Contents
Overview
Organophosphates (OPs) are a class of compounds that irreversibly inhibit acetylcholinesterase (AChE). They are used widely as agricultural pesticides and form the basis of chemical nerve agents. Poisoning is common in low- and middle-income countries — a major cause of death in South and South-East Asia from intentional self-poisoning. In the UK, occupational and accidental agricultural exposures occur, and nerve agent attacks represent an extreme version of the same mechanism. Death is from respiratory failure — bronchospasm, bronchorrhoea, and respiratory muscle paralysis.
Mechanism
OPs phosphorylate the serine residue at the active site of AChE, rendering it permanently inactive. AChE normally cleaves acetylcholine (ACh) at the synaptic cleft, terminating cholinergic transmission. Its inhibition causes ACh to accumulate at:
- Muscarinic synapses: autonomic effector organs (smooth muscle, glands, cardiac conduction)
- Nicotinic synapses: neuromuscular junction (skeletal muscle); sympathetic ganglia; adrenal medulla
- Central synapses: brain and spinal cord
Ageing: The phosphorylated AChE–OP bond spontaneously loses a side chain over time — a process called ageing — making the bond permanent and irreversible even by oximes. The rate of ageing varies by OP compound: soman ages in minutes; most agricultural OPs age over hours. The time window for pralidoxime to be effective is therefore narrow.
Clinical Features
The cholinergic toxidrome combines muscarinic, nicotinic, and CNS effects.
Muscarinic Effects (DUMBELS)
| Feature | Detail |
|---|---|
| Defecation/Diarrhoea | Hypermotility, faecal incontinence |
| Urination | Urinary incontinence |
| Miosis | Bilateral, often pinpoint — highly characteristic |
| Bradycardia / Bronchospasm / Bronchorrhoea | The lethal triad — bronchospasm and excessive secretions cause respiratory failure |
| Emesis | Nausea and vomiting |
| Lacrimation | Excessive tearing |
| Salivation / Sweating | Profuse |
Nicotinic Effects
- Fasciculations (muscle fasciculations are highly characteristic — often visible at the face, forearms, and chest)
- Muscle weakness progressing to flaccid paralysis
- Respiratory muscle paralysis (diaphragm and intercostals)
- Tachycardia (nicotinic stimulation of sympathetic ganglia may override muscarinic bradycardia)
- Hypertension
CNS Effects
- Anxiety, agitation, confusion
- Seizures (ACh accumulation in the brain causes excessive neuronal excitation)
- Loss of consciousness, coma
- Central respiratory failure (in addition to peripheral respiratory muscle paralysis)
The combination of bronchospasm, bronchorrhoea, and muscle paralysis makes respiratory failure the dominant cause of death.
Diagnosis
Diagnosis is primarily clinical — the cholinergic toxidrome in the context of potential exposure.
RBC cholinesterase (erythrocyte AChE): The most reliable biomarker. Reflects true synaptic AChE inhibition. Activity <50% of normal confirms significant poisoning; <20% correlates with severe toxicity.
Plasma cholinesterase (pseudocholinesterase, butyrylcholinesterase): A different enzyme, not the synaptic target of OPs, but also inhibited by OPs and falls more rapidly. Useful for screening but less specific; affected by liver disease, malnutrition, pregnancy, genetic variants.
Management
Decontamination
Skin and clothing contamination presents a risk to staff. All clothing must be removed (reduces dermal exposure by 80%) and the skin washed with soap and water. Staff must wear gloves and gowns during decontamination — OP compounds are absorbed through intact skin and can cause secondary poisoning in rescuers.
Oral ingestion: activated charcoal (1 g/kg) within 1–2 hours if airway is protected and there is no vomiting. NG administration may be necessary. Do not induce vomiting (aspiration risk; may worsen absorption).
Airway and Respiratory Support
Early intubation is required for any patient with reduced consciousness, respiratory failure, or inability to protect the airway from bronchorrhoea. Airway management may be complicated by bronchospasm and copious secretions.
Suxamethonium must be avoided: It is metabolised by plasma cholinesterase (pseudocholinesterase), which is inhibited by OPs. Suxamethonium will cause prolonged paralysis of many hours' duration. Use rocuronium for rapid sequence induction (with sugammadex available for reversal).
Bronchospasm: treat with bronchodilators and atropine. High-dose inhaled ipratropium may help alongside systemic atropine.
Atropine
Atropine competitively antagonises muscarinic acetylcholine receptors. It reverses the muscarinic features of OP poisoning: dries secretions, reverses bronchospasm, increases heart rate. It does not reverse nicotinic effects (muscle paralysis, fasciculations).
Dose: 2–4 mg IV bolus, doubled every 5–10 minutes until secretions dry and bronchospasm resolves. The endpoint is drying of pulmonary and oral secretions — not heart rate or pupil dilation, which are unreliable indicators.
Total atropine requirements may be very large — hundreds of milligrams in severe poisoning. Once stable, a continuous atropine infusion (10–20% of the initial loading dose per hour) maintains control.
Pralidoxime (2-PAM)
Pralidoxime is an oxime that can reactivate phosphorylated AChE by cleaving the OP–enzyme bond, restoring enzymatic function. It acts at both muscarinic and nicotinic synapses and is the only agent that can restore neuromuscular function.
Critical limitation: Pralidoxime must be given before ageing occurs. Once the OP–AChE bond has aged, it is irreversible and pralidoxime is ineffective. Most agricultural OPs age over several hours; some nerve agents (soman) age in minutes.
Dose: 30 mg/kg IV loading dose over 30 minutes, then 8–10 mg/kg/hour infusion (or 1–2 g IV bolus then repeat at 1–2 hours, then 4-hourly).
Evidence controversy: The ShamPAM trial (Eddleston et al., Lancet 2009) — a double-blind RCT — found no benefit of pralidoxime over placebo in OP pesticide poisoning in Sri Lanka and suggested possible harm. Subsequent debate has questioned the dosing adequacy and patient selection in that trial. UK guidelines continue to recommend pralidoxime in moderate-to-severe OP poisoning on mechanistic grounds and given the risk-benefit profile.
Benzodiazepines
Benzodiazepines are essential for seizure management — and should be given early to prevent seizure-induced brain injury and hyperthermia. Diazepam IV is first-line. In nerve agent exposure, high-dose benzodiazepines may be given pre-emptively before seizures occur.
ICU Supportive Care
- Ventilatory support: manage bronchospasm, reverse respiratory failure
- Continuous monitoring: ECG (QT prolongation from OP itself or from high-dose atropine), hemodynamics
- Seizure management and monitoring
- Nutritional support for prolonged ICU stay (recovery from severe OP poisoning may take weeks)
- Physiotherapy for prolonged weakness
Nerve Agents
Nerve agents (sarin, soman, VX, novichok) are military-grade OPs many times more potent than agricultural compounds. The principles of management are identical but:
- Ageing is rapid (soman ages in minutes, novichok is very stable): pralidoxime must be given immediately
- Contamination risk is extreme: Level B or C PPE required for first responders; full CBRN response
- Antidote auto-injectors (atropine + pralidoxime) are used by military personnel
- UKHSA, CBRNC specialists, and NHS HAZMAT teams should be involved immediately
- Nerve agent attacks are notifiable; police and security services are involved alongside clinical management
Viva Questions
What is the mechanism of organophosphate toxicity and why do patients die?
Organophosphates irreversibly phosphorylate acetylcholinesterase, the enzyme responsible for breaking down acetylcholine in the synaptic cleft. Inhibition of AChE allows acetylcholine to accumulate at muscarinic and nicotinic synapses throughout the body. At muscarinic sites — autonomic effector organs — this causes excessive glandular secretion (profuse salivation, lacrimation, urination, diarrhoea, bronchorrhoea), bronchospasm, bradycardia, and miosis. At nicotinic sites — the neuromuscular junction — accumulation causes initial fasciculations followed by depolarisation block and flaccid paralysis, affecting all skeletal muscles including the diaphragm and intercostal muscles. In the central nervous system, excess acetylcholine causes seizures, altered consciousness, and central respiratory failure. Death results from the combination of three converging mechanisms: bronchospasm causing obstruction, bronchorrhoea flooding the alveoli with secretions, and peripheral respiratory muscle paralysis preventing ventilation. Any one of these alone might be survivable; together they cause rapid respiratory arrest. This is why early intubation and high-dose atropine — which dries secretions and reverses bronchospasm — are the most critical time-sensitive interventions.
How do you use atropine in organophosphate poisoning and what is the clinical endpoint?
Atropine is the primary antidote for the muscarinic effects of organophosphate poisoning. It competitively blocks muscarinic acetylcholine receptors, reversing bronchospasm and drying secretions, and increasing heart rate. The starting dose is 2–4 mg IV, doubled every 5–10 minutes until the clinical endpoint is reached. The correct endpoint is drying of pulmonary secretions and resolution of bronchospasm — not heart rate and not pupil size. Targeting heart rate or pupil response leads to underdosing. A patient with severe OP poisoning may require hundreds of milligrams of atropine in the first few hours; clinicians who are unfamiliar with this scale of dosing risk underdosing the drug that can save the patient's life. Once stability is achieved, an atropine infusion at 10–20% of the total loading dose per hour maintains control. Atropine does not reverse the nicotinic effects — it will not restore muscle power or reverse fasciculations. For those effects, pralidoxime is needed, and it must be given early before enzyme ageing makes the AChE–OP bond permanent.
What is ageing in the context of organophosphate poisoning and why does it matter clinically?
Ageing refers to the spontaneous chemical modification of the phosphorylated acetylcholinesterase–organophosphate complex in which a side chain is lost from the OP, resulting in a negatively charged enzyme–inhibitor bond that is completely irreversible. Before ageing, pralidoxime (an oxime) can displace the OP compound from the active site of AChE and restore enzymatic function. After ageing, no amount of pralidoxime can break the bond — the enzyme is permanently inactivated and neurological and neuromuscular transmission can only recover as new AChE is synthesised, which takes weeks. The rate of ageing depends on the specific compound: soman (a nerve agent) ages within 2–10 minutes of exposure, making pralidoxime useless almost immediately; agricultural OPs such as parathion and chlorpyrifos age over 24–48 hours, providing a longer therapeutic window. This is why pralidoxime must be given urgently — ideally within the first hour in nerve agent exposure, and within the first few hours in agricultural OP poisoning. Beyond this window, pralidoxime is ineffective. The clinical implication is that in any suspected OP poisoning, after ensuring airway and starting atropine, pralidoxime should be initiated as a matter of urgency, without waiting for a definitive time of exposure or laboratory confirmation.