Phenyltoloxamine

Identification

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Name
Phenyltoloxamine
Accession Number
DB11160
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Feniltoloxamina
  • Phenyltoloxamine
  • Phenyltoloxaminum
External IDs
BRN 1986598
Product Ingredients
IngredientUNIICASInChI Key
Phenyltoloxamine citrate8UE48MJH8M1176-08-5ZZYHCCDMBJTROG-UHFFFAOYSA-N
Phenyltoloxamine hydrochloride56O4H6ZT2K6152-43-8HMBOWANDONYIBI-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
DologesicPhenyltoloxamine citrate (30 mg/15mL) + Acetaminophen (500 mg/15mL) + Ethanol (0.75 mL/15mL)LiquidOralLlorens Pharmaceuticals International Division1994-09-01Not applicableUs
Dologesic DFPhenyltoloxamine citrate (30 mg/1) + Acetaminophen (500 mg/1)TabletOralLlorens Pharmaceuticals International Division2009-09-01Not applicableUs
RelagesicPhenyltoloxamine citrate (29 mg/1) + Acetaminophen (500 mg/1)TabletOralInternational Ethical Labs.2015-02-152016-05-31Us
Sinutab Sa TabPhenyltoloxamine citrate (66 mg) + Acetaminophen (600 mg) + Phenylpropanolamine hydrochloride (100 mg)Tablet, extended releaseOralWarner Lambert Canada Inc.1992-12-312000-11-09Canada
TussionexPhenyltoloxamine (10 mg) + Hydrocodone (5 mg)Tablet, extended releaseOralSanofi Aventis1957-12-31Not applicableCanada
TussionexPhenyltoloxamine (10 mg) + Hydrocodone (5 mg)SuspensionOralSanofi Aventis1957-12-31Not applicableCanada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Ali-flexPhenyltoloxamine citrate (50 mg/1) + Acetaminophen (500 mg/1)TabletOralPegasus Laboratories2001-06-272012-07-01Us
Be Flex PlusPhenyltoloxamine citrate (20 mg/1) + Acetaminophen (300 mg/1) + Salicylamide (200 mg/1)Capsule, gelatin coatedOralLarken Laboratories, Inc2006-04-172010-07-13Us
Be Flex PlusPhenyltoloxamine citrate (20 mg/1) + Acetaminophen (300 mg/1) + Salicylamide (200 mg/1)Capsule, gelatin coatedOralLarken Laboratories, Inc2006-04-172010-07-13Us
BE-FLEX PlusPhenyltoloxamine citrate (20 mg/1) + Acetaminophen (300 mg/1) + Salicylamide (200 mg/1)Capsule, gelatin coatedOralLarken Laboratories, Inc.2006-04-172011-10-31Us
Flextra-650Phenyltoloxamine citrate (60 mg/1) + Acetaminophen (650 mg/1)TabletOralPegasus Laboratories2006-09-082011-11-30Us
Flextra-650Phenyltoloxamine citrate (60 mg/1) + Acetaminophen (650 mg/1)TabletOralPoly Pharmaceuticals2006-09-082011-11-30Us
Norel SRPhenyltoloxamine citrate (50 mg/1) + Acetaminophen (325 mg/1) + Chlorpheniramine maleate (8 mg/1) + Phenylephrine hydrochloride (40 mg/1)Tablet, extended releaseOralUs Pharmaceutical Corporation2008-01-012013-03-31Us
RelagesicPhenyltoloxamine citrate (50 mg/1) + Acetaminophen (650 mg/1)TabletOralInternational Ethical Labs.1995-09-162014-01-14Us
Rhinoflex-650Phenyltoloxamine citrate (50 mg/1) + Acetaminophen (650 mg/1)TabletOralCarwin Associates, Inc2000-01-312013-11-21Us
Trital SRPhenyltoloxamine citrate (50 mg/1) + Acetaminophen (325 mg/1) + Chlorpheniramine maleate (8 mg/1) + Phenylephrine hydrochloride (40 mg/1)Tablet, extended releaseOralBreckenridge Pharmaceutical, Inc.2008-03-012011-05-31Us
Categories
UNII
K65LB6598J
CAS number
92-12-6
Weight
Average: 255.361
Monoisotopic: 255.1623143
Chemical Formula
C17H21NO
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

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.

Pharmacodynamics

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.

TargetActionsOrganism
AHistamine H1 receptor
inverse agonist
Mouse
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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.

Toxicity

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.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Phenyltoloxamine H1-Antihistamine ActionDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:23282578]
  2. 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. [PubMed:5492933]
  3. 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. [PubMed:2569485]
  4. 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. [PubMed:821705]
  5. Church DS, Church MK: Pharmacology of antihistamines. World Allergy Organ J. 2011 Mar;4(3 Suppl):S22-7. doi: 10.1097/WOX.0b013e3181f385d9. [PubMed:23282332]
  6. 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. [PubMed:6483639]
  7. 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. [PubMed:13096396]
  8. Prescribing Information: Tussionex Suspension and Tablets [Link]
  9. DailyMed: Dologesic( acetaminophen, phenyltoloxamine citrate, alcool liquid) [Link]
  10. SMPDB: Phenyltoloxamine H1-Antihistamine Action [Link]
External Links
Human Metabolome Database
HMDB0240250
PubChem Compound
7077
PubChem Substance
347827928
ChemSpider
6810
BindingDB
50151046
ChEBI
135047
ChEMBL
CHEMBL186720
Wikipedia
Phenyltoloxamine

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, gelatin coatedOral
LiquidOral
TabletOral
Tablet, extended releaseOral
SuspensionOral
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0423 mg/mLALOGPS
logP3.51ALOGPS
logP3.93ChemAxon
logS-3.8ALOGPS
pKa (Strongest Basic)8.78ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity80.28 m3·mol-1ChemAxon
Polarizability29.99 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0a4i-9000000000-4846204db840aa67d3e1
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Diphenylmethane / Phenoxy compound / Phenol ether / Alkyl aryl ether / Tertiary aliphatic amine / Tertiary amine / Ether / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

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
  1. 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. [PubMed:23282578]

Drug created on December 03, 2015 09:51 / Updated on July 13, 2019 00:55