Promethazine

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Promethazine
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Clinical data
Trade namesPhenergan, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa682284
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Pregnancy
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  • AU: C
Dependence
liability		Low [2]
Addiction
liability		None-Very low [3]
Routes of
administration		By mouth, rectal, intravenous, intramuscular, topical
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Legal status
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Pharmacokinetic data
Bioavailability88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[4]
Protein binding93%[5]
MetabolismLiver glucuronidation and sulfoxidation
MetabolitesPromethazine Sulphoxide, Desmethylpromethazine, Promethazine Hydroxy[6]
Elimination half-life10–19 hours[4][7]
Duration of action4-6h (sometimes up to 12h)[8]
ExcretionKidney and Bile duct
Identifiers
  • (RS)-N,N-Dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine
CAS NumberPage Template:Plainlist/styles.css has no content.
PubChem CIDPage Template:Plainlist/styles.css has no content.
PubChem SIDPage Template:Plainlist/styles.css has no content.
IUPHAR/BPSPage Template:Plainlist/styles.css has no content.
DrugBankPage Template:Plainlist/styles.css has no content.
ChemSpiderPage Template:Plainlist/styles.css has no content.
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Chemical and physical data
FormulaC17H20N2S
Molar mass284.42 g·mol−1
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ChiralityRacemic mixture
  • S2c1ccccc1N(c3c2cccc3)CC(N(C)C)C
  • InChI=1S/C17H20N2S/c1-13(18(2)3)12-19-14-8-4-6-10-16(14)20-17-11-7-5-9-15(17)19/h4-11,13H,12H2,1-3H3 checkY
  • Key:PWWVAXIEGOYWEE-UHFFFAOYSA-N checkY
Data page
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Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, sedative, and antiemetic used to treat allergies, nausea, and vomiting. It may also help with some symptoms associated with the common cold[9] 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).[10][11][12] Promethazine is taken by mouth (oral), as a rectal suppository, or by injection into a muscle (IM).[9]

Common side effects of promethazine include confusion and sleepiness;[9] consumption of alcohol or other sedatives can make these symptoms worse.[9] It is unclear if use of promethazine during pregnancy or breastfeeding is safe.[9][11] Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing.[9] Use of promethazine by injection into a vein is not recommended, due to potential skin damage.[9] Promethazine is in the phenothiazine family of medications.[9] It is also a strong anticholinergic and at high or toxic doses can act as a deliriant.[13]

Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories.[14] It was approved for medical use in the United States in 1951.[9] It is a generic medication and is available under many brand names globally.[1] In 2023, it was the 230th most commonly prescribed medication in the United States, with more than 1 million prescriptions;[15][16] and the combination with dextromethorphan was the 252nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[17][18]

Medical uses

File:Phenergan 25mg tablets (UK).jpg
Phenergan (promethazine) blister pack 25mg tablets

Promethazine has a variety of medical uses, including:

Side effects

Some documented side effects include:

  • Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)[19]
  • Confusion in the elderly[19]
  • Drowsiness, dizziness, fatigue, more rarely vertigo
  • Known to have effects on serotonin and dopamine receptors.[23]
  • Dry mouth[19]
  • Nausea[24]
  • Respiratory depression in patients under the age of two and those with severely compromised pulmonary function[25]
  • Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to its anticholinergic effects)[19]
  • Chest discomfort/pressure (In children less than 2 years old)[19]
  • Akathisia[26]

Less frequent:

  • Cardiovascular side effects to include arrhythmias and hypotension[19]
  • Neuroleptic malignant syndrome[19]
  • Liver damage and cholestatic jaundice[19]
  • Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia[19]
  • Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia[19]

Rare side effects include:

Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.[27] 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.[28]

Promethazine is listed as one of the drugs with the highest anticholinergic activity in a study of anticholinergic burden, including long-term cognitive impairment.[29]

Overdose

Promethazine in overdose can produce signs and symptoms including CNS depression, hypotension, respiratory depression, unconsciousness, and sudden death.[30] Other reactions may include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes.[30] Atypically and/or rarely, stimulation, convulsions, hyperexcitability, and nightmares may occur.[30] Anticholinergic effects like dry mouth, dilated pupils, flushing, gastrointestinal symptoms, and delirium may occur as well.[30] Treatment of overdose is supportive and based on symptoms.[30]

Pharmacology

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects.[4] Despite structural differences, promethazine exhibits a strikingly similar binding profile to promazine,[31] another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.[32] However, dosages used therapeutically, such as for sedation, have no antipsychotic effect.[33] It acts primarily as a strong antagonist of the H1 receptor (antihistamine, Ki = 1.4 nM[34]) and a moderate mACh receptor antagonist (anticholinergic),[4] and also has weak to moderate affinity for the 5-HT2A,[35] 5-HT2C,[35] D2,[36][37] and α1-adrenergic receptors,[38] 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;[39] 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.[39]

Another notable use of promethazine is as a local anesthetic, by blockage of sodium channels.[38]

Binding to receptors in nM (Ki)
receptor Ki (nM) ref
α1A-adrenoceptor (Rat) 32 [40]
α1B-adrenoceptor (Rat) 21 [40]
α1D-adrenoceptor (Human) 90 [40]
α2A-adrenoceptor (Human) 256 [40]
α2B-adrenoceptor (Human) 24 [40]
α2C-adrenoceptor (Human) 353 [40]
Calmodulin (Human) 60000 [41][40][42]
Calmodulin (Bovine) 50000 [41][42][40]
Chloroquine resistance transporter (Plasmodium falciparum) 85000 [43][40]
D1 receptor (Human) 1372 [40]
D2 receptor (Human) 260 [40]
D3 receptor (Human) 190 [40]
H1 receptor (Human) 0.33[40]-1.4[44] [44][40]
H2 receptor (Human) 1146 [40]
M1 receptor (Human) 3.32 [40]
M2 receptor (Human) 12 [40]
M3 receptor (Human) 4.15 [40]
M4 receptor (Human) 1.06 [40]
M5 receptor (Human) 3.31 [40]
NET (Norephinephrine transporter) (Human) 4203 [40]
Prion protein (Human) 8000 [45][40]
5-HT1A receptor (Rat) 1484 [40]
5-HT2A receptor (Human) 19 [40]
5-HT2B receptor (Human) 43 [40]
5-HT2C receptor (Human) 6.48 [40]
5-HT6 receptor (Human) 1128 [40]
SERT (Serotonin transporter) (Human) 2130 [40]
Sigma1 receptor (Human) 120 [40]
OCT1 (Human) 35100 [46][40]

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.[47]

History

Promethazine was first synthesized by a group at Rhone-Poulenc (which later became part of Sanofi) led by Paul Charpentier in the 1940s.[48] The team was seeking to improve on diphenhydramine; the same line of medical chemistry led to the creation of chlorpromazine.[49]

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, Vertigon, Xepagan, Zinmet, and Zoralix.[1]

File:Promethazine bottles.jpg
Promethazine with Codeine syrup

It is also marketed in many combination drug formulations:

Recreational use

Template:Main article The recreational drug lean, also known as "purple drank" among other names, consists of promethazine mixed with Sprite and either an opiate or opioid.[10]

Product liability lawsuit

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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.[50] 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.[51] 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.[52]

References

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