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H1-Antihistamines

Q: Which specific drugs belong to first-generation H1-antihistamines?

First-generation H1-antihistamines include: Diphenhydramine — exhibits pronounced anticholinergic and local anesthetic activity.Chloropyramine — used to manage acute urticaria flare-ups.Promethazine — possesses the strongest antihistamine activity.Clemastine — possesses moderate antihistamine activity.Mebhydrolin — short-acting sedating agent.Quifenadine — sedating agent that crosses the blood-brain barrier.Dimetindene — suppresses autonomic nervous system activity.

Antihistaminica *H1*

For medical students2 min readUpdated 2026-10-10

H1-antihistamines are a pharmacological class of competitive histamine receptor antagonists used to prevent and reverse the effects of histamine. They are divided into two generations, with the key difference being their ability to cause sedation.

ClassificationTwo generations: sedating and non-sedating

CNS penetrationFirst-generation drugs readily cross the blood-brain barrier due to high lipophilicity

MetabolismSecond-generation drugs are metabolized by hepatic CYP3A4

Duration of actionFirst generation lasts 4–6 hours; second generation lasts 12–24 hours

Generation Comparison and Pharmacokinetics

The primary classification divides antihistamines into first and second generations, distinguished mainly by their sedative properties.

First-generation drugs: Exhibit pronounced sedative effects and low selectivity. In addition to H1-receptors, they block muscarinic acetylcholine receptors and $\alpha$-adrenergic receptors, leading to adverse effects. They readily cross the central nervous system due to high lipophilicity, and their duration of action is 4–6 hours.
Second-generation drugs: Characterized by high selectivity for H1-receptors and minimal penetration across the blood-brain barrier (BBB) due to low lipophilicity and active efflux by the P-glycoprotein transporter pump. They are non-sedating, and their duration of action reaches 12–24 hours.

Second-generation drugs are metabolized in the liver via the CYP3A4 isoenzyme. Some are prodrugs converted in the body into active metabolites, such as loratadine converting to desloratadine.

Clinical Indications and Special Considerations

The primary indication for H1-receptor blockers is allergic disease. They are effective for the prevention and treatment of urticaria, pruritus, allergic rhinitis, conjunctivitis, and angioedema (Quincke's edema). However, they are not the drugs of choice for anaphylactic shock or bronchial asthma.

The ability of first-generation drugs to affect the central nervous system finds specific uses:

Used as sedatives or sleep aids, e.g., diphenhydramine.
Used for the prevention of motion sickness (kinetosis).
Possess antiparkinsonian activity and may be co-administered with antipsychotics to manage extrapyramidal symptoms.

Safety Profile and Adverse Reactions

Most antihistamines are well tolerated, but their pharmacological profile results in several side effects. Anticholinergic and sedative actions can function as both therapeutic properties and adverse reactions.

Muscarinic receptor blockade effects: Dry mouth and gastrointestinal disturbances.
CNS effects: Pronounced drowsiness and lethargy.
Overdose: In children, may cause paradoxical excitation, seizures, and postural hypotension.

Cardiotoxicity associated with certain second-generation agents, such as astemizole and terfenadine, requires special attention. They can trigger cardiac arrhythmias, especially when metabolism is impaired. Concomitant administration with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, macrolides, or grapefruit juice consumption) is strictly contraindicated.

Mnemonic

1st generation: Sleep, Spryness (dryness), Speed/Heart (short duration). 2nd generation: Duration long, Domiciled (no CNS sedation).

Frequently asked questions

Which specific drugs belong to first-generation H1-antihistamines?

First-generation H1-antihistamines include:

Diphenhydramine — exhibits pronounced anticholinergic and local anesthetic activity.
Chloropyramine — used to manage acute urticaria flare-ups.
Promethazine — possesses the strongest antihistamine activity.
Clemastine — possesses moderate antihistamine activity.
Mebhydrolin — short-acting sedating agent.
Quifenadine — sedating agent that crosses the blood-brain barrier.
Dimetindene — suppresses autonomic nervous system activity.

What is the mechanism of cardiotoxicity caused by astemizole and terfenadine?

The cardiotoxicity of astemizole and terfenadine is linked to their potential to induce cardiac arrhythmias. The risk increases with slowed metabolism and elevated concentrations of the antihistamines, which can occur in liver disease, concomitant use of CYP3A4 inhibitors (ketoconazole, itraconazole, macrolides), or grapefruit juice consumption.

Which second-generation H1-antihistamines are prodrugs?

Loratadine is a second-generation H1-antihistamine prodrug. In the liver, via the CYP3A4 isoenzyme, it is metabolized into its active form, desloratadine. This pharmacokinetic conversion extends its therapeutic effect, providing a long duration of action lasting 12 to 24 hours.

What are the drugs of choice for anaphylactic shock?

Epinephrine (adrenaline) is the drug of choice and the only first-line medication for anaphylactic shock. H1-antihistamines themselves are not drugs of choice for this condition. Adjunctive intravenous medications may include:

Antihistamines — diphenhydramine, chloropyramine, promethazine.
Glucocorticoids — prednisolone, dexamethasone, hydrocortisone (in high doses).
Calcium preparations.

Why do first-generation antihistamines cause sedation while second-generation drugs do not?

First-generation drugs are highly lipophilic, allowing them to easily cross the blood-brain barrier into the central nervous system. Second-generation drugs have low lipophilicity and are actively pumped back out of the BBB endothelium into the blood by the P-glycoprotein transporter.

What are the absolute contraindications for astemizole and terfenadine?

Absolute contraindications include liver disease, concomitant use of metabolic inhibitors (such as ketoconazole, itraconazole, and macrolides), and consumption of grapefruit juice, which inhibits the CYP3A4 isoenzyme.

Are antihistamines used for bronchial asthma and anaphylactic shock?

No, antihistamines are not the drugs of choice for these conditions, and medications from other pharmacological groups must be used to treat patients.

Go deeper

Gradation of antihistamine potency among specific drugs
Local anesthetic activity of first-generation blockers and sodium channel blockade
Effect of CYP3A4 inhibitors on blood concentrations of antihistamines
Historical use of first-generation drugs for nausea and vomiting of pregnancy and reasons for discontinuation
Occupational restrictions and general contraindications for the H1-blocker class