Why this poison is interesting

Every other page in this library is organised around a molecule. This one is organised around a channel, because the clinical problem genuinely is. A patient with a wide QRS, hypotension and a falling conscious level after an overdose has the same lesion whether they took flecainide, amitriptyline, propranolol, cocaine, quinine, carbamazepine or diphenhydramine — and the immediate response is the same for all of them, before anyone knows which it was.

That convergence is the argument for treating sodium-channel blockade as an entity. The drugs share no receptor, no therapeutic class and no chemistry. What they share is an ability to sit in the pore of the fast cardiac sodium channel and slow the rate at which cardiac cells depolarise. The QRS complex is a direct read-out of that rate, which makes it something almost nothing else in toxicology is: a bedside measurement of the lesion itself, rather than of the concentration of the thing causing it.

The second reason this page exists is that the treatment is aimed at the channel rather than at the poison, and this is unusual enough to be worth stating explicitly. Sodium bicarbonate does not bind flecainide, does not accelerate its elimination — the label notes that alkaline urine actually decreases flecainide excretion¹ — and does nothing to the drug at all. It changes the environment the channel is working in. The flecainide label records the outcome without the mechanism: 8.4% intravenous sodium bicarbonate reduces the activity of flecainide.¹

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

The toxic principle

The voltage-gated sodium channel in working cardiac myocardium opens within a millisecond of the membrane reaching threshold, admits the sodium current that produces phase 0 of the action potential, and inactivates almost immediately. The rate of that upstroke determines how fast the depolarising wavefront propagates from cell to cell, and therefore how long the ventricles take to depolarise — which is what the QRS complex measures.

Three properties of the blockade explain most of the clinical behaviour.

Use-dependence: These agents bind preferentially to the open or inactivated channel and dissociate during diastole. The faster the rate, the less time for dissociation, and the greater the block. This is why the ECG deteriorates with tachycardia and why the syndrome is self-reinforcing once hypotension drives the rate up. It is also why class I agents are grouped by their dissociation kinetics — the Ic agents such as flecainide dissociate slowly and therefore block most at physiological rates. Established
pH dependence: These are mostly weak bases. Acidaemia increases the ionised fraction, and the ionised form has different access to the channel and dissociates less readily. Acidosis therefore worsens the block, which matters because a shocked, seizing patient generates acidosis, which deepens the block, which worsens the shock. The tricyclic page treats this loop in detail. Established
Extracellular sodium dependence: The current through a partially blocked channel depends on the electrochemical driving force for sodium. Raising extracellular sodium increases that driving force and partially overcomes the block, by mass action rather than by displacing the drug — the same logic as calcium in calcium-channel blocker poisoning. Inferred

The drugs that reach this channel do so from unrelated starting points, and it is worth listing them together because the list is the page's whole argument.

Class Ic antiarrhythmics — flecainide, propafenone: The purest examples: sodium-channel blockade is the therapeutic mechanism. Overdose is the therapy without a ceiling. Flecainide's label lists hypotension, seizures, bradycardia, conduction delays, asystole, extended QRS and QT intervals and ventricular arrhythmias.¹ Established
Class Ia — quinidine, disopyramide, procainamide: Sodium-channel blockade plus potassium-channel blockade, so they widen the QRS and prolong the QT. Quinine and chloroquine belong here pharmacologically, and EXTRIP recommends against extracorporeal treatment for both (1D each).⁴ Established
Tricyclic antidepressants: The commonest cause of this syndrome in UK practice, and the subject of its own page. Sodium-channel blockade is one of four mechanisms operating simultaneously there. Established
Propranolol: Membrane-stabilising activity at high concentration; its label lists QRS prolongation and ventricular arrhythmias where atenolol's does not.² See beta-blockers. Inferred
Cocaine: A local anaesthetic by origin, and it retains the class I action alongside its sympathomimetic effects — which is why a wide QRS in cocaine toxicity is treated as sodium-channel blockade rather than as sympathomimetic excess. Established
Others: Carbamazepine, diphenhydramine and other first-generation antihistamines, and local anaesthetics in systemic toxicity. Each reaches the same channel from a different therapeutic class.

Toxicokinetics

Flecainide is used here as the representative agent because it is the one whose entire pharmacology is the lesion, and because its UK label is unusually forthcoming about overdose.

Flecainide — the clean case, where the therapeutic mechanism and the toxic mechanism are the same
Parameter	Therapeutic	In overdose	Why it changes
Absorption	Almost completely absorbed; no extensive first-pass metabolism; bioavailability about 90% from tablets. Peak at 4 h for a tablet, 1 h for an oral solution, 0.67 h intravenously¹	Unchanged in kind — there is no first-pass capacity to overwhelm	The absence of first-pass metabolism means the dose swallowed translates fairly directly into systemic exposure. Unlike propranolol or diltiazem, the exposure does not rise disproportionately with dose — the danger here is potency, not non-linearity.
Therapeutic range	Generally accepted as 200 to 1000 ng/mL¹	Exceeded — but the concentration is not the clinical variable	A narrow therapeutic range in a drug whose overdose is a potentially life-threatening medical emergency¹ is the definition of a poor safety margin. The label also notes drug interactions can raise concentrations above the therapeutic range without any change in dose.¹
Protein binding	About 40%¹	Unchanged	Intermediate binding would ordinarily leave dialysis arguable. It is not, and the reason is given below — the answer comes from a measurement, not from a prediction.
Metabolism	Extensively metabolised, subject to genetic polymorphism, via CYP2D6, to m-O-dealkylated flecainide and its lactam, both of which may have some activity¹	Unchanged pathway; poor metabolisers and CYP2D6 inhibitors accumulate	A polymorphic enzyme on the only significant metabolic route is a route into toxicity without an overdose. The label notes that in patients with dosing restrictions, 6–8 days and in exceptional cases up to 20 days may elapse before steady state is reached.¹
Elimination	Mainly urinary — about 30% as unchanged drug, the remainder as metabolites; about 5% faecal¹	Decreased in renal failure, liver disease, heart failure — and in alkaline urine¹	The alkaline-urine clause is the most instructive line on this page. Bicarbonate is given in this poisoning and it reduces flecainide excretion. That is only tolerable because bicarbonate is not being given to eliminate the drug — it is being given to change the channel's environment. Confusing the two rationales would make the treatment look self-defeating.
Half-life	About 20 hours¹	Longer, as elimination falls with the cardiac output the drug is depressing	The label draws the conclusion itself: assuming a plasma half-life of approximately 20 h, these supportive treatments may need to be continued for an extended period of time.¹ This poisoning is a multi-day commitment, and that is the argument for early escalation to mechanical support rather than late.
Rate dependence	Class Ic agents dissociate slowly from the channel	Block deepens as heart rate rises	Use-dependence converts a compensatory tachycardia into a mechanism of deterioration. The physiological response to hypotension makes this specific poisoning worse, which is close to unique among the pages here. Inferred
Dialysability	—	*No. Neither dialysis nor haemoperfusion is effective; haemodialysis removes only about 1% of unchanged flecainide*¹	EXTRIP has published no recommendation for flecainide or for class I antiarrhythmics as a group³ — the workgroup's published list is the authoritative record of what it has and has not addressed. For quinine and chloroquine, which reach the same channel, it recommends against extracorporeal treatment (1D each), and assessed hydroxychloroquine as non-dialysable while declining to make a recommendation for want of three reported patients with clinical outcomes.⁴

Metabolism and the metabolites

There is no bioactivation anywhere in this syndrome. Every drug on the list arrives already able to block the channel, and metabolism reduces the effect rather than creating it. What metabolism contributes instead is variability — in who accumulates, and how fast.

Flecainide — a metabolic route that is a liability rather than a rescue

FlecainideAlready the toxic species. ~90% bioavailable, no significant first pass¹
CYP2D6 — genetically polymorphicThe single significant route. Inhibited by many antidepressants; absent in poor metabolisers¹
m-O-dealkylated flecainideMay have some activity¹
m-O-dealkylated lactam of flecainideMay have some activity¹
Urine — about 30% unchanged drugDecreased in alkaline urine¹ — which is the state bicarbonate treatment produces

Carbamazepine is the interesting exception in the other direction, and it is the reason this page exists as a syndrome rather than as a flecainide monograph: it is an anticonvulsant, prescribed by a different specialty for a different reason, and in overdose it produces the same channel lesion. The clinical syndrome does not respect the therapeutic classification.

Elimination and accumulation

The elimination story for this syndrome has one dominant feature: you cannot take the drug out, and you must wait. Flecainide's label is unusually explicit that there is no known way to rapidly remove flecainide from the system, that neither dialysis nor haemoperfusion is effective, and that supportive treatment may need to continue for an extended period given a 20-hour half-life.¹

The clinical consequence is a poisoning in which the ceiling of supportive care is reached quickly and must then be held for a long time. Flecainide's label lists inotropes, mechanical ventilation, circulatory assistance including balloon pumping, transvenous pacing for conduction block, and — on a case-by-case basis — intravenous fat emulsion and extracorporeal membrane oxygenation.¹ A summary of product characteristics reaching for ECMO is a fair indication of where this poisoning can go.

Target organs — and why those

Ventricular myocardium

TargetFast voltage-gated sodium channel (Nav1.5), phase 0 of the action potential

Why hereWorking myocardium depends on the fast sodium current for the speed of its upstroke and therefore for conduction velocity. Slow the upstroke and the depolarising wavefront propagates more slowly through the ventricle, which lengthens the QRS and creates the conduction heterogeneity that permits re-entry. The organ is targeted because it is the tissue in which this particular channel does the most important job. Established

At the bedsideQRS prolongation, ventricular arrhythmias, and ultimately asystole — all listed in flecainide's overdose section.¹ The QRS is the measurement that tracks the lesion in real time.

Sinoatrial and atrioventricular nodes

TargetConduction tissue, though nodal upstroke is calcium-dependent

Why hereIncluded with a caveat that matters: nodal cells depolarise mainly through calcium channels, so pure sodium-channel blockade affects them less directly than it affects working myocardium. Class I agents nonetheless slow conduction through the His–Purkinje system, which is sodium-dependent. This is the mechanistic difference from calcium-channel blocker poisoning, where the node is the primary casualty. Inferred

At the bedsideSinoatrial and AV block and bradycardia are listed for flecainide¹; the label suggests a transvenous pacemaker for conduction block. Pacing may fail to capture when the myocardium itself is heavily blocked.

Brain

TargetNeuronal voltage-gated sodium channels

Why hereNeurons use sodium channels for their action potentials too, and the lipophilic members of this group reach them. Flecainide's label lists seizures among overdose features.¹ Seizure then produces acidosis, which increases the ionised fraction of a weak base and deepens the cardiac block — the neurological complication feeds back onto the cardiac one. Inferred

At the bedsideSeizures¹, and in the wider group the coma and hallucinations seen with propranolol² and tricyclics. A seizure in this syndrome is a cardiac emergency as much as a neurological one.

Vasculature

TargetNot the primary lesion — a consequence of it, and of accompanying pharmacology

Why hereHypotension in flecainide poisoning is largely a failure of the pump rather than of the vessels, since reduced conduction velocity and negative inotropy both follow from the same blockade. In tricyclic poisoning an additional alpha-1 blockade contributes directly. The same syndrome therefore has different haemodynamics depending on the molecule that produced it, which is where the syndrome-level framing reaches its limit. Inferred

At the bedsideHypotension, listed first among flecainide's overdose features.¹ It responds poorly to fluid alone and drives the tachycardia that deepens the block.

Timeline of effects

Flecainide overdose — a fast onset and a very slow exit

Time

What you seeWhat is happening

0–1 hAbsorption
What you seeMay still be well. Nothing on the ECG.
What is happeningAlmost complete absorption with no significant first pass; an oral solution peaks at about 1 h, a tablet at about 4 h.¹ Channel occupancy rising.
1–4 hThe ECG moves first
What you seeQRS widening before haemodynamic collapse. The ECG is abnormal while the blood pressure is still holding.
What is happeningConduction velocity falling as channel block increases. This is the window in which the syndrome is recognisable and the patient is still compensating — and it is the reason the ECG is the monitoring tool rather than the blood pressure.
2–12 hThe feedback loop
What you seeHypotension, broad-complex arrhythmias, seizures, bradycardia and conduction block.¹
What is happeningThree loops closing at once. Hypotension drives tachycardia, and use-dependence deepens the block at higher rates. Seizure and hypoperfusion produce acidosis, which increases the ionised drug fraction and deepens the block further. Falling cardiac output reduces the drug's own elimination.¹
12–48 hThe plateau
What you seeNo further deterioration and no improvement. The patient is being held, not treated.
What is happeningHalf-life about 20 hours, no effective removal technique, and elimination impaired by the poisoning itself.¹ The label's phrase is supportive treatments may need to be continued for an extended period of time.¹ The gap here is not a latent poisoning phase — it is the absence of any way to make the poison leave faster.
DaysResolution
What you seeQRS narrows; haemodynamics recover.
What is happeningMetabolism and renal excretion finally reduce the body burden. Recovery tracks the QRS rather than any concentration.

A different kind of gap again

Sodium-channel blockade — a gap that cannot be shortened

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

This one is a gap in what medicine can do. The poison is at its target, the effect is fully expressed, and there is no intervention that shortens it. It is drawn as a hole because that is exactly what it is.

What the mechanism predicts at the bedside

The ECG is the investigation, not the drug concentration. The QRS integrates drug, metabolites, co-ingestants, pH, potassium and rate; an assay for one molecule does none of that.
A wide QRS after overdose is a syndrome-level finding and can be acted on before the drug is identified. That is the practical value of grouping these agents.
Tachycardia makes it worse, because block is use-dependent. The compensatory response to hypotension deepens the lesion.
Acidosis makes it worse, which is why a seizure in this poisoning is a cardiac problem too.
Bicarbonate is aimed at the channel, not at the drug. It does not bind or eliminate flecainide — alkaline urine actually reduces its excretion.¹ Expecting it to lower a concentration is a misunderstanding of what it is for.
A broad-complex tachycardia at around 200/min in a flecainide-exposed patient may be 1:1 conducted atrial flutter, not ventricular tachycardia — the drug slows the flutter into the range the AV node can conduct.¹
Pacing may not capture. Heavily blocked myocardium may not respond to a stimulus that would capture a normal ventricle, so a pacemaker is not a guaranteed answer to conduction block.
Plan for days, not hours. A 20-hour half-life with no removal option means supportive treatment for an extended period¹ — an argument for early escalation rather than late rescue.
Dialysis is not an option and asking for it wastes time. About 1% of unchanged flecainide is removed¹, and EXTRIP has never issued a recommendation for flecainide, or for the class I antiarrhythmics as a group, at all.³

The antidote, from the poison's side

There is no antidote in the binding-and-removing sense, and the flecainide label says so: no specific antidote is known.¹ What exists is one intervention aimed squarely at the channel, and a second aimed at the drug's physical chemistry.

This is the same intervention described on the tricyclic page, and it is worth being precise about a distinction that page also draws. Bicarbonate here is not ion trapping. In salicylate poisoning, alkalinisation ionises a weak acid and traps it out of the brain and into the urine — a genuine change in distribution and elimination. Nothing of that kind is claimed here. Bicarbonate in sodium-channel blockade acts on the channel's environment, and in flecainide's case it actively reduces urinary elimination.¹ Two treatments that look identical on a drug chart and work by unrelated mechanisms.

Sodium bicarbonate: Sodium load plus alkalosis, both acting on the channel. The only intervention aimed at the lesion itself.¹
Intravenous lipid emulsion: Named in the flecainide label as a consideration on a case-by-case basis.¹ The usual explanation is a lipid sink sequestering a lipophilic drug; it is plausible and not established.
Inotropes and vasopressors: Dopamine, dobutamine and isoprenaline are named in the label.¹ They support the circulation without touching the block, and by raising the rate they may deepen it.
Transvenous pacing: Temporarily inserting a transvenous pacemaker in the event of conduction block should be considered.¹ Capture is not guaranteed in heavily blocked myocardium.
Mechanical support: Mechanical ventilation, balloon pumping, and ECMO on a case-by-case basis.¹ For a poisoning that cannot be removed and has a 20-hour half-life, buying time is the strategy.
Extracorporeal removal: Ineffective. Neither dialysis nor haemoperfusion; about 1% of unchanged drug removed.¹ EXTRIP has issued no recommendation for this class³ and recommends against it for quinine and chloroquine.⁴

Critical appraisal

The syndrome framing has limits, and the vasculature card above is where they show. Tricyclics add alpha-1 blockade and antimuscarinic effects, class Ia agents add potassium-channel blockade and QT prolongation, propranolol adds beta-blockade, cocaine adds sympathomimetic effects. Treating the QRS is common ground; nothing beyond that is.
Bicarbonate's mechanism is inferred, and the two components are rarely separated in practice. The sodium-load and alkalosis explanations are individually well grounded in channel physiology, but the flecainide label reports only that bicarbonate reduces the activity of flecainide¹ — an outcome, not a mechanism. No study is cited here dissecting the two, and none should be assumed.
The QRS thresholds people use come from the tricyclic literature and were derived in a specific population. The tricyclic page discusses this in detail; the widely quoted figures come from a prospective cohort of 49 patients published in 1985 in which all patients survived.⁵ They are mechanistically coherent risk gradients, not validated switches, and they have not been separately validated for flecainide, carbamazepine or the others.
Use-dependence is established channel pharmacology; the clinical feedback loop built from it is inference. That tachycardia deepens block follows from the binding kinetics. That this materially drives clinical deterioration in poisoned humans is a reasonable deduction that this page cannot cite an outcome study for.
Lipid emulsion appears here because a label mentions it, not because it is proven. On a case-by-case basis¹ is the label's own framing, and it is the appropriate level of confidence.
EXTRIP's silence on class I antiarrhythmics is an absence of a recommendation, not a recommendation against. The workgroup's published list is authoritative for what has been assessed³; flecainide has not been. Its quinine and chloroquine recommendations are against (1D each), and its hydroxychloroquine position is explicitly no-recommendation for want of three reported patients with clinical outcomes.⁴ Those distinctions are easy to flatten in the retelling.
This page names no bicarbonate dose and no QRS threshold for acting. Both are management decisions and both belong to TOXBASE and NPIS. The mechanism explains why a threshold exists; it does not set one.

References

1
Flecainide Acetate 100 mg tablets — Summary of Product Characteristics. electronic medicines compendium, product 3086. Sections 4.9 (Overdose) and 5.2 (Pharmacokinetic properties). medicines.org.uk/emc/product/3086
2
Inderal 10 mg film-coated tablets (propranolol) — Summary of Product Characteristics. electronic medicines compendium, product 12858. Section 4.9 (Overdose). medicines.org.uk/emc/product/12858
3
EXTRIP Workgroup — published recommendations index. Extracorporeal Treatments in Poisoning Workgroup. Cited for the absence of any recommendation covering flecainide or class I antiarrhythmics as a group. extrip-workgroup.org/recommendations
4
EXTRIP Workgroup. Quinine / chloroquine / hydroxychloroquine — recommendations. Extracorporeal Treatments in Poisoning Workgroup. extrip-workgroup.org/quinine-chloroquine
5
Boehnert MT, Lovejoy FH Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. New England Journal of Medicine 1985 Aug 22;313(8):474–9. PMID 4022081. Cited here as the origin of the QRS thresholds in general use; see the tricyclic page for its limitations.

Sodium-channel blockade

At a glance