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Toxicology updates
1. Summon Chomchai, MD, MPH
Department of Preventive and Social Medicine
Faculty of Medicine Siriraj Hospital, Mahidol University
2. A 55 year-old-man
Found unconscious at home 1 hour PTA
1-2 hours PTA: He was seen eating Kratom and
drank ethanol
At the ED:
P 96/min, R 12/min, BP 100/70 mmHg, O2 Sat 95%
at room air
GCS: E1V1M1, pupils 2 mm
CVS and Chest: WNL, no secretion sound
Normal skin and mucosa
NS: Comatose, reflexes: 2+, plantar reflexes:
fleoxor responses
3. 0.4 mg of Naloxone was given with no
response
He was treated with supportive (IV fluid,
oxygen by canular and monitoring)
He woke up 10 hours after presentation
Admitted to ingested one handful of Kratom
and one bottle of whiskey
4. Mithragyna Speciosa Korth
A plant used in Thailand and
Malaysia
Scheduled to be illegal in
Thailand, Malaysia, Myanmar and
Australia
Increasing popularity as a drug of
abuse
Clinical Toxicology (2008) 46, 146–152
5.
6. Mithragynine and 7-hydroxymithragynine
Unknown human pharmacokinetics
Agonists of delta and delta opioid receptors:
Analgesia, euphoria and respiratory
depression
Agonist to presynaptic alpha-2 adrenergic
,adenosine and serotonin receptors
Clinical Toxicology (2008) 46, 146–152
8. Dose-dependent neuropsychiatric symptoms
Onset 10-15 minutes; duration 1 hour
◦ Low dose: Stimulation: hypertension, tachycardia,
tremor at low dose
◦ High dose: Opioid effects in high doses
Nausea, vomiting and diarrhea are commonly
reported
Clinical Toxicology (2008) 46, 146–152
9.
10. It is used in workers in Thailand
In 2003, at least 221600 people were
estimated to use Kratom in Thailand
◦ ~2% of Southern Thailand population
Purposes:
◦ Abuse: increase work endurance
◦ Medicinal use: treatment of chronic pain, cough,
weight control
◦ Reports of using kratom for treating opioid
withdrawal
Substance Use & Misuse (2006), 42:2145–2157
11. Age of first uses: 20-40 years
Regular users: use because of condonation
by family and peers as opposed to other
‘hard drugs’
Chewing leaves, drinking tea, smoking dry
leaves
Very bitter taste; usually wash the taste with
water, energizing beverages and palm juice
Adverse effects perceived by users:
constipation, tremor and headahce
Substance Use & Misuse (2006), 42:2145–2157
12. 61% of regular uses believe that they are
addicted to Kratom
Withdrawal symptoms
◦ Inability to work
◦ Pain the the back, legs and muscles
◦ Crave
Other reported withdrawal symptoms: Yawn,
rhinorrhea, myalgia, arthralgia and diarrhea
Substance Use & Misuse (2006), 42:2145–2157
13. Rarely reported
2 case in Pubmed
1 case with unconsciousness and seizures
1 case of seizures
AMS for 30 hours
Confirmed mithragynine detection in urine by
HPLC-ESI/MS/MS
No known long-term effects
J Med Toxicol. 2010 Apr 22.
Addiction. 2008 Jun;103(6):1048-50.
14. Supportive and symptomatic care
Naloxine may be considered in cases with
respiratory depression
J Med Toxicol. 2010 Apr 22.
15. A 12-year-old girl was brought to the
emergency room due to alteration of
consciousness.
Her parents gave the history of using an
over-the-counter antitussive drug, a small
yellow coated tablet, for illicit purposes.
Her habit changed from gradual to
progressive increase in the dosage of drug
use, and from occasional with a few tablets at
a time to daily doses in order to gain the
desired effect of euphoria
16. Six hours prior to hospitalization, the patient took 26 tablets
of dextromethorphan (Romilar).
She reported of feeling sleepy, with nausea and abdominal
discomfort.
Her father noted that she became increasingly confused and
brought her to the emergency department (ED).
At the ED, vital signs BP117/70 mmHg, P 122 / min, R 20/
min, T38.2o C.
The patient appeared drowsy with Glascow coma scale of 15
(E4V5M6)
She was responsive and verbalized with notably slow speech.
Nystagmus was seen, Fundoscopic examination was normal
J Med Assoc Thai 2005; 88(Suppl 8): S242-5
17. Non-opioid synthetic analog of codeine
◦ dextro-isomer of levorphanol
Actions are modulated by central sigma receptor
binding sigma receptors
Unlike most opioids, the drug is devoid of activity
at mu and delta receptors
Typical adult and pediatric doses (>12 years of
age) of DM range from 60 to 120 mg/day in
divided doses
At clinical doses, the drug produces no euphoriant,
analgesic, or dependence-producing effects
J Am Pharm Assoc. 2009;49:e20–e27
18. Metablozied by CYP 2D6 to dextrophan
◦ noncompetitively antagonize the N-methyl-D-aspartate
(NMDA) receptor and serotonin release
◦ Euphoria, hyperactivity and hallucination
In general, acute overdose of dextromethorphan
causes nausea, vomiting, hyperexcitability,
restlessness, hallucination, dizziness, drowsiness,
,lethargy, slurred speech, mydriasis, euphoria,
tachycardia, hypertension and urinary retention.
The classical opioid effects such as respiratory
depression and miosis are not commonly seen
J Am Pharm Assoc. 2009;49:e20–e27
21. Minimal: 80-100 mg
Common: 200-400 mg
Heavy: 600-1500 mg
It may be ingested or snorted
Vivid visual hallucinations and complete body
analgesia
Mild withdrawal symptoms that are similar to those
of opiate withdrawal
http//:www.erowid.org/chemicals/dxm.
23. Gastric decontamination
Naloxone therapy: shown to be effective
when used in children and for the specific
indications of hyperexcitability, altered
mental status or respiratory depression
Am J Emerg Med. 1991;9:237-238.
24. A 18 y/o woman was brought in because of
alteration of consciousness with a container of
abamestin 1.8% W/V beside her
BP 102/60 mmHg, P 64/min, R 26/min, O2sat 90%
@ room air
E1V1M2, pupils 3mm not reactive to light, normal
skin and mucosa
CVS & Chest: WNL
Abdomen: Soft normal bowel sound
NS: Flaccid tone, reflexes: 1+ upper extremities,
absent: lower extremities
25. Abamectin is a potent
antihelmintic, insecticide,
and miticide
Derived from Strepto-myces
avermitilis (species of
Actinomyces)
Abamectin: a mixture of
avermectins containing
>80% avermectin B1a and
<20% avermectin B1b
◦ Similar biological and
toxicological properties
26. Toxic effects of abamectin are usually seen
after oral ingestions
May be absorbed dermally
Following their absorption, maximum
Serum concentrations peak 2.7 to 5 hours
after oral dosing
Elimination half-life was 2.8 to10 hours
among healthy volunteers
◦ Largely excreted into the bile and feces
Clin Toxicol (Phila). 2007;45(3):299-300.
27. CNS symptoms such as incoordination,
tremor, lethargy, excitation, and mydriasis via
GABA agonistic effect
Deaths related to Abamectin ingestion are
commonly a result of respiratory failure
From our experience: shock and status
epilepticus
Clin Toxicol (Phila). 2007;45(3):299-300.
28. Only one study in the literature by Chung et al
a significant correlation between the ingested
abamectin dose and clinical severity
◦ For asymptomatic and mild poisoning, the
average ingested dose was 23.0 mg/kg
◦ Average dose for severely poisoned patients was
100.7 mg/kg ~ 280 mL
◦ CNS and gastrointestinal effects:diarrhea, nausea,
vomiting, AMS, dizziness and weakness
Ann Emerg Med. 1999 Jul;34(1):51-7.
30. Inhibitor of AchE
Bind to AchE and form a stable compound
Inactivate AchE molecule inactive
Once AchE molecules are unavailable,
continued stimulation
cholinergic overstimulation
paralysis
31.
32. Signs and Symptoms
I. Muscarinic or parasympathetic symptoms
SLUDGE + 3 KILLER Bs
II. Nicotinic/ganglionic/NM symptoms
Muscle fasciculations, progressive paralysis and
respiratory failure.
Hypertension, tachycardia, pupillary dilatation and
pallor
III. CNS symptoms
Restlessness, tremor, confusion, ataxia, slurred
speech and seizure.
33. Clinical diagnosis
Cholinesterase level
Wide normal range
RBC cholinesterase
Specific
Hardly available
Plasma cholinesterase
More available
Non-specific
35. Antagonizing muscarininc effects
Reactivating blocked cholinesterase
Treatment of muscle hyperstimulation/
seizures
Lancet. 2008 Feb 16;371(9612):597-607.
36. If the clinical presentation is not clear
◦ administer atropine 0.6– 1 mg
A marked increase in heart rate (more than
20–25 beats/min) and flushing of the skin
suggest that the patient does not have
significant cholinergic poisoning and further
atropine is not required
Lancet. 2008 Feb 16;371(9612):597-607.
37. Atropine 1.8–3 mg (three to five 0.6 mg vials)
3-5 minutes after giving atropine, check the
five markers of cholinergic poisoning(
A uniform improvement in most of the five
parameters is required
The most important parameters are air entry
on chest auscultation, heart rate, and blood
pressure
Lancet. 2008 Feb 16;371(9612):597-607.
38. Clear chest on auscultation Pupils
with no wheeze Lung sounds
Heart rate >80 beats/min
Pupils no longer pinpoint
Dry axillae
Systolic blood pressure >80
mmHg
Indicators Pitfalls
Critical Care 2004, 8:R391-R397
39. With no improvement in 3-5 minutes: double dose the
atropine until the goal is achieved
Continue doubling the dose each time that there is no
response
From a review of 22 surviving patients with OP-poisoning and
respiratory failure dose of atropine 1-75 mg(mean23.4 mg,
22.0sd) to clear the lungs, raise the pulse above 80bpm, and
restore systolic blood pressure to more than 80 mmHg
Standard textbook therapy will take
◦ Up to 1380 mins to mean dose
◦ Up to 4440 mins to 75 mg dose
J Toxicol Clin Toxicol. 2004;42(6):865-75.
Crit Care. 2004 Dec;8(6):R391-7.
40. Infusion of atropine
Rate per hour = 10-20% loading dose
Atropine intoxication: agitation, confusion, urinary
retention, hyperthermia, bowel ileus and
tachycardia
With intoxication: stop the atropine infusion and
check every 30 minnutes
Once the atropine intoxication subsides restart the
infusion at the rate 70-80% of the previous rate
Lancet. 2008 Feb 16;371(9612):597-607.
41. Oximes reactivate acetylcholinesterase
inhibited by oganophosphorus
Despite the beneficial effects of pralidoxime,
its effectiveness (and safety) has been much
debated
42. Meta-analysis of 7 studies of severe OP
poisoning
382 patients
No significant risk or harm in terms of
◦ Overall mortality
◦ Need of respiratory support
Crit Care Med. 2006 Feb;34(2):502-10.
45. A randomized controlled trial studied the effect of
very-high-dose pralidoxime
Pralidoxime iodide (2 g loading dose, then 1 g either
every hour or every 4 h for 48 h, then 1 g every 4 h
until recovery)
200 patients with moderate organophosphorus
poisoning
The high-dose regimen was associated with reduced
case fatality (1% vs 8%; odds ratio [OR] 0·12, 95% CI
0·003–0·90),
Lancet. 2006 Dec 16;368(9553):2136-41.
46. A prospective study on 802 patients self-
poisoned with chlorpyrifos, dimethoate, or
fenthion
Mortality: chlorpyrifos (8.0%), dimethoate
(23.1%), fenthion (16.2%)
Endotracheal intubation: chlorpyrifos(15.0%),
dimethoate (35.2%), fenthion (31.3%)
Patients poisoned by
◦ Diethyl OP pesticide (chlorpyrifos) responded well
to pralidoxime
◦ Dimethyl OP (dimethoate, fenthion) responded
poorly
Lancet. 2005 Oct 22-28;366(9495):1452-9.
Neth J Med. 2008 Apr;66(4):146-8.
47. Dimethoate-poisoned patients
◦ Died sooner than other pesticides
◦ Often died from hypotensive shock
Fenthion poisoning initially caused few
symptoms but many patients subsequently
required intubation
Lancet. 2005 Oct 22-28;366(9495):1452-9.
50. A double-blind randomised placebo-controlled
trial of pralidoxime chloride (2 g loading dose over
20 min, followed by a constant infusion of 0.5 g/h
for up to 7 d)
235 patients with organophosphorus insecticide
self-poisoning
Pralidoxime reactivated RBC acetylcholinesterase
significantly
Mortality was nonsignificantly higher in treatnment
group: 30/121 (24.8%) vs placebo18/114 (15.8%)
PLoS Med. 2009 Jun 30;6(6):e1000104.
53. Pralidoximes be given to all symptomatic
patients who need atropine or manifesting
neuromuscular manifestations
Pralidoxime chloride
◦ Loading dose of 30 mg/kg intravenously over 20
minutes, followed by an infusion of 8 mg/kg/h
◦ Adults: 2 g loading dose followed by 500 mg/h.
Continue until recovery (12 hours after
stopping administration of atropine or once
butyrylcholinesterase increase)
Lancet. 2008 Feb 16;371(9612):597-607.
54. In the cholinergic nervous system, diazepam
appears to decrease the synaptic release of
Ach
In CNS diazepam causes hyperpolarization of
neurons making them significantly less
susceptible to cholinergically induced
depolarization
◦ The ultimate result is cessation of propagation of
convulsions
BMJ. 2007 Mar 24;334(7594):629-34.
55. Overall effects of benzodiazepine: reducing
anxiety and restlessness, reducing muscle
fasciculation and seizures, controlling
agitation
Indications: patients poisoned with OP
whenever convulsions, agitation or
pronounced muscle fasciculation are present
Doses:
◦ Diazepam 5-10 mg (0.05-0.3 mg/kg/dose)
◦ Midazolam 5-10 mg (0.15-0.2 mg/kg/dose)
Lancet. 2008 Feb 16;371(9612):597-607.
56. A bipyridium herbicide
Toxicokinetics
◦ Rapid absorption: peak plasma level within 1-2 hours
◦ Incomplete absorption: 10-30%
◦ Distribute to tissues: Lung, Kidney
◦ Elimination: 90% eliminated within 12 -24 hours via kidney (half-life 10-12 hours)
57. Ingestion of paraquat leads to
◦ Generation of free oxygen radicals
◦ Lipid peroxidation
◦ Damaging cell membranes and leading to cell death.
Paraquat is actively taken up into type II
pneumocytes and renal tubular cells.
58.
59. Mild poisoning:
◦ Local irritation: vomiting and diarhea
◦ Ingestion of less than 20 mg/kg of paraquat ion
◦ Full recovery without sequelae
Moderate to severe:
◦ Ingestion of 20-40 mg/kg of paraquat ion
◦ GI corrosion, acute tubular necrosis, hepatitis
◦ Delayed progressive pulmonary fibrosis
◦ Delayed mortality (1-4 weeks) from hypoxia
◦ Survivors may have gradual recovery of pulmonary functions over months to years
60. Fulminant poisoning:
◦ Ingestion of more than 40 mg/kg of paraquat ion Usually die within 1-5 days
◦ GI ulceration
◦ Acute renal failure, myocardial damage, hepatic failure, pulmonary edema and
hemorrhage
◦ Multiorgran failure, shock
◦ 100% mortality regardless of management
61. Hart’s Nomogram
Plasma paraquat level drawn within 28
hours
Those with level 3 mg/L at anytime:
100% mortality
No fulminant poisoning:
2.0 mg/L at 4 hr
0.3 mg/L at 10 hr
0.1 mg/L at 24 hr
Eddleston M, Wilks MF, Buckley NA. Qjm 2003;96(11):809-24.
61
63. In a study with 53 cases of paraquat
poisoning
All patients with urinary paraquat
concentrations less than 1 µg/ml(no color
change-pale blue), within 24 h of ingestion,
survived
Cases with results more than ++ (navy
blue; >10 µg/ml) within 24 h following
ingestion have a high probability of death
Hum Toxicol1987 Jan;6(1):91-3.
64.
65.
66. A study using sodium dithionite test for plasma paraquat
as a qualitative test in 233 paraquat poisoning patients
Blood samples were drawn within 12 hours
Detection limits: concentration ≥ 2 mg/L
Levels above 2 mg/L are associated with high mortality
in many studies
Patients with a plasma paraquat level < 2.0 mg/L have
the potential for recovery with vigorous treatment
Sensitivity 0.67
Specificity 1.0
Positive predictive value 1.0
◦ Am J Med Sci2009 Nov;338(5):373-7.
67. Urine should be tested serially for 24 h after
ingestion
An early urinary semiquantitative testing may
underestimate the amount of paraquat
systemically absorbed
Crit Rev Toxicol. 2008;38(1):13-71.
68. Although quantitative plasma paraquat
concentrations have a greater predictive
value, qualitative urine and plasma may
contribute to a more rapid evaluation of
prognosis with more availability
◦Am J Med Sci2009 Nov;338(5):373-7.
69. Activated charcoal/ Fuller’s earth/ bentonite
Improve survival in animal studies
Equivocal efficacy in animal studies
Adsorbent therapy alone has never shown increase survival in human
Meredith TJ, Vale JA. Hum Toxicol 1987;6(1):49-55.
69
70. Significant clearance and improved survival shown in canine models
loaded with LD50 and LD100 dose.
No systematic study showing that hemodialysis or hemoperfusion is
efficacious in human
Possible cause of failure:
Relatively small amount cleared
While renal function is still intact, external clearance is smaller than
renal clearance
When renal failure develops, pulmonary uptake has already occurred.
Recommendation: perform charcoal hemoperfusion only if it can be
started within 4 hours.
Med J Aust 1991;154(9):617-22.
70
71. The most widely investigated and applied aspect of
specific management is immunosuppressive therapy,
especially the regimen consisitng of
◦ Cyclophosphamide
◦ Corticosteriods
Concepts: Reduction of pulmonary inflammation and
fibrosis using antiinflammatory and
immunosuppressive therapy
72. Regimen: cyclophosphamide 5
mg/kg/day and dexamethasone 24
mg/day for 14 days
Total cases = 72
Mortality: treated 20/72(27.8)% vs
historical control 42/61(68.9%)
Lancet. 1986 May 17;1(8490):1117-20.
Another study
Survival: treated 20/31(64.5%) vs
historical control 9/14(64.3%)
Hum Exp Toxicol. 1992 Mar;11(2):129-34.
73. A single-blinded randomized clinical trial in
142 paraquat-poisoned patients, pulse
therapy reduced mortality in moderate to
severe poisoning from 53/65(81.5%) to
38/56(67.9%)
Pulse therapy included
1. 15 g/kg/day of cyclophosphamide for 2
days
2. 1 g/day of methylprednisolone for 3 days
All patients also received dexamethasone
30mg/day for 14 days
Am J Respir Crit Care Med. 1999 Feb;159(2):357-60.
74. N = 23 cases of paraquat poisoned patients with
predictive mortality > 50% but < 90% by plasma
level
Initial pulse therapy:
cyclophosphamide (15 mg/kg/day, i.v., 2 days) and
methylprednisolone (1 g/day i.v., 2 days)
Followed by dexamethasone 5 mg, i.v., every 6 h until PaO2 >
80 mmHg
Randomized cases for repeated pulse therapy if
PaO2 was < 60 mmHg: 3 days of
methylprednisolone and 1 day of
cyclophosphamide
Mortality rate:
◦ control 6/7 = 85.7%
◦ Study 5/16 = 31.3% (p=0.027)
Crit Care Med. 2006 Feb;34(2):368-73.
75. A retrospective study in 54 cases
Significantly higher survival with
suppression of leucocyte or neutrophil
counts by at least 10% after the
initiation of immunosuppressive
◦ Journal Of the Chinese Medical Association2009;72(9 supplement):S20-1.
76. 12 studies using immunosuppressive therapy in
the management of paraquat poisoning
◦ Four non-randomized
◦ Six non-randomized comparing historical controls
◦ Two randomized controlled trials
The relative risk of immunosuppressive therapy in
decreasing mortality with paraquat poisoning
◦ 0.55 (95 % CI 0.39- 0.77) for the non-randomized studies
(comparing historical controls)
◦ 0.6 (95 % CI 0.27-1.34) for randomized controlled studies
Singapore Med J2007 Nov;48(11):1000-5.
77. Systematic review
3 RCT
Total cases : 164 moderate to severe cases
Inclusion criteria: Urine navy blue or drak blue and/
or plasma level in the range of mortality 50-90%
Interventions: IV cyclophosphamide and
dexamethasone
Main outcomes: mortality at the end of follow up
(at least 30 days post ingestion)
Results: RR 0.72 (95% CI 0.59 to 0.89)
Cochrane Database Syst Rev. 2010 Jun 16;6:CD008084.
