Promethazine

Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold<ref name=AHFS2018>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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).<ref name="lean" /><ref name="BNF74" /><ref>Template:Cite book</ref> Promethazine is taken by mouth (oral), as a rectal suppository, or by injection into a muscle (IM).<ref name=AHFS2018/>

Common side effects of promethazine include confusion and sleepiness;<ref name="AHFS2018" /> consumption of alcohol or other sedatives can make these symptoms worse.<ref name=AHFS2018/> It is unclear if use of promethazine during pregnancy or breastfeeding is safe for the fetus.<ref name=AHFS2018/><ref name=BNF74>Template:Cite book</ref> Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing.<ref name=AHFS2018/> Use of promethazine by injection into a vein is not recommended, due to potential skin damage.<ref name=AHFS2018/> Promethazine is in the phenothiazine family of medications.<ref name=AHFS2018/> It is also a strong anticholinergic, which produces its sedative effects. This also means high or toxic doses can act as a deliriant.<ref>Template:Cite journal</ref>

Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories.<ref>Template:Cite book</ref> It was approved for medical use in the United States in 1951.<ref name=AHFS2018/> It is a generic medication and is available under many brand names globally.<ref name=brands>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2022, it was the 198th most commonly prescribed medication in the United States, with more than 2Template:Nbspmillion prescriptions.<ref name="Top 300 of 2022">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2022, the combination with dextromethorphan was the 260th most commonly prescribed medication in the United States, with more than 1Template:Nbspmillion prescriptions.<ref name="Top 299 of 2022" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Promethazine has a variety of medical uses, including:

• Sedation<ref name=Promethazinestats/>
• 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.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• For nausea and vomiting associated with anesthesia or chemotherapy. It is commonly used postoperatively as an antiemetic. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing.<ref name=Promethazinestats/>
• For moderate to severe morning sickness and hyperemesis gravidarum: In the UK, Promethazine is the drug 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 pregnancy. Second-choice medications, which are used if Promethazine isn't tolerated or the patient cannot take it, are metoclopramide or prochlorperazine.<ref name="BNF">Template:Cite book.</ref><ref name=Promethazinestats>Template:Cite journalTemplate:CC-notice</ref>
• For allergies such as hay fever and together with other medications in anaphylaxis<ref name=AHFS2018/>
• To aid with symptoms of the common cold<ref name=AHFS2018/>
• Motion sickness,<ref name=AHFS2018/> including space sickness<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Hemolytic disease of the newborn<ref name=AHFS2018/>
• Anxiety before surgery<ref name=AHFS2018/>
• Short-term insomnia<ref name="nhs-Promethazine">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Side effects

Some documented side effects include:

• Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)<ref name=Promethazinestats/>
• Confusion in the elderly<ref name=Promethazinestats/>
• Drowsiness, dizziness, fatigue, more rarely vertigo
• Known to have effects on serotonin and dopamine receptors.<ref name="pmid28767476">Template:Cite journal</ref>
• Dry mouth<ref name=Promethazinestats/>
• Nausea<ref>National Institute for Health and Care Excellence</ref>
• Respiratory depression in patients under the age of two and those with severely compromised pulmonary function<ref>Template:Cite journal</ref>
• Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to its anticholinergic effects)<ref name=Promethazinestats/>
• Chest discomfort/pressure (In children less than 2 years old)<ref name=Promethazinestats/>
• Akathisia<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Less frequent:

• Cardiovascular side effects to include arrhythmias and hypotension<ref name=Promethazinestats/>
• Neuroleptic malignant syndrome<ref name=Promethazinestats/>
• Liver damage and cholestatic jaundice<ref name=Promethazinestats/>
• Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia<ref name=Promethazinestats/>
• Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia<ref name=Promethazinestats/>

Rare side effects include:

• Seizures<ref name=Promethazinestats/>

Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.<ref>NCQA's HEDIS Measure: Use of High Risk Medications in the Elderly Template:Webarchive</ref> 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.<ref>Template:Cite journal</ref>

Promethazine is listed as one of the drugs with the highest anticholinergic activity in a study of anticholinergic burden, including long-term cognitive impairment.<ref>Template:Cite journal</ref>

Overdose

Promethazine in overdose can produce signs and symptoms including CNS depression, hypotension, respiratory depression, unconsciousness, and sudden death.<ref name="Phenergan-Label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Other reactions may include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes.<ref name="Phenergan-Label" /> Atypically and/or rarely, stimulation, convulsions, hyperexcitability, and nightmares may occur.<ref name="Phenergan-Label" /> Anticholinergic effects like dry mouth, dilated pupils, flushing, gastrointestinal symptoms, and delirium may occur as well.<ref name="Phenergan-Label" /> Treatment of overdose is supportive and based on symptoms.<ref name="Phenergan-Label" />

Pharmacology

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects.<ref name="pmid10965395">Template:Cite journal</ref> Despite structural differences, promethazine exhibits a strikingly similar binding profile to promazine,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.<ref>Template:Cite book</ref> However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect.<ref>Template:Cite book</ref> It acts primarily as a strong antagonist of the H₁ receptor (antihistamine, K_i = 1.4 nM<ref>Template:Cite journal</ref>) and a moderate mACh receptor antagonist (anticholinergic),<ref name="pmid10965395"/> and also has weak to moderate affinity for the 5-HT_2A,<ref name="pmid8584617">Template:Cite journal</ref> 5-HT_2C,<ref name="pmid8584617" /> D₂,<ref name="pmid2932631">Template:Cite journal</ref><ref name="pmid847477">Template:Cite journal</ref> and α₁-adrenergic receptors,<ref name="JagadishPrasad2010">Template:Cite book</ref> 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 antagonist, with an EC50 of 20 μM;<ref name=":4" /> which might promote sedation in addition with the strong antihistaminergic effects of the H₁ receptor, but also as a weaker analgesic. It does not, however, affect the AMPA receptors.<ref name=":4">Template:Cite journal</ref>

Another notable use of promethazine is as a local anesthetic, by blockage of sodium channels.<ref name="JagadishPrasad2010" />

Binding to receptors in nM (K_i)

receptor	Ki (nM)	ref
α1A-adrenoceptor (Rat)	32	citation	CitationClass=web }}</ref>
α1B-adrenoceptor (Rat)	21	<ref name=":1" />
α1D-adrenoceptor (Human)	90	<ref name=":1" />
α2A-adrenoceptor (Human)	256	<ref name=":1" />
α2B-adrenoceptor (Human)	24	<ref name=":1" />
α2C-adrenoceptor (Human)	353	<ref name=":1" />
Calmodulin (Human)	60000	<ref name="Bruno_2016">Template:Cite journal</ref><ref name=":1" /><ref name=":0">Template:Cite journal</ref>
Calmodulin (Bovine)	50000	<ref name="Bruno_2016" /><ref name=":0" /><ref name=":1" />
Chloroquine resistance transporter (Plasmodium falciparum)	85000	<ref name=":2">Template:Cite journal</ref><ref name=":1" />
D1 receptor (Human)	1372	<ref name=":1" />
D2 receptor (Human)	260	<ref name=":1" />
D3 receptor (Human)	190	<ref name=":1" />
H1 receptor (Human)	0.33<ref name=":1" />-1.4<ref name=":3">Template:Cite journal</ref>	<ref name=":3" /><ref name=":1" />
H2 receptor (Human)	1146	<ref name=":1" />
M1 receptor (Human)	3.32	<ref name=":1" />
M2 receptor (Human)	12	<ref name=":1" />
M3 receptor (Human)	4.15	<ref name=":1" />
M4 receptor (Human)	1.06	<ref name=":1" />
M5 receptor (Human)	3.31	<ref name=":1" />
NET (Human)	4203	<ref name=":1" />
Prion protein (Human)	8000	<ref name="pmid12904059">Template:Cite journal</ref><ref name=":1" />
5-HT1A receptor (Rat)	1484	<ref name=":1" />
5-HT2A receptor (Human)	19	<ref name=":1" />
5-HT2B receptor (Human)	43	<ref name=":1" />
5-HT2C receptor (Human)	6.48	<ref name=":1" />
5-HT6 receptor (Human)	1128	<ref name=":1" />
SERT (Serotonin transporter) (Human)	2130	<ref name=":1" />
Sigma1 receptor (Human)	120	<ref name=":1" />
OCT1 (Human)	35100	<ref>Template:Cite journal</ref><ref name=":1" />

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 is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of enantiomers.<ref name="rxlistone">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the 1940s.<ref>Template:Cite journal</ref> The team was seeking to improve on diphenhydramine; the same line of medical chemistry led to the creation of chlorpromazine.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=brands/>

File:Atosil.jpg

Atosil syrup

It is also marketed in many combination drug formulations:

• with carbocisteine as Actithiol Antihistaminico, Mucoease, Mucoprom, Mucotal Prometazine, and Rhinathiol;
• with paracetamol (acetaminophen) as Algotropyl, Calmkid, Fevril, Phen Plus, and Velpro-P;
• with paracetamol and dextromethorphan as Choligrip na noc, Coldrex Nočná Liečba, Fedril Night Cold and Flu, Night Nurse, and Tachinotte;
• with paracetamol, phenylephrine, and salicylamide as Flukit;
• with dextromethorphan as Axcel Dextrozine and Hosedyl DM;
• with dextromethorphan and ephedrine as Methorsedyl;
• with dextromethorphan and pseudoephedrine as Sedilix-DM;
• with dextromethorphan and phenylephedrine as Sedilix-RX;
• with pholcodine as Codo-Q Junior and Tixylix;
• with pholcodine and ephedrine 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 ephedrine as Dhasedyl, Fendyl, and P.E.C.;
• with ephedrine and dextromethorphan as Dhasedyl DM;
• with glutamic acid as Psico-Soma, and Psicosoma;
• with noscapine as Tussisedal; and
• with chlorpromazine and phenobarbital as Vegetamin.<ref name=brands/>

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.<ref name="lean">Template:Cite journal</ref>

Product liability lawsuit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

In 2009, the US Supreme Court ruled on a product liability 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.

The case was appealed to the Supreme Court on grounds of federal preemption and substantive due process.<ref name=Liptak>Template:Cite news</ref> 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.<ref name="NYTimes">Template:Cite news</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>