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.

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.

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.

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.

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Adverse Taste Side Effects of Cardiovascular Medications