poisoning: from paracetamol to legal highs
TRANSCRIPT
Poisoning: from paracetamol to legal highs.
Nick Bateman
University of Edinburgh
Outline
• Epidemiology of poisoning in 2017
• 5 examples of different common problem poisons
Source: NPIS annual report 2015-16
Pharmaceutical agents: Most frequent enquiries Telephone; TOXBASE online; TOXBASE App. 2015-16
TOTAL; Telephone 47,873: TOXBASE 607,000.
Hospital admissions England 2015-16 • Total poisoning admissions 156,492
(Acute MI 153,521: Fractured femur 115,128)
– Analgesics 61,585 of which 53,008 paracetamol
– Benzodiazepines 8,698
– Antidepressants 14,290
– Antipsychotics 6,196
– Anticonvulsants 5,788
– Opioids 19,332
– Cocaine 1,207
– Other psycho-stimulants 2,292
Source https://www.gov.uk/.../statistics/hospital-admitted-patient-care-activity-2015-to-2016
2011 2012 2013 2014 2015
ALL DRUG POISONING DEATHS
2,652 2,597 2,955 3,346 3,674
Paracetamol 207 182 226 200 197
Antidepressants 393 468 466 517 447
TCAs 200 233 235 253 215
SSRIs 127 158 150 159 150
Others 84 104 124 155 133
Antipsychotics 104 102 107 126 101
Zopiclone / Zolpidem 71 83 86 100 87
Propranolol 32 39 46 54 55
Poisoning deaths 2011-2015: Prescription drugs
2011 2012 2013 2014 2015
ALL DRUG POISONING DEATHS
2,652 2,597 2,955 3,346 3,674
Any opiate 1,439 1,290 1,592 1,786 1,786
Heroin and Morphine
596 579 765 952 1,201
Methadone 486 414 429 394 434
Cocaine 112 139 169 247 320
Any amphetamine 62 97 120 151 157
Amphetamine 46 49 56 85 90
MDMA/Ecstasy 13 31 43 50 57
New Psych Sub 31 55 63 82 114
Benzodiazepines 293 284 342 372 366
Diazepam 179 207 228 258 252
Source: Office of National Statistics: Deaths related to Poisoning Sept 2016
Poisoning deaths 2011-2015: Drugs of abuse and with abuse potential
Prescription drugs most frequently associated with drug-related deaths in England in 2015
1. Tricyclic antidepressants 253
2. Paracetamol 197
3. SSRIs 150
4. Antipsychotics 103
Toxicity with tricyclic antidepressants
• Cardiovascular- arrhythmias and cardiac failure, hypotension (esp. with amitriptylline)
• CNS- Fits and Coma.
Late delirium.
Important point is that these go in parallel in the patient
MECHANISMS of TCA toxicity: 1. Na+ channel blockade, (some K+ channel blockade) 2. Amine reuptake blockade, increases local
catecholamines 3. Anticholinergic 4. Alpha blockade (amitriptylline) TREATMENT: Bicarbonate (8.4%) for wide QRS, (measure manually) Norepinephrine for vasodilatation Ventricular assist in severe cases (Discuss with NPIS)
Source TOXBASE
ACETYLCYSTEINE Replaces glutathione
Prescott LF, Health Bulletin 1978, 204-212 Prescott et al Lancet 1972
Plasma paracetamol Half life and toxicity: 30 Untreated cases
Which approach to risk assessment?
UK 1995-2012 USA since 1970s (NZ and Australia since 2008)
CHM Decision 2012
Adopt the previous ‘high risk’
line for all patients
and/or
use 75 mg/kg ingested dose
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)
First year impact of MHRA guidance
-4,000
-2,000
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
16,000
18,000
<100 100-149 150-199 >200 >24h Staggered Unknown Total
Inc
rea
se
(e
xtr
ap
ola
ted
to
UK
)
Patient category
Changes comparing year before with year after Extrapolated from data for 3 hospitals
Presentations
Admissions
NAC treatments
Nomogram bands
*MHRA estimate of additional NAC use 4,920-7,200 treatments Data from Bateman et al. Brit J Clin Pharmacol
2014 & Bateman et al. Clin Tox 2014
MHRA Est*
The cost to the NHS is estimated at £17.3 m (95% CI £13.4 to £21.5) to prevent 1 death.
An 18 year old male presented after a paracetamol overdose; 4 h paracetamol concentration is 125 mg/L (above nomogram line).
30 min after starting the infusion he developed flushing and complains of chest discomfort.
= Anaphylactoid reaction
WARING, W. S., et al 2006. Clin Tox 44: 441-442. Schmidt L. E. 2013 Clin Tox 51: 467-72
Importance of paracetamol concn. in ADR rate
1 mmol/L =150mg/L
Both studies used case note review to ascertain ADRs
Paracetamol conc & 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 vomiting All anaphylactoid
events / n OR 95% CI p events / n OR 95% CI p
All
patients (n=8351)
>100 78/340 1.09 0.78-1.53 0.618 11/340 0.19 0.10-0.37 <0.001
<=100 102/495 1 - - 73/495 1 - -
15min
infusion (n=321)
>100 27/136 0.77 0.45-1.33 0.354 3/136 0.14 0.04-0.48 <0.001
<=100 46/185 1 - - 26/185 1 - -
1 h
infusion (n=514)
>100 51/204 1.37 0.88-2.12 0.163 8/204 0.21 0.10-0.47 <0.001
<=100 56/310 1 - - 47/310 1 - -
*Controlling for age, sex and infusion rate. 1One patient that had no data on blood paracetamol concentration is excluded.
Bateman et al 2014 BJCP. doi 10.111/bcp12362
Managing anaphylactoid reactions to acetylcysteine
A. STOP infusion until reaction abates
B. Observe response to stopping infusion
C. Symptoms due to histamine release so IV chlorphenamine (10mg) initial treatment of choice if reaction not resolving
D. Nebulised salbutamol (2.5-5mg) for asthma
E. Adrenaline almost never required
F. NOT immunologically mediated. SO no clear role for steroids
RESTART acetylcysteine
TRIAL TREATMENTS
Acetylcysteine- matching duration of infusions Conventional 20.25 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 20.25 h for matching
Ondansetron 4mg IV Pre-treatment with ondansetron v saline placebo
Lancet, 2014. 383; 697-704.
Antiemetic rescue. Kaplan Meier analysis to 12 h
OR at 12 h: Modified v conventional NAC OR 0.37, 97.5% CI 0.18-0.79, P = 0.003 Ondansetron v placebo OR 0.35, 97.5% CI 0.17-0.74, P = 0.002
Patients at risk
Ondanstron/Modified 54 50 46 42 40 40 40
Ondanstron/Conventional 55 41 36 36 36 36 36
Placebo/Modified 55 50 40 37 35 33 33
Placebo/Conventional 54 27 21 21 19 18 18
0
0.1
0.2
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0 2 4 6 8 10 12
Pro
po
rti
on
of
pa
tie
nts
wit
ho
ut
an
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Time (hours)
Ondansetron / Modified
Ondansetron / Conventional
Placebo / Modified
Placebo / Conventional
Patients at risk
Ondanstron/Modified 54 53 50 50 50 50 50
Ondanstron/Conventional 55 43 40 40 40 40 40
Placebo/Modified 55 55 51 51 50 50 50
Placebo/Conventional 54 41 41 39 38 38 37
0
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Pro
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f p
atie
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w
ith
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ve
nt
Time (hours)
Ondansetron / Modified
Ondansetron / Conventional
Placebo / Modified
Placebo / Conventional
OR at 12 h: Modified vs conventional NAC OR 0.23 (0.12 to 0.43, p< 0.0001) Ondansetron vs placebo OR 1.4 (0.78 to 2.53, p= 0.198)
Anaphylactoid rescue. Kaplan Meier to 12 h
Bag 1 150mg/kg over 1h
Bag 3 100mg/kg over 16h
Bag 2 50mg/kg over 4h
Bag 1 100mg/kg over 2h
Bag 2 200mg/kg over 10h
Standard Regimen 300 mg/kg over 21h
Modified Regimen 300 mg/kg over 12h
Blood sampling 20 or 21h
Blood sampling 20h
Blood sampling 10h
ALT >100 U/L or ALT doubled or paracetamol >20 mg/L ? or INR >1.3
Extra Bag 200mg/kg Over 10h
Discontinue acetylcysteine if: INR 1.3 or less and ALT <100 U/L and ALT not doubled
Take home message
A simpler shorter acetylcysteine regimen, with 10 h blood samples 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
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 (16.2%)
Cocaine (& synons) 1,463 (18.7%)
Cocaine (& synons) 8,738 (16.1%)
GHB & analogues 1,217 (15.6%)
MDMA (& synons) 5,721 (10.6%)
MDMA (& synons) 841 (10.8%)
Heroin (& synons) 4,500 (8.3%)
SCRA Drugs of abuse 633 (8.1%)
Amfetamine (& synons) 3,742 (6.9%)
Heroin (& synons) 631 (8.1%)
Note: 51% of England metamfetamine accesses were from London (485/954)
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. GHB
D. Mephedrone
E. Metamfetamine
F. MDMA (ecstasy)
Syndromes
Sedative Stimulant Serotonin Hallucinogenic Dissociative Synthetic Cannabinoid Inhalants Poppers (Amyl Nitrite) NOTE: Drugs often mixed And not what it says on the label
Serotonin toxicity Increased muscle tone, hyperthermia, hyperthermia,
agitation, convulsions
Examples
• MDMA
• MDA
• PMA (1-(4-methoxyphenyl)-2-
aminopropane
• PMMA (N-methyl-1-(4-methoxyphenyl)-2-
aminopropane, 4-methoxy-n-methyl-amphetamine)
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
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
How much longer is the half-life of methadone than that of naloxone?
A. 2x
B. 3x
C. 4x
D. 6x
E. >6x
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
Methadone half-life 8-50 h; Naloxone IV 30-80 minutes Buprenorphine 24-40 h (sometimes with naloxone) (Morphine ~ 2-3 h)
BEWARE MULTIPLE DRUGS AND SLOW RELEASE
OPIOIDS with 2ry Pharmacology
Methadone: NMDA antagonist, K+ channel blocker
Sudden death 2ry Torsade
Tramadol: SSRI, NRI, GABA antagonist
Convulsions in OD
(unpredictable-
check for clonus)
h
Source ONS
HCN and CO • Poisoning very rare in UK.
• If patient breathing give oxygen treat acidosis and recovery likely, unless hypoxic brain injury already occurred.
• Benefits of hydroxycobalamin (Cyanide) and hyperbaric oxygen (CO) very 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 is a cause of acidosis too!!
Source: NPIS annual report 2015-16
Most frequent NPIS consultant referrals: Total 1930
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Source: NPIS annual report 2015-
