ANTIHISTAMINES

ANTIHISTAMINES

Özlem APTİ SENGKİOUN 1 Andaç SALMAN 2

⃣ PATHOGENIC MECHANISMS OF ITCH

Itching, also known as pruritus, is characterized as an uncomfortable feeling that sets off the scratching re- sponse. Itching can evolve into chronic itch after an acute condition and can be classified as pruriceptive, neuropathic, neurogenic, and psychogenic itch. 1

The pathogenic mechanisms of itch are quite di- verse. Mediators that stimulate afferent nerve fibers and cause itch (biogenic amines, proteases, cytokines, and peptides) are known.2 Although the most well- known pathway is histaminergic, itching is often ini- tiated by a nonhistaminergic trigger, such as neurode- generation and inflammation. 3

Histamine

Histamine is the most widely recognized and re- searched pruritogen. The major source of histamine in the skin is the mast cell. Histamine degranulation from mast cells after allergen exposure reads, which inter- acts with sensory C fibers.2 Histamine acts via G-pro- tein coupled receptors, and four histamine receptors (H1R, H2R, H3R, and H4R) identified to date.4

Histamine, a biogenic monoamine and neu- rotransmitter, can have different effects depending on the receptor type.5 The most common receptor of

the subtypes is H1, which is primarily responsible for allergic symptoms and pruritus. Although H2 recep- tors are primarily responsible for gastric acid secre- tion, they have been shown to play a minor role in the etiology of itch in humans. 6,7 H3 receptors are found mainly in the central nervous system (CNS), while H4 receptors are found in hematopoietic tissues and neu- ronal cells. 5

Antihistamines

Histamine receptor antagonists are effectively used in allergic and gastric diseases (anti-H1R and anti-H2R, respectively), while the effectiveness of other receptors is being studied in neurological and immune-mediat- ed disorders (anti-H3R and anti-H4R, respectively).

H1 antihistamines suppress cutaneous vascular permeability, local vasodilation, and axon reflexes related to acute allergic reactions in the skin.8 H1 an- tihistamines may also have anti-inflammatory effects due to their ‘membrane stabilizing’ properties on mast cells, basophils, and inflammatory cells.9

H1 receptor antagonists can be classified as first generation (hydroxyzine, chlorpheniramine, diphen- hydramine, clemastine, etc.) and second generation (cetirizine, levocetirizine, loratadine, fexofenadine, bilastine, rupatadine, etc.). 5

1. 1  Assist. Prof Mehmet Ali Aydınlar Faculty of Medicine, Acıbadem University, Department of Dermatology and Venereology, ozlemapti2@gmail.com, ORCID iD: 0000-0002-6980-8986

2. 2  Prof. Dr., Acıbadem Mehmet Ali Aydınlar University, School of Medicine, Department of Dermatology, andac.salman@acibadem.edu.tr ORCID iD:0000-0001-9802-2678

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Second-generation antihistamines have relatively high peripheral H1R selectivity and therefore cause fewer anticholinergic side effects. This less lipophilic group is longer acting, allowing for longer dosing in- tervals, which is a significant advantage. Differences in sedative effects among second-generation agents have been linked to binding affinity to carrier proteins in the brain. Cetirizine is less sedating than diphen- hydramine, but more sedating than fexofenadine, supporting the effect of the P-glycoprotein affinity for the transporter. 5

Antihistamines in the elderly

With an increase in life expectancy, the elderly pop- ulation has grown dramatically. The prevalence of allergic illnesses has risen dramatically across all age categories, particularly among the elderly. 10

There are several factors that affect drug pharma- cokinetics and pharmacodynamics in geriatric pa- tients. 11

• In the elderly, gastric acidity decreases, the ab- sorption surface is less, intestinal peristalsis and gastric emptying are slowed down.

• Antihistamines are less effective in treating pruri- tus in older patients and can be dangerous because of changes in body composition. In the elderly, the proportion of muscle decreases and the proporti- on of fat increases, causing changes in drug me- tabolism. For example, in the elderly, hydrophilic drugs have a lower volume of distribution than lipophilic drugs. First generation antihistamines, which are particularly lipophilic, may cause incre- ased and prolonged side effects in the elderly due to their long half-life.

• In this group, decreased albumin and carrier pro- teins cause less distribution of drugs to peripheral tissues.

• As a result of physiological aging, hepatic blood flow decreases and mitochondrial enzyme fun- ctions slow down. Changes in drug metabolism are inevitable. Furthermore, first-generation H1 antihistamines inhibit cytochrome P450 and may interact with many drugs that are metabolized in the liver. 12

• The age-related physiological decrease in creatini- ne clearance also slows down drug excretion pro-

cesses, which may increase the half-life of drugs

in the body.

• Since there may be differences in sensitivity in

  drug receptors with aging, changes in drug phar- macodynamics are part of the physiological pro- cess.

• First generation antihistamines are highly lipop- hilic and can easily cross the blood-brain barrier. This makes the elderly, who are particularly sensi- tive, more prone to side effects such as incoordi- nation, sedative changes, somnolence, dyskinesia and epilepsy. The risk of delirium is increased with concomitant use of first-generation antihistami- nes and certain drugs (e.g., benzodiazepines, nar- cotics, or tricyclic antidepressants).13

• The first generations have anticholinergic, antise- rotoninergic, and antidopaminergic properties. In the elderly, this may worsen underlying primary pathologies (urinary retention, arrhythmias, pe- ripheral vasodilation, postural hypotension, ta- chycardia, and mydriasis). Therefore, the simulta- neous use of first-generation antihistamines with monoamine oxidase inhibitors, antidepressants, and antipsychotic drugs should be avoided, espe- cially in the elderly.

• Polypharmacy is a major problem in the elderly, and increased side effects may be observed as a re- sult of drug interactions.

  According to the World Health Organization (WHO), approximately 65% to 90% of older people use some medicines, and a large percentage are multi- ple medicated. 11 The risk of drug interactions is, par- ticularly high with first-generation antihistamines, examples are listed:14

  Hydroxyzine

  + (Hydrocodone, oxycodone, tramadol) = CNS de- pression and coma

  + (Amiodarone, aripiprazole, azithromycin, cimeti- dine, escitalopram, pantoprazole, trazodone, queti- apine) = QT-interval prolongation

  + (Quetiapine) = Cardiac arrhythmias + (Topiramate) = Heat stroke

  + (Aripiprazole, cyclobenzaprine) = Drowsiness, blurred vision, difficulty urinating, confusion

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+ (Duloxetine, gabapentin, lamotrigine, SSRIs) = Drowsiness, dizziness, confusion

Diphenhydramine

+ (Alcohol, benzodiazepines, MAOIs) = CNS depres- sion, confusion, decreased motor coordination, falls

+ (Sleep medications) = Confusion, imbalance

+ (Synthetic opioids) = Drowsiness, confusion, coma

+ (Tramadol, dextromethorphan, SSRIs, pregabalin)= Increased dizziness, drowsiness, confusion, difficulty with motor coordination

+ (Dementia medications) = Worsening of cognitive symptoms

Fexofenadine

+ (Erythromycin) = Increased fexofenadine levels + (Phenytoin) = Decreased fexofenadine levels

Loratadine

+ (Ketoconazole, cimetidine, erythromycin) = In- creased loratadine levels

Anticholinergic side effects and polypharmacy

Antihistamines are well known for their anticholiner- gic side effects, including dry eyes, mydriasis, tachy- cardia, constipation, urinary retention, and dementia. The elderly are more susceptible to these side effects. 9

There are studies showing that patients over the age of 65 are given an average of six medications.15 Polypharmacy in the elderly, and particularly the use of more than one anticholinergic drug, leads to a “high anticholinergic burden score”, which is asso- ciated with an increased risk of dementia.16 The most commonly used drugs with high anticholinergic ac- tivity include first-generation antihistamines, drugs used in the treatment of incontinence, anti-Parkinson drugs, and those used in the treatment of psychiatric diseases.17

Since the number of drugs prescribed for these indications is high in the elderly, the list of antihista- mines should be questioned in detail at the beginning of treatment, and unnecessary anticholinergic load

should be avoided.

Comorbidities and antihistamines in the elderly

Comorbidities are common in the elderly; antihista- mine use may result in the worsening of underlying diseases. Therefore, systemic comorbidities should be questioned in detail before prescribing H1 anti- histamines. Patients should first be questioned about whether they have balance and memory problems, a history of falls, urinary problems , or glaucoma. More prominently in patients with narrow-angle glaucoma, antihistamines can cause serious consequences such as acute angle closure and total vision loss.14 In addi- tion, diphenhydramine is known to significantly in- crease the risk of delirium and altered consciousness. 18 First-generation antihistamines may cause balance disorders, increasing the risk of falls and resulting in fractures.19

First-generation antihistamines may have cardi- ac side effects such as QT interval prolongation and tachycardia. H1 antihistamines may also cause drows- iness, more pronounced in first-generation but also in second-generation (such as cetirizine). Because first generations cause urinary retention, elderly patients should be questioned specifically for prostatic hyper- plasia.14

A safe approach for the elderly

In the elderly, antihistamines should be used only when necessary and, if possible, second-generation antihistamines should be preferred. Second gener- ation antihistamines are less lipophilic, have a low- er risk of crossing the blood-brain barrier, and bind more specifically to the H1 receptor. As a result, they have fewer side effects. This group is preferred because drug interactions and other side effects are relatively fewer than first-generation drugs. One of the most important reasons for this is that second-generation H1 antihistamines do not cause adverse effects on the liver isoenzymes CYP34A and CYP2D62. 20

Nevertheless, antihistamine use in the elderly should be considered after a comprehensive evalua- tion of the patient’s history of comorbidities that are unresponsive to topical treatments and after a good balance of benefits and risks has been established. As

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a general approach, first-generation antihistamines should be avoided as much as possible in the elder- ly group. When evaluating each case, dose planning should be done after system evaluation, especially for renal and hepatic comorbidities. In addition, details that may be significant in the history, such as other antihistamines or psychiatric medications, should be questioned.

Commonly used in the elderly include fexofena- dine, levocetirizine/ cetirizine, loratadine, deslorata- dine, bilastine, ebastine and rupatadine. 11

Fexofenadine

Fexofenadine is a good choice for many indications, including pruritus, because it is non-sedating, even at high doses, and does not have any negative effects on psychomotor functions. 21 Fexofenadine is the major metabolite of terfenadine. In oral use, 11% is excreted by the kidneys and approximately 80% by the feces. Since only approximately 5% of the total dose is me- tabolized in the liver, it is an important advantage that it is only slightly affected by liver metabolism.22 It has been shown that no dose adjustment of fexofenadine is necessary in hepatic insufficiency. 23 Fexofenadine is considered safe in studies with doses up to 800 mg/ day, with no significant change in QT intervals ob- served. 24

Bilastine

In studies, bilastine was not metabolized in the intes- tines or liver.25 A phase I study found that two-thirds of bilastine was recovered in the feces and one-third in the urine after oral administration of 20 mg per day. 26 Bilastine is not metabolized, and the kidneys are the major elimination pathway. Therefore, it is not necessary to adjust the dose in liver failure.11 In renal failure, the increase in plasma concentrations of bilas- tine has been found to be within the safe range. How- ever, it should not be used with drugs that can inhibit

droxydesloratadine. Desloratadine is excreted 45% in the urine and 47% in the feces. 28

There are no adequate studies evaluating the suit- ability of desloratadine in renal failure. But in a study conducted on dialysis patients, no significant differ- ence was found in the half-life and Cmax or Tmax of loratadine compared to healthy volunteers.11,29 Deslo- ratadine has been established as safe in hepatic im- pairment at therapeutic doses.28 In terms of cardiac evaluation, no adverse effects of desloratadine on QT interval and electrocardiography were observed in studies. 30

Ebastine

After oral administration, ebastine is converted to its active metabolite, carebastine, after a pronounced first-pass effect.31 The liver metabolism of ebastine is mainly carried out by CYP- 450 enzymes. No dose ad- justment is required in renal insufficiency.32 No chang- es in pharmacokinetic parameters were observed in hepatic insufficiency, but studies evaluated only 10 mg and alone use.33 Since ebastine is metabolized by CYP450 enzymes, it can therefore lead to interactions with other drugs that use the system. 34 Ebastine has been shown to have no effect on the QT interval when used alone, at doses of 10 and 20 mg.35 However, it is recommended that ebastine be used with caution in patients with QT prolongation and hypokalemia. 11

Levocetirizine / Cetirizine

Levocetirizine, the R enantiomer and main active me- tabolite of cetirizine, is very little metabolized, with most of the drug being recovered in the urine.36 Al- though levocetirizine has not been studied adequately in renal failure, studies with cetirizine have shown a prolongation of its half-life and a decrease in renal clearance. 29 Cetirizine tablets, 5 mg three times a week, have been found to be safe in dialysis patients. 37 However, despite being second generation, it should be noted that cetirizine also has a sedative effect, and its half-life will be longer in the elderly, and it should be used in a semi-regular dosage in those with renal insufficiency and avoided as a first-line agent if pos- sible. 38

Levocetirizine is not metabolized in the liver, 284

P-glycoprotein in moderate or severe renal failure.

Desloratadine / Loratadine

Desloratadine, the active metabolite of loratadine, has approximately five times the antihistamine potency of loratadine.9 Desloratadine is metabolized primar- ily in the liver, with the major metabolite being 3-hy-

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Antihistamines

therefore, dose adjustment is not recommended in patients with hepatic insufficiency. 11 Levocetirizine was found to have no effect on the QT interval.39

Rupatadine

Rupatadine undergoes presystemic elimination upon oral administration and is converted into various me- tabolites. Bile is the major route of excretion. Con- comitant use of rupatadine and CYP-450 inhibitors is not recommended due to possible interactions. 40 Its use is not recommended since there are no studies on its safety in renal and hepatic failure. Rupatadine is recommended to be used with caution in patients with proarrhythmic conditions such as QT interval prolongation, hypokalemia, and bradycardia or acute myocardial ischemia.11