Allergy Medicines

TL;DR. Antihistamines split into two generations, and the difference is whether the molecule crosses into the brain. First-generation drugs (chlorphenamine, diphenhydramine, promethazine) sedate, impair driving as much as alcohol at the legal limit, and have anticholinergic effects associated with dementia risk in long-term use. Second-generation drugs work as well for allergy without any of that, and should be the default. For hay fever, steroid nasal sprays are more effective than antihistamines and are consistently under-used, largely because people use them wrongly and give up. Adrenaline is the only treatment for anaphylaxis; antihistamines do not treat it.

1. What allergy is

An immune response to something harmless. IgE antibodies specific to an allergen bind to mast cells; on re-exposure, the allergen cross-links them and the mast cell degranulates, releasing histamine, leukotrienes, prostaglandins, and cytokines within seconds to minutes.

Histamine acting on H1 receptors produces the classic effects: vasodilation (redness, flushing), increased vascular permeability (swelling, runny nose, hives), sensory nerve stimulation (itch, sneezing), and smooth muscle contraction (bronchoconstriction).

Histamine has four receptor types, which explains an otherwise confusing drug landscape:

Antihistamines are technically inverse agonists, stabilising the receptor in its inactive form rather than merely blocking it. Practically this means they work best taken before exposure, because they cannot undo histamine that has already bound and acted.

2. The two generations

Second-generation antihistamines should be the default for allergy. They are as effective, last longer, and lack the harms below. Guidelines in the UK, US, and Europe say so, and first-generation drugs remain widely sold and widely used, largely from habit and because they are cheap and appear in sleep aids.

Why first-generation drugs are a problem

Sedation and impairment. They cross into the brain and block H1 receptors there, where histamine maintains wakefulness. Driving simulator studies have found diphenhydramine impairs driving performance more than a blood alcohol concentration of 0.1 percent, above the legal limit in most places. Critically, subjective sleepiness correlates poorly with measured impairment, so people feel fine and are not.

Next-day hangover. Sedating antihistamines used as sleep aids commonly produce next-morning grogginess and impairment.

Anticholinergic burden. They block acetylcholine receptors as well, producing dry mouth, blurred vision, constipation, urinary retention, and, particularly in older people, confusion and falls. Large cohort studies have associated cumulative long-term anticholinergic exposure with increased dementia risk, and while causation is not established, this is a genuine reason to avoid habitual use. They appear on the Beers Criteria of drugs to avoid in older adults.

Tolerance to the sedative effect develops within days, so they stop working as sleep aids while the impairment and anticholinergic effects continue.

Children. Sedating antihistamines are not recommended for young children for sedation, and promethazine is contraindicated under 2 years because of respiratory depression risk.

Where first-generation drugs still have a role: severe itch where sedation is genuinely useful at night, motion sickness (cyclizine, promethazine), nausea and vertigo, and as an adjunct in palliative care.

3. What to use for what

Hay fever (allergic rhinitis)

The order of effectiveness surprises people:

Steroid nasal sprays are under-used because people use them wrongly and conclude they do not work. The three things that matter:

1. They take days to weeks to reach full effect. They are not a rescue treatment. Start them two weeks before your season begins.
2. Use them daily, not as needed. Intermittent use largely wastes them.
3. Technique: aim the spray away from the septum, toward the outer wall of the nostril (right hand to left nostril, left hand to right), do not sniff hard (which sends it down the throat), and breathe gently. Aiming at the septum causes irritation, crusting, and nosebleeds, which is the commonest reason people stop.

Systemic absorption from modern intranasal steroids is very low, and long-term use at licensed doses is considered safe, with growth in children monitored on prolonged use.

Hives (urticaria)

Second-generation antihistamines, and guidelines support increasing to up to four times the standard dose for chronic urticaria under medical supervision, which is more than most people realise is permitted. Non-sedating agents are preferred precisely so the dose can be raised.

Eye symptoms

Antihistamine or mast-cell-stabiliser eye drops (sodium cromoglicate, olopatadine) work better locally than oral drugs.

Eczema

Antihistamines do not treat eczema. The itch in eczema is largely not histamine-mediated. They are sometimes used at night for the sedation. The treatments that work are emollients, topical steroids, and topical calcineurin inhibitors.

Anaphylaxis

Antihistamines do not treat anaphylaxis. Adrenaline does.

This is the most important point in the chapter and it is widely misunderstood. Anaphylaxis is a rapidly progressing, potentially fatal reaction involving airway swelling, breathing difficulty, and circulatory collapse. Antihistamines act too slowly and do nothing for the airway or the blood pressure.

What to do:

1. Give adrenaline immediately by intramuscular auto-injector into the outer mid-thigh, through clothing if necessary. Do not wait to see whether it worsens.
2. Call emergency services and say "anaphylaxis."
3. Lie the person flat with legs raised (or sitting up if breathing is the main problem, or on their side if vomiting or unconscious). Do not stand them up or let them walk: sudden standing during anaphylaxis has caused deaths from cardiovascular collapse.
4. Give a second dose after 5 minutes if there is no improvement, which is why two auto-injectors are prescribed.
5. Go to hospital regardless of improvement, because of the risk of a biphasic reaction hours later.

Adrenaline works by constricting blood vessels (raising blood pressure and reducing swelling), relaxing airways, and stabilising mast cells. There is no situation in which giving adrenaline for suspected anaphylaxis causes more harm than withholding it. Delay in administration is the factor most consistently associated with death.

Antihistamines and steroids are given afterwards, for skin symptoms and possibly to reduce biphasic reactions, and neither is a substitute.

4. Choosing among second-generation antihistamines

Response varies individually. Trying a different one is reasonable if the first does not work.

Do not combine two antihistamines, and check cold remedies, sleep aids, and motion sickness tablets, which frequently contain a first-generation antihistamine you did not intend to take.

5. Cautions and interactions

6. Practical guidance for hay fever season

• Start the steroid nasal spray two weeks before your season.
• Use it daily, with correct technique, aimed away from the septum.
• Add a second-generation oral antihistamine for eye and general symptoms.
• Add antihistamine eye drops if the eyes dominate.
• Saline rinse to clear allergen from the nose, especially after being outside.
• Practical avoidance: shower and change clothes after being outdoors, dry washing indoors during high pollen, keep windows shut in the morning and early evening when pollen peaks, and wear wraparound sunglasses.
• If it is severe and lasts every year, ask about immunotherapy. It is the only treatment that changes the underlying disease, takes about three years, and produces lasting benefit.

7. The bottom line

• Second-generation antihistamines (loratadine, cetirizine, fexofenadine) should be the default: same efficacy, once daily, no sedation.
• First-generation antihistamines cross into the brain. Diphenhydramine impairs driving more than being at the legal alcohol limit, tolerance to the sedation develops within days, and long-term anticholinergic exposure is associated with dementia risk.
• Steroid nasal sprays are the most effective hay fever treatment and are wasted by intermittent use and bad technique. Start early, use daily, aim away from the septum.
• Antihistamines do not treat anaphylaxis. Adrenaline into the outer thigh, immediately, and call an ambulance. Do not let the person stand up.
• Check cold remedies and sleep aids for hidden first-generation antihistamines.
• Take fexofenadine with water, not fruit juice.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Histamine receptor subtypes and inverse agonism follow standard pharmacology. First-generation antihistamine impairment relative to alcohol follows Weiler et al., Annals of Internal Medicine, 2000, on diphenhydramine and driving. Anticholinergic burden and dementia risk follows Coupland et al., JAMA Internal Medicine, 2019, and Richardson et al., BMJ, 2018, with the causality caveat. The Beers Criteria listing follows the American Geriatrics Society. Intranasal corticosteroid superiority over oral antihistamines for nasal symptoms follows the ARIA guidelines and Cochrane reviews. Spray technique and septal deposition follow ENT guidance. Updosing antihistamines in chronic urticaria to four times standard dose follows the EAACI/GA2LEN/EDF/WAO urticaria guideline. Allergen immunotherapy as disease-modifying follows EAACI guidelines. Anaphylaxis management, including intramuscular adrenaline into the anterolateral thigh and the danger of standing the patient up, follows the Resuscitation Council UK guidance and Pumphrey's fatal reaction series. Montelukast neuropsychiatric events follow the FDA's 2020 boxed warning. Fexofenadine and fruit juice OATP interaction follows Dresser et al.

Open questions. Whether the anticholinergic-dementia association is causal or reflects prodromal prescribing cannot be resolved observationally, which is why the guidance is framed as prudence rather than proof.

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