Promethazine

Promethazine

1:1 mixture (racemate)
Systematic (IUPAC) name
(RS)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine
Clinical data
Trade names	Phenergan
AHFS/Drugs.com	monograph
MedlinePlus	a682284
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	US: ℞-only (injection POM(UK))
Routes of administration	Oral, rectal, IV, IM, topical
Pharmacokinetic data
Bioavailability	88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability
Protein binding	93%
Metabolism	Hepatic glucuronidation and sulfoxidation
Biological half-life	16-19 hours
Excretion	Renal and biliary
Identifiers
CAS Number	60-87-7 Y Template:CAS (hydrochloride)
ATC code	D04AA10 (WHO) R06AD02
PubChem	CID: 4927
IUPHAR/BPS	7282
DrugBank	DB01069 Y
ChemSpider	4758 Y
UNII	FF28EJQ494 Y
KEGG	D00494 Y
ChEBI	CHEBI:8461 Y
ChEMBL	CHEMBL643 Y
Chemical data
Formula	C17H20N2S
Molecular 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
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Promethazine is a neuroleptic medication and first-generation antihistamine of the phenothiazine family. The drug has strong sedative and weak antipsychotic effects. It also reduces motion sickness and has antiemetic and anticholinergic properties (via its action on the Dopamine receptor D2). In some countries it is prescribed for insomnia when benzodiazepines are contraindicated. It is available in many countries under many brand names.

Indications

• As a sedative
• For preoperative sedation and to counteract postnarcotic nausea
• To reduce nervousness, restlessness 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
• As an adjunct treatment for anaphylactoid conditions (IM/IV route preferred)
• Together with codeine or dextromethorphan against cough
• As a motion sickness or seasickness remedy when used with ephedrine or pseudoephedrine
• 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).
• Previously, it was used as an antipsychotic, although it is generally not administered for this purpose now; promethazine has only approximately 1/10 of the antipsychotic strength of chlorpromazine.
• Treatment for migraines; however, other similar medications, like Compazine, have been shown to have a more favorable treatment profile, and are used almost exclusively over promethazine.

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 (pictured).

Pharmacology

Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects. It acts primarily as a strong antagonist of the H₁ receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic), and also has weak to moderate affinity for the 5-HT_2A, 5-HT_2C, D₂, and α₁-adrenergic receptors, 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.

Side effects

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)
• Akathisia
• Paresthesia
• Short temper/irritability

Extremely rare side effects include:

• Seizures
• Neuroleptic malignant syndrome
• Euphoria (very rare, except with high IV doses and/or coadministration with opioids/CNS depressants)

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.

Society and culture

It is available in many countries under many brand names.

Product liability lawsuit

Main article: Wyeth v. Levine

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. 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.

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

See also

• Purple drank (a recreational drug concoction containing promethazine)