The Physiology and Maintenance of Respiration: A Narrative Review

The dorsal medulla is responsible for inhalation and airway defense, while the ventral medulla is responsible for exhalation [11, 19, 20]. The strength of the signal from the dorsal medulla can influence breathing, whereby increased impulse frequency results in stronger muscle contractions and deeper breathing, and decreased frequency results in passive expiration [21]. The dorsal medulla communicates with the ventral medulla by integrating input from central and peripheral receptors prior to relaying information to respiratory muscles to generate respiratory rhythm [21]. The pre-Bötzinger complex is a group of neurons located between the ventral respiratory group and the Bötzinger complex in the brainstem that also functions to control inspiration [7]. The pre-Bötzinger complex interacts with respiratory centers to ensure a smooth transition between different breathing phases, while also preventing the activation of opposing muscle groups [7]. The principal neurotransmitters involved in modulating the generation and transmission of respiratory rhythm are glutamate, gamma-aminobutyric acid (GABA), and glycine [22].

The pontine grouping allows for modulation of the intensity and frequency of medullary signals to control breathing patterns while promoting a smooth transition between inspiration and expiration [21, 23]. More specifically, the pneumotaxic center in the upper portion of the pons coordinates the speed of breathing, sends inhibitory impulses to the respiratory center, and is involved in the fine-tuning of respiratory rate [24]. The apneustic center in the lower portion of the pons also coordinates the speed of breathing but can be overridden by the pneumotaxic center to end inhalation; this region is mostly responsible for sending stimulatory impulses to the inspiratory area (prolonging inhalation) [24]. Suprapontine areas also contribute to respiration by responding to changes in internal or external environmental conditions such as exercise, hypoxia, hypercapnia, and thermal changes, as well as other processes like swallowing and coughing [18, 25]. These neuronal processes are modulated by incoming sensory input systems [26].

Mechanoreceptors are located throughout the respiratory tract in the airways, trachea, lungs, and pulmonary vessels. They provide sensory information to the respiratory center of the brain regarding the mechanical status of the lungs and chest, including the rate of breathing, lung space, and irritation triggers [11, 27]. Pulmonary stretch receptors can be classified as slowly or rapidly adapting, where slowly adapting receptors are activated during inflation of the lungs and play a critical role in the Hering–Breuer reflex (termination of inspiration and prolongation of expiration), and rapidly adapting receptors initiate defensive respiratory reflexes in response to irritants [27, 29]. Bronchopulmonary C-fiber receptors also play a role in initiating defensive respiratory reflexes in response to inhaled irritants or rapid changes in lung volume [27]. Other receptors called metaboreceptors are found in the skeletal muscle and are activated by metabolic byproducts to stimulate breathing during exercise [30].

Peripheral chemoreceptors consist of fast-acting carotid and aortic bodies that monitor the partial pressure of arterial O₂ in the blood and respond to hypercapnia or acidosis [28, 31]. Carotid body chemoreceptors are located at the bifurcation of the common carotid arteries and are responsible for the majority of the peripheral control of ventilation [28, 31, 32]. Carotid bodies are also able to sense arterial gas concentrations and pH, which initiates a rapid response (within 1–3 s) by stimulating ventilation via communication with medullary response neurons [24, 28]. Aortic bodies are located near the arch of the aorta and play a large role in regulating circulation while also responding to changes in gas concentrations [24, 28].

Central chemoreceptors are located within the ventral surface of the medulla and retrotrapezoid nucleus and are responsible for sensing pH, O₂, or CO₂ concentration changes in the brain and cerebrospinal fluid [7, 11, 26, 32, 33]. An acidic environment (increased hydrogen ions) in the brain triggers the respiratory center to initiate contraction of the diaphragm and intercostal muscles [26]. As a result, the rate and depth of respiration increase, allowing for more CO₂ to be expelled and thereby reducing CO₂ levels and hydrogen ions in the blood [26]. Conversely, low levels of CO₂ in the blood cause low levels of hydrogen ions in the brain, ultimately leading to a decrease in the rate and depth of ventilation and the slowing of breathing [26]. Taken together, these processes function to normalize pH [31]. Of all the sensory input systems, central chemoreceptors are thought to have primary control over respiration, which is ultimately carried out by respiratory muscles and the lungs [11, 33].

Barbiturates are a class of sedative-hypnotic drugs used for a variety of purposes [54]. Phenobarbital and primidone are often used in the treatment of seizures, amobarbital is used as an investigative agent for the neurological assessment of cerebral hemispheres, and secobarbital is used for insomnia [54, 63]. Barbiturates generally act on GABA_A receptors by increasing the amount of time the chloride ion channel is opened, which increases GABA receptor affinity (Table 1) [54]. These drugs can also act to increase chloride influx in the absence of GABA, which further depresses the CNS [54]. Ultimately, these processes can lead to suppression of upper airway patency and central neuronal control of ventilation [55].

Benzodiazepines are widely prescribed in general practice for their anxiolytic, sedative, anticonvulsant, and muscle relaxant effects [64]. These agents bind directly to various GABA_A receptor subtypes and increase the inhibitory effects of endogenous GABA (Table 1) [18, 56]. Benzodiazepines can depress central respiratory drive, chemoreceptor responsiveness to hypercapnia, peripheral chemoreceptors, and inspiratory and expiratory respiratory muscle strength in a dose-dependent manner, thus reducing respiration [47, 57, 58]. Benzodiazepines can also cause upper airway obstruction via relaxation of the tongue and neck [47]. Dose-dependent effects on reducing resting ventilation and the ventilatory response to hypoxia and hypercapnia can occur [18]. As such, benzodiazepine use has been associated with an increased risk of respiratory depression, especially when used in combination with opioids and alcohol [58, 65].

Nonbenzodiazepine hypnotics, such as zolpidem and zaleplon, are also referred to as Z drugs and are extremely useful in the treatment of insomnia owing to their quick onset and short duration [56]. Similarly to benzodiazepines, they too act at the GABA_A receptor, but in a more specific manner (Table 1) [56]. A consequence of their greater specificity is less anxiolytic and anticonvulsant activity [56]. Similarly to benzodiazepines, these drugs may cause respiratory depression by suppressing central respiratory drive, decreasing respiratory muscle strength, and increasing upper airway resistance [59, 60]. However, a recent clinical study found differential effects on the respiratory arousal threshold, with no reduction in upper airway muscle activity or alteration of airway collapsibility during sleep—instead, muscle activity increased during airway narrowing [66].

Opioids are often prescribed for acute and chronic pain relief, as they provide analgesia by acting on mu-opioid receptors located throughout the CNS (Table 1; Fig. 6) [47, 50, 51]. Opioid-induced respiratory depression can occur through the suppression of respiratory drive by interacting with neurons in the pons and medulla, including the pre-Bötzinger complex, or suppressing peripheral or central chemoreceptors, which impacts respiratory rhythm and blunts the normal response to hypoxemia and hypercapnia (Fig. 7) [47‐51]. Opioids also suppress neural signals to the upper airway dilator muscles, thereby impacting upper airway patency [61].

Based on their agonistic activity at the mu-opioid receptor, the impact on respiratory drive and extent of respiratory depression varies among different opioids [67, 68]. The risk of respiratory depression is greater with classic full mu-opioid receptor agonists, such as morphine, hydrocodone, and oxycodone, than it is with atypical opioids, such as tramadol, tapentadol, and buprenorphine, because these atypical opioids are mixed-mechanism drugs [1, 48, 67, 69‐71]. For example, in addition to being full mu-opioid receptor agonists, tramadol and tapentadol have been shown to activate descending pain inhibitory pathways through norepinephrine reuptake inhibition, with tramadol also acting as a serotonin reuptake inhibitor [72, 73]. Buprenorphine is a partial mu-opioid receptor agonist, an antagonist at the kappa- and delta-opioid receptors, and a full agonist at opioid receptor-like 1 [74]. Of the classic and atypical opioids, buprenorphine has unique partial agonism and signaling profiles at the mu-opioid receptor, which may result in a ceiling effect on respiratory depression but not on analgesia (Fig. 8) [67, 70, 75‐79]. Mu-opioid receptors are coupled to inhibitory proteins that, upon activation, separate from one another to engage in a variety of intracellular signaling cascades that depress neural functions [79]. Full mu-opioid receptor agonists recruit (an adaptor protein) that is associated with signaling events that lead to poor outcomes such as respiratory depression, whereas the biased signaling mechanism elicited by buprenorphine limits β-arrestin recruitment, which may contribute to an enhanced safety profile [74].

Alcohol is a widely used and abused recreational substance that contributes to approximately 15% of opioid overdose deaths [62, 80]. Alcohol is primarily metabolized in the liver by alcohol dehydrogenase to acetaldehyde, which increases CNS inhibition and decreases excitation through interactions with GABA receptors (Table 1) [62]. This can suppress central neuronal control and upper airway patency, thereby resulting in respiratory depression [62].

Diphenhydramine may also impact respiratory drive (Table 1) [81]. In addition to its use in the relief of allergy symptoms, diphenhydramine is frequently used to treat pruritus and nausea in patients who have received neuraxial opioids and was found to augment the interaction between hypoxic and hypercapnic ventilatory drive in healthy patients [81]. However, additional research is needed to determine any additional effects of diphenhydramine on respiratory drive.

Patients with chronic pain are likely to seek out herbal supplements for pain relief, which may be used in conjunction with prescription medications [82]. Some common supplements utilized for their analgesic properties, but that may also suppress the CNS, include kratom, synthetic cannabinoids, valerian root, and kava [82‐86]. Although additional research is needed to determine the specific effects of these agents on respiratory drive, clinicians must provide proper education to patients with chronic pain regarding the risks associated with concomitant use of supplements with their current prescriptions.

When analgesic drugs from different classes are combined, the resulting effects are typically synergistic rather than merely additive [87]. Synergy between CNS depressants is more common when drugs acting primarily on GABA receptors (e.g., barbiturates, benzodiazepines, Z drugs, ethanol) are combined with drugs acting on other receptor types (e.g., opioids) [87]. It is especially important to note that respiratory depression is a potentially fatal complication of opioid use and may be exacerbated by simultaneous ethanol intake [88]. One clinical trial showed that ethanol ingestion with concomitant oxycodone use resulted in clinically relevant ventilatory depression to a greater extent than when either agent was used alone [88]. The combination of an opioid, benzodiazepine, and the skeletal muscle relaxant carisoprodol is commonly referred to as the “Holy Trinity,” and these medications behave synergistically to induce respiratory depression, which could collectively result in death [89, 90]. Compared to treatment alone, the combination of opioids with benzodiazepines or alcohol has been shown to increase the risk of serious adverse respiratory events by 31% [91]. Thus, clinicians must take caution when prescribing agents that can collectively enhance the potential for serious adverse events caused by CNS depressants [92].

In addition to sedative herbal supplements and antihistamines, the concomitant use of prescription analgesics with other drug classes such as gabapentinoids can also lead to increased CNS depression [82, 93]. The prescription of the gabapentinoid drugs gabapentin and pregabalin has recently increased because physicians and patients are seeking opioid alternatives for pain relief during the opioid crisis; however, gabapentinoids are often being co-prescribed with CNS depressants, such as opioids, thereby increasing the risk of life-threatening and fatal respiratory depression [93, 94]. The increased risk of adverse events with concomitant use of CNS depressants and other medications and supplements must be considered prior to the prescription or recommendation of multiple agents.