Case Approach in Toxicology

Winai Wananukul Ramathibodi Hospital

All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy. Paracelsus (1493 - 1541)

Determination of Clinical Toxicity

N-Acetyltransferase-2 (NAT-2) Polymorphism

Dose

Route of Exposure

Host

Differential Diagnosis of Asymptomatic Patients who have history of Substances Overdose:

In Adequate Dose for Developing Toxicity Nontoxic Substances Ingestion Delayed Onset of Toxicity

Decontamination
Airway Skin Parenteral

Increase Elimination
Circulation

Antidotes

GI.

Tissues & Organs

No further recommended !

MDC

Hemodialysis, Hemoperfusion

Charcoal

Limit! 1 hours after ingestion only

Head Down Left Lateral Decubitus In Awake Patient

Whole Bowel Irrigation

Agent: Polyethylene glycol Electrolyte Solution (PEG-ES) Mechanism: Cleanses the bowel by enteral administration of large amount of an osmotically balanced PEG-ES, induces liquid stool.
PEG Electrolyte

Epidemiology of Toxic Exposure

(Ramathibodi Poison Center: 2001- 2003) 7,718 Cases

Recommended for ingestion of: sustained- release/ enteric-coated tablets iron, heavy metals, body packers
Pesticide 45% Medical Products 20% Household Products 19% Occupational Products 7% Natural Toxins 5% Misc. 4%

(Ramathibodi Poison Center: 2001-2003) 3,541 Cases

Plant growth regulator 2.0% Miticide 5.0% Synergist 0.6%

Classification of Pesticide Exposure

20 .
2 . . ER : HR 120/min, BP 170/100 mmHg, RR 22/min. Unconsciousness, Pupils 1 mm. in diameter Salivation and sweating Coarse crepitation bilaterally Reactive bowel sound No fassiculation

Mollusticide 1.5% Fungicide 0.7% Miscellaneous 1.8%

Rodenticides 17%

Herbicides 22%

Insecticides 50%

What is Organophosphate & Carbamate Poisoning ? State of Acetylcholine Excess It is a combination of

Muscarinic receptor Nicotinic receptor CNS (unspecified)

Organophosphate VS. Carbamate Poisoning Reversible vs. Irreversible Inhibition

Reversible vs. Irreversible clinical poisoning Time of clinical course

Atropine Muscarinic Effects

Heart rate Sweating Secretion Pupils

Blood brain barrier penetration

CNS symptoms (after exclude hypoxic effects)

2 PAM AChE Inhibitions

ESTERATIC SITE

Nicotinic Muscarinic

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2 PAM Nicotinic Effects
Motor Power + (Muscarinic Effects)

CC PI PE

. 30 . PR 130/min, BP 80/50 mmHg, RR 20/min Unconsciousness, generalized tonic-clonic seizure Pupil 5 mm, react to light

Insecticides
Organophosphate Carbamate Organochlorine
DDT Endosulfan

Classification of Insecticide Exposure

(Ramathibodi Poison Center: 2001-2003)

1,725 Cases
Organochlorine 7% Others 5% Unknown 5% Organophosphate 28%

Pyrethroids
Cypermethrin pyrethrins

Combined 10%

Pyrethroid 20% Carbamate 25%

Lambda-cyhalothrin 2.5% W/V

(Ramathibodi Poison Center: 2001-2003) 3,541 Cases

Plant growth regulator 2.0% Miticide 5.0% Synergist 0.6%

Classification of Pesticide Exposure

(Ramathibodi Poison Center: 2001-2003)

Classification of Herbicide Exposure 864 Cases

Others 9%

Mollusticide 1.5% Fungicide 0.7% Miscellaneous 1.8%

Chloroacetanilide 9% Chlorophenoxy 10%

Unknown 4%

Rodenticides 17%

Paraquat 24%
Herbicides 22% Insecticides 50%

Glycine 44%

50
PI Round up . 1 PE P 80/min, BP 110/70 mmHg, RR 18/min, T 37C erythema in oral mucosa pupil 4 mm., react to light Heart: normal S1, S2 no murmur Lung: clear Abdomen: soft, not tender

Herbicides
Paraquat Glyphosate 2,4 D (Chlorophenoxy compounds) Others

Glyphosate 48% W/V

property: strong irritant

Paraquat 27.6% W/V

dye: blue or green emetic drug property: strong irritant

Dithionite test

20
PI 1 . PE Unremarkable

alkaline sodium dithionate

Paraquat

Classification of Rodenticide Exposure

Warfarin

(Ramathibodi Poison Center: 2001-2003) 541 Cases

Zinc phosphide

Long acting anticoaggulant 8.3%

Unknown 5.4%

Long acting anticoaggulant

Warfarin 41.8%

Zinc phosphide 44.5%

55.2% 53.4% 17.7% 16.3% 4.0%
100% 80% 60% 40% 20% 0%
PQ OC OP Survive CB Gly ZnP Pyr Death

16
. 2

2.1%

0.5%

 20 6 . 60 2 . .
Is she really intoxicated from paracetamol

NHCOCH3

Paracetamol
450

Conjuga tion
OH
5-1 0%

NHCOCH3

NHCOCH3

90 - 95

+
Sulfate Glucoronide
1-

Cyt. P

NHCOCH3

4%

O NHCOCH3 Glutathione

NHCOCH3

NAPQI
X OH

OH

GSH KIDNEYS Cell Death

N A cetyl Cysteine

What should predict the risk to develop paracetamol induced hepatic injury in the early phase?

300 200 150

90% of cases will have enzyme > 1000 if no Treatment

60% of cases will have enzyme > 1000 if no Treatment

The blood paracetamol level.

Blood level (mcg/ml)

Recommending of Treatment

12

16

20 24

Hours after ingestion

From Rumack BH, et al. Arch Intern Med 1981;141:380 5. -

Efficacy of NACs
Px group Px delay <10 hr (>200Line)
Oral NAC IV. NAC 527 62 935 38 1462 100 6.1 1.6 26.4 52.6 19.1 21.0 0.0 0.0 1.1 5.3 0.7 2.0

Billirubin level & Prognosis

Peak Serum Total Bilirubin < 4 mg% > 4 mg% 22/22 (100%) 1/19 ( 5%) 0/22 (0%) 18/19 (95%)* No Encephalopathy Encephalopathy

% pt with % pts. dying from hepatic damage hepatic failure

Px delay 10-24 hr (>200Line)

Oral NAC IV.

Px delay <24 hr (>200Line)

Oral NAC IV. NAC

Among 18 pt. with encephalopathy, 12/18 (66.7%) Died. Cark R, et al. Lancet 1973;7:66-9.

Supportive Px only

57

58.0

5.3

Predictors for Paracetamol induced Fulminant Hepatic Failure

N-Acetylcystein & Paracetamol induced hepatitis

With NAC Retrospective Study (N =33) Without NAC 58% 75% 80% 68%

pH of Arterial blood gas Peak of the serial Prothrombin time (PT) Serum Creatinine

Died Hepatic Coma Died Cerebral edema

37% 51% 52% 40%

Prospective Randomized Study (N=50 )

Harrison PM, et al. Br Med J 1990;335:1572-3. Keays R, et al. Br Med J 1991;303:1026-9.

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PI 6 Vixol Pink 50 ml.
PE P 110/min, BP 90/60, RR 24/min, T 37.8 C Erythema or soft palate and posterior pharynx, no stridor Lung : clear Abdomen : tender at epigastrium, no guarding or rigidity, normal bowel sound

Caustic Agents
Soap Nonionic detergent Anionic detergent Cathionic detergent Acid Hypochlorite Alkali

Irritant

Corrosive (caustic) agent

10

Contraindication for Gastric Lavage

Corrosive Agents Drugs caused rapid deterioration of consciousness

Ineffectiveness of Activated Charcoal

Strong Acid & Alkali Alcohol Cyanide Elemental Metal

22
. PE BP 80/50 mmHg, HR 110/min, RR 8/min, T 36 C Unconscious, not response to pain Pupil 1 mm. in diameter, not react to light No localizing sign Lung: fine crepitation bilateral Otherwise: normal

Therapeutic Diagnosis for Unconscious Patients

50% Dextrose in Water 50 ml. Naloxone 2-10 mg iv Thiamine 50 -100 mg iv.

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Psychotropic Agents
Sedative Hypnotics Benzodiazepines Antidepressants
Tricyclic antidepressants Selective serotonin reuptake inhibitors

Autonomic (ANS.) Signs

Antipsychotics Opiates Barbiturates

Stimulant Hallucinogens Amphetamine & derivatives Cocaine Caffeine Marihuana LSD Ketamine Volatile substance

Pulse Blood Pressure Respiration Temperature

Skin Secretion Bowel sound & Bowel movement Urinary Bladder

Pupils
Differentiate between Structural vs. Metabolic Equal in Size? React to light? Differentiate Among the Causative Agents Nonspecific Interpretation with Precaution

Suspected CNS Suppression Intoxication

Anticholinergic Signs

No
Respiratory Suppression

Yes
Constricted Pupils

Yes
Opiates

Suspected CNS Suppression Intoxication

22
. PE BP 80/50 mmHg, HR 110/min, RR 8/min, T 36 C Unconscious, not response to pain Pupil 1 mm. in diameter, not react to light No localizing sign Lung: fine crepitation bilateral Otherwise: normal
Anticholinergic Signs

No
Respiratory Suppression

No
Phenobarbital

Yes
Constricted Pupils

Yes
Opiates

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Barbiturate Overdose
Diagnostic Tools
Can mimic brain death Skin Blisters (6%) Blood & urine barbiturate Therapeutic diagnostic: None, But need to be R/O opiate toxicity

Drugs Eliminated by RAC.

Phenobarbital Phenytoin Theophylline Salicylates Carbamazepine Dapsone

Choice of Hemodialysis & Hemoperfusion

Hemodialysis Lithium Bromide Ethanol Methanol Ethylene Glycol Salicylates Hemoperfusion Barbiturate Theophylline Disopyramide Meprobamate

Suspected CNS Suppression Intoxication

Anticholinergic Signs

No
Respiratory Suppression

No

Benzodiazepine

No
Phenobarbital

Yes
Constricted Pupils

Yes
Opiates

Benzodiazepine Overdose
Yes

Suspected CNS Suppression Intoxication

Diagnostic Tools
Blood & Urine Benzodiazepine Therapeutic Diagnostic: ?? Flumazenil

TCA

Dilated Pupils

Yes

Anticholinergic Signs

No
Respiratory Suppression

No

Benzodiazepine

No
Phenobarbital

Yes
Constricted Pupils

Yes
Opiates

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Tricyclic Antidepressants (TCA) Overdose

Diagnostic Tools
Blood & Urine TCAs EKG: Widening of QRS complexes R in aVR Therapeutic Diagnostic: None

QRS Complexes As a Predictor for TCAs Toxicity

Yes

Suspected CNS Suppression Intoxication

QRS Duration
> 0.10 sec >0.16 sec

Risk
Seizure Ventricular Arrhythmias

TCA

Dilated Pupils

Yes

Anticholinergic Signs

No
Phenothiazine

No
Respiratory Suppression

No

Benzodiazepine

No
Phenobarbital

Yes
Constricted Pupils

Yes
Opiates

22
CC 3 . . PI 1 . . 3 . . . RR 40/min, BP 80/50 mmHg, HR 120/min. Pupil 4 mm. intubate ET tube drip dopamine high dose

22
Na 136, K 6.2, Cl 100, CO2 5.2 mEq/L

14

Compounds inducing anion gap metabolic acidosis

Acetylene Adrenaline (epinephrine) Benzyl alcohol -Adrenergic agents Boric acid Caffeine Carbon monoxide Colchicines Cyanide Ethanol (ketoacidosis) Ethylene glycol Formaldehyde Hydrogen sulphide Iron Isoniazid Methanol Ritodrine Salicylates

Alcohol R-C-OH Ethanol CH3-C-OH Methanol H-C-OH

Aldehyde H R-C=O H CH3-C=O H H-C=O

Acid OH R-C=O OH CH3-C=O H H-C=O

CO2 CO2 CO2 CO2

Alcohol R-C-OH

Aldehyde H R-C=O

Acid OH R-C=O OH HO O=C-C=O

CO2 CO2

22
Na 136, K 6.2, Cl 100, CO2 5.2 mEq/L 6 . Hemodialysis 4 . Pupil 2 mm RTL off adrenaline methanol

Ethylene Glycol HH HO-C-C-OH O=C-C=O OH CH3-C- CH3 Isopropanol

O CH3-C- CH3

Choice of Hemodialysis & Hemoperfusion Hemodialysis

Lithium Bromide Ethanol Methanol Ethylene Glycol Salicylates

Hemoperfusion
Barbiturate Theophylline Disopyramide Meprobamate

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Classified by Local & Systemic Toxicity With Cytotoxin

Hematotoxins Neurotoxins Myotoxins

Venomous Snakes

Classified by Local & Systemic Toxicity With Cytotoxin

Hematotoxins Neurotoxins Myotoxins (GPV) (MPV)

Venomous Snakes

Without Cytotoxin

Without Cytotoxin
(RV)

Classified by Local & Systemic Toxicity With Cytotoxin

Hematotoxins Neurotoxins Myotoxins (GPV) (MPV) (C) (KC)

Venomous Snakes

Classified by Local & Systemic Toxicity With Cytotoxin

Hematotoxins Neurotoxins Myotoxins (GPV) (MPV) (C) (KC) (Sea snakes)

Venomous Snakes

Without Cytotoxin
(RV) (BK) (MK)

Without Cytotoxin
(RV) (BK) (MK)

68
CC PI - 6 . 2-3 2-3 2 . 1 . intubate respirator

16

Horseshoe Crabs

Tetrodotoxin/Saxitoxin
Found in:
Puffer fish Ivory shell, Trumpet shell Horseshoe crab (Carcinoscopius rotundicauda) Blue-ringed octopus Newt salamander

Puffer fish Poisoning

Clinical Staging

5
5 . 2 5 arrest , CPR 3 BP drop drip high dose dopamine

1: Oral paresthesia, GI symptoms 2: Generalized paresthesia, motor paralysis 3: Aphonia, dysphagia, respiratory distress 4: Respiratory paralysis, coma, shock
(Ogura, 1971)

5
, , ,

Botulinum Toxin
Mechanism of Toxicity Botulism Toxin Heat Sensitive Block Acetylcholine (ACh) release Neuromuscular junction Presynaptic Ganglion Postsynaptic Ganglion of Sympathetic and Parasympathetic

17

Botulism

Clinical Manifestation Onset: 12 -48 hours after ingestion Symptoms & Signs Gastrointestinal Occulobalbar Descending paralysis from balbar to respiratory failure
Visual Disturbance Dysphagia Dysarthria Dry mouth

Botulinum Toxin
Sources Sausage Ham Canned Food Asparagus Green bean Pepper Bamboo shoot

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Methemoglobinemia
Definitions: Methemoglobin is an abnormal hemoglobin which ferrous ion (Fe2+) in hemoglobin is oxidize to ferric ion (Fe3+)

Methemoglobinemia
1. Non-functional hemoglobin in RBCs 2. Oxygen Association curve shift to have more affinity with hemoglobin 3. Change in the pigment and RBCs

Differential diagnosis of Central cyanosis Deoxyhemolobinemia Methemoglobinemia Sulfhemolobinemia

Cyanosis
5 g of deoxyhemoglobin causes visible cyanosis 5 g represents 33% of hemoglobin 1.5 g/dL of methemoglobin causes visible cyanosis 1.5 g represents 10% of all hemoglobin (15 g/dL) 0.5 g/dL of sulfhemoglobin causes visible cyanosis 1.5 g represents 3% of all hemoglobin (15 g/dL)

19

Methemoglobinemia Laboratory Tests

Bed side Pulse oxymeter low O2 saturation Arterial Blood Gas (ABG) metabolic acidosis, normal PaO2 & O2 saturation Electrolyte high anion gap metabolic acidosis

Oxidative Stress

Hemolytic Anemia

Methemoglobinemia

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