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      Dantrolene is not the answer to 2,4-dinitrophenol poisoning: more heated debate

      Author(s): , ,
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      Journal: BMJ Case Reports
      Publisher: BMJ

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          Abstract

          There has been a resurgence in the use of 2,4-dinitrophenol, C 6H 4N 2O 5 (DNP) recently as an illegal weight loss drug. We present a case of a healthy 25-year-old girl who took two tablets of DNP, purchased from an overseas online retailer. She was managed with aggressive, invasive cooling measures and 2.5 mg kg –1 dantrolene. Despite this, her temperature continued to rise exponentially to 41.5°C. Cardiac arrest occurred and resuscitation was unsuccessful. To our knowledge, this is the first reported case of the ineffective use of dantrolene in acute DNP poisoning. We review the pathophysiology of DNP toxicity and argue that the use of dantrolene therapy is biochemically implausible, based on poor evidence and likely to be futile. We have contacted the UK National Poisons Information Service (NPIS/TOXBASE) to propose changes to the management of acute DNP toxicity.

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          2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death.

          Johann Grundlingh, Paul I. Dargan, Marwa El-Zanfaly … (2011)
          2,4-Dinitrophenol (DNP) is reported to cause rapid loss of weight, but unfortunately is associated with an unacceptably high rate of significant adverse effects. DNP is sold mostly over the internet under a number of different names as a weight loss/slimming aid. It causes uncoupling of oxidative phosphorylation; the classic symptom complex associated with toxicity of phenol-based products such as DNP is a combination of hyperthermia, tachycardia, diaphoresis and tachypnoea, eventually leading to death. Fatalities related to exposure to DNP have been reported since the turn of the twentieth century. To date, there have been 62 published deaths in the medical literature attributed to DNP. In this review, we will describe the pattern and pathophysiology of DNP toxicity and summarise the previous fatalities associated with exposure to DNP.
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            Dantrolene--a review of its pharmacology, therapeutic use and new developments.

            Sandra T Krause, F Wappler, M Fiege … (2004)
            Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.
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              Mitochondrial uncoupling as a target for drug development for the treatment of obesity.

              Toni M Brand, Michelle J. Harper, Ian K. Dickinson (2001)
              Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.
              Article 0 comments Cited 50 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: BMJ Case Reports
                Abbreviated Title: BMJ Case Rep
                Publisher: BMJ
                ISSN (Electronic): 1757-790X
                Publication date Created: December 19 2018
                Publication date Created: December 2018
                Publication date (Electronic): December 19 2018
                Publication date (Print): December 2018
                Volume: 11
                Issue: 1
                Page: e225323
                Article
                DOI: 10.1136/bcr-2018-225323
                PMC ID: 6303589
                PubMed ID: 30573533
                SO-VID: 152ac7a7-6482-48df-bf30-8a1cc9d10eff
                Copyright © © 2018
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                http://www.bmj.com/company/legal-information/terms-conditions/legal-information/tdm-licencepolicy

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