Organophosphates

Function

Nerve Gas

Classification

Common nerve gasses are categorized into 3 groups, as mentioned below.

• G series: The Germans developed the G series during World War II, which includes sarin, woman, and tabun.
• V series: The V series was developed by the British and encompasses VE, VG, VM, VR, and VX nerve gases.
• Novichok: Novichok, which means a "newcomer," was developed in the former Soviet Union during the late 70s and early 80s and introduced a new dimension to nerve agents.

Adverse effects

The adverse effects of nerve gases on the body can be profound.[5] Nerve gas induces overstimulation of muscarinic and nicotinic receptors due to ACh accumulation, thereby leading to seizures, agitation, and centrally induced respiratory arrest at high doses. Peripheral overstimulation of these receptors can result in a cholinergic crisis, marked by excessive sweating, salivation, lacrimation, miosis-induced blurred vision, and respiratory distress due to bronchorrhea and bronchospasm.[6] Chronic exposure to nerve gas, such as sarin, may result in neuroendocrine manifestations,[7][3][8] such as delayed neurotoxicity, chronic neurotoxicity, and endocrine disruption.

Pesticides

The most commonly used organophosphate pesticides include parathion, chlorpyrifos, diazinon, dichlorvos, phosmet, fenitrothion, tetrachlorvinphos, azamethiphos, azinphos-methyl, malathion, and methyl parathion.

Carbamates

Carbamates are another class of insecticides and bear a chemical resemblance to organophosphate pesticides. They are carbamic acid derivatives, leading to the carbamylation of AChE at neuronal synapse levels. The binding of carbamates to AChE is reversible, with an approximate 24-hour duration of action.

History

Pioneers in nerve gas research include 2 French organic chemists—Jean Louis Lassange and Philippe de Clermont [Cobilinschi, C. 2022. DOI: 10.55453/rjmm.2022.125.2.11]. In the early 1930s, German scientist Willy Lange initially described toxidromes associated with nerve gas exposure, characterized by a choking sensation and vision impairment.[9] Exposure of the nervous system to organophosphates can cause these cholinergic effects. German chemist Gerhard Schrader conducted experiments on using these substances as insecticides.[10][9][10]

Before World War II, the Nazis in Germany recognized the military potential of these chemicals, leading to the development of the G series of nerve gases during the war, including sarin, tabun, and soman. Subsequently, the British successfully synthesized the VX nerve gas, surpassing the G series in potency and effectiveness. The United States entered the field of organophosphate synthesis after a few American companies gained access to Gerhard Schrader's research work during the postwar period. These synthesized organophosphates were primarily utilized as insecticides, with parathion and malathion emerging as the first organophosphate pesticides manufactured in the United States.

Nerve gas, a chemical warfare agent, has been used since World War I, including World War II and the Gulf War, and continues to be used up to the present day. Notably, in 2013, nerve gas was utilized during the conflict in Syria.[11][12] During times of peace, one of the most significant instances of nerve gas deployment occurred in 1994 and 1995, when sarin was used for acts of terrorism in Japan.[12]

Mechanism of Action

In 1920, Otto Loewi demonstrated that ACh is a chemical intermediary, transmitting nerve impulses across synapses from one nerve to another.[13] ACh is a neurotransmitter derived from acetyl-coenzyme A (acetyl-CoA). Acetylcholine (ACh) is a neurotransmitter formed from acetyl-CoA, which in turn is produced from glucose and choline through the catalytic action of choline acetyltransferase. ACh is stored within presynaptic membranes in packages, known as vesicles, which are released upon stimulation.

AChE uses a hydrolytic process to degrade the neurotransmitter ACh into choline and acetate, effectively terminating its effect on the muscarinic and nicotinic receptors.[3] Organophosphates can bind to AChE irreversibly and prevent the breakdown of ACh. This "liberation" of ACh results in the overstimulation of both muscarinic and nicotinic receptors, which are widely distributed in the body.

Nicotinic Receptors

Nicotinic receptors are of 2 types—central (neuronal) and peripheral (neuromuscular). Central nicotinic receptors, also known as NN or N2, are located in the central nervous system (CNS). They can also be found in the sympathetic and parasympathetic ganglia of the peripheral nervous system (PNS) and the adrenal medulla. Peripheral nicotinic receptors, or NM or N1, are located at the neuromuscular junctions. The N1 neuromuscular junction can cause fasciculation and muscular weakness, whereas the N2 autonomous nervous system is associated with hypertension and tachycardia.

Muscarinic Receptors

All 5 subtypes of muscarinic receptors, M1 to M5, are distributed throughout the CNS. Postganglionic muscarinic receptors provide parasympathetic innervation to the heart, exocrine glands, and smooth muscles of the internal organs. Sympathetic postganglionic fibers provide innervation to the sweat glands.[14][15]

Stimulation of each specific receptor yields distinct clinical signs and symptoms, as mentioned below.[16]

• M2 receptors in the heart: Hypotension and bradycardia
• M2 and M3 receptors in the eyes: Miosis
• M2 and M3 receptors in the gastrointestinal system: Abdominal cramps, drooling, and salivation
• M2 and M3 receptors in the respiratory system: Bronchospasm, bronchorrhea, and rhinorrhea
• M2 and M3 receptors in the smooth muscles of internal organs: Abdominal cramps and urinary urgency
• M1 to M5 receptors in the CNS: Seizure, anxiety, and agitation

Issues of Concern

Exposure to Organophosphate

Data on exposure to nerve gas and organophosphate pesticides are very limited. Most exposure to organophosphate pesticides occurs in rural areas where extensive use of herbicides, pesticides, and insecticides is prevalent. This exposure can occur either accidentally or intentionally. Organophosphate exposure can be via food products such as wheat, flour, and cooking oil. In addition, ant and roach sprays might also be a potential source of exposure. The exposure routes include inhalation, direct contact, or ingestion.

Approximately 3 million people globally are exposed to organophosphates, resulting in around 300,000 fatalities. In the United States, about 8000 cases of organophosphate exposure are reported, with very few resulting in death. Since 2013, stricter government regulations have been implemented for the sale of organophosphates. The Geneva Convention of 1925 classified the sale of nerve gas as a war crime. The most recent extensive use of nerve gas is documented in the ongoing conflict in Syria.

Clinical Significance

Although organophosphates have potential benefits as pesticides, their utilization carries inherent risks. As regulations governing the use of organophosphates in this industry have become more stringent, exposures and toxicity have declined, but they have not been completely eradicated. In addition, the threat of organophosphates being utilized as chemical warfare agents persists, making identifying toxicity a crucial concern for the healthcare system. Given their substantial health hazards, healthcare practitioners should be familiar with recognizing the signs and symptoms of toxic exposure and the corresponding treatment protocols.

Adverse Effects of Organophosphate

The adverse effects of exposure to organophosphate pesticides can be categorized based on the duration of exposure, as mentioned below.

• Acute effects: Occur within minutes to 24 hours
• Subacute effects: Occur between 24 hours and 2 weeks
• Chronic effects: Extend beyond weeks to years

The primary consequence of acute organophosphate exposure is poisoning, as organophosphate pesticides can enter the body through the skin, integumentary system, respiratory system via inhalation, or direct ingestion. The most rapid clinical manifestation of organophosphate pesticides is seen via inhalation. Chronic exposure to organophosphates can induce the same effects as those observed in acute exposure. However, in cases of chronic exposure, individuals may also experience memory loss, speech impairment, lack of coordination, and impaired judgment. Chronic exposure to organophosphates can also cause flu-like symptoms, including nausea, vomiting, malaise, and weakness, as well as it has also been associated with peripheral polyneuropathy.

Exposure to certain organophosphates has been associated with a potential risk of cancer. According to a report from the International Agency for Research on Cancer, pesticides such as malathion, diazinon, tetrachlorvinphos, and parathion are categorized as possible carcinogens. The hallmark of exposure to either organophosphate pesticides or nerve gas is the ability of these substances to inhibit the action of AChE—the enzyme responsible for the breakdown of ACh. Organophosphate pesticides form irreversible bonds with AChE, affecting its function in the plasma, red blood cells, and at synapses in both the PNS and CNS. The buildup of ACh leads to the overstimulation of both nicotinic and muscarinic receptors.[17][18]

Complications Related to Organophosphate Exposure

The complications arising from nerve gas or organophosphate pesticide exposure are system-specific, as they are linked to the affected systems. The clinical manifestations of these complications result from the overstimulation of both nicotinic and muscarinic receptors.[19] Organophosphates predominantly exhibit their clinical presentation in the respiratory, gastrointestinal, CNS, cardiovascular, and renal systems.

Respiratory System

In the respiratory system, exposure to organophosphate pesticides may lead to complications such as aspiration pneumonia resulting from excessive salivation, progressive respiratory failure stemming from weakened respiratory muscles, notably the diaphragm, severe bronchospasm, and noncardiogenic pulmonary edema.[18]

Cardiovascular System

In the respiratory system, exposure to organophosphate pesticides may lead to complications such as arrhythmias, especially ventricular tachycardia, bradycardia, hypertension, hypotension, and prolonged QTc.[20][21]

Central Nervous System

Exposure to organophosphate pesticides in the CNS may lead to complications such as psychosis, seizure, change in mental status, and hallucination.[22][23]

Gastrointestinal and Metabolic Systems 

Exposure to organophosphate pesticides can result in various complications within the gastrointestinal and metabolic systems, including electrolyte imbalances due to fluid and electrolyte losses from the gastrointestinal tract,[24] pancreatitis, hyperglycemia, and reduced bicarbonate levels.[5][25]  

Renal System

Exposure to organophosphate pesticides in the renal system can cause acute kidney injury.[26] Limited case reports have documented acute kidney injury linked to organophosphate pesticide exposure, typically managed through conservative approaches or hemoperfusion treatment.[27][26][28]

Treatment

All healthcare team members must adhere to personal protective equipment protocols, which include wearing gowns, gloves, and eye protection. These precautions are crucial due to the potential for patient contamination and exposure, primarily through bodily fluids such as emesis and diarrhea. Although limited evidence supports a substantial risk of secondary poisoning when universal precautions are followed, vigilance remains essential.[29] The initial step of managing exposure in patients involves decontamination. All clothing should be promptly removed and securely bagged. The patient should be bathed with soap and water, ensuring that this process does not hinder resuscitation efforts for a critically ill patient. 

Antidotal therapy with atropine, a muscarinic antagonist, competes with ACh and effectively reverses muscarinic signs of toxicity. The initial dose for adults is 2 to 5 mg, administered intravenously (IV), and 0.05 mg/kg IV for children until they reach the adult dose. If the patient does not respond to the treatment, the dose can be doubled every 3 to 5 minutes until respiratory secretions clear and bronchoconstriction subsides. Notably, atropine does not reverse nicotinic symptoms such as muscle fasciculations and weakness.

Pralidoxime (2-PAM) is recommended as an AChE activator, with the potential to prevent the irreversible inactivation of the enzyme. The process of aging, in which the AChE enzyme is irreversibly inhibited, is a time-sensitive phenomenon that depends on the specific organophosphate agent. Administering 2-PAM before this aging process theoretically restores the enzyme and reverses toxicity.

Pralidoxime is administered as a loading dose of 30 mg/kg over 30 minutes, followed by a continuous infusion of 8 mg/kg/h for a maximum of 7 days. Caution should be exercised to avoid rapid administration, potentially resulting in cardiac arrest. To mitigate any exacerbation of muscarinic symptoms, it is advisable to administer atropine before pralidoxime. Controversy surrounds the efficacy of 2-PAM, with a study indicating no clear benefit and potential harm.[4] Pending further research, the World Health Organization advises the combined use of both atropine and pralidoxime in treating organophosphate toxicity. 

Enhancing Healthcare Team Outcomes

Exposure to organophosphates can pose a life-threatening risk. To optimize patient outcomes and ensure patient safety, the early recognition of toxidromes associated with organophosphate poisoning is imperative. Swift coordination and transfer of care from the emergency room to the intensive care unit should be facilitated.

An interprofessional approach involving the active participation of all healthcare providers, including clinicians, specialists, particularly toxicologists, mid-level practitioners, nurses, and pharmacists, is pivotal for achieving a favorable clinical outcome. A valuable resource to consider is the Poison Control Center, accessible nationwide in the United States at 1-800-222-1222.