Promethazine
Developed in 1946 when a team of scientists from French pharmaceutical company Rhône-Poulenc combined phenothiazine and a diamine side chain of diphenhydramine in order to create the synthetic compound promethazine2. Paul Charpentier, lead scientist, is credited with the discovery of promethazine, as well as helping to immerse Rhône-Poulenc into the company we now know as Sanofi3. Merely seeking to find a better antihistamine than diphenhydramine, Charpentier and his team synthesized a compound with a wide range benefits.
Promethazine is a first-generation H1 receptor antagonist, antihistamine, and antiemetic medication with strong sedative effects that has been sold under the name brands of Phenergan and Phenadoz. Since its introduction, promethazine has been used for prevention and treatment of nausea and vomiting caused by narcotic therapy, migraine episodes, morning sickness, and cancer chemotherapy4. Also, promethazine is used to treat allergic symptoms such as itching, runny nose, sneezing, itchy or watery eyes, hives, and itchy skin rashes, as well as to prevent motion sickness4. Another benefit from promethazine, one which I have seen first-hand in the UK Medical Center OR Pharmacy, is that it can be used as a pre-/post-operative surgical analgesic and hypnotic.
The phenothiazine derivative has a multi-target mechanism of action that includes: blocking postsynaptic mesolimbic dopaminergic receptors in the brain, strongly blocking alpha-adrenergic effects which in turn depresses the release of hypothalamic and hypophyseal hormones, competing with histamine for the H1 receptor, and lastly a muscarinic-blocking effect that may be responsible for antiemetic activity4. The result of these mechanisms induce bronchoconstriction, vasodilation, and spasmodic contractions of GI smooth muscle5.
The adverse drug event profile of promethazine includes: dizziness, sleepiness, dry mouth, N&V, altered cardiac conduction causing life threatening arrhythmias, CNS depression, photosensitivity, temperature regulation impairment, as well as a US boxed warning for serious tissue injury related to promethazine injections3. Anti-cholinergic effects such as constipation, blurred vision, urinary region, and xerostomia are also a main concern as patients with decreased GI motility, urinary retention problems, GI or urinary obstructions, or visual problems will all have to be closely monitored3.
Important pharmacokinetic information regarding promethazine includes its hepatic metabolism by hydroxylation using CYP2D6 and N-demethylation via CYP2B6. Promethazine is 93% protein bound, which helps generate an effect duration of 4-6 hours and a half life of 16-19 hours4,6. Absorption of oral promethazine is rapid and approximately 88%, but with a large first pass effect its systemic bioavailability is limited and approximately 25%, leaving substantial room for improvement (5). Oral and intramuscular promethazine has an onset of action of approximately 20 minutes, whereas IV promethazine has an onset of approximately 5 minutes6.
Being closely related to ondansetron as an antiemetic medication, promethazine has the upside of being available as a rectal suppository, whereas ondansetron has the advantage of being available as a sublingual tablet or oral film. Ondansetron has risks associated with Serotonin syndrome that promethazine doesn’t, but promethazine has breathing impairment risk factors that make it contraindicated for children under the age of two2. Promethazine also requires patients to increase their intake of dietary riboflavin, whereas ondansetron lacks this requirement5.
One of the most detrimental aspects of promethazine is the unfortunate fact that it causes heavy sedation in many patients. This of course is brought on by promethazine’s mechanism of action that correlates with most first generation antihistamines. However, ondansetron has greatly improved upon the typically undesired sedative effect that comes with promethazine by changing the mechanism of action to a serotonin 5-HT3 receptor antagonist2. Therefore, decreasing the antiemetics role in sedation by changing the medication’s target allows ondansetron to be a better option for patients that have the need to stay awake for daily activities.
First approved on May 5th, 1958 Promethazine HCl and many of its generics have been produced by quite a few companies, including Akorn Pharmaceuticals, and supplied by an abundant amount of wholesalers, including McKesson. McKesson is a major pharmaceutical wholesaler with a total revenue of over $208 billion, up 5% from last year. McKesson CEO, John Hammergren, has helped the company build an operating income of $672 million, but has lost a net income of 138 million (144%) compared to last year.
Preclinical toxicology of promethazine studies showed possible overdose symptoms such as mild CNS and cardiovascular depression, profound hypotension, respiratory depression, and unconsciousness. One efficacy study that compared promethazine to ondansetron found that the percentage of relief of nausea and vomiting at 3 hours were 67% and 71% respectively5.
Overall there have been five patents for promethazine hydrochloride. Patients differ by what type of dosage form the company supplies: Able supplies a rectal suppository, Kvk Tech supplies an oral tablet, Amneal Pharms supplies an oral syrup, Sandoz supplied an oral tablet (patent was approved in 1982), and Teva supplied an oral tablet (patent was approved in 1985).
Promethazine was recently in a phase 3 parallel group clinical trial (Identifier #NCT01827293) with lorazepam in order to compare the efficacy of IV promethazine with lorazepam on peripheral vertigo in emergency department settings.8 Primary outcomes were to observe changes in vertigo intensity, whereas secondary outcomes sought out to determine safety and adverse event occurrences. Specific exclusion criteria were laid out, including emetic medication use within the past 24 hours and known allergy to either of the medications.
In 2015, there was an urgent drug recall for promethazine DM syrup by MooreMedical. The recall expressed concern about possible polypropylene particles contaminating the dispensed product. They instructed customers to review complete details of affected products, quarantine and discontinue the product, and contact the MooreMedical regulatory affairs department if they were affected by the product.
References
(1) C. Cantisani, S. Ricci, T. Grieco, et al., “Topical Promethazine Side Effects: Our Experience and Review of the Literature,” BioMed Research International, vol. 2013, Article ID 151509, 9 pages, 2013. https://doi.org/10.1155/2013/151509.
(2) IODINE, “Compare Zofran vs Phenergan.” IODINE API, accessed Sept. 21st from https://www.iodine.com/compare/zofran-vs-phenergan
(3) Laguna Treatment Hospital, “What is Promethazine, And How Can It Be Abused?” American Addiction Centers. Retrieved Sept. 20th, 2018 from https://lagunatreatment.com/promethazine-abuse/
(4) Lexicomp, “Promethazine (Lexi-Drugs).” Wolters Kluwer. Retrieved Sept. 20th, 2018 from https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7563#fbnlist
(5) Moser, JD., “No more than necessary: safety and efficacy of low-dose promethazine.” Ann Pharmacotherapy. Jan 2006, 40(1):45-8. ePub 2005 Dec 13.
(6) National Center for Biotechnology Information. PubChem Compound Database; CID=4927, https://pubchem.ncbi.nlm.nih.gov/compound/4927 (accessed Sept. 21, 2018).
(7) Peters RJ Jr, Kelder SH, Markham CM,: “Beliefs and social norms about codeine and promethazine hydrochloride cough syrup (CPHCS) onset and perceived addiction among urban Houstonian adolescents: an addiction trend in the city of lean.” J Drug Educ. 2003;33(4):415-25. [PubMed:15237866]
(8) Shadi, Asadollahi, “Promethazine vs. Lorazepam for Treatment of Vertigo.” ClinicalTrials.gov, Shahid Beheshti University of Medical Sciences, June 2013, https://clinicaltrials.gov/ct2/show/study/NCT01827293
Bibliography
C. Cantisani, S. Ricci, T. Grieco, et al., “Topical Promethazine Side Effects: Our Experience and Review of
the Literature,” BioMed Research International, vol. 2013, Article ID 151509, 9 pages, 2013
. https://doi.org/10.1155/2013/151509.
IODINE, “Compare Zofran vs Phenergan.” IODINE API, accessed Sept. 21st from
https://www.iodine.com/compare/zofran-vs-phenergan
Laguna Treatment Hospital, “What is Promethazine, And How Can It Be Abused?” American Addiction
Centers. Retrieved Sept. 20th, 2018 from https://lagunatreatment.com/promethazine-abuse/
Lexicomp, “Promethazine (Lexi-Drugs).” Wolters Kluwer. Retrieved Sept. 20th, 2018 from
https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7563#fbnlist
National Center for Biotechnology Information. PubChem Compound Database; CID=4927,
https://pubchem.ncbi.nlm.nih.gov/compound/4927 (accessed Sept. 21, 2018).
Ogbru, Omudhome. “Promethazine.” MedicineNet. Accessed Sept 21st, 2018 from
https://www.medicinenet.com/promethazine/article.htm
Page, C.B.: QJM: An International Journal of Medicine, Volume 102, Issue 2, 1 February 2009, Pages 123
–131, https://doi.org/10.1093/qjmed/hcn153
Peters RJ Jr, Kelder SH, Markham CM,: “Beliefs and social norms about codeine and promethazine
hydrochloride cough syrup (CPHCS) onset and perceived addiction among urban Houstonian
adolescents: an addiction trend in the city of lean.” J Drug Educ. 2003;33(4):415-25.
[PubMed:15237866]
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