CARBOSTEN WITH PROMETHAZINE

Indications

• Allergic conditions such as hay fever
• Motion sickness
• Nausea and vomiting
• Sedation
• Insomnia associated with urticaria
• Pruritus

Dosage

Children: Child 2–4 years: 5 mg twice daily, alternatively 5–15 mg once daily, dose to be taken at night. Child 5–9 years: 5–10 mg twice daily, alternatively 10–25 mg once daily, dose to be taken at night. Child 10–17 years: 10–20 mg 2–3 times a day, alternatively 25 mg once daily, dose to be taken

Adults: 10–20 mg 2–3 times a day, alternatively 25 mg once daily, dose to be taken at night.

Mechanism of action

Promethazine hydrochloride works by antagonizing H1 histamine receptors, which inhibits the actions of histamine, a chemical involved in allergic reactions. Additionally, it has anticholinergic effects, which can help in reducing nausea and motion sickness by affecting the vestibular system.

Pharmacodynamics

Promethazine exhibits sedative, antiemetic, and antihistaminic properties. The sedative effects are due to its ability to cross the blood-brain barrier and block central H1 receptors, while the antiemetic effects are mediated through its action on the chemoreceptor trigger zone and vestibular pathways. The anticholinergic activity contributes to its effectiveness in controlling motion sickness.

Pharmacokinetics

Promethazine is well absorbed following oral administration, with peak plasma concentrations occurring within 1-2 hours. It has a long half-life of approximately 10-19 hours, allowing for once or twice daily dosing in most indications. The drug is extensively metabolized in the liver, primarily through cytochrome P450 enzymes, and eliminated mainly via urine. It is also noted for its potential for accumulation in patients with impaired hepatic function.

Contra-indications

• Hypersensitivity to promethazine or any of its components
• Patients with a history of angle-closure glaucoma
• Patients with severe respiratory depression
• Children under 2 years of age (unlicensed use for sedation)

Adverse effects

• Drowsiness
• Dizziness
• Blurred vision
• Dry mouth
• Nausea
• Urinary retention
• Paradoxical excitability in children
• Agranulocytosis
• Seizures
• Insomnia
• Skin reactions
• Leukopenia
• Anxiety
• Restlessness
• Fatigue
• Photosensitivity reaction

Interactions

• Increased sedative effects when used with alcohol or other CNS depressants
• Anticholinergic effects may be enhanced when used with other anticholinergic agents
• May interact with other antihistamines, increasing the risk of side effects

Precautions

• Use with caution in elderly patients due to increased susceptibility to anticholinergic side effects
• May cause sedation; caution patients about performing tasks requiring alertness (e.g., driving)
• Monitor for increased effects in combination with other sedatives
• Not suitable for long-term use in children under 2 years of age without specialist advice

Pregnancy

Most manufacturers advise avoidance during pregnancy; however, no evidence of teratogenicity has been established. Use in late pregnancy may lead to adverse effects in neonates.

Breast-feeding

Most antihistamines are excreted in breast milk; while not known to be harmful, manufacturers typically advise against use during breastfeeding.

Storage

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

Formulations

• Tablets: 10 mg, 25 mg
• Oral solution: 5 mg/5 mL
• Injection: 25 mg/mL

Indications

• Chronic bronchitis
• Cystic fibrosis
• Chronic obstructive pulmonary disease (COPD)
• Acute exacerbations of respiratory conditions associated with mucus overproduction

Dosage

Children: For children, the dosage must be determined based on age and weight according to the BNF for Children; refer to the latest guidelines for specific dosing recommendations.

Adults: The usual adult dose is 600 mg once daily, which may vary based on specific conditions and patient response.

Mechanism of action

Carbocisteine acts by stimulating the sialyl transferase enzyme, which helps to restore the equilibrium between sialomucins and fucomucins in bronchial mucus. This mechanism reduces mucus viscosity, enhances mucociliary clearance, and may exhibit antioxidant properties by activating protein kinase B (Akt) phosphorylation, as well as inhibiting inflammatory pathways such as NF-κB and ERK1/2 MAPK. Additionally, it reduces the expression of intracellular adhesion molecule 1 (ICAM-1), which may help limit viral infections in the respiratory tract.

Pharmacodynamics

Carbocisteine is effective in decreasing sputum viscosity, thus alleviating symptoms like cough, dyspnea, and fatigue. Its mucolytic action contributes to the prevention of pulmonary infections by facilitating mucus clearance from the respiratory system. The drug also shows anti-inflammatory properties and reduces oxidative stress, which can be beneficial in respiratory diseases characterized by inflammation.

Pharmacokinetics

Carbocisteine is absorbed from the gastrointestinal tract and has a bioavailability that allows for effective systemic activity. It undergoes metabolic processes in the liver, with metabolites contributing to its therapeutic effects. The elimination half-life and excretion pathways are not specifically detailed, but like many mucolytics, its effects are generally observed within hours after administration.

Contra-indications

• Active peptic ulceration

Adverse effects

• Dizziness
• Fever
• Headache
• Nausea
• Skin reactions

Precautions

• Use with caution in patients with ischaemic heart disease and stroke

Pregnancy

Manufacturer advises avoid in first trimester. Use only if potential benefit outweighs risk, as toxicity in animal studies has been observed.

Breast-feeding

Manufacturer advises to avoid for 12 hours after administration.

Storage

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

Formulations

• Carbocisteine 50 mg per 1 ml oral solution sugar-free | 300 ml
• Carbocisteine 250 mg/5 ml oral solution sugar-free | 300 ml
• Carbocisteine 375 mg capsules
• Carbocisteine 750 mg/10 ml solution for injection

Indications

• Allergic reactions
• Nausea and vomiting
• Motion sickness
• Sedation
• Anxiety and tension

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing recommendations.

Mechanism of action

Promethazine functions as a competitive antagonist of histamine H1 receptors, which diminishes the effects of histamine in allergic reactions. It also antagonizes post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. This multifaceted action is responsible for its sedative properties, utility in anxiety and tension, as well as its effectiveness in controlling nausea and vomiting.

Pharmacodynamics

Promethazine exhibits its antihistaminic effects by blocking H1 receptors, leading to reduced allergic response, sedation, and antiemetic effects. The sedative effects typically last between 4 to 6 hours, although they can extend up to 12 hours. Caution is advised regarding potential CNS and respiratory depression, as well as a reduced seizure threshold and possible bone marrow suppression.

Pharmacokinetics

Promethazine is absorbed from the gastrointestinal tract and has a variable bioavailability. It is extensively metabolized in the liver, primarily via the cytochrome P450 enzyme system, and has a long half-life, which contributes to its prolonged effects. The drug is excreted primarily in urine as metabolites. Its pharmacokinetic profile can be influenced by factors such as age and liver function.

Contra-indications

• Hypersensitivity to promethazine or any of its components.
• Children under 2 years of age due to the risk of severe respiratory depression.
• Comatose states or patients with severe central nervous system depression.

Adverse effects

• Drowsiness
• Dizziness
• Dry mouth
• Blurred vision
• Constipation
• Confusion
• Extrapyramidal symptoms
• Severe respiratory depression
• Hypotension

Interactions

• Increased sedation with alcohol and CNS depressants.
• May enhance the effects of other antihistamines.
• Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase the risk of severe side effects.

Precautions

• Use with caution in patients with asthma, cardiovascular disease, or glaucoma.
• Monitor for signs of respiratory depression, particularly in pediatric and elderly patients.
• Caution advised when driving or operating machinery due to sedative effects.

Pregnancy

Promethazine is classified as category C. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

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

Storage

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

Formulations

• Tablets
• Syrup
• Injection

Mechanism of action

The hypersecretion of mucus characterizes serious respiratory conditions including asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). It blocks bacterial adherence to cells, preventing pulmonary infections. Glycoproteins (fucomucins, sialomucins and sulfomucins) regulate the viscoelastic properties of bronchial mucus. Increased fucomucins can be found in the mucus of patients with COPD. Carbocisteine serves to restore equilibrium between sialomucins and fucomucins, likely by intracellular stimulation of sialyl transferase enzyme, thus reducing mucus viscosity. A study found that L-carbocisteine can inhibit damage to cells by hydrogen peroxide (H2O2) by activating protein kinase B (Akt) phosphorylation, suggesting that carbocisteine may have antioxidant effects and prevent apoptosis of lung cells. There is some evidence that carbocisteine suppresses NF-κB and ERK1/2 MAPK signalling pathways, reducing TNF-alpha induced inflammation in the lungs, as well as other inflammatory pathways. An in-vitro study found that L-carbocisteine reduces intracellular adhesion molecule 1 (ICAM-1), inhibiting rhinovirus 14 infection, thereby reducing airway inflammation.

Pharmacodynamics

Due to its mucolytic effects, carbocisteine significantly reduces sputum viscosity, cough, dyspnea and fatigue. Additionally, it prevents pulmonary infections by decreasing accumulated mucus in the respiratory tract; this is especially beneficial in preventing exacerbations of COPD caused by bacteria and viruses. It has in-vitro anti-inflammatory activity with some demonstrated action against free radicals.

Mechanism of action

Promethazine is a an antagonist of histamine H1, post-synaptic mesolimbic dopamine, alpha adrenergic, muscarinic, and NMDA receptors. The antihistamine action is used to treat allergic reactions. Antagonism of muscarinic and NMDA receptors contribute to its use as a sleep aid, as well as for anxiety and tension. Antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center make promethazine useful in the treatment of nausea and vomiting. Promethazine is a phenothiazine derivative with potent sedative properties. Although the drug can produce either CNS stimulation or CNS depression, CNS depression manifested by sedation is more common with therapeutic doses of promethazine. The precise mechanism of the CNS effects of the drug is not known. Although it has been reported that the drug has slight antitussive activity, this may result from its anticholinergic and CNS depressant effects. In therapeutic doses, promethazine appears to have no substantial effect on the cardiovascular system. Although rapid IV administration of promethazine may produce a transient fall in blood pressure, blood pressure usually is maintained or slightly elevated when the drug is given slowly. Promethazine hydrochloride is a phenothiazine derivative which possesses antihistaminic, sedative, antimotion-sickness, antiemetic, and anticholinergic effects. Promethazine is a competitive H1 receptor antagonist, but does not block the release of histamine. Structural differences from the neuroleptic phenothiazines result in its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties. The development of phenothiazine derivatives as psychopharmacologic agents resulted from the observation that certain phenothiazine antihistaminic compounds produced sedation. In an attempt to enhance the sedative effects of these drugs, promethazine and chlorpromazine were synthesized. Chlorpromazine is the pharmacologic prototype of the phenothiazines. The pharmacology of phenothiazines is complex, and because of their actions on the central and autonomic nervous systems, the drugs affect many different sites in the body. Although the actions of the various phenothiazines are generally similar, these drugs differ both quantitatively and qualitatively in the extent to which they produce specific pharmacologic effects. /Phenothiazine General Statement/ For more Mechanism of Action (Complete) data for Promethazine (18 total), please visit the HSDB record page.

Pharmacodynamics

Promethazine is is a histamine H1 antagonist that can be used for it's ability to induce sedation, reduce pain, and treat allergic reactions. Promethazine's effects generally last 4-6h but can last up to 12h. Patients should be counselled regarding CNS and respiratory depression, reduce seizure threshold, and bone marrow depression.