Action and mechanism

[ANTI-ALLERGIC], [HISTAMINE H1 ANTAGONIST]. Dimenhydrinate is an equimolecular complex of diphenhydramine and a theophylline derivative, 7-chloro-theophylline. Diphenhydramine is an ethanolamine derivative that competitively, reversibly, and non-specifically blocks H1 receptors, reducing the systemic effects of histamine. It causes vasoconstriction and decreased vascular permeability, reducing the redness and swelling associated with allergies. It partially alleviates symptoms associated with allergic reactions, such as eye redness and nasal congestion. It also produces a mild bronchodilator effect and reduces skin itching.
Dimenhydrinate is a non-specific H1 antagonist, meaning it can also antagonize other receptors, such as central and peripheral cholinergic receptors. By crossing the blood-brain barrier and blocking H1 and muscarinic receptors, it produces sedation, but milder than that caused by ethanolamines.

- [MUSCARINIC CHOLINERGIC ANTAGONIST (M)], antiemetic. Dimenhydrinate is a non-specific antagonist capable of also blocking other receptors, such as central or peripheral muscarinic receptors. Blockade of H1 and central cholinergic receptors could exert an antiemetic effect, although this is not fully understood. It has been shown that this drug can inhibit vestibular stimulation, primarily inhibiting stimuli originating in the otolic system, and at higher doses, in the semicircular canals. Tolerance to the antiemetic effects has been observed after continued use.

Pharmacokinetics

Oral route:

- Absorption: Dimenhydrinate is well absorbed in the intestine, but undergoes extensive first-pass hepatic metabolism. After administration of a dose, the effects appear within 15-30 minutes, and their duration is 3-6 hours. The Tmax is 2 hours.

- Distribution: Dimenhydrinate is widely distributed throughout the body, crossing the blood-brain and placental barriers. It is also excreted in small amounts in breast milk.

- Metabolism: It is metabolized quickly and almost completely in the liver.

- Elimination: The metabolites are eliminated in the urine.

Instructions

- [MOTION SICKNESS]. Prevention and treatment of [NAUSEA], [VOMITING] and [VERTIGO] associated with travel.

Posology

- Adults and adolescents over 12 years: 50-100 mg/4-6 h. Maximum dose 400 mg/24 h.

- Children aged 7-12 years: 25-50 mg/6-8 h. Maximum dose 150 mg/24 h.

- Children 2-6 years: 12.5-25 mg/6-8 h. Maximum dose 75 mg/24 h.

- Children under 2 years: safety and efficacy have not been evaluated.
Administer at least 30 minutes before travel, and preferably 1-2 hours before.

Guidelines for proper administration

Administer with food, water, or milk to reduce gastric discomfort.

- Tablets: swallow the tablets whole or dissolved in juice or sugary drinks.

Contraindications

- Hypersensitivity to any component of the medication. Cross-reactions with other antihistamines may occur, therefore the use of any H1 antihistamine is not recommended in patients who have experienced hypersensitivity to any compound in this group.

- [ASTHMATIC CRISIS]. According to some authors, dimenhydrinate could worsen asthma, so its use is not recommended in an acute attack.

- [PORPHYRIA]. H1 antihistamines have been associated with the onset of porphyric attacks, so they are not considered safe in these patients.

Precautions

- [RENAL IMPAIRMENT]. Safety and efficacy have not been evaluated in patients with renal impairment, but dimenhydrinate metabolites are eliminated in the urine, so accumulation could occur. Since these metabolites may be active, it may be necessary to prolong the dosing periods in patients with renal impairment, especially in moderate or severe cases (creatinine clearance less than 60 ml/minute).

- [HEPATIC IMPAIRMENT]. Dimenhydrinate is extensively metabolized by the liver. In cases of hepatic impairment, an increase in plasma concentration may occur, with the consequent risk of adverse effects. Dosage adjustment may be necessary in these patients depending on the degree of hepatic function.

Patients suffering from glaucoma, benign prostatic hyperplasia or urinary bladder obstruction, high blood pressure, cardiac arrhythmia, myasthenia gravis, stenosing peptic ulcer, or intestinal obstruction. Due to the anticholinergic effects of dimenhydrinate, these conditions may worsen; therefore, extreme caution is advised, and treatment should be discontinued if any deterioration occurs.

- Lower respiratory tract diseases, such as asthma, emphysema, or chronic obstructive pulmonary disease (COPD). According to some authors, H1 antihistamines may decrease the volume of bronchial secretions, increasing their viscosity, due to their anticholinergic effects, which could worsen these conditions. However, there is limited clinical evidence; nevertheless, extreme caution is recommended in these patients. As a general rule, their use is not recommended in patients with asthma attacks (see Contraindications).

- [EPILEPSY]. Caution should be exercised in epileptic patients, as antihistamines have occasionally been associated with paradoxical reactions of hyperexcitability, even at therapeutic doses, and could therefore lower the seizure threshold.

- [APPENDICITIS]. Due to its antiemetic effects, it could interfere with the diagnosis of appendicitis. It is recommended to rule out appendicitis beforehand in patients with vomiting of unknown origin.

- Ototoxicity. Dimenhydrinate may have a beneficial effect in cases of vertigo, tinnitus, and dizziness, so it could mask ototoxicity induced by ototoxic drugs such as parenteral aminoglycosides, carboplatin, cisplatin, chloroquine, and erythromycin, among others.

- Photosensitivity. Dimenhydrinate may cause photosensitivity, so it is recommended to avoid sun exposure during treatment and to protect yourself with sunscreens.

- Extreme temperatures. H1 antihistamines may worsen heat exhaustion and heat stroke due to the decreased sweating caused by their anticholinergic effects. Patients taking these medications are advised to avoid exposure to very high temperatures, especially young children, the elderly, and people with serious chronic illnesses. It is also advisable to follow appropriate hygiene and dietary measures, such as adequate ventilation and hydration.

Advice to the patient

- Administer when symptoms appear, with food to reduce gastric discomfort. In sensitive individuals, it may be administered 1-2 hours before travel.

- Administration may be repeated during the trip, provided that the intervals between doses are respected and the maximum recommended dose is not exceeded.

- It can cause drowsiness, so caution is advised when driving, and it should not be combined with drugs or other sedatives such as alcohol.

- Patients undergoing treatment with sedative drugs are not advised to self-medicate with dimenhydrinate products without consulting a doctor.

- It is advisable to avoid sun exposure during treatment.

- Any chronic conditions the patient has must be reported to the doctor before starting treatment.

- Exposure to extreme temperatures should be avoided during the use of this medication; stay in a cool environment and stay adequately hydrated.

Special warnings

- Dimenhydrinate may mask the ototoxic effects of some drugs, so it is recommended to periodically assess acoustic function in patients treated with these drugs.

- Before using this medication in patients with vomiting of unknown origin, it is recommended to rule out the presence of appendicitis.

- It is recommended to monitor the patient's hydration in case of a heat wave, and especially if the patient is a young child, an elderly person or a person with a serious illness.

Due to the anti-allergic effects of this medication, it may produce false negatives in skin tests for hypersensitivity to antigenic extracts. It is recommended to discontinue administration of this medication at least 72 hours before the test.

Interactions

Dimenhydrinate may mask the symptoms induced by ototoxic drugs by reducing vertigo or dizziness. Similarly, it may potentiate the photosensitizing effects of other active ingredients that cause photosensitivity reactions. Furthermore, drug interactions have been described with the following active ingredients:

- Ethyl alcohol. The combined administration of alcohol and dimenhydrinate could potentiate the sedative effects of both substances. It is recommended to avoid alcohol consumption during treatment.

- Anticholinergics (antiparkinsonian drugs, tricyclic antidepressants, MAOIs, neuroleptics). Administration of dimenhydrinate with other anticholinergic drugs may potentiate anticholinergic effects; therefore, this combination should be avoided.

- Sedatives (opioid analgesics, barbiturates, benzodiazepines, antipsychotics). Concomitant administration of dimenhydrinate with a sedative drug may potentiate the hypnotic effect. Extreme caution is advised.

Pregnancy

FDA Pregnancy Category B. Studies in rats and rabbits using doses 20-25 times the human dose have not shown evidence of fetal harm. Adequate and well-controlled studies in humans have not been conducted. However, dimenhydrinate has been used in cases of hyperemesis gravidarum without significant adverse effects. Nevertheless, there are reports of a possible association between administration during the last two weeks of pregnancy and the development of retrolental fibroplasia in premature infants. Although the possibility of fetal harm appears remote, this drug should only be used when the benefits outweigh the potential risks.

Lactation

Dimenhydrinate may inhibit lactation due to its anticholinergic effects. It is also excreted in breast milk in small amounts, although it is unknown whether these amounts could affect the infant. However, infants are more sensitive to anticholinergic reactions and may more frequently experience paradoxical hyperexcitability reactions. It is recommended to discontinue breastfeeding or avoid administering this medication.

Children

Dimenhydrinate is not recommended for use in children under two years of age, especially neonates and infants, as they may be more susceptible to anticholinergic adverse effects. In children over two years of age, cases of paradoxical reactions with hyperexcitability have been reported, particularly at high doses; therefore, it should be used with caution.

Seniors

The elderly are more sensitive to the adverse effects of antihistamines, such as dizziness, sedation, confusion, hypotension, and hyperexcitability, as well as to anticholinergic effects (dry mouth, urinary retention, precipitation of glaucoma). Antihistamines can be used in patients over 65 years of age, but extreme caution should be exercised. If side effects persist or are severe, treatment should be discontinued.

Effects on driving

Dimenhydrinate can substantially impair the ability to drive and/or operate machinery. Patients should avoid operating dangerous machinery, including automobiles, until they are reasonably certain that the medication does not adversely affect them.

Adverse reactions

The side effects of dimenhydrinate are usually mild and transient, and are more frequent during the first few days of treatment. Like other ethanolamines, dimenhydrinate primarily causes drowsiness and anticholinergic effects, but there is significant interindividual variability in the frequency and intensity of symptoms, affecting young children and the elderly most often. The most common adverse reactions are:

- Digestive. [NAUSEA], [VOMITING], [CONSTIPATION], [DIARRHEA], [EPIGASTRIC PAIN], [ANOREXIA], [DRY MOUTH]. These symptoms may be reduced by taking the antihistamine with food.

Neurological/psychological. Drowsiness is common (1-9%), especially at the start of treatment, and usually decreases after 2-3 days. Headache, vertigo, and dizziness have also been reported. Rarely, cases of paradoxical excitability have been observed, particularly in young children. This hyperexcitability presents with insomnia, nervousness, confusion, tremor, irritability, euphoria, delirium, palpitations, and even seizures.

- Cardiovascular. Occasionally, and usually in cases of overdose, tachycardia, palpitations, and other cardiac arrhythmias such as extrasystoles or heart block may occur. These effects could be due to anticholinergic activity. Hypotension or hypertension have occasionally been reported.

- Respiratory. Occasionally, there may be an increase in the viscosity of bronchial secretions, which can make breathing difficult.

- Genitourinary. Urinary retention and sexual impotence may occur due to cholinergic blockade.

- Hematological. [HAEMOLYTIC ANEMIA], [AGRANULOCYTOSIS], [LEUCOPENIA], [THROMBOPENIA] or [PANCITOPENIA] have rarely been described.

- Ocular. Due to anticholinergic activity, [GLAUCOMA] and [VISUAL DISTURBANCES] such as [MYDRIASIS], [BLURRED VISION] or [DIPLOPIA] could occur.

- Allergic/dermatological. Hypersensitivity reactions may occur following systemic administration of antihistamines, which can even lead to anaphylaxis. Photosensitivity reactions may also occur following intense exposure to sunlight, with dermatitis, pruritus, exanthematous eruptions, and erythema.

Overdose

Symptoms: Symptoms usually appear within 2 hours, although they can last up to 18 hours, and are often variable, being more severe in children and adults over 65. Moderate central nervous system depression with sedation and apnea, cardiovascular collapse, hyperexcitability with insomnia, hallucinations, tremors or seizures, and anticholinergic symptoms such as dry mouth, blurred vision, and urinary retention have been described. Fever exceeding 41.8°C may also occur.
In the most severe cases, especially in children, the symptoms could worsen, with hypotension, seizures, respiratory depression, loss of consciousness, coma, and death appearing.
Treatment: Treatment will consist of the usual measures aimed at promoting drug elimination. Administering emetics is usually ineffective. However, gastric lavage may be beneficial if less than 3 hours have passed since ingestion.
The patient should be kept calm to minimize central nervous system stimulation. Seizures can be treated with diazepam in adults and phenobarbital in children at a dose of 5–6 mg/kg. Hypotension can be treated with vasopressors, although epinephrine should be avoided as it may further lower blood pressure.
If necessary, intubation and assisted ventilation may be required. The use of analeptics is not recommended as they may induce seizures.