In this article we will discuss about:- 1. Antidotes and their Mechanisms of Action 2. Antidotal Procedures (Pathways and Measures).
Antidotes and their Mechanisms of Action:
Antidote to poisons may be chemical, physiological or pharmacological in nature. It counteracts the principal effects of a given poison. Yet a very few direct antidotes are known. The number is increasing with increasing knowledge of the pharmacology and biochemistry of poisons.
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A few of the antidotes along with their mechanisms of action are summarised below:
Mechanism I:
BAL, or dimercaprol, is often useful as an antidote for poisoning by lead, arsenic, and mercury. It is most effective against arsenic. BAL exhibits its greatest efficacy when it is administered soon after the exposure to the toxicant. Once poisoning is well-established, BAL has little value in any poisoning.
Calcium ethylene diamine tetraacetate (calcium EDTA) has usefulness as a chelating agent in lead poisoning.
Oximes, such as protopam chloride, 2-PAM, and DAM are useful in the treatment of organophosphorus compounds- Protopam and other members of this group act to reverse cholinesterase inhibition and are, therefore, specific antidotes. They do require some time to act; therefore, they should be used in conjunction with atropine.
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Chemicals like cystine and monoacetin provide protection against poisoning because they inhibit the metabolic oxidation of the compounds to more toxic ones from less toxic precursors.
There is still another group of antidotes which specifically accelerate the excretion of poisons, for example calcium salts promote excretion of strontium and radium.
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Another group of antidotes include chemicals which compete with poisons for essential receptors, for example, nalorphin competes with morphine antidote for the receptor sites.
Vitamin K is useful in any poisoning involving a prolongation of clotting time due to a prothrombin deficiency, such as that due to warfarin.
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Atropine and antihistamines act by blocking receptors for the agents which are responsible for the toxic effects e.g., organophosphorus insecticides and histamines.
Methylene blue can be used to produce methemoglobinemia in cyanide poisoning, and, oddly enough, it can be used to reduce methemoglobinemia in nitrite and chlorate poisoning. The activity of methylene blue may be enhanced by the simultaneous use of ascorbic acid to reduce methemoglobinemia.
It may be pertinent to mention that some of the antidotes have toxic properties of their own and can complicate the clinical picture as to make it impossible to save the patient. Thus, toxicology has assumed a great practical importance in search of superior antidotes.
Antidotal Procedures (Pathways and Measures):
Antidotal therapy, in fact, is chiefly based upon the following three aspects:
1. Procedures which diminish absorption/ translocation of poisons
2. Procedures which enhance termination of action of poisons, and
3. Procedures which elevate the threshold level of toxicity.
1. Procedures Applied to Diminish Absorption/Translocation of Poisons:
By this procedure efforts are made to prevent absorption/translocation of poisons into the blood and to eliminate them from their sites of contact especially in the case of contact or ingested poisons.
In case of contact poisons, viz., acids and pesticides, the affected part is washed thoroughly with warm water to eradicate the poison molecules. The wounds are then subjected to healing agents.
In case of ingested poisons, elimination of poison from the sufferer’s (victim) gut is done by the following methods:
(i) By the use of emetics which induce vomiting
(ii) By the use of gastric lavage
(iii) By the use of cathartics
(iv) By the use of chemicals.
(i) By the Use of Emetics (Vomiting-Inducing Agents):
Vomiting may be induced mechanically also, viz., by tickling the back of the pharynx in case of conscious patients.
Chemically, vomiting may be induced by using the following:
Ipecac grain or syrup, if available, may be given to induce emesis. The conventional emetic dose for children is 15 ml and for adolescent and adults is 30 ml — followed by 200-250 ml of water.
One teaspoonful of dry mustard is dissolved in one glass of lukewarm water. One-fourth of this mixture is given to the victim followed by a glass of warm water. The procedure is repeated after every 1-2 minute which induces vomiting.
Excess table salt dissolved in lukewarm water in large quantities induces vomiting.
A mixture of ZnSO4 and CuSO4 in 1% solution may induce vomiting.
Apomorphine hydrochloride has been proved a potent vomiting-inducing agent. The major disadvantage of apomorphine hydrochloride is its inactivity by oral intake. It is, therefore, generally given through parenteral routes. Subcutaneous injection of this drug in 0.006 g concentration produces vomiting in few minutes.
(ii) By the Use of Gastric Lavage:
When vomiting fails after emetic treatment and, sometimes, even after vomiting, the unabsorbed poison is physically removed from the stomach by gastric lavage. This method is applied by physicians in hospitals. In this method a wide tube is applied to wash the stomach and suck out the stomach contents with fluid.
(iii) By the Use of Cathartics:
The use of cathartics hasten the passage of poisons through the G.I. tract. After about one hour of the ingestion of the poison — and in case of decreased bowel motility which slows down the passage of ingested poisons through the G.I. tract — certain oil or saline cathartics enhance the passage of bowel, thereby the poisons. Thus, the deleterious effects of poisons is diminished. In general, saline cathartics are more effective than the oil cathartics.
In addition to physical removal of poisons from the stomach, their virtual removal may be accomplished by the use of chemical substances that effectively react with, firmly bind with, or adsorb, those poisons.
Such chemical substances may be grouped into three:
(a) Neutralisers
(b) Chelating agents, and
(c) Adsorbents.
When the nature of the metal poison is unknown, universal antidote may be applied to the victim and, if the chemical nature of the poison is known, specific chemical substances may be used to neutralise the poisonous effect of the toxicant as given below:
The chemical substances which form more stable complex with metallic toxicants — thereby affecting their absorption and ultimately reduce their toxicity — are called chelating agents. In brief, chelating agents are used to reduce the absorption and translocation of metallic poisons/toxicants.
Some common chelating agents are:
i. British Anti-Lewistic (BAL) or Dimercaprol:
It is applied in inactivating the compounds of arsenic, mercury, antimony, bismuth, chromium, cobalt, copper, nickel, zinc and thallium. Dimercaprol-metal complexes are relatively nontoxic and are subsequently excreted in the urine or feces. Dimercaprol contains thio (-SH) group.
It chelates with lead.
3. Ethyl Diamine Tetra Acetate (EDTA):
It is a commonly used chelating agent and forms stable and relatively non-toxic complexes with metallic compounds of As, Pb, Hg, Fe, Ca and Co. The complexes are easily excreted by the kidney along with urine.
It is used in iron poisoning by reducing its absorption from gut. It converts iron into inactive, non-toxic water soluble form and is eliminated in urine.
This chelating agent is especially used in lead poisoning.
It forms stable complexes with Cu, Pb and Hg and thus facilitates the excretion of these metals through the kidney. It is usually recommended to be ingested orally and thus has advantage over Na-Ca EDTA.
Activated charcoal is the commonly used adsorbent to diminish absorption and translocation of toxicants. If activated charcoal is not available, several other adsorbents may be used. For instance, a highly adsorptive clay known as montmorillonite is more palatable but inferior than powdered charcoal.
2. Procedures Applied to Enhance Termination of Action of Poisons:
The procedures employed to enhance the termination of action of poisons may broadly be divided into two groups:
(a) Physical procedures, and
(b) Chemical procedures.
Enhancing termination of action of poisons, the commonly applied physical procedures include:
(i) Diuresis,
(ii) Dialysis, and
(iii) Hemoperfusion.
Ion-trapping and increased urine flow are the two basic aspects involved in diuresis. Once the poison is ionized, then reabsorption from the renal tubules is impaired, ultimately resulting in more elimination in the urine. For certain poisons, forced diuresis by the use of fluids and diuretics may enhance the rate of their elimination. Commonly used diuretic drugs are urea, mannitol and furosomatidedide. These are actually osmotic diuretics and prove more effective than water diuretics. These drugs inhibit ADH release, reduce water reabsorption and raise urine output.
This technique is based on the passage of poisons through a semipermeable dialysis membrane and ultimate removal of poisons in dialysate against the concentration gradient. Since the dialysis involves movement of poison molecules, it is partly dependent on the molecular weight of the poisonous compounds which are highly serum- protein bound and, having large volume of distribution, are either not dialyzable or poorly removed by this method. The lipid dialysis is recommended for the removal of lipophilic poisons but, owing to their large volume of distribution, only a small percentage is removed even after 4-6 hours of dialysis.
It is a recent technique. The blood is passed through a column of charcoal or adsorbent resin for the removal of extracorporeal poisons. The poisons occupying large volume of distribution are poorly removed by this technique. However, some poisons are better removed because of absorptive capacity of the column.
The poisons (toxicants) exert deleterious effects on account of their interaction with suitable receptors at the specific sites. The removal of poison from the effector sites before their interaction with receptors terminates their action. The chelates have been proved effective for establishing inactive complexes which detoxify especially the metallic poisons. Not only this, the chelates also promote the elimination of poisons in urine. Chelates also raise the water- solubility of the poisons.
3. Procedures Applied to Elevate Threshold Level of Toxicity:
A certain level of concentration of a poison exerts deleterious effect. This concentration of the poison is termed the threshold concentration and toxicity exerted is termed threshold level of toxicity.
Actually, antidotes increase threshold of toxicity without affecting the concentration of poisons at the effector sites by the following mechanisms:
(i) They directly antagonize the system affected by the poisons and enhance a physiologically opposing system, and
(ii) They block the response exerted by the poisons on some physiological mechanism.
Antidotal procedures—where the toxicity levels of the poisons are elevated by specific antidotes — are termed elevating threshold level of toxicity of poisons.
Various physiological antidotes are used to elevate threshold level of toxicity.
Some important physiological antidotes are described below which elevate threshold level of toxicity or produce opposite physiological function to that of poison molecule:
(I) Atropine for Morphine Poisoning:
Morphine depresses respiratory center, initiates unconsciousness and death. As a physiological antidote, atropine stimulates respiratory center and thus prevents unconsciousness.
(II) Atropine for Pilocarpine Poisoning:
Pilocarpine produces miosis, i.e., contraction of the eye. As a physiological antidote, atropine produces mydriasis, i.e., dilation and thus inhibits miosis.
(III) Coramine, Caffine, Cardiazole and Strychnine for Morphine Poisoning:
Morphine depresses respiratory centre, initiates unconsciousness and death.
The mentioned three physiological antidotes raise the sensitivity of the respiratory center and bring back normal blood pH.
(IV) Naloxone for Morphine Poisoning:
Naloxone exerts same effects as atropine.
(V) Nalorphine for Morphine Poisoning:
As morphine exerts Cheyne-Stokes respiration, the nalorphine given intravenously prevents deleterious effects of morphine by stimulating respiratory center.
(VI) Thiamine Hydrochloride for Ethyl Alcohol Poisoning:
Thiamine hydrochloride diminishes the toxicity of ethyl alcohol and helps its excretion in urine.
(VII) Calcium for Magnesium Poisoning:
Magnesium has been known to cause depression of CNS and paralysis of motor neurons. Calcium as physiological antidote exerts opposite effect and reduces magnesium poisoning.
(VIII) Calcium for Lead Poisoning:
Lead, after deposition in bones, causes damage to bone. Calcium intake in equal doses helps in repairing bones.
(IX) Sodium Thiosulphate and Dicobalt EDTA for Cyanide Poisoning:
Cyanide exerts toxicity to cellular respiration. The physiological antidotes named above produce stimulation of cellular respiratory system.
(X) Niacinamide for Vacor (Rodenticide) Poisoning:
Vacor, a popular rodenticide, acts on NAD and obstructs their functions. Niacinamide counters the destructed NAD and helps in formation of normal NAD.
(XI) Atropine and Phenobarbital for BHC Poisoning:
BHC, a widespread organochlorine insecticide, poisons the nervous system and raises the B.P. Atropine prevents nerve poisoning and phenobarbital lowers the B.P. These two thus act as physiological antidotes.
(XII) Pyridoxine Aldosine Methiodide (PAM) for Organophosphorus Insecticide Poisoning:
Organophosphorus insecticides actually block action of cholinesterase enzyme and thus raise action of acetylcholine that produces excessive muscular activity. PAM as a physiological antidote inhibits release of acetylcholine and prevents muscular convulsions.
(XIII) Inhalation of O2 with 7% CO2 for Respiratory Poisons like CO and HCN:
CO and HCN convert hemoglobin into methemoglobin and inhibit normal gaseous transport. O2 with 7% CO2, when inhaled, stimulates respiratory center of brain and raises the rate of respiration. In this way it lowers the toxicity of CO and HCN.
(XIV) Picrotoxin for Barbiturate Poisoning:
Barbiturate acts as a muscle poison by depressing muscular activity. Picrotoxin produces strong muscular convulsions.