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.