INTRODUCTION:

Due to a variety of factors, including physical and cognitive impairments, various concomitant diseases, and polypharmacy, pruritus is the most prevalent skin complaint among the elderly, who make up the fastest-growing demographic segment in the globe.¹ There is currently no well-recognized treatment. Nowadays, treating pruritus in the elderly requires a customized, unique strategy that takes into account the patient's overall health, the intensity of their symptoms, and the side effects of medication.

The majority of patients require daily antihistamines (AHs) to manage their pruritus.² Actually, topical AH has been shown to work instantly, greatly reducing pruritus in people with xerotic skin, eczematous dermatitis, or insect bites. It was demonstrated that topical AH decreased histamine for at least two hours after a single application.³ Patients with insect stings, pruritus, or sunburns are increasingly using these topical medications due to their widespread use, low cost, and nonprescription nature, particularly in Italy. According to reports, topical AH relieves eczema-related pruritus quickly. However, because of its brief duration of effect, patients must use it multiple times daily. AHs have negative effects and organ-specific effectiveness, just like histamine.⁴

Promethazine:

The ideal antihistamine should have low to no BrH1R occupancy, high PrH1R occupancy, and strong selectivity for the H(1)-receptor. A phenothiazine derivative is promethazine (PM) ((RS)-N,N-dimethyl-1-(10H-phenothiazine-10-yl)propan-2-amine hydrochloride) (Figure 1). It is an antihistamine, antiemetic, and first-generation H1 receptor antagonist that also has potent sedative effects.⁵ Promethazine has an effect on voltage-dependent ion channels, including sodium, calcium, or potassium channels, as well as ligand-gated ion channels such as purinergic P2 or cholinergic ACh receptors. In addition to these actions, promethazine inhibits the mitochondrial permeability transition pore and the brain Na⁺K⁺-ATPase. Since its initial release in 1946, it has been used to prevent and treat nausea and vomiting brought on by narcotic therapy, migraines, chemotherapy for cancer, and other conditions.⁶ In addition to preventing motion sickness, it is used to treat post-operative nausea and vomiting, as a sedative or sleep aid, particularly for cancer patients, and to treat allergic symptoms such as itching, runny nose, sneezing, itchy or watery eyes, hives, and itchy skin rashes. PM works by inhibiting histamine H1 receptors without preventing histamine from being secreted. Sedation is a common symptom of CNS depression at therapeutic dosages. Whereas brain H(1)-receptor (BrH1R) blocking results in somnolence, exhaustion, increased appetite, diminished cognitive functions (reduced memory and learning), seizures, aggressive behavior, and other symptoms, peripheral H(1)-receptor (PrH1R) activation causes allergy symptoms. Additionally, first-generation oral AHs (FGAHs) have strong antimuscarinic, anti-α-adrenergic, and antiserotonin actions that can cause symptoms like agitation, confusion, dry mouth, tachycardia, constipation, urine retention, and visual abnormalities such as mydriasis, photophobia, and diplopia. Because FGAHs disrupt the circadian sleep-wake cycle, they are not appropriate for usage as sleeping aids due to their somnolence. Although topical first-generation antihistamines are still prescribed by general practitioners and pharmacists far too frequently without considering potential side effects as a first-line treatment for a number of dermatological issues, second-generation oral antihistamines are the recommended first-line treatment option for allergic rhinitis and urticaria.^7-12

Figure 1. Promethazine

Absorption, Distribution, Metabolism, Elimination:

The gastric tract absorbs PM effectively. The administration of promethazine intramuscularly (25mg) or orally (25 to 50mg) results in peak plasma concentrations after 2 to 3 hours. Peak plasma concentrations were seen approximately eight hours after promethazine in a suppository formulation was administered rectally. About 25% is oral bioavailability. According to reports, rectal bioavailability is 23%. Promethazine has a high apparent volume of distribution after oral and intramuscular injection, and it is widely dispersed in bodily tissues. Gas chromatography has shown that promethazine is 93% protein-bound, while HPLC has reported that it is 76–80% protein-bound. When administered intravenously at term, promethazine quickly crosses the placenta and is present in the cord blood in 1.5 minutes. The blood-brain barrier is crossed by promethazine. It has been calculated that promethazine has an elimination half-life of 12 to 15 hours after oral ingestion. Blood levels of promethazine decreased bioexponentially with a terminal elimination half-life of 12 hours following intravenous injection of 12.5mg.⁹ Promethazine sulfoxide and, to a lesser extent, desmethyl promethazine are the main products of PM metabolism. The liver is the primary site of metabolism, and the medication undergoes significant first-pass hepatic biotransformation, which accounts for the 25% oral bioavailability. Though to a smaller extent than previously thought, metabolism also takes place in the intestinal wall. Since circulation levels are likely below analytical detection limits due to a combination of sluggish absorption, a lower dose (50 percent oral), and bypass of first-pass metabolism in the liver, the sulfoxide metabolite has not been found following intramuscular treatment⁷. Hepatic metabolism is principally responsible for its removal. Promethazine metabolites were not determined to have any pharmacological or toxicological activity. Breast milk has not been shown to contain promethazine.⁸

Clinical Use:

Due to its strong sedative effects, PM is frequently administered at night to alleviate allergy symptoms. Promethazine has also been used to treat allergic reactions and drug hypersensitivity reactions, particularly in emergency situations. Asthma, pneumonia, and other lower respiratory tract diseases can also be treated with it; in fact, quaternary salts of promethazine are utilized to make inhalation treatment for bronchial spasm relief. Promethazine works well to avoid motion sickness when taken before travel. Higher or more frequent dosages can be used to treat vomiting from different causes.¹³ PM application is a low-cost, painless, side-effect-free, surgery- and hospitalization-free method of treating hemorrhoids.^14–16 Promethazine has been used to treat levodopa-induced dyskinesia in Parkinson's disease patients and extrapyramidal abnormalities in children brought on by metoclopramide. Promethazine has been used to treat levodopa-induced dyskinesia in Parkinson's disease patients and extrapyramidal abnormalities in children brought on by metoclopramide. Since promethazine was found to cause less nausea than chloral hydrate alone, it has been proposed that promethazine and chloral hydrate can be used together to provide sedation in young children undergoing dental treatments. Although topical application is not advised owing to skin sensitization reactions, promethazine is available in certain countries as a 2% cream without a prescription for the treatment of burns, insect bites, and allergic skin disorders. The different treatment indications and adverse effects are influenced by all of these pharmacological characteristics. (Table 1).

Table 1. PM clinical use.

Common use	Other less common uses
In an emergency, allergic conditions	To manage children's extrapyramidal disorders
Pneumonia and asthma	To induce drowsiness during pediatric dental procedures
Additional diseases of the lower respiratory tract	As a 2% cream for burns, bug bites, and allergic skin disorders
Drug that introduces sleep through the nose
Premedication for anesthesia, especially in obstetrics

Pharmacology and Toxicology:

Toxicodynamics:

Because of the complexity of promethazine's pharmacology, toxicological pathways are not fully known. According to the majority of reference materials, promethazine's anticholinergic effects at muscarinic receptors are the primary cause of its toxicity. Atropine exhibits many of the same symptoms and indicators as poisoning. Physostigmine has been used to cure severe symptoms such as seizures, hallucinations, hypertension, and arrhythmias when anticholinergic effects are present. Promethazine may have toxic effects similar to those of antipsychotic phenothiazines in addition to anticholinergic effects. Promethazine's antidopaminergic effects may be the cause of hypotension and extrapyramidal symptoms.¹⁷

Pharmacodynamics:

Histamine H1 receptors mediate the cerebral and peripheral actions of histamine, which are counteracted by the phenothiazine antihistamine promethazine. Histamine is not inhibited by the medication at H2 receptors. The majority of histamine's smooth muscle-stimulating effects on the H1 receptors in the gastrointestinal tract, uterus, big blood arteries, and bronchial muscle are competitively inhibited by antihistamines. Histamine's effects on H1 receptors also successfully counteract increased capillary permeability, edema development, flare, and pruritus. Promethazine seems to work by obstructing H1 receptor sites, which stops histamine from acting on cells. Promethazine is believed to have sedative effects because it quickly crosses the blood-brain barrier and blocks the brain's H1 receptors. Promethazine, like other phenothiazines, has antidopaminergic effects but is not used in clinical settings for its antipsychotic effects. Promethazine may have an antiemetic effect because it blocks dopaminergic receptors in the medulla's chemoreceptor trigger zone (CTZ). It has also been demonstrated that promethazine inhibits calmodulin. The authors have proposed that promethazine's inhibition of calmodulin may be a mechanism underlying the cellular blockage of histamine production.¹⁸

Toxicity:

Because there is little information on the precise amount consumed in overdose instances, the lowest fatal exposure and maximum tolerable exposure in adult human subjects have not been precisely determined. In humans, peak plasma levels after therapeutic oral dosages of 30 to 50mg have varied between 11 and 23 ng/mL. Plasma levels of 48ng/mL were linked to adverse effects after intramuscular administration. Promethazine is easily obtained in syrup form for children and is frequently used to calm small children. It's probable that the dosage is frequently too high, resulting in poisoning symptoms. Children ages 5 to 12 have been reported to experience CNS toxicity with survival following an unintentional consumption of 200–500mg of promethazine (12.5–28mg/kg). A two-year-old child who had previously consumed 200mg of promethazine tablets was confirmed dead.¹⁹

Main Adverse Effects:

Serious respiratory issues or mortality in children under two are the most common side effects recorded. Adult overdose is typically characterized by central nervous system depression, which can lead to drowsiness and coma, occasionally followed by excitation. Excitation, hallucinations, dystonias, and even seizures are indications of CNS stimulation, which predominates in young children. Typically, there are anticholinergic symptoms such as mydriasis, dry mouth, and impaired vision. Numerous cardiorespiratory symptoms, including respiratory depression, tachycardia, hypertension or hypotension, and extrasystoles, can also be signs of overdosage. The most frequent side effect is most likely sedation, which might range from light drowsiness to deep sleep. There have been reports of muscle weakness, lassitude, dizziness, and impaired coordination. Constipation, diarrhea, nausea, and epigastric distress are examples of gastrointestinal side effects. Additionally, promethazine may result in immunoallergic responses. Rarely, leucopenia and agranulocytosis have happened, and they typically happen to people taking promethazine with other medications that are known to have these side effects. A number of newborns or young children who were getting regular doses of promethazine have had respiratory depression, sleep apnea, and SIDS.^19-23

Diagnosis:

A complete medical history and the identification of physical signs and symptoms consistent with medication-induced allergic responses are necessary for the diagnosis of drug allergy. Diagnostic studies such as skin testing, graded challenges, and induction of drug tolerance procedures might also be necessary, depending on the results of the physical examination and history. Many other organ systems, including the renal, hepatic, and hemolytic systems, may be affected, even though skin reactions are the most typical outward manifestation of drug-induced allergic reactions. Patients who present with a central anticholinergic syndrome should always be evaluated for antihistamine poisoning. Promethazine levels in urine and blood can be measured.^24-26

Diagnostic Tests:

IgE-mediated (type I) reactions can be diagnosed with the help of skin testing techniques, including skin prick testing (SPT) and intradermal testing, which involves injecting the allergen into the skin's dermis. Positive skin tests for these medications support the diagnosis of a type I hypersensitivity reaction and validate the presence of antigen-specific IgE. A negative skin test does not always mean that a particular IgE is not present. There are just a few medications for which serum-specific IgE testing is available. By giving subtherapeutic amounts over time and monitoring the patient for any possible reactions, these tests are typically performed to ascertain whether a patient may experience an adverse reaction to a specific medication. If the patient has previously had a potentially fatal reaction to the substance in question, they are not recommended. Graded challenges and drug tolerance-induction techniques have the potential to be dangerous and should only be carried out by qualified staff in facilities with easily accessible resuscitation equipment.^27-30

Risk Factors:

Age, gender, genetic polymorphisms, certain viral infections, and medication-related characteristics (e.g., frequency of exposure, mode of administration, and molecular weight) are all linked to an elevated chance of developing a drug allergy. Drug allergies are more common in women than in men and usually affect young to middle-aged persons. A higher risk of immunologic reactions to medications has also been associated with genetic variations in the human leukocyte antigen (HLA), a gene product of the major histocompatibility complex, and viral infections, including Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Genetic variations in medication metabolism affect a person's susceptibility to drug allergies. Furthermore, compared to oral administration, topical, intramuscular, and intravenous routes of administration are more likely to result in adverse medication reactions, with intravenous administration being linked to more severe reactions. A large single dose is less likely to cause hypersensitivity reactions than repeated or prolonged high doses. Atopic patients are more likely to experience severe allergic reactions even when they do not have a higher risk of medication allergies.³¹

Management:

If necessary, general measures such as maintaining proper breathing and cardiovascular function must be implemented, along with symptomatic supportive care. Even if gastric emptying is postponed for up to two hours, it may still be successful. Given the possibility of the patient acquiring a coma or psychosis, it is usually not advisable to induce vomiting. Activated charcoal administration would be ideal. It is no longer advised to utilize a cathartic. Gastric lavage, which involves an endotracheal tube with a cuff inflated to prevent aspiration of the stomach contents, may be helpful if there are no convulsions. Phenytoin or intravenous diazepam (recommended) can be used to manage seizures. In mild situations, posture should be used to address hypotension; in more severe cases, fluids or pressor medications may be used. Parenteral sodium nitroprusside may be necessary in cases of severe hypertension. Intravenous diphenhydramine usually causes dystonic responses. Slow intravenous injections of physostigmine have been used in cases of significant anticholinergic effects. Physostigmine use, however, is seen as contentious.³²

DISCUSSION:

One of the many methods used to enhance PM's tolerability profile, especially with regard to adverse effects on the stomach and kidneys, is topical application, which is commonly used for moderate acute and chronic itching disorders. Topicals, however, have the potential to cause photosensitivity. PM has frequently been linked to photosensitivity reactions among its various topically applied uses. Its chemical structure and the range of chemical reactions that result in the phototoxic effects may be responsible for the increased frequency of such negative reactions. A range of immunologically induced hypersensitivity reactions with different mechanisms and clinical manifestations are included in PM allergy. In addition to lowering a patient's quality of life, this kind of adverse drug response (ADR) can result in treatment delays, pointless tests, and even death. Diagnosing the illness might be difficult because of its wide range of symptoms. It is important to consider drug cross-reactivity while selecting substitute agents. There are two types of promethazine ARs: predictable reactions, which can happen to everyone, and unpredictable reactions, which can only happen to vulnerable people. The most prevalent kind of adverse drug responses (ADRs) are predictable reactions, which are typically dose dependent and associated with the drug's known pharmacologic properties (e.g., side effects, overdose, and drug interactions). About 20–25% of individuals who experience adverse medication reactions have unpredictable reactions, which are typically unrelated to the drug's pharmacologic activities. Between 15% and 25% of patients in our daily dermatological clinical practice experience promethazine ARs; 7% of patients experience severe responses. In conclusion, it is a strong photosensitizer that causes numerous concurrent photocontact allergies to different photosensitizers, some of which share structural components. Because oral or other medications are known to cause cross-responses, frequent and extensive use of these treatments may cause sensitization and increase the risk of systemic allergic reactions. Patients should be advised by doctors and pharmacists about the dangers of using topical medications, which are frequently sold as over-the-counter medications. Drug withdrawal or substitution can reverse adverse photosensitivity reactions, which are quicker than photoallergy and primarily manifest as phototoxic reactions.

CONCLUSION:

Keeping primary healthcare and pharmacists informed about the issue is crucial due to its pervasive nature. A lack of medication information, a pharmacovigilance program, and a disregard for fundamental prescribing principles may be the causes of the irrational drug therapy and prescribing errors observed in primary care practice. The FDA reiterated the issue of promethazine tissue damage in 2009, along with recommendations for preventing harm. The FDA also announced that manufacturers must now include a boxed warning about the risk of serious tissue damage for intravenous injections. It would also be helpful to raise awareness of skin reactions, which are too frequently underestimated. If at all feasible, take PM off of the formulary or warn the pharmacist not to provide it without a prescription; instead, use substitutes when necessary; and in the event of a reaction, contact a dermatologist to encourage sensible medication use. This article's goal has been to inform medical professionals who might not have known about the issue. Above all, we listed a number of actions that should be performed to reduce the likelihood of negative consequences. Given the increasing prevalence of promethazine allergy as a clinical issue, evaluation by a dermatologist or allergist is crucial for accurate diagnosis and treatment of the illness, but particularly for addressing improper information and prescribing practices.

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