Generation comparison and pharmacokinetics
The main principle in classifying antihistamines is their division into first and second generation. The primary criterion for distinction between them is the ability to cause a sedating effect.
- First-generation drugs: exhibit a pronounced sedative effect and low selectivity. In addition to H1 receptors, they block M-cholinergic and $\alpha$-adrenergic receptors, leading to adverse reactions. They easily cross the central nervous system due to high lipophilicity, and their duration of action is 4–6 hours.
- Second-generation drugs: are characterized by high selectivity for H1 receptors and practically do not cross the blood-brain barrier (BBB) due to low lipophilicity and active efflux mediated by the P-glycoprotein transport pump. They do not cause a sedative effect, and their duration of action reaches 12–24 hours.
Metabolism of second-generation drugs occurs in the liver involving the CYP3A4 isoenzyme. Some of them are prodrugs and are converted in the body into active metabolites, for example, loratadine is converted into desloratadine.
Clinical indications and application features
The main indication for prescribing H1 receptor blockers is allergic diseases. They are effective for the prevention and treatment of urticaria, pruritus, allergic rhinitis and conjunctivitis, as well as angioedema (angioneurotic edema). However, it is important to consider limitations: these agents are not drugs of choice in anaphylactic shock and bronchial asthma.
The ability of first-generation drugs to affect the central nervous system finds specific separate applications:
- Used as sedatives or sleeping aids, for example, diphenhydramine.
- Used for the prevention of motion sickness (kinetosis).
- They possess antiparkinsonian activity and can be prescribed together with neuroleptics to correct extrapyramidal disorders.
Safety Profile and Adverse Reactions
Most antihistamines are well tolerated, but their pharmacological profile accounts for a number of side effects. Anticholinergic and sedative actions can act as both therapeutic properties and adverse reactions.
- Effects of M-cholinergic receptor blockade: dry mouth and gastrointestinal dysfunction.
- CNS effects: pronounced drowsiness and lethargy.
- Overdose: in children, it can cause paradoxical excitation, seizures, and postural hypotension.
Special attention should be paid to the cardiotoxicity of certain second-generation drugs, such as astemizole and terfenadine. They can provoke cardiac arrhythmias, especially when metabolism is impaired. Their co-administration with CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, macrolides, or grapefruit juice consumption) is strictly contraindicated.
Briefly: answers to topical questions
Which specific drugs belong to first-generation H1-antihistamines?
First-generation H1-antihistamines include the following specific drugs:
- Diphenhydramine — has pronounced M-anticholinergic and local anesthetic activity.
- Chloropyramine — used to relieve exacerbations of acute urticaria.
- Promethazine — possesses the strongest antihistamine activity.
- Clemastine — has moderate antihistamine activity.
- Mebhydrolin — a short-acting sedative drug.
- Quifenadine — a sedative drug that crosses the blood-brain barrier.
- Dimindene — suppresses autonomic nervous system activity.
What is the mechanism of the cardiotoxic action of astemizole and terfenadine?
The cardiotoxicity of astemizole and terfenadine is related to their ability to cause cardiac arrhythmias. The risk increases with slowed metabolism and elevated concentrations of antihistamines, which can occur in liver disease, concomitant use of metabolism/CYP3A4 inhibitors (ketoconazole, itraconazole, macrolides), or consumption of grapefruit juice.
Which second-generation H1-antihistamines are prodrugs?
Among second-generation H1-antihistamines, loratadine is a prodrug. In the liver, under the influence of the CYP3A4 isoenzyme, it undergoes metabolism and converts into its active form — desloratadine. Such pharmacokinetic transformation helps prolong the therapeutic effect of the drug, providing a long-lasting action of 12 to 24 hours.
Which drugs are the drugs of choice in anaphylactic shock?
The drug of choice and the only first-line medication in anaphylactic shock is adrenaline (epinephrine). H1-antihistamines themselves are not drugs of choice for this condition. As adjuvant pharmacotherapy, the following may be administered intravenously:
- Antihistamines — diphenhydramine, chloropyramine, promethazine.
- Glucocorticoids — prednisolone, dexamethasone, hydrocortisone (in high doses).
- Calcium preparations.
1st generation: Sleep, Dryness, Heart (short duration). 2nd generation: Long-acting, stays at Home (no central sedation).
Class and exam questions
Why do 1st-generation drugs cause a sedative effect, while 2nd-generation drugs do not?
1st-generation drugs have high lipophilicity, allowing them to easily cross the blood-brain barrier into the central nervous system. 2nd-generation drugs have low lipophilicity and are actively pumped out of the BBB endothelium back into the blood by the P-glycoprotein transporter protein.
What are the absolute contraindications for the use of astemizole and terfenadine?
Absolute contraindications include liver disease, concurrent use of metabolic inhibitors (such as ketoconazole, itraconazole, and macrolides), and consumption of grapefruit juice, which inhibits the CYP3A4 isoenzyme.
Are antihistamines used in bronchial asthma and anaphylactic shock?
No, in these conditions antihistamines are not drugs of choice, and medications from other pharmacological groups are used to help patients.
What else to study on this topic
- Gradation of antihistamine activity of specific drugs
- Local anesthetic activity of 1st-generation blockers and sodium channel blockade
- Effect of CYP3A4 inhibitors on blood concentrations of antihistamines
- Historical aspect of using 1st-generation drugs for nausea and vomiting of pregnancy and reasons for abandoning it
- Professional restrictions and general contraindications for the H1-blocker group
Master the entire topic in the «Pharmacology» course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "H1-antihistamines" and another 5,304 subjects
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 116 video lessons on the subject
Other topics in the section "Agents Regulating Immune Processes"
Free video lessons: pharmacologyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.