Promethazine

Promethazine

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	P (UK) ℞-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
Protein binding	93%
Metabolism	Hepatic glucuronidation and sulfoxidation
Half-life	10-19 hours
Excretion	Renal and biliary
Identifiers
CAS number	60-87-7 Y 58-33-3 (hydrochloride)
ATC code	D04AA10 R06AD02, R06AD05
PubChem	CID 4926
DrugBank	APRD00601
ChemSpider	4759 N
UNII	FF28EJQ494 Y
KEGG	D00494 Y
ChEBI	CHEBI:8461 Y
ChEMBL	CHEMBL643 Y
Chemical data
Formula	C17H20N2S
Mol. mass	284.42 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Promethazine is a first-generation antihistamine of the phenothiazine family. The drug has anti-motion sickness, antiemetic, and anticholinergic effects, as well as a strong sedative effect and in some countries is prescribed for insomnia when benzodiazepines are contraindicated. It is available over-the-counter in the United Kingdom, Australia, Switzerland, and many other countries, but by prescription in the United States (brand names Phenergan, Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan, and Sominex in the UK).

Indications

• As a sedative
• For preoperative sedation and to counteract postnarcotic nausea
• As antiallergic medication to combat hay fever (allergic rhinitis), etc. To treat allergic reactions it can be given alone or in combination with oral decongestants like 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 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.
• Also used to potentiate any opiates. Commonly combined with pethidine (AKA, meperidine, or Demerol) in a brand called Mepergan, a meperidine/promethazine combination. Also frequently used in conjunction with codeine, in a syrup form. The combination leads to more powerful euphoric effects than with codeine alone.

Chemistry

Chemically, promethazine hydrochloride appears as a white to faint yellow crystalline powder that is practically odorless. Slow oxidation may occur upon prolonged exposure to air usually causing blue discoloration. Promethazine as the hydrochloride salt is freely soluble in water and somewhat soluble in alcohol. Promethazine is a chiral compound, occurring as a mixture of enantiomers (pictured).

Promethazine, 10-(2-dimethylaminopropyl)phenothiazine, is synthesized by alkylating phenothiazine with 1-dimethylamino-2-propylchloride:

Pharmacology

Promethazine is a phenothiazine derivative that 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 property of promethazine is that it is a local anesthetic, via 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 2 and in those with severely compromised pulmonal 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
• 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).

Product liability lawsuit

Main article: Wyeth v. Levine

In 2009, the U.S. 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 that drug manufacturers can be held liable for injuries if warnings of potential adverse effects (approved by the U.S. Food and Drug Administration, "FDA") are deemed insufficient by state courts.

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

See also

• Purple drank (a recreational drug concoction containing promethazine)

External links

• "Promethazine". U.S. National Library of Medicine and National Institutes of Health. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682284.html.