The
oral antacid, aluminum hydroxide, is commonly used for the treatment of acid
indigestion, gastroesophageal reflux disease and even to reduce phosphate
absorptions in patients with hyperphosphatemia secondary to chronic kidney
disease. Due to its presence as an ingredient in several over-the-counter
(OTC) products, such as Maalox and Mylanta, it is plausible that it could be
used by patients without the consultation or knowledge of a healthcare
provider. While this may not be a problem if that patient is on no other
medications, it could result in the loss of thyroid control in hypothyroid
patients taking levothyroxine (synthetic T4) therapy.1-3 This would be
especially true in patients who take aluminum containing products within 2-4
hours of taking their levothyroxine.(1,3) In fact, pharmacokinetic drug
interaction studies have shown that thyroid stimulating hormone (TSH;
thyrotropin) concentrations increase from an average of 2.62 mU/L up to 7.19
mU/L (normal range or control 0.5 - 5.0 mU/L).(3) This increase would
suggest a significant loss of thyroid control. It appears that the
interaction comes from a reduction in the absorption of levothyroxine.
Most clinicians will say that aluminum or other di- or tri-valent cations will
"chelate" with levothyroxine to prevent absorption, but what does
that actually mean?
What
is the exact mechanism by which aluminum hydroxide actually decreases the
absorption of levothyroxine?
- A basic evaluation of the chemical structure of
levothyroxine reveals that each levothyroxine molecule has one carboxyl group
(R-COOH) as part of its structure.(1,4) The important thing to note about
this carboxyl group as it relates to an interaction with aluminum is its
ionization state (i.e., whether it is charged or uncharged). The carboxyl
group becomes negatively charged when it releases its hydrogen (H+) ion.
- This process is determined by its pKa, which is the pH where there the
medication is present equally in its ionized and nonionized states. The
pKa for carboxyl groups is approximately 1.8 to 2.4.5 Therefore, a pH
above this pKa would result in a greater percentage of the carboxyl groups on
levothyroxine being ionized (or in their negatively charged state).
- Depending on other medications being taken by the patient and the type of food
ingested, the pH of the stomach can easily range from 1 to 6; thus, it is
likely that the pKa of the carboxyl group will be exceeded. However, even
if the patient only takes the aluminum hydroxide along with the levothyroxine
on an empty stomach, the aluminum hydroxide itself can interact with
hydrochloric acid from the stomach to form aluminum chloride and water thereby
increasing the gastric pH.
- Therefore, the magnitude of change in gastric
pH (whether it is from aluminum hydroxide itself or from the combination of
aluminum hydroxide and other medications) will influence the amount of ionized
carboxyl groups found on levothyroxine. Once this ionization has started
to occur, the exposed and negatively charged group on levothyroxine can then
bind to the positively charged aluminum (Al3+) ion that was present in the
medication or supplement administered.
- This final reaction is what most
clinicians refer to when they say that aluminum or a cation (positively charged
molecule) can "chelate" levothyroxine. The degree or
significance of this interaction is, however, dependent on the time of their
exposure to one another and the pH of the environment at the time.
- The
current product package inserts for levothyroxine products recommend separating
the dose of aluminum containing products from levothyroxine by at least 4
hours.(1) This will provide sufficient time for the absorption of
levothyroxine without the presence or interaction of aluminum. This drug
interaction with a common OTC medication highlights the importance for doing a
thorough medication use evaluation.
