POISONING

AND ANTIDOTES

Ngatidjan

Department of Pharmacology and Therapy

Faculty of Medicine UGM
 ACUTE POISONING
 House hold
 Insecticides – rodenticides, acid – base / alkaline chemicals etc.

 Drugs – medicines
 Narcotics, analgesics, OAD, -blockers, ARB, Ca-antagonists, etc.

 Animal – plants
 Snake bites, insect bites – sting, jelly fish, datura sp., cyanide
containing cassava and beans, etc.

 Industry materials
 Methanol and other solvents, pesticides, acid – base chemicals.
Ngatidjan POISNANTIDOTES 2018 2
 THERAPEUTICAL PROCESS

Establish diagnosis of intoxication

(taking history, clinical and laboratory examinations)

Clinical intervention
(surgical, drug therapy, etc.)
what kind of drug (age, BW, main and concomitant disease, genetic)
how much (the dose, frequency)
how to give (route of administration)
Ngatidjan POISNANTIDOTES 2018 3
 THERAPY OF POISONING

Establish the diagnosis of intoxication

(taking history, clinical and laboratory examinations)

Understand the course of poisoning

(Toxicodynamics and toxicokinetiks of suspect poison / toxic substance)

 Physiological disturbances
 Mechanism of poisoning
 Site action of poison / toxic substances
 Fate of poison / toxic substance in the body

Ngatidjan POISNANTIDOTES 2018 4

Diagnosis of acute intocication
Physical – clinical examination :
- skin  pale, chery red, cyanotics, dry, wet, etc.
- eye – pupil  miosis, mydriasis, dry, unisochoric, etc.
- mouth  dry, hypersalivation, asymetrics, etc.
- heart  tachycardia, bradycardia, arrhythmia, etc.
- lung  normal, hyperventilation, etc.
- abdomen  hypoactivity, methalic sound, etc.
- pulse  rythmic, weak, normal, tachy– or bradycardia, etc.
- blood pressure  high BP, low BP, etc.
scientific guessing
- symptom  causative agent
- sign
Ngatidjan POISNANTIDOTES 2018 5
 Diagnosis of acute intocication
Laboratory examination
- the rest toxin or suspect substance
- the rest of suspect material
- washing container
- vomiting material
- gastric lavage
- urine
- blood - serum
- etc. identify of suspected toxin
- medical aspect - therapy
- medico legal aspect
Ngatidjan POISNANTIDOTES 2018 6
Laboratory examination (paracetamol intoxication)

7
 harmless substance, specific measure
good vital function 1. emesis
consciousness 2. gastric lavage
3. adsorbent
4. antidotal agents
harmful
5. forced diuresis
6. dialysis
7. hemoperfusa
vital function vital function
disturbed undisturbed 2. 3. 4. 5. 6. 7.

good vital function

unconsciousness cardiopulmonary
resuscitation

vital function disturbed

8
 THERAPY OF ACUTE INTOXICATION

• Supportive / nonspecific measurements

• Specific measurements
o inhibit further absorption of toxic substances

o increase elimination process

o inhibit or antagonize of toxic effects

Ngatidjan POISNANTIDOTES 2018 9
THERAPY OF ACUTE INTOXICATION
Specific measurements
 Inhibit further absorption of suspected toxic agent
• Emesis, gastric lavage, adsorbent, laxants.

 Increase the elimination of suspected agent

• Forced diuresis, dialysis, hemoperfusion, acidify or
alkalinize of urine

 Inhibit or antagonize the emerging toxic effects

• Give antidote
Ngatidjan POISNANTIDOTES 2018 10
ANTIDOTES
Counteract the effects of the poison by :
 Neutralizing the toxic substance (poison)
 antigen-antibody reaction (physiological antidotes),
to chelate  chemical binding (chemical antidote)

 Antagonize the poison physiological effects

o activation of the opposing nerve system,
o competitiveness in metabolism
o competitiveness on molecule targets (e.g. receptors)
 physiological antodeotes
Ngatidjan POISNANTIDOTES 2018 11
Chemical Antidotes
 Chelators :
EDTA and CaNa2EDTA (edatamil) for Pb, Au and Cd intoxication
BAL (dimercaprol) for As, Pb, Fe, Se, and U intoxication
diferoxamine (for Fe intoxication)
penicilamine (for Cu, Hg and Zn intoxication)

 KMnO4 (oxidize the alkaloids  for alkaloids intoxication)

 Activated charcoal
Ngatidjan POISNANTIDOTES 2018 12
CaNa2-edetate

(Lullman et al., 2005)

13
DIMERCAPROL (BAL : British Anti Lewesite)
o Dithiol,2,3-dimercaptopropanol

o Metal chelator
for inorganic or elemental mercury, As (arsen) toxicity and Pb.

o As (arsen) bind to sulfhydryl – SH – group ( cell damage)

 effective at lo concentration

 administered up to 1 hrs after skin contaminatios.

o Dimercaprol

 3 mg / kg i.m. (every 4 hrs for 2 days,  every 12 hrs for 7 - 10 days)

Ngatidjan POISNANTIDOTES 2018 14

Dimercaprol (BAL)

(Lullman et al., 2005)

15
Physiological antidote
• acetylcystein (for acetaminophen intoxication)
• anticonvulsants (for caffeine – convulsants intoxication)
• atropine (for AChE inhibitor intoxication)
• antihistamines (for histamine intoxication)
• calcium gluconate (for inhalant exposure  injury 
Ca-gluconate 5% nebulizer for HF : hydrogen fluoride,
10% intraveous for Ca2+ antagonist intoxication)
• ethanol (for methanol intoxication)
Ngatidjan POISNANTIDOTES 2018 16
Physiological antidote
• ephedrine (for sympathetic blocked caused by spinal
block anesthesia  5 – 10 mg intravenously)

• naloxone, naltrexone (for morphine / opiate intoxication)

• natrium bicarbonate (to correct life threatening acidosis :
caused by methanol, ethylene glycol, cyclic antidepressant,
salicylate, and phenobarbital intoxication)
• neostigmine (for coral snake, cobra and other neurotoxic
snake bite poisoning)

• protamine sulphate (for heparin intoxication)

Ngatidjan POISNANTIDOTES 2018 17
ETHANOL
 For methanol and ethylene glycol intoxication.
 Competitive inhibition on alcohol dehydrogenase
 inhibits the formation of formic acid.
 Can be given orally or intravenously

ethanol methanol
alcoholdehydrogenase

formaldehyde
acetaldehyde
alcoholdehydrogenase

acetic acid  further metabolism formic acid  toxic to retina

Ngatidjan POISNANTIDOTES 2018 18
Cyanide intoxication
CN-
Cytochrome oxydase
– Na-nitrit

Hb++ metHb+++ Cyano cytochrome

nitrite +
CN-

– Na-thiosulfat
Cyano-metHb Cytochrome oxydase

rhodanase  CN-

metHb reductase
Thiocyanat metHb+++ Hb++
Ngatidjan POISNANTIDOTES 2018 19
Physiological antidote
• atropine as antidote for
cholinergic drug poisoning
 cholinergic drugs  stimulate r-M
o direct r-M stimulstion (muscarine, pilocarpine)
o
indirectly r-M stimulation (inhibit AChE)
 carbamate or organophosphates insecticides
 atropine or atropinic drugs,
block r-M,
 prevent the stimulation of r-M.

 competitive antagonism.
Ngatidjan POISNANTIDOTES 2018 20
 Atropine vs organophosphate
(OP) / Carbamate intoxication

OP / carmabate  inhibit AChE

 let ACh accummulated in the SC
 stimulation of r-M and r-N
(predominantly stimulation of r-M)
 symptoms & sign of intoxication

Atropine block r-M

 prevent stimulation of r-M by ACh

(Rang et al., 2004)

21
 LD-50 (mg/ kg) in rat
ORGANOPHOSPHATE orally perdermally

– TEP (tetraetylpyrophosphate), 1,1 2,4

– Mevinphos 6,1 4,7
– Azinphosmethyl 13 220
– Parathion 13 21
– Chlorphenvinphos 15 31
– Dichlorvos 80 107
– Diazinon 108 200
Ngatidjan POISNANTIDOTES 2018 22
ORGANOPHOSPHATE LD-50 (mg/ kg) in rat
orally perdermally

– Dimethoate, 215 260

– Trichlorvon 630 > 2.000
– Chlorothion 880 > 1.500
– Malathion 1375 > 4.000
– Ronnel 1250 > 5.000
– Abate 8.000 4.000
Ngatidjan POISNANTIDOTES 2018 23
 LD-50 (mg/ kg) in rat
CARBAMATES orally perdermally

– Propoxur 83 > 2.400

– Carbaryl 850 > 4.000

– Mobam 150 > 2.000

– Temik 0,8 3,0

– Zectran 37 > 1.500

Ngatidjan POISNANTIDOTES 2018 24
ORGANOPHOSPHATES and CARBAMATES

Organophosphates and Carbamates

Inhibits cholinesterase

Acetylcholine accumulation (in synaptic clefts)

Sympathetic nerve, autonomic ganglia, motor end plate, etc.

Cholinergic receptor stimulation (r-M and r-N)

Symptoms of acute intoxication

Ngatidjan POISNANTIDOTES 2018 25
Sign & symptom of acute intoxication
• Exocrine glands  r-M (increase salivation, lacrimation, perspiration)
• Eyes  r-M (miosis, blurred vision)
• GI tract  r-M (vomiting, diarrhea, abdominal cramp)
• Respiratory tract  r-M (bronchial, hypersecretion, brochoconstriction),
• Bladder  r-M (urinary frequency),
• Cardiovasc system  r-M (bradycardia, hypotension),
• Cardiovasc system  r-N (tachycardia, transient hypertension),
• Skeletal muscle  r-N (muscle fasciculation, twitching, weakness, etc),
• CNS  r-M and r-N (dizziness, lethargy, fatigue, headache, confusion, coma, etc).

Ngatidjan POISNANTIDOTES 2018 26

Symptoms of acute intoxication
 30 – 60 minutes
(after the insecticide enter into the body)
 Maximal symptoms
(2 – 8 hours after the insecticide enter into the body)
 Headache, chest discomfort, tremor palpepra and tongue,
blurred vision
 Nausea, hypersecretion saliva and lacrima,
 Vomiting, sweaty, fasciculation,
 Diarrhea, miosis, dyspnea, convulsion, cardiac arrest.
Ngatidjan POISNANTIDOTES 2018 27
Therapy (in moderate to severe case)
 Airway facilitation  from mucous material,
 Atropine injection  intravenous 2 mg
repeat every 15 minutes  until reverse of the symptoms,
 pallor of the face become redness,
 hypersalivation  dry mouth,
 bradycardia  slight tachycardia (critical),
 sweaty  dry skin,

 Cholinesterase reactivator  oximes (pralidoxim etc.)

Ngatidjan POISNANTIDOTES 2018 28
Acetaminophen (paracetamol, APAP : N-acetyl p-aminophenol)

Side effect  caused by NABQI

- Hemolytic anemia
- Liver damage (large dose)
(7-10%)
Paracetamol (90-93%)

NABQI (N-asetyl benzoquinoneimine) conjugation

gluthation  (sulfate or glucuronate)

conjugation
(sulfate or glucuronate)

excretion excretion

Ngatidjan POISNANTIDOTES 2018 29

Paracetamol intoxication

• Large dose of paracetamol.

its metabolite  NABQI (hepatotoxic)

• Acetylcysteine.
o stimulate gluthation syntesis.
o substitute gluthation.

 facilitates NABQI elimination

31
Ngatidjan POISNANTIDOTES 2018 31
NALOXONE : for opiate intoxication
• 0.5 mg intravenously (depend on the severity of intoxication)

• use ventilator (before respiratory the occurrence of depression)

• 1 – 2 mg in non tolerant patient (to morphine and other opiate)

• may cause acute pulmonary edema

• in chronic use of morphine, may cause withdrawal

symptoms
Ngatidjan POISNANTIDOTES 2018 32
Carbonmonoxide (CO)
Carbonmonoxide

CarboxyHb

OxyHb

Oxygenation

Hypoxia / tissue anoxia

Ngatidjan POISNANTIDOTES 2018 33
Carbonmonoxide (CO)
Haldane equation

COHb (PCO)
--------- = M -------- at blood pH  M = 245
HbO2 (PO2)

If PCO : 1/245 PO2  COHb = HbO2

 50% Hb bind to CO   O2 transport capacity by 50%
Ngatidjan POISNANTIDOTES 2018 34
CO INTOXICATION
Symptoms :
 No symptom if COHb < 2% (nonsmokers)
< 5% (smokers)

 Cardiovascular symptoms  COHb > 5%

 Fatal cases  COHb > 50%

Ngatidjan POISNANTIDOTES 2018 35
CO INTOXICATION
Symptoms :
 Chery red  skin and mucous membrane

 Normal respiratory  there is no dyspnea

PO2 decrease asmuch as 1/245
 Oxygen transport capacity decrease 50%
(because chemoreceptor is not activate by carbonate)

 Hypoxia  increasing COP  reflectory

tachycardia
Ngatidjan POISNANTIDOTES 2018 36
CO INTOXICATION
Therapy :
1. Stop and prevent further contact to CO,
2. Arteficial respiratory,
3. Give oxygen
- t1/2 (half recovery time) at normal air (1 atm.)  80’
- t1/2 in O2 1 atm.  30 minutes.
- t1/2 in O2 3 atm. (hyperbaric)  23 menit
4. Give also CO2 5 - 7% in oxygen (to stimulate respiiration)
5. Exchange transfusion for moribund
Ngatidjan POISNANTIDOTES 2018 37
HYPERBARIC CHAMBER

38
List of recommended antidote
• activated charcoal (general adsorbent)
• antivenin polyvalent (for crotalidae snake bite)
• antivenin Lactrodectus (for black widow spider bite)
• atropine (for ACh E inhibitor intoxication)
• botulinal antitoxin (ABE trivalent)
(for botulinus intoxication)
• cyanide kit (amylnitrite, Na-nitrite and Na-thiosulfate)
(for cyanide poisoning)
Ngatidjan POISNANTIDOTES 2018 39
List of recommended antidote
• deferoxamine mesylate (for Fe intoxication)
• dextrose water solution (50%, 20%)  for hypoglycemic agent
intoxication (insulin and OAD)

• diazepam, midazolam (for seizure – occurring in intoxication)

• digoxin specific antibodies (for digoxin intoxication)
• dimercaprol – BAL (for As, Pb, Hg poisoning)
• diphenhydramine (for histamine containing food or other histamine
containing material poisoning)
Ngatidjan POISNANTIDOTES 2018 40
List of recommended antidote
• ethanol 100% or 10% (for methanol intoxication)
• ipecac, syrup of (for emeticum – to induce emesis)
• naloxone (for opioid intoxication)
• oxygen hyperbaric (for CO and cyanide poisoning)
• phenobarbiton injection (anticonvulsant)
• phenytoin injection (anticonvulsant)
• pralidoxime (for / as AChE reactivator)
Ngatidjan POISNANTIDOTES 2018 41
ngatidjansp@gmail.com

Thanks for the attention