Pholcodine

Identification

Summary

Pholcodine is an opioid antitussive used to suppress unproductive coughing.

Generic Name
Pholcodine
DrugBank Accession Number
DB09209
Background

Pholcodine formula is 3-o-morpholinoethylmorphine and it is classified as an antitussive which is defined as an opioid cough suppressant. It belongs to the opioid family of compounds and it is widely used.1 Pholcodine activity is the suppression of unproductive cough and it also has a mild sedative effect with little or no analgesic effects.2 Pholcodine is not prescribed in the United States where it is classed as a Schedule I drug. It is categorized as Class B drug in the UK and officially taken out of the shelves in 2008. Pholcodine is not approved in Canada.

Type
Small Molecule
Groups
Approved, Illicit
Structure
Weight
Average: 398.4953
Monoisotopic: 398.220557458
Chemical Formula
C23H30N2O4
Synonyms
  • folcodina
  • Pholcodine
External IDs
  • IDS-NP-011(SECT.2)

Pharmacology

Indication

Pholcodine is indicated as a cough suppressant for the temporary relief of non-productive dry cough. It is stated to present a required label indication of "temporary relief of dry cough."5 Cough is the respiratory movement that occurs after an irritation signal is transmitted to the central nervous system and further stimulates the medulla oblongata. This stimulation causes a motor output that is sent through motoneurons to the respiratory muscles. A non-productive cough is a type of cough characterized by the absence of sputum, and it has a large inspiration that will cause continuous coughing.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination for symptomatic treatment ofCough caused by common coldCombination Product in combination with: Triprolidine (DB00427)•••••••••••••••••
Symptomatic treatment ofCoughing••••••••••••
Used in combination for symptomatic treatment ofFlu like symptomCombination Product in combination with: Triprolidine (DB00427)•••••••••••••••••
Symptomatic treatment ofFlu caused by influenza••••••••••••
Used in combination for symptomatic treatment ofIrritative coughCombination Product in combination with: Triprolidine (DB00427)•••••••••••••••••
Contraindications & Blackbox Warnings
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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.6 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.7

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."7

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Humans
AKappa-type opioid receptor
antagonist
Humans
UDelta-type opioid receptor
antagonist
Humans
Absorption

After oral administration of 60 mg of pholcodine, the Tmax and Cmax are reported to be 1.3 hours and 26.3 ng/ml. In the same administration, the AUC in plasma and saliva are reported to be 1.67 and 6.61 mg h/l respectively. The absorption of pholcodine is reported to represent approximately 88% of the administered dose.1

Volume of distribution

The reported volume of distribution depends on the pharmacokinetic model and it can be of 265L based on a one-compartment model to 3207L in a two-compartment model.4

Protein binding

The protein binding of pholcodine is of approximately of 21-23% and it tends to have a slight variation depending if the administration is chronic.1

Metabolism

The metabolism of pholcodine seems to be very slow4 and due to the elimination profile, it is thought that most of the administered dose undergoes metabolism. There is some evidence in preclinical trials that indicate that morphine is a minor metabolite of pholcodine and that it accounts for 1% of the administered dose.1

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Route of elimination

After oral administration of pholcodine, the serum concentration peaks and declines in a monoexponential manner. The percent of the dose excreted unchanged is of approximately 25-30%. Part of the administered dose is composed by metabolites that can be recovered in urine. From the administered dose, the fecal excretion corresponds to the 5% of the administered dose as unchanged pholcodine.1

Half-life

After oral administration of 60 mg of pholcodine, the half-life in plasma, saliva and urine are 45, 55 and 45 hours respectively.1

Clearance

After oral administration of 60 mg of pholcodine, the clearance rate was reported to be 126 ml/min.1

Adverse Effects
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Toxicity

Generally, pholcodine is significantly less toxic than codeine. Nonetheless, it is important to consider the significant depressive respiratory effect.7

Pathways
Not Available
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.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Pholcodine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Pholcodine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Pholcodine which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Pholcodine which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Pholcodine which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
Not Available

Products

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Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DHACODINE SYRUP 15 mg/5 mlSyrup15 mg/5mlOralDRUG HOUSES OF AUSTRALIA PTE. LTD.1989-12-06Not applicableSingapore flag
DURO-TUSS FORTE COUGH LIQUID 45 mg/15 mlElixir45 mg/15mLOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED1993-01-18Not applicableSingapore flag
DURO-TUSS REGULAR COUGH LIQUID 15 mg/15 mlElixir15 mg/15mlOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED1993-01-18Not applicableSingapore flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Difflam? Blackcurrant Sugar Free Cough LozengesPholcodine (5.5 mg) + Benzydamine hydrochloride (1.5 mg) + Cetylpyridinium chloride (1.33 mg)LozengeOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED2009-01-22Not applicableSingapore flag
DURO-TUSS DECONGESTANT LINCTUSPholcodine (15 mg/15ml) + Pseudoephedrine hydrochloride (60 mg/15ml)ElixirOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED1994-02-02Not applicableSingapore flag
Duro-Tuss Dry Cough Lozenges (Orange flavoured)Pholcodine (5.5 mg) + Cetylpyridinium chloride (1.33 mg)LozengeOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED1999-01-21Not applicableSingapore flag
DURO-TUSS EXPECTORANT COUGH LIQUIDPholcodine (15 mg/15mL) + Bromhexine hydrochloride (12 mg/15mL)ElixirOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED1994-02-02Not applicableSingapore flag
Duro-Tuss? Lemon Dry Cough LozengesPholcodine (5.50 mg) + Cetylpyridinium chloride (1.33 mg)LozengeOralINOVA PHARMACEUTICALS (SINGAPORE) PTE. LIMITED2010-07-04Not applicableSingapore flag

Categories

ATC Codes
R05DA08 — Pholcodine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Morphinans
Sub Class
Not Available
Direct Parent
Morphinans
Alternative Parents
Phenanthrenes and derivatives / Tetralins / Coumarans / Aralkylamines / Alkyl aryl ethers / Piperidines / Morpholines / Trialkylamines / Secondary alcohols / Oxacyclic compounds
show 4 more
Substituents
Alcohol / Alkyl aryl ether / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Coumaran / Dialkyl ether / Ether
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
morphinane alkaloid, organic heteropentacyclic compound (CHEBI:53579)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
LPP64AWZ7L
CAS number
509-67-1
InChI Key
GPFAJKDEDBRFOS-FKQDBXSBSA-N
InChI
InChI=1S/C23H30N2O4/c1-24-7-6-23-16-3-4-18(26)22(23)29-21-19(5-2-15(20(21)23)14-17(16)24)28-13-10-25-8-11-27-12-9-25/h2-5,16-18,22,26H,6-14H2,1H3/t16-,17+,18-,22-,23-/m0/s1
IUPAC Name
(1S,5R,13R,14S,17R)-4-methyl-10-[2-(morpholin-4-yl)ethoxy]-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10,15-tetraen-14-ol
SMILES
[H][C@@]12OC3=C(OCCN4CCOCC4)C=CC4=C3[C@@]11CCN(C)[C@]([H])(C4)[C@]1([H])C=C[C@@H]2O

References

General References
  1. Chen ZR, Bochner F, Somogyi A: Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies. Br J Clin Pharmacol. 1988 Oct;26(4):445-53. [Article]
  2. Florvaag E, Johansson SG: The Pholcodine Case. Cough Medicines, IgE-Sensitization, and Anaphylaxis: A Devious Connection. World Allergy Organ J. 2012 Jul;5(7):73-8. doi: 10.1097/WOX.0b013e318261eccc. [Article]
  3. Murata A, Taniguchi Y, Hashimoto Y, Kaneko Y, Takasaki Y, Kudoh S: Discrimination of productive and non-productive cough by sound analysis. Intern Med. 1998 Sep;37(9):732-5. [Article]
  4. Findlay JW, Fowle AS, Butz RF, Jones EC, Weatherley BC, Welch RM, Posner J: Comparative disposition of codeine and pholcodine in man after single oral doses. Br J Clin Pharmacol. 1986 Jul;22(1):61-71. [Article]
  5. Australian government [Link]
  6. United Nations Office on Drugs and Crime [Link]
  7. WHO [Link]
Human Metabolome Database
HMDB0041984
KEGG Drug
D07385
PubChem Compound
5311356
PubChem Substance
310265116
ChemSpider
4470854
RxNav
33431
ChEBI
53579
ChEMBL
CHEMBL2105224
ZINC
ZINC000004217287
Wikipedia
Pholcodine
MSDS
Download (51.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableCompletedTreatmentCoronavirus Disease 2019 (COVID‑19)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SyrupOral15 mg/5ml
LozengeOral
LozengeOral1.5 mg
ElixirOral15 mg/15ml
LozengeOral1.33 mg
ElixirOral12 mg/15mL
SolutionOral
ElixirOral45 mg/15mL
ElixirOral15 mg/15ml
LiquidOral
SyrupOral5 mg/15ml
SyrupOral5 mg/5ml
SyrupOral
LiquidOral
SyrupOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)91ºC'MSDS'
boiling point (°C)577.8ºC at 760 mmHg'MSDS'
water solubilitySlightly soluble'MSDS'
logP1.08Molbase
pKa9.3Moffat, 1986
Predicted Properties
PropertyValueSource
Water Solubility0.489 mg/mLALOGPS
logP1.09ALOGPS
logP1.14Chemaxon
logS-2.9ALOGPS
pKa (Strongest Acidic)13.78Chemaxon
pKa (Strongest Basic)9.19Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area54.4 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity111.7 m3·mol-1Chemaxon
Polarizability43.76 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
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-MSsplash10-0udi-4129000000-92c59129a2ae67580584
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-0009000000-33300690f92a51d6bd52
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-2009000000-1a8376c31fc01e70e8b3
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0029000000-f1945a4d948887372fbb
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-2109000000-6355e2d3cb4e3b7c38f3
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-1097000000-1cce7d6eefc76feb9753
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-03ka-6109000000-36b4cdbfe257518cee62
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-200.7849795
predicted
DarkChem Lite v0.1.0
[M-H]-193.37703
predicted
DeepCCS 1.0 (2019)
[M+H]+200.1250795
predicted
DarkChem Lite v0.1.0
[M+H]+196.6371
predicted
DeepCCS 1.0 (2019)
[M+Na]+200.6316795
predicted
DarkChem Lite v0.1.0
[M+Na]+204.13437
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. EMBL-EBI [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da
References
  1. EMBL-EBI [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. EMBL-EBI [Link]

Drug created at October 20, 2015 19:39 / Updated at May 07, 2021 21:06