RECODIN

Indications

• Mild to moderate pain
• Short-term treatment of acute moderate pain
• Dry or painful cough

Dosage

Children: Children aged 12-17 years: 30-60 mg every 6 hours if required for a maximum of 3 days; maximum 240 mg per day. Use is contraindicated in children under 12 years.

Adults: 30 mg 3-4 times daily; usual dose 15-60 mg 3-4 times daily; maximum dose 240 mg per day.

Mechanism of action

Codeine is metabolized in the liver to morphine, which binds to mu-opioid receptors in the central nervous system, resulting in analgesia. This action alters the perception of and response to painful stimuli, providing relief from pain. Additionally, it may reduce the cough reflex through action on the cough center in the medulla.

Pharmacodynamics

As an opioid, codeine has a dose-dependent effect on pain relief and is associated with side effects typical of opioids, such as sedation, constipation, and potential respiratory depression. Its efficacy varies significantly among individuals due to genetic differences in metabolism, particularly involving the CYP2D6 enzyme, which converts codeine to morphine.

Pharmacokinetics

Codeine phosphate is well absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism in the liver, where it is converted to its active metabolite, morphine, and other metabolites. The peak plasma concentration occurs approximately 1-2 hours after oral administration. Codeine has a half-life of 3-4 hours, and both codeine and its metabolites are eliminated primarily via the kidneys.

Contra-indications

• Children under 12 years old
• Patients of any age known to be CYP2D6 ultra-rapid metabolisers
• Acute ulcerative colitis
• Antibiotic-associated colitis
• Children under 18 years who undergo the removal of tonsils or adenoids

Adverse effects

• Drowsiness
• Constipation
• Nausea
• Vomiting
• Dizziness
• Dry mouth
• Fatigue
• Malaise
• Mood alterations
• Hypotension
• Hypothermia
• Increased intracranial pressure
• Nightmares
• Muscle rigidity
• Lymphadenopathy
• Pancreatitis

Interactions

• CNS depressants (e.g. benzodiazepines, alcohol)
• MAO inhibitors
• Other opioids
• Antidepressants
• Antipsychotics
• Antihistamines

Precautions

• Use with caution in patients with respiratory depression
• History of substance abuse
• Cardiac arrhythmias
• Gallstones
• Mild to moderate pain in adolescents aged 12–18 years with breathing problems

Pregnancy

Codeine phosphate should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. There is a risk of neonatal opioid withdrawal syndrome if used in late pregnancy.

Breast-feeding

Codeine phosphate is not recommended for breastfeeding mothers due to the risk of opioid toxicity in infants. It is present in breast milk and the metabolism of codeine can vary significantly between individuals.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Codeine phosphate 30 mg capsules
• Codeine phosphate 30 mg tablets
• Combination products with paracetamol (e.g. Kapake, Solpadol, Tylex, Zapain)

Indications

• Allergic rhinitis (hay fever)
• Urticaria (hives)
• Allergic conjunctivitis
• Common cold symptoms

Dosage

Children: For children aged 6-12 years, the dose is typically 2 mg every 4 to 6 hours, not exceeding 12 mg per day. For children under

Adults: The usual adult dose for chlorpheniramine is 4 mg every 4 to 6 hours, not to exceed 24 mg per day.

Mechanism of action

Chlorpheniramine binds to the histamine H1 receptor, preventing endogenous histamine from exerting its effects. This leads to temporary relief from symptoms such as sneezing, pruritus, and increased vascular permeability associated with allergic reactions. The drug competes with histamine for H1-receptor sites on effector cells, thus antagonizing most of the pharmacological effects of histamine, including its actions on smooth muscle and vascular permeability.

Pharmacodynamics

In allergic reactions, allergens trigger the degranulation of mast cells and basophils, leading to the release of histamine. Chlorpheniramine, as an H1 antagonist, competes for receptor binding, effectively blocking histamine-induced effects, such as itching, vasodilation, and bronchoconstriction. This results in relief from symptoms like sneezing, watery eyes, and nasal discharge.

Pharmacokinetics

Chlorpheniramine is well absorbed from the gastrointestinal tract. It undergoes hepatic metabolism and its effects can last for several hours. The onset of action is typically observed within 1 to 2 hours following oral administration, with peak effects occurring around 2 to 6 hours. The drug is eliminated primarily through urine, with a half-life ranging from 12 to 15 hours, though this can vary based on individual factors.

Contra-indications

• Hypersensitivity to chlorpheniramine or any component of the formulation
• Acute asthma attacks
• Severe hypertension
• Narrow-angle glaucoma
• Prostatic hypertrophy

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Blurred vision
• Constipation
• Urinary retention
• Confusion
• Headache

Interactions

• Alcohol
• CNS depressants
• MAO inhibitors
• Anticholinergic agents
• Beta-blockers

Precautions

• Use with caution in patients with cardiovascular disease
• Caution in patients with liver or kidney impairment
• Avoid in elderly patients due to increased risk of sedation and anticholinergic effects
• May impair the ability to drive or operate machinery

Pregnancy

Chlorpheniramine should be used in pregnancy only if clearly needed. Consult medical professionals for guidance.

Breast-feeding

Chlorpheniramine is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Syrup
• Oral suspension

Indications

• Mild to moderate pain relief
• Cough suppression
• Cough associated with tuberculosis
• Insomnia due to cough

Dosage

Children: Refer to

Adults: Refer to the BNF for specific dosing guidelines for adults.

Mechanism of action

Codeine exerts its analgesic and antitussive effects mainly through the agonism of mu-opioid receptors in the central nervous system. Although only a small portion of codeine is metabolized to morphine, the analgesic effect is believed to be mediated by codeine-6-glucuronide, which has an affinity for mu receptors and can be converted to morphine-6-glucuronide, a more potent metabolite. The activation of G-proteins reduces intracellular cAMP and calcium levels, leading to hyperpolarization of nociceptive neurons and impaired pain signal transmission. Additionally, codeine suppresses the cough reflex by acting on the cough center in the medulla.

Pharmacodynamics

Codeine is classified as a weak narcotic pain reliever and cough suppressant. It increases pain tolerance and reduces discomfort while also inducing sedation, drowsiness, and respiratory depression. Codeine's antitussive action is effective particularly in cases of cough associated with tuberculosis and insomnia due to coughing. Furthermore, it may decrease intestinal motility, leading to constipation, and chronic use can result in obstructive bowel disease in susceptible individuals.

Pharmacokinetics

Codeine is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1 to 2 hours after administration. It is metabolized primarily in the liver by the cytochrome P450 system, particularly CYP2D6, which converts a small percentage to morphine. Codeine has a variable half-life, typically ranging from 3 to 4 hours. It is excreted mainly in the urine, primarily as metabolites.

Contra-indications

• Hypersensitivity to codeine or any of its components
• Severe respiratory depression
• Acute or severe bronchial asthma or hypercapnia
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOIs
• Paralytic ileus

Adverse effects

• Sedation
• Drowsiness
• Respiratory depression
• Constipation
• Nausea
• Vomiting
• Dry mouth
• Dizziness
• Headache
• Itching or rash

Interactions

• bupropion+codeine: Unknown (decreases efficacy)
• cinacalcet+codeine: Unknown (decreases efficacy)
• terbinafine+codeine: Unknown (decreases efficacy)
• rifampicin+codeine: Unknown (decreases exposure)

Precautions

• Use with caution in patients with a history of substance use disorder
• Monitor for signs of respiratory depression, especially in opioid-naïve patients
• Caution in elderly patients or those with impaired hepatic or renal function
• Risk of addiction, abuse, and misuse
• Avoid abrupt discontinuation in patients on prolonged therapy

Pregnancy

Use only if clearly needed, as codeine may affect the fetus. Prolonged use during pregnancy may lead to neonatal withdrawal syndrome.

Breast-feeding

Caution is advised as codeine is excreted in breast milk and may cause respiratory depression in nursing infants.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets
• Oral solution
• Syrup
• Combination products with other analgesics or cough suppressants

Mechanism of action

Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. Antihistamines antagonize, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa. /Antihistamines/ H1 antagonists inhibit most responses of smooth muscle to histamine. Antagonism of the constrictor action of histamine on respiratory smooth muscle is easily shown in vivo and in vitro. /Histamine Antagonists: H1 Antagonists/ H1 antagonists strongly block the action of histamine that results in increased permeability and formation of edema and wheal. /Histamine Antagonists: H1 Antagonists/ Within the vascular tree, the H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by H1 receptors on endothelial cells. Residual vasodilatation reflects the involvement of H2 receptors on smooth muscle and can be suppressed only by the concurrent administration of an H2 antagonist. Effects of the histamine antagonists on histamine induced changes in systemic blood pressure parallel these vascular effects. /Histamine Antagonists: H1 Antagonists/ Many of the H1 antagonists tend to inhibit responses to acetylcholine that are mediated by muscarinic receptors. These atropine like actions are sufficiently prominent in some of the drugs to be manifest during clinical usage ... . /Histamine Antagonists: H1 Antagonists/

Pharmacodynamics

In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H₁-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H₁-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies.

Mechanism of action

Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors. Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine. However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine. Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα_i, causing a decrease in intracellular cAMP and Ca²⁺ level. This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals. Codeine causes suppression of the cough reflex by a direct effect on the cough center in the medulla of the brain and appears to exert a drying effect on respiratory tract mucosa and to increase viscosity of bronchial secretions.

Pharmacodynamics

**General effects** Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression. **Antitussive activity** This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing. Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla. **Effects on intestinal motility** Codeine may reduce intestinal motility through both a local and possibly central mechanism of action. This may possibly lead to constipation. The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility. **Effects on the central nervous system** Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the _mu_ opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine. Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system. **Effects on blood pressure** This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms. **Effects on chronic cancer pain and other types of pain** Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours. Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms,.