Rational application of antihistamines and attention I. Classification of antihistamines.
(A) according to the mechanism of action classification can be divided into H1 receptor blockers, H2 receptor blockers, histamine blockers.
1, H1 receptor blockers are: diphenhydramine, paracetamol, cycloheximide, promethazine (non-nagin), cetirizine, avastin, loratadine, terfenadine, imipramine, etc.
2, H2 receptor blockers: cimetidine, ranitidine, etc.
3, histamine blockers: such as ketotifen, trinostat, zapstat, etc.
(B) H1 receptor blockers according to the chemical structure of the drug classification
1, ethanolamine class: such as Benadryl, Chaiphenhydramine, Clomastine.
2, hydrocarbon amines: chlorpheniramine (paracetamol), trepropidin (Kemin, carve free), the second generation of antihistamines Avastin (Xinminli or Xinminle) is a derivative of trepropidin.
3, piperidine: Cyproheptadine, second-generation loratadine, terfenadine (Mindy), fexofenadine, astemizole, imipramine, ibastine structure also belongs to the piperidine class.
4, piperazines: hydroxyzine (Antalac), dechlorinated hydroxyzine (Keminizine), chlorocyclizine (Comfrel), the second generation of cetirizine is a derivative of hydroxyzine.
5.Phenothiazines: promethazine (fenagan), methaqualazine (Polymarine).
6.Other: Doxorubicin, chlordiazepoxide.
Second, the indications of antihistamines.
Antihistamines play a role in all inflammatory reactions in which mast cells or basophils degranulate and release histamine.
(A) Metabolic reactions are mainly type I metabolic diseases, such as urticaria, angioedema, atopic dermatitis, anaphylaxis, drug rash, etc. triggered by metabolic mechanisms. In other type II, III, IV allergic reactions, although these drugs are also commonly used in clinical practice, the efficacy and exact mechanism are unknown.
(B) Non-metabolic reactions
1.Pseudo-allergic reactions, such as urticaria, angioedema and drug rash caused by histamine releasing agents.
2.Physical urticaria and urticaria caused by other non-allergic reactions.
3.Non-reactive insect bite reaction.
4, used for various pruritic diseases, the exact mechanism and efficacy is unknown, may be due to its sedative or drowsy effect, but also may be due to the role of anti-5-hydroxytryptamine and other inflammatory mediators.
Antihistamines (antihistamine antibodies) cannot destroy histamine, have no chemical antagonistic or neutralizing effect with histamine, and cannot stop or reduce the release of histamine, so they have no therapeutic effect on a variety of skin allergy symptoms such as skin erythema and edema exhibited by patients at the time of consultation, but only prevent the further development of allergic reactions to a certain extent.
H1 receptor blockers without central inhibitory effects generally have no or little antipruritic effect. In addition, the itching unrelated to histamine, such as eczema dermatitis itching, only the application of drugs with a central inhibitory effect can have some antipruritic effect.
Third, the application of antihistamines precautions.
(A) the knowledge of medicinal chemistry to guide the use of drugs should not be used in combination of several situations.
1, a drug and its derivatives (or optical isomers) such as loratadine + loratadine such as Avastin (Ximinli) + Treprolidine (Kemin) chlorpheniramine (paracetamol) + dextrochlorpheniramine 2, the basic chemical structure of similar antihistamines loratadine + cycloheximide loratadine + terfenadine (or Xismin) cetirizine + hydroxyzine (or dechloroxazine) Polymarin + fenagine (b) to pharmacodynamics Guide rational drug use 1, antihistamine: mechanism – competitive anti-H1 receptors.
2. Problems.
(1) inappropriate indications: for non-histamine-mediated symptoms.
(2) H1 receptors: the limitations of antagonists and the contradiction of high expectations.
(3) Attention to H1 receptor selectivity.
In addition to H1 receptor receptors, other mechanisms may exist.
(1) membrane protective effect: ketotifen, loratadine, imipramine, etc.
(2) inhibit the expression of adhesion molecules: loratadine, cetirizine, etc.
(3) Inhibit the chemotaxis of eosinophils: loratadine, cetirizine, imipramine, etc.
(3) Use the principle of pharmacokinetics to guide the clinical use of drugs
1. Onset of action ≠ time to peak
(1) The onset of action time depends on the binding rate of the drug and H1 receptor.
(2) Maintenance time depends on the dissociation rate of drug and H1 receptor.
2.Metabolic pathway of the drug (liver, kidney), metabolic enzymes (CYP-4503A4, 2D6, glucuronidation), metabolites, pharmacological activity of metabolites.
3.The excretion of drugs.
(4) Drug elimination half-life: determine the drug delivery interval, drug accumulation, drug interactions.
(D) drug synergy between some antihistamines (most first-generation antihistamines, second-generation astemizole, terfenadine) through drug metabolism (CYP-4503A4) metabolism; certain drugs such as azole antifungal drugs (ketoconazole), macrolide antibiotics (such as erythromycin), statin lipid-lowering drugs (such as simvastatin), can inhibit the above CYP-4503A4; combined After application, the blood concentration of terfenadine or astemizole increases; loratadine can be metabolized through two pathways, CYP-4503A4 and CYP-4502D6; imipramine: 65% is metabolized through glucuronide.
Drugs that inhibit CYP-4503A4 alone do not increase the blood concentration of loratadine, but if cimetidine, which inhibits CYP-4502D6, is taken at the same time, the blood concentration of loratadine can be increased.
1, with cytochrome P450 enzyme inhibitors such as pyrrole antifungal drugs and macrolide antibiotic drugs cautiously taken at the same time antihistamines are: imipramine, loratadine (keratan), ibastine (Kestin), fexofenadine hydrochloride (Ledofy), terfenadine (Mindi).
2. Antihistamines with ketoconazole and erythromycin without cardiovascular side effects include: cetirizine, levocetirizine, desloratadine, and clomastine.
Tricyclic antidepressants (doxepin) cannot be used in combination with cimetidine because of the interaction with hepatic cytochrome P450 enzyme system, making drug concentration fluctuations, and also cannot be used in combination with sympathomimetic drugs such as adrenaline.
Precautions for clinically used antihistamines.
Time to peak blood concentration (Tmax) of antihistamines Suitable for age Can be combined with ketoconazole and macrocyclic lipids Can be combined with cimetidine Cetirizine 30-60 minutes ≥ 2 years old √ √ levocetirizine 0.7-1 hours ≥ 2 years old √ √ loratadine 0.5-1 hours ≥ 2 years old × × Desloratadine 3 hours ≥ 12 years √ √ Ebastine 2.64 hours ≥ 2 years √ √ Imipramine 1.5 hours ≥ 12 years × × × Azelastine 4.2 hours ≥ 12 years √ √ Fexofenadine hydrochloride 2.6 hours ≥ 6 years × √ Stastine hydrochloride 30 minutes onset of action ≥ 3 years √ √ Fumagastine 30 minutes onset of action 2-5 hours > 2 years √ √ (v) Adverse cardiac effects of antihistamines 1. Group A: Drugs have cardiac effects at their antihistamine concentrations. Such as terfenadine, astemizole, diphenhydramine, hydroxyzine.
2. Group B: drugs have cardiac effects only at concentrations higher than their antihistamine concentrations. Such as chlorpheniramine, cyproheptadine, epalrestine, ipratropium, mepyramine.
3. Group C: Drugs without cardiac effects. Such as avastin, cetirizine, loratadine, ketotifen, mepiquatrazine (Polymarine), clomastine.