Promethazine is predominantly metabolized to promethazine sulfoxide, and minorly to desmethylpromethazine and a hydroxy metabolite. Hydroxylation of promethazine is predominantly mediated by CYP2D6.
Promethazine hydrochloride is metabolized in the liver, with the sulfoxides of promethazine and N-desmethylpromethazine being the predominant metabolites appearing in the urine.
Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (eg, 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs. There is limited evidence to indicate that some phenothiazines (eg, chlorpromazine) may induce their own metabolism. /Phenothiazine General Statement/
First order kinetics observed for oxidation of promethazine HCl in aqueous solution. Reaction rate was pH dependent up to pH 5. Cu ions increased rates as did Fe. Under anaerobic conditions, Cu and Fe were required for the reaction. Isolation of products carried out by tlc.
Incubation of promethazine (Ia) and desmethylpromethazine (Ib) with 9000g supernatant fractions of rabbit liver homogenate resulted in formation of N-dealkylated, N-oxygenated and ring-hydroxylated products. The N-oxidation products identified by t.l.c. and mass spectra using synthetic reference products are promethazine-N-oxide (IX) and the nitrone (VIII), which is believed to be formed chemically and metabolically from the metabolite N-hydroxydesmethylpromethazine (VII).
IDENTIFICATION: Promethazine hydrochloride is a systemic antihistamine. White or faintly yellow. On prolonged exposure to air it is slowly oxidized, becoming blue in color. It is soluble in water, alcohol and chloroform. It is practically insoluble in either and acetone. Indications: Promethazine is used for the treatment of allergic symptoms, often given at night because of its marked sedative effects. Drug hypersensitivity reactions have also been treated with promethazine. Promethazine is usually given orally for the treatment of allergic conditions but can be given by deep intramuscular injection or slow intravenous injection in emergencies. Promethazine is sometimes used for its sedative effects and in some countries is marketed for this purpose, including the sedation of young children. Promethazine is used as an anesthetic premedication to produce sedation, reduce anxiety and also to reduce post operative nausea and vomiting. The drug is often given in conjunction with an opiate analgesic such as meperidine, particularly in obstetrics. Taken before travelling, promethazine is effective in preventing motion sickness. Vomiting from other causes can be treated with higher or more frequent doses. Other less common uses: Promethazine has been used to control extrapyramidal disorders in children caused by metoclopramide and levodopa induced dyskinesias in patients with Parkinson's disease. In young children undergoing dental procedures it has been suggested that promethazine be used in conjunction with chloral hydrate to produce sedation as there was a lower incidence of nausea than when chloral hydrate was administered alone. HUMAN EXPOSURE: Main risks and target organs: Promethazine is a phenothiazine derivative with potent antihistaminic properties. In therapeutic doses, CNS depression manifested by sedation is a frequent occurrence. In adults, overdosage is usually characterized by CNS depression resulting in sedation and coma sometimes followed by excitement. In young children CNS stimulation is dominant, symptoms include excitation, hallucinations, dystonias and occasionally seizures. Anticholinergic manifestations such as dry mouth, mydriasis and blurred vision are usually present. Overdosage may also present with various cardiorespiratory symptoms such as respiratory depression, tachycardia, hypertension or hypotension and extrasystoles. Summary of clinical effects: Toxic Reactions from Promethazine Central nervous system: Depression and/or stimulation. Sedation, coma, confusion, disorientation. Hallucinations, hyperreflexia, toxic psychoses and seizures. CNS excitation predominates in young children. Respiratory: Respiratory depression can occur. Cardiovascular: Tachycardia, bradycardia, hypertension, hypotension and extrasystoles. Dermatological: Allergic contract dermatitis and photoallergy. Head, Eye, Ear, Nose and Throat: Fixed or dilated pupils, blurred vision, diplopia. Dry mouth, nasal stuffiness. Others: Urinary retention, constipation. Hyperpyrexia has been reported. Contraindications: Newborn and premature infants, lactation and as a treatment for asthma. Patients receiving large doses of other CNS depressants or patients who are comatose. Hypersensitivity to promethazine and other phenothiazines. Patients receiving therapy with monoamine oxidase inhibitors (MAOI). Patients with narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, bladder neck obstruction. Because of a possible link between phenothiazine use and Sudden Infant Death Syndrome or infant sleep apnea, authorities in the U.S. have stated that promethazine is contraindicated in children under two years of age. Promethazine should be used with caution in patients with impaired liver function, a history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, hypertension and diabetes. Epileptic patients may experience an increase in the severity of seizures when treated with promethazine and the drug may be contraindicated in these patients. The drug should not be used in dehydrated children or children with acute infections due to increased susceptibility to dystonias. Concurrent administration of promethazine with alcohol or other CNS depressants will cause increased drowsiness. Promethazine should be used in pregnancy only when the potential benefits justify the possible risks to the fetus. Routes of entry : Oral: Tablets, solution, syrup and elixir are noted as the oral exposure. Dermal: Topical cream. Parenteral: Preparations available for intramuscular and intravenous injection. Other: Rectal suppositories are available in some countries. Absorption by route of exposure: The drug is well absorbed from the gastrointestinal tract. Peak plasma concentrations occur after 2 to 3 hours when promethazine is administered orally or intramuscularly. Following rectal administration of promethazine in a suppository formulation, peak plasma concentrations were observed after about 8 hours. Oral bioavailability is approximately 25%. Rectal bioavailability has been reported at 23%. Distribution by route of exposure: Promethazine is widely distributed in body tissues and has a large apparent volume of distribution following oral and intramuscular administration. Promethazine has been reported to be 93% protein bound when determined by gas chromatography and as 76 to 80% protein bound when determined by HPLC. Promethazine rapidly crosses the placenta, appearing in the cord blood within 1.5 minutes when given intravenously at term. Promethazine crosses the blood brain barrier. Biological half-life by route of exposure: The elimination half life of promethazine following oral administration has been estimated to be within the range of 12 to 15 hours. After intravenous administration of 12.5 mg, blood concentrations of promethazine declined biexponentially with a terminal elimination half life of 12 hours. Metabolism: Promethazine is metabolized principally to promethazine sulphoxide and to a lesser degree desmethylpromethazine. In a study of 7 subjects, peak plasma concentrations of the sulfoxide metabolite occurred earlier after oral administration than after intravenous administration. It was concluded that the major site of metabolism is the liver and that the drug is subjected to extensive first-pass hepatic biotransformation, explaining the oral bioavailability of 25%. Metabolism also occurs in the gut wall but to a lesser degree than earlier postulated. The sulphoxide metabolite has not been detected after intramuscular dosing as circulating levels are probably below analytical detection limits, due to a combination of slow absorption, lower dose (50% of oral) and bypass of first pass metabolism in the liver. Elimination by route of exposure: Elimination of promethazine is primarily due to hepatic metabolism. In eight subjects given oral doses of 0.6% of an administered dose was excreted unchanged in the urine within 24 hours, while 10.3% was excreted as promethazine sulfoxide (the major metabolite). Most oxidized metabolites of other phenothiazines are biologically inactive. No evidence was found to suggest that metabolites of promethazine are pharmacologically or toxicologically active. Promethazine has not been reliably detected in breast milk. Mode of action: Toxicodynamics: The pharmacology of promethazine is complex and for this reason toxicological mechanisms are not completely understood. Most reference texts suggest that the toxicity of promethazine is mainly due to its anticholinergic actions at muscarinic receptors. Many of the signs and symptoms of poisoning are similar to those observed with atropine. In the presence of anticholinergic effects, serious manifestations such as seizures, hallucinations, hypertension and arrhythmias have been noted. As well as anticholinergic effects, promethazine can also exhibit toxic effects typical of antipsychotic phenothiazines. Hypotension and extrapyramidal signs may be attributable to antidopaminergic actions of promethazine. Pharmacodynamics: Promethazine is a phenothiazine antihistamine, antagonizing the central and peripheral effects of histamine medicated by histamine H1 receptors. The drug does not antagonize histamine at H2 receptors. Antihistamines competitively antagonize most of the smooth muscle stimulating actions of histamine on the H1 receptors of the gastrointestinal tract, uterus, large blood vessels and bronchial muscle. Increased capillary permeability and edema formation, flare and pruritus, resulting from actions of histamine on H1 receptors, are also effectively antagonized. Promethazine appears to act by blocking H1 receptor sites, preventing the action of histamine on the cell. Promethazine rapidly crosses the blood brain barrier and it is thought that the sedative effects of antihistamines are due to blockade of H1 receptors in the brain. Promethazine has strong anticholinergic properties, blocking the responses to acetylcholine that are mediated by muscarinic receptors. These atropine like actions are responsible for most of the side effects observed in clinical use of the drug. Promethazine also has anti motion sickness properties which may be due to central antimuscarinic action. In concentrations several times higher than those required to antagonize histamine, promethazine exhibits local anesthetic effects. Promethazine has also been shown to inhibit calmodulin. Calmodulin inhibition by promethazine could be a mechanism involved in the blockade of histamine secretion at cellular level. Toxicity: Human data: Adults: Minimum lethal exposure and maximum tolerated exposure have not been clearly defined in human subjects, due mainly to the lack of data on the exact amount ingested in cases of overdosage. Children: Promethazine is readily available in syrup form which is often administered to sedate young children. It is likely that in many cases the dose is excessive, leading to symptoms of toxicity. CNS toxicity with survival has been reported in children aged 5 to 12 years after accidental ingestion of promethazine. Death was reported in a two year old child with a history of ingestion of promethazine as tablets. Teratogenicity: A number of investigations have been performed to assess the teratogenic potential of promethazine. These studies failed to show and association between promethazine exposure in the first trimester of pregnancy and malformations. Current opinion is that these studies were not adequate or sufficiently controlled to establish whether promethazine is safe to use in pregnancy with respect to possible adverse effects on the fetus. Use late in pregnancy may result in EEG changes in the neonate. Promethazine should be used in pregnancy only when the potential benefits justify the possible risks to the fetus. Mutagenicity: There was no evidence of promethazine induced mutagenesis in the Ames microbial mutagen test. No relevant human or animal data available to date. Interactions: Concomitant administration of promethazine and other CNS depressants (ethanol, narcotics, other phenothiazines and antihistamines, barbiturates and benzodiazepines) may lead to excessive CNS depression and possible respiratory depression. The combination of promethazine and tricyclic antidepressant drugs (e.g. amitriptyline, doxepin) or other drugs with anticholinergic actions, may result in additive anticholinergic effects. Many preparations containing promethazine also contain other drugs, such as codeine, dextromethorphan, phenylephrine and ephedrine. The toxic effects of these drugs must be considered if compound preparations have been ingested. Main adverse effects: Sedation, ranging from mild drowsiness to deep sleep, is probably the most common adverse effect. Anticholinergic effects such as dryness of the mouth, nose and throat, blurred vision, mydriasis, poor accommodation, sweating and thickening of bronchial secretions are frequent. Dizziness, lassitude, disturbed co-ordination and muscular weakness have all be reported. Gastrointestinal effects including epigastric distress, nausea, diarrhea or constipation can occur. Promethazine can also cause immunoallergic reactions. Leucopenia and agranulocytosis have occurred rarely, and usually in patients receiving promethazine in combination with other drugs known to cause these effects. Jaundice and thrombocytopenic purpura have been reported rarely. Extrapyramidal effects can occur, especially at high doses. Cardiovascular side effects are occasionally seen after injection; tachycardia, bradycardia, mild transient hypertension and hypotension have all been noted. Venous thrombosis has been reported at the site of intravenous injections. Arteriospasm and gangrene may follow inadvertent intra-arterial injection. Respiratory depression, sleep apnea and sudden infant death syndrome (SIDS) have occurred in a number of infants or young children who were receiving usual doses of promethazine. These reports suggest that promethazine and other CNS depressants may cause sudden death, especially in apnea prone infants, and that these drugs should be avoided in infants even though a causal relationship has been established. Clinical effects: Acute poisoning: Ingestion: Overdosage may result in CNS depression followed by stimulation (excitation, agitation, hyperreflexia). In young children or teenagers, CNS stimulation is usually dominant. Symptoms resemble anticholinergic overdose and may include fixed and dilated pupils, flushed face, fever, dry mouth, excitation, hyperreflexia, dystonias, hallucinations and tonic clonic seizures. Periods of excitation may alternate with somnolence and catatonia. Hypertension or hypotension may be noted in agitated or comatose patients respectively. Tachycardia and extrasystoles have been reported. While coma appears to occur more frequently in adults, it may do so because of co-ingestion of ethanol. Skin exposure: Topical application of promethazine has resulted in systemic toxic effects, especially in young children. Symptoms reported include visual hallucinations, peripheral anticholinergic signs, drowsiness, agitation, irritability, tachycardia and myoclonus. Topical application of promethazine may cause contact dermatitis. Parenteral exposure: Rapid intravenous administration of promethazine may cause hypotension. Tachycardia, bradycardia and faintness have all been reported with parenteral promethazine. Chemical irritation and necrotic lesions have resulted on rare occasions following subcutaneous injection of promethazine and the drug should not be administered by this route. Extravasation should also be avoided. Accidental intra-arterial injection can cause chemical irritation and arteriospasm leading to impaired circulation and gangrene. There are case reports of amputation as a result of intra-arterial injection of promethazine. Chronic poisoning: Ingestion: Promethazine has rarely been associated with obstructive jaundice which is usually reversible if the drug is discontinued. Leukopenia and agranulocytosis have been reported rarely, usually in conjunction with other agents known to have caused these effects. Thrombocytopenic purpura has also been reported. As with other phenothiazines, promethazine can cause photosensitivity reactions. Long term use of the antipsychotic phenothiazines has been associated with many adverse reactions including, blood dyscrasias, hepatotoxicity, ocular changes, dermatological disorders and allergic reactions. The possibility that these could occur with prolonged administration of promethazine should not be ruled out. Skin exposure: Topical administration of promethazine can cause allergic reactions (contact dermatitis, pruritic), inflammation and also photosensitivity. Parenteral exposure: Venous thrombosis has been reported at the site of intravenous injections. Course, prognosis, cause of death: Mild cases of overdosage may manifest simply as excessive drowsiness or mild CNS excitation in children or teenagers. With increasing dose coma may develop, or more frank symptoms of CNS excitation, for example, hallucinations, delirium, hyperreflexia. There is little indication in the literature that the severity of the poisoning can be related to the appearance of signs and symptoms such as extrapyramidal effects, hypertension or hypotension. Treatment is symptomatic and the appearance of specific effects cannot be relied upon when assessing the severity of poisoning. It is generally agreed that as the severity of the poisoning increases serious anticholinergic effects usually appear along with seizures, hypertension and arrhythmias, delirium or coma. Death due to respiratory arrest has been reported in association with promethazine poisoning. Systematic description of clinical effects: Since formulations containing promethazine in combination with other drugs are available, it may alter the clinical picture from the following description. Cardiovascular: Acute tachycardia and extrasystoles have been reported. Hypotension, or even cardiac shock may develop after antihistamine overdose. Hypertension has also occurred. Respiratory: Acute: Stridor, wheezing and bronchospasm have been reported after a single dose. Respiratory arrest has been reported following overdose. Acute dystonic reactions including opisthotonos, oculogyric crisis and facial dyskinesias have occurred following promethazine overdose. In one report, onset of dystonias was delayed for 24 hours after a large promethazine overdose. Other neurological effects associated with promethazine poisoning: Extensor plantar reflexes. Encephalopathy have been reported in a five year old child. Gastrointestinal: The anticholinergic properties of the drug may cause dry mouth and slow the rate of gastric emptying. Hepatic: Chronic promethazine has rarely been associated with obstructive jaundice which is usually reversible following discontinuance of the drug. Urinary: Renal: Acute urinary retention due to anticholinergic actions have been reported with promethazine toxicity. Other: Promethazine overdose has reported to produce a characteristic rose coloration of urine, however this was due to hematuria in one case. Endocrine and reproductive systems: Promethazine was considered to be unsafe in patients with acute porphyria although there is conflicting experimental evidence on porphyrinogenicity. Dermatological: Acute or chronic: Urticaria has been reported following oral ingestion. Photosensitivity (principally photoallergic dermatitis) can occur following topical or systemic administration of antihistamines, including promethazine. The reaction may manifest as eczema, pruritic, papular rash or erythema. Promethazine may also cause sensitization following topical use, giving rise to an allergic contact dermatitis. Eye, ear, nose throat: local effects: Acute: Anticholinergic effects on the eye include, mydriasis, fixed pupils, blurred vision, diplopia and general visual disturbances. Oculogyric crisis has been reported following overdose. Dryness of the nose and nasal stuffiness have been noted. Anticholinergic effects include dryness of the mouth and throat. Facial erythema has been noted. Hematological: Chronic leucopenia and agranulocytosis have been reported rarely in patients receiving promethazine in combination with other drugs known to cause these effects. Thrombocytopenic purpura has been reported with promethazine. A case of allergic agranulocytosis has been reported, however this patient was taking larger than normal doses for approximately four weeks. Discontinuing the promethazine resulted in the eventual complete recovery of the patient. Serious blood dyscrasias have occurred with the antipsychotic phenothiazines and the possibility that these could occur with promethazine should not be discounted. Immunological: Chronic promethazine is a potent sensitizer particularly following topical application. Promethazine can exert immunosuppressive effects resulting in potentially adverse reactions, infections. Metabolic: Fluid and electrolyte disturbances: Hypokal emia has been reported. Other: Hyperthermia following promethazine ingestion has been reported. Allergic reactions: Photoallergic dermatitis can occur following topical or systemic administration of promethazine. Topically applied promethazine can cause allergic contact dermatitis. Special risks: Pregnancy: Promethazine is commonly used in obstetrics as an adjunct to opiate analgesia and as a sedative. The drug rapidly crosses the placenta, appearing in cord blood within one and a half minutes of an intravenous dose. The use of promethazine during labour has been associated rarely with neonatal respiratory depression. Transient behavioral and EEG changes have also been described in neonates. Promethazine has been shown to markedly impair platelet aggregation in the newborn but less so in the mother. Immunological disturbances have been described in a few infants whose mothers had been treated with promethazine during pregnancy. The clinical significance of these effects are unknown. ANIMAL/PLANT STUDIES: Promethazine has not been shown to be teratogenic in rats receiving oral doses of 2-4 times the maximum recommended human dosage.
Like other H1-antagonists, promethazine competes with free histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. The relief of nausea appears to be related to central anticholinergic actions and may implicate activity on the medullary chemoreceptor trigger zone.
Despite widespread use and similarity to phenothiazines, promethazine has not been clearly linked to liver test abnormalities or to clinically apparent liver injury. The reason for its safety may relate to low daily dose and limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines
A 25mg dose of intramuscular promethazine reaches a Cmax of 22ng/mL. Intravenous promethazine reaches a Cmax of 10.0ng/mL, with a Tmax of 4-10h, and an AUC of 14,466ng\*h/mL. Oral promethazine is only 25% bioavailable due to first pass metabolism. Oral promethazine reaches a Cmax of 2.4-18.0ng/mL, with a Tmax of 1.5-3h, and an AUC of 11,511ng\*h/mL.
An intravenous dose of promethazine is 0.64% eliminated in the urine as the unchanged parent drug, 0.02-2.02% in the urine as desmethylpromethazine, 10% in the urine as promethazine sulfoxide.
The intravenous clearance of promethazine is approximately 1.14L/min. The renal clearance of promethazine is 5.9mL/min and the renal clearance of promethazine sulfoxide is 90.4mL/min.
Promethazine is well absorbed from the GI tract and from parenteral sites. Plasma concentrations of promethazine required for sedative effects are unknown. The onset of sedative effects occurs within 20 minutes following oral, rectal, or IM administration, and within 3-5 minutes following IV administration. The duration of sedative effects varies but may range from 2-8 hours depending on the dose and route of administration.
Photo- and Radiation-Chemical Generation and Thermodynamic Properties of the Aminium and Aminyl Radicals Derived fromN-Phenylglycine and (N-Chloro,N-phenyl)glycine in Aqueous Solution: Evidence for a New Photoionization Mechanism for Aromatic Amines
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
申请人：Parion Sciences, Inc.
公开号：US20140171447A1
公开（公告）日：2014-06-19
This invention provides compounds of the formula I:
and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
