Identification

Name
Dihydrocodeine
Accession Number
DB01551
Type
Small Molecule
Groups
Approved, 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.

Structure
Thumb
Synonyms
  • DHC
External IDs
IDS-ND-008(SECT.2) / NSC-231319
Product Ingredients
IngredientUNIICASInChI Key
Dihydrocodeine bitartrate8LXS95BSA95965-13-9ZGSZBVAEVPSPFM-HYTSPMEMSA-N
Dihydrocodeine hydrochloride9073288YPO36418-29-8VMZXMTVGOAQUEN-FFHNEAJVSA-N
Dihydrocodeine hydroiodide6D04Y0152T5965-15-1QXBJOHDQNJOLNA-FFHNEAJVSA-N
Dihydrocodeine phosphate5D9XI60ASE24204-13-5HFBYLYCMISIEMM-FFHNEAJVSA-N
Active Moieties
NameKindUNIICASInChI Key
CodeineunknownUX6OWY2V7J76-57-3OROGSEYTTFOCAN-DNJOTXNNSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Acetaminophen, Caffeine and Dihydrocodeine BitartrateDihydrocodeine bitartrate (16 mg/1) + Acetaminophen (325 mg/1) + Caffeine (30 mg/1)TabletOralLarken Laboratories Inc.2016-10-04Not applicableUs
Acetaminophen, Caffeine and Dihydrocodeine BitartrateDihydrocodeine bitartrate (32 mg/1) + Acetaminophen (712.8 mg/1) + Caffeine (60 mg/1)TabletOralMikart, Inc.2006-10-06Not applicableUs
Acetaminophen, Caffeine and Dihydrocodeine BitartrateDihydrocodeine bitartrate (32 mg/1) + Acetaminophen (712.8 mg/1) + Caffeine (60 mg/1)TabletOralBoca Pharmacal, Inc.2007-04-032013-05-23Us
Acetaminophen, Caffeine, Dihydrocodeine BitartrateDihydrocodeine bitartrate (16 mg/1) + Acetaminophen (320.5 mg/1) + Caffeine (30 mg/1)CapsuleOralPreferreed Pharmaceuticals Inc.2015-09-112018-03-05Us
Acetaminophen, Caffeine, Dihydrocodeine BitartrateDihydrocodeine bitartrate (16 mg/1) + Acetaminophen (320.5 mg/1) + Caffeine (30 mg/1)CapsuleOralXspire Pharma2015-08-05Not applicableUs
Acetaminophen, Caffeine, Dihydrocodeine BitartrateDihydrocodeine bitartrate (16 mg/1) + Acetaminophen (320.5 mg/1) + Caffeine (30 mg/1)CapsuleOralbryant ranch prepack2015-08-052017-05-31Us
Acetaminophen, Caffeine, Dihydrocodeine BitartrateDihydrocodeine bitartrate (16 mg/1) + Acetaminophen (320.5 mg/1) + Caffeine (30 mg/1)CapsuleOralMesource Pharmaceuticals2015-08-052017-03-31Us
Aspirin, Caffeine, and Dihydrocodeine BitartrateDihydrocodeine bitartrate (16 mg/1) + Acetylsalicylic acid (356.4 mg/1) + Caffeine (30 mg/1)CapsuleOralCaraco Pharmaceutical Laboratories, Ltd.2012-10-01Not applicableUs
dihydrocodeine bitartrate and aspirin and caffeine DCDihydrocodeine bitartrate (16 mg/1) + Acetylsalicylic acid (356.4 mg/1) + Caffeine (30 mg/1)CapsuleOralEUSA Pharma (USA), Inc.2011-04-252012-12-31Us
Dihydrocodeine Bitartrate, Acetaminophen and CaffeineDihydrocodeine bitartrate (32 mg/1) + Acetaminophen (712.8 mg/1) + Caffeine (60 mg/1)TabletOralPhysicians Total Care, Inc.2008-05-20Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Centussin DhcDihydrocodeine bitartrate (3 mg/5mL) + Brompheniramine maleate (4 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL)LiquidOralCenturion Labs2009-11-242016-05-02Us
ColdcoughDihydrocodeine bitartrate (7.5 mg/5mL) + Chlorpheniramine maleate (2.0 mg/5mL) + Pseudoephedrine hydrochloride (15 mg/5mL)SyrupOralBreckenridge Pharmaceutical, Inc.2003-07-012011-08-31Us
Coldcough PDDihydrocodeine bitartrate (3 mg/5mL) + Chlorpheniramine maleate (2 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL)SyrupOralBreckenridge Pharmaceutical, Inc.2003-07-012011-12-31Us
DiHydro CPDihydrocodeine bitartrate (7.5 mg/5mL) + Chlorpheniramine maleate (2 mg/5mL) + Pseudoephedrine hydrochloride (15 mg/5mL)SyrupOralCypress Pharmaceuticals, Inc.2007-02-152011-08-26Us
Dihydrocodeine BPM Phenyleph HClDihydrocodeine bitartrate (3 mg/5mL) + Brompheniramine maleate (4 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL)LiquidOralRiver's Edge Pharmaceuticals, LLC2010-03-012012-02-29Us
Dihydrocodeine/ BPM/ Phenyleph HClDihydrocodeine bitartrate (3 mg/5mL) + Brompheniramine maleate (4 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL)LiquidOralKylemore Pharmaceuticals, LLC2010-12-132012-12-31Us
Donatuss DCDihydrocodeine bitartrate (7.5 mg/5mL) + Guaifenesin (50 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL)SyrupOralLaser Pharmaceuticals Llc2009-10-072013-09-30Us
Duohist DHDihydrocodeine bitartrate (7.25 mg/5mL) + Chlorpheniramine maleate (2 mg/5mL) + Phenylephrine hydrochloride (5 mg/5mL)LiquidOralBreckenridge Pharmaceutical, Inc.2008-04-012010-06-30Us
EndaCof DHDihydrocodeine bitartrate (3 mg/5mL) + Brompheniramine maleate (4 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL)LiquidOralLarken Laboratories, Inc.2009-09-232011-11-30Us
J-cof DhcDihydrocodeine bitartrate (7.5 mg/5mL) + Brompheniramine maleate (3 mg/5mL) + Pseudoephedrine hydrochloride (15 mg/5mL)LiquidOralJayMac Pharmaceuticals2008-06-302013-08-12Us
International/Other Brands
Codidol / Contugesic / Dehace / DF-118 Forte / Dicogesic / Hydrocodin / Remedacen
Categories
UNII
N9I9HDB855
CAS number
125-28-0
Weight
Average: 301.3801
Monoisotopic: 301.167793607
Chemical Formula
C18H23NO3
InChI Key
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

Pharmacology

Indication

Dihydrocodeine 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/]

Associated Conditions
Pharmacodynamics

Possible opioid related side effects include, but are not limited to, drowsiness, nausea, headache, dry mouth, constipation, difficulty passing urine, and mild euphoria.

Mechanism of action

Dihydrocodeine is metabolized to dihydromorphine -- a highly active metabolite with a high affinity for mu opioid receptors. [3]

Absorption

Bioavailability 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 binding
Not 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 elimination

Renal elimination and urinary excretion. [1]

Half life

4h

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]

Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(2-benzhydryloxyethyl)diethyl-methylammonium iodideThe risk or severity of adverse effects can be increased when (2-benzhydryloxyethyl)diethyl-methylammonium iodide is combined with Dihydrocodeine.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Dihydrocodeine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Dihydrocodeine is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when 3,4-Methylenedioxyamphetamine is combined with Dihydrocodeine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Dihydrocodeine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Dihydrocodeine is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when Dihydrocodeine is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of serotonin syndrome can be increased when Dihydrocodeine is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbirateroneThe metabolism of Dihydrocodeine can be decreased when combined with Abiraterone.
Food Interactions
  • Alcohol may enhance CNS depressant effects

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
KEGG Drug
D01481
PubChem Compound
5284543
PubChem Substance
46506478
ChemSpider
4447600
ChEBI
135276
ChEMBL
CHEMBL1595
PharmGKB
PA449322
Drugs.com
Drugs.com Drug Page
Wikipedia
Dihydrocodeine
ATC Codes
N02AA58 — Dihydrocodeine, combinationsN02AA08 — Dihydrocodeine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentPain NOS1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • A-S Medication Solutions LLC
  • Boca Pharmacal
  • Caraco Pharmaceutical Labs
  • Leitner Pharmaceuticals LLC
  • Mikart Inc.
  • Nucare Pharmaceuticals Inc.
  • Pamlab LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmedix
  • Physicians Total Care Inc.
  • West-Ward Pharmaceuticals
  • Zerxis Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral
LiquidOral
CapsuleOral
SyrupOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)112.5 °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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0009000000-0621835c3e6c1a244d1c
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0009000000-215351ab6e3d6923cb7a
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0239000000-d9a28afb4f2a26a792fb
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0f6t-0931000000-8f6a91fec0761febddae
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-006t-0910000000-b17807fd1304c69ce71d
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-0009000000-422aaa0732f083783954
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-0009000000-6826eb02e5bf4f87fde7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0udi-0359000000-b1a87ac83b5ead5b10ba
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0f6t-0941000000-85f127ae74a67d7544d7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-006t-0910000000-fc3b87d3fb93d21f90f4
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-062d-0900000000-c8e88928923875169e0b

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 / Anisoles / Aralkylamines / Alkyl aryl ethers / Piperidines / Trialkylamines / Secondary alcohols / Cyclic alcohols and derivatives
show 4 more
Substituents
Morphinan / Phenanthrene / Tetralin / Coumaran / Anisole / Alkyl aryl ether / Aralkylamine / Piperidine / Benzenoid / Cyclic alcohol
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
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]
  2. Kirkwood LC, Nation RL, Somogyi AA: Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol. 1997 Dec;44(6):549-55. [PubMed:9431830]
  3. Schmidt H, Vormfelde Sv, Klinder K, Gundert-Remy U, Gleiter CH, Skopp G, Aderjan R, Fuhr U: Affinities of dihydrocodeine and its metabolites to opioid receptors. Pharmacol Toxicol. 2002 Aug;91(2):57-63. [PubMed:12420793]
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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]

Drug created on July 31, 2007 07:10 / Updated on October 10, 2018 21:53