codeine, phenylephrine, and promethazine

Action and Spectrum

Actions and spectrum: 

promethazine, codeine, and phenylephrine are combination drugs used to treat the common cold and flu, such as congestion, cough, and runny nose. 

promethazine is a first-generation antihistamine that acts by blocking the action of histamine, which is released by the body in response to allergic reaction. This helps to relieve symptoms such as itching, sneezing, and runny nose. 

codeine is a narcotic cough suppressant that acts by blocking the reflex action of cough in the brain. It also has a mild analgesic (pain-relieving) effect. 

phenylephrine is a decongestant that acts by narrowing the blood vessels of nasal passages, thereby reducing swelling and congestion. 

The combination of these three medications can help relieve the symptoms of the common cold and flu by addressing congestion, coughing, and other symptoms. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

codeine 

• Drowsiness 
• Constipation

Frequency not defined (codeine) 

Dizziness 

Headache 

Malaise 

Restlessness 

Weakness 

Hypotension 

Bradycardia 

Respiratory depression 

Nausea 

Xerostomia 

Urticaria 

Urination decreased 

Histamine release 

Confusion 

False well being 

Lightheadedness 

Paradoxical CNS stimulation 

Seizure 

Blurred vision 

Tachycardia 

Dyspnea 

Anorexia 

Vomiting 

Rash 

Ureteral spasm 

LFT’s increased 

Anaphylactoid reaction  

Frequency Not Defined (phenylephrine) 

Reflex bradycardia 

Headache 

Rebound congestion 

Pulmonary edema 

HTN
Anxiety 

Burning 

Sneezing 

Extravasation  

Frequency Not Defined (promethazine) 

Confusion (common) 

Adverse effects (blurred vision, dry mouth) 

Extrapyramidal symptoms 

Bradycardia Leukopenia (rare) 

Obstructive jaundice 

Sedation (common) 

Disorientation (common) 

Photosensitivity 

Tachycardia 

Agranulocytosis (rare) 

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Children younger than 12 years old. 
• Nursing mothers. 
• Patients with hypersensitivity to this medication. 
• Patients with respiratory depression. 
• Patients on monoamine oxidase inhibitor (MAOI) therapy or who have received MAOIs within the past 14 days. 
• Patients with severe central nervous system depression or coma. 
• Patients with severe respiratory impairment. 
• Patients with narrow-angle glaucoma.

Caution: 

• Respiratory depression: the combination of codeine and promethazine can cause respiratory depression, which is more likely to occur in patients who are elderly, debilitated, or suffering from conditions that can affect respiratory function. 
• Central nervous system depression: the combination of codeine and promethazine can cause central nervous system depression, which can impair cognitive and motor functions. Caution should be exercised while operating heavy machinery or driving. 
• Risk of addiction: codeine is an opioid and can be habit-forming. Patients with a history of substance abuse or addiction should be closely monitored while taking codeine. 
• Hypotension: phenylephrine can cause a decrease in blood pressure. Caution should be exercised while administering phenylephrine to patients with hypotension or other cardiovascular conditions. 
• Glaucoma: promethazine can increase intraocular pressure and worsen symptoms of glaucoma. It should be used under caution in patients with a history of glaucoma. 
• Liver and renal impairment: codeine is primarily metabolized by the liver, and its clearance can be reduced in patients with liver impairment. Similarly, phenylephrine can be cleared by the kidneys, and its clearance can be reduced in patients with renal impairment. 
• Pediatrics: the combination of codeine and promethazine is not recommended for children below the age of 12, as it can cause respiratory depression and death.

Comorbidities: 

• Respiratory depression: The use of promethazine and codeine can lead to respiratory depression, especially in patients with underlying respiratory diseases, such as asthma or chronic obstructive pulmonary disease (COPD). 
• Central nervous system depression: The combination of promethazine and codeine can cause central nervous system depression, leading to drowsiness, sedation, and impaired mental and physical abilities. Patients with underlying conditions that affect the central nervous system, such as Parkinson’s disease, multiple sclerosis, or epilepsy, may experience an exacerbation of their symptoms. 
• Liver and kidney disease: codeine is metabolized in the liver and excreted by the kidneys. Patients with liver or kidney disease may have impaired metabolism and excretion, leading to the accumulation of the drug in the body and an increased risk of side effects. 
• Cardiovascular disease: phenylephrine is a vasoconstrictor and can cause an increase in blood pressure and heart rate. Patients with underlying cardiovascular disease, such as hypertension, coronary artery disease, or arrhythmias, may be at increased risk of adverse effects. 
• Glaucoma: phenylephrine can cause an increase in intraocular pressure and worsen the symptoms of glaucoma. Patients with glaucoma should avoid using this medication or use it with caution under the supervision of a healthcare provider. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: C 

Lactation: It is also not recommended to be used during breastfeeding, as it may be excreted in breast milk and cause harm to a nursing infant.  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

promethazine is a first-generation antihistamine with anticholinergic, sedative, and antiemetic properties. It acts by blocking the action of histamine and acetylcholine in the body.

codeine is an opioid pain medication that acts by binding to mu-opioid receptors in the spinal cord, brain and other parts of the body. phenylephrine is a nasal decongestant that acts by constricting the blood vessels of nasal passages, which reduces inflammation and nasal congestion. 

When these drugs are combined, promethazine and phenylephrine work together to reduce inflammation and relieve nasal congestion, while codeine provides pain relief. Additionally, promethazine and codeine work together to suppress coughing. 

The combination of promethazine, codeine, and phenylephrine is used to treat symptoms associated with the common cold, flu, allergies, and other respiratory infections.  

Pharmacodynamics: 

• promethazine: It is a first-generation antihistamine with anticholinergic, sedative, and antiemetic effects. It competitively antagonizes histamine at H1 receptor sites, thereby preventing the histamine-mediated symptoms of allergic reactions such as itching, swelling, and vasodilation. It also blocks muscarinic acetylcholine receptors, leading to blurred vision, dry mouth, urinary retention, and constipation.  
• codeine: It is an opioid analgesic that works by binding to mu-opioid receptors in the central nervous system (CNS) and producing analgesia, sedation, and a sense of euphoria. It also has antitussive effects, which means that it suppresses coughing by decreasing the sensitivity of the cough center in the medulla oblongata. 
• phenylephrine: It is a sympathomimetic drug that acts as an alpha-adrenergic agonist. It stimulates alpha-1 adrenergic receptors in blood vessels, causing vasoconstriction and an increase in the blood pressure. This effect is used to treat hypotension and nasal congestion.

Pharmacokinetics: 

Absorption 

• promethazine: Well, absorbed following oral administration, with peak plasma levels observed in 2 to 4 hours. It is also available as a rectal suppository and as an injectable solution. 
• codeine: Rapidly absorbed from the gastrointestinal tract after oral administration, with peak plasma levels observed in 1 to 2 hours. 
• phenylephrine: Well, absorbed following oral administration, with peak plasma levels observed in 1 to 2 hours. 

Distribution 

• promethazine: Highly bound to plasma proteins, widely distributed in the body, and crosses the blood-brain barrier. 
• codeine: Widely distributed throughout the body and crosses the blood-brain barrier. 
• phenylephrine: Widely distributed throughout the body. 

Metabolism 

• promethazine: Metabolized in the liver by CYP450 enzymes into its primary metabolites, including sulfoxides and N-demethylated derivatives. 
• codeine: Metabolized in the liver by CYP450 enzymes into its primary metabolite, morphine. 
• phenylephrine: Metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). 

Elimination and excretion 

• promethazine: Excreted in the urine and feces, with a terminal elimination half-life of 10 to 19 hours. 
• codeine: Excreted in the urine, primarily as morphine, with an elimination half-life of 3 to 4 hours. 
• phenylephrine: Excreted in the urine as metabolites, with a terminal elimination half-life of 2.5 to 3 hours. 

Adminstartion

Administration: 

promethazine, codeine, and phenylephrine are typically administered orally in the form of a tablet or syrup. The specific dosing instructions may vary on the individual patient, the condition being treated, and other factors. It is important to follow the dosing instructions provided by the healthcare provider or the medication label. 

Patients should also be advised to take the medication with food or milk to reduce the risk of gastrointestinal side effects. It is also important to avoid alcohol while taking this medication as it may increase the risk of certain side effects. 

In addition, patients should not take this medication for longer than prescribed and should not exceed the recommended dose. If symptoms do not improve or worsen, patients should contact their healthcare provider for further evaluation. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: codeine, phenylephrine, and promethazine 

Pronounced: [ KOE-deen, FEN-il-EFF-rin, and-pro-METH-a-zeen ]  

Why do we use codeine, phenylephrine, and promethazine? 

promethazine, codeine, and phenylephrine is a combination medication used for the relief of cough and upper respiratory allergies or a common cold. codeine is an opioid pain medication that acts by binding to the opioid receptors of the brain to decrease pain perception and provide a cough suppressant effect.

promethazine is an antihistamine medication that blocks the action of histamine, a natural substance produced by the body during an allergic reaction. phenylephrine is a decongestant that acts by narrowing the blood vessels of nasal passages to reduce swelling and congestion. 

This combination medication is typically used for short-term symptomatic relief of cough, nasal congestion, runny nose, sneezing, and watery eyes associated with respiratory allergies or a common cold. However, it should be used with caution due to the potential for abuse and addiction associated with codeine.