DOXAPRAM HYDROCHLORIDE

Details

Stereochemistry	RACEMIC
Molecular Formula	C24H30N2O2.ClH.H2O
Molecular Weight	432.983
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.Cl.CCN1CC(CCN2CCOCC2)C(C1=O)(C3=CC=CC=C3)C4=CC=CC=C4

InChI

InChIKey=ZOMBFZRWMLIDPX-UHFFFAOYSA-N

InChI=1S/C24H30N2O2.ClH.H2O/c1-2-26-19-22(13-14-25-15-17-28-18-16-25)24(23(26)27,20-9-5-3-6-10-20)21-11-7-4-8-12-21;;/h3-12,22H,2,13-19H2,1H3;1H;1H2

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00561
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/14879s044lbl.pdf

Doxapram is an analeptic agent (a stimulant of the central nervous system). The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate. A pressor response may result following doxapram administration. Provided there is no impairment of cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of catecholamines has been noted. Doxapram produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. It is thought to stimulate the carotid body by inhibiting certain potassium channels. Used as temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Potassium channel subfamily K member 3 10 Target ID: CHEMBL2321613 Sources: http://www.drugbank.ca/drugs/DB00561	Inhibitor 8297
Potassium channel subfamily K member 9 6 Target ID: CHEMBL2321614 Sources: http://www.drugbank.ca/drugs/DB00561	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Drug-induced postanesthesia respiratory depression 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/14879s044lbl.pdf	Secondary		Approved 8429	Doxapram Approved Use Postanesthesia a. When the possibility of airway obstruction and/or hypoxia have been eliminated, doxapram may be used to stimulate respiration in patients with drug-induced postanesthesia respiratory depression or apnea other than that due to muscle relaxant drugs. b. To pharmacologically stimulate deep breathing in the postoperative patient. Drug-Induced Central Nervous System Depression Exercising care to prevent vomiting and aspiration, doxapram may be used to stimulate respiration, hasten arousal, and to encourage the return of laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS depression due to drug overdosage. Chronic Pulmonary Disease Associated with Acute Hypercapnia Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease. Launch Date 1965
Chronic pulmonary disease associated with acute hypercapnia 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/14879s044lbl.pdf	Primary		Approved 8429	Doxapram Approved Use Postanesthesia a. When the possibility of airway obstruction and/or hypoxia have been eliminated, doxapram may be used to stimulate respiration in patients with drug-induced postanesthesia respiratory depression or apnea other than that due to muscle relaxant drugs. b. To pharmacologically stimulate deep breathing in the postoperative patient. Drug-Induced Central Nervous System Depression Exercising care to prevent vomiting and aspiration, doxapram may be used to stimulate respiration, hasten arousal, and to encourage the return of laryngopharyngeal reflexes in patients with mild to moderate respiratory and CNS depression due to drug overdosage. Chronic Pulmonary Disease Associated with Acute Hypercapnia Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease. Launch Date 1965

C_max

Value	Dose	Co-administered	Analyte	Population
0.96 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32901	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		DOXAPRAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
272 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32901	1.5 mg/kg single, intravenous dose: 1.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DOXAPRAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
596 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32901	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	DOXAPRAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
51927 ng × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9109960	0.55 mg/kg bw 1 times / day steady-state, intravenous dose: 0.55 mg/kg bw route of administration: Intravenous experiment type: STEADY-STATE co-administered:	DOXAPRAM plasma	Equus caballus population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
3.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32901	1.5 mg/kg single, intravenous dose: 1.5 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	DOXAPRAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
7.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32901	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:	DOXAPRAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
121 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9109960	0.55 mg/kg bw 1 times / day steady-state, intravenous dose: 0.55 mg/kg bw route of administration: Intravenous experiment type: STEADY-STATE co-administered:	DOXAPRAM plasma	Equus caballus population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
21% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9109960	0.55 mg/kg bw 1 times / day steady-state, intravenous dose: 0.55 mg/kg bw route of administration: Intravenous experiment type: STEADY-STATE co-administered:		DOXAPRAM plasma	Equus caballus population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
3 mg/kg single, intravenous Studied dose Dose: 3 mg/kg Route: intravenous Route: single Dose: 3 mg/kg Sources: https://pubmed.ncbi.nlm.nih.gov/3371147	unhealthy, infants n = 3 Health Status: unhealthy Condition: idiopathic apnea Age Group: infants Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/3371147	Sources: https://pubmed.ncbi.nlm.nih.gov/3371147

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP1A2 1054 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2C19 991 CYP2E1 667 CYP3A5 395 CYP3A7 110

Drug as victim

Target	Modality	Activity
CYP2C19 991	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	negligible
CYP3A7 110	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	negligible
CYP1A2 1054	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	no
CYP2A6 543	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	no
CYP2B6 664	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	no
CYP2C8 693	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	no
CYP2E1 667	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	no
CYP3A4 1737	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	yes
CYP3A5 395	substrate 3367 Sources: https://link.springer.com/article/10.1007/s00431-014-2416-1 Page: 8.0	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:681848	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:681848
ChemicalBook	CB4245654	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4245654
MolPort	MolPort-005-933-844	https://www.molport.com/shop/molecule-link/MolPort-005-933-844
eMolecules	901795	https://www.emolecules.com/cgi-bin/more?vid=901795

PubMed

Title	Date	PubMed
Electroencephalographic effect of doxapram hydrochloride in humans.	1966	4388361
Side effects of doxapram infusion.	1976 Sep	964272
Panic attacks induced by doxapram.	1993 Feb 15	8471685
Adverse events with continuous doxapram infusion against late postoperative hypoxaemia.	1996	8737758
Second-degree atrioventricular heart block after doxapram administration.	1998 Jul	9672531
Effect of doxapram on cerebral blood flow velocity in preterm infants.	2004 Apr	15127312
Transient hyperoxia and residual cerebrovascular effects in the newborn rat.	2004 Mar	14681497
High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial.	2004 Nov	15499141
Effects of doxapram HCl on laryngeal function of normal dogs and dogs with naturally occurring laryngeal paralysis.	2004 Oct	15509290
Doxapram treatment for apnea in preterm infants.	2004 Oct 18	15494987
Doxapram inhibits carotid sinus baroreceptors in rabbits.	2005 Apr	15757507
[Determinants of doxapram utilization: a survey of practice in the French Neonatal and Intensive Care Units].	2005 Feb	15694538
Doxapram-induced panic attacks and cortisol elevation.	2005 Feb 28	15741000
Olfactory stimulation prevents apnea in premature newborns.	2005 Jan	15629985
Prediction of panic response to a respiratory stimulant by reduced orbitofrontal cerebral blood flow in panic disorder.	2005 Jul	15994724
Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.	2005 May 12	15848118
Doxapram and developmental delay at 12 months in children born extremely preterm.	2005 Nov	16303710
Doxapram increases corticotropin-releasing factor immunoreactivity and mRNA expression in the rat central nucleus of the amygdala.	2005 Nov	16269353
Doxapram only slightly reduces the shivering threshold in healthy volunteers.	2005 Nov	16243996
Ovalbumin sensitization alters the ventilatory responses to chemical challenges in guinea pigs.	2005 Nov	16024517
Brain hemodynamic effects of doxapram in preterm infants.	2006	16158005
[Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion].	2006 Aug	16939923
A new look at the respiratory stimulant doxapram.	2006 Fall-Winter	17227289
Chemical immobilization of adult female Weddell seals with tiletamine and zolazepam: effects of age, condition and stage of lactation.	2006 Feb 9	16469105
Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants.	2006 Jun 19	16784533
The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration.	2006 Mar	16492828
Doxapram shortens recovery following sevoflurane anesthesia.	2006 May	16636029
European Academy of Paediatrics, Barcelona, Spain, October 7-10, 2006. Abstracts.	2006 Nov	17242961
Doxapram and aminophylline on bispectral index under sevoflurane anaesthesia: a comparative study.	2006 Nov	16895622
[Determination of methamphetamine in whole blood by capillary zone electrophoresis after solid phase extraction].	2006 Oct 15	17190148
[Analysis of 37 drugs in whole blood by HPLC after solid phase extraction].	2006 Oct 15	17190147
Dynamic QT/RR relationship of cardiac conduction in premature infants treated with low-dose doxapram hydrochloride.	2007	17614751
HPA axis activity in patients with panic disorder: review and synthesis of four studies.	2007	16845643
Comparison of the effects of caffeine and doxapram on respiratory and cardiovascular function in foals with induced respiratory acidosis.	2007 Dec	18052748
Creatine supplementation attenuates corticosteroid-induced muscle wasting and impairment of exercise performance in rats.	2007 Feb	17053101
[Sensory stimulations for the treatment of idiopathic apneas of prematurity].	2007 May	17320360
The effect of doxapram on brain imaging in patients with panic disorder.	2007 Oct	17560768
Respiratory irregularity and stress hormones in panic disorder: exploring potential linkages.	2008	17557312
Managing acute on chronic respiratory failure: a guide to non-invasive ventilation.	2008 Aug	18783091
Difficult extubation in low birthweight infants.	2008 May	18006566
Comparative study on effectiveness of doxapram and pethidine for postanaesthetic shivering.	2009 Apr-Jun	20387350
Neuroimaging in anxiety disorders.	2009 Jun	18568288
Effects of serotonin agonists and doxapram on respiratory depression and hypoxemia in etorphine-immobilized impala (Aepyceros melampus).	2010 Apr	20688644
Chronic hypoxia increases the gain of the hypoxic ventilatory response by a mechanism in the central nervous system.	2010 Aug	20489036
The clinical practice of CPCR in small animals: an internet-based survey.	2010 Dec	21166977
Glial cells are involved in the exciting effects of doxapram on brainstem slices in vitro.	2010 Jul	20140700
Respiratory inductive plethysmography as a method for measuring ventilatory parameters in conscious, non-restrained dogs.	2010 Jul-Aug	20435149
Respiratory and cardiovascular effects of doxapram and theophylline for the treatment of asphyxia in neonatal calves.	2010 Mar 15	20022095
Emergence agitation in adults: risk factors in 2,000 patients.	2010 Sep	20526708
Evaluation of respiratory function in freely moving Beagle dogs using implanted impedance technology.	2010 Sep-Oct	20601021

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose for I.V. administration is 0.5 – 1 mg/kg for a single injection and at 5-minute intervals. Careful observation of the patient during administration and for some time subsequently are advisable. The ma ximum total dosage by I.V. injection is 2 mg/kg.

Route of Administration: Intravenous

In Vitro Use Guide

Doxapram (1-100 uM) caused rapid, reversible and dose-dependent inhibitions of K+ currents recorded in type I cells of the neonatal rat carotid body (IC50 approximately 13 uM).

Name

Type

Language

DOXAPRAM HYDROCHLORIDE

Official Name

English

DOXAPRAM HYDROCHLORIDE MONOHYDRATE

Common Name

English

(±)-1-ETHYL-4-(2-MORPHOLINOETHYL)-3,3-DIPHENYL-2-PYRROLIDINONE MONOHYDROCHLORIDE MONOHYDRATE

Systematic Name

English

2-PYRROLIDINONE, 1-ETHYL-4-(2-MORPHOLINOETHYL)-3,3-DIPHENYL-, HYDROCHLORIDE

Systematic Name

English

Doxapram hydrochloride [WHO-DD]

Common Name

English

DOXAPRAM HYDROCHLORIDE [USP MONOGRAPH]

Common Name

English

2-PYRROLIDINONE, 1-ETHYL-4-(2-(4-MORPHOLINYL)ETHYL)-3,3-DIPHENYL-, HYDROCHLORIDE (1:1)

Systematic Name

English

NSC-170958

Code

English

1-ETHYL-4-(2-MORPHOLINOETHYL)-3,3-DIPHENYL-2-PYRROLIDINONE HYDROCHLORIDE

Systematic Name

English

2-PYRROLIDINONE, 1-ETHYL-4-(2-(4-MORPHOLINYL)ETHYL)-3,3-DIPHENYL-, MONOHYDROCHLORIDE, MONOHYDRATE, (±)-

Common Name

English

DOPRAM

Brand Name

English

STIMULEXIN

Brand Name

English

DOXAPRAM HYDROCHLORIDE HYDRATE [JAN]

Common Name

English

2-PYRROLIDINONE, 1-ETHYL-4-(2-MORPHOLINOETHYL)-3,3-DIPHENYL-, MONOHYDROCHLORIDE

Common Name

English

DOXAPRAM HYDROCHLORIDE [USAN]

Common Name

English

NSC-760347

Code

English

DOXAPRAM HYDROCHLORIDE MONOHYDRATE [MI]

Common Name

English

DOXAPRAM HYDROCHLORIDE [EP MONOGRAPH]

Common Name

English

DOXAPRAM HCL

Common Name

English

DOXAPRAM HYDROCHLORIDE [USP-RS]

Common Name

English

DOXAPRAM HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

DOXAPRAM HYDROCHLORIDE [MART.]

Common Name

English

DOXAPRAM HYDROCHLORIDE HYDRATE

Common Name

English

AHR-619

Code

English

DOXAPRAM HYDROCHLORIDE [VANDF]

Common Name

English

DOXAPRAM HYDROCHLORIDE [GREEN BOOK]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C47795