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308 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-acetylcysteine with acetaminophen intoxication.

Chelating agents (A) serve as antidotes in poisoning with heavy metals. They act to complex and, thus, “inactivate” heavy metal ions. Chelates (from Greek: chele = pincer [of crayfish]) represent complexes between a metal ion and molecules that carry several binding sites for the metal ion. Because of their high af nity, chelating agents “attract” metal ions present in the organism. The chelates are nontoxic, are excreted predominantly via the kidney, and maintain a tight organometallic bond 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 through cell membranes and must be given parenterally. Because of its high binding af nity, 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 (B). 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 Streptomyces pilosus. The substance possesses a very high iron-binding capacity butdoes notwithdraw 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 bloodletting 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 disease) and of lead ions. It can be given orally. Two additional indications are cystinuria and rheumatoid arthritis. In cystinuria, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In rheumatoid arthritis, penicillamine can be used as a basal regimen (p.332). 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; p.74), nephrotoxicity, bone marrow depression, and taste disturbances.

Apart from specific antidotes (if they exist), the treatment of poisonings also calls for symptomatic measures (control of blood pressure and blood electrolytes; monitoring of cardiac and respiratory function; prevention of toxin absorption by activated charcoal). An important step is early emptying of the stomach by gastric lavage and, if necessary, administration of an osmotic laxative. Use of emetics (saturated NaCl solution, ipecac syrup, apomorphine s.c.) is inadvisable.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Antidotes and Treatment of Poisonings

309

A. Chelation of lead ions by EDTA

 

 

 

Na2Ca-

 

 

2Na+

Ca2+

 

 

 

 

EDTA

 

 

 

 

 

 

CH2

N

CH2

 

 

 

 

C

CH2

 

 

O-

O

 

 

 

N

 

 

O-

CH2

CH2

C

 

C

 

 

 

O

 

 

 

 

 

 

 

O-

O

 

 

 

O-

 

 

CH2

C

 

 

 

 

 

O

 

EDTA: Ethylenediamine tetra acetate

 

 

 

B. Chelators

Dimercaprol (i.m.)

 

Deferoxamine

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

 

C

 

H2C

 

 

CH

 

CH2

 

 

 

 

OH

 

 

 

HN

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OO

 

 

 

 

SH SH

 

 

 

 

 

 

 

 

 

 

 

NH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Arsenic, mercury,

 

 

 

O

3+

O

 

 

 

 

O

 

Fe

N

gold ions

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C O

 

 

 

 

 

O C

 

DMPS

 

 

 

 

O

 

 

 

N

 

 

 

 

 

 

CH3

 

 

 

 

 

 

 

3 H+

 

 

 

 

NH2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H C

 

 

CH

 

 

CH

2

 

 

S

 

 

 

O

Na+

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SH SH

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

Dimercaptopropane sulfonate

D-Penicillamine

CH3

*

H3C C CH COOH

HS NH2

β, β -Dimethylcysteine chelation with

Cu2+ and Pb2+

Dissolution of cystine stones: Cysteine-S-S-Cysteine

Inhibition of collagen polymerization

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

310 Antidotes

Reactivators of phosphorylated acetylcholinesterase (AChE). Certain organic phosphoric acid compounds bind with high af n- ity to a serine OH group in the active center of AChE and thus block the hydrolysis of acetylcholine. As a result, the organism is poisoned with its own transmitter substance, acetylcholine. This mechanism operates not only in humans and warm-blooded animals but also in lower animals, ACh having been “invented” early in evolution. Thus, organophosphates enjoy widespread application as insecticides. Time and again, their use has led to human poisoning because these toxicants can enter the body through the intact skin or inhaled air. Depending on the severity, signs of poisoning include excessive parasympathetic tonus, ganglionic blockade, and inhibition of neuromuscular transmission leading to peripheral respiratory paralysis. Specific treatment of the intoxication consists in administration of extremely high doses of atropine and reactivation of acetylcholinesterase with pralidoxime or obidoxime (A).

Unfortunately, the organophosphates have been misused as biological weapons. InWorldWarII,theywerestockpiledonboth sides but not deployed. The ef cacy of the poisonswassubsequently“demonstrated”in smaller local armed conflicts in developing countries. In the present global situation, the fear has arisen that organophosphates may be used by terrorist groups. Thus, understanding the signs of poisoning and the principles of treatment are highly important.

Tolonium chloride (toluidine blue). Browncolored methemoglobin, containing trivalent 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.

Antidotes for cyanide poisoning (B). 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. CNbinds with high af nity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain. 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 sulfurtransferase. As a therapeutic measure, sodium thiosulfate can be given i.v. to promote formation of thiocyanate, which is eliminated inurine. However, this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methemoglobin forming agent 4-dimethylamino- phenol, which rapidly generates trivalent iron from divalent iron in hemoglobin. Competition between methemoglobin and cytochrome oxidase for CNions favors the formation of cyanmethemoglobin. Hydroxycobalamin (= vitamin B12a) is an alternative, very effective antidote because its central cobalt atom binds CNwith high af nity to generate cyanocobalamin (= vitamin B12).

Ferric ferrocyanide (“Berlin blue” [B]) is used to treat poisoning with thallium salts (e.g., in rat poison), 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 (B).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Antidotes and Treatment of Poisonings

311

A. Reactivation of ACh-esterase by an oxime

 

 

 

 

O

Acetylcholine

CH3

H

 

Pralidoxime

O

 

H C C O

CH

CH

N+ CH

N H

 

 

3

 

2

2

3

 

C

 

 

 

 

 

 

CH3

 

H3C

+

 

 

 

 

 

 

 

N

 

 

 

 

 

 

CH3

CH3

 

 

 

 

 

 

 

CH2

CH2

 

 

 

 

 

 

 

O

O

 

 

CH3

CH3

 

 

P

O

 

 

CH2

CH2

 

 

O

H

 

O

O

Paraoxon residue

 

N

 

 

 

C

Aldoxime

 

 

 

 

 

 

 

 

P

O

 

 

H

H3C

+

 

 

N

O

 

 

 

 

O

 

 

 

Serine

ACh-esterase

 

Serine

ACh-esterase

 

 

molecule

 

 

Oxime-phosphonate

 

 

 

 

 

 

formation

 

 

Inhibition of

 

 

 

 

 

 

ACh-esterase

 

Release of

 

 

by paraoxon

 

active center

B. Poisons and antidotes

 

 

 

 

 

 

 

 

SCN-

 

FeIII-Hb

 

 

Substances forming

synthetase

 

Tolonium chloride

 

methemoglobin

 

 

 

 

FeIII4 [FeII(CN)6] 3

e.g.,

NO2

Nitrite

 

 

 

 

(toluidine blue)

H2N

 

Aniline

 

 

 

Tl+ =

 

 

 

 

 

 

 

Thallium

O2N

 

Nitrobenzene

 

 

 

ion

 

 

 

 

Na2S2O3

 

DMAP

 

 

 

FeII-Hb

 

CN-

 

 

 

 

 

 

HCN

 

Tl+

 

 

 

 

 

 

 

FeIII-Hb

 

 

 

 

 

Tl+

 

 

 

 

 

 

 

CH3

 

 

 

 

 

 

 

N

+

NH2

 

 

 

 

 

S

 

 

Vitamin B12

 

H3C

N

Cl

Fe3+

 

 

 

 

CH3

 

 

 

 

 

Tolonium chloride

Arrest of O2

Vitamin B12a

Tl excretion

 

(toluidine blue)

 

utilization

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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