Identification
- Summary
Phenyltoloxamine is a medication used to treat minor aches and pains.
- Brand Names
- Zflex
- Generic Name
- Phenyltoloxamine
- DrugBank Accession Number
- DB11160
- Background
Phenyltoloxamine is an antihistamine drug with sedative and analgesic effects. It is a H1 receptor blocker and a member of the ethanolamine class of antihistaminergic drugs. It is available in combination products that also contain other analgesics and antitussives such as acetaminophen. Phenyltoloxamine citrate is the more common salt form that acts as an active ingredient in pharmaceutical products and promotes hay fever relief via reversing the effects of histamine. Phenyltoloxamine acts as an adjuvant analgesic, which augments the analgesic effect of acetaminophen. It also potentiates the effects of other drugs, such as codeine and codeine derivatives.
Although phenyltoloxamine's ability to potentiate the effects of analgesics may be explained in part by its chemical nature as a first-generation H1 antihistamine that is capable of crossing the blood-brain barrier and causing tranquilizing effects at CNS histamine receptors, many of the drug's specific pharmacokinetics are not readily available - perhaps also because many early (phenyltoloxamine was involved in studies as early as the 1950s) first-generation antihistamines were not optimally investigated 1. Nevertheless, phenyltoloxamine is used to a fairly limited extent in contemporary medicine, with only very few products involving it as an active ingredient.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Phenyltoloxamine (DB11160)
- Weight
- Average: 255.361
Monoisotopic: 255.1623143 - Chemical Formula
- C17H21NO
- Synonyms
- Feniltoloxamina
- Phenyltoloxamine
- Phenyltoloxaminum
- External IDs
- BRN 1986598
Pharmacology
- Indication
The primary therapeutic use for which phenyltoloxamine is currently indicated is as an adjuvant therapy in various combination products containing an analgesic(s) (either narcotic or non-narcotic), where it is expected to potentiate the pain relieving, anti-tussive, etc. effect(s) of the analgesic component of the product.
In that regard, some of these aforementioned combination products are typically indicated for the temporary relief of minor aches and pains like headache, muscular aches, backaches, minor arthritis pain, common cold, toothaches, menstrual cramps, etc 9; or perhaps for the treatment of exhausting or non-productive cough, associated with cold or with upper respiratory allergic condition that does not respond to non-narcotic antitussives 8.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination for symptomatic treatment of Bronchitis Combination Product in combination with: Guaifenesin (DB00874), Codeine (DB00318) •••••••••••• •••••••• •••••••• •••••••• •••••••• ••••• Used in combination for symptomatic treatment of Coughing Combination Product in combination with: Codeine (DB00318), Guaifenesin (DB00874) •••••••••••• •••••••• •••••••• •••••••• •••••••• ••••• Used in combination to manage Minor aches and pains Combination Product in combination with: Ethanol (DB00898), Acetaminophen (DB00316) ••• ••• •••••• Used in combination to manage Minor aches and pains Combination Product in combination with: Acetaminophen (DB00316) ••• ••• •••••• - Associated Therapies
- Contraindications & Blackbox Warnings
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As a member of the first generation H1 antihistamines, it is known that phenyltoloxamine - like virtually all first generation H1 antihistamines - has a propensity for crossing the blood-brain barrier and acting on H1 histamine receptors there to interfere with neurotransmission 1. The most common results of this kind of first generation H1 antihistamine CNS neurotransmission interference are adverse effects like drowsiness, sedation, somnolence, and fatigue 1. Given these effects, under specific circumstances like a patient experiencing a pain or a cough that may be preoccupying all of their waking energy and attention, it is perhaps possible that the sedative and tranquilizing characteristics of phenyltoloxamine may be the factors that contribute to its apparent adjunctive analgesic 3,4 and antitussive actions 8,2.
- Mechanism of action
As a first-generation H1 antihistamine, phenyltoloxamine interferes with the agonist activity of histamine at the H1 receptor and are ostensibly used to attenuate inflammatory processes as a means to treat conditions like allergic rhinitis, allergic conjunctivitis, and urticaria 10. Reduction of the activity of the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) immune response transcription factor via the phospholipase C and phosphatidylinositol (PIP2) signaling pathways also serves to decrease antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors 10. Moreover, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release 10.
Additionally, first-generation antihistamines like phenyltoloxamine readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects, like nervousness and insomnia 10. By comparison, second-generation antihistamines are more selective for H1 receptors in the peripheral nervous system and do not cross the blood-brain barrier, resulting in fewer adverse drug effects overall 10.
Furthermore, although some studies propose that phenyltoloxamine may possess some intrinsic antispasmodic and distinct local anesthetic properties 7, the specific mechanisms of action for these effects have not been formalized. Also, even though the combination of phenyltoloxamine's ability to cross the blood-brain barrier and cause various tranquilizing effects may explain to some extent how it may be able to potentiate analgesic effects 3,4, there are also studies that observed no potentiating effects associated with phenyltoloxamine use either 6.
Target Actions Organism AHistamine H1 receptor inverse agonistMouse - Absorption
Readily accessible data regarding the absorption of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Volume of distribution
Readily accessible data regarding the volume of distribution of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Protein binding
Readily accessible data regarding the protein binding of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Metabolism
Readily accessible data regarding the metabolism of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Route of elimination
Readily accessible data regarding the primary route of elimination of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Half-life
Readily accessible data regarding the half-life of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Clearance
Readily accessible data regarding the clearance of phenyltoloxamine is not available. In fact, many first-generation H1 antihistamines have never had their pharmacokinetics (ie. absorption, distribution, metabolism, and elimination) optimally investigated 1.
- Adverse Effects
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Toxicity after overdose may involve CNS effects like extreme drowsiness, lethargy, confusion, delirium, and coma in adults; paradoxical excitation, irritability, hyperactivity, insomnia, hallucinations, seizures, and respiratory depression or arrest in infants and young children, CNS adverse effects predominate o er cardiac adverse effects; death may occur within hours after ingestion of drug in untreated patients; rhabdomyolysis has also been reported 1.
- Pathways
Pathway Category Phenyltoloxamine H1-Antihistamine Action Drug action - Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Phenyltoloxamine citrate 8UE48MJH8M 1176-08-5 ZZYHCCDMBJTROG-UHFFFAOYSA-N Phenyltoloxamine hydrochloride 56O4H6ZT2K 6152-43-8 HMBOWANDONYIBI-UHFFFAOYSA-N - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Codipront Capsule Phenyltoloxamine (10 mg) + Codeine phosphate hemihydrate (30 mg) Capsule, extended release Oral RX PHARMA PTE. LTD. 2007-07-30 Not applicable Singapore 
Dologesic Phenyltoloxamine citrate (30 mg/15mL) + Acetaminophen (500 mg/15mL) + Ethanol (0.75 mL/15mL) Liquid Oral Llorens Pharmaceuticals International Division 1994-09-01 Not applicable US 
Dologesic DF Phenyltoloxamine citrate (30 mg/1) + Acetaminophen (500 mg/1) Tablet Oral Llorens Pharmaceuticals International Division 2009-09-01 Not applicable US Relagesic Phenyltoloxamine citrate (29 mg/1) + Acetaminophen (500 mg/1) Tablet Oral International Ethical Labs. 2015-02-15 2016-05-31 US Sinutab Sa Tab Phenyltoloxamine citrate (66 mg / tab) + Acetaminophen (600 mg / tab) + Phenylpropanolamine hydrochloride (100 mg / tab) Tablet, extended release Oral Warner Lambert Canada Inc. 1992-12-31 2000-11-09 Canada 
- Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Ali-flex Phenyltoloxamine citrate (50 mg/1) + Acetaminophen (500 mg/1) Tablet Oral Pegasus Laboratories 2001-06-27 2012-07-01 US Be Flex Plus Phenyltoloxamine citrate (20 mg/1) + Acetaminophen (300 mg/1) + Salicylamide (200 mg/1) Capsule, gelatin coated Oral Larken Laboratories, Inc 2006-04-17 2010-07-13 US Be Flex Plus Phenyltoloxamine citrate (20 mg/1) + Acetaminophen (300 mg/1) + Salicylamide (200 mg/1) Capsule, gelatin coated Oral Larken Laboratories, Inc 2006-04-17 2010-07-13 US BE-FLEX Plus Phenyltoloxamine citrate (20 mg/1) + Acetaminophen (300 mg/1) + Salicylamide (200 mg/1) Capsule, gelatin coated Oral Larken Laboratories, Inc. 2006-04-17 2011-10-31 US Flextra-650 Phenyltoloxamine citrate (60 mg/1) + Acetaminophen (650 mg/1) Tablet Oral Pegasus Laboratories 2006-09-08 2011-11-30 US
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Diphenylmethanes
- Direct Parent
- Diphenylmethanes
- Alternative Parents
- Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Trialkylamines / Organopnictogen compounds / Hydrocarbon derivatives
- Substituents
- Alkyl aryl ether / Amine / Aromatic homomonocyclic compound / Diphenylmethane / Ether / Hydrocarbon derivative / Organic nitrogen compound / Organic oxygen compound / Organonitrogen compound / Organooxygen compound
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- K65LB6598J
- CAS number
- 92-12-6
- InChI Key
- IZRPKIZLIFYYKR-UHFFFAOYSA-N
- InChI
- InChI=1S/C17H21NO/c1-18(2)12-13-19-17-11-7-6-10-16(17)14-15-8-4-3-5-9-15/h3-11H,12-14H2,1-2H3
- IUPAC Name
- [2-(2-benzylphenoxy)ethyl]dimethylamine
- SMILES
- CN(C)CCOC1=CC=CC=C1CC1=CC=CC=C1
References
- General References
- Simons FE, Simons KJ: H1 antihistamines: current status and future directions. World Allergy Organ J. 2008 Sep;1(9):145-55. doi: 10.1097/WOX.0b013e318186fb3a. [Article]
- Dotti A: [Clinical trial of the antitussive action of an association of codeine plus phenyltoloxamine]. G Ital Mal Torace. 1970 May-Jun;24(3):147-57. [Article]
- Sunshine A, Zighelboim I, De Castro A, Sorrentino JV, Smith DS, Bartizek RD, Olson NZ: Augmentation of acetaminophen analgesia by the antihistamine phenyltoloxamine. J Clin Pharmacol. 1989 Jul;29(7):660-4. [Article]
- Gilbert MM, De Sola Pool N, Schecter C: Analgesic/calmative effects of acetaminophen and phenyltoloxamine in treatment of simple nervous tension accompanied by headache. Curr Ther Res Clin Exp. 1976 Jul;20(1):53-8. [Article]
- Church DS, Church MK: Pharmacology of antihistamines. World Allergy Organ J. 2011 Mar;4(3 Suppl):S22-7. doi: 10.1097/WOX.0b013e3181f385d9. [Article]
- Forbes JA, Barkaszi BA, Ragland RN, Hankle JJ: Analgesic effect of acetaminophen, phenyltoloxamine and their combination in postoperative oral surgery pain. Pharmacotherapy. 1984 Jul-Aug;4(4):221-6. [Article]
- HOEKSTRA JB, TISCH DE, RAKIETEN N, DICKISON HL: Pharmacological properties of a new antihistaminic agent, phenyltoloxamine (Bristamin). J Am Pharm Assoc Am Pharm Assoc. 1953 Oct;42(10):587-93. [Article]
- Prescribing Information: Tussionex Suspension and Tablets [Link]
- DailyMed: Dologesic (Acetaminophen, Phenyltoloxamine citrate, and Ethanol) Oral Liquid [Link]
- SMPDB: Phenyltoloxamine H1-Antihistamine Action [Link]
- External Links
- Human Metabolome Database
- HMDB0240250
- PubChem Compound
- 7077
- PubChem Substance
- 347827928
- ChemSpider
- 6810
- BindingDB
- 50151046
- 33408
- ChEBI
- 135047
- ChEMBL
- CHEMBL186720
- ZINC
- ZINC000000001931
- Wikipedia
- Phenyltoloxamine
Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule, gelatin coated Oral Capsule, extended release Oral Capsule, extended release Oral 30 mg Liquid Oral Tablet Oral Tablet, extended release Oral Suspension Oral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0423 mg/mL ALOGPS logP 3.51 ALOGPS logP 3.93 Chemaxon logS -3.8 ALOGPS pKa (Strongest Basic) 8.78 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 12.47 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 80.28 m3·mol-1 Chemaxon Polarizability 29.99 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 173.1220865 predictedDarkChem Lite v0.1.0 [M-H]- 156.18098 predictedDeepCCS 1.0 (2019) [M+H]+ 173.4198865 predictedDarkChem Lite v0.1.0 [M+H]+ 158.53902 predictedDeepCCS 1.0 (2019) [M+Na]+ 173.1077865 predictedDarkChem Lite v0.1.0 [M+Na]+ 164.63216 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Mouse
- Pharmacological action
- Yes
- Actions
- Inverse agonist
- General Function
- In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system. Involved in circadian rhythm of locomotor activity and exploratory behavior. Also involved in responsiveness to pertussis toxin through its control of susceptibility to histamine hypersensitivity and enhancement of antigen-specific delayed-type hypersensitivity responses.
- Specific Function
- Calcium ion transmembrane transporter activity
- Gene Name
- Hrh1
- Uniprot ID
- P70174
- Uniprot Name
- Histamine H1 receptor
- Molecular Weight
- 55681.225 Da
References
- Simons FE, Simons KJ: H1 antihistamines: current status and future directions. World Allergy Organ J. 2008 Sep;1(9):145-55. doi: 10.1097/WOX.0b013e318186fb3a. [Article]
Drug created at December 03, 2015 16:51 / Updated at February 21, 2021 18:52