Promethazine

Promethazine

by Dalton Lovins


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.

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) National Center for Biotechnology Information. PubChem Compound Database; CID=4927, https://pubchem.ncbi.nlm.nih.gov/compound/4927 (accessed Sept. 21, 2018).

(6) 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]


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]