Why this poison is interesting

Almost every page in this library describes a poison that is used up. It binds something, or is metabolised into something, or is excreted, and the injury ends when the exposure ends. Paraquat is not consumed by the reaction that causes the damage. It accepts an electron from NADPH, becomes a radical, hands that electron to molecular oxygen to make superoxide, and returns to exactly the molecule it was. Then it does it again. One molecule of paraquat is not one unit of damage; it is a catalyst for as long as there is NADPH and oxygen to work with.

The second reason is the organ selectivity, which has a clean and unusual answer. Most target-organ questions in toxicology are answered by susceptibility — this tissue has a high oxygen demand, that one has a low antioxidant reserve. Here the answer is transport. Gawarammana and Buckley's systematic review of the human literature states that paraquat is "actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis".¹ The lung is not more vulnerable to paraquat; it is fuller of it.

The third is that this page has no antidote section worth the name, and the honest version of that is more useful than a hopeful one. The same review records that "the case fatality is very high in all centres despite large variations in treatment".¹ When outcome does not vary with treatment across centres that treat very differently, that is information about the treatments.

A poison is a drug whose kinetics have escaped its pharmacology.

The toxic principle

Paraquat is a bipyridylium cation — two linked pyridine rings, each carrying a permanent positive charge. That charge is responsible for almost everything about the molecule's behaviour: it makes paraquat highly water-soluble, it keeps it out of fat, it makes it a substrate for cation transporters, and it makes it an excellent electron acceptor.

The cycle has two steps and no end. Step one: a cellular reductase, drawing on NADPH, donates a single electron to paraquat, producing the paraquat monocation radical. Step two: that radical donates the electron to molecular oxygen, producing superoxide and regenerating paraquat unchanged. The net effect of one full turn is that one NADPH has been partly consumed and one superoxide radical has been created — and the poison is exactly where it started.

The downstream damage is not one process. The review describes reactive oxygen species causing cellular damage "via lipid peroxidation, activation of NF-κB, mitochondrial damage and apoptosis in many organs".¹ Those are four different lesions with four different timescales — a membrane attacked chemically within minutes, a transcriptional inflammatory programme over hours, a bioenergetic failure, and a controlled cell-death programme that takes days to express itself. The clinical course tracks the slowest of them, which is why the lung fails long after the poison has been excreted.

Toxicokinetics

The kinetics are the least remarkable thing on this page and that is precisely the point. A poison that is incompletely absorbed and gone from the plasma within a day should be survivable. The kinetics of the plasma and the kinetics of the injury have come apart completely.

Paraquat — unremarkable kinetics attached to an unsurvivable injury
Parameter	Therapeutic	In overdose	Why it changes
Absorption	"Rapidly but incompletely absorbed" from the gut¹	Same — the fraction absorbed is small and sufficient	Incomplete absorption is not protective here, because the injury is catalytic rather than stoichiometric. A small absorbed fraction still supplies a molecule that is never used up.
Distribution	Two-compartment: "kinetics of distribution into these target tissues can be described by a two-compartment model"¹	Actively concentrated in lung tissue against a concentration gradient¹	The most important row in the library's target-organ arguments. Selectivity here is achieved by a transporter rather than by tissue susceptibility — the lung is loaded, not merely exposed. Compare digoxin, where a huge volume of distribution means the blood is where the poison is not.
Metabolism	None of consequence — paraquat is not bioactivated	None	There is no oxon, no NAPQI and no formate here. The molecule that was swallowed is the molecule that does the damage, which puts paraquat with nitrous oxide and against most of Band A.
Elimination	"Largely eliminated unchanged in urine within 12 to 24 hours"¹	Renal excretion falls as paraquat destroys the kidney	A self-defeating elimination route. The organ that clears the poison is one of the organs the poison injures, so the clearance falls exactly when it is most needed — the same structural trap as the renal limb of lithium toxicity.
Plasma concentration	—	Prognostic: "plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis"¹	A level that predicts outcome and does not direct treatment. This is the opposite of paracetamol's nomogram, and it is an uncomfortable thing to have available — the appraisal returns to it.
Oxygen tension	—	A determinant of the rate of injury, not a parameter of the poison	The second half of the redox cycle consumes molecular oxygen, so tissue oxygen tension behaves like a kinetic variable of the poisoning. No other page in this library has a row like this. Inferred
Dialysability	—	"Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course"¹. EXTRIP has never addressed paraquat²	An absence that is genuinely uninformative, for a reason worth naming. The question is not whether paraquat can be removed from blood — it is small, water-soluble and poorly protein-bound, so it can be. The question is whether removing it from blood matters once it has been transported into the lung against a gradient, and the review's answer is that it does not.

Metabolism and the metabolites

There is no metabolism and there are no metabolites — the same opening as the nitrous oxide page, for a different reason. What follows is not the metabolism of paraquat but the metabolic cycle paraquat inserts itself into, and the crucial feature of the diagram is that it is a loop rather than a chain.

The cycle that never terminates — and what it costs the cell each turn

Paraquat dicationNot metabolised. Water-soluble, permanently charged, excreted unchanged within 12–24 h¹
Concentrated in lung tissueThe step that chooses the organ¹ — uptake, not vulnerability
Paraquat monocation radicalThe reduced form. NADPH is spent here — and NADPH is also what regenerates glutathione
Superoxide, and paraquat regenerated unchangedThe loop closes. The poison returns to the top of this diagram and the cell has lost reducing power and gained a radical
Radical attack on membrane lipidsLipid peroxidationDirect structural damage to alveolar cell membranes¹
Redox-sensitive transcriptionNF-κB activationThe inflammatory programme¹ — and the rationale, such as it is, for immunosuppression
Mitochondrial injuryBioenergetic failure and apoptosis"Mitochondrial damage and apoptosis in many organs"¹ — cell death on a timescale of days
Alveolar epithelial destruction, then proliferative fibrosisThe endpoint. Pneumonitis and lung fibrosis¹ — arriving after the poison has been excreted

Two things are being consumed and neither of them is the poison

Each turn of the cycle costs the cell NADPH and molecular oxygen, and produces superoxide. NADPH is not only the fuel for the cycle — it is also what regenerates reduced glutathione, the cell's principal defence against exactly the radicals being produced. The poison spends the antioxidant currency in order to manufacture the thing the antioxidant defends against. That double action is the mechanistic case for antioxidant therapy, and it is the reason the case is more persuasive than the evidence: the review records that antioxidants such as acetylcysteine and salicylate "might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions" and that "there are no published human trials".¹ Inferred

Elimination and accumulation

Paraquat is eliminated quickly and completely, and it does not accumulate. The damage accumulates, and so does the fibrosis that follows the damage. That inversion is shared with nitrous oxide, and the clinical consequence is the same: nothing measurable at the point of deterioration reflects the exposure that caused it.

Two clinical consequences follow. A well-looking patient after a paraquat ingestion is not a reassured patient, and the assessment that matters is exposure history plus a plasma concentration, not the appearance of the chest. And the injury is not modifiable at the point where it becomes visible — by the time the fibrosis is radiologically apparent, the alveolar cells whose loss caused it are long dead.

Where this latent phase sits among the others

Paraquat — the body responding to an injury that is already complete

The other 26 kinds of latent phase in this library

Amphetamines and MDMA — a hormone acting normally on a kidney behaving normally, while the patient supplies the water
Antipsychotics — a physical object in the stomach — extended-release quetiapine forming a pharmacobezoar
Arsenic — a tissue declaring on its own timetable rather than the poison's — the arsenic is excreted within days, but the nail that was growing while it circulated does not show its white transverse line for several weeks
Arsine and stibine — a red cell mass haemolysing faster than a kidney can cope with — the exposure is over, the haemolysis is silent until the urine changes colour, and the renal failure that follows is the cause of death
Beta-blockers — a repolarisation lesion waiting for an ectopic beat to fall inside it — sotalol prolongs the QT and then, for hours, nothing happens
Calcium-channel blockers — a tablet that has not yet dissolved
Carbon monoxide — an inflammatory process continuing after the poison itself has gone
Chlorine and ammonia — paraquat's cause at its shortest — the time an injured alveolar epithelium takes to leak
Cocaine — a package that has not yet failed — the calcium-channel blocker's cause moved outside the tablet, where wrapping integrity cannot be measured
Digoxin — distribution of the drug to its target — which that page argues is not a latent phase in the paracetamol sense at all
Ethylene glycol — paracetamol's cause with a different enzyme — glycolate accumulating behind glycolate oxidase while the patient looks merely drunk
GHB and GBL — not the poisoning but its withdrawal — a half-life under an hour means admission for any reason interrupts round-the-clock redosing
Hydrofluoric acid — an ion diffusing far enough to reach a nerve ending — and the thinner the solution, the further it travels before anybody feels it
Iron — a true remission — the corrosive injury settling while absorbed iron moves into the cells it will poison, so the patient improves on their way to the dangerous phase
Ketamine — nitrous oxide's cause on a longer clock — urothelial damage accumulating over months to years of repeated exposure
Lead — bone giving lead back — a store with a half-life of 10 to 30 years releasing its contents when pregnancy, lactation, menopause or osteoporosis resorbs it, so the blood concentration rises after the exposure has ended
Lithium — transport across cell membranes
Mercury — distribution on two clocks — tissue concentrations peaking within 24 hours everywhere except the brain, which is not reached until 2 to 3 days, and which then cannot let the poison out again
Methaemoglobin inducers — paracetamol's cause at its shortest — one to four hours manufacturing the toxic species
Methanol — paracetamol's cause again — formate accumulating behind a folate-dependent disposal step that primates perform poorly
Nitrous oxide — damage accumulating to a threshold
Opioids — an antidote wearing off before the poison does — renarcotisation, the only gap in this set that treatment creates rather than reveals
Organophosphate insecticides — a fat store emptying — and, separately, a second and unexplained lesion declaring itself at a neuromuscular junction the first phase had already left
Paracetamol — time spent manufacturing a toxic metabolite
Sodium-channel blockade — a gap that cannot be shortened
Thallium — hair on its own clock rather than the poison's — sensory symptoms come first and the alopecia that makes the diagnosis obvious follows them, well after the interval in which treatment is recommended

The gap is not between poison and effect but between effect and its consequence — which is what paraquat shares with the chlorine and severe ammonia exposures, and with nothing else in the set.

Target organs — and why those

This is the page where the organ section has the most satisfying answer in the library, because for once the mechanism of selectivity is a measured transport process rather than a plausible story about relative vulnerability.

Lung — alveolar epithelium

TargetAlveolar epithelial cells, which concentrate paraquat by active transport

Why hereParaquat is "actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis".¹ Uptake against a gradient is a transporter, not a diffusion gradient and not a susceptibility — the cell spends energy accumulating the thing that kills it, presumably because the transporter's real substrate is a physiological cation the molecule resembles. The lung is then also the tissue with the highest oxygen tension in the body, which supplies the second half of the redox cycle. Two independent reasons pointing at the same organ. Established

At the bedsideEarly: often a clear chest and normal saturations, which is the trap. Later: progressive hypoxaemia, pneumonitis, then proliferative fibrosis that does not reverse. This is the organ that determines the outcome, and the appearance of the chest early on says little about it.

Mouth, pharynx and oesophagus

TargetMucosal surfaces in direct contact with concentrated liquid

Why hereA chemical burn, entirely separate from the redox injury and obeying the ordinary rules of corrosive contact — concentration and contact time. It has nothing to do with transporters or with oxygen and it is the only injury on this page that is complete at the moment of exposure. Established

At the bedsidePainful oral and pharyngeal ulceration appearing within hours, dysphagia, drooling, and the risk of perforation and mediastinitis. It is also a useful sign of a genuine ingestion when the history is unclear.

Kidney — proximal tubule

TargetTubular cells handling a cation they must both transport and survive

Why here"Paraquat also causes renal and liver injury."¹ The kidney is exposed to the highest concentrations of any organ because it is the excretory route, and the proximal tubule concentrates cations by design. The injury is therefore self-amplifying: damaged tubules excrete paraquat less well, so the exposure of every other organ rises. Inferred

At the bedsideAcute kidney injury within the first days, and a falling urine output that is simultaneously an organ failure and a reason the poison stays longer.

Liver

TargetHepatocytes

Why hereNamed directly in the review alongside renal injury.¹ The liver receives the portal blood after an ingestion and therefore sees the highest concentration of any organ early, before distribution. The mechanism is the general redox one rather than anything hepatocyte-specific, and this card is deliberately the weakest on the page. Inferred

At the bedsideTransaminitis and hyperbilirubinaemia in the first days. Rarely the cause of death, and clinically overshadowed by the lung and the kidney.

Timeline of effects

Paraquat — a burn, a false recovery, and a lung that closes

Time

What you seeWhat is happening

Minutes–hoursCorrosive phase
What you seeBurning mouth and throat, vomiting, abdominal pain, oral and pharyngeal ulceration, dysphagia.
What is happeningDirect chemical injury to mucosa on contact. Nothing here is redox chemistry, and the severity of this phase reflects concentration and contact time rather than absorbed dose.
0–24 hAbsorption and excretion
What you seeGastrointestinal symptoms; the patient may look no worse than a caustic ingestion.
What is happening"Rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12 to 24 hours."¹ Meanwhile the lung is loading, by active transport against a gradient.¹
1–3 daysRenal and hepatic injury
What you seeRising creatinine, falling urine output, transaminitis.
What is happeningRedox injury in the organs of highest exposure. Renal failure reduces the only meaningful clearance route, so every other tissue's exposure rises.
2–5 daysThe well-looking interval
What you seeChest clear, saturations normal, the patient often feels improved. The plasma paraquat has largely gone.
What is happeningThe alveolar epithelium is already destroyed; the proliferative response has not yet begun. Nothing measurable at this moment reflects the injury that has occurred, and nothing done at this moment can undo it.
5–14 daysProliferative pulmonary fibrosis
What you seeProgressive breathlessness and refractory hypoxaemia. The commonest cause of death and the reason the poisoning is feared.
What is happeningFibroblast proliferation replacing destroyed alveolar epithelium. Oxygen given to treat the hypoxaemia can feed the residual redox cycling, which is the cruellest constraint in the band. Inferred
WeeksSurvival or not
What you seeSurvivors of a smaller exposure may recover with impaired gas transfer. "The case fatality is very high in all centres despite large variations in treatment."¹
What is happeningOutcome is determined by the absorbed dose and by how much alveolar epithelium was lost in the first days, which is why prognosis is predictable from an early plasma concentration¹ and why late treatment changes so little.

What the mechanism predicts at the bedside

Contact NPIS immediately on suspicion, not on confirmation. Everything that might help is early, and the window closes while the patient still looks well.
A clear chest is not reassurance. The alveolar injury precedes any radiological or oximetric sign by days.
Oral ulceration is evidence of a real ingestion when the history is uncertain, and it is a separate injury from the one that will determine the outcome.
Restrict supplemental oxygen unless hypoxia is immediately life-threatening. The second half of the redox cycle consumes molecular oxygen, and a multi-centre retrospective cohort of 416 patients found liberal oxygen associated with higher mortality after adjustment for age, creatinine and paraquat concentration.³ An association in a design that cannot exclude confounding by indication — the appraisal states the limit. Inferred
"Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed."¹
Haemodialysis and haemoperfusion are "unlikely to change the clinical course"¹, because the poison has already been transported out of the blood and into the lung.
A plasma paraquat concentration predicts outcome¹ and does not select a treatment — which makes it a difficult number to have, and an honest one.
Immunosuppression is widely practised on very weak evidence¹, and a reader should know that before being told it is standard.
Renal failure is not just an organ failure here — it is a loss of the only clearance route, and it worsens the exposure of everything else.
Nothing about the plasma level at the time of deterioration reflects the injury, because by then the poison is gone and the fibrosis is the disease.

The antidote, from the poison's side

There is no antidote, and this section exists to say so carefully rather than to fill the space. The library's other pages ask what an antidote does about the mechanism; here the question is why each candidate fails against it, and the failures are instructive.

Why a receptor antagonist is impossible: There is no receptor. Paraquat is not an agonist of anything — it is an electron acceptor participating in redox chemistry, and there is no binding site to compete for. The whole class of antidote that works for opioids, benzodiazepines and digoxin is unavailable in principle.
Why an enzyme blocker is impossible: There is no bioactivating enzyme. Fomepizole works for ethylene glycol and methanol because a single enzyme stands between the parent and the toxin. Paraquat is already the toxin, and the reductases that reduce it are many and essential.
Why removal is too late: "Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course."¹ The molecule is small, water-soluble and dialysable in the physical-chemistry sense — and it has been actively transported into the lung against a gradient before removal can begin.¹ EXTRIP has never addressed it.²
Immunosuppression — dexamethasone, cyclophosphamide, methylprednisolone: The rationale is real: NF-κB activation is part of the documented mechanism¹, and the fatal lesion is a proliferative inflammatory one. The evidence is not: "Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak."¹ A widely practised treatment described by a systematic review as resting on very weak evidence is a treatment-efficacy claim contested by its own source. Traditional teaching
Antioxidants — acetylcysteine, salicylate: Mechanistically the most attractive candidate on the page, since the cycle both generates radicals and spends the NADPH that regenerates glutathione. The review states they "might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions" and immediately that "there are no published human trials".¹ A mechanism is not a result, and this page declines to present it as one.
Withholding oxygen: The one intervention that follows directly from the redox cycle, and the only one this page treats as mechanistically sound. It is still an inference: no human trial cited here tests it. Inferred
Decontamination: "Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed."¹ Adsorption of an unabsorbed cation is the one place where an intervention acts before the transporter does.

Critical appraisal

The immunosuppression badge is a treatment-efficacy downgrade, not a mechanism downgrade, and it uses the exemption this library has already stated for the cyproheptadine badges: where an absence of trial evidence is itself the relevant finding, an absence can justify the badge. The review's phrase is "widely practised, but evidence for efficacy is very weak"¹ — an assessment of the evidence, not merely a gap in it.
The oxygen claim is the page's largest inference, and an earlier draft of this appraisal overstated the emptiness of the evidence. It said a search for a human trial had found none. That was the result of a failed keyword search, not of the literature: a multi-centre retrospective cohort of 416 patients reports mortality of 87.8% with liberal oxygen against 73.7% without (p = 0.007), with adjusted odds ratios of 4.71 (95% CI 1.533–14.471) at 28 days and 5.97 (1.692–21.049) overall, adjusted alongside age, creatinine and blood paraquat concentration.³ The badge stays at inferred rather than rising, because this is a retrospective cohort with obvious confounding by indication — sicker patients receive oxygen — only partly addressed by adjusting for paraquat concentration. What changed at audit is the honesty of the claim about the evidence, not the strength of the recommendation.
The polyamine transporter is not named on this page, deliberately. The review supports active uptake against a concentration gradient¹; the identity of the transporter is standard pharmacology that no cited source here establishes, and naming it would be a precision the citation does not carry.
The kidney and liver cards are inference, badged as such. The review states that paraquat causes renal and liver injury¹; the why here accounts offered — highest excretory exposure, highest portal exposure — are this page's reconstruction, not findings.
No lethal dose, no minimum lethal dose and no ingested volume appears anywhere on this page, and none should. Paraquat is the poison in this library where that policy matters most, because the relationship between a small ingested volume and a fatal outcome is exactly the fact that would be misused. Prognostic plasma concentrations are referred to as existing and are not printed.
The four-patterns section records a miss rather than forcing a fit. Four Band A pages already do this and the honesty is load-bearing: a poison that is regenerated by its own toxic mechanism is not described by patterns built around kinetics escaping pharmacology.
The corrosive injury and the redox injury are kept separate throughout, because conflating them produces the false reassurance that a patient with a comfortable mouth has had a small exposure.
EXTRIP's silence² is recorded for consistency. Here it is uninformative in an unusual way: the physical chemistry says paraquat is removable, and the review says removing it does not change the course¹ — so the unasked question already has a clinical answer.

References

1
Gawarammana IB, Buckley NA. Medical management of paraquat ingestion. British Journal of Clinical Pharmacology 2011 Nov;72(5):745–57. PMID 21615775. (Systematic search of human studies reporting toxicokinetics, mechanisms, clinical features, prognosis and treatment. "Paraquat is rapidly but incompletely absorbed and then largely eliminated unchanged in urine within 12-24 h." "Paraquat generates reactive oxygen species which cause cellular damage via lipid peroxidation, activation of NF-κB, mitochondrial damage and apoptosis in many organs." "Kinetics of distribution into these target tissues can be described by a two-compartment model." "Paraquat is actively taken up against a concentration gradient into lung tissue leading to pneumonitis and lung fibrosis." "Paraquat also causes renal and liver injury." "Plasma paraquat concentrations, urine and plasma dithionite tests and clinical features provide a good guide to prognosis." "Activated charcoal and Fuller's earth are routinely given to minimize further absorption. Gastric lavage should not be performed." "Elimination methods such as haemodialysis and haemoperfusion are unlikely to change the clinical course." "Immunosuppression with dexamethasone, cyclophosphamide and methylprednisolone is widely practised, but evidence for efficacy is very weak." "Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical scavenging, anti-inflammatory and NF-κB inhibitory actions. However, there are no published human trials." "The case fatality is very high in all centres despite large variations in treatment.")
2
EXTRIP Workgroup — published recommendations index. Extracorporeal Treatments in Poisoning Workgroup. Cited for the absence of any recommendation covering paraquat. extrip-workgroup.org/recommendations
3
Lin XH, Pan HY, Cheng FJ, et al. Association between liberal oxygen therapy and mortality in patients with paraquat poisoning: a multi-center retrospective cohort study. PLoS One 2021 Jan 15;16(1):e0245363. PMID 33449962. (Four medical institutions in Taiwan, Chang Gung Research Database, January 2004 to December 2016; 416 patients. Oxygen given before marked hypoxia was defined as liberal. Mortality 87.8% with liberal oxygen versus 73.7% without, p = 0.007; 28-day mortality adjusted odds ratio 4.71, 95% CI 1.533–14.471; overall mortality aOR 5.97, 95% CI 1.692–21.049. Mortality was also associated with age, blood creatinine and blood paraquat concentration, for which the analysis adjusts. The authors conclude that unless the evidence of hypoxia is clear, oxygen therapy should be avoided because it is associated with increased mortality. Retrospective, and open to confounding by indication — sicker patients receive oxygen — which is why this page keeps the badge at inferred. The study's own hypoxia threshold and its paraquat concentrations are deliberately not printed here.)

Paraquat

At a glance