spontaneous continued clonus) | ||
+ | * Injuries while delirious (self-inflicted or iatrogenic) | ||
+ | * Respiratory failure | ||
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+ | **Seizures** | ||
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+ | The probability of seizures from venlafaxine ([[http:// | ||
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+ | |**Venlafaxine dose (mgs)** |**Median Probability of Seizures (95% credible interval)** | | ||
+ | |1000|0.05 (0.03-0.08)| | ||
+ | |5000|0.19 (0.09-0.35)| | ||
+ | |10000|0.75 (0.30-0.96)| | ||
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+ | ==== Cardiac effects ==== | ||
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+ | Venlafaxine has been reported to cause cardiotoxicity with fatal ventricular fibrillation having been produced by an ingestion of 8.4g. Other cases involving ventricular arrhythmias have also ingested very large (> 7g) overdoses. | ||
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+ | However a review of data from 369 ECGs in 273 ingestions with a median ingested dose of 1500 mg (range 75mg to 13 500mg), showed that only minor cardiovascular effects were observed. Abnormal QT heart rate pairs were only observed in 22 (6%) of patients when plotted on the [[http:// | ||
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+ | The small number of patients who developed a QRS duration > 120 ms had ingested > 5g and hence consistent with previous cases showing that cardiotoxicity was related to significant dose ingestions. | ||
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+ | ===== INVESTIGATIONS ===== | ||
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+ | ==== ECG ==== | ||
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+ | Patients ingesting venlafaxine who develop an abnormal ECG (increased QRS duration) should be monitored until the ECG returns to normal. This is much more likely in ingestions > 5g and cardiac monitoring should be considered routinely in large ingestions however is not necessary for the more common smaller ingestions. | ||
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+ | ==== Other investigations ==== | ||
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+ | Patients with serotonin toxicity should have electrolytes, | ||
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+ | ===== DIFFERENTIAL DIAGNOSIS ===== | ||
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+ | Includes poisoning with any other serotonergic drug, all causes of serotonin toxicity and tricyclic antidepressants. | ||
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+ | ===== TREATMENT ===== | ||
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+ | Treatment is a combination of supportive care. Serotonin antagonists can be considered in more severe cases. | ||
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+ | The use of serotonin antagonists appears to avoid the need for aggressive intervention in some cases and reduces symptoms of toxicity in most patients. Since chlorpromazine can theoretically lower the seizure threshold it should be used with considerable caution in venlafaxine poisoning. | ||
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+ | ==== Supportive ==== | ||
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+ | * IV access & fluids | ||
+ | * Titrated benzodiazepines to manage agitation and muscle rigidity | ||
+ | * In more severe cases patients with serotonin toxicity may require aggressive treatment which may include ventilation, | ||
+ | * Our experience is that patients with extreme rigidity, carbon dioxide retention and hypotension respond well to muscle paralysis and ventilation | ||
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+ | ==== GI Decontamination ==== | ||
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+ | Oral [[: | ||
+ | Activated charcoal should be given to any patients who co-ingest venlafaxine with a monoamine oxidase Inhibitor. | ||
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+ | [[: | ||
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+ | ===== Treatment of specific complications ===== | ||
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+ | ==== Cardiac effects ==== | ||
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+ | No specific antidote exists for venlafaxine induced cardiac arrhythmias, | ||
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+ | ==== Seizures ==== | ||
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+ | High dose [[: | ||
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+ | ==== Elimination enhancement ==== | ||
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+ | There is no evidence of enhanced elimination with forced diuresis, urinary pH manipulation, | ||
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+ | ===== LATE COMPLICATIONS ===== | ||
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+ | Discharge after clinical toxicity has resolved. There are no specific long term sequelae. | ||
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+ | ===== REFERENCES ===== | ||
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+ | Colbridge MG, Volans GN. Venlafaxine in overdose - Experience of the National Poisons Information Service (London Centre). J.Toxicol.Clin.Toxicol. 1999; | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | Herrington LF, Gorman SE. Pediatric ingestion of Effexor (venlafaxine). J.Toxicol.Clin.Toxicol. 1996; | ||
+ | [[http:// | ||
+ | Isbister GK. [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | Kokan L, Dart RC. Life threatening hypotension from venlafaxine overdose. Ann.Emerg.Med. 1996; | ||
+ | [[http:// | ||
+ | Med 1997; 15(4): | ||
+ | Kumar VV, Oscarsson S, Friberg LE, Isbister GK, Hackett LP, Duffull SB.
[[http:// | ||
+ | Kumar VV, Oscarsson S, Friberg LE, Isbister GK, Hackett LP, Duffull SB. The effect of decontamination procedures on the pharmacokinetics of venlafaxine in overdose. Clin Pharmacol Ther 2009, Oct; | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | [[http:// | ||
+ | Thorsson B, Snook C, Thorgeirsson G. Survival after prolonged cardiac arrest from venlafaxine (abstract 125). J Toxicol Clin Toxicol 2000; | ||
+ | Troy SM, DiLea C, Martin PT, Leister CA, Fruncillo RJ, Chiang ST. Pharmacokinetics of once-daily venlafaxine extended release in healthy volunteers. Current Therapeutic Research 1997; | ||
+ | [[http:// | ||
+ | Whyte IM, Dawson AH. Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose. J Toxicol Clin Toxicol 2001; 39(3):255. \\ | ||
+ | Woo OF, Vredenburg M, Freitas P, Olson KR. Seizures after venlafaxine overdose: A case report. J.Toxicol.Clin.Toxicol. 1995; | ||
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+ | \\ | ||
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wikitox/2.1.11.9.2.4.4_venlafaxine.txt · Last modified: 2018/09/01 09:00 by 127.0.0.1