Promethazine
 | |
| Clinical data | |
|---|---|
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682284 |
| Pregnancy category |
|
| Routes of administration | Oral, rectal, IV, IM, topical |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 88% absorbed but after first-pass metabolism reduced to 25% absolute bioavailability[1] |
| Protein binding | 93% |
| Metabolism | Hepatic glucuronidation and sulfoxidation |
| Elimination half-life | 10-19 hours[1][2] |
| Excretion | Renal and biliary |
| Identifiers | |
| |
| CAS Number |
|
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.000.445 |
| Chemical and physical data | |
| Formula | C17H20N2S |
| Molar mass | 284.42 g/mol g·mol−1 |
| 3D model (JSmol) | |
| |
| |
  (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).[3]
Indications
- As a sedative[4]
- For preoperative sedation and to counteract postnarcotic nausea[4]
- 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.[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 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 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).[7]
Promethazine, 10-(2-dimethylaminopropyl)phenothiazine, is synthesized by alkylating phenothiazine with 1-dimethylamino-2-propylchloride:[8][9]
File:Promethazine synthesis.png
Pharmacology
Promethazine is a phenothiazine derivative that 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-HT2A,[10] 5-HT2C,[10] D2,[11][12] and α1-adrenergic receptors,[13] 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.[13]
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 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 [14]
- Paresthesia
- Short temper/Irritability
Extremely rare side effects include:
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 US & UK), promethazine is contra-indicated in children less than 2 years age, and strongly cautioned against in children between 2 - 6 years age, due to problems with respiratory depression and sleep apnoea. [15]
Product liability lawsuit
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.[16] 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.[17] 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 [18]
See also
- Purple drank (a recreational drug concoction containing promethazine)
References
- ^ a b c d Strenkoski-Nix LC, Ermer J, DeCleene S, Cevallos W, Mayer PR (2000). "Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects". American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists. 57 (16): 1499–505. PMID 10965395.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Paton DM, Webster DR (1985). "Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines)". Clinical Pharmacokinetics. 10 (6): 477–97. PMID 2866055.
- ^ RxList: Promethazine
- ^ a b c d e RxList Indications for Promethazine.
- ^ British National Formulary (2001). "4.6 Drugs used in nausea and Vertigo - Vomiting of pregnancy". BNF (45 ed.).
{{cite book}}: Unknown parameter|month=ignored (help). - ^ [1].
- ^ http://www.rxlist.com/cgi/generic/phenergan.htm RxList: Promethazine Description
- ^ P. Charpentier, U.S. patent 2,530,451 (1950)
- ^ S.B. Sidney, J.A. Nicholson, U.S. patent 2,607,773 (1952)
- ^ a b Fiorella D, Rabin RA, Winter JC (1995). "The role of the 5-HT2A and 5-HT2C receptors in the stimulus effects of hallucinogenic drugs. I: Antagonist correlation analysis". Psychopharmacology. 121 (3): 347–56. PMID 8584617.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Seeman P, Watanabe M, Grigoriadis D; et al. (1985). "Dopamine D2 receptor binding sites for agonists. A tetrahedral model". Molecular Pharmacology. 28 (5): 391–9. PMID 2932631.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Burt DR, Creese I, Snyder SH (1977). "Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain". Science. 196 (4287): 326–8. doi:10.1126/science.847477. PMID 847477.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Jagadish Prasad, P. (2010). Conceptual Pharmacology. Universities Press. pp. 295, 303, 598. ISBN 978-81-7371-679-9. Retrieved 27 November 2011.
- ^ Cordingley Neurology
- ^ Starke P, Weaver J, Chowdhury B. Boxed warning added to promethazine labeling for pediatric use. N Eng J Med. 2005;352(5):2653.
- ^ Liptak, Adam (2001-09-18). "Drug Label, Maimed Patient and Crucial Test for Justices". The New York Times. Retrieved 2008-10-31.
- ^ Stout, David (2009-03-04). "Drug Approval Is Not a Shield From Lawsuits, Justices Rule". The New York Times. Retrieved 2009-03-04.
- ^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm182169.htm
External links
- "Promethazine". U.S. National Library of Medicine and National Institutes of Health.