An analeptic, in

medicine Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pract ...

, is a

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

. The term "analeptic" typically refers to respiratory analeptics (for example,

doxapram Doxapram hydrochloride (marketed as Dopram, Stimulex or Respiram) is a respiratory stimulant. Administered intravenously, doxapram stimulates an increase in tidal volume, and respiratory rate. Mechanism of action Doxapram stimulates chemorecep ...

). Analeptics are central nervous system (CNS) stimulants that include a wide variety of medications used to treat depression, attention deficit hyperactivity disorder (

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

), and

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapnia ...

. Analeptics can also be used as

convulsants A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent exc ...

, with low doses causing patients to experience heightened awareness, restlessness, and

rapid breathing Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing. In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea b ...

. The primary medical use of these drugs is as an

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

recovery tool or to treat emergency

. Other drugs of this category are prethcamide,

pentylenetetrazole Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convuls ...

, and

nikethamide Nikethamide is a stimulant which mainly affects the respiratory cycle. Widely known by its former trade name of Coramine, it was used in the mid-twentieth century as a medical countermeasure against tranquilizer overdoses, before the advent of ...

. Nikethamide is now withdrawn due to risk of convulsions. Analeptics have recently been used to better understand the treatment of a

barbiturate Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...

overdose. Through the use of agents, researchers were able to treat

obtundation Obtundation refers to less than full alertness (altered level of consciousness), typically as a result of a medical condition or trauma. There is a huge range of potential causes including head injury, interruption of blood circulation, impaired ...

and respiratory depression.

Medical use

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 Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation f ...

remifentanil Remifentanil is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications fo ...

, and

sevoflurane Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflura ...

. 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

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

apnea of prematurity Apnea of prematurity is defined as cessation of breathing by a premature infant that lasts for more than 20 seconds and/or is accompanied by hypoxia or bradycardia. Apnea is traditionally classified as either ''obstructive, central, or mixed''. Ob ...

, and

bronchopulmonary dysplasia Bronchopulmonary dysplasia (BPD; part of the spectrum of chronic lung disease of infancy) is a chronic lung disease in which premature infants, usually those who were treated with supplemental oxygen, require long-term oxygen. The alveoli that are ...

in newborn infants. Caffeine is a weak

bronchodilator A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lun ...

, which explains the relief of the effects of asthma. Some preliminary research indicates that caffeine reduces the incidence of

cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sensa ...

and cognitive delay, but additional research is needed. Apnea of prematurity is officially described as a cessation of breathing for more than 15–20 seconds, usually accompanied by

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

and

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

. This cessation of breathing is due to the underdevelopment of the body's respiratory control center, the

medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is a cone-shaped neuronal mass responsible for autonomic (involun ...

, 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. Bronchopulmonary dysplasia is common in infants with

low birth weight Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an infant of or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal intensi ...

(<2500g) and very low birth weight (<1500g) 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

potassium channel blocker Potassium channel blockers are agents which interfere with conduction through potassium channels. Medical uses Arrhythmia Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic age ...

ampakines Ampakines, also stylized as AMPAkines, are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor ...

serotonin receptor agonist A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of the ...

s, and

adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...

antagonists. Two common potassium channel blockers are doxapram and GAL-021. Both act on potassium channels in

carotid bodies The carotid body is a small cluster of chemoreceptor cells, and supporting sustentacular cells. The carotid body is located in the adventitia, in the bifurcation (fork) of the common carotid artery, which runs along both sides of the neck. The ca ...

. 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 Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

, which in turn leads to opening of

voltage-gated calcium channels Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabili ...

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 channel BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the ce ...

s, or big potassium channels, which are activated by a change in membrane electron potential or by an increase in internal calcium. AMPA

Ampakines Ampakines, also stylized as AMPAkines, are a subgroup of AMPA receptor positive allosteric modulators with a benzamide or closely related chemical structure. They are also known as "CX compounds". Ampakines take their name from the AMPA receptor ...

are the second common form of analeptics, which elicit a different mechanism for an analeptic response. They bind to

AMPA receptors The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate ( iGluR) that mediates fast synaptic transmission in the cent ...

, or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, within the

pre-Bötzinger complex The preBötzinger complex, sometimes written pre-Bötzinger complex (preBötC), is a functionally and anatomically specialized site in the ventral-lateral region of the lower medulla oblongata (i.e., lower brainstem). The preBötC is part of the ven ...

. The pre-Bötzinger complex is part of the

ventral respiratory group The respiratory center is located in the medulla oblongata and pons, in the brainstem. The respiratory center is made up of three major respiratory groups of neurons, two in the medulla and one in the pons. In the medulla they are the dorsal res ...

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 In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

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 In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

and

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

. At this time,

CX717 CX717 is an ampakine compound created by Christopher Marrs and Gary Rogers in 1996 at Cortex Pharmaceuticals. It affects the neurotransmitter glutamate, with trials showing the drug improves cognitive functioning and memory. Approval process In ...

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 Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. Benefits support its short-term use. It is taken by mouth, and it may take up to fo ...

and

Mosapride Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates gastric emptying throughout the whole of the gastroin ...

successfully increased respiration in animals by binding to serotonin receptors which are

G protein coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

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

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 Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

, 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 Minute ventilation (or respiratory minute volume or minute volume) is the volume of gas inhaled (inhaled minute volume) or exhaled (exhaled minute volume) from a person's lungs per minute. It is an important parameter in respiratory medicine due ...

Doxapram

Doxapram is an

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

CNS and respiratory stimulant that is typically used to treat respiratory depression caused by anesthesia or

chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...

. It can also be used as a treatment for neonatal apnea, but it can be dangerous, so caution must be taken. Doxapram has been used to treat respiratory depression in

drug overdoses A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended.

, but is not effective for many drugs. The side effects of doxapram are rare, but with overdose,

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...

spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles. ...

, and hyperactive reflexes have been seen to occur.

Methylxanthines caffeine and theophylline

The naturally occurring compounds

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...

and

theophylline Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...

are structurally classified as methylated

xanthines Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, ...

. Side effects typically seen with the use of xanthines include jitters, over-energetic behavior, and

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

. Less common side effects can include

diuresis Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pro ...

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

irritation, and rarely

ringing in the ears Tinnitus is the perception of sound when no corresponding external sound is present. Nearly everyone experiences a faint "normal tinnitus" in a completely quiet room; but it is of concern only if it is bothersome, interferes with normal hearin ...

. At high doses, they can also cause

psychological dependence Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms—e.g. anxiety and anhedonia—upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent expo ...

History

After their introduction in the early 20th century, analeptics were used to study the new life-threatening problem of

barbiturate overdose Barbiturate overdose is poisoning due to excessive doses of barbiturates. Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe ( respiratory depression). Complica ...

. Prior to the 1930s, naturally occurring stimulants such as

camphor Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel ('' Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the k ...

and

were used in the treatment of barbiturate overdose. Between 1930 and 1960, synthetic analeptics such as

pentylenetetrazol Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convuls ...

, bemegride,

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

, and

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...

replaced the naturally occurring compounds in treating

overdose. Recently, analeptics have been turned to the treatment of ADHD due to more efficient ways to treat barbiturate overdoses. One of the first widely used analeptics was

strychnine Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eye ...

, which causes CNS excitation by antagonizing the inhibitory neurotransmitter

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

. Strychnine is subcategorized as a

convulsant A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent exc ...

along with

picrotoxin Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Gree ...

and

bicuculline Bicuculline is a phthalide-isoquinoline compound that is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from ''Dicentra cucullaria'', '' Adlumia ...

, 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 Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despi ...

and as an

adulterant An adulterant is caused by the act of adulteration, a practice of secretly mixing a substance with another. Typical substances that are adulterated include but are not limited to food, cosmetics, pharmaceuticals, fuel, or other chemicals, that ...

in drugs such as

heroin Heroin, also known as diacetylmorphine and diamorphine among other names, is a potent opioid mainly used as a recreational drug for its euphoric effects. Medical grade diamorphine is used as a pure hydrochloride salt. Various white and brow ...

. 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 Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), am ...

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 Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. Arterie ...

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.

References

External links

* {{Medicine, state=collapsed Psychoanaleptics