Introduction
Anticholinergic medications are potentially inappropriate for older adults1,2. Clinical experience and research demonstrate an increased risk of serious adverse drug events and mortality related to the use of anticholinergic drugs in older adults (table 1). Due to variability in the anticholinergic activity of individual medications, one in isolation may fail to cause any noticeable effect but when two or three anticholinergic agents are combined the total anticholinergic burden can result in adverse events3–10. Anticholinergic medications may cause mild adverse effects such as; flushing, mydriasis with loss of accommodation, fever, constipation, urinary retention11, or more serious effects such as cardiovascular events10, delirium or cognitive impairment5,12,13. These adverse effects can result in emergency department visits14, hospital admission7 or death10. As older adults are at increased risk of these sequelae, the pharmacokinetics, pharmacodynamics, expected effect and toxicity are important to understand in this population.
Cytochrome P450 (CYP) enzymes mediate the metabolism and pharmacologic activity of anticholinergic medications. Age, sex and genetics can cause variation in CYP enzyme activity which may increase exposure to anticholinergic drugs and influence their clinical effect or toxicity15. The purpose of this review is to analyze the current knowledge on how age, sex, and genetic polymorphisms of CYP2D6, CYP2C19 and CYP3A4 affect the pharmacokinetics (absorption, distribution, metabolism, excretion) and subsequent pharmacologic response of anticholinergic drug, to equip clinicians with an understanding to better predict and avoid anticholinergic adverse events in older adults.

Methods

Data Sources for Review

The PubMed database was searched using all dates available (1950-January 2020) with the initial search terms age, sex, anticholinergic agent and pharmacokinetics. Results of the preliminary search lacked recent studies including human subjects (see appendix 1). A second search included limits of human subjects, English language and clinical trials. In this directed search each term; sex, age and CYP2C19, CYP2D6, CYP3A4 (the most common CYP enzymes involved in the metabolism of anticholinergic drugs), were searched in combination with anticholinergic and pharmacokinetics. This second search identified more specific and more recent studies. Anticholinergic drugs were considered any drugs appearing on the anticholinergic cognitive burden scale16. This review was not meant to be an exhaustive summary of all available literature on the topic but instead a review of the literature to inform clinical decision making about anticholinergic drug use in older adults. If insufficient studies were identified on a topic, further search was completed using the specific pharmacokinetic parameter of interest with each of the search terms sex, age and CYP2C19, CYP2D6 and CYP3A4. The Web of Science database was consulted to find citing articles. Further articles were taken from review articles examined during the literature searches.

Results

Anticholinergic Receptors and Signaling
The term anticholinergic agent refers to drugs that antagonize the muscarinic acetylcholine (M) receptor. The M receptor is a G-protein coupled receptor (GPCR) that resides on the cell membrane. It is comprised of 7 alpha helices that span the cell membrane and possesses an extracellular binding domain. When activated, the GPCR undergoes conformational change that induces dissociation of the trimeric G protein-complex into the free and active Gα and Gβγ subunits. The Gα and Gβγ subunits activate enzyme effectors or ion channels which regulate intracellular concentrations of secondary messengers such as cAMP, cGMP, diacylglycerol, IP3, DAG, arachidonic acid, sodium, potassium or calcium cations depending on the receptor subtype17. Gα and Gβγ activity is terminated by activation of an endogenous high-affinity GTPase located in the Gα subunit which hydrolyzes the terminal γ-phosphate of Gα-GTP to Gα-GDP which then binds Gβγ to reform the trimeric G protein- complex18,19. In response to prolonged signaling, receptors can be internalized by separation from the effector and binding to small endosomes. This desensitizes the receptor by reducing the number of receptors on the cell surface. This occurs in response to receptor phosphorylation which is often related to a hormone response19,20. The five M receptor subtypes and their associated functional response to agonism and antagonism are described in figure 1. M1, M3 and M5 receptors all couple with Gq/11 and lead to release of calcium from the sarcoplasmic reticulum. M2 and M4 receptors are coupled to Gi proteins and their activation leads to inhibition of adenylyl cyclase21,22.
Serum Anticholinergic Activity and Anticholinergic Burden
M receptor antagonists have limited therapeutic use and are predominantly bladder antispasmodics used to treat urinary incontinence. Many other medications have anticholinergic properties despite the M receptor not being the intended receptor for effect23,24. Such agents tend to have a lower level of anticholinergic activity. However, when multiple drugs with low levels of anticholinergic activity are combined the cumulative anticholinergic activity and anticholinergic burden increases23,25–27.
Anticholinergic activity is dependent upon many factors, including: the drug’s binding to the M receptor, its absorption and distribution to tissues (including the brain), its concentration in circulation, intestinal and hepatic cytochrome P450 (CYP) metabolism and drug transport, the presence of any active metabolites that are produced, and the rate of elimination of the parent drug and active metabolites from the body. Since pharmacokinetics can be affected by sex, age or genetic polymorphisms (CYP enzymes) these all must be understood to quantify total anticholinergic activity and rationalize the use of anticholinergic medications in clinical practice.

Sex

Sex differences in pharmacokinetics have been explored with respect to some anticholinergic medications. Results of studies that examined sex differences in anticholinergic drug pharmacokinetics as their primary objective are listed in table 2.