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Identification
NameCodeine
Accession NumberDB00318  (APRD00120)
Typesmall molecule
Groupsapproved, illicit
Description

An opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-olNot AvailableIUPAC
3-MethylmorphinNot AvailableIS
3-methylmorphineNot AvailableNot Available
CodeinGermanPh. Eur. 7
CodeínaSpanishINN
CodéineNot AvailableDCF
Codeine anhydrousNot AvailableNot Available
CodeinumNot AvailablePh. Eur. 7
L-CodeineNot AvailableNot Available
MethylmorphineNot AvailableNot Available
morphine 3-methyl etherNot AvailableNot Available
Morphine monomethyl etherNot AvailableNot Available
morphine monomethyl etherNot AvailableNot Available
morphine-3-methyl etherNot AvailableNot Available
Salts
Name/CAS Structure Properties
Codeine Hydrochloride
Thumb Not applicable DBSALT001068
Codeine Phosphate
52-28-8
Thumb
  • InChI Key: WUXLCJZUUHIXFY-FFHNEAJVSA-N
  • Monoisotopic Mass: 397.129038639
  • Average Mass: 397.3594
DBSALT000030
Codeine Sulfate
6854-40-6
Thumb
  • InChI Key: REJWPZYIFAQSIK-FFHNEAJVSA-N
  • Monoisotopic Mass: 397.119522785
  • Average Mass: 397.443
DBSALT000031
Brand names
NameCompany
ActacodeSigma
BisoltusBoehringer Ingelheim
BromopharQualiphar
BronchicumSanofi-Aventis
BronchodinePharmacobel
CodantAntigen
CodedrillPierre Fabre
CodeinCristália
CodeisanBelmac
CoderpinaFrycia Centro América
CodicalmWelti
CodinexPinewood
CougelHwang's
CoutanMey See
DincoCenter
FarmacodFarmacom
GalcodineThornton & Ross
PectoralSiphat
TussoretMaxMedic
Brand mixtures
Brand NameIngredients
Allfen CD; Allfen CDX; Codar® GF; Dex-Tuss; Guaiatussin AC; Iophen C-NR; M-Clear; M-Clear WC; Mar-Cof® CG; Robafen ACGuaifenesin and Codeine
Ascomp® with Codeine; Fiorinal® with Codeine; Fiorinal®-C 1/2; Fiorinal®-C 1/4; Tecnal C 1/2; Tecnal C 1/4Butalbital, Aspirin, Caffeine, and Codeine
Benylin® 3.3 mg-D-E; Calmylin with CodeineGuaifenesin, Pseudoephedrine, and Codeine
CoActifed®; Covan®; ratio-CotridinTriprolidine, Pseudoephedrine, and Codeine
Codar® D; EndaCof-DC; Notuss®-DCPseudoephedrine and Codeine
Fioricet® with CodeineButalbital, Acetaminophen, Caffeine, and Codeine
Mersyndol® With CodeineAcetaminophen, Codeine, and Doxylamine
Phenylhistine DH [OTC]; Tricode® ARChlorpheniramine, Pseudoephedrine, and Codeine
ratio-Emtec; ratio-Lenoltec; Triatec-30; Triatec-8; Triatec-8 Strong; Tylenol Elixir with Codeine; Tylenol No. 1; Tylenol No. 1 Forte; Tylenol No. 2 with Codeine; Tylenol No. 3 with Codeine; Tylenol No. 4 with CodeineAcetaminophen and Codeine
Triacin-CCodeine + Triprolidine + Pseudoephedrine
Categories
CAS number76-57-3
WeightAverage: 299.3642
Monoisotopic: 299.152143543
Chemical FormulaC18H21NO3
InChI KeyOROGSEYTTFOCAN-DNJOTXNNSA-N
InChI
InChI=1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3-6,11-13,17,20H,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1
IUPAC Name
(1S,5R,13R,14S,17R)-10-methoxy-4-methyl-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(OC)C=CC4=C3[C@@]11CCN(C)[C@]([H])(C4)[C@]1([H])C=C[C@@H]2O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassAlkaloids and Derivatives
ClassMorphinans
SubclassNot Available
Direct parentMorphinans
Alternative parentsBenzylisoquinolines; Phenanthrenes and Derivatives; Tetralins; Benzofurans; Anisoles; Alkyl Aryl Ethers; Piperidines; Secondary Alcohols; Tertiary Amines; Polyamines
Substituentsphenanthrene; tetralin; benzofuran; anisole; phenol ether; alkyl aryl ether; benzene; piperidine; secondary alcohol; tertiary amine; polyamine; ether; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the 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.
Pharmacology
IndicationFor treatment and management of pain (systemic). It is also used as an antidiarrheal and as a cough suppressant.
PharmacodynamicsCodeine, an opiate agonist in the CNS, is similar to other phenanthrene derivatives such as morphine. It is selective for the mu receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine. The principle therapeutic action is analgesia. Codeine concentrations do not correlate with brain concentration or relief of pain. The minimum effective concentration is highly variable is influenced by numerous factors, including but not limited to, age, previous opioid use, age, and general medical condition. However, the effective dose for patients that have developed tolerance is significantly higher than the opioid-naive patients.
Mechanism of actionOpiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
AbsorptionWell absorbed following oral administration with a bioavailability of approximately 90%. Maximum plasma concentration occurs 60 minutes post-administration. Food does not effect the rate or extent of absorption of codeine.
Volume of distribution

Apparent volume of distribution = 3-6 L/kg

Protein binding7-25% bound to plasma proteins.
Metabolism

Hepatic. Codeine is a prodrug, itself inactive, but demethylated to the active morphine by the liver enzyme CYP2D6 to morphine. 70-80% of the dose undergoes glucuronidation to form codeine-6-glucuronide. This process is mediated by UDP-glucuronosyltransferase UGT2B7 and UGT2B4. 5-10% of the dose undergoes O-demethylation to morphine and 10% undergoes N-demethylation to form norcodeine. CYP2D6 mediates the biotransformation to morphine. CYP3A4 is the enzymes that mediates the conversion to norcodiene. Morphine and norcodeine are further metabolized and undergo glucuronidation. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Both morphine and morphine-6-glucuronide are active and have analgesic activity. Norcodiene and M3G do not have any analgesic properties.

SubstrateEnzymesProduct
Codeine
morphineDetails
Codeine
norcodeineDetails
Codeine
Codeine-6-glucuronideDetails
Route of elimination90% of the total dose of codeine is excreted through the kidneys, of which 10% is unchanged codeine.
Half lifePlasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours.
ClearanceNot Available
ToxicityRespiratory depression, sedation and miosis and common symptoms of overdose. Other symptoms include nausea, vomiting, skeletal muscle flaccidity, bradycardia, hypotension, and cool, clammy skin. Apnea and death may ensue.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Codeine Action PathwayDrug actionSMP00405
Codeine Metabolism PathwayDrug metabolismSMP00621
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
rs3892097 CYP2D6*4A Allele, homozygotePoor drug metabolizer, lower dose requirements1782973
Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
rs5030655 CYP2D6*6T deletion, homozygotePoor drug metabolizer, lower dose requirements1782973
Cytochrome P450 2D6
Gene symbol: CYP2D6
UniProt: P10635
Not AvailableCYP2D6*5Deletion, homozygotePoor drug metabolizer, lower dose requirements1782973
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9966
Blood Brain Barrier + 0.9979
Caco-2 permeable + 0.8867
P-glycoprotein substrate Substrate 0.8631
P-glycoprotein inhibitor I Inhibitor 0.5435
P-glycoprotein inhibitor II Non-inhibitor 0.8724
Renal organic cation transporter Inhibitor 0.638
CYP450 2C9 substrate Non-substrate 0.7698
CYP450 2D6 substrate Substrate 0.9274
CYP450 3A4 substrate Substrate 0.7796
CYP450 1A2 substrate Non-inhibitor 0.6494
CYP450 2C9 substrate Non-inhibitor 0.8866
CYP450 2D6 substrate Inhibitor 0.6978
CYP450 2C19 substrate Non-inhibitor 0.8256
CYP450 3A4 substrate Non-inhibitor 0.8899
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.747
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.9567
Biodegradation Not ready biodegradable 0.9935
Rat acute toxicity 2.8450 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8556
hERG inhibition (predictor II) Non-inhibitor 0.8615
Pharmacoeconomics
Manufacturers
  • Roxane laboratories inc
Packagers
Dosage forms
FormRouteStrength
Injection, solutionParenteral15 mg/mL; 30 mg/mL
SolutionOral30 mg/5 mL
TabletOral15 mg, 30 mg, 60 mg
Tablet, delayed releaseOral50 mg, 100 mg, 150 mg, 200 mg
Prices
Unit descriptionCostUnit
Codeine phosphate powder8.25USDg
Codeine Phosphate 30 mg/ml1.31USDml
Codeine sulfate 60 mg tablet0.86USDtablet
Codeine sulfate 30 mg tablet0.76USDtablet
Codeine ph 30 mg/ml syringe0.54USDml
Codeine ph 15 mg/ml syringe0.49USDml
Codeine sulfate 15 mg tablet0.43USDtablet
Ratio-Codeine 30 mg Tablet0.09USDtablet
Ratio-Codeine 15 mg Tablet0.07USDtablet
Ratio-Codeine 5 mg/ml Syrup0.03USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point157.5 °CPhysProp
boiling point250 °C at 2.20E+01 mm HgPhysProp
water solubility9000 mg/L (at 20 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP1.19AVDEEF,A ET AL. (1996)
logS-1.52ADME Research, USCD
pKa8.21 (at 25 °C)LIDE,DR (1995)
Predicted Properties
PropertyValueSource
water solubility5.77e-01 g/lALOGPS
logP1.2ALOGPS
logP1.34ChemAxon
logS-2.7ALOGPS
pKa (strongest acidic)13.78ChemAxon
pKa (strongest basic)9.19ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count1ChemAxon
polar surface area41.93ChemAxon
rotatable bond count1ChemAxon
refractivity84.6ChemAxon
polarizability31.95ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Nagaraj R. Ayyangar, Anil R. Choudhary, Uttam R. Kalkote, Vasant K. Sharma, “Process for the preparation of codeine from morphine.” U.S. Patent US4764615, issued May, 1912.

US4764615
General Reference
  1. Schroeder K, Fahey T: Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001831. Pubmed
  2. Vree TB, van Dongen RT, Koopman-Kimenai PM: Codeine analgesia is due to codeine-6-glucuronide, not morphine. Int J Clin Pract. 2000 Jul-Aug;54(6):395-8. Pubmed
  3. Srinivasan V, Wielbo D, Tebbett IR: Analgesic effects of codeine-6-glucuronide after intravenous administration. Eur J Pain. 1997;1(3):185-90. Pubmed
External Links
ResourceLink
KEGG DrugD03580
KEGG CompoundC06174
PubChem Compound5284371
PubChem Substance46507764
ChemSpider4447447
ChEBI16714
ChEMBLCHEMBL485
Therapeutic Targets DatabaseDAP000213
PharmGKBPA449088
Drug Product Database593451
RxListhttp://www.rxlist.com/cgi/generic/codphos.htm
Drugs.comhttp://www.drugs.com/cdi/codeine-phosphate-soluble-tablets.html
WikipediaCodeine
ATC CodesN02AA08R05DA04R05DA12
AHFS Codes
  • 48:08.00
  • 28:08.08
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(52.5 KB)
Interactions
Drug Interactions
Drug
AlvimopanIncreases levels by receptor binding competition. Discontinue opioid administration at least 7 days prior to administrating Alvimopan.
CimetidineCimetidine may decrease the therapeutic effect of codeine by decreasing its metabolism to its active metabolite, morphine. Monitor for changes in the therapeutic effect of codeine if cimetidine is initiated, discontinued or dose changed.
Dihydroquinidine barbiturateQuinidine decreases the analgesic effect of codeine
QuinidineQuinidine decreases the analgesic effect of codeine
Quinidine barbiturateQuinidine decreases the analgesic effect of codeine
TerbinafineTerbinafine may decrease the efficacy of Codeine by inhibiting active metabolite production. Consider an alternate analgesic or monitor for effectiveness of Codeine.
TriprolidineThe CNS depressants, Triprolidine and Codeine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food Interactions
  • Avoid alcohol.
  • Take with food, food reduces irritation.
  • To avoid constipation: increase your daily intake of fiber (beans, whole grains, vegetables).

Targets

1. Mu-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: partial agonist

Components

Name UniProt ID Details
Mu-type opioid receptor P35372 Details

References:

  1. Grond S, Sablotzki A: Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. Pubmed
  2. Takahama K, Shirasaki T: Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs. Cough. 2007 Jul 9;3:8. Pubmed
  3. Freissmuth M, Beindl W, Kratzel M: Binding and structure-activity-relation of benzo[f]isoquinoline- and norcodeinone-derivatives at mu-opioid receptors in the rat cerebral cortex. Br J Pharmacol. 1993 Dec;110(4):1429-36. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Kappa-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: partial agonist

Components

Name UniProt ID Details
Kappa-type opioid receptor P41145 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Takahama K, Shirasaki T: Central and peripheral mechanisms of narcotic antitussives: codeine-sensitive and -resistant coughs. Cough. 2007 Jul 9;3:8. Pubmed
  4. Mignat C, Wille U, Ziegler A: Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci. 1995;56(10):793-9. Pubmed

3. Delta-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Delta-type opioid receptor P41143 Details

References:

  1. Ortiz MI, Castro-Olguin J, Pena-Samaniego N, Castaneda-Hernandez G: Probable activation of the opioid receptor-nitric oxide-cyclic GMP-K+ channels pathway by codeine. Pharmacol Biochem Behav. 2005 Dec;82(4):695-703. Epub 2006 Jan 4. Pubmed
  2. Mignat C, Wille U, Ziegler A: Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci. 1995;56(10):793-9. Pubmed
  3. Loghin F, Popa DS, Socaciu C: Influence of glutethimide on rat brain mononucleotides by sub-chronic codeine treatment. J Cell Mol Med. 2001 Oct-Dec;5(4):409-16. Pubmed
  4. Advenier C, Girard V, Naline E, Vilain P, Emonds-Alt X: Antitussive effect of SR 48968, a non-peptide tachykinin NK2 receptor antagonist. Eur J Pharmacol. 1993 Nov 30;250(1):169-71. Pubmed
  5. Karlsson JA, Lanner AS, Persson CG: Airway opioid receptors mediate inhibition of cough and reflex bronchoconstriction in guinea pigs. J Pharmacol Exp Ther. 1990 Feb;252(2):863-8. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Zhou SF: Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723. Pubmed
  2. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  3. Duquette PH, Peterson FJ, Crankshaw DL, Lindemann NJ, Holtzman JL: Studies of the metabolic N- and O-demethylation of [6-3H]codeine. Drug Metab Dispos. 1983 Sep-Oct;11(5):477-80. Pubmed
  4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Duquette PH, Peterson FJ, Crankshaw DL, Lindemann NJ, Holtzman JL: Studies of the metabolic N- and O-demethylation of [6-3H]codeine. Drug Metab Dispos. 1983 Sep-Oct;11(5):477-80. Pubmed
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

4. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. UDP-glucuronosyltransferase 2B7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B7 P16662 Details

References:

  1. FDA label

6. UDP-glucuronosyltransferase 2B4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B4 P06133 Details

References:

  1. FDA label

Transporters

1. Solute carrier family 22 member 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 1 O15245 Details

References:

  1. Tzvetkov MV, Pereira JN, Meineke I, Saadatmand AR, Stingl JC, Brockmoller J: Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem Pharmacol. 2013 Jul 5. pii: S0006-2952(13)00390-0. doi: 10.1016/j.bcp.2013.06.019. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:09