Loratadine
Loratadine is an antiallergic drug belonging to the group of second-generation H1-histamine receptor blockers. Drugs in this group have the ability to block the effect of histamine on the body, relieve smooth muscle spasms induced by this mediator, reduce the permeability of capillary walls, neutralize the hypotensive effect of histamine, and prevent the development of allergic reactions. The effectiveness of drugs that suppress the effect of histamine on the corresponding receptors has been known for a long time. However, a number of undesirable side reactions associated with the use of classical antihistamines did not allow us to talk about NIK as the first choice drugs for the treatment of allergies. We are talking, first of all, about their inhibitory effect on the central nervous system (sedative and depressive effect). The synthesis of new antihistamines, not inferior in activity to their predecessors, but devoid of the side effects characteristic of the latter, made it possible to solve this problem. Loratadine is a relatively new, pronounced antihistamine that has a rapid and long-lasting effect and is devoid of clinically significant side effects on the central nervous system (this feature of loratadine is associated with its inability to penetrate the blood-brain barrier). In its antihistamine activity, it is superior to diphenhydramine (better known as Diphenhydramine), astemizole, terfenadine, and promethazine. In addition to antiallergic, the drug has antiexudative and antipruritic effects.
When taken orally, the drug is quickly absorbed in the digestive tract and undergoes almost complete metabolic transformations. The maximum concentration of the active substance in the blood plasma is observed 1-1.5 hours after administration. When taken with food, loratadine increases its bioavailability by 40% (and its active metabolite descarboethoxyloratadine by 15%). The half-life of the drug is 8.4 hours, its active metabolite is 28 hours. Loratadine is excreted in equal proportions by the kidneys and intestines. Studies have shown that the drug is a selective blocker of histamine H1 receptors: even in high doses sufficient to block histamine-determined bronchospasm, it only has a minor effect on platelet-activating factor and methacholine. Unlike chlorpheniramine, diphenhydramine, promethazine and mequitazine, loratadine does not have anticholinergic activity. In clinical studies, it was demonstrated that loratadine in a single daily dose of 10 mg had no effect on cognitive function, which makes it possible to take this drug for people whose work involves managing potentially dangerous mechanisms, incl. driving a car. Direct contraindications to taking the drug are pregnancy, breastfeeding and individual intolerance to loratadine. The drug does not enhance the effect of ethanol.
Choosing an antihistamine: a pharmacologist's view
For citation. Kareva E.N. Choosing an antihistamine: a pharmacologist’s view // RMJ. 2021. No. 12. pp. 811–816.
Antihistamines (AGDs) are the first line of treatment for most allergic diseases.
They are predominantly over-the-counter products; they have long been firmly established in our practice and have been used for more than half a century. Often the choice of these drugs is carried out empirically or even left to the patients, but there are many nuances that determine how effective a particular drug will be for a particular patient, which means that the choice of these drugs must be approached no less responsibly than, for example, the choice antibiotics. Each specialist in his clinical practice has probably encountered situations when a particular drug did not have the desired clinical effect or caused hyperergic reactions. What does this depend on and how can you minimize the risks? Variability in response to a drug is most often associated with the activity of metabolic enzymes in the patient’s liver; the situation is aggravated in the case of polypharmacy (5 or more prescribed drugs at the same time). Therefore, one of the real ways to reduce the risk of an inadequate response of the body to a drug is to choose a drug that is not metabolized in the liver. In addition, when choosing an antihypertensive, it is important to evaluate the following parameters: the strength and speed of onset of the effect, the possibility of long-term use, the benefit/risk ratio (efficacy/safety), ease of use, the possibility of use for concomitant pathology in combination with other drugs in a given patient, the route of elimination , need for dose titration, price. To solve this problem, consider the current information on histamine and antihistamines. Histamine and its role in the body
Histamine in the human body performs a number of physiological functions, plays the role of a neurotransmitter and is involved in many pathobiological processes (Fig. 1).
The main depot of histamine in the body is mast cells and basophils, where it is found in the form of granules in a bound state. The largest number of mast cells are localized in the skin, mucous membranes of the bronchi and intestines. Histamine realizes its activity exclusively through its own receptors. Modern ideas about the functional load of histamine receptors, their localization and mechanisms of intracellular signaling are shown in Table 1.
In addition to physiological functions, histamine is involved in the development of an inflammatory process of any nature. Histamine causes itching, sneezing and stimulates secretion of the nasal mucosa (rhinorrhea), contraction of smooth muscles of the bronchi and intestines, tissue hyperemia, dilatation of small blood vessels, increased vascular permeability to water, proteins, neutrophils, and the formation of inflammatory edema (nasal congestion). Not only with allergic diseases, but also with any pathological processes with a pronounced inflammatory component, the level of histamine in the body is always increased. This is indicated for chronic infectious and inflammatory diseases of the respiratory and urogenital tracts, acute respiratory viral infections, and influenza [1–3]. Moreover, the daily amount of histamine in urine during influenza is approximately the same as during exacerbation of allergic diseases. Therefore, a pathogenetically justified and clinically useful step is to reduce the activity of the histamine system in conditions of its increased activity. In principle, the histaminergic activity of the body can be suppressed either through a decrease in the amount of free histamine (inhibition of synthesis, activation of metabolism, inhibition of release from the depot), or through blockade of histamine receptor signals. In clinical practice, drugs have been used that stabilize mast cell membranes, thereby preventing the release of histamine. However, when using them, you have to wait a long time for the desired effect to occur, and the therapeutic effectiveness of this group of drugs is very moderate, so they are used exclusively for prophylactic purposes. A quick and pronounced effect is achieved when using antihistamines.
Classification of antihistamines
According to the classification adopted by the European Academy of Allergists and Clinical Immunologists, all antihistamines are divided into 2 generations depending on their effect on the central nervous system.
First-generation antihistamines
H1-antagonists of the first generation penetrate the blood-brain barrier (BBB) and can both stimulate and suppress the functioning of the central nervous system (Fig. 2). As a rule, the latter happens in most patients. A sedative effect when taking first generation AGPs is subjectively noted by 40–80% of patients. The lack of sedative effect in individual patients does not exclude the objective negative impact of these drugs on cognitive functions, which patients may not pay attention to (ability to drive, learn, etc.). Dysfunction of the central nervous system is observed even when using minimal doses of these drugs. The effect of first-generation antihypertensive drugs on the central nervous system is the same as when using alcohol and sedatives. Stimulation has been observed in some patients receiving conventional doses of antihypertensives and is manifested by restlessness, nervousness and insomnia. Typically, central excitation is characteristic of an overdose of first generation AGPs; it can lead to convulsions, especially in children.
When taking AGP of the first generation, in addition to the sedative effect and effect on cognitive functions, the following are observed: • short-term effect (forced use 3-4 times a day); • rapid development of tachyphylaxis (it is necessary to change the drug every 7–10 days); • low selectivity of action: in addition to histamine H1 receptors, they block acetylcholine, adrenaline, serotonin, dopamine receptors and ion channels, causing many side effects: tachycardia, dry mucous membranes, increased sputum viscosity. They can increase intraocular pressure, interfere with urination, cause stomach pain, constipation, nausea, vomiting, and increase body weight [4, 5]. That is why these drugs have a number of serious restrictions for use among patients with glaucoma, benign prostatic hyperplasia, cardiovascular pathology, etc. In acute poisoning of first generation AGPs, their central effects pose the greatest danger: the patient experiences agitation, hallucinations, ataxia, incoordination, convulsions, etc. Fixed, dilated pupils on a flushed face, together with sinus tachycardia, urinary retention, dry mouth and fever are very similar to signs of atropine poisoning. In children with an overdose of first-generation antihypertensive drugs, agitation and convulsions may occur, so experts in many countries are calling for the refusal of this group of drugs in the treatment of children or their use under strict supervision. In addition, sedation can impair children's learning and performance at school.
II generation antihistamines
New AGPs (II generation) do not penetrate the BBB and do not have a sedative effect (Fig. 2). Note: III generation drugs have not yet been developed. Some pharmaceutical companies present new drugs that have appeared on the pharmaceutical market as AGP III - the newest generation. They tried to classify metabolites and stereoisomers of modern AGPs as the third generation. However, it is currently believed that these drugs belong to the second generation AGPs, since there is no significant difference between them. According to the Consensus on Antihistamines, it was decided to reserve the name “third generation” to designate antihistamines synthesized in the future, which will differ from known compounds in a number of basic characteristics. Unlike older drugs, II generation AGPs practically do not penetrate the BBB and do not cause a sedative effect, so they can be recommended to drivers, people whose work requires concentration, schoolchildren and students. The term “practically” is used here, because in very rare cases and when taking second-generation drugs, cases of sedation are possible, but this is rather an exception to the rule and depends on the individual characteristics of the patient. Second-generation antihypertensives are capable of selectively blocking H1 receptors, quickly providing a clinical effect with a long-lasting effect (for 24 hours), and, as a rule, are not addictive (no tachyphylaxis). Due to their higher safety profile, they are preferred for elderly patients (over 65 years of age).
Antihistamines of the 2nd generation
Pharmacokinetic features Metabolism of AGPs of the 2nd generation
All AGPs of the 2nd generation are divided into 2 large groups, depending on the need for metabolic activation in the liver (Fig. 3).
The need for metabolic activation in the liver is associated with a number of problems, the main of which are the danger of drug interactions and the late onset of the maximum therapeutic effect of the drug. Concomitant use of two or more drugs that are metabolized by the liver may result in changes in the concentration of each drug. In the case of parallel use of an inducer of drug metabolism enzymes (barbiturates, ethanol, St. John's wort, etc.), the rate of antihistamine metabolism increases, the concentration decreases and the effect is not achieved or is weakly expressed. With the simultaneous use of liver enzyme inhibitors (antifungal azoles, grapefruit juice, etc.), the metabolic rate of AGP slows down, which causes an increase in blood levels and an increase in the frequency and severity of side effects. The most successful option for antihypertensive drugs are drugs that are not metabolized in the liver, the effectiveness of which does not depend on concomitant therapy, and the maximum concentration is achieved in the shortest possible time, which ensures a rapid onset of action. An example of such a second-generation antihypertensive drug is cetirizine.
The speed of onset of the effect of AGP of the second generation
One of the most important aspects of the drug’s action is the speed of onset of the effect. Among the second generation AGPs, the shortest period of achieving Cmax was observed for cetirizine and levocetirizine. It should be noted that the antihistamine effect begins to develop much earlier and is minimal for drugs that do not require prior activation in the liver, for example, cetirizine - after 20 minutes (Table 2).
Distribution of II generation AGP
The next most important characteristic of a drug is the volume of distribution. This indicator indicates the predominant localization of the drug: in plasma, intercellular space or inside cells. The higher this indicator, the more the drug enters the tissues and inside the cells. The small volume of distribution indicates that the drug is predominantly located in the vascular bed (Fig. 4). For AGP, localization in the bloodstream is optimal because its main target cells (immunocompetent blood cells and vascular endothelium) are represented here.
The values of the volume of distribution (liter/kg) for II generation AGPs are as follows in increasing order: cetirizine (0.5) < fexofenadine (5.4–5.8) < desloratadine (49) < ebastine (100) < loratadine (119) (Fig. . 5). The small volume of distribution ensures: a) high concentrations of this AGP on the surface of target cells, therefore, precisely targeted action and high therapeutic efficacy; b) lack of accumulation in parenchymal organs and safety of use.
Features of pharmacodynamics
The pharmacological effects of antihypertensive drugs are mediated by histamine receptors, selectivity for different subtypes, the strength and duration of binding to which varies between drugs. A distinctive characteristic of the second generation AGP cetirizine is its high affinity - the ability to bind histamine H1 receptors for a long time: their occupancy 4 hours after taking the drug is 90%, after 24 hours - 57%, which exceeds similar indicators of other AGPs. The most important property of antihistamines is their ability to reduce the expression of histamine H1 receptors, thereby reducing the sensitivity of tissues to histamine [8, 9]. According to the strength of the antihistamine effect, second-generation antihistamines can be arranged in the following order: cetirizine >> ebastine > fexofenadine >> loratadine (Fig. 6) [10].
The antiallergic effect of individual antihypertensive drugs (cetirizine) includes the so-called additional, extra-H1-receptor effect, together with which the anti-inflammatory effect of the drug is realized. Side effects of AGP
Side effects of antihypertensive drugs include anticholinergic effects (dry mouth, sinus tachycardia, constipation, urinary retention, blurred vision), adrenolytic effects (hypotension, reflex tachycardia, anxiety), antiserotonin (increased appetite), central antihistamine effects (sedation, increased appetite), blockade potassium channels in the heart (ventricular arrhythmia, QT prolongation) [11]. The selectivity of the action of drugs on target receptors and the ability to penetrate or not penetrate the BBB determine their effectiveness and safety [12]. Among the second generation AGPs, the drugs cetirizine and levocetirizine have the lowest affinity for M-cholinergic receptors, and therefore an almost complete absence of anticholinergic action (Table 3) [13].
Some antihypertensive drugs that can cause AR are terfenadine and astemizole. Due to the ability to cause a potentially fatal arrhythmia - atrial fibrillation (metabolic disturbance due to liver disease or in the presence of CYP3A4 inhibitors), terfenadine and astemizole have been prohibited for use since 1998 and 1999. respectively. Among the currently available antihypertensive drugs, ebastine and rupatadine have cardiotoxicity and are not recommended for use in persons with a prolonged QT interval or hypokalemia. Cardiotoxicity increases when taken simultaneously with drugs that prolong the QT interval - macrolides, antifungals, calcium channel blockers, antidepressants, fluoroquinolones.
Cetirizine
Cetirizine occupies a special place among second generation drugs.
Along with all the advantages of non-sedating antihistamines, cetirizine demonstrates properties that distinguish it from a number of new generation drugs and ensure its high clinical efficacy and safety [5, 14]. In particular, it has additional antiallergic activity, a rapid onset of effect, and there is no risk of interaction with other drugs and food, which opens up the possibility of safely prescribing the drug to patients with concomitant diseases. The effect of cetirizine consists of its influence on both phases of allergic inflammation. The antiallergic effect includes the so-called extra-H1 receptor effect: inhibition of the release of leukotrienes, prostaglandins in the nasal mucosa, skin, bronchi, stabilization of mast cell membranes, inhibition of eosinophil migration and platelet aggregation, suppression of ICAM-1 expression by epithelial cells [7, 15] . Many authors, both foreign and domestic, consider cetirizine to be the standard of modern AGP. It is one of the most studied antihypertensive drugs, having proven its effectiveness and safety in many clinical studies. For patients who respond poorly to other antihypertensive drugs, cetirizine is recommended [16]. Cetirizine fully meets the requirements for modern antihypertensive drugs [17]. Cetirizine is characterized by a half-life of 7–11 hours, the duration of the effect is 24 hours, after a course of treatment the effect lasts up to 3 days, with long-term use – up to 110 weeks, no addiction is observed. The duration of the effect of cetirizine (24 hours) is explained by the fact that the effect of AGP is determined not only by the plasma concentration, but also by the degree of binding to plasma proteins and receptors. Cetirizine is practically not metabolized in the liver and is excreted primarily by the kidneys, so it can be used even in patients with impaired liver function. But for patients with renal failure, a dose adjustment of the drug is required. Cetrin is an effective, high-quality generic cetirizine at an affordable price.
Currently, cetirizine preparations, in addition to the original (Zyrtec), are registered with 13 generic drugs from different manufacturers [18]. The relevant issue is the interchangeability of generic cetirizine, their therapeutic equivalence to the original drug and the choice of the optimal drug for the treatment of allergic diseases. The stability of the therapeutic effect and the therapeutic activity of the reproduced drug are determined by the features of the technology, the quality of the active substances and the range of excipients. The quality of drug substances from different manufacturers may vary significantly. Any change in the composition of excipients may be accompanied by pharmacokinetic deviations (decreased bioavailability and the occurrence of side effects) [18]. The generic must be safe to use and equivalent to the original drug. Two drugs are considered bioequivalent (pharmacokinetically equivalent) if, after administration by the same route (for example, orally) in the same dose and schedule, they have the same bioavailability (the proportion of the drug that enters the bloodstream), the time to reach the maximum concentration and the level of this concentration in the blood, half-life and area under the time-concentration curve. The listed properties are necessary for the proper effectiveness and safety of the drug. According to the recommendations of the World Health Organization, the bioequivalence of a generic drug should be determined in relation to the officially registered original drug. Bioequivalence studies have become mandatory for drug registration since 2010. The FDA (Food and Drug Administration, USA) annually issues and publishes the “Orange Book” with a list of drugs (and their manufacturers) that are considered therapeutic. equivalent to the original ones. In addition, it is important to pay attention to compliance with international manufacturing standards (GMP) when manufacturing drugs. Unfortunately, not all manufacturers (especially domestic ones) have production facilities that meet GMP requirements, and this may affect the quality of drugs, and therefore the effectiveness and safety of generics. Thus, when choosing generics, there are a number of reliable guidelines: the authority of the manufacturer, compliance with GMP, inclusion in the FDA Orange Book [19]. All of the above criteria are fully met by the drug Cetrin from Dr. Reddy's Laboratories Ltd. Cetrin is produced by an international pharmaceutical company whose production sites are GMP certified. It is bioequivalent to the original drug [20] and is included in the FDA Orange Book as a drug with proven therapeutic equivalence. In addition, Cetrin has a long-term successful experience of use in Russia and a large own evidence base. A comparative study of the therapeutic efficacy and pharmacoeconomics of cetirizine preparations from different manufacturers in the treatment of chronic urticaria showed that the largest number of patients who achieved remission were in the groups receiving Zyrtec and Cetrin, while the best results in terms of cost-effectiveness were demonstrated by therapy with Cetrin [21, 22 ]. The long history of use of Cetrin in domestic clinical practice has proven its high therapeutic effectiveness and safety. Cetrin is a drug that meets the practical need of clinical medicine for an effective and safe antihistamine drug available to a wide range of patients.
LORATADINE (tablets)
to which the drug is named, and the usual additives are milk sugar, starch and traditional magnesium stearate.
One must think that this is the minimum required: the allergy remedy itself should contain less “chemicals” so that the patient does not inadvertently develop an allergy to one of the components. ~~~ RESULT ~~~
Surprisingly, just one tablet of Loratadine, taken at bedtime, was enough. By morning the skin condition returned to normal. I don't know where the second one went. Probably, she went to consolidate the result. True, Baziron also had to be abandoned. But, it seems to me, this is the ABC: if some drug has an undesirable side effect, then you should stop taking it and try to find a replacement.
Naturally, it is difficult for me to say whether Loratadine will be as effective if the allergen cannot be eliminated. Simply put, I don’t know if it will cope with seasonal allergies to pollen and so on. But from an inadequate reaction of the body to medications (cosmetics and the like), if you stop using them, I think it will help you too.
~~~ SIDE ~~~
But it wasn't. At all. Having heard that antiallergic drugs cause drowsiness, we took a pill at night.
“However, he generally denies the presence of side effects. Although the instructions list headaches, gastrointestinal disorders, and drowsiness. But it is said that these symptoms did not occur more often when using Loratadine during clinical studies than in the control group using a “pacifier.” That is, just a coincidence, an accident.
~~~ SPECIAL INSTRUCTIONS ~~~
However, it is recommended to refrain from activities that require increased attention and quick reactions. We must assume that we are talking about driving a car or an airplane. In my opinion, at school, in the classroom, attention will also not be superfluous.
~~~ PRICE ~~~
A small package, with one blister for ten tablets, cost me only seventy rubles. It seems that it is also expensive. But there was no time to look for cheaper places.
~~~ RECOMMENDATIONS ~~~
For cases like ours, I can recommend this antihistamine: inexpensive and effective. Available without a prescription, it can be given to children from the age of three years. Which, in general, indirectly speaks about its safety.
PS Well, if you are constantly faced with allergies, then you probably understand the remedies for them better than me.
PPS Still, writing reviews is a useful activity for the author himself. I touched on the topic of antihistamine medications and thought about it myself: okay, itchy dermatosis, but such a terrible thing as allergic angioedema, which can even lead to death, can be acquired for a completely trivial reason: if it’s not a mosquito, then a bee has bitten, or tried it while being on vacation in distant countries, exotic cuisine - and you're done. They wrote that there are allergies to physical activity (work). You should definitely have some anti-allergy pills, like Loratadine, on hand, just in case.
