Antidotes

Antidotes and treatment of poisonings
Drugs used to counteract drug overdosage
are considered under the appropriate
headings, e.g., physostigmine with
atropine; naloxone with opioids; flumazenil
with benzodiazepines; antibody
(Fab fragments) with digitalis; and
N-acetyl-cysteine with acetaminophen
intoxication.
Chelating agents serve as antidotes
in poisoning with heavy metals.
They act to complex and, thus, “inactivate”
heavy metal ions. Chelates (from
Greek: chele = claw [of crayfish]) represent
complexes between a metal ion
and molecules that carry several binding
sites for the metal ion. Because of
their high affinity, chelating agents “attract”
metal ions present in the organism.
The chelates are non-toxic, are excreted
predominantly via the kidney,
maintain a tight organometallic bond
also in the concentrated, usually acidic,
milieu of tubular urine and thus promote
the elimination of metal ions.
Na2Ca-EDTA is used to treat lead
poisoning. This antidote cannot penetrate
cell membranes and must be given
parenterally. Because of its high binding
affinity, the lead ion displaces Ca2+ from
its bond. The lead-containing chelate is
eliminated renally. Nephrotoxicity predominates
among the unwanted effects.
Na3Ca-Pentetate is a complex of diethylenetriaminopentaacetic
acid (DPTA)
and serves as antidote in lead and other
metal intoxications.
Dimercaprol (BAL, British Anti-Lewisite)
was developed in World War II
as an antidote against vesicant organic
arsenicals . It is able to chelate various
metal ions. Dimercaprol forms a liquid,
rapidly decomposing substance
that is given intramuscularly in an oily
vehicle. A related compound, both in
terms of structure and activity, is dimercaptopropanesulfonic
acid, whose
sodium salt is suitable for oral administration.
Shivering, fever, and skin reactions
are potential adverse effects.
Deferoxamine derives from the
bacterium Streptomyces pilosus. The
substance possesses a very high ironbinding
capacity, but does not withdraw
iron from hemoglobin or cytochromes.
It is poorly absorbed enterally and must
be given parenterally to cause increased
excretion of iron. Oral administration is
indicated only if enteral absorption of
iron is to be curtailed. Unwanted effects
include allergic reactions. It should be
noted that blood letting is the most effective
means of removing iron from the
body; however, this method is unsuitable
for treating conditions of iron overload
associated with anemia.
D-penicillamine can promote the
elimination of copper (e.g., in Wilson’s
disease) and of lead ions. It can be given
orally. Two additional uses are cystinuria
and rheumatoid arthritis. In the former,
formation of cystine stones in the
urinary tract is prevented because the
drug can form a disulfide with cysteine
that is readily soluble. In the latter, penicillamine
can be used as a basal regimen
. The therapeutic effect
may result in part from a reaction with
aldehydes, whereby polymerization of
collagen molecules into fibrils is inhibited.
Unwanted effects are: cutaneous
damage (diminished resistance to mechanical
stress with a tendency to form
blisters), nephrotoxicity, bone marrow
depression, and taste disturbances.


Antidotes for cyanide poisoning
(A). Cyanide ions (CN-) enter the organism
in the form of hydrocyanic acid
(HCN); the latter can be inhaled, released
from cyanide salts in the acidic
stomach juice, or enzymatically liberated
from bitter almonds in the gastrointestinal
tract. The lethal dose of HCN can
be as low as 50 mg. CN- binds with high
affinity to trivalent iron and thereby arrests
utilization of oxygen via mitochondrial
cytochrome oxidases of the
respiratory chain. An internal asphyxiation
(histotoxic hypoxia) ensues while
erythrocytes remain charged with O2
(venous blood colored bright red).
In small amounts, cyanide can be
converted to the relatively nontoxic
thiocyanate (SCN-) by hepatic “rhodanese”
or sulfur transferase. As a therapeutic
measure, thiosulfate can be given
i.v. to promote formation of thiocyanate,
which is eliminated in urine. However,
this reaction is slow in onset. A
more effective emergency treatment is
the i.v. administration of the methemoglobin-
forming agent 4-dimethylaminophenol,
which rapidly generates
trivalent from divalent iron in hemoglobin.
Competition between methemoglobin
and cytochrome oxidase for CN- ions
favors the formation of cyanmethemoglobin.
Hydroxocobalamin is an alternative,
very effective antidote because its
central cobalt atom binds CN- with high
affinity to generate cyanocobalamin.
Tolonium chloride (Toluidin
Blue). Brown-colored methemoglobin,
containing tri- instead of divalent iron,
is incapable of carrying O2. Under normal
conditions, methemoglobin is produced
continuously, but reduced again
with the help of glucose-6-phosphate
dehydrogenase. Substances that promote
formation of methemoglobin (B)
may cause a lethal deficiency of O2. Tolonium
chloride is a redox dye that can
be given i.v. to reduce methemoglobin.
Obidoxime is an antidote used to
treat poisoning with insecticides of the
organophosphate type (p. 102). Phosphorylation
of acetylcholinesterase
causes an irreversible inhibition of acetylcholine
breakdown and hence flooding
of the organism with the transmitter.
Possible sequelae are exaggerated
parasympathomimetic activity, blockade
of ganglionic and neuromuscular
transmission, and respiratory paralysis.
Therapeutic measures include: 1.
administration of atropine in high dosage
to shield muscarinic acetylcholine
receptors; and 2. reactivation of acetylcholinesterase
by obidoxime, which
successively binds to the enzyme, captures
the phosphate residue by a nucleophilic
attack, and then dissociates
from the active center to release the enzyme
from inhibition.
Ferric Ferrocyanide (“Berlin
Blue,” B) is used to treat poisoning with
thallium salts (e.g., in rat poison), the
initial symptoms of which are gastrointestinal
disturbances, followed by nerve
and brain damage, as well as hair loss.
Thallium ions present in the organism
are secreted into the gut but undergo
reabsorption. The insoluble, nonabsorbable
colloidal Berlin Blue binds thallium
ions. It is given orally to prevent absorption
of acutely ingested thallium or to
promote clearance from the organism
by intercepting thallium that is secreted
into the intestines.