Mechanisms by which pharmacologic agents may contribute to fatigue.

Fatigue is a common side effect of medications. This review summarizes some of the mechanisms by which drugs may cause fatigue. One major mechanism by which medications can cause fatigue is by central nervous system (CNS) depression. CNS depression can result from decreased excitatory activity, as is commonly seen with some anticholinergic agents, centrally acting alpha-agonists, and anticonvulsants. CNS depression can also result from increased inhibitory activity within the CNS, as is seen with benzodiazepines and barbiturates, which augment the effects of the inhibitory neurotransmitter, gamma-aminobutyric acid. Opioids also increase inhibitory CNS activity through their interactions with the various subtypes of opioid receptors. Acting outside of the CNS, medications may cause fatigue as a result of either a true or a functional anemia by a number of mechanisms. Bone marrow toxicity, which results in decreased hematopoiesis, is such a mechanism. This is commonly seen with antineoplastics agents, but can also be observed in association with a wide variety of medication classes, including anticonvulsants, antidepressants, and antimicrobial agents. Another way that medications can cause anemia is by increased red blood cell destruction, as is seen with immune hemolytic anemia. Additionally, medications may cause a functional anemia through alteration of the heme group within the hemoglobin molecule, as is seen in methemoglobinemia. Finally, many drugs, including placebos, cause fatigue by unknown mechanisms. In addition to causing fatigue, some medications may be used to help relieve fatigue, although this drug class is limited in number at this point in time.