Analeptic

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Doxapram

An analeptic, in

convulsants, with low doses causing patients to experience heightened awareness, restlessness, and rapid breathing.[1]
The primary medical use of these drugs is as an anesthetic recovery tool or to treat emergency respiratory depression.[2] Other drugs of this category are
pentylenetetrazole, and nikethamide. Nikethamide is now withdrawn due to risk of convulsions. Analeptics have recently been used to better understand the treatment of a barbiturate overdose. Through the use of agents, researchers were able to treat obtundation and respiratory depression.[3]

Medical use

Doxapram

Analeptics have been used throughout history for two main purposes, to help patients recover from anesthesia more efficiently and to manage respiratory distress and apnea, particularly in infants.

Anesthesia recovery

Analeptics can be used to increase the speed of recovery from propofol, remifentanil, and sevoflurane. In clinical settings, analeptics such as doxapram have been used to help patients recover from anesthesia better, as well as to remove some of the potential negative side effects of potent anesthetics.

Respiratory distress management

The three most prevalent clinical analeptic uses of caffeine are in the treatment of

hypoxia.[6] This cessation of breathing is due to the underdevelopment of the body's respiratory control center, the medulla oblongata
, in premature infants.

Ample research also suggests that caffeine significantly reduces the occurrence of bronchopulmonary dysplasia, which is a chronic lung disorder defined by the need for supplemental oxygen after a postmenstrual age of 36 weeks.[6] Bronchopulmonary dysplasia is common in infants with low birth weight (<2500 g) and very low birth weight (<1500 g) who received mechanical ventilator machines to help manage respiratory distress syndrome. Currently, no treatment is known for bronchopulmonary dysplasia, as the risks of treatment are generally thought to outweigh the necessity for using a mechanical ventilator. Caffeine only reduces occurrence.

Theophylline is no longer used as a respiratory analeptic in newborn infants. Theophylline has a very narrow therapeutic index, so its dosages must be supervised by direct measurement of serum theophylline levels to avoid toxicity.

Mechanism of action

Analeptics are a diverse group of medications that work through a variety of chemical pathways; analeptic medications work through four main mechanisms to stimulate respiration. Analeptics can act as

ampakines, serotonin receptor agonists, and adenosine
antagonists.

Two common potassium channel blockers are doxapram and

voltage-gated calcium channels and neurotransmitter release. This begins the process of relaying the signal to the CNS. Doxapram blocks leaky potassium channels in the tandom pore domain family of potassium channels, while GAL-021 blocks BK channels, or big potassium channels, which are activated by a change in membrane electron potential or by an increase in internal calcium.[7]

AMPA

glutamate and ampakines mirror glutamate's interaction with the receptors. Ligand binding causes AMPA receptors to open and allow for sodium ions to flow into the cell, leading to depolarization and signal transduction. At this time, CX717 is the most successful ampakine in human trials and has very few side effects.[7]

The third common mechanism of which analeptics take advantage is to act as serotonin receptor agonists.

G protein coupled receptors which, upon activation, induce a secondary messenger cascade and in this case that cascade leads to an analeptic response.[7]

With respect to breathing, caffeine acts as a competitive

respiratory minute volume
.

Doxapram

Doxapram is an

drug overdoses, but is not effective for many drugs. The side effects of doxapram are rare, but with overdose, hypertension, tachycardia, tremors, spasticity, and hyperactive reflexes have been seen to occur.[9]

Methylxanthines caffeine and theophylline

Caffeine

The naturally occurring compounds

gastrointestinal irritation, and rarely ringing in the ears. At high doses, they can also cause psychological dependence.[9]

History

After their introduction in the early 20th century, analeptics were used to study the new life-threatening problem of barbiturate overdose. Prior to the 1930s, naturally occurring stimulants such as camphor and caffeine were used in the treatment of barbiturate overdose.[10] Between 1930 and 1960, synthetic analeptics such as nikethamide, pentylenetetrazol, bemegride, amphetamine, and methylphenidate replaced the naturally occurring compounds in treating barbiturate overdose. Recently, analeptics have been turned to the treatment of ADHD due to more efficient ways to treat barbiturate overdoses.[11]

One of the first widely used analeptics was

GABA receptors instead of glycine. Strychnine was used until the early 20th century, when it was found to be a highly toxic convulsant. Strychnine is now available as a rodenticide and as an adulterant in drugs such as heroin.[1] The other two convulsants antagonize GABA receptors, but neither is commonly accessible today.[1]

Doxapram use is declining in humans, though it is an effective CNS and respiratory stimulant, primarily because of shorter-lasting

cerebral blood flow and increased cerebral oxygen requirement. This resulted in these infants having higher chances of developing mental delays than infants not treated with the drug.[2]
Thus, doxapram has been eliminated from many treatments for humans because of its potential dangers.

References

  1. ^
    doi:10.1016/j.mpaic.2014.10.005
    .
  2. ^
    doi:10.1053/j.jepm.2011.04.011
    .
  3. PMID 22323949
    .
  4. S2CID 14277779
    .
  5. PMID 17989382
    .
  6. ^
    S2CID 22587234
    .
  7. ^
    PMID 25343036
    .
  8. S2CID 14277779
    .
  9. ^
    ISBN 978-1437717112
    .
  10. PMID 9120893
    .
  11. PMID 9120893
    .
  12. PMID 23791825
    .
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