In this article we will discuss about:- 1. Meaning of Antidotes 2. Classification of Antagonists 3. Pharmacological Assessments of Certain Antidote Actions.
Meaning of Antidotes:
The chemical compounds which produce deleterious effects on living tissue of animals are termed ‘poisons’. The effect of most poisons depends on the quantity consumed and the age and physical condition of animals.
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An antidote is strictly defined as ‘a remedy for counteracting a poison’ or substances which prevent action of poisons are called ‘antidotes’, and procedures applied to reduce toxicity in acute poisoning are termed antidotal procedures.
Toxicity of a chemical in an animal may also be either increased or decreased by simultaneous or consecutive exposure to another chemical. If this combined effect is equal to the sum of the effect of each substance given alone, the interaction is considered to be additive, e.g., combinations of most organphosphorus pesticides on cholinesterase activity.
If the combined effect is greater than the sum, the interaction is considered to be synergistic, e.g., CCl4 and ethanol on the liver. The term ‘potentiation’ is used to describe the situation in which the toxicity of substances on an organ is markedly increased by another substance which itself has no effect on that organ. For example, Isopropanol has no effect on the liver, but it can considerably increase the hepatotoxicity in presence of CCl4.
The exposure of a chemical to an organism may thus reduce the toxicity of another and the chemical reaction thus produces a less toxic product. This phenomenon is known as chemical antagonism, e.g., Chelation of heavy metals by dimercaprol.
In toxicology, the poison or toxicant may also be referred to as agonist and its antidote as ‘antagonist’. In practice, an antidote may be considered a physiological agent which reverses or prevents the development of symptoms and signs of poisoning. Such antidote may either be chemical or pharmacological or physiological in nature.
Classification of Antagonists:
Based on the mechanism of action, the antagonists are classified as:
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These agents compete directly with agonist for receptor sites and if sufficient concentration is reached, the agonist is displaced from the receptor site and its actions are terminated, e.g.:
(i) Naloxone for opiate (sleep drug) poisoning
(ii) O2 for CO2 intoxications
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(iii) Naloxone for morphine and other related narcotics
(iv) Edrophonium for neuromuscular exciting agents, viz., curare.
Therefore, competitive antagonism exists only when the agonist and antagonist act on the same receptor.
2. Non-Competitive Antagonist:
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These antidotes act by producing a physiologic effect which competes with that produced by the agonist. An example of this mechanism is use of atropine for treating organophosphate or carbamate insecticide poisoning. The organophosphate or carbamate insecticide inhibit the enzyme acetylcholinesterase at the nerve ending and the result is an elevated level of acetylcholine producing excessive stimulations.
Atropine competes with the effects of the elevated level of acetylcholine, but not directly with insecticides. Other example of non-competitive antagonist is the use of haloalkylamine for cyclopropane, a serious toxic agent. Non-competitive antidotes are also termed physiological antidotes.
These antidotes, in fact, neutralise the reactions of agonists or poisons or toxicants, e.g., administration of sodium thiosulphate for cyanide poisoning results in neutralization of the cyanide ion (CN–) by forming a non-toxic compound, sodium thiocyantae. Another example of this type is AgNO3 (silver nitrate) as agonist and NaCl (Sodium chloride) as antagonist or antidote.
The reaction is:
The silver chloride so formed in the form of precipitate is removed.
The third example of this class is Trivalent organic arsenicals as agonist and Ferric (Fe3+) oxide (hydrate) as antagonist. Arsenic is found in two forms — trivalent and pentavalent. Former is more toxic than the latter.
When sufficient amount of ethanol (ethyl alcohol) is administered to the person poisoned with methanol (methyl alcohol) or ethylene glycol, the ethanol blocks the metabolism of the methanol or ethylene glycol. Thus serious toxicity — which results from the formation of toxic metabolites — is prevented. In this way ethyl alcohol acts as an antidote (antagonist) for methyl alcohol (the agonist or poison).
5. Oxidation-Reduction Reactions:
The person with methemoglobinemia have a significant portion of iron (Fe3+) in their circulating hemoglobin. In this state, the oxygen-carrying capacity of the red blood cells is decreased. Methylene blue reduces the methemoglobin in normal hemoglobin and, therefore, reverses the toxic effects.
The chelating-agents with multiple free valancies bind metal molecules, forming a stable complex which is excreted from the body and thus prevent the toxicity.
The most commonly used chelating agents are:
(i) Deferoxamine for iron poisoning
(ii) Calcium EDTA (Ethylene-diamine-tetra- acetic acid) for lead and zinc poisoning, and
(iii) Dimercaprol (BAL) (British-anti-Lewistic) for arsenic poisoning.
7. Mechanical Agents:
These antidotes check the further translocation of poisons from the portal entry.
Example 1:
In case of poisoning by strychnine (an alkaloid poison), finely powdered activated charcoal in 150 mg/g dosage, absorbs the poison molecules within its pores. Powdered charcoal is very effective as its one gm absorbs 5,000 mg of strychnine.
Example 2:
Intake of fats, egg-albumen etc. forms a thick coating over gastrointestinal mucosa and prevents the translocation of the toxicants or poisons into the blood. Thus, by using mechanical antidotes, the systemic as well as the local toxicity of poisons is prevented. These antidotes are chiefly used in the cases of irritants poisoning.
8. Universal Antidote:
The chemical substances which are applied over unknown toxicities or poisoning are known as universal antidotes. For example — two parts of burned powdered toast, one part of milk of magnesia and one part of strong tea may be applied in any unknown poisoning.
The burned powdered toast is a source of carbon, the milk of magnesia is a source of magnesium oxide and the strong tea is a source of tannic acid. The carbon absorbs poisons, magnesium oxide has a soothing effect on mucus membrane of the stomach and a laxative action that tends to neutralise poisons, and tannic acid tends to neutralise caustic alkaline substances, if present in poison.
9. Other Examples:
N-Acetylcysteine is used as an antidote for acetaminophen acting as agonist and diphenylhydramine for treating phenothiazine-induced adverse reactions.
Certain other practices should also be adopted to minimise the toxic effects in the body, based on the principles of antidotes. First, the poison must be diluted. This may be accomplished by letting the sufferer drink as much water as possible. A large volume of water also promotes vomiting. Next, the stomach should be emptied. This is usually done by stimulating the vomiting reflex.
Warm salt water, soapy water of substances such as tartar or mustard often induce vomiting. If this fails, the sufferer may gag himself into vomiting by holding his finger to the base of the tongue. After the sufferer has been induced to vomit, it is useful to give milk or universal antidote.
Another way in the treatment of poisons is to eliminate it from the systemic circulation. However, as with ethyl alcohol, methyl alcohol, ether, benzene and acetone, the elimination may be aided by breathing deeply in order to expel the substance with the exhaled air. Drinking as much fluid as possible will aid in excretion through kidneys. The use of sodium sulphate and sodium phosphate may aid in the elimination of some poisons from blood by way of the liver, bile and digestive system.
If sleep-producing drugs — such as opium or morphine — have been taken, it is best to keep the patient awake by giving strong coffee. In instance of strychnine poisoning, any stimulant should be avoided and the sufferer should be kept under doctor’s supervision as quiet as possible.
Antidotes to poison may be physiological, chemical or pharmacological in nature.
To date, very few direct antidotes are known. Their number is increasing with increasing knowledge of the pharmacology and biochemistry of poisons.
Pharmacological Assessments of Certain Antidote Actions:
1. Antidote for Halogens, Cyanides and Hyrocyanic Acid:
The sodium thiosulphate (Na2S2O3) is employed as an antidote in poisoning by halogens, cyanide compounds and hydrocyanic acid. The use of sodium thiosulphate is based on its property of evolving sulphur.
The reaction of thiosulphate against potassium cyanide poisoning may be expressed as:
The formed potassium thiocyanate is much less poisonous than potassium cyanide. Therefore, sodium thiosulphate should be taken as first aid in poisoning by hydrocyanic acid or its salts.
Sodium nitrite is also used as an antidote in cyanide poisoning. In this case it is introduced intravenously in form of 1% solution up to 5 ml.
Sodium thiosulphate with HCl acid has been found to heal itching.
The formed finely dispersed sulphur and the SO2 – that has a high parasiticidal effect – stops the itching:
Sodium thiosulphate can also be used as an antidote in poisoning by arsenic, mercury and lead. It is administered intravenously in allergic diseases, in the form of a 30% aqueous solution.
All the arsenic compounds are highly poisonous. Arsenic poisoning results in sharp collapse, muscular weakness and, in the long run, paralysis and death. In acute arsenic poisoning apomorphine, an alkaoid, is given subcutaneously as an emetic and gastric lavage is used. A preparation called arsenic antidote (Antidotum Arsenic, a mixture of burnt magnesia and iron (III) sulphate) can be employed. These substances are kept separately in the pharmacy and are poured together when needed.
The reaction of these two substances form iron (III) hydroxide (Fe(OH)3) and magnesium sulphate (MgSO4):
The freshly precipitated iron hydroxide is, in fact, the antidote, because with arsenic it forms iron (III) arsenite (FeAsO3), a compound insoluble in the gastric juice. Moreover, the freshly precipitated iron hydroxide adsorbs arsenic compounds, while the magnesium sulphate formed in the reaction acts as a purgative and facilitates the excretion of the poison from the body. This is why it is recommended to prepare this antidotes extempore because only freshly precipitated iron hydroxide has adsorbing properties.
A more effective method against arsenic poisoning is the use of a supersaturated alkaline solution of hydrogen sulphide in water with the addition of magnesium sulphate. The preparation is dispensed in 100 ml bottles. Its composition (in grams) is H2S 0.5 – 0.7, NaOH 0.1, NaHCO3 1.25, and MgSO4 0.38. The mechanism of action of this antidote consists in that the reagent forms insoluble compounds with arsenic and, therefore, precipitates are not absorbed.
In acute arsenic poisoning, the administration of this antidote is preceded by giving 3 gm of citric acid or 4 gm of tartaric acid or 1.5 tablespoons of vinegar essence diluted in 300 ml of water. In this case, it is recommended to drink albumin water.
Soluble mercury salts are very poisonous. The first sign of mercury poisoning is a sharp metallic taste in mouth, pain in the stomach, vomiting loose bowels (diarrhea) and cardiac depression. Persons suffering from kidney ailments are especially sensitive to mercury preparations.
First aid in mercury poisoning consists of in taking of a metal antidote (Antidotum metallosum) or a suspension of activated carbon. One must simultaneously take albumin water, milk, or burnt magnesia with water. Sodium chloride and food product containing it must not be used because this can enhance the poisoning owing to the formation of another soluble and poisonous mercury dichloride.
Another antidote used in mercury salt poisoning is sodium calcium edetate, also known as tetacin calcium, a white crystalline powder. In its chemical structure tetacin calcium is a cyclic compound in which the calcium can be substituted by ions of heavy metals with the formation of water-soluble complexes having a low toxicity.
The complexes are rapidly excreted with the urine, which underlies the use of this preparation as an antidote in poisoning by heavy metals salts:
