Poisoning: from paracetamol to legal highs.

Transcription

1 Poisoning: from paracetamol to legal highs. or Something old, something new, something borrowed, something blue. Nick Bateman University of Edinburgh

2 Question 1 Which of the following agents was associated with the greatest number of drug-related deaths in England in 2014? A. Amfetamines B. Cocaine C. Morphine D. Paracetamol E. Tricyclic antidepressants F. Don t know

3 Answer Question 1 Which of the following was associated with the greatest number of drug-related deaths in England in 2014? Deaths A. Amfetamines 151 B. Cocaine 247 C. Morphine 952 D. Paracetamol 200 E. Tricyclic antidepressants 517 F. Don t know

4 Drugs of abuse and with abuse potential All drug poisoning deaths 2,747 2,652 2,597 2,955 3,346 Any opiate 1,527 1,439 1,290 1,592 1,786 Heroin and Morphine Methadone Cocaine Any amphetamine Amphetamine MDMA/Ecstasy PMA / PMMA Cannabinoids New Psych Sub Benzodiazepines Diazepam Source: Office of National Statistics: Deaths related to Poisoning Sept 2015

5 Substance All drug poisoning deaths Prescription drugs 2,747 2,652 2,597 2,955 3,346 Paracetamol Antidepressants TCAs SSRIs Others Antipsychotics Zopiclone / Zolpidem Barbiturates

6 Toxicity with antidepressants Cardiovascular- arrhythmias and cardiac failure, hypotension (esp. with amitriptylline) CNS- Fits and Coma, late delirium. MECHANISMS: Na + channel blockade, (some K + channel blockade), Amine reuptake blockade, increases local catecholamines. Anticholinergic Alpha blockade (amitriptylline) TREATMENT: Bicarbonate for wide QRS, Mg ++ for wide QT (measure manually) Norepinephrine for vasodilatation? Insulin and glucose for myocardial failure and Intralipid

7 Question 2 An 18 year old male presents after a paracetamol overdose. He is deemed to need acetylcysteine as his 4 h paracetamol concentration is 125 mg/l (above nomogram line). 30 min after starting the infusion he develops flushing and complains of chest discomfort Which of the following is the most appropriate action in addition to stopping the infusion?

8 Question 2 Which of the following is the most appropriate action in addition to stopping the infusion? A. Intramuscular adrenaline [0.5 ml of 1:1000 epinephrine (0.5 mg)] B. IV chlorphenamine (10mg) and hydrocortisone (200mg) C. Nebulised salbutamol (2.5-5mg) D. Hydrocortisone (200mg IV) E. Observe response to stopping infusion F. Don t know

9 Answer Question 2 A. Intramuscular adrenaline [0.5 ml of 1:1000 epinephrine (0.5 mg)] B. IV chlorphenamine (10mg) and hydrocortisone (200mg) C. Nebulised salbutamol (2.5-5mg) D. Hydrocortisone (200mg IV) E. Observe response to stopping infusion F. Don t know First line treatment chlorphenamine 10mg IV AND Continue acetylcysteine

10 Importance of paracetamol concn. in ADR rate 1 mmol/l =150mg/L WARING, W. S., et al Clin Tox 44: Schmidt L. E Clin Tox 51: Both studies used case note review to ascertain ADRs

11 Adopt the previous high risk line for all patients and/or use 75 mg/kg ingested dose CHM Decision 2012 AND Change initial NAC infusion from 15 min to 1 h Estimated to prevent 1 death about every 2 years in UK. No data to support 1 h infusion (anectodal from N America, inadequate study from Australia)

12 Paracetamol concn & infusion rate on ADRs: 15 min or 1 hr Odds ratios of adverse events to treatment by presenting blood paracetamol > or <= 100 mg/l* All patients (n=835 1 ) All vomiting All anaphylactoid events / n OR 95% CI p events / n OR 95% CI p >100 78/ / <0.001 <= / / min infusion (n=321) >100 27/ / <0.001 <=100 46/ / h infusion (n=514) >100 51/ / <0.001 <=100 56/ / *Controlling for age, sex and infusion rate. 1 One patient that had no data on blood paracetamol concentration is excluded. Bateman et al 2014 BJCP. doi /bcp12362

13 Increase (extrapolated to UK) First year impact of MHRA guidance 18,000 16,000 14,000 12,000 10,000 Presentations Admissions NAC treatments Changes comparing year before with year after Extrapolated from data for 3 hospitals The cost to the NHS is estimated at 17.3 m (95% CI 13.4 to 21.5) to prevent 1 death. 8,000 6,000 4,000 MHRA Est* 2, ,000 < >200 >24h Staggered Unknown Total -4,000 Nomogram bands *MHRA estimate of additional NAC use 4,920-7,200 treatments Patient category Data from Bateman et al. Brit J Clin Pharmacol 2014 & Bateman et al. Clin Tox 2014

14 TRIAL TREATMENTS Acetylcysteine- matching duration of infusions Conventional h acetylcysteine regimen 150mg/kg in 200mL, 15 min; 50mg/kg in 0.5L, 4 h ; 100mg/kg in 1 L, 16 h (British National Formulary 2009) Modified 12 h acetylcysteine regimen 100mg/kg in 200 ml, 2h; 200mg/kg 1L, 10h infusion; followed by 0.5L 5% dextrose to h for matching Ondansetron 4mg IV Pre-treatment with ondansetron v saline placebo Lancet, ;

15 Proportion of patients without an event Proportion of patients without an event Antiemetic rescue. Kaplan Meier analysis to 12 h Anaphylactoid rescue. Kaplan Meier to 12 h Ondansetron / Modified Ondansetron / Conventional Placebo / Modified Placebo / Conventional Ondansetron / Modified Ondansetron / Conventional Placebo / Modified Placebo / Conventional Time (hours) Time (hours) Patients at risk Ondanstron/Modified Ondanstron/Conventional Placebo/Modified Placebo/Conventional OR at 12 h: Modified v conventional NAC OR 0.37, 97.5% CI , P = Ondansetron v placebo OR 0.35, 97.5% CI , P = Patients at risk Ondanstron/Modified Ondanstron/Conventional Placebo/Modified Placebo/Conventional OR at 12 h: Modified vs conventional NAC OR 0.23 (0.12 to 0.43, p< ) Ondansetron vs placebo OR 1.4 (0.78 to 2.53, p= 0.198)

16 Take home message A simpler shorter acetylcysteine regimen, with 12 h blood samples, and linked to newer approaches of assessing risks of hepatic injury, offers potential for reducing:- ADRs hospital length of stay medication errors. In addition earlier identification of at risk patients on treatment will allow study of earlier increased NAC treatments. Studies ongoing to facilitate full licence

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18 TOXBASE top 5 accesses Drugs of Abuse: England and London 2015/16 England London TOTAL 54,094 TOTAL 7,801 SCRA Drugs of abuse 8,770 Cocaine (& synons) 1,463 (16.2%) (18.7%) Cocaine (& synons) 8,738 (16.1%) MDMA (& synons) 5,721 (10.6%) Heroin (& synons) 4,500 (8.3%) Amfetamine (& synons) 3,742 (6.9%) Note: 51% of England metamfetamine accesses are from London (485/954) GHB & analogues 1,217 (15.6%) MDMA (& synons) 841 (10.8%) SCRA Drugs of abuse 633 (8.1%) Heroin (& synons) 631 (8.1%)

19 Question 3 A 19 year old woman presents after taking an unknown drug of abuse at a night club. She is confused, has dilated pupils and is noted to have marked ankle clonus. Which of the following drugs is she most likely to have ingested? A. Cannabis B. Cocaine C. Mephedrone D. Metamfetamine E. MDMA (ecstasy) F. Something else

20 Question 3 A 19 year old woman presents after taking an unknown drug of abuse at a night club. She is confused, has dilated pupils and is noted to have marked ankle clonus. Which of the following drugs is she likely to have ingested? A. Cannabis B. Cocaine C. Mephedrone (cathinone) D. Metamfetamine E. MDMA (ecstasy) (SEROTONIN SYNDROME) F. Something else

21 Syndromes Sedative Stimulant Serotonin Hallucinogenic Dissociative Synthetic Cannabinoid Inhalants Poppers NOTE: Drugs often mixed And not what it says on the label

22 Serotonin toxicity Examples MDMA MDA PMA (1-(4-methoxyphenyl)-2- aminopropane PMMA (N-methyl-1-(4-methoxyphenyl)-2- aminopropane, 4-methoxy-n-methylamphetamine) Management Benzodiazepines Avoid serotoninergics e.g. alfentanyl and suxamethonium (adds to risk of hyperpyrexia and hyperkalaemia) Aggressive cooling Consider neuromuscular paralysis Cyproheptadine? Expect Multiple Organ Failure

23 SCRA toxidrome Unlike cannabis More behavioural disturbance Some more toxic than others RS Respiratory depression CVS Tachycardia or bradycardia CNS Seizures Agitation / psychosis Other Renal failure Metabolic acidosis MDMB-CHMICA

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25 Question 4 How much longer is the half-life of methadone than that of naloxone? A. 2x B. 3x C. 4x D. 6x E. >6x F. Don t know

26 Question 4 How much longer is the half-life of methadone than that of naloxone? A. 2 x B. 3 x C. 4 x D. 6 x E. >6 x F. Don t know Methadone half-life 8-50 h; Naloxone minutes (Morphine ~ 2-3 h) ALSO BEWARE MULTIPLE DRUGS AND SLOW RELEASE

27 Source ONS OPIOIDS with 2 ry Pharmacology Methadone: NMDA antagonist, K + channel blocker Sudden death 2ry Torsade Tramadol: SSRI, NRI, GABA antagonist Convulsions in OD (unpredicatablecheck for clonus) h

28 Question 5 A 45 year old bus driver presented to hospital complaining his appearance had changed over his lunch break. He was otherwise asymptomatic. What is the likely cause? A. Beetroot in sandwich B. Carbon monoxide C. Hydrogen Cyanide D. Isobutyl nitrite E. Undiagnosed cyanotic heart disease F. Don t know

29 Question 5 A 45 year old bus driver presented to hospital complaining his appearance had changed over lunch. He was otherwise asymptomatic. What is the likely cause? A. Beetroot in sandwich B. Carbon monoxide C. Hydrogen Cyanide D. Isobutyl nitrite (Poppers) E. Undiagnosed cyanotic heart disease F. Don t know METHAEMOGLOBINAEMIA

30 Causes of methaemoglobinaemia Local anaesthetics Chlorates Nitrates Sulphonamides and dapsone Aniline dyes All cause massive (1000 fold) increase in methaemoglobin production Treatment of symptomatic patients (> 30% methaemoglobin) is methylonium chloride (methylene blue) and oxygen.

31 Cyanosis from HCN and CO Very rare in practice If patient breathing give oxygen treat acidosis and recovery likely, unless hypoxic brain injury already occurred Benefits of hydroxycobalamin (Cyanide) and hyperbaric oxygen (CO) uncertain, so no reason to use either in routine practice (eg smoke inhalation). Lactic acidosis is a surrogate for toxicity with cyanide, but very non specific, and will normally recover with resuscitation and fluid. (remember ethanol as a cause of acidosis too)

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