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Identification
NameDihydrocodeine
Accession NumberDB01551
TypeSmall Molecule
GroupsApproved, Illicit
Description

Dihydrocodeine is an opioid analgesic used as an alternative or adjunct to codeine to treat moderate to severe pain, severe dyspnea, and cough.

It is semi-synthetic, and was developed in Germany in 1908 during an international search to find a more effective antitussive agent to help reduce the spread of airborne infectious diseases such as tuburculosis. It was marketed in 1911. [Wikipedia]

Structure
Thumb
Synonyms
DHC
Remedacen
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
CodidolNot Available
ContugesicNot Available
DehaceNot Available
DF-118 ForteNot Available
DicogesicNot Available
HydrocodinNot Available
RemedacenNot Available
Brand mixtures
NameLabellerIngredients
Acetaminophen, Caffeine, Dihydrocodeine BitartrateXspire Pharma Llc
Aspirin, Caffeine, and Dihydrocodeine BitartrateCaraco Pharmaceutical Laboratories, Ltd
Centussin DhcCenturion Labs, Llc
Dihydrocodeine Bitartrate, Acetaminophen and CaffeinePhysicians Total Care, Inc.
J-cof DhcJay Mac Pharmaceuticals
J-max DhcJay Mac Pharmaceuticals
Poly Hist DhcPoly Pharmaceuticals, Inc.
Poly-tussin EXPoly Pharmaceuticals, Inc.
SynalgosCaraco Pharma Inc.
TrezixWra Ser Llc
Salts
Name/CASStructureProperties
Dihydrocodeine bitartrate
Thumb
  • InChI Key: ZGSZBVAEVPSPFM-HYTSPMEMSA-N
  • Monoisotopic Mass: 451.184231531
  • Average Mass: 451.467
DBSALT000048
Dihydrocodeine hydrobromide
ThumbNot applicableDBSALT000049
Dihydrocodeine hydrochloride
36418-29-8
Thumb
  • InChI Key: VMZXMTVGOAQUEN-FFHNEAJVSA-N
  • Monoisotopic Mass: 337.144471346
  • Average Mass: 337.841
DBSALT000050
Dihydrocodeine hydroiodide
5965-15-1
Thumb
  • InChI Key: QXBJOHDQNJOLNA-PKHFJCIDNA-N
  • Monoisotopic Mass: 429.080087059
  • Average Mass: 429.2925
DBSALT000051
Dihydrocodeine methyliodide
ThumbNot applicableDBSALT000052
Dihydrocodeine phosphate
Thumb
  • InChI Key: HFBYLYCMISIEMM-FFHNEAJVSA-N
  • Monoisotopic Mass: 399.144688703
  • Average Mass: 399.3753
DBSALT000053
Dihydrocodeine sulfate
ThumbNot applicableDBSALT000054
Dihydrocodeine tartrate
ThumbNot applicableDBSALT000055
Categories
UNIIN9I9HDB855
CAS number125-28-0
WeightAverage: 301.3801
Monoisotopic: 301.167793607
Chemical FormulaC18H23NO3
InChI KeyInChIKey=RBOXVHNMENFORY-DNJOTXNNSA-N
InChI
InChI=1S/C18H23NO3/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,4-5,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1
IUPAC Name
(1S,5R,13R,14S,17R)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0¹,¹³.0⁵,¹⁷.0⁷,¹⁸]octadeca-7(18),8,10-trien-14-ol
SMILES
[H][C@@]12OC3=C(OC)C=CC4=C3[C@@]11CCN(C)[C@]([H])(C4)[C@]1([H])CC[C@@H]2O
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassMorphinans
Sub ClassNot Available
Direct ParentMorphinans
Alternative Parents
Substituents
  • Morphinan
  • Benzylisoquinoline
  • Phenanthrene
  • Tetralin
  • Benzofuran
  • Anisole
  • Aralkylamine
  • Alkyl aryl ether
  • Benzenoid
  • Piperidine
  • Cyclic alcohol
  • Tertiary aliphatic amine
  • Tertiary amine
  • Secondary alcohol
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationDihydrocodeine is used for the treatment of moderate to severe pain, including post-operative and dental pain [2]. It can also be used to treat chronic pain [1], breathlessness and coughing. In heroin addicts, dihydrocodeine has been used as a substitute drug, in doses up to 2500mg/day to treat addiction. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014322/]
PharmacodynamicsPossible opioid related side effects include, but are not limited to, drowsiness, nausea, headache, dry mouth, constipation, difficulty passing urine, and mild euphoria.
Mechanism of actionDihydrocodeine is metabolized to dihydromorphine -- a highly active metabolite with a high affinity for mu opioid receptors. [3]
Related Articles
AbsorptionBioavailability is low (approximately 20%) if administered orally. This may be due to poor gastrointestinal absorption. It is also likely due to pre-systemic metabolism by the liver and intestinal wall. [2] The AUCs after oral and intravenous administration are similar (3203ug/l/h and 3401ug/l/h, respectively). [2] Time to peak values are 1.6 and 1.8hours for a 30mg and 60mg dose, respectively. The concentrations achieved were 71.8 ug/1 and 146 ug/1, respectively. [2]
Volume of distribution

The disposition of dihydrocodeine is described as a two compartment model. 2

Protein bindingNot Available
Metabolism

Metabolized in the liver by CYP 2D6 into an active metabolite, dihydromorphine, and by CYP 3A4 into secondary primary metabolite, nordihydrocodeine. A third primary metabolite is dihydrocodeine-6-glucuronide. [1] The time for mean peak concentration in acid metabolites is 1.76h and 1.98h for a 30 and 60mg dose, respectively. The concentrations achieved were 563 ug/1 and 1476 ug/1, respectively. [2]

Route of eliminationRenal elimination and urinary excretion. [1]
Half life4h
Clearance

Plasma clearance is approximately 300ml/min. 2

The pharmacokinetics of dihydrocodeine and active metabolite dihydromorphine have been reported to be linear. 1

The decline in plasma dihydrocodeine concentrations after intravenous administration has been described as bi-exponential, with a sleep decline in the initial 2h following administration, followed by a mono-exponential decline thereafter. Clearance was not dose dependent. 2

ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9942
Blood Brain Barrier+0.9974
Caco-2 permeable+0.8388
P-glycoprotein substrateSubstrate0.8754
P-glycoprotein inhibitor IInhibitor0.5937
P-glycoprotein inhibitor IINon-inhibitor0.9652
Renal organic cation transporterInhibitor0.5676
CYP450 2C9 substrateNon-substrate0.831
CYP450 2D6 substrateSubstrate0.9143
CYP450 3A4 substrateSubstrate0.7941
CYP450 1A2 substrateNon-inhibitor0.8554
CYP450 2C9 inhibitorNon-inhibitor0.9074
CYP450 2D6 inhibitorInhibitor0.7395
CYP450 2C19 inhibitorNon-inhibitor0.7689
CYP450 3A4 inhibitorNon-inhibitor0.8114
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.957
Ames testNon AMES toxic0.8074
CarcinogenicityNon-carcinogens0.9522
BiodegradationNot ready biodegradable0.9857
Rat acute toxicity2.9382 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9058
hERG inhibition (predictor II)Non-inhibitor0.8246
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral
Liquidoral
Tabletoral
Syruporal
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point112.5 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility2.38 mg/mLALOGPS
logP1.58ALOGPS
logP1.55ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)14.15ChemAxon
pKa (Strongest Basic)9.33ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area41.93 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity83.64 m3·mol-1ChemAxon
Polarizability32.82 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Igor Likhotvorik, “Preparation of dihydrocodeine from codeine.” U.S. Patent US06887999, issued May 03, 2005.

US06887999
General References
  1. Ammon S, Hofmann U, Griese EU, Gugeler N, Mikus G: Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing. Br J Clin Pharmacol. 1999 Sep;48(3):317-22. [PubMed:10510141 ]
  2. Rowell FJ, Seymour RA, Rawlins MD: Pharmacokinetics of intravenous and oral dihydrocodeine and its acid metabolites. Eur J Clin Pharmacol. 1983;25(3):419-24. [PubMed:6628531 ]
  3. Schmidt H, Vormfelde SV, Walchner-Bonjean M, Klinder K, Freudenthaler S, Gleiter CH, Gundert-Remy U, Skopp G, Aderjan R, Fuhr U: The role of active metabolites in dihydrocodeine effects. Int J Clin Pharmacol Ther. 2003 Mar;41(3):95-106. [PubMed:12665158 ]
External Links
ATC CodesN02AA08N02AA58
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AbciximabDihydrocodeine may increase the anticoagulant activities of Abciximab.
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Dihydrocodeine.
AcenocoumarolDihydrocodeine may increase the anticoagulant activities of Acenocoumarol.
AcepromazineAcepromazine may increase the hypotensive activities of Dihydrocodeine.
AcetazolamideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Acetazolamide.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Acetylsalicylic acid.
AlteplaseDihydrocodeine may increase the anticoagulant activities of Alteplase.
AmilorideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Amiloride.
AmitriptylineAmitriptyline may increase the antiplatelet activities of Dihydrocodeine.
AmphetamineAmphetamine may increase the analgesic activities of Dihydrocodeine.
AnistreplaseDihydrocodeine may increase the anticoagulant activities of Anistreplase.
AzelastineDihydrocodeine may increase the central nervous system depressant (CNS depressant) activities of Azelastine.
BaclofenThe risk or severity of adverse effects can be increased when Baclofen is combined with Dihydrocodeine.
BendroflumethiazideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Bendroflumethiazide.
BenzphetamineThe risk or severity of adverse effects can be increased when Benzphetamine is combined with Dihydrocodeine.
BortezomibThe metabolism of Dihydrocodeine can be decreased when combined with Bortezomib.
BrimonidineBrimonidine may increase the central nervous system depressant (CNS depressant) activities of Dihydrocodeine.
BumetanideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Bumetanide.
ButorphanolButorphanol may decrease the analgesic activities of Dihydrocodeine.
CathinoneCathinone may increase the analgesic activities of Dihydrocodeine.
ChlorothiazideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Chlorothiazide.
ChlorphentermineThe risk or severity of adverse effects can be increased when Chlorphentermine is combined with Dihydrocodeine.
ChlorthalidoneThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Chlorthalidone.
Citric AcidDihydrocodeine may increase the anticoagulant activities of Citric Acid.
ClenbuterolThe risk or severity of adverse effects can be increased when Clenbuterol is combined with Dihydrocodeine.
CollagenaseThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Collagenase.
CyclothiazideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Cyclothiazide.
DalteparinDihydrocodeine may increase the anticoagulant activities of Dalteparin.
DesmopressinThe risk or severity of adverse effects can be increased when Desmopressin is combined with Dihydrocodeine.
DexketoprofenThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Dexketoprofen.
DiclofenamideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Diclofenamide.
DicoumarolDihydrocodeine may increase the anticoagulant activities of Dicoumarol.
DobutamineThe risk or severity of adverse effects can be increased when Dobutamine is combined with Dihydrocodeine.
DopamineThe risk or severity of adverse effects can be increased when Dopamine is combined with Dihydrocodeine.
DoxofyllineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Doxofylline.
Edetic AcidDihydrocodeine may increase the anticoagulant activities of Edetic Acid.
EluxadolineDihydrocodeine may increase the activities of Eluxadoline.
EnoxaparinDihydrocodeine may increase the anticoagulant activities of Enoxaparin.
EpinephrineThe risk or severity of adverse effects can be increased when Epinephrine is combined with Dihydrocodeine.
Etacrynic acidThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Ethacrynic acid.
EthanolThe risk or severity of adverse effects can be increased when Ethanol is combined with Dihydrocodeine.
EthoxzolamideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Ethoxzolamide.
Ethyl biscoumacetateDihydrocodeine may increase the anticoagulant activities of Ethyl biscoumacetate.
FenoterolThe risk or severity of adverse effects can be increased when Fenoterol is combined with Dihydrocodeine.
FludrocortisoneThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Fludrocortisone.
FluvoxamineThe metabolism of Dihydrocodeine can be decreased when combined with Fluvoxamine.
Fondaparinux sodiumDihydrocodeine may increase the anticoagulant activities of Fondaparinux sodium.
FormoterolThe risk or severity of adverse effects can be increased when Formoterol is combined with Dihydrocodeine.
FurosemideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Furosemide.
HeparinDihydrocodeine may increase the anticoagulant activities of Heparin.
HomoharringtonineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Homoharringtonine.
HydrochlorothiazideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Hydrochlorothiazide.
HydroflumethiazideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Hydroflumethiazide.
IcosapentThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Icosapent.
IndapamideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Indapamide.
Insulin HumanDihydrocodeine may increase the hypoglycemic activities of Insulin Regular.
IobenguaneThe therapeutic efficacy of Iobenguane can be decreased when used in combination with Dihydrocodeine.
IsoprenalineThe risk or severity of adverse effects can be increased when Isoprenaline is combined with Dihydrocodeine.
KetorolacThe risk or severity of adverse effects can be increased when Ketorolac is combined with Dihydrocodeine.
LabetalolThe risk or severity of adverse effects can be increased when Labetalol is combined with Dihydrocodeine.
LimaprostLimaprost may increase the antiplatelet activities of Dihydrocodeine.
LorazepamThe risk or severity of adverse effects can be increased when Lorazepam is combined with Dihydrocodeine.
MephentermineThe risk or severity of adverse effects can be increased when Mephentermine is combined with Dihydrocodeine.
MetaraminolThe risk or severity of adverse effects can be increased when Metaraminol is combined with Dihydrocodeine.
MethamphetamineThe risk or severity of adverse effects can be increased when Methamphetamine is combined with Dihydrocodeine.
MethoxamineThe risk or severity of adverse effects can be increased when Methoxamine is combined with Dihydrocodeine.
MetolazoneThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Metolazone.
MexiletineThe metabolism of Dihydrocodeine can be decreased when combined with Mexiletine.
MidodrineThe risk or severity of adverse effects can be increased when Midodrine is combined with Dihydrocodeine.
NaphazolineThe risk or severity of adverse effects can be increased when Naphazoline is combined with Dihydrocodeine.
NicorandilThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Nicorandil.
NorepinephrineThe risk or severity of adverse effects can be increased when Norepinephrine is combined with Dihydrocodeine.
Omega-3 fatty acidsOmega-3 fatty acids may increase the antiplatelet activities of Dihydrocodeine.
OrciprenalineThe risk or severity of adverse effects can be increased when Orciprenaline is combined with Dihydrocodeine.
OxymetazolineThe risk or severity of adverse effects can be increased when Oxymetazoline is combined with Dihydrocodeine.
ParoxetineParoxetine may increase the antiplatelet activities of Dihydrocodeine.
PerindoprilDihydrocodeine may decrease the antihypertensive activities of Perindopril.
PhenindioneDihydrocodeine may increase the anticoagulant activities of Phenindione.
PhenmetrazineThe risk or severity of adverse effects can be increased when Phenmetrazine is combined with Dihydrocodeine.
PhenprocoumonDihydrocodeine may increase the anticoagulant activities of Phenprocoumon.
PhentermineThe risk or severity of adverse effects can be increased when Phentermine is combined with Dihydrocodeine.
PhenylephrineThe risk or severity of adverse effects can be increased when Phenylephrine is combined with Dihydrocodeine.
PhenylpropanolamineThe risk or severity of adverse effects can be increased when Phenylpropanolamine is combined with Dihydrocodeine.
ProcyclidineThe risk or severity of adverse effects can be increased when Procyclidine is combined with Dihydrocodeine.
QuinidineQuinidine may decrease the analgesic activities of Dihydrocodeine.
RamosetronDihydrocodeine may increase the activities of Ramosetron.
ReteplaseDihydrocodeine may increase the anticoagulant activities of Reteplase.
RidogrelDihydrocodeine may increase the anticoagulant activities of Ridogrel.
RitodrineThe risk or severity of adverse effects can be increased when Ritodrine is combined with Dihydrocodeine.
SalmeterolThe risk or severity of adverse effects can be increased when Salmeterol is combined with Dihydrocodeine.
SpironolactoneThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Spironolactone.
StreptokinaseDihydrocodeine may increase the anticoagulant activities of Streptokinase.
SulodexideDihydrocodeine may increase the anticoagulant activities of Sulodexide.
TalniflumateThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Talniflumate.
TenecteplaseDihydrocodeine may increase the anticoagulant activities of Tenecteplase.
TerbutalineThe risk or severity of adverse effects can be increased when Terbutaline is combined with Dihydrocodeine.
TicrynafenThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Ticrynafen.
TorasemideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Torasemide.
TositumomabThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Tositumomab.
TreprostinilDihydrocodeine may increase the anticoagulant activities of Treprostinil.
TriamtereneThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Triamterene.
TrichlormethiazideThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with Trichlormethiazide.
UrokinaseDihydrocodeine may increase the anticoagulant activities of Urokinase.
Valproic AcidThe serum concentration of Valproic Acid can be increased when it is combined with Dihydrocodeine.
VenlafaxineVenlafaxine may increase the antiplatelet activities of Dihydrocodeine.
Vitamin EVitamin E may increase the antiplatelet activities of Dihydrocodeine.
WarfarinDihydrocodeine may increase the anticoagulant activities of Warfarin.
Food Interactions
  • Alcohol may enhance CNS depressant effects

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
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.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on July 31, 2007 07:10 / Updated on December 08, 2015 14:30