Identification

Name
Pholcodine
Accession Number
DB09209
Type
Small Molecule
Groups
Approved, Illicit
Description

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.

Structure
Thumb
Synonyms
Not Available
External IDs
IDS-NP-011(SECT.2)
Categories
UNII
LPP64AWZ7L
CAS number
509-67-1
Weight
Average: 398.4953
Monoisotopic: 398.220557458
Chemical Formula
C23H30N2O4
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[9.6.1.0¹,¹³.0⁵,¹⁷.0⁷,¹⁸]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

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.

Structured Indications
Not Available
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
Human
AKappa-type opioid receptor
antagonist
Human
UDelta-type opioid receptor
antagonist
Human
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 slow[4] 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]

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]

Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolinePholcodine may increase the serotonergic activities of 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.Experimental
AmphetaminePholcodine may increase the serotonergic activities of Amphetamine.Approved, Illicit, Investigational
BenmoxinPholcodine may increase the serotonergic activities of Benmoxin.Withdrawn
BrofarominePholcodine may increase the serotonergic activities of Brofaromine.Experimental
CaroxazonePholcodine may increase the serotonergic activities of Caroxazone.Withdrawn
FurazolidonePholcodine may increase the serotonergic activities of Furazolidone.Approved, Investigational, Vet Approved
HarmalinePholcodine may increase the serotonergic activities of Harmaline.Experimental
HydracarbazinePholcodine may increase the serotonergic activities of Hydracarbazine.Experimental
IproclozidePholcodine may increase the serotonergic activities of Iproclozide.Withdrawn
IproniazidPholcodine may increase the serotonergic activities of Iproniazid.Withdrawn
IsocarboxazidPholcodine may increase the serotonergic activities of Isocarboxazid.Approved
MebanazinePholcodine may increase the serotonergic activities of Mebanazine.Withdrawn
Methylene bluePholcodine may increase the serotonergic activities of Methylene blue.Approved, Investigational
MethylnaltrexoneThe risk or severity of adverse effects can be increased when Pholcodine is combined with Methylnaltrexone.Approved
MinaprinePholcodine may increase the serotonergic activities of Minaprine.Approved
MoclobemidePholcodine may increase the serotonergic activities of Moclobemide.Approved, Investigational
NaloxegolThe risk or severity of adverse effects can be increased when Pholcodine is combined with Naloxegol.Approved
NialamidePholcodine may increase the serotonergic activities of Nialamide.Withdrawn
OctamoxinPholcodine may increase the serotonergic activities of Octamoxin.Withdrawn
PargylinePholcodine may increase the serotonergic activities of Pargyline.Approved
PhenelzinePholcodine may increase the serotonergic activities of Phenelzine.Approved
PheniprazinePholcodine may increase the serotonergic activities of Pheniprazine.Withdrawn
PhenoxypropazinePholcodine may increase the serotonergic activities of Phenoxypropazine.Withdrawn
PirlindolePholcodine may increase the serotonergic activities of Pirlindole.Approved
PivhydrazinePholcodine may increase the serotonergic activities of Pivhydrazine.Withdrawn
ProcarbazinePholcodine may increase the serotonergic activities of Procarbazine.Approved, Investigational
RasagilinePholcodine may increase the serotonergic activities of Rasagiline.Approved
SafrazinePholcodine may increase the serotonergic activities of Safrazine.Withdrawn
SelegilinePholcodine may increase the serotonergic activities of Selegiline.Approved, Investigational, Vet Approved
ToloxatonePholcodine may increase the serotonergic activities of Toloxatone.Approved
TranylcyprominePholcodine may increase the serotonergic activities of Tranylcypromine.Approved, Investigational
Food Interactions
Not Available

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. [PubMed:3190994]
  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. [PubMed:23283141]
  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. [PubMed:9804079]
  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. [PubMed:3741728]
  5. Australian government [Link]
  6. United Nations Office on Drugs and Crime [Link]
  7. WHO [Link]
External Links
Human Metabolome Database
HMDB0041984
KEGG Drug
D07385
PubChem Compound
5311356
PubChem Substance
310265116
ChemSpider
4470854
ChEBI
53579
ChEMBL
CHEMBL2105224
Wikipedia
Pholcodine
ATC Codes
R05DA08 — Pholcodine
MSDS
Download (51.7 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
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-MSNot Available
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 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
Morphinan / Phenanthrene / Tetralin / Coumaran / Alkyl aryl ether / Aralkylamine / Morpholine / Oxazinane / Piperidine / Benzenoid
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
morphinane alkaloid, organic heteropentacyclic compound (CHEBI:53579)

Targets

Kind
Protein
Organism
Human
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
Human
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
Human
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 on October 20, 2015 13:39 / Updated on May 01, 2018 23:57