Antidotes 2012

ANTIDOTES
IN THE THERAPY OF INTOXICATION
Ngatidjan
Department of Pharmacology and Therapeutics

Faculty of Medicine UGM
Ngatidjan ANTIDOTES-2012 1
harmless substance specific measure
good vital sign 1. emesis
2. gastric lavage
conscious
3. adsorbent
4. antidote
harmful substance
5. forced diuresis
6. dialysis
7. hemoperfusion
disturbances good
of vital function vital function 2. 3. 4. 5. 6. 7.
good vital function

unsciousness cardiopulmonal
resuscitation
disturb of vital function 2

Therapy of acute intoxication
First aid  assessment of ABCD
(airway – breathing, brain, circulation, disability)
 cardiopulmonary resuscitation
 prevent the progression of intoxication

 keep the victim away from source of poison
 decontamination (wash the area of body
contact, emesis, gastric lavage, laxant)
3
Specific measurements
1. inhibit further absorption of toxic substance
 emesis, gastric lavage, adsorbent, laxant.
2. increase the elimination of toxic substance

 forced diuresis, dialysis, hemoperfussion,
acidification and alkalinization of urine
3. inhibit or counteract the toxic effects
 give antidotes 4
Antidotes
Substance used to counteract the effects of poison :
 Neutralize the toxic substance (poison)

(antigen-antibody reaction, chelation, chemical binding)
 Antagonize the poison physiological effects

(activation of the opposing nerve system, competitiveness in
metabolism or receptors)
Antidotes
Counteract the effects of the poison by :
 Chemical reaction  chemical antidotes
 Physiological reaction  physiological antidotes
It can be  Specific antidotes

 Nonspecific antidotes
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
CaNa2-edetate
• EDTA (ethylenediamine tetraacetic acid)
• To chelate many heavy metals  especially Pb
• An ionic freely water soluble compound
• Vd is small  extracellular fluid compartment
• Excretion via kidney  half life 20 – 60 minutes
• Should be given intramuscularly

CaNa2-edetate
DIMERCAPROL (BAL : British Anti Lewesite)
• Dithiol,2,3-dimercaptopropanol
• Metal chelator
for inorganic or elemental mercury, As (arsen) toxicity and Pb.
• As (arsen) bind to sulfhydryl – SH – group ( cell damage)
 effective at lo concentration
 administered up to 1 hrs after skin contaminatios.
• Dimercaprol
 3 mg / kg i.m. (every 4 hours for 2 days, than every 12 hours for 7 –
10 days)
Dimercaprol (BAL)
Activated charcoal
• Fine black odorless powder
• To adsorb the toxic molecules
• Adsorptive capacity
depends on its internal surface area and external pores  diameter
• May decrease the absorption of drugs given in the same time

(aspirin, acetaminophen, barbiturates, phenytoin, theophyline,
cyclic antidepresants)
• Best administered as a water slurry

Physiological antidote
• ethanol (for methanol intoxication)
• anticonvulsants (for caffeine intoxication)
• atropine (for AChE inhibitor intoxication)
• antihistamines (for histamine intoxication)
• anticonvulsants (for chlorine intoxication)
• naloxone (for morphine intoxication)
• acetylcystein (for acetaminophen intoxication)
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
acetaldehyde formaldehyde
alcoholdehydrogenase
acetic acid  further metabolism formic acid  toxic to retina

Cyanide intoxication
CN- Cytochrome oxydase
– Na-nitrit
Hb++ metHb+++ Cyano cytochrome

nitrite +
CN-
– Na-thiosulfat Cyano-metHb Cytochrome oxydase
CN-
rhodanase 
metHb reductase
Thiocyanat metHb+++ Hb++16
• atropine as antidote for
cholinergic drug poisoning
 cholinergic drugs  stimulate r-M
(direct or indirectly by inhibit AChE)
 atropine or atropinic drugs,
block r-M,
 prevent the stimulation of r-M (by ACh or muscarinic durg).
 competitive antagonism.
Atropine vs organophosphate /
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
• physostigmine as antidote for
anticholinergic poisoning
 reverse coma, seizures, severe myoclonic and
choreoathetoid activities caused by anticholinergic drugs
 reverse peripheral manifestation such as mydriasis,
hyperthermia, dry skin and mucosa, tachycardia,
constipation, urine retention etc.
 transverse blood brain barrier.
 inhibit AChE  ACh accumulation

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

(sulfate or glucuronate)
gluthation 
conjugation
(sulfate or glucuronate)
excretion excretion
Paracetamol intoxication
• Large dose of paracetamol.
• Acetylcysteine.
 stimulate gluthation syntesis.
 substitute gluthation.
 facilitates NABQI elimination
22
APAP
(N-acetyl-p-aminophenol, acetaminophen)
NABQI
(N-acetylbenzoquinoneimin)
[Ca2+]
Blocked by EGTA
(ethylene glycol bis tetra acetic acid)
Activation of endonucleases
DNA damage
(single strand breaks)
Ngatidjan
Necrotic cell death
ANTIDOTES-2012
23
23
APAP
(N-acetyl-p-aminophenol, acetaminophen)
Acetyl systeine
(electron donor NABQI
NABQI guluronate (N-acetylbenzoquinoneimin)
sulphate
[Ca2+]
Activation of endonucleases
DNA damage
renal excretion (single strand breaks)
Necrotic cell death
24
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)
• 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)
• 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)
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
HYPERBARIC CHAMBER
29
HYPERBARIC CHAMBER
30
18/11/2009 Ngatidjan, ANTIDOTES 31

Antidotes 2012

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ANTIDOTES

IN THE THERAPY OF INTOXICATION

Department of Pharmacology and Therapeutics

good vital function

disturb of vital function 2

 prevent the progression of intoxication

2. increase the elimination of toxic substance

3. inhibit or counteract the toxic effects

 Neutralize the toxic substance (poison)

 Antagonize the poison physiological effects

It can be  Specific antidotes

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)

• To chelate many heavy metals  especially Pb

• An ionic freely water soluble compound

• Vd is small  extracellular fluid compartment

• Excretion via kidney  half life 20 – 60 minutes

• Should be given intramuscularly

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

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

 administered up to 1 hrs after skin contaminatios.

 3 mg / kg i.m. (every 4 hours for 2 days, than every 12 hours for 7 –

• To adsorb the toxic molecules

• May decrease the absorption of drugs given in the same time

• Best administered as a water slurry

• Competitive inhibition on alcohol dehydrogenase

 inhibits the formation of formic acid.

• Can be given orally or intravenously

acetic acid  further metabolism formic acid  toxic to retina

Hb++ metHb+++ Cyano cytochrome

– Na-thiosulfat Cyano-metHb Cytochrome oxydase

Atropine block r-M

 transverse blood brain barrier.

 inhibit AChE  ACh accumulation

Side effect  caused by NABQI

NABQI (N-asetyl benzoquinoneimine) conjugation

• Large dose of paracetamol.

 stimulate gluthation syntesis.

 facilitates NABQI elimination

Necrotic cell death

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

• use ventilator (before respiratory the occurrence of depression)

• may cause acute pulmonary edema

• in chronic use of morphine, may cause withdrawal

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