Venlafaxine

Journal of Clinical Psychopharmacology, Vol. 16, No.3, SUPPL 2, June, 1996

Effexor(Venlafaxine)를 개발한 미국 와이어스 사의 연구 결과 Daily 300mg을 넘지 않는다면 안전하게 이용할 수 있는 약이라고 결론 내림.

Emergency Medicine Clinics of North America Vol.18, Issue 4. Nov. 2000

Venlafaxine Adverse event profile similar to the SSRIs One adverse effect associated with venlafaxine use is a mild elevation of diastolic pressure. => This occurs in up to 13% of patients Dose related, Most commonly with doses greater than 200 to 300 mg/day Not much is known about the mechanism of venlafaxine.

Overdose The most commonly reported symptoms Sinus tachycardia, Decreased level of consciousness Brief & Self-limited seizure => Benzodiazepine Hypotension => IV hydration & Vasopressor

Emergency Medicine Clinics of North America Vol. 25, (2007) 477-497

Inhibition of the reuptake of serotonin, norepinephrine Cardiac sodium channel block CNS depressoin, Seizure, Tachycardia, Conduction abnormalities 대개 Seizure가 Initial symptom으로 나타나며 Conduction abnormality는 이후에 나타남. Most recently, the US FDA has alerted physicians to an increased risk of fatal outcome with an overdose of venlafaxine as compared with other SSRIs

Clinical features in overdose Altered mentation, Blurred vision, Tremor, Nausea, Vomiting, Hypotension, Tachycardia Seizure, Cardiac conduction disturbances, Priapism Treatment in overdose 음독 후 6~8시간이 지나도 특별한 증상이 보이지 않더라도 적어도 12시간 가량 Monitoring 하며 관찰해야 한다. Supportive care Conduction disturbances => IV Sodium bicarbonate Torsade de pointes => IV Magnesium sulfate

British Journal of Clinical Pharmacology 2007, 64 : 2, 192-197

Introduction Venlafaxine Phenylethylamine derivative, Introduced in 1994 Mechanism Inhibition of Serotonin & Norepinephrine Neuroral reuptake Predictable adverse effects Tachycardia, Increased blood pressure, Fatigue, Headache, Dizziness, Dry mouth. QT prolongation : >200mg daily In British, between 1998 and 2000 – 12.7 deaths per million Medicines & Healthcare products Regulatory Agency Amended the licence for venlafaxine use within the UK in 2004 Contraindication Pre-existing cardiac disease, HTN, Arrhythmia Methods Retrospective Casenote review Patients admitted to the Royal Infirmary of Edinburgh January 2000 ~ June 2006 Data Age, Gender, Stated date, Time of overdose, Quantity ingested, Type & Quantity of any coingested drugs & alcohol, Clinical history of heart disease Heart rate, Blood pressure, PR interval, QRS duration, QT interval, Mydriasis Tachycardia – 100회/분 이상 High BP – 140/85 기준 QTc interval - >450msec Mydriasis – diameter > 6mm Arrhythmia 36 years old woman, Venlafaxine 3g SVT => Resolved shortly after administraion of IV Sodium bicarbonate. 30 years old woman, Venlafaxine 3.25g Atrial fibrillation => Resolved spontaneously 55 years old man, Venlafaxine Unknown amount Frequent Ventricular ectopic beats => Resolved spontaneously

Conclusions Venlafaxine overdose is associated with sympathomimetic cardiovascular effects and prolonged QTc, irrespective of coingested drugs. Positve correlation between the stated venlafaxine dose and QTc, in the absence of coingested drugs, suggests a causal relationship.

Goldfrank’s Toxicologic Emergencies, 8th edition Neal E. Flomenbaum, MD, FACP, FACEP., Mary Ann Howland, PHARMD, DABAT, FAACT, etc. Chapter 70, p1076

Serotonin/Norepinephrine Reuptake Inhibitors Venlafaxine Rapid downregulation of central β–adrenergic receptors Faster onset of antidepressant effect Overdose – Nausea, Vomiting, Dizziness, Tachycardia, CNS depression, Hypotension, Hyperthermia, Elevated hepatic enzyme concentration, Seizure Sodium channel blocking effect – QRS prolongation, VT… Sodium bicarbonate may be helpful in attenuating these cardiotoxic effects

Venlafaxine is a phenylethylamine derived antidepressant and serotonin-norepinephrine-reuptake inhibitor.1 Similar to tricyclic antidepressant (TCA), patients with venlafaxine overdoses can develop neurotoxicity with altered mentation, seizures, and coma as well as cardiovascular toxicity with autonomic instability.2,3 Supportive care, prevention of seizures (via sedatives such as benzodiazepines), and reversing cardiac interval abnormalities (ie sodium bicarbonate for QRS prolongation) are cornerstones in the management of venlafaxine overdoses.4 In animal studies, venlafaxine induces cardiotoxicity through a mechanism similar to TCA's and other type IA and IC antidysrhythmics via myocardial sodium channel blockade.5 Cardiotoxicity manifest with QRS prolongation which may deteriorate into wide-complex dysrhythmias, hypotension, and death.6,7 Of clinical relevance, metabolic acidosis (such as in a post-seizure state) can significantly increase sodium channel inhibitor binding and therefore worsen cardiotoxicity. In an acidic environment, more of the ionized drug is present to freely bind sodium channels.8 Like for most sodium channel blocking xenobiotics, sodium bicarbonate remains the treatment of choice and should be administered empirically once evidence of cardiotoxicity, such as QRS interval prolongation, has manifested.9 This report illustrates the clinically relevant phenomenon of worsened cardiotoxicity after seizure in the setting of a sodium channel inhibitor and highlights the need for prompt intervention by emergency clinicians.