Antidotes in Clinical Toxicology-Critical Review

Abstract

Poisoning and overdose are very important aspects in medicine and toxicology. Chemical weapons pose a threat to civilians, and emergency medicine principles must be followed when dealing with patients who have been poisoned or overdosed. Antidotes have been used for centuries and modern research has led to the development of new antidotes that can accelerate the elimination of toxins from the body. Although some antidotes have become less relevant due to modern intensive care techniques, they can still save lives or reduce the severity of toxicity. The availability of antidotes is crucial, especially in developing countries where intensive care facilities may be limited. This article aims to provide information on specific antidotes, their recommended uses, and potential risks and new uses. In the case of poisoning, supportive therapies are most often used; however, in many cases, the administration of an appropriate antidote saves the patient's life. In this review, we reviewed the literature on selected antidotes used in the treatment of poisonings. We also characterised the antidotes (bio)chemically. We described the cases in which they are used together with the dosage recommendations. We also analysed the mechanisms of action. In addition, we described alternative methods of using a given substance as a drug, an example of which is N-acetylcysteine, which can be used in the treatment of COVID-19. This article was written as part of the implementation of the project of the Polish Ministry of Education and Science, "Toxicovigilance, poisoning prevention, and first aid in poisoning with xenobiotics of current clinical importance in Poland", grant number SKN/SP/570184/2023.

Keywords: antidotes; critical care; toxicology; toxin therapy.

Figure 1

Ethanol prevents methanol from bonding with ADH, the metabolism of which leads to more toxic metabolites.

Figure 2

Scheme of calcium homeostasis between bones, blood, small intestine, kidneys and thyroid gland (based on [80]). Parathyroid hormone (PTH) raises blood calcium levels by activating calcium uptake in the kidneys and releasing it from the bones. Additionally, PTH stimulates the production of 1,25-dihydroxyvitamin D3 in kidney cells. This vitamin regulates the absorption of calcium in the intestines, its reabsorption in the kidneys, and its release from the bones.

Figure 3

Mechanism of action of dantrolene. Dantrolene is a unique muscle relaxant that targets ryanodine receptors (RYR), which are responsible for intracellular calcium release in muscle cells. By binding to these receptors, it reduces excessive calcium release from the sarcoplasmic reticulum, leading to muscle relaxation and preventing muscle contractions.

Figure 4

The idea of the action of flumazenil as antidote. 1. Benzodiazepine poisoning—attachment of benzodiazepine to the GABA receptor—centripetal chloride influx. 2. Administration of flumazenil as an antidote. 3. Flumazenil competes with benzodiazepine for the GABA receptor binding site. 4. Attachment of flumazenil to the GABA receptor—reduction of afferent chloride influx. 5. Ending of the flumazenil effect—if the initial dose and concentration of benzodiazepines are high, due to the longer duration of action of benzodiazepines, resedation may occur and the entire cycle is repeated until the desired clinical effect is obtained.

Figure 5

Glucagon exerts its inotropic and chronotropic cardiac effects by activating adenylate cyclase and increasing cAMP levels independently, bypassing β-receptors.

Figure 6

Chemical structure of insulin.

Figure 7

“L-carnitine shuttle” (based on [131]). VPA is activated in the cytosol, forming valproyl-CoA with reduced acetyl-CoA-SH. It then crosses the outer mitochondrial membrane as valproylcarnitine. Inside the mitochondrial matrix, valproylcarnitine is converted back to valproyl-CoA by PCT2 for slow β-oxidation. Carnitine prevents valproyl-CoA accumulation.

Figure 8

Mechanism of action of methylene blue. Methylene blue, in the presence of NADPH, converts to leucomethylene blue by obtaining electrons from NADH via complex I in the electron transport chain (ETC) within the inner mitochondrial membrane. Leucomethylene blue reduces methaemoglobin to haemoglobin.

Figure 9

Mechanism of action naloxone (based on Straus, M. et al. [156]). Naloxone binds to the mu-receptor but does not activate the receptor response like an agonist. Additionally, it blocks the binding of an agonist that would activate the receptor. This makes naloxone an effective antidote for opioid overdose due to its pharmacological properties.

Figure 10

Chemical structure of starch.

Figure 11

Chemical structure of amylose.

Figure 12

Chemical structure of amylopectin.