SYSTEMATIC REVIEW

Pharmaco-nutrient interactions a systematic review of

zinc and antihypertensive therapy
L. A. Braun,1,2 F. Rosenfeldt3

1
Department of Pharmacy, The
SUMMARY
Review criteria Alfred Hospital, Melbourne,
Background: Antihypertensive medicines are to known to cause diverse distur- We undertook a systematic review of electronic Vic., Australia
2
Monash Alfred Psychiatric
bances to electrolyte homeostasis; however, their potential to affect zinc is less databases and collected all English language
Research Centre, Melbourne,
well known. The primary aim was to explore whether antihypertensive medicines articles, which reported on results from clinical
Vic., Australia
studies, which were relevant to meeting the aims 3
have the potential to affect zinc status. Methods: A review of electronic databases Cardiothoracic Research Unit,
of the review. We only included studies when the Department of Surgery, Monash
was undertaken. Full-length English language articles describing clinical trials
full-length article was available so that important University, Melbourne, Vic.,
involving antihypertensive medicines and reporting on zinc measurements were details, such as number of study participants, Australia
reviewed. Results: Eight eligible studies were identified which involved the use of medicines used, time frames for use and zinc
ACE inhibitors, thiazide diuretics, beta blockers, or ARB drugs of which five measures were clearly reported. Correspondence to:
included a control group Studies used urinary zinc excretion, plasma zinc levels or Lesley Braun,
Message for the clinic Pharmacy Department, Alfred
erythrocyte zinc as key measures of zinc status. Studies reported increased urinary Hospital, Commercial Road,
The take home message for clinicians is that
zinc losses for captopril (from 50 mg day), enalapril (20 mg day), losartan current evidence suggests that patients using ACE Melbourne, Vic., 3004,
(50 mg day), losartan (50 mg day) together with hydrochlorothiazide inhibitors, ARBs and thiazides long-term could be Australia
(12.5 mg day), captopril (75 mg day) together with frusemide (40 mg day) and Tel.: +61 3 9076 2408
at risk of low zinc. Clinicians should consider the
Fax: +61 3 9076 3407
stand-alone hydrochlorothiazide (25 mg day). Serum levels of zinc decreased with possibility of low zinc nutriture in patients with
Email: l.braun@alfred.org.au
captopril (50150 mg day), verapamil (240 mg day), atenolol (50150 mg day) poor dietary intakes, the elderly people and
and the combination of losartan (50 mg day) and hydrochlorothiazide diabetic patient who has taken these medications Disclosures
(12.5 mg day), eryrthrocyte levels decreased with use of valsartan (80 mg day) long-term. A trial of zinc supplements in suspected LB and FR have received
cases of low zinc is a safe option. research funding from
and in some studies for captopril, but not for metoprolol (100 mg day), atenolol nutraceutical companies
(50150 mg day), verapamil (240 mg day), doxazosin (4 mg day) or amlodipine however the latter were not
10 mg day). Major limitations were that most studies were small and did not involved in any aspect of this
report on dietary zinc intake. Conclusion: The available evidence suggests that review.

use of ACE inhibitors and angiotensin 2 receptor antagonists or thiazide diuretics

have the potential to reduce zinc levels in hypertensive patients. Additional
research using larger participant numbers and accounting for dietary zinc intakes
are required.

routes, the gastrointestinal tract, the kidneys and

Introduction
Zinc is an essential trace element that is vital in
maintaining normal physiology and cellular functions
and is the second most abundant trace metal in the
body, after iron (1). It is required for the catalytic
function of at least 300 enzymes in the body and
plays an important role in the structure of proteins,
cell membranes, regulating gene expression and has
an influence on nerve impulse transmission, hor-
mone release and required for the synthesis and
action of insulin (2).
The main site of zinc absorption in the gastroin-
testinal tract is the proximal small intestine where it
is absorbed into enterocytes using a carrier-mediated
process. Zinc storage occurs mainly in the liver and
kidney and zinc losses occur via three primary
body surface (e.g. shed skin cells and sweat),
although the majority of zinc filtered by the kidneys
is reabsorbed under normal conditions (3).
Unlike iron, zinc cannot be readily mobilised from
body stores when dietary intakes are inadequate or
zinc losses suddenly become pronounced. Only a
small exchangeable zinc pool exists in the human
body, which is sufficient for a few days utilisation
before homeostatic responses are triggered. When
homeostatic mechanisms fail to conserve zinc stores
and ensure requirements are met, clinical symptoms
of zinc deficiency develop. This highlights the impor-
tance of a regular zinc supply.
Conservative estimates suggest that 25% of the
worlds population is at risk of zinc deficiency (4). It
is not just the poor that are at greater risk of

2012 John Wiley & Sons Ltd

Int J Clin Pract, August 2013, 67, 8, 717725. doi: 10.1111/ijcp.12040 717
718 Pharmaco-nutrient interactions
deficiency, but also those living in relatively affluent
countries who rarely consume foods rich in bioavail-
able zinc and consume foods that are rich in bio-
availability inhibitors, chiefly phytates (4)
Hypertension is prevalent in Western societies and
most commonly treated with antihypertensive medi-
cines that are prescribed long-term. Resistant hyper-
tension has been estimated to make up 2030% of
those diagnosed with hypertension and is commonly
treated with combination therapy, which may prove
more effective for some patients, but also raises the
risk of adverse consequences (5). It is known that
antihypertensive medicines cause diverse disturbances
to electrolyte homeostasis and drug-induced electro-
lyte alterations are relatively common with the use of
diuretics, angiotensin converting enzyme (ACE)
inhibitors and angiotensin 2 receptor blockers
(ARBs) (6).
The possibility that long-term use of antihyperten-
sive medicines affect zinc pharmacokinetics is of partic-
ular relevance for patients with conditions associated
with disturbances of zinc homeostasis, such as diabetes,
liver cirrhosis, bowel diseases and impaired immune
function and for those people at risk inadequate dietary
zinc intakes and more likely to use combination ther-
apy, such as the elderly people (7).
The primary aim of this systematic review was to
explore whether commonly prescribed antihyperten-
sive medicines have the potential to affect zinc sta-
tus.
Methods
In this review, we searched MEDLINE and Science
Direct for relevant clinical studies using the keywords
zinc and diuretic, thiazide, beta-blocker, beta tension, but no change in erythrocyte zinc levels
receptor antagonist, angiotensin converting enzyme
inhibitor, ACE inhibitor, angiotensin receptor fied diet to alter their lipid profile, which was suc-
inhibitor, ARB calcium channel blocker and the cessful after 6 months. Unfortunately, dietary zinc
disease-specific terms hypertension and blood pres-
sure, Reference lists of articles reviewed were system-
atically examined for further relevant studies. Only
full-text articles limited to the English language and
studies that involved adult cohorts taking antihyper-
tensive medicines were considered.
Results
Eight clinical studies met the inclusion criteria for
this systematic review (Table 1). Studies had been
conducted since the 1980s involving various antihy-
pertensive agents, including thiazide diuretics, fru-
semide, ACE inhibitors (mainly captopril, but also
enalapril, perindopril), losartan and valsartan, the
calcium channel blocker amlodipine and several beta
blockers (metoprolol, atenolol). The most commonly
used measures were urinary zinc excretion and
plasma zinc levels with some studies reporting on
erythrocyte zinc levels. Typically, studies involved
only a small number of participants; however, five
studies included an untreated control group adding
more rigour to their findings. Several intervention
studies were also identified thereby enabling compar-
isons between baseline and after treatment effects. Of
all the relevant studies identified, only one consid-
ered the effects of dietary zinc intake.
Thiazide diuretics
Thiazide diuretics are widely used for volume reduc-
tion and hypertension and have been shown to
induce zincuria in two small pilot studies (8,9).
According to one study, a significant 60% increase in
24-h zinc excretion was observed (8). A larger study
conducted by Khedun et al. (1995) evaluated serum
zinc in 39 middle aged hypertensive men who had
taken hydrochlorothiazide for at least 6 months and
compared it to 27 unmedicated, healthy middle aged
controls (10). Serum zinc levels were shown to be
significantly lower in 20 of the treated patients.
Beta blockers
Two studies have investigated the effects of beta-
blocker usage on zinc (11,12). One study found no
significant effects on plasma or erythrocyte zinc levels
for metoprolol (100 mg day) taken for 3 months
when compared with a healthy, untreated group used
as controls (11). In contrast, another study found a
significant decrease in serum zinc after 3 months and
again after 6 months of atenolol (50150 mg day)
use by people with mild or moderate essential hyper-
(12). In this study, patients were also put on a modi-
intakes were not compared before or after the test
period, hence, the contribution of a modified diet
cannot be ruled out.
Calcium channel blockers
The effect of 3 months treatment with amlodipine
(10 mg daily) on plasma and erythrocyte zinc was
tested in 20 hypertensive volunteers and compared
with 51 healthy, untreated controls (11). After the
test period, no significant changes were seen for
either plasma or erythrocyte zinc measures when
compared with the untreated group.
ACE inhibitors
Abu-Hamdan et al. (1988) measured plasma zinc lev-
els and urinary zinc excretion in 31 hypertensive
2012 John Wiley & Sons Ltd
Int J Clin Pract, August 2013, 67, 8, 717725
 Table 1 Results from clinical trials

Patient Antihypertensive
Clinical trial N characteristics drug therapy Treatment period Zinc measures and results ( total range) Other relevant findings

Koren-Michowitz 17 Mild-to-moderate Losartan (50 mg day) 4 weeks on sole Urinary Zn creatinine ratio: There was a significant correlation
et al. (2005) (18) hypertensive patients with Losartan (50 mg day) therapy Treatment with losartan resulted in a significant increase between baseline serum Zn levels and

2012 John Wiley & Sons Ltd

normal renal and hydrochlorothiazide Additional 4 weeks from 0.020 0.004 lg mg to 0.034 0.005 lg mg the degree of change in serum Zn
function (12.5 mg day) of combination (p = 0.02) after losartan hydrochlorothiazide
therapy Treatment with losartan hydrochlorothiazide produced a treatment.
significant increase from 0.034 0.005 lg mg Patients with higher baseline serum Zn
to 0.053 0.008 lg mg (p = 0.03) levels had more pronounced decreases

Int J Clin Pract, August 2013, 67, 8, 717725

Serum zinc: in serum Zn after treatment
Treatment with losartan hydrochlorothiazide produced Four patients with hypozincemia at
a significant decrease from 80.0 4.0 lg dl at baseline baseline, had no change to serum Zn
to 74.0 3.0 lg dl (p = 0.007) levels & remained below the normal
reference range after both treatment
periods.
Abu-Hamdan 31 Hypertensive Captopril 266 > 6 months Plasma zinc:
et al. (1988) (14) patients (n = 17) (34) mg day < 6 months High-dose captopril users had significantly lower plasma
and unmedicated Captopril 104 zinc than controls; (91 3 vs. 100 3 mcgm dl,
hypertensive (40) mg day p < 0.05)
controls (n = 14) Un-medicated controls Urinary zinc excretion:
High-dose captopril users had significantly higher zinc
excretion than controls; 1017 89 vs. 609 76
micrograms day, p < 0.005)
Golik et al. 28 Hypertensive Captopril 100 mg day > 3 months Urinary zinc excretion:
(1990) (15) patients (n = 19) Enalapril 20 mg day Captopril use significantly increased 24 h urinary excretion
and healthy Untreated hypertensives compared to other groups
controls (n = 9) Healthy controls Erythrocyte zinc:
Captopril use significantly reduced red cell zinc compared
to other groups
No significant change to erythrocyte zinc for enalapril
Urinary zinc creatinine:
significantly increased in both ACE inhibitor groups
compared to the untreated controls; captopril treatment
had the greatest effect
Pharmaco-nutrient interactions
719
 720
Table 1 Continued

Patient Antihypertensive
Clinical trial N characteristics drug therapy Treatment period Zinc measures and results ( total range) Other relevant findings

Golik et al. 44 Hypertensive Captopril (75 mg day) > 3 months Urinary zinc excretion:
(1990) (17) patients (n = 36) Hydrochlorothiazide captopril, hydrochlorothiazide, combination captopril
and healthy (25 mg day) and hydrochlorothiazide resulted in significantly greater
control group Captopril (75 mg day) zincuria than controls and untreated hypertensives
(n = 8) and hydrochlorothiazide Controls vs captopril vs hydrochlorothiazide vs captopril
(25 mg day) and hydrochlorothiazide vs untreated hypertensives
Captopril (75 mg day) 473 vs 1550 vs 1196 vs 1230 vs 404 (lg 24 h)
and frusemide Serum zinc:
(40 mg day) No significant differences between groups
Un treated hypertensive
controls
Pharmaco-nutrient interactions

Healthy controls
Golik et al. 52 Hypertensive Captopril 6 months Serum zinc: *Drug doses not reported
(1998) (11) patients (n = 42) Enalapril Remained unchanged from baseline for all three groups
and healthy Unmedicated healthy 24 h urinary zinc excretion:
controls (n = 10) controls A significant increase was observed for captopril compared
to baseline (1244 154 lg 24 h vs 461 32
(p < 0.001)
No significant change for enalapril treatment
Intracellular zinc:
Captopril treatment resulted in a significant decrease from
5.8 2.4 to 3.9 1.2 nmol mg protein (p < 0.01)
Enalapril treatment resulted in a significant decrease from
5.3 2.5 to 4.1 2.3 nmol mg protein (p = 0.04)
No significant changes for controls
Baykal et al. 153 Hypertensive Valsartan (80 mg day) 3 months Intra-erythrocyte zinc (lg dl):
(2003) (13) patients (n = 102) Metoprolol Valsartan induced a significant decrease from 8.84 2.45
healthy controls (100 mg day) to 6.58 2.42 lg ml (p = 0.005)
(n = 51) Doxazosin (4 mg day) Metoprolol, doxazosin and amlodipine did not induce a
Amlodipine significant change to erythrocyte zinc
(10 mg day)
Trasobares 35 Heart failure Treatment: ACE 3660 h after Serum zinc (lg dl):
et al. (2007) (26) (n = 11) patients inhibitors and treatment Serum zinc levels were lower in the treated group
and healthy age frusemide further commenced compared to controls (67.27 vs 87.32) (p = 0.001)
matched controls treatment details Urinary zinc excretion:
(n = 24) not reported Urinary zinc excretion was significantly higher in the treated
group compared to controls (2.24 vs 0.21) (p < 0.001)

Int J Clin Pract, August 2013, 67, 8, 717725

2012 John Wiley & Sons Ltd
 Pharmaco-nutrient interactions 721

patients, 17 of whom were taking captopril (13). Of

At baseline, no difference in serum or

those receiving captopril, 11 were described as long-

red cell zinc between controls and

term, high-dose users (more than 6 months,
266 34 mg day) and the remaining six as short-
Other relevant findings

term, lower dose users (less than 6 months,

104 40 mg daily dose). Compared with non-
hypertensives captopril using controls, the long-term captopril
users were found to have significantly lower plasma
zinc and higher urinary zinc losses, whereas no
significant differences were seen for the short-term,
lower dose captopril users.
The response to captopril and enalapril may be

No significant changes seen for any group at 3 or 6 months

somewhat different with regards to zinc losses as
reported by Golick et al. (14). In one study, long-
a significant reduction for all treatment groups after

Hypertensive group vs controls : 113.17 23.98 vs

Captopril baseline vs 6 months 116.63 13.05 vs

term use of captopril (75 mg daily) significantly

atenolol baseline vs 6 months 114.76 19.67 vs
3 months (p < 0.01) and 6 months (p < 0.001)

increased renal zinc loss and induced a significant

Zinc measures and results ( total range)

decrease in red blood cell zinc. In contrast, mild

zincuria was observed in the long-term enalapril
108.12 35.37 vs 94.43 24.84

(20 mg day) group without causing depletion of red

Verapamil baseline vs 6 months

cell zinc levels. The zinc:creatinine ratio in 24 h urine

Intra-erythrocyte zinc (lg dl):

was significantly increased in hypertensives taking

either captopril or enalapril with the greatest change
Serum Zn (lg dl):

observed for the captopril group (14).

107.11 20.88

101.52 20.58

102.09 21.95

More recently, an intervention study evaluating

the effects of 6 months use of captopril or enalap-
ril on the zinc status of 44 patients with newly
diagnosed hypertension identified significantly
increased urinary zinc excretion for the captopril
Treatment period

treated group only and decreased intracellular zinc

levels in both treatment groups compared with
untreated controls (15). Another intervention study
6 months

identified that hypertensive patients taking ramipril

(5 mg daily) for 3 months experienced decreased
plasma zinc and a non-significant decrease in
erythrocyte zinc levels compared with baseline lev-
Verapamil 240 mg day

els (11).
Antihypertensive

50150 mg day

50150 mg day

Comparisons between captopril, hydrochlorothia-

drug therapy

zide and frusemide on urinary zinc:creatinine ratios

Captopril

Atenolol

have been made by Golick et al. (16). The study

comprised of five different patient groups. Four
groups had essential hypertension and were treated
for at least 3 months with stand-alone captopril
patients (n = 30)

controls (n = 30)

(75 mg day), hydrochlorothiazide (25 mg day) or

characteristics

and healthy
Hypertensive

the combination of captopril and hydrochlorothia-

Patient

zide, or captopril and frusemide (40 mg day). The

fifth group comprised of untreated hypertensive
patients acting as controls. Patients on monotherapy
displayed significantly increased urinary zinc creati-
60
N

nine ratios, whereas those on combination therapy

Table 1 Continued

did not.
et al. (1995) (12)

In contrast, a small study of 10 untreated hyper-

Rubio-Luengo
Clinical trial

tensive patients of normal weight and without diabe-

tes identified they had increased urinary zinc
excretion at baseline, which was normalised after
1-month treatment with perindopril (17).

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Int J Clin Pract, August 2013, 67, 8, 717725
722 Pharmaco-nutrient interactions
ARBs
The effect of 4 weeks treatment with losartan
(50 mg daily) as stand-alone treatment or in combi-
nation with 12.5 mg hydrochlorothiazide on zinc lev-
els was investigated in 17 hypertensive patients (18).
Results revealed that both treatments induced zinc
depletion mediated by significantly increased urinary
zinc losses with the greatest effect observed for the
combination treatment. In addition, serum zinc con-
centrations gradually decreased during the study for
both treatment groups. In particular, a significant
correlation was identified between baseline serum Zn
levels and the degree of change in serum Zn after lo-
sartan +hydrochlrohiazide treatment whereby
patients with higher baseline serum Zn levels had
more pronounced decreases in serum Zn after treat-
ment. Of note, patients use of vitamin supplements
was ceased prior to trial commencement and dietary
intake of zinc was monitored and remained
unchanged throughout the test period.
Baykal et al. (2003) identified that use of valsartan
(80 mg daily) by hypertensive patients significantly
reduced plasma zinc and erythrocyte zinc levels after
3 months of treatment when compared with baseline
levels (11). Decreases in zinc levels were consistent
with mild deficiency.
Discussion
Electrolyte disturbances are frequently observed in
relation with antihypertensive therapy and often con-
sidered when selecting optimal treatment. This
review has identified a number of clinical studies,
which suggest that disturbances to zinc nutrition
should also be considered, particularly when antihy-
pertensive therapy is used long term.
The available clinical studies have identified that
zinc levels are affected with long-term use of several
commonly prescribed antihypertensive drugs as mea-
sured by increases in urinary zinc losses, decreases in
plasma zinc levels or erythrocyte zinc. In most
instances, there is only evidence of a potential effect
on zinc from one measure e.g. decreased erythrocyte
zinc for valsartan or changes to urinary zinc excre-
tion with enalapril or hydrochlorothiazide. In few
instances, we have evidence from multiple measures,
e.g. decreased serum zinc and increased urinary
losses when losartan and hydrochlorothiazide are
combined or the effect of captopril shown to
decrease plasma and erythrocyte zinc and increase
urinary zinc losses.
In the case of beta blockers, the evidence is partic-
ularly sparse. Serum zinc levels decreased with the
use of atenolol (50150 mg day), but no effect
was seen for erythrocyte zinc for either atenolol or
metoprolol (100 mg day); however, there is no pub-
lished data on urinary zinc excretion for either drug.
These gaps in evidence and the use of different
measures make interpretation of the evidence diffi-
cult. Although this is indicative of the need for addi-
tional research, it also highlights the problems
inherent in assessing human zinc nutrition, which
are affected by homeostatic adaptations to zinc-poor
situations and issues related to analytical chemistry.
Zinc homeostasis
Major zinc deposits lie in the bone and muscle and are
not readily responsive to changes in dietary zinc or
urinary zinc loss. Instead, the human body draws from
a small functional zinc pool located within the liver
and other tissues for a few days, which allows zinc to
rapidly exchange with the plasma. Once the functional
zinc pool is depleted, deficiency ensues (19).
As part of the bodys homeostatic response, gas-
trointestinal absorption is proportionally increased
when dietary zinc intake decreases (20). This
response may prove sufficient compensation in the
acute phase or when zinc losses are minor, but prove
insufficient with long-term medicine use or when
losses become more pronounced. The observations
made by Abu-Handan et al. (1988) illustrate the
point by finding that high-dose captopril used for
greater than 6 months had a more marked effect on
urinary zinc losses and decreased plasma zinc than
lower dose captopril, used for a shorter period (13).
It also appears that homeostatic responses may be
influenced by the level of existing zinc body stores.
In the study by Koren-Michowitz et al. (18), volun-
teers with higher baseline serum zinc displayed more
pronounced serum zinc decreases than those with
hypozincaemia at baseline who showed no change
with medicine use and remained below the normal
reference ranges after treatment. These findings are
similar to those from animal studies, which describe
a conservation effect where tissue zinc levels are
maintained under conditions of zinc-poor diets and
deprivation (21).
Whether zinc homeostasis remains effective in
people with hypertension has been the subject of
some investigation as loss of zinc homeostasis can be
both cause and effect of high blood pressure (22).
Two small studies suggest that people with untreated
hypertension may have altered homeostatic responses
to zinc, with increased gastrointestinal absorption
and increased urinary excretion observed (17,23).
Potential interaction mechanisms
The evidence of a potential interaction between sev-
eral classes of antihypertensive drugs and zinc is
slowly emerging and far from complete. Despite this,
2012 John Wiley & Sons Ltd
Int J Clin Pract, August 2013, 67, 8, 717725

several proposed mechanisms of action provide bio-
logical plausibility to support the available findings.
Clinical studies suggest that the interaction mecha-
nism has a pharmacokinetic basis and is most likely
caused by inhibition of kidney zinc reabsorption
resulting in zincuria. Whether drug treatment also
affects zinc absorption from the gastrointestinal tract
or other routes of excretion, such as the faeces or
skin, remains unknown.
ACE inhibitors are structurally classified as sul-
phydryl containing ACE inhibitors, such as captopril,
di-carboxyl containing ACE- inhibitors, such as per-
indopril, enalapril and ramipril and phosphonate
containing ACE- inhibitors, such as fosinopril, on
the basis of their binding with ACE. It is well estab-
lished that structural changes to a drug can affect its
activity, an observation which may explain the differ-
ences found for the effects of different ACE- inhibi-
tors on zinc.
It has been proposed that the sulphydryl group
acts as a chelating agent and binds to bivalent metals
such as zinc, thereby inducing zincuria (15). This
theory has been used to explain why captopril has a
more potent effect on zinc levels, as measured by
changes in urine, serum and erythrocytes, when com-
pared with enalapril whose effects are relatively less
impressive. Clinical studies comparing other di-
carboxyl containing ACE inhibitors, such as ramipiril
and perindopril ,to sulphydryl containing ACE inhib-
itors have not been conducted, hence, this theory
remains poorly tested.
More recent research has identified that losartan
also induces urinary zinc losses confirming that the
presence of a sulphydryl group is not essential for
significant zincuria to ensue. The observation that
valsartan induces decreased erythrocyte zinc levels
argues for a class effect possibly related to hemody-
namic or metabolic effects of angiotensin II (18).
Zinc handling in the kidney involves both proxi-
mal and distal reabsorption of filtered zinc, mecha-
nisms which are facilitated by the Na H antiporter.
Angiotensin II is a potent inducer of the Na H an-
tiporter in the proximal tubule, an effect which
increases sodium chloride and bicarbonate reabsorp-
tion. As such, another proposed mechanism for the
ACE-inhibitor ARB interaction with zinc suggests
that blocking angiotensin II causes decreased renal
Na H antiporter activity and a resultant decrease in
tubular reabsorption of zinc leading to zincuria
(18).
Thiazides are amongst the most commonly pre-
scribed diuretics used in hypertension treatment and
are known to inhibit NaCl transport in the distal
tubule. It is herein where zinc reabsorption is also
likely to be affected, resulting in increased urinary
2012 John Wiley & Sons Ltd
Int J Clin Pract, August 2013, 67, 8, 717725
Pharmaco-nutrient interactions 723
zinc losses. Interestingly, thiazide diuretics also
decrease glucose tolerance, unmasking latent diabetes
mellitus during therapy, a consequence, which may
in part be mediated by zinc losses and is worthy of
further investigation.
Beta blockers affect the regulation of circulation
by reducing myocardial contractility and cardiac out-
put and as a consequence of treatment, also reduce
the secretion of renin with a resulting fall in the level
of angiotensin II (24). Theoretically, decreased tubu-
lar reabsorption of zinc may occur as a result of
decreasing angiotensin II levels, much in the same
way that ARBs and ACE inhibitors cause zincuria.
To date, there are no published studies, which have
reported on the effect of beta blockers on urinary
zinc excretion, hence, this theory remains untested.
Clinical significance
Drug-nutrient interactions are an important yet
poorly appreciated category of adverse drug interac-
tions. The effect of antihypertensive medicines on
magnesium, sodium, potassium and calcium are well
documented; however, the effect on zinc is less well
known (6).
Although zinc is ubiquitous in food, low dietary
zinc intake is not uncommon as many food com-
pounds, such as phytate, oxalate, polyphenols and
fibre can form complexes with zinc and inhibit its
gastrointestinal absorption (20).
Long-term use of some antihypertensive drugs
may result in reduced zinc nutriture which becomes
significant in patients already at risk for zinc defi-
ciency such as those with Type 2 diabetes, alcoholism
and malabsorption syndromes, as well as renal insuf-
ficiency (25). The elderly people may be at particular
risk of deficiency caused by their compromised renal
function, tendency to inadequate diets and use of
multiple medications, which can affect appetite and
gastrointestinal function.
Zinc is such a critical element in human health that
even a small deficiency can lead to significant adverse
outcomes, such as anorexia, loss of appetite, smell and
taste failure and compromised immune function (22)
(See Table 2). Furthermore, concurrent zinc deficiency
can complicate the clinical features of several chronic
diseases, such as atherosclerosis, some malignancies,
neurological disorders and age-related degenerative
diseases (21). Zinc deficiency complicates clinical con-
sequences by adversely affecting immunological status,
increasing oxidative stress and increasing generation
of inflammatory cytokines, which can play an impor-
tant causative role in disease. As such, it is important
to assess zinc status in cases where low zinc status may
affect clinical outcomes and potentially lead to frank
deficiency if left unaddressed.
724 Pharmaco-nutrient interactions

Table 2 Signs and symptoms of human zinc deficiency (21)

Body system Clinical signs and symptoms

Central nervous system
Integumentary changes
Gastrointestinal manifestations
Impaired growth and development
Altered reproductive biology
Impaired immunity
Behavioural changes, anorexia, depression, psychosis, hypogeusia, hyposmia, night blindness, seizure disorder, impaired
cognitive performance
Bullous, pustular lesions; keratotic lesions; rough skin; loss of scalp, facial and body hair; impaired wound healing
Diarrhoea, impaired nutrient digestion and absorption
Linear growth retardation; weight loss
Oligospermia; hypogonadism and reduced potency; fetal teratogenesis
Recurrent infections; reduced delayed cutaneous hypersensitivity

The most common test used for zinc status is
measuring circulating concentrations of zinc (in
plasma or serum) followed by whole-blood zinc.
Although measuring circulating zinc is a relatively
uncomplicated process, it only represents a very
small pool of zinc in the body, and is easily influ-
enced by other factors, such as stress and infection,
prolonged fasting and the oral contraceptive pill
(21). Erythrocyte levels can remain stable in the pres-
ence of deficiency and decline much later than
serum, platelets or lymphocytes so are not the ideal
indicator of zinc status either. Confounding factors
should be considered when interpreting test results,
such as increased zinc losses, as a result of recent
haemorrhagia or gastrointestinal wastage into stool.
Because of the difficulties in determining an indi-
viduals zinc status, building a clinical picture sugges-
tive of low zinc is useful (Table 2). It has been
suggested that a therapeutic trial of zinc supplemen-
tation where low zinc is suspected is a reliable
approach to assessing the prevalence of zinc defi-
ciency. People responding to supplementation with a
functional improvement, such as improved appetite,
accelerated growth and improved physiological or
cognitive performance could be classified retrospec-
tively as zinc deficient (21). Ideally, detection and
treatment of suboptimal zinc levels before frank defi-
ciency develops is the optimal approach thereby pre-
venting more serious consequences from developing.
Limitations
The information included in this review results from
an extensive literature search, however, was limited
to English language articles that were available in
their entirety. The limitations of the present data are
largely based on the small sample sizes of the studies
and lack of information about dietary zinc intakes
and whether these changed during the test periods.
Large prospective studies using several measures
and taking into account important confounders, such
as dietary zinc, are necessary to truly examine the
influence of antihypertensive medicines on zinc status.
Conclusion
Good clinical care extends beyond mere diagnosis
and treatment of disease to the appreciation that
nutrient deficiencies can accompany effective drug
therapy and result in adverse consequences if left un-
managed. The available evidence suggests that long-
term use of thiazide diuretics, ACE inhibitors and
angiotensin 2 receptor antagonists may reduce zinc
levels in many, but not all hypertensive patients. The
evidence is most consistent for long-term captopril;
however, there is research also suggesting decreased
zinc for other ACE inhibitors, thiazide diuretics and
ARBs (valsartan 80 mg day; losartan 50 mg day)
whereas the effects of beta blockers on zinc nutrition
remains uncertain.
The clinical significance of these drug-nutrient
interactions needs to be considered on a case-by-case
basis and large-scale recommendations cannot yet be
made until larger studies are performed which take
into account dietary zinc intakes and confirm current
findings. Theoretically, the significance of drug-
induced changes to zinc status is of most relevance
to people at greatest risk of deficiency such as the
elderly or diabetic patient and those patients taking
antihypertensive medicines long-term. It is also of
most concern in those people where decreased zinc
levels will have the greatest clinical consequences.
Author contributions
LB developed the concept, undertook the review and
drafted the article, FR undertook a critical revision of
the article and aided in writing the final manuscript.

2012 John Wiley & Sons Ltd

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10 Khedun SM, Naicker T, Maharaj B. Zinc, hydro- prospective open-label study. Am J Hypertens 2005;
References chlorothiazide and sexual dysfunction. Cent Afr J 18: 35863.
Med 1995; 41: 3125. 19 Lowe NM, Fekete K, Decsi T Methods of assess-
1 Little PJ, Bhattacharya R, Moreyra AE, Korichneva
11 Baykal Y, Yilmaz MI, Celik T et al. Effects of anti- ment of zinc status in humans: a systematic review.
IL. Zinc and cardiovascular disease. Nutrition 2010;
hypertensive agents, alpha receptor blockers, beta Am J Clin Nutr 2009; 89:2040S51S.
26: 10507.
blockers, angiotensin-converting enzyme inhibitors, 20 Groff J, Gropper S. Advanced Nutrition and Human
2 Braun L, Cohen M. Herbs and Natural Supplements
angiotensin receptor blockers and calcium channel Metabolism, 3rd edn. Belmont, USA: Wadsworth,
An Evidence Based Guide, 3rd edn. Sydney: Else-
blockers, on oxidative stress. J Hypertens 2003; 21: 1999.
vier; 2010.
120711. 21 Solomons N Zinc. In: Encyclopedia of Food Sciences
3 Hambidge KM, Miller LV, Westcott JE, Sheng X,
12 Rubio-Luengo MA, Maldonado-Martin A, Gil- and Nutrition, Benjamin Caballero, ed. 2nd edn.
Krebs NF. Zinc bioavailability and homeostasis. Am
Extremera B, Gonzalez-Gomez L, Luna del Castillo Elsevier, 2003: 627783.
J Clin Nutr 2010; 91: 1478S83S.
JD. Variations in magnesium and zinc in hyperten- 22 Tubek S. Role of zinc in regulation of arterial blood
4 Maret W, Sandstead HH. Zinc requirements and
sive patients receiving different treatments. Am J pressure and in the etiopathogenesis of arterial
the risks and benefits of zinc supplementation. J
Hypertens 1995; 8: 68995. hypertension. Biol Trace Elem Res 2007; 117: 3951.
Trace Elem Med Biol 2006; 20: 318.
13 Abu-Hamdan DK, Desai H, Sondheimer J, Felicetta 23 Tubek S. Increased absorption of zinc from alimen-
5 Calhoun DA, Jones D, Textor S et al. Resistant
J, Mahajan S, McDonald F. Taste acuity and zinc tary tract in primary arterial hypertension. Biol
hypertension: diagnosis, evaluation, and treatment:
metabolism in captopril-treated hypertensive male Trace Elem Res 2001; 83: 318.
A scientific statement from the American Heart
patients. Am J Hypertens 1988; 3: 303S8S. 24 Oates J, Brown N. Chapter 33: Antihypertensive
Association Professional Education Committee of
14 Golik A, Modai D, Averbukh Z et al. Zinc metabo- agents and the drug therapy of hypertension. In:
the Council for High Blood Pressure Research. Cir-
lism in patients treated with captopril versus ena- Hardman J, eds. Goodman and Gilmans The Phar-
culation 2008; 117: e51026.
lapril. Metabolism 1990; 39: 6657. macological Basis of Therapeutics, 10 edn. Sydney:
6 Liamis G, Milionis H, Elisaf M. Blood pressure
15 Golik A, Zaidenstein R, Dishi V et al. Effects of cap- McGraw-Hill, 2001: 883.
drug therapy and electrolyte disturbances. Int J Clin
topril and enalapril on zinc metabolism in hyperten- 25 Reyes AJ, Olhaberry JV, Leary WP, Lockett CJ, van
Pract 2008; 62: 157280.
sive patients. J Am Coll Nutr 1998; 17: 758. der Byl K. Urinary zinc excretion, diuretics, zinc
7 Jansen J, Karges W, Rink L. Zinc and diabetes
16 Golik A, Averbukh Z, Cohn M et al. Effect of deficiency and some side-effects of diuretics. S Afr
clinical links and molecular mechanisms. J Nutr
diuretics on captopril-induced urinary zinc excre- Med J 1983; 64: 93641.
Biochem 2009; 20: 399417.
tion. Eur J Clin Pharmacol 1990; 38: 35961. 26 Trasobares E, Corbaton A, Gonzalez-Estecha M
8 Wester PO. Urinary zinc excretion during treat-
17 Tubek S. Urinary zinc excretion is normalized in et al. Effects of angiotensin-converting enzyme inhi-
ment with different diuretics. Acta Med Scand 1980;
primary arterial hypertension after perindopril bitors (ACE i) on zinc metabolism in patients with
208: 20912.
treatment. Biol Trace Elem Res 2006; 114: 12733. heart failure. J Trace Elem Med Biol 2007; 21
9 Golik A, Modai D, Weissgarten J et al. Hydrochlo-
18 Koren-Michowitz M, Dishy V, Zaidenstein R et al. (Supp. 1): 5355.
rothiazide-amiloride causes excessive urinary zinc
The effect of losartan and losartan hydrochlorothi-
excretion. Clin Pharmacol Ther 1987; 42: 424.
azide fixed-combination on magnesium, zinc, and Paper received June 2012, accepted September 2012
nitric oxide metabolism in hypertensive patients: a

2012 John Wiley & Sons Ltd

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