Promethazine

1:1 mixture (racemate)
Systematic (IUPAC) name
(RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682284
Pregnancy cat.	C (AU) C (US)
Legal status	℞-only (US) (injection POM(UK))
Routes	Oral, rectal, IV, IM, topical
Pharmacokinetic data
Bioavailability	88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[1]
Protein binding	93%
Metabolism	Hepatic glucuronidation and sulfoxidation
Half-life	16-19 hours[1][2]
Excretion	Renal and biliary
Identifiers
CAS number	60-87-7 Y 58-33-3 (hydrochloride)
ATC code	D04AA10 R06AD02, R06AD05
PubChem	CID 4927
DrugBank	DB01069
ChemSpider	4758 Y
UNII	FF28EJQ494 Y
KEGG	D00494 Y
ChEBI	CHEBI:8461 Y
ChEMBL	CHEMBL643 Y
Chemical data
Formula	C17H20N2S
Mol. mass	284.42 g/mol
SMILES S2c1ccccc1N(c3c2cccc3)CC(N(C)C)C
InChI 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 Y Key:PWWVAXIEGOYWEE-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Promethazine is a neuroleptic medication and first-generation antihistamine of the phenothiazine family. The drug has strong sedative and weak antipsychotic effects. At the same time it causes motion sickness reduction and has antiemetic, and anticholinergic properties. In some countries it is prescribed for insomnia when benzodiazepines are contraindicated. It is available in many countries under the brand names Phenergan, Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan, and Sominex.^[3]

Indications [edit]

• As a sedative^[4]
• For preoperative sedation and to counteract postnarcotic nausea^[4]
• To reduce nervousness, restlesness and agitation caused by psychiatric conditions (used for this purpose mainly in Europe)
• As antiallergic medication to combat hay fever (allergic rhinitis), etc., or to treat allergic reactions, alone or in combination with oral decongestants such as pseudoephedrine^[4]
• As an adjunct treatment for anaphylactoid conditions (IM/IV route preferred)^[4]
• Together with codeine or dextromethorphan against cough
• As a motion sickness or seasickness remedy when used with ephedrine or pseudoephedrine^[4]
• To combat moderate to severe morning sickness and hyperemesis gravidarum: In the UK, promethazine is drug of first choice, being preferred as an older drug with which there is a greater experience of use in pregnancy (second in line being metoclopramide or prochlorperazine).^[5]
• Previously, it was used as an antipsychotic,^[6] although it is generally not administered for this purpose now; promethazine has only approximately 1/10 of the antipsychotic strength of chlorpromazine.
• Also, it is used to potentiate any opiates, commonly combined with pethidine (meperidine, or Demerol) in a brand called Mepergan, a meperidine/promethazine combination. It is frequently used in conjunction with codeine, in a syrup form. The combination leads to more powerful euphoric effects than with codeine alone.
• Treatment for migraines

Chemistry [edit]

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 (pictured).^[7]

Promethazine, 10-(2-dimethylaminopropyl)phenothiazine, is synthesized by alkylating phenothiazine with 1-chloro-2-(dimethylamino)propane in the presence of sodium amide:^[8][9][10]

Pharmacology [edit]

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects.^[1] It acts primarily as a strong antagonist of the H₁ receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic),^[1] and also has weak to moderate affinity for the 5-HT_2A,^[11] 5-HT_2C,^[11] D₂,^[12][13] and α₁-adrenergic receptors,^[14] where it acts as an antagonist at all sites, as well.

Another notable use of promethazine is as a local anesthetic, by blockade of sodium channels.^[14]

Side effects [edit]

Some common side effects include:

• Tardive dyskinesia
• Confusion in the elderly
• Drowsiness, dizziness, fatigue, more rarely vertigo
• Dry mouth
• Respiratory depression in patients under age of two and in those with severely compromised pulmonary function
• Constipation
• Chest discomfort/pressure (typically in cases when patient is already taking medication for high blood pressure)
• Euphoria (very rare, except with high IV doses and/or coadministration with opioids/CNS depressants)
• Akathisia ^[15]
• Paresthesia
• Short temper/irritability

Extremely rare side effects include:

• Seizures
• Neuroleptic malignant syndrome

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly. (See NCQA’s HEDIS Measure: Use of High Risk Medications 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 apnoea. ^[16]

Product liability lawsuit [edit]

In 2009, the US Supreme Court ruled on a product liability case involving promethazine. Diana Levine, a woman suffering from 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.^[17] 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.^[18] 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.

On September 9, 2009, the FDA required a black box warning for injection be put on promethazine, stating the contraindication for subcutaneous administration. The preferred administrative route is intramuscular, which reduces risk of surrounding muscle and tissue damage.^[19]

See also [edit]

• Purple drank (a recreational drug concoction containing promethazine)

References [edit]

External links [edit]

• "Promethazine". U.S. National Library of Medicine and National Institutes of Health.