Why this poison is interesting

An antihistamine overdose is not a histamine problem. Blocking peripheral H1 receptors is a remarkably safe thing to do — the cetirizine label reports 400 to 500 mg to an adult producing no symptoms at all, and 400 mg in a 14-year-old producing only mild symptoms.³ If H1 blockade were the toxic action, every antihistamine would behave like that. Chlorphenamine and promethazine do not, and the difference has nothing to do with the receptor they are named after.

What separates them is where the molecule can go and what else it binds on arrival. The older agents are lipophilic tertiary amines that cross into the brain freely and are unselective: they block muscarinic receptors, and several of them block the fast cardiac sodium channel as well. The newer agents are, functionally, the same H1 antagonism with the central nervous system taken out of the picture — and their overdoses are correspondingly dull.

That claim has been measured rather than assumed, which is unusual for a mechanism this widely taught. Brain H1 receptor occupancy can be quantified in living humans with positron emission tomography using a labelled tracer, and Yanai and colleagues propose exactly this as an objective classification of antihistamines into sedating, less-sedating and non-sedating categories according to their sedative effects.⁴ A drug class sorted by an imaging measurement of its own target, in the organ where the harm happens.

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

The toxic principle

Four actions, of which only the first is the licensed one, and only the first is harmless.

Peripheral H1 blockade — the therapeutic action: Effective against urticaria and allergic rhinitis and toxicologically near-silent. The cetirizine figures are the cleanest demonstration available: at 40 to 50 times a therapeutic dose, an adult had no symptoms at all.³ Established
Central H1 blockade — the sedation, and the excitation: Histamine is a wakefulness transmitter, and blocking its receptor in the brain produces somnolence. Promethazine enters the brain²; the label describes adults becoming drowsy and lapsing into coma.² The same block produces the opposite picture in children — see the callout below. Established
Muscarinic blockade — the reason this page has an anticholinergic facet: The first-generation molecules are structurally promiscuous and antagonise muscarinic acetylcholine receptors. Chlorphenamine's label lists anticholinergic effects and toxic psychosis among overdose features¹; cetirizine's lists mydriasis, tachycardia and urinary retention among effects that could suggest an anticholinergic effect after at least five times the daily dose.³ The full syndrome, and the argument about its antidote, is on the anticholinergic toxidrome page. Established
Cardiac channel effects — the reason to do an ECG: Two separate lesions, not one. Promethazine's label states that high doses (supratherapeutic doses) can cause ventricular arrhythmias including QT prolongation and torsade de pointes² — a repolarisation problem. Separately, diphenhydramine and other first-generation antihistamines are named on the sodium-channel blockade page as agents that widen the QRS — a depolarisation problem, with a different marker and a different treatment. Established

The second-generation agents were designed to keep the first action and lose the second. Cetirizine's overdose profile is the result: symptoms mainly associated with CNS effects or with effects that could suggest an anticholinergic effect, at at least five times the recommended daily dose, including confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor and urinary retention.³ Present, but requiring a multiple of the dose and producing a syndrome the label describes in the conditional.

Toxicokinetics

The three UK labels used here are of very different vintages and depths, and the gaps are as informative as the figures. Promethazine's pharmacokinetics section runs to four sentences and contains no number at all.

Three antihistamines — where the drug goes decides which poisoning it produces
Parameter	Therapeutic	In overdose	Why it changes
Chlorphenamine — absorption	Well absorbed; effects develop within 30 minutes, maximal within 1 to 2 hours, lasting 4 to 6 hours¹	Faster onset than the duration of effect suggests	The therapeutic duration and the elimination half-life disagree, which is the row's whole point — see the half-life row below. A drug whose effect appears to wear off at 6 hours is still being eliminated many hours later.
Chlorphenamine — half-life	12 to 15 hours¹; about 22% of an oral dose excreted unchanged in urine, the rest as monodesmethyl and didesmethyl derivatives¹	Prolonged; a long observation period for a drug bought without a prescription	A half-life two to three times the apparent duration of clinical effect is a trap for early discharge. The label does not state whether the two named metabolites are active, and this page does not assume either way.
Promethazine — distribution	Distributed widely in the body; enters the brain and crosses the placenta; slowly excreted via urine and bile²	Central effects are the expected effects, not a complication	This is the entire pharmacokinetic case for why promethazine is a more dangerous overdose than cetirizine, and the label states it in one sentence with no quantity attached. Biliary excretion with slow clearance also raises the possibility of enterohepatic recirculation, which the label does not address and this page does not claim.
Cetirizine — distribution and elimination	Peak at about 1 hour, blood levels in the order of 0.3 µg/mL; terminal half-life approximately 10 hours in adults and 6 hours in children aged 6–12; a high proportion... bound to human plasma proteins; about two thirds of the dose recovered in urine³	Linear — plasma levels are linearly related to the dose given³	A comparable half-life to chlorphenamine and a dramatically milder overdose. That comparison is the argument of this page in a single row: two drugs cleared on the same timescale, differing almost entirely in whether they reach the brain.
Brain penetration	Measurable directly. PET with a labelled tracer gives cortical H1 receptor occupancy of 6.47 ± 10.5% for desloratadine and 13.8 ± 7.00% for loratadine at therapeutic doses (n = 8, P = 0.103)⁵	The property that separates the generations	The one pharmacokinetic variable on this page that is measured in the organ that matters rather than inferred from plasma. Yanai and colleagues propose occupancy as the objective basis for classifying these drugs as sedating, less-sedating or non-sedating.⁴ Note the wide standard deviations and small sample — this is a demonstration of a difference in kind, not a precise ranking.
Dialysability	—	No. Cetirizine is not effectively removed by dialysis³. Chlorphenamine's label states that haemoperfusion may be used in severe cases¹ — haemoperfusion, not haemodialysis, and with no supporting data given	EXTRIP has addressed no antihistamine; its published index covers 22 poisons and contains none of them.⁶ The chlorphenamine sentence is worth flagging rather than repeating: haemoperfusion is now rarely available in UK practice, the label offers no evidence for it, and an absence of an EXTRIP assessment is not an endorsement of an alternative.

Metabolism and the metabolites

No antihistamine here is bioactivated to a toxic species, and the toxicity is the parent drug's. Chlorphenamine is metabolised to monodesmethyl and didesmethyl derivatives, with about 22% excreted unchanged.¹ Cetirizine is largely excreted unchanged, about two-thirds of the dose appearing in urine with a urinary excretion half-life consistent with the terminal one.³ Promethazine's label describes slow excretion by urine and bile without naming a metabolite at all.²

Two antihistamines, one receptor, and the barrier that decides the poisoning

H1 antagonist, swallowedThe same pharmacological class and the same licensed indication for both branches
Lipophilic tertiary amine — chlorphenamine, promethazine, diphenhydramineEnters the brain² and binds muscarinic receptors and, for some, the fast sodium channel
Second generation — cetirizine, loratadine, desloratadineCortical H1 occupancy of 6–14% at therapeutic doses⁵; 400–500 mg gave an adult no symptoms³
The blood-brain barrier — the step that separates the two poisoningsOccupancy measured by PET is the basis of an objective sedating / less-sedating / non-sedating classification⁴
Central H1, muscarinic and channel blockadeSedation or excitation, anticholinergic features, convulsions, QT prolongation and torsade¹²
Peripheral H1 blockade onlyMild and dose-multiple-dependent: confusion, mydriasis, tachycardia, urinary retention at five or more times the daily dose³

Elimination and accumulation

None of these drugs has a dramatic accumulation story, and the practically important number is the mismatch between how long a first-generation antihistamine appears to work and how long it takes to leave. Chlorphenamine's effects are maximal within 1 to 2 hours and last 4 to 6 hours, while its plasma half-life is 12 to 15 hours.¹

Promethazine's slow excretion via urine and bile² compounds this, and its label offers nothing quantitative to work with. A label that describes elimination as slow and provides no half-life is telling you that the observation period is a clinical judgement rather than a calculation — which is a reason to route the decision through TOXBASE rather than through this page.

Target organs — and why those

Brain — H1 receptors

TargetCentral histamine H1 receptors on the wakefulness pathways

Why hereHistamine is one of the arousal transmitters, and central H1 blockade removes part of the drive to be awake. The organ is targeted only by the drugs that can reach it, which is the page's central claim and the one property that has been measured directly: cortical H1 occupancy of about 6% for desloratadine and 14% for loratadine at therapeutic doses⁵, against a classification in which the sedating agents occupy far more of the receptor pool.⁴ Established

At the bedsideSomnolence and coma in adults; excitation, ataxia, incoordination, athetosis and hallucinations in children.² Convulsions occur in both, and coma or excitement may precede their occurrence.²

Brain — muscarinic receptors

TargetCentral muscarinic acetylcholine receptors, blocked incidentally

Why hereA separate lesion in the same organ, and the reason this page carries an anticholinergic facet. The first-generation molecules do not distinguish sharply between the amine receptors, so central muscarinic blockade accompanies central H1 blockade. Two blocks in one organ producing two opposite conscious levels is why the presentation is unpredictable: H1 blockade sedates, muscarinic blockade agitates and confuses, and which predominates varies. Chlorphenamine's label lists both sedation and toxic psychosis.¹ The syndrome is set out in full on the anticholinergic toxidrome page. Inferred

At the bedsideAgitated delirium, hallucinations, dystonic reactions¹, and peripherally mydriasis, tachycardia and urinary retention — all three of which appear even on the cetirizine label at high multiples of the dose.³

Heart — repolarisation

TargetDelayed cardiac repolarisation and the QT interval

Why hereThe heart is targeted because these molecules interact with cardiac potassium handling as well as with amine receptors — a property entirely unrelated to their indication. The organ is selected by molecular promiscuity rather than by any distribution phenomenon. Promethazine's label is explicit that supratherapeutic doses can cause QT prolongation and torsade de pointes.² Established

At the bedsideQT prolongation and torsade de pointes²; chlorphenamine's label lists arrhythmias and cardiovascular collapse and directs that hypotension and arrhythmias be treated vigorously.¹

Heart — depolarisation

TargetThe fast cardiac sodium channel, for some members of the class

Why hereA second and mechanistically distinct cardiac lesion, kept as its own card because the marker and the treatment differ. Diphenhydramine and other first-generation antihistamines are named among the agents that reach the fast sodium channel and widen the QRS.⁷ Two cardiac cards on one page is not duplication: one is a QT problem and one is a QRS problem, and confusing them leads to the wrong intervention. Established

At the bedsideQRS widening, broad-complex arrhythmia and hypotension — the syndrome, its marker and its treatment are on the sodium-channel blockade page. Sodium bicarbonate is aimed at the channel, not at the antihistamine.

Timeline of effects

First-generation antihistamine overdose — early, unpredictable in direction, and slower to clear than it looks

Time

What you seeWhat is happening

0–30 minAbsorption
What you seeLittle or nothing.
What is happeningChlorphenamine is well absorbed and its effects develop within 30 minutes.¹ No latent phase and nothing to manufacture — the drug arrives as the poison.
30 min – 2 hThe syndrome declares, in one direction or the other
What you seeEither sedation or agitated delirium, and there is no reliable way to predict which. Anticholinergic signs: dry mouth, mydriasis, tachycardia, urinary retention.¹³
What is happeningEffects maximal within 1 to 2 hours.¹ Central H1 and central muscarinic blockade acting simultaneously and in opposite directions on conscious level; peripheral muscarinic blockade producing the physical signs.
1–6 hThe window in which the ECG matters
What you seeConvulsions may occur, and coma or excitement may precede their occurrence.² Arrhythmias, hypotension, cardiovascular collapse in severe cases.¹
What is happeningTwo independent cardiac lesions to look for: a wide QRS from sodium-channel blockade⁷, and a long QT with torsade from delayed repolarisation.² The treatments differ, which is why the distinction is worth making at the bedside rather than in retrospect.
4–6 hThe apparent recovery
What you seeSedation lightens. The patient looks better.
What is happeningChlorphenamine's clinical effects last 4 to 6 hours¹ — but its half-life is 12 to 15 hours.¹ The fall in receptor occupancy below the therapeutic threshold is not the same event as the fall below the toxic one.
12–24 hElimination
What you seeFull resolution in the uncomplicated case.
What is happeningAbout 22% excreted unchanged, the rest as demethylated derivatives.¹ Promethazine is slower and its label gives no figure at all.²

What the mechanism predicts at the bedside

Ask which generation it was, because they are two different poisonings. Cetirizine at 400–500 mg gave an adult no symptoms³; a comparable multiple of a first-generation dose does not behave that way.
Do an ECG, and read it twice — once for the QRS and once for the QT. They are separate lesions with separate treatments: sodium-channel blockade⁷ and delayed repolarisation.²
Do not expect sedation. Both first-generation labels describe excitation as well as depression¹², and in children excitation is the described picture rather than the exception.²
A convulsion may arrive from either direction of conscious level — the promethazine label says coma or excitement may precede it.²
Look for the anticholinergic signs, because they identify the class quickly: dry skin, mydriasis, tachycardia, urinary retention. Even cetirizine's label lists mydriasis, tachycardia and urinary retention at high multiples of the dose.³
Do not discharge on apparent recovery at six hours. The therapeutic duration of chlorphenamine is 4 to 6 hours and the half-life is 12 to 15.¹
Dialysis is not an option. Cetirizine is not effectively removed by dialysis³, EXTRIP has assessed no antihistamine⁶, and the haemoperfusion sentence on the chlorphenamine label¹ carries no evidence with it.
Charcoal is the decontamination the label actually supports, most effective within an hour.¹ The ipecacuanha and gastric lavage advice on the promethazine label² is quoted on this page as a historical artefact, not as guidance.
Whether to give physostigmine for the delirium is a real question with real evidence on both sides — it is set out on the anticholinergic toxidrome page rather than here.

The antidote, from the poison's side

There is no antihistamine antidote and there could not usefully be one, because the receptor whose blockade could be competed at is not the receptor causing the trouble. Every intervention here is aimed at one of the incidental actions.

Sodium bicarbonate: For the QRS, not for the antihistamine. It acts on the channel's environment rather than on the drug — the argument is made in full on the sodium-channel blockade page and applies unchanged here.⁷
Benzodiazepines: Named on both first-generation labels for convulsions — treated with diazepam or another suitable anticonvulsant², and CNS convulsions may be treated with i.v. diazepam.¹
Activated charcoal: The one decontamination measure with current support on these labels, most effective if given within an hour of ingestion.¹
Physostigmine: Deliberately not discussed here. It is an answer to the muscarinic component rather than to the antihistamine, its evidence is genuinely contested, and the contraindication that matters most — a wide QRS — is a property some of these drugs produce. The whole argument is on the anticholinergic toxidrome page.
Magnesium and the usual measures for torsade: For the repolarisation lesion promethazine's label names.² Again, aimed at the arrhythmia rather than at the drug.
Histamine: Mentioned only to be dismissed. Competing at H1 with an agonist would treat the least dangerous action of the poison and worsen everything else. There is no version of this page in which the antidote is aimed at the receptor in the drug's name.

Critical appraisal

The occupancy figures are small-sample human data and are printed with their spread for that reason. Nakamura's study is eight healthy male volunteers in a double-blind crossover; cortical H1 receptor occupancy was 6.47 ± 10.5% for desloratadine and 13.8 ± 7.00% for loratadine, a difference that did not reach significance (P = 0.103), and subjective sleepiness did not differ significantly between either drug and placebo.⁵ The figures support the claim that second-generation agents barely occupy brain H1 receptors. They do not support any ranking between them, and this page makes none.
No first-generation occupancy figure appears on this page, because none could be verified from a source cited here. The classification into sedating, less-sedating and non-sedating categories is Yanai's⁴; the numerical contrast a reader might expect — a high occupancy figure for chlorphenamine or diphenhydramine set against the 6–14% above — is deliberately absent rather than estimated.
The muscarinic-versus-H1 explanation for sedation-or-agitation is this page's inference. Both labels describe both directions of conscious level¹²; neither attributes them to different receptors, and neither explains the age difference. The mechanism is plausible, standard and uncited, and it is badged inferred accordingly rather than presented as established.
The receptor-occupancy explanation for the gap between a 4–6 hour effect and a 12–15 hour half-life is likewise an inference, not a measurement. The two figures are the label's¹; the reconciliation is this page's.
No evidence-tier downgrade appears anywhere on this page, and the candidate was considered and rejected. The obvious one would be second-generation antihistamines are safe in overdose — but no source contests it: the cetirizine label supports it³, and the PET data support the mechanism.⁴⁵ An absence of contrary evidence is not a citation for the doubt. The same reasoning that withheld a badge from iron applies.
The lethal-dose figure on the chlorphenamine label is not reproduced anywhere on this page, and no toxic dose, dose per kilogram or plasma concentration threshold appears either.
The claim that first-generation antihistamines block cardiac sodium channels is carried by an existing page in this library rather than by a source fetched for this one.⁷ It is standard and it is asserted on the sodium-channel blockade page for diphenhydramine specifically. Neither chlorphenamine's nor promethazine's label states it, and an auditor should test whether this page over-generalises from diphenhydramine to the whole first generation. The organ card is worded to describe some members of the class for that reason.
The biliary excretion of promethazine is quoted as the label states it and no enterohepatic recirculation is claimed — the temptation to convert slowly excreted via urine and bile² into a recirculation mechanism was declined.

References

1
Piriton Allergy Tablets (chlorphenamine maleate) — Summary of Product Characteristics. electronic medicines compendium, product 3927. Sections 4.9 (Overdose) and 5.2 (Pharmacokinetic properties). The estimated lethal dose stated in section 4.9 is deliberately not reproduced on this page. medicines.org.uk/emc/product/3927
2
Phenergan 25 mg tablets (promethazine hydrochloride) — Summary of Product Characteristics. electronic medicines compendium, product 5588. Sections 4.9 (Overdose) and 5.2 (Pharmacokinetic properties). medicines.org.uk/emc/product/5588
3
Piriteze Hayfever & Allergy 10 mg Film Coated Tablets (cetirizine hydrochloride) — Summary of Product Characteristics. electronic medicines compendium, product 341. Sections 4.9 (Overdose) and 5.2 (Pharmacokinetic properties). medicines.org.uk/emc/product/341
4
Yanai K, Yoshikawa T, Yanai A, et al. The clinical pharmacology of non-sedating antihistamines. Pharmacology & Therapeutics 2017 Oct;178:148–156. PMID 28457804. Cited for the proposal that brain H1 receptor occupancy, measured by PET, classifies antihistamines objectively as sedating, less-sedating or non-sedating.
5
Nakamura T, Hiraoka K, Harada R, et al. Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine. Pharmacology Research & Perspectives 2019 Aug;7(4):e00499. PMID 31338198. Eight healthy male volunteers, double-blind crossover, [11C]-doxepin PET.
6
EXTRIP Workgroup — published recommendations index. Extracorporeal Treatments in Poisoning Workgroup. Cited for the absence of any recommendation covering any antihistamine. extrip-workgroup.org/recommendations
7
Sodium-channel blockade — ResusDoc Toxicology. The companion page in this library, which names diphenhydramine and the first-generation antihistamines among the agents reaching the fast cardiac sodium channel, and sets out the QRS marker and the bicarbonate rationale. /sodium-channel-blockade.html

Antihistamines

At a glance