H1 antihistamines
Drugs that block the histamine H1 receptor. First-generation ones cross into the brain and sedate; second-generation ones mostly do not.
What they are
H1 antihistamines treat allergic rhinitis, allergic conjunctivitis, urticaria and itching, and some are used for nausea, motion sickness, vertigo and sleep. First-generation agents (diphenhydramine, chlorphenamine, hydroxyzine, promethazine, cyproheptadine, cyclizine, meclozine) are lipophilic, cross the blood–brain barrier and also block muscarinic, alpha-adrenergic or serotonin receptors. Second-generation agents (loratadine, desloratadine, cetirizine, fexofenadine) are less lipophilic and are pumped out of the brain by P-glycoprotein, so they cause little sedation. In anaphylaxis they only ease itching and hives: epinephrine is the treatment.
Mechanism of action
The H1 receptor is a Gq-coupled receptor with some activity even without histamine. H1 antihistamines are inverse agonists: they bind it and stabilise its inactive form, so histamine cannot raise inositol trisphosphate and calcium. This prevents the itch, sneezing, watery secretions, vasodilation and capillary leak that histamine causes. In the brain, histamine keeps us awake, which explains why the agents that enter the brain cause drowsiness. The older agents also block muscarinic receptors (dry mouth, urinary retention, confusion), alpha-1 receptors (low blood pressure) and, for cyproheptadine, serotonin receptors.
Target: Histamine H1 receptor (HRH1), Gq-coupled
Drugs in this class
- LoratadineA once-daily second-generation antihistamine for hay fever and allergic itch that rarely causes drowsiness.Histamine H1 receptor
- CetirizineA second-generation antihistamine for hay fever and hives; it acts fast and is the most likely of its group to cause…Histamine H1 receptor
- DiphenhydramineThe classic sedating first-generation antihistamine: allergy, sleep, motion sickness and drug-induced dystonia, with…Histamine H1 receptor
- ChlorphenamineA first-generation antihistamine found in many cold and allergy products; it sedates less than diphenhydramine but…Histamine H1 receptor
- CyproheptadineA sedating antihistamine that also blocks serotonin receptors; known for increasing appetite and as an antidote in…Histamine H1 receptor
- FexofenadineThe least sedating second-generation antihistamine; fruit juices and some antacids reduce its absorption.Histamine H1 receptor
- HydroxyzineA sedating antihistamine used for itch, anxiety and sedation before surgery; it can prolong the QT interval.Histamine H1 receptor
- PromethazineA strongly sedating phenothiazine antihistamine for nausea, allergy and sedation; never under age 2, and the injection…Histamine H1 receptor
- DesloratadineThe active metabolite of loratadine, a once-daily non-sedating antihistamine for allergic rhinitis and chronic hives.Histamine H1 receptor
- MeclozineA piperazine antihistamine used to prevent and treat nausea, vomiting and dizziness of motion sickness and vertigo.Histamine H1 receptor
- CyclizineA piperazine antihistamine anti-sickness medicine for nausea, vomiting, motion sickness and vertigo; on the WHO…Histamine H1 receptor
- DoxylamineA sedating first-generation antihistamine: an over-the-counter sleep aid and, with pyridoxine, a treatment for nausea…Histamine H1 receptor
- DimenhydrinateA sedating H1 antihistamine (a salt of diphenhydramine) used to prevent and treat the nausea, vomiting and vertigo of…Histamine H1 receptor (and muscarinic receptors)
Others in the class
- Levocetirizine
- Bilastine
- Rupatadine
- Doxylamine
- Dimenhydrinate
- Ketotifen
Test yourself
Think of the answer, then tap the question to see it.
Why do first-generation antihistamines cause drowsiness while second-generation ones rarely do?
They are lipophilic and cross the blood–brain barrier, where histamine maintains wakefulness; second-generation agents are less lipophilic and are pumped out by P-glycoprotein.
Which effects of diphenhydramine come from muscarinic blockade?
Dry mouth, blurred vision, urinary retention, constipation, tachycardia and confusion, especially in older adults.
What is the first drug in anaphylaxis, and what role do H1 antihistamines have?
Intramuscular epinephrine; H1 antihistamines are only an add-on for itching and hives once the airway and circulation are treated.
How do H1 antihistamines act at the receptor: as neutral antagonists or as inverse agonists?
As inverse agonists: they stabilise the inactive form of the H1 receptor, which has some activity even without histamine.
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Antihistamines - NHS (NHS, 2023); DailyMed - DIPHENHYDRAMINE HYDROCHLORIDE injection (DailyMed (U.S. National Library of Medicine), 2026); Cetirizine: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.