Coffee—Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine
American Journal of Hypertension
Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine
David G. Bailey
George K. Dresser
Brad L. Urquhart
David J. Freeman
John Malcolm Arnold
OBJECTIVES A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2 × 300 ml), felodipine maximum recommended dose (10 mg), and coffee plus felodipine were tested in middle-aged normotensive subjects.
blood pressure; calcium channel blockers; coffee; drug interactions; felodipine; hypertension; pharmacodynamics; pharmacokinetics
Coffee is a globally popular beverage. More than half of the
population over the age of 18 years has purchased an
estimated $40 billion of coffee each year in the United States
alone.1 Coffee can acutely increase blood pressure.2–4 Caffeine
alone also caused an acute pressor response, while
decaffeinated coffee lacked this effect.2,3 Thus, caffeine appears to be
the major active constituent responsible for modifying blood
pressure. Following ingestion of coffee, brachial systolic and
diastolic blood pressure increased and heart rate modestly
decreased likely as a result of enhanced arterial resistance
and withdrawal of baroreflex-mediated sympathetic activity,
respectively.5–8 Aortic systolic blood pressure was enhanced
by the additional mechanism of greater arterial stiffness that
caused the pressure pulse wave from left ventricular
contraction to return sooner adding more to systolic pressure and
reducing further coronary artery perfusion.9–14 Pulse
pressure was heightened through an inotropic effect.15
The acute actions of coffee have been proposed as a
trigger for adverse cardiovascular events.3 Subsequently, coffee
or caffeine consumed less than daily was associated with
myocardial infarction and stroke.16–18 Regular daily
ingestion had a minimal effect on blood pressure from tolerance
development and was not linked with these outcomes.2–4,19
Thus, the duration of time without coffee appears to be an
important determinant of circulatory effects. This interval
has been reported to be 4–5 times the elimination
halflife of caffeine (range: 2–10 hours) which would result in a
more than 95% decrease of plasma caffeine concentration.2,3
A recent survey found that 17% percent of 1,355 consumers
ingested coffee only 2 or fewer days per week.20 Thus, a large
1Lawson Health Research Institute, London Health Sciences Centre,
Western University, London, Ontario, Canada; 2Department of Medicine,
Schulich School of Medicine and Dentistry, Western University, London,
Ontario, Canada; 3Department of Physiology and Pharmacology,
Schulich School of Medicine and Dentistry, Western University, London,
number of people who routinely ingest coffee or caffeine less
than daily may have a regular undesirable pressor response.
Clinical pharmacodynamic interaction investigations
between coffee and antihypertensive drugs have been
reported in only 2 studies conducted more than 3 decades
ago to our knowledge.21,22 Coffee-mediated pressor effect
was not altered by a thiazide diuretic or beta-blocker
(propranolol or metoprolol) in normotensive or hypertensive
individuals. In contrast, caffeine-associated elevation of
blood pressure was prevented by the dihydropyridine
calcium channel blocker, nifedipine.23 However, nifedipine was
administered as an immediate release capsule which caused
rapid absorption and marked vasodilatation. Since this
formulation was linked with higher cardiovascular
morbidity and mortality, it is no longer recommended for clinical
Current evidence-based hypertension guidelines provide
no advice either for or against coffee consumption during
pharmacotherapy.27–30 However, a recent meta-analysis
showing that the acute effects of caffeine were associated
with reduced efficacy of an antihypertensive drug concluded
that formal interaction studies are now necessary in order to
establish more precise recommendations for combinations
of coffee and a specific type of antihypertensive medication.4
We investigated the acute interaction between a
commonly consumed amount of consistently brewed black
coffee and a representative dihydropyridine calcium channel
blocker, felodipine, given as the slow-release formulation at
maximum recommended dose. Middle-aged normotensive
subjects avoided ingestion of coffee and other sources of
caffeine for 2 days before testing. Hemodynamics (peripheral
and central) and pharmacokinetics (caffeine and felodipine)
Thirteen subjects (4 men and 9 women; mean age 52 years
(range, 31–65 years); 9 coffee consumers/4 noncoffee
consumers) were tested. They were healthy as determined by
medical history, physical examination and routine
hematologic, and serum chemical testing. No subject had significant
illness within the preceding 2 weeks, received an
investigational drug within the previous 4 weeks or had a history
of cardiac, renal, hepatic, gastrointestinal disease, or drug/
alcohol abuse. The University of Western Ontario Research
Ethics Board for Health Sciences Research Involving Human
Subjects approved the study and all subjects provided
written informed consent.
An acute 3-way crossover, randomized, open-labelled
hemodynamic and pharmacokinetic investigation was
conducted. Each study day was separated by an interval of at least
1 week. Subjects avoided coffee, other caffeine-containing
foods, grapefruit, Seville orange (marmalades), lime,
pommelo, tobacco, alcoholic drinks, medications (prescription
or over-the-counter), or natural health products for 48 hours
before each study day. Testing was preceded by a 10-hour
overnight fast. On each study day, female participants had a
urine test prior to administration of any study intervention
to confirm that they were not pregnant. Hemodynamics and
plasma drug concentrations were determined at baseline
and hourly intervals to 8 hours after administration of the
treatment. The treatments were as follows: (i) black coffee,
(ii) water plus felodipine, and (iii) black coffee plus
felodipine. Water at room temperature or black coffee (300 ml)
were ingested twice, once at study hour 0 (baseline) and
again at hour 1. Black coffee was made from a single source
of medium-roasted beans (Columbian Supremo,
idrinkcoffee.com, Milton, ON, Canada). The beans were ground to
medium coarseness and 3 tablespoons per 300 ml of cold
double-distilled water were freshly brewed in a Starbucks
Barista Aroma Grand Thermal Coffee Maker. Felodipine
was given at the maximum recommended dose as a 10 mg
extended-release tablet (Plendil; Astra Pharma, Mississauga,
ON, Canada) at study hour 0. A standardized lunch was
provided 4 hours after drug dosing (noon) which consisted of a
sandwich, ginger ale and ice cream sandwich. Tobacco and
other caffeine-containing foods were not permitted during
Peripheral (brachial systolic and diastolic blood pressure
and heart rate) and central (aortic systolic, pulse, and
augmentation blood pressure) measurements were the mean of
at least 3 sitting readings after 5 minutes of rest. The
respective instruments used were BpTRU Vital Signs Monitor
(BpTRU Medical Devices, Coquitlam, BC, Canada) and
SphygmoCor CP Pulse Wave Analysis System—Research
(AtCor Medical, Itasca, IL).
Assay of felodipine and primary metabolite
Plasma samples were analyzed according a modified
previously published method.31 Sensitivity was increased by
extracting plasma (500 µl) with toluene (250 µl) containing
the internal standard (H165/04; AB Haessle, Gothenburg,
Sweden) by gentle oscillation of the mixture overnight
followed by centrifugation and freezing of the aqueous phase
at −20 °C before injecting the extract (1 µl) of supernatant
toluene phase. The retention times of felodipine,
dehydrofelodipine, and internal standard were 20.1, 14.5, and 21.7
minutes, respectively. The coefficients of variation for plasma
felodipine and dehydrofelodipine concentrations were 4.7%
and 2.9% at 1.0 ng/ml (n = 5). The limit of detection was
0.25 ng/ml for both.
Assay of caffeine
Plasma and coffee samples were quantified for caffeine
based on an earlier procedure.32 The method employed solid
phase extraction followed by analysis on a Waters H-class
Ultra Performance Liquid Chromatography system
coupled to a Waters photodiode array detector. Briefly, plasma
(200 µl) was diluted with water (800 µl) and internal standard
American Journal of Hypertension 29(
) December 2016 1387
(7-β-hydroxypropyl theophylline, 50 µg/ml) solution (50 µl).
The samples were then passed across Strata-X solid phase
extraction cartridges (Phenomenex, Torrance, CA) followed
by water (2 × 1 ml) and 20% methanol/water wash solution
(1 ml). The analytes were eluted into clean dry glass test
tubes with methanol (1 ml) containing 0.1% triethylamine
and 0.1% trifluoroacetic acid and evaporated to dryness.
The residue was reconstituted in 0.1% acetic acid in water
(200 µl). Analytes were separated on a Phenomenex Kinetex
XB-C18 (50 × 2.1 mm, 1.7 µm) column maintained at 40 °C
using an isocratic mobile phase consisting of 5 mM KH2PO4
with 0.1% triethylamine (pH = 4.0) and acetonitrile in a ratio
of 90:10. The column was washed with 80% acetonitrile for 1
minute and re-equilibrated at initial conditions for 1 minute
prior to the next injection. Caffeine and 7-β-hydroxypropyl
theophylline were eluted with retention times of 0.64
minutes and 0.82 minutes, respectively, and were well resolved
from matrix components and other contaminants. Caffeine
and internal standard 7-β-hydroxypropyl theophylline were
monitored at 270 nm. The coefficient of variation of the assay
was 5.8% with a limit of accurate quantitation of 0.2 µg/ml.
The assay of caffeine in coffee was the same except that
samples were diluted 125-fold prior to solid phase extraction.
The area under the plasma drug concentration-time
profile (AUC) was calculated from 0 to 8 hours by the linear
trapezoidal method. Plasma peak drug concentrations (Cmax)
and the time to reach Cmax (tmax) were obtained directly from
the experimental data. The terminal elimination rate
constant (ke) was determined by log-linear regression of the
final data points (at least 3). The apparent elimination
halflife of the log-linear phase (t1⁄2) was calculated as 0.693/ke.
Analysis of variance for repeated measures was used for
initial comparisons among the groups. For those analyses
with P <0.05, Bonferroni test for multiple comparisons was
subsequently conducted between selected pairs of
treatments. Linear regression analysis was used to assess
relationships between study parameters. Results are presented as the
mean ± SEM or 95% confidence interval.
Coffee. Brachial (systolic, diastolic) and aortic (systolic,
pulse, augmentation) blood pressures with coffee alone
increased above baseline by hour 1 (Figure 1). Heart rate
decreased. Since the changes from baseline compared to study
hours 1–4 were similar, the average of these 4 measurements
was calculated to determine the overall treatment effect
during this timeframe (Table 1). Hemodynamic parameters were
fundamentally altered following lunch from hours 5 to 8.
Individual responses for brachial (systolic, diastolic) and
aortic (systolic) blood pressures 1–4 hours with coffee alone,
1388 American Journal of Hypertension 29(
) December 2016
respectively, ranged from a modest decrease (−3, −3, −3 mm
Hg) to a marked increase (17, 10, 17 mm Hg) compared to
baseline (Figure 2).
Coffee plus felodipine. Brachial (systolic, diastolic) and
aortic (systolic) blood pressures 1–4 hours with coffee plus
felodipine were elevated compared to those with felodipine
alone. Brachial blood pressures 5–8 hours were also higher.
Individual pressure differences were variable. At the
lowest range, 1 individual had brachial (systolic, diastolic) and
aortic (systolic) 1- to 4-hour pressure readings, respectively,
decreased by −13, −2, and −15 mm Hg with coffee plus
felodipine compared to felodipine alone, respectively. This
individual also had a nonpressor effect with coffee alone (−3, −3,
−3 mm Hg) and nearly double the plasma felodipine
concentration with the combination (AUC0–4 5.6 vs. 3.4 ng h/ml).
At the highest range, another individual had blood pressures
correspondingly increased by 23, 10, 27 mm Hg with coffee
plus felodipine compared to felodipine alone. This subject
additionally had a minor pressor effect with coffee alone
(2, 3, 5 mm Hg) and a markedly lower plasma felodipine
concentration with the combination (AUC0−4, 1.2 vs. 6.2 ng h/ml).
Pharmacokinetics and pharmacodynamics
Caffeine. All plasma concentrations of caffeine just
before testing were unquantifiable (<0.2 µg/ml) on the 3
study days in all but 1 subject (0.3 and 0.6 µg/ml).
The pharmacokinetics and dose of caffeine were not
different between coffee alone and coffee plus felodipine (Table 2).
The first cup of coffee alone produced a plasma caffeine
concentration at hour 1 that was associated with higher
blood pressure (Figure 3). Although the second cup directly
thereafter almost doubled plasma caffeine concentrations
between hours 2 and 4 compared to hour 1, no further
increase in blood pressure was observed. Plasma caffeine
concentrations between hours 5 and 8 remained elevated
above that at hour 1.
Felodipine. The pharmacokinetics of felodipine and its
single primary inactive metabolite, dehydrofelodipine, were
not different between felodipine alone and coffee plus
felodipine (Table 3).
Higher plasma felodipine concentration was associated
with greater reduction in diastolic blood pressure among
individuals (Figure 4). These relationships differed between
treatments such that more than doubling of the felodipine
concentration would be required with coffee to produce an
equivalent reduction of blood pressure.
Caffeine had a mean half-life approximating 9 hours in
this investigation. This explains its overall unquantifiable
baseline plasma concentration on study days following no
coffee and other caffeine-containing foodstuffs for 2 days.
Consumption of coffee caused clear hemodynamic changes
that were manifest during 1–4 hours of the study. However,
the food at lunch caused additional actions making
interpretation of the effect of coffee complicated during 5–8
Coffee elevated brachial (systolic, diastolic) and aortic
(systolic, pulse pressure) blood pressure consistent with
previous findings.2,3 It also enhanced the aortic augmentation
pressure from greater arterial stiffness. However, this
accounted for only 20% of the rise in aortic (systolic) blood
pressure indicating that this mechanism was a minor
component. Variability was high among subjects. The effect was
of sufficient magnitude that consumption of coffee prior to a
Coffee + felodipine
29.8 ± 2.4
71.8 ± 11.5
5.3 ± 0.4
2.4 ± 0.2
8.3 ± 1.0
274.0 ± 10.2
routine medical examination might result in the diagnosis of
hypertension in certain individuals.4
Hemodynamics were altered soon after coffee ingestion
and sustained for several hours.2,4 Importantly, we now
report that hemodynamics were not further altered
following the second serving of coffee despite an almost doubling
in plasma caffeine concentration. This suggests that there is
a threshold in terms of the effect of caffeine consumption
on hemodynamics. Thus, the first serving of coffee
containing caffeine 127 mg was associated with acute maximum
hemodynamic changes. The 300ml volume of coffee used
in this study routinely contains 120–240 mg of caffeine.2,3
A lower dose of caffeine, which can be found in other
foodstuffs, might have a similar outcome but this information is
not available to our knowledge.34 Such data would offer
better knowledge of the overall potential for caffeine to cause
adverse pressor effects and misdiagnosis of patients with
The interaction between coffee and felodipine provided
the key aspects of this investigation. Since caffeine and
felodipine had similar pharmacokinetics when given alone
or combined, it indicated that the hemodynamic changes had
primarily a pharmacodynamic basis. One potential
explanation is that caffeine-mediated vasoconstriction modified the
vasodilatory effect of felodipine on arterial vessel resistance
vasodilatation. Pressor actions of coffee were not abolished
during both 1- to 4- and 5- to 8-hour study periods even by
felodipine at the maximum recommended 10 mg dose.
The difference in blood pressure between coffee plus
felodipine and felodipine alone was variable among
individuals. At the lowest range, 1 subject had lower blood pressure
with the combination. This individual also had no pressor
effect with coffee alone and increased felodipine AUC with
the combination. At the highest range, another subject had
higher blood pressure with coffee plus felodipine. This
individual additionally had a pressor effect with coffee alone
and reduced felodipine AUC with the combination. Thus,
the outcome with the combination may be the summation
of pressor response by caffeine and alteration of felodipine
pharmacokinetics by coffee. This is likely individual—
dependent and unpredictable before exposure.
Higher plasma felodipine concentration is correlated with
greater reduction in blood pressure.35 We demonstrated that
coffee altered this relationship. More than double the plasma
felodipine concentration could overcome the average pressor
effect caused by coffee. If blood pressure were assessed after
consumption of coffee, it is possible that the hypertension
healthcare provider might increase the dose of felodipine
or another dihydropyridine calcium channel blocker
having equivalent blood pressure-lowering efficacy.36 Given
the transient effect of caffeine, there might be greater risk
of adverse drug effects especially during the period without
coffee for the occasional consumer. Hypotension, shock, or
acute kidney injury from excessive dose of dihydropyridine
calcium channel blockers may occur in older patients.37,38
Tolerance to the pressor effect of coffee and caffeine is
known to occur with repeated administration.2–4,19 However,
more recent reports indicated that this process is
unpredictable. For example, 1 randomized, double-blind crossover
study assessed caffeine at low (100 mg) or high (200 mg) dose
3 times daily (equivalent to 3 or 6 cups of coffee per day) or
placebo for 5 days in healthy adult men (n = 49) and women
(n = 48).39 Half of the subjects displayed complete loss of
pressor effect while the other half showed little reduction.
These 2 groups did not differ in caffeine dose, gender,
pretreatment blood pressures, or saliva caffeine concentration.
Another study of similar design but differing by extending
blood pressure monitoring to 24 hours had the same
essential outcomes.40 Thus, high scientific quality data suggested
that some daily coffee consumers might also have an
interaction like that observed in this investigation. On the other
hand, coffee contains additional vasoactive substances
(chlorogenic acid, hydroxyhydroquinone, cafestol, kahweol) that
might modify the interaction and would require testing.2–4
A possible shortcoming of this study might be
variability in the normal routine of coffee consumption of subjects
before the start of the study. The pressor effect may be less
for those with daily compared to infrequent ingestion. Yet,
this response to coffee appears to return after avoidance for
4–5 elimination half-lives of caffeine.2,3 Thus, subjects in
this study were without caffeine-containing foods for 2 days
before testing, had a mean caffeine elimination half-life less
than 9 hours (range: 4–15 hours) and recorded an overall
unquantifiable pretreatment plasma caffeine concentration
on study days. Although the main active metabolite
paraxanthine was not measured, the timeframe of 2 days was
adequate for its removal as well.2 On the other hand, a longer
period may be required for some individuals to return
completely to baseline responsiveness. In this case, this suggests
that the data in this study might underestimate the full
magnitude of differences between treatments.
Since a time control arm of the study involving water
alone was not included, it might be argued that the effects of
felodipine and coffee on blood pressure were not adequately
shown. Yet, identical baseline values and consistent direction
and magnitude of change with felodipine and coffee to that
reported previously supported this approach.
In summary, 2 days abstaining from coffee was sufficient
to eliminate caffeine from the systemic circulation. Coffee
containing caffeine (127 mg) caused maximum pressor
effect by 1 hour after intake, which was sustained for several
hours and potentially clinically important in some
individuals. Coffee plus felodipine 10 mg (maximum recommended
dose) elevated blood pressure above felodipine alone through
a pharmacodynamic interaction. This suggests that coffee
consumption acutely blocks the beneficial antihypertensive
effect of felodipine. Our study indicates that an increase of
more than double the dose of felodipine would be required
to abolish the pressor effect of coffee, but this approach has
the possibility to augment the risk of adverse drug events.
Based on our data, occasional coffee consumption may
adversely impact the management of hypertensive patients
treated with dihydropyridine calcium channel blockers.
The authors wish to thank Linda Asher RN for her
contributions related to the organization and conduct of this
clinical trial and Alvin Tieu, BSc, for his assistance in the
determination of plasma caffeine concentrations. This study
was funded by an operational grant from the Heart and Stoke
Foundation of Ontario (NA 7122). http://www.clinicaltrials.
gov Identifier: NCT02232269.
The authors declared no conflict of interest.
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