PHENSEDYL-P COMBINATION PRODUCT COUGH SYRUP

Indications

• Reversal of hypotension from spinal or epidural anesthesia
• Reversible airways obstruction (e.g., asthma, bronchospasm)
• Nasal congestion

Dosage

Children: For children aged 1 month to 11 years, the dose is 1 mg/kg/hour by intravenous infusion, adjusted according to plasma-theophylline concentration. For children aged 12 to 17 years, administer 500–700 micrograms/kg/hour by intravenous infusion, also adjusted according to plasma-theophylline concentration.

Adults: For reversal of hypotension, administer 3–7.5 mg by slow intravenous injection every 3–4 minutes, adjusting according to response, with a maximum of 9 mg per dose. For airways obstruction, 30–60 mg may be given orally three times a day.

Mechanism of action

Ephedrine acts by stimulating adrenergic receptors, leading to bronchodilation and vasoconstriction. It increases the release of norepinephrine from sympathetic nerve endings, enhancing its action on alpha and beta-adrenergic receptors, which results in increased peripheral resistance and cardiac output.

Pharmacodynamics

Ephedrine exhibits both alpha- and beta-adrenergic activity. Its alpha-adrenergic effects lead to vasoconstriction, while beta-adrenergic stimulation results in bronchodilation. The drug also has a mild central nervous system stimulant effect, which can contribute to side effects such as anxiety and insomnia.

Pharmacokinetics

Ephedrine is well-absorbed from the gastrointestinal tract and is distributed widely throughout the body. It has a relatively long half-life due to its resistance to metabolism. The drug is primarily excreted unchanged in the urine. Its pharmacokinetic profile can be influenced by factors such as renal function and the presence of other medications that may affect its clearance.

Contra-indications

• Hypersensitivity to ephedrine or any of its components
• Severe hypertension
• Tachyarrhythmias
• Severe coronary artery disease
• Hyperthyroidism
• Prostatic hypertrophy

Adverse effects

• Anxiety
• Headache
• Insomnia
• Nausea
• Tremor
• Dry mouth
• Dizziness
• Cardiac arrhythmias
• Hypertension
• Urinary retention
• Myocardial infarction
• Psychotic disorders
• Pulmonary edema

Interactions

• Other sympathomimetics
• Xanthines (e.g., theophylline)
• Monoamine oxidase inhibitors
• Antihypertensive agents
• Antidepressants
• Corticosteroids

Precautions

• Use with caution in patients with diabetes mellitus
• Caution in elderly patients
• Hypertension
• Ischaemic heart disease
• Glaucoma (risk of angle-closure)
• Chronic obstructive pulmonary disease

Pregnancy

Manufacturer advises avoidance due to potential risks, including increased fetal heart rate.

Breast-feeding

Present in breast milk; manufacturer advises avoidance due to reported irritability and disturbed sleep in infants.

Storage

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

Formulations

• Oral suspension
• Oral solution
• Tablets (15 mg, 30 mg)
• Solution for injection (30 mg per 10 ml)

Indications

• Dry cough
• Cough caused by respiratory infections

Dosage

Children: For children aged 6-11 years, the recommended dose is 2-5 mg taken 3-4 times a day. For children aged 12-17 years, the dosage is 5-10 mg taken 3-4 times a day. Pholcodine should be avoided in children under 6 years.

Adults: For adults, the typical dosage is 5-10 mg taken 3-4 times a day.

Mechanism of action

Pholcodine exerts its effects directly on the cough center in the medulla oblongata, acting on peripheral reflexogenic receptors to suppress the cough reflex. This mechanism allows pholcodine to alleviate coughing without significantly impacting respiratory function.

Pharmacodynamics

Therapeutic doses of pholcodine do not typically cause respiratory depression, CNS excitation, or other side effects commonly associated with narcotics. It selectively targets the cough center while preserving respiratory activity, thus reducing the risk of addiction and psychological dependence. However, it is noted to have a stronger respiratory depression effect compared to codeine and can induce hypotension similar to codeine. Additional pharmacological effects include histamine release induction, anti-histaminic activity, anti-acetylcholinic action, anti-convulsant properties, and mild tranquilizing effects.

Pharmacokinetics

Pholcodine is absorbed well when taken orally and is metabolized in the liver. Its pharmacokinetic profile indicates it is distributed widely throughout the body. The elimination half-life and specific metabolic pathways are not detailed in the provided sources, but it is important to consider hepatic and renal function when prescribing.

Contra-indications

• Known hypersensitivity to pholcodine or any of its components
• Severe hepatic impairment
• Severe renal impairment
• Children under 6 years of age

Adverse effects

• Drowsiness
• Nausea
• Constipation
• Dry mouth
• Dizziness
• Hypotension

Interactions

• Caution with other cough and cold preparations that may contain similar active ingredients
• May interact with central nervous system depressants, enhancing sedative effects
• Caution is advised when combined with antihistamines

Precautions

• Use with caution in patients with respiratory conditions
• Care should be taken to administer the correct dose, especially in children
• Avoid use in patients with a history of substance abuse

Pregnancy

Pholcodine should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Pholcodine is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

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

Formulations

• Pholcodine 5 mg/5 mL linctus
• Pholcodine 10 mg/5 mL linctus strong
• Pholcodine 2 mg/mL oral solution
• Pholcodine sugar-free linctus

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

• Bronchial asthma
• Hypotension
• Nasal congestion
• Cardiac arrest

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing information.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Ephedrine acts by activating alpha-adrenergic and beta-adrenergic receptors. Directly, it stimulates these receptors, leading to vasoconstriction (alpha-1), increased cardiac chronotropy and inotropy (beta-1), and bronchodilation (beta-2). Indirectly, it inhibits norepinephrine reuptake and promotes the release of norepinephrine from nerve cells, resulting in prolonged sympathetic stimulation.

Pharmacodynamics

Ephedrine elevates blood pressure through increased heart rate and cardiac output, while also variably raising peripheral resistance. It induces bronchodilation through beta-adrenergic receptor activation in the lungs. Additionally, it enhances urine outflow resistance by stimulating alpha-adrenergic receptors in bladder smooth muscle. The therapeutic dose range is broad, with potential dosages from 5mg to 50mg, and caution is advised regarding the risk of hypertension and tachyphylaxis.

Pharmacokinetics

Ephedrine is rapidly absorbed and reaches peak plasma concentrations within 1 to 2 hours following oral administration. It is metabolized in the liver and excreted primarily via the kidneys. The duration of action is variable, but it generally lasts for 2 to 4 hours. Its pharmacokinetic profile can be influenced by individual patient characteristics, including renal function.

Adverse effects

• Tachycardia
• Hypertension
• Palpitations
• Nervousness
• Dizziness
• Nausea
• Vomiting

Interactions

• mianserin+ephedrine: Unknown (decreases effects)
• volatile halogenated anaesthetics+ephedrine: Unknown (additive effect)

Precautions

• Use with caution in patients with cardiovascular disorders
• Monitor blood pressure and heart rate during treatment
• Consider potential for tachyphylaxis with prolonged use

Pregnancy

Use only if clearly needed, as safety in pregnancy has not been established.

Breast-feeding

Caution is advised; ephedrine may pass into breast milk.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Oral tablets
• Injectable solution

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 mechanism of action of pholcodine is directly performed in the medulla oblongata. In this site, it exerts analgesic properties on the peripheric reflexogenic receptors. This site is commonly known as the "cough center."

Pharmacodynamics

The therapeutic doses of pholcodine have been shown not to cause depression of respiration, CNS excitation or other side effects associated with narcotics. It is thought that the impact of pholcodine is selective on the cough center without affecting the respiratory center. Pholcodine is not euphorigenic, and thus, psychological dependence is unlikely. Clinical trials have not shown any evidence of addiction after prolonged administration of pholcodine. It is well reported that pholcodine presents a more considerable respiratory depression effect than codeine and it causes hypotension in the same degree than codeine. Some other noted impacts of pholcodine in preclinical trials are: 1) the induction of histamine release, 2) anti-histaminic effect, 3) anti-acetylcholinic action, 4) anti-convulsant action and 5) mild tranquilizing action.

Mechanism of action

Ephedrine is a direct and indirect sympathomimetic amine. As a direct effect, ephedrine activates alpha-adrenergic and beta-adrenergic receptors. As an indirect effect, it inhibits norepinephrine reuptake and increases the release of norepinephrine from vesicles in nerve cells. These actions combined lead to larger quantities of norepinephrine present in the synapse for more extended periods of time, increasing stimulation of the sympathetic nervous system. Ephedrine acts as an agonist of alpha-1, beta-1 and beta-2-adrenergic receptors. The stimulation of alpha-1-adrenergic receptors causes the constriction of veins and a rise in blood pressure, the stimulation of beta-1-adrenergic receptors increases cardiac chronotropy and inotropy, and the stimulation of beta-2-adrenergic receptors causes vasodilation and bronchodilation. Ephedrine alkaloids are members of a large family of sympathomimetic compounds that include dobutamine and amphetamine. Members of this family increase blood pressure and heart rate by binding to alpha- and beta-adrenergic receptors present in many parts of the body, including the heart and blood vessels. These compounds are called sympathomimetics because they mimic the effects of epinephrine and norepinephrine, which occur naturally in the human body. In addition to their direct pharmacological effects, many of these compounds also stimulate the release of norepinephrine from nerve endings. The release of norepinephrine further increases the sympathomimetic effects of these compounds, at least transiently. Ephedrine does not contain a catechol moiety, and it is effective after oral administration. The drug stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Stimulation of the alpha-adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of beta-adrenergic receptors in the lungs promotes bronchodilation. Ephedrine stimulates both alpha- and beta-adrenergic receptors. It is believed that beta-adrenergic effects result from stimulation of the production of cyclic adenosine 3',5'-monophosphate (AMP) by activation of the enzyme adenyl cyclase, whereas a-adrenergic effects result from inhibition of adenyl cyclase activity. In contrast to epinephrine, ephedrine also has an indirect effect by releasing norepinephrine from its storage sites. With prolonged use or if doses are given frequently, ephedrine may deplete norepinephrine stores in sympathetic nerve endings and tachyphylaxis may develop to the cardiac and pressor effects. Tachyphylaxis to the bronchial effects of the drug may also occur, but it is not the result of norepinephrine depletion.

Pharmacodynamics

Ephedrine increases blood pressure by stimulating heart rate and cardiac output and variably increasing peripheral resistance. It causes bronchodilation due to the activation of beta-adrenergic receptors in the lungs. By stimulating alpha-adrenergic receptors in bladder smooth muscle cells, ephedrine also increases the resistance to the outflow of urine. The therapeutic window of ephedrine is wide, as patients can be given doses of 5mg up to 50mg. Patients should be counselled regarding the pressor effects of sympathomimetic amines and the risk of tachyphylaxis. Also, the use of ephedrine for hypotension prophylaxis is associated with a higher risk of hypertension, compared to when ephedrine is used to treat hypotension.

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.