What medications affect the respiratory system and can cause respiratory depression?

From the Guidelines

Several medications can depress the respiratory system beyond opioids, including central nervous system depressants like benzodiazepines, barbiturates, and sleep medications, which can significantly reduce respiratory drive. These medications can have synergistic effects on the brain's respiratory control centers in the medulla oblongata, potentially leading to severe respiratory compromise or arrest 1.

Key Medications Causing Respiratory Depression

• Central nervous system depressants like benzodiazepines (diazepam, lorazepam, alprazolam), barbiturates (phenobarbital), and sleep medications (zolpidem, eszopiclone) can significantly reduce respiratory drive.
• Anesthetics, including propofol and ketamine, also cause respiratory depression.
• Muscle relaxants such as baclofen and carisoprodol can weaken respiratory muscles.
• Anticonvulsants like gabapentin and pregabalin may cause respiratory depression, particularly in higher doses.
• Certain antipsychotics (clozapine, quetiapine) and antihistamines with sedating properties (diphenhydramine, hydroxyzine) can also affect breathing.

Special Considerations

• Alcohol, though not a medication, significantly depresses respiration and dangerously compounds these effects when combined with the medications mentioned.
• Patients with underlying respiratory conditions like sleep apnea, COPD, or advanced age are at particularly high risk for these adverse effects.
• The risk of respiratory depression increases substantially when these substances are used together, as they can have synergistic effects on the brain's respiratory control centers in the medulla oblongata, potentially leading to severe respiratory compromise or arrest 1.

From the FDA Drug Label

The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Central Nervous System Depressants The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death.

Medications that can depress the respiratory system:

• CYP3A4 inhibitors: ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil
• Central nervous system depressants: other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol These medications can increase the risk of respiratory depression when used with fentanyl transdermal system 2, 2.

From the Research

Medications Affecting the Respiratory System

Other medications that can affect the respiratory system and depress it include:

• Opioids, which can induce respiratory depression via activation of μ-opioid receptors at specific sites in the central nervous system, including the pre-Bötzinger complex 3
• Benzodiazepines, which can increase the risk of respiratory depression when combined with opioids 4
• Other opioid agonists, such as morphine and fentanyl, which can affect breathing with onset and offset profiles determined by opioid transfer to the receptor site 3

Mechanisms of Respiratory Depression

The mechanisms of opioid-induced respiratory depression involve:

• Activation of μ-opioid receptors in the central nervous system, including the pre-Bötzinger complex and other brainstem respiratory centers 5
• Decreased sensitivity of peripheral chemoreceptors to carbon dioxide and decreased activity in the central respiratory centers 6
• Modulatory signal pathways involving GIRK and KCNQ potassium channels, which remain poorly understood 5

Reversal of Respiratory Depression

Reversal of opioid-induced respiratory depression has relied heavily on naloxone, which also reverses analgesia, but mismatches between the half-lives of naloxone and opioids can make it difficult to clinically safely avoid respiratory depression 3, 5