7-Inactivation of the absorbed poison

• The use of specific antidotes: the ideal antidote

should be specific in action, available by all routes
of administration, with no side effects and cheap.

A. Chelating Agents
• These are compounds used to form stable
complexes ‘chelates’ with metals.
• Chelates are water soluble, non-toxic and easily
excreted from the body.
• chelating agents:
• BAL
• Penicillamine
• EDTA
• Deferroxamine
• Others
Dimercaprol – BAL (British Antilewisite)
• BAL is clinically useful for treating acute and
chronic poisoning by organic or inorganic arsenal
and for protecting against mercury-induced renal
damage.
• Not effective in treating mercury-induced
neurological conditions or CNS damage. Not
useful to chelate cadmium, iron or selenium
because the chelate can partially dissociate in
urine and enhance renal damage.
• Must be given parentally (I.M.).
Water-soluble derivatives of BAL : (less toxic, more
effective)
• Dimercaptopropionic acid sodium sulfonate DMPA
• Dimercaptosuccinic acid DMSA ,SUCCIMER
BAL blood concentrations are best achieved and maintained by
giving repeated doses within the first 4 hours after poisoning.
Excessive large doses should be avoided because of possible
side effects. Dosage of BAL is designed to assure the
formation of a 2:1 complexes (2 molecules of BAL: 1 molecule
of metal).
N.B. BAL –Hg complex is more lipid soluble than Hg and can
cross the B.B.B. but since it is very stable and not
dissociated, it is non-toxic to the brain (methyl and
etheylmercury are lipid soluble, they cross the brain leading
to encephalophathy).
Side effect of BAL:
1) Nausea, vomiting, diarrhea, colics and salivation, sweating,
lacrimation and convulsions.
2) Cardiovascular toxicity leading to rise in B.P.
3) Kidney damage (can be avoided by urine alkalinization with
NaHCO3).
4) Liver toxicity (BAL cannot be used with patients having
liver damage).
Penicillamine
• It is specific for copper poisoning in some
people with genetic deficiency of
ceruloplasmin (Cu-binding protein).
• These people develop Wilson’s disease upon
accumulation of copper in their liver,
kidney and brain (death in a young age)
• Side effects of Penicillamine they include:
allergy, anaphylactic shock, nephrotoxicity,
bone marrow depression, aplastic anemia
and crystaluria.
People with genetic deficiency of ceruloplasmin can
be also treated with :

 N-acetyl penicillamine (NAP): less toxic and

more efficient.

 TETA (triethylene tetramine = cuprid triene)

water soluble and less toxic than penicillamine.

 Small doses of potassium sulfide K2S. It is given

orally and I.M for most metals (specially Cu).
 EDTA
• Calcium disodium EDTA (Versinate) is used to chelate
metals that are more tightly bound to EDTA than calcium
(i.e. can replace calcium from EDTA) like : Pb, Zn, Cr, Cd,
Ni, Fe.
• Versinate is not used for treatment of toxicity due to Li,
Ba, Mg, Sr because these metals cannot displace calcium
from versinate.
• Versinate is given by slow I.V. injection diluted with saline
for 5 days and then stopped for 2 days to avoid chelation
of essential body metals.
• Side effects of versinate hypotension, bone marrow
depression, crystaluria because it is not metabolized in the
body.
• Derivatives of EDTA
• Cobalt EDTA (Co-EDTA = Kelocyanor) used in the
treatment of cyanide poisoning.
• Deferoxamine ‘Desferal’ or ‘Deferoxamine mesylate’
– It is an iron chelating agent given for iron poisoning or for
removal of iron from the body.
– It can be given orally (to chelate the unabsorbed part of
iron), it is not absorbed orally. It is also given parenterally
for toxicity with FeSO4 or Fe gluconate in children.
– Desferal can chelate iron present in ferritin, transferrin and
hemosiderin but not that of hemoglobin, myoglobin or
cytochromes.
– Desferal can be also used to chelate iron overload resulting
from blood transfusion in the following non-iron deficiency
anaemias:
• Thalasemias (Cooley’s anemia): in which the β-chain of
hemoglobin is reduced.
• Sickeld cell anemia: in which there is a change in the
sequence of one amino acid in the globin chain.
• Side effect of desferal: allergy at the site of injection,
hypo tension tachycardia, red colored urine.
Other methods for treatment of iron toxicity:
o Gastric lavage with NaHCO3
o Sodium phosphate enema
 Note that:

Dimercaprol I.M.
Penicillamine Oral.

Calcium disodium EDTA (Versinate) Slow I.V. injection

Deferoxamine
Orally (to chelate the unabsorbed part of iron), it is not
absorbed orally. It is also given parenterally for removal of
the absorbed part, eg. for toxicity with FeSO4 or Fe
gluconate in children.
8-Use of SPECIFIC ANTIDOTE IF PRESENT (accoding to
MOA)
A. Antidotes that combine with a toxic material to
give a non-toxic complex

1-Protamin for heparin toxicity

2-Vitamin K for toxicity with oral anticoagulants
3-Sodium thiosulfate for iodine or bromine toxicity
4-Ammonium acetate or 1% ammonia for HCHO poisoning to
form a hexamine.
5-Cobalt containing antidotes:
o Co-EDTA (Kelocyanor for cyanide poisoning)
o Hydroxy-cobalamine (for cyanide poisoning)
6-Antibodies SUCH AS:
o Serum Ab prepared in horse for paraquat and Soman (nerve
gas)
o Fab/digoxin Ab for digoxin poisoning prepared by anti venom
for scorpion and snake venoms
o Antibotulinum for botulism
B. Antidotes that prevent lethal synthesis
• Examples:
-Ethyl Alcohol in case of methyl alcohol poisoning;
– Methyl alcohol is converted in the body by the enzyme
‘alcohol dehydrogenase’ into formaldehyde and then to
formic causing irreversible damage of the optic nerve
and blindness.
– Ethanol has more affinity to the enzyme alcohol
dehydrogenase than methanol leading to stopping the
formation of formic acid.
– Glyceryl monoacetin in fluroacetate poisoning:
fluoroacetate is converted into fluorocitrate which
stops the Kerb’s cycle. Glyceryl monoacetin can
compete with fluoroacetate to prevent the lethal
synthesis.
– Ethylene Glycol is converted in the body to oxalic acid
(toxic), ethanol is used to stop this reaction.
C. Antidotes accelerating the conversion of a toxic
compound into a non-toxic compound
• Sodium thiosulfate is used in the treatment of cyanide
poisoning. Cyanide kit is composed of:
• Sodium thiosulfate
• Amyl nitrite injection
• Sodium nitrite injection
• Antidotes that increase detoxifying substances in the
body
• E.g. Cyanide toxicity is due to the binding of cyanide to
the Fe 3+ in cytochrome oxidase
• for CN to not bind with cytochromes, This is done by
converting a part of hemoglobin into methemoglobin
achieved by oxidation with sodium nitrite or amyl nitrite
(ingredients in the cyanide kit)
• Cyanide will combine with metHb to give
cyanmethemoglobin.
D. Antidotes that dissociate the poison–enzyme complex:
• E.g. poisoning with organophosphorous cpds (insecticides
and war gases) is treated by:
i-Oximes and oxooximes which are cholinesterase
reactivators that help in the hydrolysis of the complex
formed between organophosphorous cpds and cholinesterase
before aging of the enzyme (after enzyme aging, it cannot be
regenerated).
Examples:
• PA2M (pyridine aldoxime methyl iodide)
• TMB4 toxogonin (obidoxime) which is more effective and
less toxic than PA2M
• DAM (diacetylmono-oxime)
• MINA (monoisonitrosoacetone)
• DAM and MINA can cross the B.B.B. to treat CNS effects
of organophsphorous cpds
ii-Atropine till full atropinization to block
muscarinic effect of accumulated acetylcholine.
iii-Magnesium parenterally to block nicotinic
effect of accumulated acetycholine.
N.B. Poisoning by carbamates is never treated by
cholinesterase reactivator because they increase
their toxicity.
E. Antidotes which act on toxic metabolism:
• E.g. paracetamol poisoning: 4% of paracetamol
is metabolized by cytochrome. This metabolite
(N-Acetyl-p-benzoquinoneimine) is toxic
because it can react with glutathione.
N-Acetyl-p-benzoquinoneimine (NAPQI , TOXIC)
• This is conjugated with Glutathione
• Glutathione stored in the body
• Produces a NON TOXIC metabolite
• Glutathione stores are used up by the excess
Paracetamol ( i.e. depleted)
• A high dose of paracetamol (>15 gm) can deplete
glutathione from keeping normal level of gluthathione.
• Toxic Metabolite build up
• Binds IRREVERSIBLY to Hepatic Cell membranes
• Resulting in LIVER NECROSIS
 N - Acetylcysteine
• Specific Antidote – MOA: a glutathione precursor
• Limits the formation and accumulation of NAPQI
• Powerful anti-inflammatory and antioxidant
effects
• IV infusion or oral tablets (also oral methionine)
• 150mg/Kg over 15 min; 50mg/Kg over next 4 hrs;
100mg/kg over next 16 hrs up to 36hrs
• Beyond 10 hours, NAC efficacy progressively
decreases
• S/Es nausea, flushing, urticaria, bronchospasm,
angioedema, fever, chills, hypotension, hemolysis
and rarely, cardiovascular collapse
F-Pharmacological antidotes:
• Naloxone for opioids
• Flumazenil for benzodiazepines
G-Physiological antidotes:
• Adrenaline for histamine anaphylactic
shock
• Intravenous fluids for hypotension
• Diazepam for convulsant poisons
• Methylene blue for methemoglobinemia
• Antiscorpion and antivenoms
• Vitamin K for oral anticoagulants
• Protamine for heparin
 Factors influencing toxicity
• Dose ingested
• Excessive cytochrome P450 activity due to induction
by chronic alcohol or other drug use eg carbamazepine,
phenytoin, isoniazid, rifampin
• Decreased capacity for glucuronidation or sulfation
• Depletion of glutathione stores due to malnutrition or
chronic alcohol ingestion
Measures for prevention of poisoning
• Drugs should be well closed and kept away from the
reach of children.
• Elderly patients have usually amnesia and show ‘drug
automatism’ i.e. they take the drug dose several times
therefore special care must be take.
• Keep drugs in their original containers and never use
food containers for poisonous substances, also all
containers should be labeled.
• Poison control centers should be consulted.