Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine,

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

, and

antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...

used to treat

allergies Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

. It may also help with some symptoms associated with the

common cold The common cold, or the cold, is a virus, viral infectious disease of the upper respiratory tract that primarily affects the Respiratory epithelium, respiratory mucosa of the human nose, nose, throat, Paranasal sinuses, sinuses, and larynx. ...

and may also be used for sedating people who are agitated or anxious, an effect that has led to some recreational use ( especially with codeine). Promethazine is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

(oral), as a rectal suppository, or by injection into a muscle (IM). Common side effects of promethazine include confusion and sleepiness; consumption of

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

or other sedatives can make these symptoms worse. It is unclear if use of promethazine during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

is safe for the fetus. Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing. Use of promethazine by injection into a vein is not recommended, due to potential skin damage. Promethazine is in the phenothiazine family of medications. It is also a strong

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

, which produces its

effects. This also means high or toxic doses can act as a

deliriant Deliriants are a subclass of hallucinogen. The term was coined in the early 1980s to distinguish these drugs from psychedelics such as LSD and dissociatives such as ketamine, due to their primary effect of causing delirium, as opposed to th ...

. Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories. It was approved for medical use in the United States in 1951. It is a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

and is available under many brand names globally. In 2022, it was the 198th most commonly prescribed medication in the United States, with more than 2million prescriptions. In 2022, the combination with

dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

was the 260th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Promethazine has a variety of medical uses, including: * Sedation * In Germany, it is approved for the treatment of agitation and agitation associated with underlying psychiatric disorders with a maximum daily dose of 200 mg. * For nausea and vomiting associated with anesthesia or chemotherapy. It is commonly used postoperatively as an

. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing. * For moderate to severe morning sickness and hyperemesis gravidarum: In the UK, Promethazine is the

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

of first choice. Promethazine is preferred during pregnancy because it is an older drug and there is more data regarding the use of it during

. Second-choice medications, which are used if Promethazine isn't tolerated or the patient cannot take it, are

metoclopramide Metoclopramide is a medication used to treat nausea, vomiting, gastroparesis, and gastroesophageal reflux disease. It is also used to treat migraine headaches. Common side effects include feeling tired, diarrhea, akathisia, and tardive dyski ...

or prochlorperazine.. * For allergies such as

hay fever Allergic rhinitis, of which the seasonal type is called hay fever, is a type of rhinitis, inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a Allergy, type I hypersensitivity re ...

and together with other medications in

anaphylaxis Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typicall ...

* To aid with symptoms of the

Motion sickness Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include ...

, including space sickness *

Hemolytic disease of the newborn Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...

Anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

before surgery * Short-term

Side effects

Some documented

side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

include: * Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism) * Confusion in the elderly * Drowsiness, dizziness, fatigue, more rarely

vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...

* Known to have effects on

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and dopamine receptors. * Dry mouth * Nausea * Respiratory depression in patients under the age of two and those with severely compromised pulmonary function * Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to its anticholinergic effects) * Chest discomfort/pressure (In children less than 2 years old) * Akathisia Less frequent: * Cardiovascular side effects to include arrhythmias and hypotension * Neuroleptic malignant syndrome * Liver damage and cholestatic jaundice * Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia * Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia Rare side effects include: *

Seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly. In many countries (including the US and UK), promethazine is contraindicated in children less than two years of age, and strongly cautioned against in children between two and six, due to problems with respiratory depression and sleep apnea. Promethazine is listed as one of the drugs with the highest anticholinergic activity in a study of anticholinergic burden, including long-term cognitive impairment.

Overdose

Promethazine in

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

can produce signs and symptoms including CNS depression,

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

, respiratory depression,

unconsciousness Unconsciousness is a state in which a living individual exhibits a complete, or near-complete, inability to maintain an awareness of self and environment or to respond to any human or environmental stimulus. Unconsciousness may occur as the r ...

, and sudden death. Other reactions may include hyperreflexia, hypertonia,

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, athetosis, and extensor-plantar reflexes. Atypically and/or rarely,

stimulation Stimulation is the encouragement of development or the cause of activity in general. For example, "The press provides stimulation of political discourse." An interesting or fun activity can be described as "stimulating", regardless of its physic ...

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

s, hyperexcitability, and nightmares may occur.

Anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

effects like dry mouth, dilated pupils, flushing,

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

symptoms, and delirium may occur as well. Treatment of overdose is supportive and based on symptoms.

Pharmacology

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects. Despite structural differences, promethazine exhibits a strikingly similar binding profile to promazine, another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5. However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect. It acts primarily as a strong

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.H₁ receptor (

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...

, ''K''_i = 1.4 nM) and a moderate mACh receptor antagonist (

), and also has weak to moderate

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the 5-HT_2A, 5-HT_2C, D₂, and α₁-adrenergic receptors, where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selective

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. which might promote sedation in addition with the strong

rgic effects of the H₁ receptor, but also as a weaker

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

. It does not, however, affect the

AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate Glutamic acid (symbol Glu or E; kn ...

receptors. Another notable use of promethazine is as a

local anesthetic A local anesthetic (LA) is a medication that causes absence of all sensation (including pain) in a specific body part without loss of consciousness, providing local anesthesia, as opposed to a general anesthetic, which eliminates all sensati ...

, by blockage of sodium channels.

Chemistry

Solid promethazine hydrochloride is a white to faint-yellow, practically odorless, crystalline powder. Slow oxidation may occur upon prolonged exposure to air, usually causing blue discoloration. Its hydrochloride

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

is freely soluble in water and somewhat soluble in alcohol. Promethazine is a

chiral Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek language, Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is dist ...

compound, occurring as a mixture of

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

History

Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of

Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...

) led by Paul Charpentier in the 1940s. The team was seeking to improve on

diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...

; the same line of medical chemistry led to the creation of

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

Society and culture

As of July 2017, it is marketed under many brand names worldwide: Allersoothe, Antiallersin, Anvomin, Atosil, Avomine, Closin N, Codopalm, Diphergan, Farganesse, Fenazil, Fenergan, Fenezal, Frinova, Hiberna, Histabil, Histaloc, Histantil, Histazin, Histazine, Histerzin, Lenazine, Lergigan, Nufapreg, Otosil, Pamergan, Pharmaniaga, Phenadoz, Phenerex, Phenergan, Phénergan, Pipolphen, Polfergan, Proazamine, Progene, Prohist, Promet, Prometal, Prometazin, Prometazina, Promethazin, Prométhazine, Promethazinum, Promethegan, Promezin, Proneurin, Prothazin, Prothiazine, Prozin, Pyrethia, Quitazine, Reactifargan, Receptozine, Romergan, Sominex, Sylomet, Xepagan, Zinmet, and Zoralix. Atosil

It is also marketed in many

combination drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

formulations: * with carbocisteine as Actithiol Antihistaminico, Mucoease, Mucoprom, Mucotal Prometazine, and Rhinathiol; * with

paracetamol Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

(acetaminophen) as Algotropyl, Calmkid, Fevril, Phen Plus, and Velpro-P; * with

and

as Choligrip na noc, Coldrex Nočná Liečba, Fedril Night Cold and Flu, Night Nurse, and Tachinotte; * with

, phenylephrine, and salicylamide as Flukit; * with

as Axcel Dextrozine and Hosedyl DM; * with

and

ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

as Methorsedyl; * with

and pseudoephedrine as Sedilix-DM; * with

and phenylephedrine as Sedilix-RX; * with pholcodine as Codo-Q Junior and Tixylix; * with pholcodine and

as Phensedyl Dry Cough Linctus; * with pholcodine and phenylephedrine as Russedyl Compound Linctus; * with pholcodine and phenylpropanolamine as Triple 'P'; * with codeine as Kefei and Procodin; * with codeine and

as Dhasedyl, Fendyl, and P.E.C.; * with

and

as Dhasedyl DM; * with

glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...

as Psico-Soma, and Psicosoma; * with noscapine as Tussisedal; and * with

and phenobarbital as Vegetamin.

Recreational use

The recreational drug lean, also known as purple drank among other names, often contains a combination of promethazine with codeine-containing cold medication.

Product liability lawsuit

In 2009, the

US Supreme Court The Supreme Court of the United States (SCOTUS) is the highest court in the federal judiciary of the United States. It has ultimate appellate jurisdiction over all Federal tribunals in the United States, U.S. federal court cases, and over Stat ...

ruled on a

product liability Product liability is the area of law in which manufacturers, distributors, suppliers, retailers, and others who make products available to the public are held responsible for the injuries those products cause. Although the word "product" has ...

case involving promethazine. Diana Levine, a woman with a migraine, was administered Wyeth's Phenergan via IV push. The drug was injected improperly, resulting in gangrene and subsequent amputation of her right forearm below the elbow. A state jury awarded her $6 million in

punitive damages Punitive damages, or exemplary damages, are damages assessed in order to punish the defendant for outrageous conduct and/or to reform or deter the defendant and others from engaging in conduct similar to that which formed the basis of the lawsuit. ...

. The case was appealed to the Supreme Court on grounds of

federal preemption In the law of the United States, federal preemption is the invalidation of a U.S. state law that conflicts with federal law. The rules of preemption seek to restrict it to only where it is explicit or necessary. In the course of adjudicating ...

and

substantive due process due process is a principle in United States constitutional law that allows courts to establish and protect substantive laws and certain fundamental rights from government interference, even if they are unenumerated elsewhere in the U.S. Consti ...

. The Supreme Court upheld the lower courts' rulings, stating that "Wyeth could have unilaterally added a stronger warning about IV-push administration" without acting in opposition to federal law. In effect, this means drug manufacturers can be held liable for injuries if warnings of potential adverse effects, approved by the US Food and Drug Administration (FDA), are deemed insufficient by state courts. In September 2009, the FDA required a boxed warning be put on promethazine for injection, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces the risk of surrounding muscle and tissue damage.

References

{{Authority control Antiemetics Antimigraine drugs CYP2D6 inhibitors Dimethylamino compounds H1 receptor antagonists HERG blocker Hypnotics M1 receptor antagonists M2 receptor antagonists M3 receptor antagonists M4 receptor antagonists M5 receptor antagonists NMDA receptor antagonists Phenothiazines Sodium channel blockers Sigma receptor modulators Wikipedia medicine articles ready to translate