Wikipedia

Promethazine

Promethazine,sold under the brand namePhenerganamong others, is afirst-generation antihistamine,sedative,andantiemeticused to treatallergies,insomnia,andnausea.It may also help with some symptoms associated with thecommon cold[4]and may also be used forsedatingpeople who are agitated or anxious, an effect that has led to somerecreational use(especially with codeine).[5][6][7]Promethazine is takenby mouth(oral), as arectal suppository,or byinjection into a muscle(IM).[4]

Promethazine
Clinical data
Trade namesPhenergan, many others[1]
AHFS/DrugsMonograph
MedlinePlusa682284
License data
Pregnancy
category
  • AU:C
Routes of
administration		By mouth,rectal,intravenous,intramuscular,topical
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[2]
Protein binding93%
MetabolismLiverglucuronidationandsulfoxidation
Eliminationhalf-life10–19 hours[2][3]
ExcretionKidneyandBile duct
Identifiers
  • (RS)-N,N-Dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.000.445Edit this at Wikidata
Chemical and physical data
FormulaC17H20N2S
Molar mass284.42g·mol−1
3D model (JSmol)
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,12H2,1-3H3checkY
  • Key:PWWVAXIEGOYWEE-UHFFFAOYSA-NcheckY
(verify)

Common side effects of promethazine include confusion and sleepiness;[4]consumption ofalcoholor other sedatives can make these symptoms worse.[4]It is unclear if use of promethazine duringpregnancyorbreastfeedingis safe for the fetus.[4][6]Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing.[4]Use of promethazine by injection into a vein is not recommended, due to potential skin damage.[4]Promethazine is in thephenothiazinefamily of medications.[4]It is also a stronganticholinergic,which produces itssedativeeffects. This also means high or toxic doses can act as adeliriant.[8]

Promethazine was made in the 1940s by a team of scientists fromRhône-Poulenclaboratories.[9]It was approved for medical use in the United States in 1951.[4]It is ageneric medicationand is available under many brand names globally.[1]In 2021, it was the 188th most commonly prescribed medication in the United States, with more than 2million prescriptions.[10][11]In 2021, the combination withdextromethorphanwas the 289th most commonly prescribed medication in the United States, with more than 600,000 prescriptions.[10][12]

Medical uses

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Promethazine has a variety of medical uses, including:

Side effects

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Some documentedside effectsinclude:

  • Tardive dyskinesia,pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)[13]
  • Confusion in the elderly[13]
  • Drowsiness, dizziness, fatigue, more rarelyvertigo
  • Known to have effects onserotoninand dopamine receptors.[18]
  • Dry mouth[13]
  • Nausea[19]
  • Respiratory depressionin patients under age of two and in those with severely compromised pulmonary function[20]
  • Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to its anti-cholinergic effects)[13]
  • Chest discomfort/pressure (In children less than 2 years old)[13]
  • Akathisia[21]

Less frequent:

  • Cardiovascular side effects to include arrhythmias and hypotension[13]
  • Neuroleptic malignant syndrome[13]
  • Liver damage and cholestatic jaundice[13]
  • Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia[13]
  • Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermia[13]

Rare side effects include:

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.[22]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.[23]

Promethazine is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.[24]

Overdose

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Promethazine inoverdosecan produce signs and symptoms includingCNS depression,hypotension,respiratory depression,unconsciousness,and sudden death.[25]Other reactions may includehyperreflexia,hypertonia,ataxia,athetosis,andextensor-plantar reflexes.[25]Atypically and/or rarely,stimulation,convulsions,hyperexcitability, andnightmaresmay occur.[25]Anticholinergiceffects likedry mouth,dilated pupils,flushing,gastrointestinalsymptoms, anddeliriummay occur as well.[25]Treatment of overdose is supportive and based on symptoms.[25]

Pharmacology

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Promethazine, a phenothiazine derivative, is structurally different from theneurolepticphenothiazines, with similar but different effects.[2]Despite structural differences, promethazine exhibits a strikingly similar binding profile topromazine,[26]another phenothiazine compound. Both promethazine and promazine exhibit comparable neuroleptic potency, with a neuroleptic potency of 0.5.[27]However, dosages used therapeutically, such as for sedation or sleep disorders, have no antipsychotic effect.[28]It acts primarily as a strongantagonistof theH1receptor(antihistamine,Ki= 1.4 nM[29]) and a moderatemACh receptorantagonist (anticholinergic),[2]and also has weak to moderateaffinityfor the5-HT2A,[30]5-HT2C,[30]D2,[31][32]andα1-adrenergic receptors,[33]where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selectiveNMDA receptorantagonist,with an EC50 of 20 μM;[34]which might promote sedation in addition with the strongantihistaminergiceffects of theH1receptor,but also as a weakeranalgesic.It does not however affect theAMPAreceptors.[34]

Another notable use of promethazine is as alocal anesthetic,by blockage ofsodium channels.[33]

Binding to receptors in nM(Ki)
receptor Ki(nM) ref
α1A-adrenoceptor (Rat) 32 [35]
α1B-adrenoceptor (Rat) 21 [35]
α1D-adrenoceptor (Human) 90 [35]
α2A-adrenoceptor (Human) 256 [35]
α2B-adrenoceptor (Human) 24 [35]
α2C-adrenoceptor (Human) 353 [35]
Calmodulin (Human) 60000 [36][35][37]
Calmodulin (Bovine) 50000 [36][37][35]
Chloroquine resistance transporter (Plasmodium falciparum) 85000 [38][35]
D1 receptor (Human) 1372 [35]
D2 receptor (Human) 260 [35]
D3 receptor (Human) 190 [35]
H1 receptor (Human) 0.33[35]-1.4[39] [39][35]
H2 receptor (Human) 1146 [35]
M1 receptor (Human) 3.32 [35]
M2 receptor (Human) 12 [35]
M3 receptor (Human) 4.15 [35]
M4 receptor (Human) 1.06 [35]
M5 receptor (Human) 3.31 [35]
NET (Human) 4203 [35]
Prion protein (Human) 8000 [40][35]
5-HT1A receptor (Rat) 1484 [35]
5-HT2A receptor (Human) 19 [35]
5-HT2B receptor (Human) 43 [35]
5-HT2C receptor (Human) 6.48 [35]
5-HT6 receptor (Human) 1128 [35]
SERT (Serotonin transporter) (Human) 2130 [35]
Sigma1 receptor (Human) 120 [35]
OCT1 (Human) 35100 [41][35]

Chemistry

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Solid promethazinehydrochlorideis a white to faint-yellow, practically odorless, crystalline powder. Slow oxidation may occur upon prolonged exposure to air, usually causing blue discoloration. Itshydrochloridesaltis freely soluble in water and somewhat soluble in alcohol. Promethazine is achiralcompound, occurring as a mixture ofenantiomers.[42]

History

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Promethazine was first synthesized by a group atRhone-Poulenc(which later became part ofSanofi) led by Paul Charpentier in the 1940s.[43]The team was seeking to improve ondiphenhydramine;the same line of medical chemistry led to the creation ofchlorpromazine.[44]

Society and culture

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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.[1]

Atosil syrup

It is also marketed in manycombination drugformulations:

Recreational use

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The recreational druglean,also known as purple drank among other names, often contains a combination of promethazine with codeine-containingcold medication.[5]

Product liability lawsuit

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Main article:Wyeth v. Levine

In 2009, theUS Supreme Courtruled on aproduct liabilitycase involving promethazine. Diana Levine, a woman with a migraine, was administeredWyeth's Phenergan viaIV push.The drug was injected improperly, resulting ingangreneand subsequent amputation of her right forearm below the elbow. A state jury awarded her $6 million inpunitive damages.

The case was appealed to the Supreme Court on grounds offederal preemptionandsubstantive due process.[45]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.[46]In effect, this means drug manufacturers can be held liable for injuries if warnings of potential adverse effects, approved by theUS Food and Drug Administration(FDA), are deemed insufficient by state courts.

In September 2009, the FDA required aboxed warningbe put on promethazine for injection, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces risk of surrounding muscle and tissue damage.[47]

References

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