1. Introduction This document presents background information and toxicological assessment of diphenhydramine, a first-generation antihistamine.

Diphenhydramine is most commonly used to treat seasonal allergies, but it is also used as an antiemetic, sleep aid, sedative, and CNS depressant. Because of its many uses, diphenhydramine is a widely used drug. 2. Identification Diphenhydramine is a first-generation antihistamine which has the molecular formula C17H21NO. Some common brand names are as follows: Benadryl, Alledryl, Diphenylhydramine, Benhydramine, Dihidral, Probedryl, Benzhyydraminum. Overall, there are 249 different names for diphenhydramine (or diphenhydramine mixtures) medicine . Diphenhydramine is available in the forms of capsules, injections, tablets, creams, gels and elixirs. 3. Pharmacology Diphenhydramine can be used as a local anesthetic, anti-allergic agent, antiemetic, histamine H1 antagonist and sedative. Antihistamines are used in the treatment of allergies due to inhalant allergens and foods. Antihistamines are used for the symptomatic treatment of itching associated with allergic reactions and cold urticaria. Antihistamines are used with epinephrine for anaphylactic reactions after the acute reactions have been controlled, and to lessen the allergic reactions to blood or plasma. Diphenhydramine is used for the symptomatic treatment of Parkinsons syndrome in combination with centrally acting anticholinergic agents. Diphenhydramine is used as a non-barbiturate cough suppressant for colds or allergies. Diphenhydramine is used for the prevention and treatment of the nausea, vomiting, dizziness, that is associated with vertigo. Diphenhydramine is used for its sedative effect. 3.1 Drug warnings H1 antagonists are most useful when treating the sudden onset of allergic reactions. Diphenhydramine only treats the symptoms; it does not prevent the production of histamines. First-generation H1 antagonists can both stimulate and depress the CNS. Stimulation is rarely observed with correct dosage, but it can be a sign of mild to moderate poisoning. Diphenhydramine typically depresses the CNS. The most common side effect is sedation. For individuals suffering from insomnia, this is the desired reaction. For most individuals, however, this is a negative side effect. If ones case is the latter, they should avoid operating heavy machinery or automobiles. Common side effects that involve the digestive tract are as follows: loss of appetite, vomiting, nausea, stomach pain, and constipation or diarrhea. This effect can be reduced by ingesting the medicine with meals.

Other side effects that are caused by the anticholinergic reactions of diphenhydramine include dry mouth, coughing, urinary retention, urinary frequency, and painful urination. Side effects that impact the cardiovascular system are as follows: palpitations, low blood pressure, migraines and weakness of the hands. [1] Drug allergy rarely occurs from oral exposure. It is more common to see a drug allergy resulting from topical use. Presence in breast milk is rare, but should be avoided in nursing mothers because of transference risk. 3.2 Persons susceptible to negative side effects of diphenhydramine Newborn or premature infants should not be given diphenhydramine because of an increased susceptibility CNS excitation and lowered seizure threshold. Elderly persons should also avoid diphenhydramine because nausea, somnolence, confusion, and hypotension may occur. Also, hematological complications are extremely rare, but can occur. 3.3 Toxicity and Lethal Dose In infants, severe toxicity occurs around 10 to 15 mg/kg; lowest lethal dose was 11.6 mg/kg. In young children, oral doses of less than 7.5 mg/kg should have little to no toxic effect. In adults, severe toxicity typically occurs after ingesting 1 or more grams. The lowest lethal dose for an adult was 25 mg/kg. Prolonged exposure/ high volume exposure to topical treatment can result in toxicity. [4] 3.4 Toxicity symptoms Mild overdose symptoms are as follows: sedation, anticholinergic effects, tachycardia, hypertension, nausea and vomiting. Moderate overdose symptoms are as follows: confusion, distress, hallucinations. Severe poisoning symptoms are as follows: neurosis, seizures, coma, hypotension and rare but possible renal failure

3.5 Treatment for overexposure In the case of oral exposure, for mild toxicity, closely monitor the affected person. Charcoal tablets could be beneficial if taken soon after ingestion of the drug. In the case of severe toxicity, tracheal intubation will maintain open airways, and stomach pumping could be beneficial if ingestion of the drug (more than 1 gram) was recent. 4. Pharmacodynamics Diphenhydramine belongs to the ethanolamine class of antihistamines. Ethanolamine antihistamines have significant antimuscarinic effects and cause sedation in majority of individuals 5. Biomedical Effects 5.1 Mechanism of action Antihistamines are used to treat allergies not by eliminating histamine, but by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, responses mediated by histamine. H1 antagonists inhibit most effects of histamine on smooth muscle. For example, diphenhydramine antagonizes the constrictor action of histamine on smooth muscle in the respiratory tract. Diphenhydramine counteracts the effects of histamine on the capillaries, which in turn can reduce the intensity of allergy symptoms. Diphenhydramine also crosses the bloodbrain barrier and antagonizes the H1 receptors centrally. A side effect of this is sedation. Like many other first-generation antihistamines, diphenhydramine is an effective antimuscarinic. Diphenhydramine is an effective antiparkinson treatment because it has blocking properties on the muscarinic acetylcholine receptors in the brain. Diphenhydramine can be used as a local anesthetic because it can act as an intracellular sodium channel blocker. Diphenhydramine can inhibit the reabsorption of serotonin. 5.2 Absorption Diphenhydramine is absorbed with maximum activity occurring in approximately one hour. It is relatively well absorbed, and its plasma concentration is quickly increased after oral

administration. The intestinal absorption mechanisms of diphenhydramine, have been explained by the passive diffusion of nonionic compounds according to the pH-partition theory. [3] 5.2 Distribution Diphenhydramine is widely distributed, and it crosses into the placenta, enters breast milk, and crosses the blood-brain barrier. 5.3 Protein binding 98-99% 5.4 Metabolism Diphenhydramine is metabolized by the liver and kidneys. Approximately 95% of the ingested dose is metabolized by the liver. 5.5 Excretion Minute unaltered amounts of diphenhydramine are excreted in the urine. Most excretion appears as the products of metabolic transformation in the liver, which are often excreted within 24 hours. H1 antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. [1] 5.6 Half-life 1-4 hours [2] 5.7 Interactions Concurrent use of ototoxic medications with diphenhydramine may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. [2] Concurrent use of monoamine oxidase (MAO) inhibitors with diphenhydramine may prolong and intensify the anticholinergic and CNS depressant effects of diphenhydramine. Therefore, concurrent use is not recommended. Concurrent use with alcohol or other CNS depression-producing medications may cause the CNS depressant effects of either these medications or antihistamines. Anticholinergic effects may occur when anticholinergics are used concurrently with diphenhydramine. Patients should report occurrence of gastrointestinal problems in a timely manner since paralytic ileus may occur with concurrent therapy.

Concurrent use of other photosensitizing medications with diphenhydramine may cause additive photosensitizing effects. [2]

1. (Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 584) 2. (USP Convention. USPDI - Drug Information for the Health Care Professional. 15 th ed. Volume 1. Rockville, MD: United States Pharmacopeial Convention, Inc., 1995. (Plus updates.), p. 305) 3. http://jpet.aspetjournals.org/content/290/1/388.full.pdf+html) 4. ([Rumack BH POISINDEX(R) Information System Micromedex, Inc., Englewood, CO, 2013; CCIS Volume 156, edition expires May, 2013. Hall AH & Rumack BH (Eds): TOMES(R) Information System Micromedex, Inc., Englewood, CO, 2013; CCIS Volume 156, edition expires May, 2013.] **PEER REVIEWED** )