H₁ antagonists, also called H₁ blockers, are a class of

medications Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

that block the action of

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

at the H₁ receptor, helping to relieve

allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...

s; other agents may have antihistaminergic action but are not true antihistamines. In common use, the term "antihistamine" refers only to H₁-antihistamines. Virtually all H₁-antihistamines function as

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

s at the histamine H₁-receptor, as opposed to neutral

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.

Medical uses

H₁-antihistamines are used clinically to treat histamine-mediated allergic conditions. These indications may include:Rossi S (Ed.) (2004). ''

Australian Medicines Handbook Australian Medicines Handbook (AMH) is a peer-reviewed medicines prescribing guide for Australian health professionals. The handbook is available in paper and digital formats and is supplemented by the ''AMH Aged Care Companion'' and the ''AMH ...

2004''.

Adelaide Adelaide ( , ; ) is the list of Australian capital cities, capital and most populous city of South Australia, as well as the list of cities in Australia by population, fifth-most populous city in Australia. The name "Adelaide" may refer to ei ...

: Australian Medicines Handbook. *

Allergic rhinitis Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a type I hypersensitivity reaction. Signs a ...

* Allergic

conjunctivitis Conjunctivitis, also known as pink eye or Madras eye, is inflammation of the conjunctiva, the thin, clear layer that covers the white surface of the eye and the inner eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness ...

* Allergic dermatological conditions (

contact dermatitis Contact dermatitis is a type of acute or chronic inflammation of the skin caused by exposure to chemical or physical agents. Symptoms of contact dermatitis can include itchy or dry skin, a red rash, bumps, blisters, or swelling. These rashes ...

) *

Rhinorrhea Rhinorrhea (American English), also spelled rhinorrhoea or rhinorrhœa (British English), or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is an extremely common condition. It is a common symptom of allergie ...

(runny nose) *

Urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...

Angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

* Diarrhea *

Pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

(

atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. Atopic dermatitis is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditi ...

, insect bites) * Anaphylactic or anaphylactoid reactions—adjunct only First-generation H₁-antihistamines can act on the central nervous system. As a result, they are also used for: * Nausea, vomiting, and

motion sickness Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include ...

* Sedation H₁-antihistamines can be administered topically (through the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

nose A nose is a sensory organ and respiratory structure in vertebrates. It consists of a nasal cavity inside the head, and an external nose on the face. The external nose houses the nostrils, or nares, a pair of tubes providing airflow through the ...

, or

eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

s) or systemically, based on the nature of the allergic condition. The authors of the American College of Chest Physicians Updates on Cough Guidelines (2006) recommend that, for cough associated with the common cold, first-generation antihistamine-decongestants are more effective than newer, non-sedating antihistamines. First-generation antihistamines include

diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...

(Benadryl), carbinoxamine (Clistin), clemastine (Tavist),

chlorpheniramine Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken orally (by mouth). The medication takes effect within two hour ...

(Chlor-Trimeton), and brompheniramine (Dimetane). However, a 1955 study of "antihistaminic drugs for colds," carried out by the U.S. Army Medical Corps, reported that "there was no significant difference in the proportion of cures reported by patients receiving oral antihistaminic drugs and those receiving oral placebos. Furthermore, essentially the same proportion of patients reported no benefit from either type of treatment."

Side effects

Adverse drug reaction An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this ...

s are most commonly associated with the first-generation H₁-antihistamines. This is due to their relative lack of selectivity for the H₁-receptor and their ability to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. The most common adverse effect is sedation; this "side-effect" is utilized in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H₁-antihistamines include dizziness,

tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...

, blurred vision,

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

, incoordination,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, increased appetite leading to

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, tremor,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and vomiting,

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, dry mouth, and dry cough. Infrequent adverse effects include urinary retention, palpitations,

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

and

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

. The newer, second-generation H₁-antihistamines are far more selective for peripheral histamine H₁-receptors and have a better tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include drowsiness, fatigue, headache, nausea, and dry mouth. Continuous and/or cumulative use of

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

medications, including first-generation antihistamines, is associated with a higher risk for cognitive decline and dementia in older people.

Pharmacology

In type I hypersensitivity allergic reactions, an

allergen An allergen is an otherwise harmless substance that triggers an allergic reaction in sensitive individuals by stimulating an immune response. In technical terms, an allergen is an antigen that is capable of stimulating a type-I hypersensitivi ...

(a type of

antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

) interacts with and cross-links surface IgE

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...

s and

basophil Basophils are a type of white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and f ...

s. Once the allergen cross-links

Immunoglobulin E Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isoform") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε ...

, tyrosine kinases rapidly signal into the cell, leading to cell degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, the histamine can react with local or widespread tissues through

histamine receptor The histamine receptors are a class of G protein–coupled receptors which bind histamine as their primary endogenous ligand. Histamine is a neurotransmitter involved in various physiological processes. There are four main types of histamine recep ...

s. Histamine, acting on H₁-receptors, produces

pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...

, flushing,

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common bei ...

, increase in

vascular permeability Vascular permeability, often in the form of capillary permeability or microvascular permeability, characterizes the permeability of a blood vessel wall–in other words, the blood vessel wall's capacity to allow for the flow of small molecules ( ...

and potentiation of pain. While H₁-antihistamines help against these effects, they work only if taken before contact with the allergen. In severe allergies, such as

anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

, these effects may be of life-threatening severity. Additional administration of

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...

, often in the form of an

autoinjector An autoinjector (or auto-injector) is a medical device for injection of a premeasured dose of a particular drug. Most autoinjectors are one-use, disposable, spring-loaded syringes (prefilled syringes). By design, autoinjectors are easy to use an ...

, is required by people with such hypersensitivities.

First-generation (unselective)

These are the oldest H₁-antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic

acetylcholine receptor An acetylcholine receptor (abbreviated AChR) or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptor ...

(

) antagonists as well. These agents also commonly have action at α-adrenergic receptors and/or

5-HT receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the Central nervous system, central and peripheral nervous systems ...

s. This lack of receptor selectivity is the basis of the poor tolerability profile of some of these agents, especially when compared with the second-generation H₁-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

Classes

The first H₁-antihistamine discovered was piperoxan, by Ernest Fourneau and Daniel Bovet (1933) in their efforts to develop a

guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy ( ), is a species of rodent belonging to the genus ''Cavia'', family Caviidae. Animal fancy, Breeders tend to use the name "cavy" for the ani ...

animal model for

at the

Pasteur Institute The Pasteur Institute (, ) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines for anthrax and rabies. Th ...

Paris Paris () is the Capital city, capital and List of communes in France with over 20,000 inhabitants, largest city of France. With an estimated population of 2,048,472 residents in January 2025 in an area of more than , Paris is the List of ci ...

. Bovet went on to win the 1957

Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, acco ...

for his contribution. Following their discovery, the first-generation H₁-antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties.

Common structural features

* Two aromatic rings, connected to a central carbon, nitrogen, or CO * Spacer between the central X and the amine, usually 2–3 carbons in length, linear, ring, branched, saturated, or unsaturated * Amine is substituted with small alkyl groups, e.g., CH₃ Antihistamine

X = N, R1 = R2 = small alkyl groups
X = C
X = CO * Chirality at X can increase both the potency and selectivity for H1-receptors * For maximum potency, the two aromatic rings should be oriented in different planes ** For example, the tricyclic ring system is slightly puckered, and the two aromatic rings lie in different geometrical planes, giving the drug a very high potency.

Second-generation

Second-generation H₁-antihistamines are newer drugs that are much more selective for peripheral H₁ receptors as opposed to the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

H₁ receptors and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing effective relief of allergic conditions. Most of these compounds have peripheral selectivity because they are

zwitterion In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively and negatively charged functional groups. : (1,2- dipolar compounds, such as ylides, are sometimes excluded from ...

ic at physiological pH (around pH 7.4). As such, they are very polar, meaning they are less likely to cross the

and act mainly outside the central nervous system. Examples of systemic second-generation antihistamines include: *

Acrivastine Acrivastine is a medication used for the treatment of allergies and hay fever. It is a second-generation H1-receptor antagonist antihistamine (like its base molecule triprolidine) and works by blocking histamine H1 receptors. This non-sedating ...

(Benadryl Allergy Relief (UK), Semprex-D (US)) * Astemizole (Hismanal) – withdrawn * Bepotastine (Talion, Bepreve) * Bilastine (Blexten, Fortecal, Lendin) *

Cetirizine Cetirizine is a second-generation antihistamine, second-generation Peripherally selective antihistamine used to treat allergic rhinitis (hay fever), dermatitis, and urticaria (hives). It is taken by mouth. Effects generally begin within thirty ...

(Zyrtec, Benadryl Allergy One a Day Relief (UK)) *

Desloratadine Desloratadine sold under the brand name Aerius among others, is a tricyclic H1 antagonist, H1 inverse agonist that is used to treat allergy, allergies. It is an active metabolite of loratadine. It was patented in 1984 and came into medical u ...

(Aerius) * Ebastine (Evastin, Kestine, Ebastel, Aleva, Ebatrol) *

Fexofenadine Fexofenadine, sold under the brand name Allegra among others, is an antihistamine medication used in the treatment of allergy symptoms such as allergic rhinitis and urticaria. Therapeutically, fexofenadine is a selective peripheral H1 blocke ...

(Allegra) *

Ketotifen Ketotifen is an antihistamine medication and a mast cell stabilizer used to treat allergic conditions such as conjunctivitis, asthma, and urticaria (hives). Ketotifen is available in ophthalmic (eye drops or drug-eluting contact lenses) and o ...

(Zaditor) – also

mast cell stabilizer Mast cell stabilizers are medications used to prevent or treat certain allergic disorders. They block mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators. One suspected pharmacody ...

; sometimes classified as a first-generation antihistamine, see Ketotifen § Classification * Levocetirizine (Xyzal) *

Loratadine Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis (hay fever) and hives. It is also available in drug combinations such as loratadine/pseudoephedrine, in whic ...

(Claritin) * Mizolastine (Mizollen) * Quifenadine (Phencarol, Фенкарол) * Rupatadine (Rupafin) *

Terfenadine Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi) and was marketed under various brand names, including Seldane in the United States, Triluda ...

(Seldane (US), Triludan (UK), and Teldane (Australia)) – withdrawn Examples of topical second-generation antihistamines include: * Azelastine * Levocabastine *

Olopatadine Olopatadine, sold under the brand name Patanol among others, is an antihistamine medication used to decrease the symptoms of allergic conjunctivitis and allergic rhinitis (hay fever). It is used as eye drops or as a nasal spray. The eye drops ...

Regulation

Over-the-counter

H₁ receptor antagonists that are approved for

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...

sale in the United States include the following.

First-generation

Common/marketed: * Brompheniramine (Dimetapp, Dimetane) *

Chlorpheniramine Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken orally (by mouth). The medication takes effect within two hour ...

(Chlor-Trimeton) *

Dimenhydrinate Dimenhydrinate, also known as diphenhydramine/8-chlorotheophylline salt and sold under the brand names Dramamine and Gravol, among others, is an over-the-counter medication used to treat motion sickness and nausea. Dimenhydrinate is a theocl ...

(Dramamine, Gravol) – combination of

and 8-chlorotheophylline *

Diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...

(Benadryl) * Doxylamine (Unisom) Uncommon/discontinued: * Chlorcyclizine * Dexbrompheniramine * Dexchlorpheniramine * Methapyrilene * Phenindamine * Pheniramine * Phenyltoloxamine * Pyrilamine * Thenyldiamine * Thonzylamine * Triprolidine

Second-generation

(Zyrtec) *

(Allegra) * Levocetirizine (Xyzal) *

(Alavert, Claritin)

References

External links

* {{DEFAULTSORT:H1 Antagonist

Medical uses

Side effects

Pharmacology

First-generation (unselective)

Classes

Common structural features

Second-generation

Regulation

Over-the-counter

First-generation

Second-generation

See also

References

External links