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Identification
Name Codeine
Accession Number DB00318 (APRD00120)
Type small molecule
Groups illicit, approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Codeine anhydrous
L-Codeine
Methylmorphine
Morphine monomethyl ether
Norcodeine, N-Methyl
Norcodine, N-Methyl
Salts Not Available
Brand names
Name Company
Codicept
Coducept
Brand mixtures
Brand Name Ingredients
Co-codamol codeine + acetaminophen
Categories
  • Narcotics
  • Analgesics
  • Opiate Agonists
  • Antitussives
  • Analgesics, Opioid
  • Antitussive Agents
CAS number 76-57-3
Weight Average: 299.3642
Monoisotopic: 299.152143543
Chemical Formula C18H21NO3
InChI Key InChIKey=OROGSEYTTFOCAN-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Morphine and Derivatives
  • Alkaloids and Alkaloid Derivatives
Substructures
  • Morphinans
  • Benzofurans
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Naphthalenes
  • Phenols and Derivatives
  • Morphine and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Phenylpiperidines
  • Aliphatic and Aryl Amines
  • Catechols
  • Alkaloids and Alkaloid Derivatives
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Phenylpropylamines
  • Alcohols and Polyols
  • Cyclohexenes and Derivatives
  • Phenyl Esters
  • Amphetamines
  • Catecholamines and Derivatives
  • Piperidines
Pharmacology
Indication For treatment and management of pain (Systemic), also used as an Antidiarrheal and as a cough suppressant.
Pharmacodynamics Codeine, an opiate agonist in the CNS, is similar to other phenanthrene derivatives such as morphine. Codeine, in combination with guaifenesin or iodinated glycerol, is used as a cough suppressant and, as a single agent or in combination with acetaminophen or other products, is used for pain control and as an antidiarrheal agent.
Mechanism of action Opiate 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.
Absorption Well absorbed following oral administration with a bioavailability of approximately 90%.
Volume of distribution Not Available
Protein binding 7-25%
Metabolism Hepatic. Codeine is a prodrug, itself inactive, but demethylated to the active morphine by the liver enzyme CYP2D6.
Route of elimination Not Available
Half life 2-4 hours
Clearance Not Available
Toxicity Respiratory 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
Pathway Name SMPDB ID
Smp00405 Codeine Pathway SMP00405
Pharmacoeconomics
Manufacturers
  • Roxane laboratories inc
Packagers
Dosage forms
Form Route Strength
Liquid Intramuscular
Liquid Oral
Solution Intramuscular
Syrup Oral
Tablet Oral
Prices
Unit description Cost Unit
Codeine phosphate powder 8.25 USD g
Codeine Phosphate 30 mg/ml 1.31 USD ml
Codeine sulfate 60 mg tablet 0.86 USD tablet
Codeine sulfate 30 mg tablet 0.76 USD tablet
Codeine ph 30 mg/ml syringe 0.54 USD ml
Codeine ph 15 mg/ml syringe 0.49 USD ml
Codeine sulfate 15 mg tablet 0.43 USD tablet
Ratio-Codeine 30 mg Tablet 0.09 USD tablet
Ratio-Codeine 15 mg Tablet 0.07 USD tablet
Ratio-Codeine 5 mg/ml Syrup 0.03 USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 157.5 °C PhysProp
boiling point 250 °C at 2.20E+01 mm Hg PhysProp
water solubility 9000 mg/L (at 20 °C) YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP 1.19 AVDEEF,A ET AL. (1996)
logS -1.52 ADME Research, USCD
pKa 8.21 (at 25 °C) LIDE,DR (1995)
Predicted Properties
Property Value Source
water solubility 5.77e-01 g/l ALOGPS
logP 1.2 ALOGPS
logP 1.34 ChemAxon
logS -2.7 ALOGPS
pKa (strongest acidic) 13.78 ChemAxon
pKa (strongest basic) 9.19 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 41.93 ChemAxon
rotatable bond count 1 ChemAxon
refractivity 84.6 ChemAxon
polarizability 31.95 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Compound C06174 Link_out
PubChem Compound 5284371 Link_out
PubChem Substance 46507764 Link_out
ChemSpider 4447447 Link_out
ChEBI 16714 Link_out
ChEMBL 16714 Link_out
Therapeutic Targets Database DAP000213 Link_out
PharmGKB PA449088 Link_out
Drug Product Database 593451 Link_out
RxList http://www.rxlist.com/cgi/generic/codphos.htm Link_out
Drugs.com http://www.drugs.com/cdi/codeine-phosphate-soluble-tablets.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Codeine Link_out
ATC Codes
  • N02AA08
  • R05DA04
  • R05DA12
AHFS Codes
  • 48:08.00
  • 28:08.08
PDB Entries Not Available
FDA label Not Available
MSDS show (52.5 KB)
Interactions
Drug Interactions
Drug Interaction
Alvimopan Increases levels by receptor binding competition. Discontinue opioid administration at least 7 days prior to administrating Alvimopan.
Cimetidine Cimetidine 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 barbiturate Quinidine decreases the analgesic effect of codeine
Quinidine Quinidine decreases the analgesic effect of codeine
Quinidine barbiturate Quinidine decreases the analgesic effect of codeine
Terbinafine Terbinafine may decrease the efficacy of Codeine by inhibiting active metabolite production. Consider an alternate analgesic or monitor for effectiveness of Codeine.
Triprolidine The 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

Pharmacological action: yes
Actions: partial agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for beta-endorphin

Organism class: human
UniProt ID: P35372 Link_out
Gene: OPRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: partial agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for dynorphins. May play a role in arousal and regulation of autonomic and neuroendocrine functions

Organism class: human
UniProt ID: P41145 Link_out
Gene: OPRK1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: agonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Highly stereoselective. receptor for enkephalins

Organism class: human
UniProt ID: P41143 Link_out
Gene: OPRD1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19