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An analeptic, in medicine, is a type of central nervous system (CNS) stimulant. The term analeptic typically refers to respiratory stimulants (e.g., doxapram). Analeptics include a wide variety of medications used to treat depression, attention deficit hyperactivity disorder (ADHD), and respiratory depression. Analeptics can also be used as convulsants, with low doses causing patients to experience heightened awareness, restlessness, and Tachypnea. The primary medical use of these drugs is as an anesthetic recovery tool or to treat emergency Hypoventilation. Other drugs of this category are prethcamide, 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 Nikethamide is now withdrawn due to risk of convulsions.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.
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. 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 stimulant 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.
Two common potassium channel blockers are doxapram and GAL-021. Both act on potassium channels in Carotid body. These cells are responsible for sensing low concentrations of oxygen and transmitting information to the CNS, ultimately leading to an increase in respiration. Blocking the potassium channels on the membranes of these cells effectively depolarizes the membrane potential, which in turn leads to opening of 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 , or big potassium channels, which are activated by a change in membrane electron potential or by an increase in internal calcium. Ampakines are the second common form of analeptics, which elicit a different mechanism for an analeptic response. They bind to AMPA receptors, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, within the pre-Bötzinger complex. The pre-Bötzinger complex is part of the ventral respiratory group and the induction of long-term potentials in the postsynaptic membrane of these neurons leads to an increased respiratory rate. The endogenous AMPA receptor ligand is 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.
The third common mechanism of which analeptics take advantage is to act as serotonin receptor agonists. Buspirone and mosapride successfully increased respiration in animals by binding to serotonin receptors which are G protein coupled receptors which, upon activation, induce a secondary messenger cascade and in this case that cascade leads to an analeptic response.
With respect to breathing, caffeine acts as a competitive adenosine antagonist. Researchers discovered this by administering adenosine or its derivatives are finding that the effects were opposite to that of caffeine. Increased adenosine levels are known to cause depression of spontaneous electrical activity of the neurons, inhibition of neurotransmission, and decreased release of neurotransmitters. Adenosine inhibits respiratory drive by blocking the electrical activity of respiratory neurons. Caffeine, as an adenosine antagonist, stimulates these respiratory neurons causing enhancement of respiratory minute volume.
One of the first widely used analeptics was strychnine, which causes CNS excitation by antagonizing the inhibitory neurotransmitter glycine. Strychnine is subcategorized as a convulsant along with picrotoxin and bicuculline, though these convulsants inhibit 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. The other two convulsants antagonize GABA receptors, but neither is commonly accessible today.
Doxapram use is declining in humans, though it is an effective CNS and respiratory stimulant, primarily because of shorter-lasting anesthetic agents becoming more abundant, but also because some research has shown potential side effects in infants. Some studies on preterm infants found that doxapram causes decreased 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. Thus, doxapram has been eliminated from many treatments for humans because of its potential dangers.
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