Why this poison is interesting

Chloroquine and hydroxychloroquine are the antimalarials that kill quickly. Where quinine threatens the eyes and the heart over hours, the 4-aminoquinolines can cause rapid cardiovascular collapse — cardiac arrest may be the presenting feature — from direct myocardial toxicity.²³ They are membrane-stabilising sodium-channel blockers, so they sit in the library's sodium-channel blockade family, and their defining management lesson is unusual: with no antidote and no possibility of removal, survival was improved by a combination of early ventilation, diazepam and adrenaline.⁴

They block cardiac sodium channels and more. The 4-aminoquinolines are membrane-stabilising (quinidine-like) agents that widen the QRS, prolong the QT, and depress myocardial contractility, producing hypotension, arrhythmia and cardiac arrest.²³ Established
They cannot be removed. Chloroquine has one of the largest volumes of distribution in therapeutics — it is taken up into tissues throughout the body, with a terminal half-life measured in weeks — so dialysis is futile, and EXTRIP recommends against it.¹² Established
The advance was supportive, not pharmacological. A prospective study found that combining immediate mechanical ventilation with diazepam and adrenaline improved survival in severe chloroquine poisoning — the nearest thing to a specific strategy, and a supportive one.⁴

The 4-aminoquinolines are the poisons you cannot pull back out — so the victory was learning to hold the patient through the first hours, not to remove the drug.

The toxic principle

The toxic principle is cardiac: membrane-stabilising sodium-channel blockade with additional effects on repolarisation and contractility, producing conduction delay, arrhythmia and pump failure. A characteristic hypokalaemia accompanies it, and the central nervous system is involved through seizures and reduced consciousness.

Sodium-channel blockade slows conduction and depresses the myocardium. The 4-aminoquinolines are quinidine-like membrane stabilisers: they widen the QRS, and their negative inotropy and vasodilatation cause the hypotension that can progress to cardiogenic shock and pulmonary oedema.²³ Established
Repolarisation is prolonged. QT prolongation with a risk of torsades de pointes is part of the picture, alongside ventricular tachycardia and fibrillation; intraventricular conduction defects with a wide QRS are more common than atrioventricular block.² Established
Hypokalaemia is a shift, not a loss. Hypokalaemia is common in severe poisoning and its depth correlates with severity, but it reflects an intracellular shift of potassium rather than a true deficit — which is why aggressive replacement risks rebound hyperkalaemia as the drug wears off.² Established

Toxicokinetics

Chloroquine and hydroxychloroquine — fast to act, vast in distribution, slow to leave
Parameter	Therapeutic	In overdose	Why it changes
Absorption	Rapidly and almost completely absorbed; chloroquine bioavailability about 89%, peak 1–6 h; hydroxychloroquine peak about 1.8 h²³	Rapid, so cardiotoxicity can appear shortly after ingestion²³	Fast, near-complete absorption is why cardiac arrest can be a presenting feature: the drug reaches the myocardium quickly, and there is little warning before collapse.
Protein binding	Chloroquine approximately 50–70%²	Moderate — but not the reason removal fails	As with colchicine, it is not the binding that defeats the dialyser here; it is the volume of distribution. The binding is only moderate, yet removal is still futile.
Volume of distribution	Enormous — widely distributed and retained in tissues (eyes, kidney, liver, lungs); chloroquine detectable in plasma for weeks after a single dose²	Unchanged and decisive — a vast Vd leaves almost no drug in the blood at any moment	This is the central kinetic fact. A drug distributed into tissues throughout the body on this scale presents a negligible fraction to the blood, so an extracorporeal circuit removes essentially nothing — the basis for the EXTRIP 'against' recommendation.
Metabolism	Hepatic; chloroquine's principal metabolite is monodesethylchloroquine (itself active)²; hydroxychloroquine handled similarly³	Hepatic metabolism, but clearance is intrinsically slow	Metabolism is slow and the active metabolite prolongs the pharmacology, but in acute overdose the parent-drug cardiotoxicity dominates the early, dangerous hours.
Elimination	Slow and multi-exponential; chloroquine distribution half-life 2–6 days and terminal half-life 10–60 days; renal excretion of unchanged drug over weeks²	Extremely prolonged — the drug persists for weeks, though the acute danger is in the first hours	The weeks-long terminal half-life is a striking fact about these drugs, but it is not what kills: the lethal event is early cardiovascular collapse, not chronic accumulation. The slow tail matters for retinopathy in chronic use, not for the acute overdose.
Dialysability	—	Not dialysable — EXTRIP recommends against it for chloroquine (1D) and assessed hydroxychloroquine as non-dialysable¹	The enormous volume of distribution makes extracorporeal removal pointless. EXTRIP's recommendation against chloroquine dialysis (and its finding that hydroxychloroquine is non-dialysable) follows directly from the pharmacokinetics, and redirects effort to supporting the circulation through the first hours.

Metabolism and the metabolites

Chloroquine is metabolised by the liver to monodesethylchloroquine (an active metabolite) and excreted slowly in the urine over weeks; hydroxychloroquine is handled similarly.²³ There is no toxic metabolite that explains the acute cardiotoxicity — the parent 4-aminoquinoline is the poison — and the metabolic facts matter mainly to explain the long persistence and the chronic ocular toxicity, not the acute emergency.

4-aminoquinolines — a parent-drug cardiotoxin that the body cannot quickly clear or a circuit remove

Chloroquine / hydroxychloroquine (ingested)Toxic as the parent drug — membrane-stabilising sodium-channel blockade, negative inotropy, QT prolongation²³
Hepatic metabolismMonodesethylchloroquine (active)Active metabolite; prolongs pharmacology but not the driver of the acute event²
Tissue uptake (enormous Vd)Drug retained in tissues for weeksWhere the drug mostly is — and why dialysis removes nothing¹²
Slow renal excretionUrinary elimination over weeksThe eventual exit; terminal half-life 10–60 days²

What changes the answer

The drug — chloroquine is generally more acutely toxic than hydroxychloroquine, though both can be lethal.²³ Established
Age — children and infants are especially vulnerable to small amounts.²³
The potassium — its depth marks severity, but it is a shift, so replacement must be cautious.² Established
Co-ingested QT-prolonging or sodium-channel-blocking drugs compound the cardiotoxicity. Inferred

Elimination and accumulation

The 4-aminoquinolines are eliminated very slowly — distribution half-lives of days and terminal half-lives of weeks — but this slow clearance is not the acute problem. The drug sits in tissues far from the blood, so the acute overdose cannot be shortened by removal; the task is to support the circulation through the early cardiotoxic hours while the body tolerates a drug it cannot quickly shed.

The EXTRIP position

EXTRIP assessed the antimalarials together and reached a clear position for this pair.¹

Against extracorporeal treatment for chloroquine (1D) — a strong recommendation on very low quality evidence, following from the enormous volume of distribution.¹
Hydroxychloroquine assessed as non-dialysable, with no recommendation developed because of limited clinical data and, despite the lack of biological plausibility for dialysis, too few reported patients to meet the workgroup's minimum.¹
So removal is off the table for both, and the management is supportive — the ventilation–diazepam–adrenaline approach for severe chloroquine poisoning, cautious potassium handling, and sodium-channel-directed care.³⁴

Target organs — and why those

Heart

TargetCardiac sodium channels, repolarising currents and myocardial contractility

Why hereThe 4-aminoquinolines are membrane-stabilising sodium-channel blockers with negative inotropy and QT-prolonging effects, so they slow conduction, weaken the pump and destabilise rhythm.²³ Established

At the bedsideHypotension (very common), a wide QRS, QT prolongation, ventricular tachycardia and fibrillation, torsades (typically later), cardiogenic shock and cardiac arrest — the usual cause of death.² A wide QRS triggers sodium bicarbonate, as in the sodium-channel blockade family.

Potassium homeostasis (systemic)

TargetTranscellular potassium distribution

Why hereThe drugs shift potassium into cells, producing a hypokalaemia whose depth tracks severity but which reflects distribution, not loss.² Established

At the bedsideHypokalaemia common in severe poisoning; a marker of severity, managed cautiously because potassium replacement can overshoot into hyperkalaemia as the drug redistributes out.

Central nervous system

TargetDirect CNS effects

Why hereThe 4-aminoquinolines exert direct central effects at toxic concentrations.²³ Inferred

At the bedsideHeadache, dizziness, drowsiness, visual disturbance and, in serious poisoning, restlessness, excitability, convulsions and reduced consciousness; coma is less common than the cardiovascular collapse.²

Respiratory system

TargetCentral respiratory drive and the consequences of collapse

Why hereRespiratory arrest is described as part of the rapid collapse, and respiratory failure accompanies severe cardiovascular compromise.²³ Inferred

At the bedsideRespiratory arrest can be an early event; early mechanical ventilation is part of the survival-improving combination, protecting the airway and supporting gas exchange through the cardiotoxic phase.⁴

Timeline of effects

The 4-aminoquinoline timeline is short and steep: little warning, then rapid cardiovascular collapse within the first hours. Unlike much of this band there is no meaningful latent phase — the lethal event is early — so the management is immediate and supportive.

Chloroquine / hydroxychloroquine — rapid collapse, not a delayed decline

Time

What you seeWhat is happening

0–1 hEarly / rapid onset
What you seeNausea and vomiting, drowsiness, visual disturbance and agitation — but cardiac arrest may be a presenting feature, so the early phase can be the crisis.
What is happeningRapid, near-complete absorption delivers the drug to the myocardium quickly;²³ sodium-channel blockade and negative inotropy begin to destabilise conduction and pressure almost at once.
1–6 hCardiovascular collapse
What you seeHypotension progressing to cardiogenic shock and pulmonary oedema, a widening QRS, ventricular arrhythmia and, in this family, torsades developing after several hours; hypokalaemia, convulsions and reduced consciousness.
What is happeningMaximal membrane-stabilising cardiotoxicity: conduction slowed, contractility depressed, repolarisation prolonged, potassium shifted intracellularly.²³ This is the lethal window, and the one the ventilation–diazepam–adrenaline combination is designed to carry the patient through.⁴
Hours to daysRecovery or slow tail
What you seeSurvivors of the early phase stabilise over hours; the drug itself persists for weeks, but the acute cardiovascular threat recedes once the first hours are survived and potassium normalises.
What is happeningAs tissue redistribution and slow metabolism reduce the effective myocardial concentration, conduction and contractility recover; the intracellular potassium shift reverses, which is why earlier aggressive replacement risks rebound hyperkalaemia.² The weeks-long terminal half-life pertains to tissue retention, not to continuing acute danger. Established

What the mechanism predicts at the bedside

Why the management is supportive, front-loaded and specific at once

Because the drug cannot be removed and there is no antidote, and because the lethal event is early cardiovascular collapse, the rational strategy is to pre-empt the collapse: early mechanical ventilation, diazepam and adrenaline, the combination Riou and colleagues showed improved survival.⁴ It is supportive in nature but specific in form — a defined bundle for a defined, rapid threat. Established

Why a wide QRS means bicarbonate here too

The 4-aminoquinolines are sodium-channel blockers, so a widening QRS carries the same meaning and the same response as in the tricyclic antidepressant and sodium-channel blockade group: it marks significant cardiotoxicity and is the conventional trigger for sodium bicarbonate.² The family membership tells you how to read the ECG. Established

Why the potassium must be handled with restraint

The hypokalaemia is an intracellular shift, not a deficit,² so its depth is useful as a severity marker but dangerous as a replacement target — potassium given to correct the number can overshoot into hyperkalaemia when the drug redistributes and the shift reverses. The mechanism predicts caution, and potassium management is deliberately left to TOXBASE and NPIS.

Why dialysis is pointless despite the drug lingering for weeks

It is tempting to reason that a drug with a weeks-long half-life must be worth removing, but the enormous volume of distribution means almost none of it is ever in the blood,¹² so a dialyser cleans a compartment the drug has largely left. EXTRIP recommends against it for chloroquine and found hydroxychloroquine non-dialysable;¹ the effort belongs with the circulation, not the circuit.

The antidote, from the poison's side

There is no specific antidote to the 4-aminoquinolines, and the drug cannot be removed — so what stands in an antidote's place is a trial-supported supportive combination, and it is the page's central practical point.

Early mechanical ventilation, diazepam and adrenaline improved survival in severe chloroquine poisoning in a prospective study (ten of eleven treated patients survived versus one of eleven controls);⁴ diazepam is thought to have a specific protective effect on chloroquine cardiotoxicity, and the hydroxychloroquine label notes parenteral diazepam as beneficial in reversing it.³ Established
Sodium bicarbonate for the wide-QRS cardiotoxicity, as for the other sodium-channel blockade agents.²
Cautious potassium management, because the hypokalaemia is a shift that will reverse.²
No role for dialysis, because the volume of distribution puts the drug beyond reach;¹ the definitive care is to carry the patient through the early hours, not to clear the drug.

Critical appraisal

The sodium-channel-blockade cardiotoxicity is well established and clinically load-bearing.²³ It places the 4-aminoquinolines with the tricyclics, explains the wide QRS, the arrhythmia and the pump failure, and justifies both sodium bicarbonate and the front-loaded supportive strategy.
The Riou combination is the strongest treatment evidence in the band, and unusually so. Established A prospective comparison showing ten of eleven treated patients surviving against one of eleven controls (P = 0.0003)⁴ is a striking result for a toxicology intervention; the page cites the survival benefit while deliberately not reproducing the ingested-dose threshold the study used to define severity, in keeping with the editorial boundary.
The non-removability is stated by EXTRIP and by the pharmacokinetics.¹² The enormous volume of distribution, not the moderate protein binding, is the reason — a distinction the page is careful to draw, because it is the same logic as colchicine's and the opposite of salicylate's.
The hypokalaemia-as-shift claim is important and well supported. Established The label records hypokalaemia as common in severe poisoning,² and the shift (rather than deficit) interpretation is standard toxicological teaching; the page flags the replacement trap prominently because the intuitive response is the wrong one.
Chloroquine and hydroxychloroquine are treated together by shared mechanism, with difference in degree noted. The labels describe shared actions and a shared overdose picture;²³ the page says hydroxychloroquine is generally less acutely toxic without over-claiming a clean separation, and an auditor should confirm the combined treatment is justified rather than a conflation — the EXTRIP assessment grouped them for the same reason.
The weeks-long half-life is correctly de-emphasised for the acute case. Established The page is explicit that the terminal half-life pertains to tissue retention and chronic retinopathy, not to the acute emergency, to prevent the half-life being misread as a reason for prolonged acute instability or for removal.

References

1
EXTRIP Workgroup. Berling I, King JD, Shepherd G, et al. Extracorporeal Treatment for Chloroquine, Hydroxychloroquine, and Quinine Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. J Am Soc Nephrol 2020;31(10):2475–89. PubMed 32963091 · recommendation set at extrip-workgroup.org/quinine-chloroquine. Source of the strong recommendation against extracorporeal treatment for chloroquine (1D, very low quality evidence), and of the assessment that hydroxychloroquine is non-dialysable with no recommendation developed owing to limited clinical data and too few reported patients. Read from the workgroup's published recommendation page; verified 13 Sep 2026.
2
Avloclor Tablets (chloroquine phosphate) — Summary of Product Characteristics, Alliance. emc product 5490. §4.9 and §5.2 fetched and read in full. Source of the statements that chloroquine is highly toxic in overdose with children particularly susceptible, that the chief features are circulatory collapse from a potent cardiotoxic effect, respiratory arrest and coma with rapid progression, that hypokalaemia is common and metabolic acidosis may develop, the neurological and cardiac features (wide QRS, bradyarrhythmias, QT prolongation, ventricular tachycardia, torsades developing after about 8 hours, ventricular fibrillation; intraventricular conduction defects more common than AV block), that death is usually from direct myocardial toxicity, the resuscitation note about persisting with chest compression until adrenaline and diazepam can be given, the ~89% bioavailability and 1–6 h peak, the wide tissue distribution and retention, the 2–6 day distribution and 10–60 day terminal half-lives, the 50–70% protein binding, and the active metabolite monodesethylchloroquine. Fatal-dose figures in the label were deliberately not reproduced. Verified 13 Sep 2026.
3
Hydroxychloroquine sulfate 200 mg Film-coated Tablets — Summary of Product Characteristics. emc product 1764. §4.9 and §5.2 fetched and read in full. Source of the statement that overdose with the 4-aminoquinolines is dangerous, particularly in infants; the symptom and rhythm/conduction list (headache, visual disturbances, cardiovascular collapse, convulsions, hypokalaemia; QT prolongation, torsades, ventricular tachycardia and fibrillation, wide QRS, bradyarrhythmias, nodal rhythm, AV block, followed by sudden potentially fatal respiratory and cardiac arrest appearing shortly after overdose); the statement that parenteral diazepam is beneficial in reversing chloroquine cardiotoxicity; the note that hydroxychloroquine has actions, pharmacokinetics and metabolism similar to chloroquine; the rapid near-complete absorption with a mean 1.8 h peak; and the multiphasic elimination. Fatal-dose figures in the label were deliberately not reproduced. Verified 13 Sep 2026.
4
Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. N Engl J Med 1988;318(1):1–6. PubMed 3336379. Prospective study of a combination of immediate mechanical ventilation, diazepam and adrenaline (epinephrine) in severe chloroquine poisoning. Source of the survival benefit — ten of eleven patients receiving the combination survived versus one of eleven controls (P = 0.0003). The ingested-dose threshold the study used to define severity was deliberately not reproduced. Verified 13 Sep 2026 from the abstract.
5
TOXBASE — chloroquine; hydroxychloroquine. National Poisons Information Service. toxbase.org (NHS login required. NPIS: 0344 892 0111. The authoritative UK source for risk stratification, the indications and conduct of ventilation/diazepam/adrenaline, potassium management and decontamination. Login-gated, so not quoted here.)

Chloroquine and hydroxychloroquine

At a glance