First-generation antihistamines have several indications that primarily include nausea and vomiting secondary to motion sickness and vertigo, but can secondarily be used for allergic rhinitis, insomnia, allergic reactions, parkinsonism, and antitussive.
Nasal allergies, allergic dermatosis, anaphylaxis in combination with epinephrine, insomnia, prevention of motion sickness, antiemetic, management of parkinsonian symptoms including extrapyramidal symptoms
Off-label: Oral mucositis
Motion sickness and vertigo
Allergic conditions, antitussive, motion sickness, surgical analgesic/hypnotic, sedation
Off-label: Nausea and vomiting associated with pregnancy
Nausea and vomiting of pregnancy
During pregnancy, up to 10% of patients will require pharmacotherapy to treat their nausea and vomiting. The American College of Obstetricians and Gynecologists have recommended a combination of oral vitamin B6 and doxylamine succinate as a first-line treatment after conservative measures have failed including brat diet. Doxylamine succinate is an antihistamine and has a similar mechanism of action as other antihistamines. This combination has been studied in over 6000 patients and controls and shows no evidence of teratogenicity and randomized controlled clinical trials showed a 70% reduction in nausea and vomiting. Doxylamine succinate is the only FDA Pregnancy Category A medication approved for nausea and vomiting of pregnancy. For breakthrough nausea and vomiting, diphenhydramine and promethazine can be added. Analysis of over 200,000 females, antihistamines have shown no congenital disabilities and no serious maternal or fetal outcomes.
It should be noted antihistamines such as diphenhydramine and dimenhydrinate carry a similar efficacy in reducing postoperative nausea and vomiting as dexamethasone and droperidol. However, antihistamines are typically not the first-line treatment. In Eskander's randomized controlled clinical trial, one group used only intravenous opioids and the other group used intravenous opioids in addition to intravenous promethazine for nausea and vomiting. The study showed patients were discharged from the PACU an average of 19.2 minutes earlier in the opioid and promethazine group. Each patient was discharged when their Aldrete score was 9 or higher. Based on this study, promethazine may warrant further study to include in PACU medications. However, sedation and extrapyramidal side effects can limit promethazine's use for nausea and vomiting.
Gan had a randomized controlled clinical trial that tested 2 groups' response to antiemetics after undergoing gynecological laparoscopic surgery. One group took promethazine only and the second group received a combination of granisetron and promethazine. The clinical trials tested for the total response rate, the incidence of nausea, vomiting, use of rescue antiemetics, nausea severity, activity level, and patient satisfaction. The overall response rate was higher in the combination group, and maximum nausea was lower in the combination group. Gan’s study showed the combination of both granisetron and promethazine are more effective in post-operative nausea and vomiting and post-discharge nausea and vomiting.
H1 receptors in central areas include area postrema and vomiting center in the vestibular nucleus. Also, many of the antihistamines have anticholinergic properties that block muscarinic receptors at the same sites. Antihistamines must cross the blood-brain barrier to affect the central nervous system.
Dosing (Nausea and Vomiting)
Diphenhydramine: 25 to 50 mg orally (PO) every 6 hours, as needed.
Dimenhydrinate: 50 to 100 mg PO every 6 hours, as needed.
Meclizine (mainly used for motion sickness and vertigo): 25 every 6 hours, as needed.
Promethazine: PO, intramuscular (IM), rectal, or intravenous (V) of 12.5 to 25 mg every 6 hours, as needed
Many anticholinergic effects including central nervous system (CNS) depression, fatigue, paradoxical vomiting, blurred vision, xerostomia, worsening of narrow-angle glaucoma.
According to Beers criteria, all first-generation antihistamine histamines carry a higher risk for severe adverse events to the elderly with diphenhydramine and hydroxyzine posing an even higher risk for adverse events including CNS depression. They block CYP 2D6, which diminish the effects of codeine, tramadol, and tamoxifen in the geriatric population.
Neuroleptic malignant syndrome has increased the risk of occurring when combined with phenothiazines and antipsychotic drugs. Hyperpyrexia, muscle rigidity, altered mental status, tachycardia, irregular pulse, irregular blood pressure, and cardiac dysrhythmias are typical manifestations of the disease.
Promethazine (Black Box Warning): Injection can cause tissue injury including but not limited to tissue necrosis, gangrene, abscesses, venous thrombosis, and amputation. The preferred route of injection is intramuscular and never subcutaneous. Discontinue injection if there is any burning or pain out of fear of perivascular extravasation or arterial injection. Using injectable promethazine is not advised.
Children younger than 2 years of age are at risk of respiratory depression while taking promethazine.
Hypersensitivity to medication or other phenothiazines is a contraindication. Patients with lower respiratory tract symptoms including asthma should use antihistamines especially for children under the age of 2.
Ten percent to 15% of females have taken antihistamines during pregnancy for treatment of allergic reactions and nausea. Diphenhydramine, loratadine have been safely used during pregnancy. However, antihistamine usage during breastfeeding is contraindicated because they may inhibit lactation due to decreased maternal serum prolactin concentrations. When antihistamines are needed, second-generation antihistamines are preferred in the breastfeeding population.
The therapeutic index of first-generation antihistamines depends on several factors including the disease (allergic rhinitis, vomiting, nausea, urticaria, motion sickness, vertigo, parkinsonian, insomnia), formulation (by mouth, intranasal, intravenous, intramuscular), and the population (pediatric, adult, elderly). All antihistamines cause anticholinergic effects; however, diphenhydramine causes the most anticholinergic and cardiac toxicity effects. Anticholinergic effects include cutaneous vasodilation, hydroceles, hidrotic hyperthermia, noninteractive eye injuries is, delirium, hallucinations, urinary retention. Cardiac toxicity effects include tachycardia and prolonged QTC. Special monitoring of patients with epilepsy, chronic alcohol abuse or pre-existing heart because the conditions may decrease the safety profile of antihistamines especially with a narrow therapeutic index medication such as diphenhydramine.
Initial treatment should be with stabilization of the airway, monitoring breathing, and circulation. The patient should receive supplemental oxygen, continuous pulse oximetry, intravenous access, and an ECG. In patients with prolonged QRS intervals or arrhythmias, sodium bicarbonate can be used. Benzodiazepines can be used to address agitation and seizures. Hypothermia treatment includes evaporative cooling. If no altered mental status is present and ingestion of anticholinergic agent is likely, activated charcoal can be given. If the airway access is threatened, consider intubation instead. Supportive care is usually adequate however in patients with peripheral and central anticholinergic toxicity, administration of anticholinesterase inhibitor, physostigmine may be warranted. Consultation with a medical toxicologist or regional poison center is recommended before administration. Caution should be given to patients with cardiac abnormalities, reactive airway disease, or gastrointestinal obstruction. Atropine should be available bedside in case of an overdose of physostigmine.
Antihistamine toxicity usually manifests itself as anticholinergic poisoning. This requires an interprofessional team of nurses, physicians, laboratory technologists, pharmacist to narrow down the differential diagnosis. Without proper management, a patient can receive incorrect treatment and could cause cardiac arrest. A patient with delirium, seizures or tachycardia has a wide range of diagnoses when initially admitted. When a diagnosis of anticholinergic toxicity is suspected, a healthcare provider should perform a screening test. Finger-stick glucose, acetaminophen levels, salicylate levels, ECG, and a pregnancy test for women of childbearing age should be taken. Monitoring the patient for any cardiac arrhythmias or altered mental status will further dictate treatment. Physicians should use benzodiazepines for agitation, but physostigmine may be more effective (Grade IV and Grade V). A toxicologist should be consulted if physostigmine is needed. The patient should be placed on a cardiac monitor, have resuscitation equipment and atropine available at the bedside when physostigmine is administered.
Once the patient is stabilized, they will need a thorough history to assess for any underlying psychiatric problems, medication noncompliance, exposure, or medical problems causing increased concentration of the offending medication. If there is any question of the etiology of the poisoning, please call the United States Poison Control network at 1-800-222-1222.