Doxapram

[Hammilton]

Good Morning everyone (It's 1:42a here, so I'm assuming it's still AM for most of you )

While I was working on the repository tonight I came across a drug I've known about for a bit, but I don't think I've ever noticed the structure.

Doxapram is a respiratory stimulant (not sure what the mechanism is, though) that has the PEA skeleton in it- although that's not relevant to it's activity as far as I know.

What is more interesting is that it fulfills the morphine rule perfectly:

What I'm wondering is if it was synthesized in the process of looking for opiates or if it came about independently. Does anyone know if it was assayed for affinity? Obviously it's not an agonist, but is it an antagonist?

If anyone knows what paper it was originally published in, I'd be very grateful!

 

[wungchow]

No idea what receptors it targets but I found this interesting:

. It can antagonise the respiratory depressant effects of opiate analgesics without inhibition of their analgesic properties. It is usually given as an intravenous injection of 1-1.5mg/kg repeated after one hour.

source: http://priory.com/cmol/doxapram.htm

Reminds me of dextromoramide, an open chain opioid similar to methadone.

 

[MurphyClox]

Not the first paper, but one of the oldest:

"A new analeptic agent: doxapram hydrochloride (Dopram)."
JAMA: The journal of the American Medical Association 1966, 196(10), p.855
(no abstract available)

That's the actually the oldest that I could find, But I think there must be some older patent on it:
"USE OF A NEW ANALEPTIC, DOXAPRAM HYDROCHLORIDE, DURING GENERAL ANESTHESIA AND RECOVERY."
NOE F E; BORRILLO N; GREIFENSTEIN F E
Anesthesia and analgesia 1965, 44, p.206


Here is some info on receptor affinities/actions:

"Stimulation of carotid chemoreceptors and ventilation by doxapram in the cat."
Nishino, T.; Mokashi, A.; Lahiri, S.
Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology 1982, 52(5), p.1261-5.

Abstract

The effects of small doses of doxapram [CAS:309-29-5] (< 0.5 mg/kg i.v.) on carotid chemoreceptor activity and ventilation were studied in cats anesthetized with a-chloralose. The effects were studied at several levels of partial pressures of O and CO2 in arterial blood (paO and paCO2, resp.). Doxapram stimulated the discharge rate of the carotid chemoreceptor afferents by the same magnitude at all levels of paO and paCO2 studied. However, the ventilatory effect of doxapram was more than additive to the concomitant stimulation by hypoxia or hypercapnia. This ventilatory effect was eliminated by sectioning the carotid sinus and aortic nerves. Apparently, the ventilatory stimulus due to doxapram is dependent on the excitatory input from the peripheral chemoreceptors.

"Effects of doxapram on carotid chemoreceptor activity in newborn kittens."
Biology of the Neonate 1993, 64(1), p.26-35.

Abstract

Doxapram is a respiratory stimulant which acts on peripheral chemoreceptors and central respiratory neurons in a dose-dependent fashion in the adult cat. In the newborn, the mechanisms of action of doxapram are still unclear. To evaluate the effects of doxapram on the carotid chemosensory discharge and its relationship with dopaminergic mechanisms in the carotid body, two groups of kittens less than 13 days old, anesthetized, artificially ventilated and paralyzed, were prepd. for the recording of a single or a few chemosensory afferents of the carotid sinus nerve. The chemosensory activity was recorded under five conditions of inspired gas mixts. (21 and 8% O2 in N2, 100% O2, 5 and 10% CO2 in O2). Group 1 (n = 9) received only doxapram and group 2 (n = 8 ) was pretreated with haloperidol (1 mg/kg), a dopamine D2-receptor blocker, before receiving doxapram. Doxapram significantly stimulated the discharge rate of the carotid chemoafferents under all conditions of inspired gas. The chemosensory discharge was increased by haloperidol, and was raised further after doxapram by an amt. similar to group 1. For instance, in normoxia, the activity increased from 2.9 ± 0.4 to 7.5 ± 0.9 impulse/s (mean ± SEM, p < 0.01) in group 1 and from 3.8 ± 0.6 to 9.1 ± 1.0 impulse/s (p < 0.01) in group 2. These results indicate that the mechanisms of response of carotid chemoreceptor to doxapram are developed in the newborn kitten and doxapram acts independent of the dopaminergic mechanisms in the carotid body.

Peace! Murphy

 

[MurphyClox]

Some more:

"Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction."
Takahashi, Toru; Osanai, Shinobu; Nakano, Hitoshi; Ohsaki, Yoshinobu; Kikuchi, Kenjiro.
Respiratory Physiology & Neurobiology 2005, 147(1), p.1

Abstract

To det. if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca2+-free soln., neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not obsd. Also, we investigated the various K+ channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K+ channel activators; NS-1619 as a Ca2+-sensitive K+ channel activator; and halothane as a TASK-like background K+ channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.

...and it's definitively p.m. here. Dark like a bear's arse...

 

[Hammilton]

That's interesting; what I'm really interesting in though is whether or not it has any affinity for any of the opiate receptors (as an antagonist, this is).

It doesn't seem to have ever been assayed for affinity at these other sites- which is odd, because if I was looking at a drug that antagonised respiratory depression induced by opiates, I'd certainly want to know if it had any affinity for those receptors, even if it had other relevant activity.

 

[CH3CH2OH]

Why would this compound not be used in place of traditional opioid antagonists in order to avoid the withdrawal/pain associated with the traditional antagonists? I mean wouldnt this be very useful for patients whose pain is not controlled adequetly but their respiration is too depressed to allow for higher dosing?

Sorry if this is too far off-topic.

 

[mad_scientist]

Doxapram is not an opioid antagonist; it does not block the effects of opioids, nor does it induce withdrawal syndrome in opioid dependent patients. It is a directly acting respiratory stimulant, which acts though a pathway distinct from that of opioids and stimulates the respiratory centre sufficiently to override the respiratory depression from the opioid.

Doxapram is sometimes used to counteract respiratory depression in severe pain patients so that higher doses of opioids can be used, but this is unusual and not standard practice, mainly because of the side effects which can include panic attacks and convulsions, as well as nausea and vomiting (which high dose opioids can induce by themselves so combining two pro-nauseant drugs is almost certain to make the patient vomit everywhere).

So mainly they only use it in emergencies for when a patient actually goes into respiratory arrest, it is particularly useful for polydrug intoxications (e.g. opioids + benzos) where naloxone alone is not sufficient to get the patient breathing again.