Adverse Taste Side Effects of Cardiovascular Medications
by Jennifer Zervakis, Ph.D., and Susan S. Schiffman, Ph.D.
| Geriatric Times |
 |
January/February 2002 |
|
Vol. III |
|
Issue 1 |
Cardiovascular disease remains the leading cause of death in the United
States, despite our increased knowledge of the contributing factors and
research into interventions and prevention. Medications used to treat
cardiovascular disease are extensively prescribed, with prescription drug costs
in the United States at $27.1 billion and drug costs for antihypertension alone
at $12.3 billion (American Heart Association [AHA], 2000). The range of
pharmacological interventions utilized in the treatment and control of heart
disease includes diuretics, adrenergic blockers, angiotensin converting enzyme
(ACE) inhibitors, calcium channel blockers and antiarrhythmic drugs.
According to the Physicians' Desk Reference (PDR), taste side effects
are one of the more common complaints for some heart medications, and these
impairments can not only affect a patient's quality of life but can interfere
with patient compliance (Schiffman, 1997). Adverse side effects can especially
impact patient compliance for antihypertensive medications, in which the
disease itself may be symptomless but treatment can be lifelong. In addition,
taste disturbances in the elderly can lead to decreased food intake and weight
loss -- and ultimately poor health outcomes -- in a population already at risk
for nutritional deficiencies.
Clinical observations such as those listed in the PDR are helpful in
identifying potential chemosensory side effects. However, experimental data are
needed in order to quantify taste effects of medications and to learn more
about the mechanisms underlying medication-related taste impairment. One such
investigation examined the effect of topical application of heart medications
on taste. In Zervakis et al. (2000), taste detection thresholds (the point at
which a subject correctly distinguished the stimulus from water) of nine
medications were determined in subjects. The effect of topical application of
these medications to the tongue on subjects' ratings of the drugs and of other
taste stimuli was then assessed. This was studied to determine whether effects
of topical application of the medication (akin to the situation in which the
drug is secreted into the saliva) are related to taste effects of medications
when taken systemically.
Six antihypertensive drugs were tested: captopril (Capoten, Capozide, ACE
inhibitor), diltiazem hydrochloride (HCl) (Cardizem, calcium channel blocker),
enalapril maleate (Vaseretic, ACE inhibitor), hydrochlorothiazide (diuretic),
labetalol HCl (Normodyne, Trandate, adrenergic receptor blocker) and
propranolol HCl (Inderal, ß-adrenergic receptor blocker). Three
antiarrhythmia drugs were tested: mexiletine HCl (Mexitil), procainamide HCl
(Procanbid) and propafenone HCl (Rythmol).
Elderly individuals were included because the majority of patients on heart
medications are older than age 65 (AHA, 2000), and elderly patients generally
experience proportionally more medication side effects than young patients
(Dawling and Crome, 1989; Parker et al., 1995). Next, the effect of lingual
drug application on taste evaluations of nine taste stimuli was evaluated in
healthy young individuals.
Method
Subjects. The subjects were healthy nonsmokers. Elderly subjects
ranged in age from 69 years to 82 years (mean age=74 years). Young subjects
ranged in age from 19 years to 44 years (mean age=26 years).
Threshold studies. Taste detection thresholds were determined for
each drug using the triadic forced-choice ascending-series method described in
Zervakis et al. (2000). In addition, at four times higher than the detection
threshold concentration, subjects were asked to rate the taste quality of each
drug using 14 common taste descriptors (e.g., sweet, salty, sour) on nine-point
scales ranging from 0 (none at all) to 8 (maximal intensity).
Suprathreshold studies. The effect of each drug's lingual application
on intensity and descriptor ratings of nine tastants was evaluated. The
tastants (and their predominant tastes) were the following: sodium chloride
(NaCl) (salty), potassium chloride (KCl) (salty, bitter, sour), calcium
chloride (CaCl2) (bitter, salty), sucrose
(sweet), quinine HCl (bitter), citric acid (sour), capsaicin (pungent,
burning), n-ethyl-p-menthane-3-carboxamide (WS-3) (menthol-like taste) and
ferrous sulfate (FeSO4) (metallic). Solutions
for the seven water-soluble tastants were prepared in deionized water;
capsaicin and WS-3 were dissolved in ethanol and then dried on paper discs. For
all medications except labetalol, two concentrations of each tastant were
tested. Subjects rated the taste of the tastant before and after topical
application of the medication applied at a concentration slightly above taste
detection threshold.
Results
Thresholds. The taste detection thresholds along with the standard
errors for each drug in water are given in Table 1.
The elderly group demonstrated numerically, but not statistically
significantly, higher detection thresholds than the healthy young group for the
drugs using t-tests (p>0.05). Hydrochlorothiazide did not demonstrate a
taste during pretesting; no thresholds were performed.
Taste profiles. The taste profiles for each drug are illustrated in
Figures a-h. Each figure shows the taste profile of
the drug at four times the average detection threshold for both the young and
elderly group. Descriptors with an average rating of less than 1 (very weak)
are not included.
As these figures show, the young group rated the taste of most drugs as
primarily bitter (with additional metallic or medicinal qualities) and
captopril and enalapril maleate as primarily sour. The elderly group rated all
drugs as primarily bitter. Additionally, the elderly included many more side
tastes in their taste descriptions. Therefore, although the elderly group's
thresholds did not statistically differ from the young group's, their
descriptions qualitatively differed. This may be evidence of subclinical
dysgeusia (distortion of taste) in elderly people, even though the older
participants in this study were healthy and taking minimal medications.
Suprathreshold studies. Ratings of the tastant before versus after
topical application of each drug solution were compared. An overview of the
significant taste effects of topical application of antihypertensive drugs to
the tongue is given in Table 2a. An overview of the
significant taste effects of topical application of antiarrhythmia drugs is
given in Table 2b.
The medications in the study had varying effects on taste; this was expected
because different classes of cardiovascular drugs were examined. Captopril was
found to reduce the intensity of sucrose and KCl. This is consistent in part
with a previous psychophysical study in which patients on captopril for a short
period of time (<six months) had higher recognition thresholds for sucrose
and NaCl (Abu-Hamdan et al., 1988); patients on long-term captopril treatment
experienced declines in thresholds for all four basic tastes. It is not known
how captopril causes taste changes. Captopril is one of a number of drugs that
contain a sulfhydryl group. It has been hypothesized that medications with an
active sulfhydryl group induce hypogeusia in part via zinc deficiency (Jaffe,
1986).
Topical application of labetalol decreased the taste qualities of CaCl2 and quinine HCl and increased ratings of
capsaicin. Diltiazem increased taste qualities of CaCl2, sucrose and citric acid and decreased the
intensity of WS-3. The pattern of increasing the perceived intensity of some
tastants while decreasing others may be related to reports of taste distortion
and dysgeusia for these two drugs, according to the PDR.
Hydrochlorothiazide also exhibited a similar pattern of increasing the
perceived intensity of some tastes (CaCl2),
and decreasing others (sucrose, WS-3).
Enalapril and propranolol did not demonstrate much effect on taste when
applied to the tongue. Like captopril, enalapril is an ACE inhibitor, but,
unlike captopril, it does not have a sulfhydryl group. Switching from captopril
to enalapril can sometimes resolve taste disturbances (Rucinska et al., 1989).
The incidence of clinical taste effects of propranolol is very low.
Propafenone's primary clinical taste complaint is a bitter or metallic taste
(Dinh et al., 1988). Propafenone demonstrated low detection thresholds and was
described as very bitter by participants. Additionally, a lingual application
of propafenone reduced the intensity and perceived bitterness of quinine HCl,
presumably due to taste adaptation. In this study, the average detection
threshold for propafenone (0.048 mM) was above the therapeutic concentration of
the drug in plasma (0.00384 mM) or saliva (0.0016 mM) (Mason et al., 1987).
However, three of the 12 young subjects detected propa-fenone at the lowest
concentration tested (0.00195 mM), close to the therapeutic concentration of
propafenone in saliva. It is possible that a certain percentage of individuals
may perceive the taste of propafenone in saliva, even at therapeutic drug
levels.
Both mexiletine and procainamide demonstrated taste effects on numerous
taste stimuli. These results could account for reports of dysgeusia for these
medications. Although a controlled amount of medication was used in the lingual
application studies performed here, procainamide concentrations in saliva
during therapeutic use may differ widely from plasma concentrations (Koup et
al., 1975); this is also true for mexiletine. The concentration of the drug in
saliva varies depending on a number of factors, including the individual's
salivary pH.
Summary
The present study indicates that heart medications can affect taste at the
peripheral (taste receptor) level. The mechanism of how medications induce
clinical taste changes is not fully understood. Medications may affect taste
through a number of pathways (Ackerman and Kasbekar, 1997), including effects
on peripheral receptors, nerve damage, nutritional/metabolic disturbances and
central nervous system interactions. Additional studies must be performed to
further understand why some patients experience taste effects and others do
not. Particular efforts should be made to minimize taste side effects in the
elderly, due to their potential impact on medication compliance and nutritional
well-being.
Dr. Zervakis is research associate in the department of
psychiatry at Duke Medical Center. She studies the effect of medications,
disease and the aging process on taste perception.
Dr. Schiffman is professor of medical psychology at the department of
psychiatry at Duke Medical Center. She is an internationally recognized
authority on taste and smell whose recent research has focused on how taste and
odor influence food intake and nutritional status, with an emphasis on taste
and smell issues in the aging population.
References
Abu-Hamdan DK, Desai H, Sondheimer J et al. (1988), Taste acuity and zinc
metabolism in captopril-treated hypertensive male patients. Am J Hypertens 1(3
pt 3):303S-308S.
Ackerman BH, Kasbekar N (1997), Disturbances of taste and smell induced by
drugs. Pharmacotherapy 17(3):482-496.
AHA (2000), 2001 Heart and Stroke Statistical Update. Dallas: American Heart
Association. Available at: www.americanheart.org/downloadable/heart/
4838_HSSTATS2001_1.0.pdf. Accessed Nov. 20, 2001.
Dawling S, Crome P (1989), Clinical pharmacokinetic considerations in the
elderly. An update. Clin Pharmacokinet 17(4):236-263.
Dinh H, Baker BJ, de Soyza N, Murphy ML (1988), Sustained therapeutic
efficacy and safety of oral propafenone for treatment of chronic ventricular
arrhythmias: a 2-year experience. Am Heart J 115(1 pt 1):92-96.
Jaffe IA (1986), Adverse effects profile of sulfhydryl compounds in man. Am
J Med 80(3):471-476.
Koup JR, Jusko WJ, Goldfarb AL (1975), pH-dependent secretion of
procainamide into saliva. J Pharm Sci 64(12):2008-2010.
Mason WD, Lanman RC, Kirsten EB (1987), Plasma and saliva propafenone
concentrations at steady state. J Pharm Sci 76(6):437-440.
Parker BM, Cusack BJ, Vestal RE (1995), Pharmacokinetic optimisation of drug
therapy in elderly patients. Drugs Aging 7(1):10-18.
Rucinska EJ, Small R, Mulcahy WS et al. (1989), Tolerability of long term
therapy with enalapril maleate in patients resistant to other therapies and
intolerant to captopril. Med Toxicol Adverse Drug Exp 4(2):144-152.
Schiffman SS (1997), Taste and smell losses in normal aging and disease.
JAMA 278(16):1357-1362.
Zervakis J, Graham BG, Schiffman SS (2000), Taste effects of lingual
application of cardiovascular medications. Physiol Behav 68(3):405-413.