This is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure. It does not affect the contractility of the heart when regular doses are administered. Muscle rigidity
If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult. The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers. Wooden chest syndrome
A prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known as wooden chest syndrome. The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.Wooden chest syndrome is reversed by naloxone and is believed to be caused by a release of noradrenaline, which activates α-adrenergic receptors and also possibly via an activation of cholinergic receptors.Wooden chest syndrome is unique to the most powerful opioids—which today comprise fentanyl and its analogs—while other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree. Overdose
Fentanyl poses an exceptionally high overdose risk in humans, due to having an extremely unpredictable fatal dosage when mixed with other drugs. In its pure form, overdoses are only moderately unpredictable, with most overdose deaths occurring at serum concentrations of between 150 and 250 ng/mL.
Whereas opioids like codeine, hydrocodone, oxycodone, and hydromorphone are synthesized by simple modifications of morphine, fentanyl and its relatives are synthesized by modifications of meperidine. Meperidine is a fully synthetic opioid, and other members of the phenylpiperidine family like alfentanil and sufentanil are complex versions of this structure. Like other opioids, fentanyl is a weak base that is highly lipid-soluble, protein-bound, and protonated at physiological pH. All of these factors allow it to rapidly cross cellular membranes, contributing to its quick effect in the body and the central nervous system. Mechanism of action
Fentanyl, like other opioids, acts on opioid receptors. These receptors are G-protein-coupled receptors, which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus. The extracellular N-terminus is important in differentiating different types of binding substrates. When fentanyl binds, downstream signaling leads to the inhibitory effects, such as decreased cAMP production, decreased calcium ion influx, and increased potassium efflux. This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation of nociceptive signals, resulting in analgesic effects.As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine. It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to more easily penetrate the central nervous system.