INTERACCIONES MEDICAMENTOSAS

BIBLIOGRAFA CASO CLNICO N 01

Checking Interactions For:
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Interactions.
Propranolol Hydrochloride
[PROPRANOLOL HYDROCHLORIDE]
ENALAPRIL
[ENALAPRIL MALEATE]
Spironolactone
[SPIRONOLACTONE]
Aspirin
[ASPIRIN]
Digoxin
[DIGOXIN]

Go To Interaction Type:
Click on a link to skip to Interaction.
Drug-Drug Interactions (5 results)
Drug-Food Interactions (2 results)
Drug-Lab Interactions (4 results)
Drug-Ethanol Interactions (2 results)
Drug-Pregnancy Interactions (5 results)
Drug-Lactation Interactions (5 results)

All Severities (contraindicated through

minor)
All Documentation (excellent through
unlikely)

Drug-Drug Interactions: (5 results)

Severity

Documentation Summary

ENALAPRIL --Spironolactone
MAJOR
GOOD

Concurrent use of POTASSIUM-SPARING

DIURETICS and ANGIOTENSIN CONVERTING
ENZYME INHIBITORS may result in hyperkalemia.

Spironolactone --Digoxin
MAJOR

GOOD

Concurrent use of DIGOXIN and SPIRONOLACTONE

may result in digoxin toxicity (nausea, vomiting,
cardiac arrhythmias).

ENALAPRIL --Aspirin
MODERATE

EXCELLENT

Concurrent use of ASPIRIN and ENALAPRIL may

result in decreased effectiveness of enalapril.

Propranolol Hydrochloride --Digoxin

MODERATE GOOD

Spironolactone --Aspirin
MODERATE

FAIR

Concurrent use of DIGOXIN and BETAADRENERGIC BLOCKERS may result in AV block

and possible digoxin toxicity.
Concurrent use of ASPIRIN and SPIRONOLACTONE
may result in decreased spironolactone effectiveness.

Drug-Food Interactions: (2 results)

Severity

Documentation Summary

MODERATE

GOOD

Concurrent use of DIGOXIN and FOOD may result in

decreased peak digoxin concentrations.

Propranolol Hydrochloride
MODERATE

GOOD

Concurrent use of PROPRANOLOL and FOOD may

result in increased propranolol concentrations.

Digoxin

Drug-Lab Interactions: (4 results)

Severity

Documentation Summary

MINOR

GOOD

ASPIRIN may result in false increases in

acetaminophen levels due to acetaminophen assay
interference.

MINOR

GOOD

NONSTEROIDAL ANTIINFLAMMATORY AGENTS

may result in falsely positive fecal hemoccult tests due
to NSAID-induced gastrointestinal bleeding.

Spironolactone
MINOR

GOOD

SPIRONOLACTONE may result in false increases in

digoxin levels due to digoxin assay interference.

FAIR

ASPIRIN may result in falsely increased glucose

measurement due to assay interference.

Aspirin

Aspirin

Aspirin
MINOR

Drug-Ethanol Interactions: (2 results)

Severity

Documentation Summary

MODERATE

GOOD

Concurrent use of ETHANOL and ASPIRIN may result

in increased gastrointestinal blood loss.

FAIR

Concurrent use of PROPRANOLOL and ETHANOL

may result in increased or decreased propranolol
plasma levels.

Aspirin

Propranolol Hydrochloride
MINOR

Drug-Pregnancy Interactions: (5 results)

Severity

Summary

MAJOR

Aspirin is rated as US FDA Category D. Studies, adequate wellcontrolled or observational, in pregnant women have demonstrated a
risk to the fetus. However, the benefits of therapy may outweigh the
potential risk.

MAJOR

Enalapril Maleate is rated as US FDA Category D. Studies, adequate

well-controlled or observational, in pregnant women have
demonstrated a risk to the fetus. However, the benefits of therapy
may outweigh the potential risk.

MODERATE

Digoxin is rated as US FDA Category C. Animal studies have shown

an adverse effect and there are no adequate and well-controlled
studies in pregnant women. (OR) No animal studies have been
conducted and there are no adequate and well-controlled studies in
pregnant women.

Aspirin

ENALAPRIL

Digoxin

Propranolol Hydrochloride
MODERATE

Propranolol is rated as US FDA Category C. Animal studies have

shown an adverse effect and there are no adequate and wellcontrolled studies in pregnant women. (OR) No animal studies have
been conducted and there are no adequate and well-controlled
studies in pregnant women.

Spironolactone
MODERATE

Spironolactone is rated as US FDA Category C. Animal studies have

shown an adverse effect and there are no adequate and wellcontrolled studies in pregnant women. (OR) No animal studies have
been conducted and there are no adequate and well-controlled
studies in pregnant women.

Drug-Lactation Interactions: (5 results)

Severity

Summary

MAJOR

According to the American Academy of Pediatrics, Aspirin should be

given with caution during breast-feeding.

MAJOR

According to the American Academy of Pediatrics, Enalapril Maleate

is compatible with breast-feeding.

MAJOR

According to the American Academy of Pediatrics, Spironolactone is

compatible with breast-feeding.

MINOR

According to the American Academy of Pediatrics, Digoxin is

compatible with breast-feeding.

Aspirin

ENALAPRIL

Spironolactone

Digoxin

Propranolol Hydrochloride
MINOR

According to the American Academy of Pediatrics, Propranolol is

compatible with breast-feeding.

1974-2006 Thomson MICROMEDEX. All rights reserved.

ENALAPRIL - SPIRONOLACTONE

Warning: Concurrent use of POTASSIUM-SPARING DIURETICS and ANGIOTENSIN

CONVERTING ENZYME INHIBITORS may result in hyperkalemia.

Clinical Management: Although such increases are usually transient, monitor serum potassium
levels for persistent elevations in patients on this combination, especially in patients with renal
dysfunction or diabetes and the elderly. Severe arrhythmias and death have been reported from
hyperkalemia with such combinations.

Onset: Delayed
Severity: Major
Documentation: Good
Probable Mechanism: increased potassium retention secondary to lowered aldosterone levels
Summary: Angiotensin-converting enzyme (ACE) inhibitors lower aldosterone levels and can
cause potassium retention (Prod Info Prinivil, 2003). Concurrent use of potassium-sparing diuretics
(spironolactone, canrenoate potassium, amiloride, triamterene) and an ACE inhibitor has been
reported to increase serum potassium by 1 to 1.5 mEq/L when compared to either drug used alone
(Armayor & Lopez, 1988; Burnakis & Mioduch, 1984). This has occasionally resulted in significant
arrhythmias and death (Lakhani, 1986; Johnston et al, 1992).

Literature:
A study evaluated the safety of adding an ACE inhibitor (captopril) to a thiazide/potassium-sparing
diuretic in 332 hypertensive patients whose blood pressure had not normalized with the diuretics
alone. There was only one case of hyperkalemia (6 mmol/liter) and a very low incidence of
hypotension (1.6%) (Schohn et al, 1990).
The effect of adding spironolactone to an ACE inhibitor and a loop diuretic was evaluated in 214
patients with severe chronic congestive heart failure. Patients were randomized to one of five parallel
treatment groups: placebo or spironolactone at a single daily dose of 12.5 mg, 25 mg, 50 mg, or 75
mg for 12 weeks. Hypokalemia (serum potassium less than 3.4 mmol/L) occurred in 10% of placebotreated patients and in 0.5% of the spironolactone group. The incidence of hyperkalemia (serum
potassium greater than or equal to 5.5 mmol/L) was 5% for the placebo group, whereas it was 5%,
13%, 20%, and 24% for the 12.5-, 25-, 50- and 75-mg spironolactone treatment groups, respectively.
Predictors of hyperkalemia included the use of ACE inhibitors other than captopril, ACE inhibitor
dose, and baseline elevation of serum creatinine or potassium levels. The authors concluded that
daily doses of 12.5 mg to 25 mg of spironolactone coadministered with conventional therapy of ACE
inhibitors, loop diuretics, and digitalis are relatively safe, provided that serum potassium levels are
monitored (Anon, 1996).

Reference(s):
Anon : Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a
loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study
(RALES)). Am J Cardiol 1996; 78:902-907.
Armayor GM & Lopez LM: Lisinopril: a new angiotensin-converting enzyme inhibitor. Drug Intell Clin
Pharm 1988; 22:365-372.
Burnakis TG & Mioduch HJ: Combined therapy with captopril and potassium supplementation. A
potential for hyperkalemia. Arch Intern Med 1984; 144(12):2371-2372.
Johnston RT, de Bono DP & Nyman CR: Preventable sudden death in patients receiving angiotensin
converting enzyme inhibitors and loop/potassium sparing diuretic combinations. Int J Cardiol 1992;
34:213-215.
Lakhani M: Complete heart block induced by hyperkalemia associated with treatment with a
combination of captopril and spironolactone (letter). Br Med J 1986; 293:271.
Product Information: Prinivil(R), lisinopril. Merck & Co., Inc., Whitehouse Station, NJ, 04/2003.
Schohn DC, Spiesser R, Wehrlen M et al: Aldactazine/captopril combination, safe and effective in
mild to moderate systemic hypertension: report on a multicenter study of 967 patients. Am J Cardiol
1990; 65:4K-6K.
Copyright 1974-2007 Thomson MICROMEDEX. All Rights Reserved.

DIGOXIN SPIRONOLACTONE

Warning: Concurrent use of DIGOXIN and SPIRONOLACTONE may result in digoxin toxicity
(nausea, vomiting, cardiac arrhythmias).

Clinical Management: During concomitant use of digoxin and spironolactone , monitor the
patient's clinical response and serum digoxin levels to adjust digoxin dosage; downward dosage
adjustments may be necessary. False elevation of digoxin levels may occur with some testing
methods.

Onset: Delayed
Severity: Major
Documentation: Good
Probable Mechanism: inhibition of active tubular secretion of digoxin
Summary: Three possible mechanisms of drug interaction between digoxin and spironolactone
have been described in the literature. Concomitant use of digoxin and spironolactone may result in
increased digoxin plasma levels due to decreased digoxin renal clearance (Prod Info Lanoxicaps,
2003; Hedman et al, 1992; Fenster et al, 1984; Waldorff et al, 1978; Steiness, 1974). Spironolactone
may displace digoxin from tissue binding sites (Waldorff et al, 1978); further studies are needed to
evaluate whether this displacement involves the receptor sites where digoxin exerts its therapeutic
effect. Also, spironolactone and its metabolites can interfere with digoxin radioimmunoassay tests
causing artificially high serum digoxin level results (Thomas & Maddox, 1981).

Literature:
The mechanism of renal handling of digoxin and spironolactone were evaluated (Steiness, 1974).
Simultaneous measurements of inulin and digoxin clearances were performed in 13 digitalized
patients with chronic congestive heart disease. Nine of the patients were subsequently treated with
spironolactone 100 mg daily for 10 days, and the measurements of inulin and digoxin clearances
were repeated. The mean concentration of plasma digoxin increased from 0.8 ng/mL to 1 ng/mL (p
less than 0.01). The data suggests that spironolactone decreases tubular secretion of digoxin in the
distal segment of the renal tubulus. Digoxin radioimmunoassays free of cross-reactivity with
spironolactone and its metabolites were utilized in this study (Thomas & Maddox, 1981).
A study was performed on four patients with arteriosclerotic heart disease and four healthy
volunteers (Waldorff et al, 1978). The subjects were administered 0.75 mg digoxin intravenously,
producing serum levels of 0.93 to 2.4 ng/mL. The subjects then received spironolactone 100 mg
twice daily for five days followed by another digoxin 0.75 mg intravenous dose. Digoxin serum levels
were 1.1 to 3.55 ng/mL. During spironolactone administration plasma and renal clearance of digoxin
and digoxin volume of distribution decreased significantly. The authors concluded that both the
loading dose and maintenance dosage for digoxin may need to be reduced when taking
spironolactone concurrently; also, further studies are needed to evaluate whether spironolactone
displaces digoxin from receptor sites where digoxin exerts its therapeutic effect. Digoxin
radioimmunoassays free of cross-reactivity with spironolactone and its metabolites were utilized in
this study (Thomas & Maddox, 1981).
The effect of quinidine and spironolactone on the pharmacokinetics of digoxin were studied in six
normal subjects who each received digoxin alone, digoxin with quinidine, digoxin with spironolactone,
and digoxin with both quinidine and spironolactone (Fenster et al, 1984). Spironolactone and
quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearance and
prolonged the elimination half-life of digoxin. However, this study may not be valid due to the possible
inclusion of spironolactone metabolites by the digoxin radioimmunoassay utilized (Hedman et al,
1992).

Digoxin kinetic and hemodynamic studies were evaluated in six healthy volunteers during digoxin
administration alone and digoxin plus spironolactone or triamterene (Waldorff et al, 1983).
Spironolactone reduced renal tubular secretion of digoxin and attenuated digoxin's positive inotropic
effect. Results also indicated a drug-receptor interaction between spironolactone metabolites and
digoxin at the hypothesized inotropic digitalis receptor. However, this study may not be valid due to
the possible inclusion of spironolactone metabolites by the digoxin radioimmunoassay utilized.
The effect of spironolactone on digoxin pharmacokinetics in pediatric patients with ventricular septal
defects were studied (Koren, 1985). Twenty-three children (2 weeks to 3 1/2 years in age; 1.5 to 15
kg in weight) were concurrently administered digoxin 9.3 +/- 4.7 mcg/kg/day and spironolactone 2.4
+/- 0.9 mg/kg/day. None of the 23 children exhibited digoxin serum concentrations greater than 2.2
ng/mL or signs of toxicity. A second group of eight children (2 weeks to 3 1/2 years in age) received
digoxin 7.5 mcg/kg/day as a single agent for at least 14 days; spironolactone 2.96 +/- 0.65 mg/kg/day
was then added to the regimen. None of the eight children had elevated serum digoxin levels
following administration of spironolactone.
Spironolactone used concurrently with digoxin can interfere with the radioimmunoassay commonly
used for monitoring digoxin serum levels. This occurs due to the structural similarity of spironolactone
and its metabolites to digoxin (Silber et al, 1979; Huffman, 1974; Wood & Wachter, 1979; Thomas &
Maddox, 1981; Koren, 1985; Pleasants et al, 1989; Foukaridis, 1990). However, many clinicians
(Ravel, 1975; Pers Comm, 1982a; Pers Comm, 1982b) have reported negligible interference with
digoxin radioimmunoassay if therapeutic doses of spironolactone are administered.

Reference(s):
Fenster PE, Hager WD & Goodman MM: Digoxin-quinidine-spironolactone interaction. Clin
Pharmacol Ther 1984; 36:70-73.
Foukaridis GN: Influence of spironolactone and its metabolite canrenone on serum digoxin assays.
Ther Drug Monit 1990; 12:82-84.
Hedman A, Angelin B, Arvidsson A et al: Digoxin-interactions in man: spironolactone reduces renal
but not biliary digoxin clearance. Eur J Clin Pharmacol 1992; 42:481-485.
Huffman DH: The effect of spironolactone and canrenone on digoxin radioimmunoassay. Res
Commun Chem Pathol Pharmacol 1974; 9:787.
Koren G: Interaction between digoxin and commonly coadministered drugs in children. Pediatrics
1985; 75:1032-1037.
Personal Communication: Adam Myers, MD. Denver General Hospital, Denver, CO, Aug, 1982a.
Personal Communication: Earl W Sutherland, MD, PhD, Assistant Professor of Medicine. University
of Colorado School of Medicine, Denver, CO, Aug, 1982b.
Pleasants RA, Williams DM, Porter RS et al: Reassessment of cross-reactivity of spironolactone
metabolites with four digoxin immunoassays. Ther Drug Monit 1989; 11:200-204.
Product Information: Lanoxicaps(R), digoxin. GlaxoSmithKline, Research Triangle Park, NC,
10/2003.
Ravel R: Negligible interference by spironolactone and prednisone in digoxin radioimmunoassay.
Clin Chem 1975; 21:1801.
Silber B, Sheiner LB, Powers JL et al: Spironolactone-associated radioimmunoassay interference.
Clin Chem 1979; 25:48-50.
Steiness E: Renal tubular secretion of digoxin. Circulation 1974; 50:103-107.

Thomas RW & Maddox RR: The interaction of spironolactone and digoxin: a review and evaluation.
Ther Drug Monit 1981; 3:117-120.
Waldorff S, Andersen JD, Heeboll-Nielsen N et al: Spironolactone-induced changes in digoxin
kinetics. Clin Pharmacol Ther 1978; 24:162-167.
Waldorff S, Hansen PB, Egeblad H et al: Interactions between digoxin and potassium sparing
diuretics. Clin Pharmacol Ther 1983; 33:418-423.
Wood WG & Wachter C: A critical appraisal of a further three new commercial digoxin
radioimmunoassay kits with reference to cross-reacting substances. J Clin Chem Clin Biochem
1979; 17:77-83.
Copyright 1974-2007 Thomson MICROMEDEX. All Rights Reserved.

ENALAPRIL ASPIRIN
Warning: Concurrent use of ASPIRIN and ENALAPRIL may result in decreased effectiveness of
enalapril.

Clinical Managemet: Although studies have suggested an interaction between enalapril and
aspirin, the clinician should weigh the benefits against the risks of combining these two agents.

Onset: Rapid
Severity: Moderate
Documentation: Excellent
Probable Mechanism: inhibition of prostaglandin synthesis
Summary: In patients who had suffered an acute myocardial infarction, the concomitant
administration of aspirin and enalapril was shown to have a negative effect on the long-term mortality
rate (Nguyen et al, 1997). When these two drugs were administered together to severe heart failure
patients, aspirin eliminated the increase in cardiac output seen when enalapril was given alone (Hall
et al, 1992). Aspirin was found to significantly impair the antihypertensive effect of enalapril in one
study (Guazzi et al, 1998), but another showed that aspirin in doses of 81 mg to 325 mg daily had no
effect on blood pressure in essential hypertensives receiving enalapril (Nawarskas et al, 1999).
Researchers conducted a double-blind, randomized study of the hemodynamic effects of aspirin and
ticlopidine when combined with enalapril. The study demonstrated a significant decrease in systemic
vascular resistance (SVR) in the enalapril and ticlopidine group, versus no significant difference in
the enalapril and aspirin group. There were also significant decreases in total pulmonary resistance
(TPR) in both groups (Spaulding et al, 1998). Further studies need to be conducted to determine
whether the aspirin-ACEI interaction occurs in patients with either hypertension, coronary artery
disease, or heart failure and whether interindividual susceptibilities to the interaction are likely to be
present. Studies to determine the optimal dose of aspirin with concomitant ACEI therapy also need to
be conducted (Nawarskas & Spinler, 2000).

Literature:
A retrospective subgroup analysis of data from the Cooperative New Scandinavian Enalapril Survival
Study II (CONSENSUS II) was conducted to determine the long-term mortality of patients on both
aspirin and enalapril following an acute myocardial infarction (AMI). The CONSENSUS II study
involved 6090 patients with AMI who were treated with enalapril or placebo. In this analysis, the
effect of enalapril in patients using aspirin at randomization was compared to the effect of the same
drug in those not using aspirin at baseline. Researchers found that aspirin antagonized the effect of

enalapril on mortality at the end of the study. More research is needed to confirm this interaction and
its health implications (Nguyen et al, 1997).
Eighteen patients with chronic but stable severe heart failure were studied to determine if a standard
dose of aspirin interacts relevantly with enalapril. Subjects were given a double placebo, enalapril (10
mg) plus placebo and enalapril (10 mg) plus aspirin (350 mg) on three consecutive days according to
a double-blind, randomized, crossover protocol. Enalapril, when given before aspirin, caused a
significant decrease in systemic vascular resistance, left ventricular filling pressure and total
pulmonary resistance together with a significant increase in cardiac output. When enalapril was given
with or on the day after aspirin, significant changes were not seen in any of these variables. These
results may be related to the fact that angiotensin-converting enzyme (ACE) inhibitors stimulate
prostaglandin synthesis, which causes vasodilation, and aspirin will inhibit the prostaglandin
synthesis process (Hall et al, 1992).
In a randomized, cross-over study, thirteen patients with congestive heart failure (CHF) who were
already receiving maintenance treatment with an angiotensin-converting enzyme (ACE) inhibitor
were given a single dose of captopril 25 mg with either aspirin 236 mg or placebo. It is known that
patients with CHF have increased plasma levels of prostaglandins I2 and E2 (PGI2, PGE2), which
have vasodilating capabilities. When captopril was given alone, there was no significant change in
the plasma levels of PGI2 and PGE2, or in the level of the vasoconstrictor thromboxane A2 (TXA2.)
However, when captopril was administered with aspirin, significant reductions in PGE2 and TXA2
were seen, although the hemodynamic alterations were similar to those seen after captopril was
administered alone. These results suggest that the use of aspirin should be avoided in patients with
CHF, especially when an ACE inhibitor is also being used (VanWijngaarden et al, 1994).
A study evaluated the effect of aspirin on the antihypertensive effect of enalapril in 52 patients with
hypertension. Patients were divided into two groups based on the severity of hypertension. Group 1
had 26 patients with mild to moderate hypertension and group 2 had 26 patients with severe
hypertension. All patients were previously untreated or inadequately treated for hypertension before
entering the study. Patients in group 2 also received nifedipine and atenolol, in addition to enalapril. A
decrease in antihypertensive effect was observed in 50% of group 1 patients and 57% of group 2
patients; the decrease in mean arterial pressure was 63% and 91% in patients that responded to
aspirin from group 1 and group 2, respectively (Guazzi et al, 1998).
In a double-blind, randomized study of the hemodynamic effects of aspirin and ticlopidine combined
with enalapril, 20 patients were given either 500 mg of ticlopidine or 325 mg of aspirin daily for seven
days. After administration of enalapril 10 mg, hemodynamic measurements were performed via a
balloon-tipped catheter inserted in the pulmonary artery. Several measurements were taken, but only
systemic vascular resistance (SVR) and total pulmonary resistance (TPR) were significantly
impacted. The mean baseline SVR was 1741 dyne.s.cm-5 for the ticlopidine group, which was
decreased to 1364 dyne.s.cm-5. The mean baseline SVR for the aspirin group was 1528 dyne.s.cm5, which was decreased to 1395 dyne.s.cm-5. The mean baseline TPR measurements were 572 and
502 dyne.s.cm-5, respectively, and were decreased to 393 and 337 dyne.s.cm-5, respectively. The
authors further indicated that ticlopidine has no adverse interaction with enalapril (Spaulding et al,
1998).
In analyzing mortality data from 11,575 patients with coronary artery disease who were screened for
the Bezafibrate Infarction Prevention (BIP) trial, a total of 1247 patients were identified who were
receiving therapy with an angiotensin-converting enzyme (ACE) inhibitor. This group was then
broken down to 618 patients who were also receiving aspirin in addition to an ACE inhibitor, and a
control group of 579 patients who were only receiving an ACE inhibitor. Neither the dose or indication
of the ACE inhibitor nor the dose of aspirin were recorded. After five years, there were 155 deaths
(27%) in the control group versus 119 deaths (19%) in the ACE inhibitor plus aspirin group. Even
after adjustments for age, medical history, and other medications, the risk of mortality was still lower
in aspirin users. A subgroup analysis of 464 patients with congestive heart failure (CHF) treated with
an ACE inhibitor showed 221 patients (48%) receiving aspirin and 243 patients not receiving aspirin.
In this subgroup, patients taking aspirin had a lower mortality rate (24%) than non-aspirin users
(34%) after five years. The findings of this study contradict the findings of the SOLVD, CONSENSUS
II, GUSTO-I, and GISSI-3 trials, and supports the use of aspirin in patients with coronary artery
disease who are also treated with an ACE inhibitor (Leor et al, 1999).

Twenty-six patients with stable congestive heart failure (CHF) due to idiopathic cardiomyopathy were
divided into two groups. Group 1 consisted of 18 patients receiving an ACE inhibitor (enalapril 20 mg
daily), and group 2 was made up of eight patients not receiving therapy with an ACE inhibitor. Aspirin
325 mg daily was given consecutively for eight weeks. Pulmonary function tests were performed to
determine forced expiratory volume in 1 second (FEV1), vital capacity (VC), maximal voluntary
ventilation (MVV), and diffusing lung capacity for carbon monoxide (DLCO). In group 1, aspirin
decreased exercise tolerance time, peak exercise oxygen uptake and tidal volume, and increased
the relation of minute ventilation to carbon dioxide production. Similar effects were not seen in group
2, who were not receiving an ACE inhibitor. It appears as if lung prostaglandin production is
enhanced in patients with CHF who are receiving ACE inhibitor therapy, and the coadministration of
aspirin is deleterious to this process. These results may be relevant in CHF patients due to ischemic
heart disease. It remains unknown whether lower doses of aspirin would have the same negative
effect on ventilatory gas exchange and exercise capacity (Guazzi et al, 1999).
A summary of recently published literature investigating the clinical significance of an interaction
between aspirin and angiotensin converting enzyme inhibitors (ACEIs) in patients with cardiovascular
diseases was performed. After reviewing much of the data two generalizations are made: dosage of
aspirin of 100 mg/day or less does not appear to affect prostaglandin production and thus interact
little with ACEIs, whereas higher doses have a higher risk, and some patients may, for an unknown
reason, be more susceptible to this interaction. It is postulated, although still not entirely understood,
that inhibition of prostaglandin synthesis by aspirin is the major mechanism by which aspirin may
negate the benefits of ACEIs. The possibility also exists that ACEIs negate the benefits of aspirin by
ACEI-induced increases in prostaglandins nullifying the decrease in prostaglandins seen with aspirin
(Nawarskas & Spinler, 2000).
In some patients taking an ace inhibitor (ACEI), a dose-related effect of aspirin may adversely affect
survival. A retrospective, cohort study described 344 patients with a principal discharge diagnosis of
CHF at the Institute of Cardiology, University of Milan, from January 10, 1990 to December 31, 1999.
The outcome variable of the study was death from any cause during the maximum follow-up of 10
years (average follow-up was 3.1 years). The patients were classified into 3 groups, based on the
use of an ACEI alone (group 1 (n equal 235)), an ACEI with aspirin at a daily dose of 160 mg or less
(group 2 (n equal to 45)), or an ACEI with aspirin at a daily dose of 325 mg or more (group 3 (n equal
to 64)). After an average follow-up of 37.6 months, there were 134 (39%) deaths, of which 84 (36%)
were in group 1, 15 (33%) were in group 2, and 35 (55%) were in group 3. Using the Kaplan-Meier
approach, survival was similar in groups 1 and 2, and significantly (p equal to 0.009) worse in group
3. After adjusting for potential confounding factors (including treatment, age, smoking, and diabetes
mellitus) a time dependent multivariate Cox proportional hazards regression analysis revealed that
the combination of an ACEI and aspirin at a high dose was independently associated with the risk of
death (hazard ratio, 1.03; p to equal 0.01). The combination of an ACEI and aspirin at a low dose
was not related to mortality (hazard ratio, 1.02; p equal to 0.18). These results demonstrate that there
is a dose-dependent counteraction of aspirin to ACEIs that may affect survival in some patients with
CHF (Guazzi et al, 2003).

Reference(s):
Guazzi M, Brambilla R, Reina G et al: Aspirin-angiotensin-converting enzyme inhibitor
coadministration and mortality in patients with heart failure. Arch Intern Med 2003; 163:1574-1579.
Guazzi M, Pontone G & Agostoni P: Aspirin worsens exercise performance and pulmonary gas
exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors. Am
Heart J 1999; 138:254-260.
Guazzi MD, Campodonico J, Celeste F et al: Antihypertensive efficacy of angiotensin converting
enzyme inhibition and aspirin combination. Clin Pharmacol Ther 1998; 63:79-86.
Hall D, Zeitler H & Rudolph W: Counteraction of the vasodilator effects of enalapril by aspirin in
severe heart failure. J Am Coll Cardiol 1992; 20:1549-1555.
Leor J, Reicher-Reiss H, Goldbourt U et al: Aspirin and mortality in patients treated with angiotensinconverting enzyme inhibitors. J Am Coll Cardiol 1999; 33:1920-1925.

Nawarskas J & Spinler S: Update on the interaction between aspirin and angiotensin-converting
enzyme inhibitors. Pharmacotherapy 2000; 20(6):698-710.
Nawarskas JJ, Townsend RR, Cirigliano MD et al: Effect of aspirin on blood pressure in hypertensive
patients taking enalapril or losartan. Am J Hypertens 1999; 12:784-789.
Nguyen KN, Aursnes I & Kjekshus J: Interaction between enalapril and aspirin on mortality after
acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril
Survival Study II (CONSENSUS II). Am J Cardiol 1997; 79:115-119.
Spaulding C, Charbonnier B, Cohen-Solal A et al: Acute hemodynamic interaction of aspirin and
ticlopidine with enalapril. Results of a double-blind, randomized comparative trial. Circulation 1998;
98:757-765.
VanWijngaarden J, Smit AJ, DeGraeff PA et al: Effects of acetylsalicylic acid on peripheral
hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme
inhibitors. J Cardiovasc Pharmacol 1994; 23:240-245.
Copyright 1974-2007 Thomson MICROMEDEX. All Rights Reserved.

PROPRANOLOL DIGOXIN
Warning: Concurrent use of DIGOXIN and BETA-ADRENERGIC BLOCKERS may result in AV
block and possible digoxin toxicity.

Clinical Management: When beta blockers and digoxin are to be given concomitantly, carefully
monitor ECG and digoxin serum concentrations. Adjust doses accordingly. A decrease in digoxin
dose by at least 25% should be considered in children coadministered carvedilol, with further
adjustments as required after a new steady state occurs.

Onset: Delayed
Severity: Moderate
Documentation: Good
Probable Mechanism: additive cardiac effects, possible increased bioavailability of digoxin
Summary: The combined use of beta blockers and digoxin may result in additive prolongation of
atrioventricular (AV) conduction time. To avoid the development of symptomatic bradycardia or heart
block, caution is warranted when this combination of medications is given. Bradycardia was more
common in patients receiving concomitant digoxin and sotalol than in patients receiving digoxin alone
(Singh et al, 1991). Such additive interactions have also been reported with ophthalmic
administration of beta blockers (Rynne, 1980). The bioavailability of digoxin has been increased by
9% to 20% when coadministered with carvedilol and esmolol (Wermeling et al, 1994; Lowenthal et al,
1985), and elevated digoxin concentrations have also been reported with timolol (Rynne, 1980).
Bioavailability of digoxin after oral coadministration of talinolol was significantly increased in ten
volunteers (Westphal et al, 2000). This is presumably caused by competition for intestinal Pglycoprotein. Carvedilol increases serum concentrations of digoxin in children, and its dose may
need to be reduced to avoid toxicity (Ratnapalan et al, 2003).

Literature:

The effect of adding sotalol (80-320 mg daily) to digoxin in a placebo controlled trial was studied.
Heart rates were lower in the sotalol group and two of the 24 patients had to cease sotalol therapy
due to excessive asymptomatic bradycardia (Singh et al, 1991).
A 91-year old female with a history of arteriosclerosis, cardiac failure, and glaucoma was admitted to
the hospital for palpitations and shortness of breath. Her medications included digoxin, furosemide,
ophthalmic timolol, and ophthalmic pilocarpine. On admission, her heart rate was 35 to 50 beats per
minutes (bpm) and irregular, her blood pressure was 160/90, and digoxin serum concentration was
2.6 ng/dL. ECG showed slow junctional rhythm with nonconducted P waves and left bundle branch
block with an anterior hemiblock. She was diagnosed with digoxin toxicity. Bradycardia continued
after digoxin withdrawal. After the discontinuation of timolol, her heart rate increased to 65 to 75 bpm
and the arrhythmia cleared completely (Rynne, 1980).
A 14-day course of carvedilol, given to 12 patients with mild to moderate hypertension, resulted in
small increases in digoxin bioavailability, but the increases were not clinically significant (Wermeling
et al, 1994). Changes in digoxin pharmacokinetics included increases in area under the
concentration-time curve (14%), maximum concentration (32%), renal clearance (26%), and urinary
excretion (45%).
An infusion of esmolol (6-hour infusion at 300 mcg/kg/min) with steady-state digoxin serum
concentrations (0.8 to 2 ng/mL) in 12 healthy male subjects had no effect on esmolol
pharmacokinetics. Digoxin serum levels were increased by 9% to 19% at four hours post-infusion
compared to digoxin therapy alone (Lowenthal et al, 1985).
Coadministration of oral talinolol (100 mg) increased the area under the concentration-time curve
(AUC) of talinolol from 0-6 hours by 18%. The area under the curve of digoxin from 0-72 hours was
increased by 23% with coadministration of talinolol. The maximum serum levels of digoxin were
increased by 45%. When talinolol 30 mg intravenous was coadministered with oral digoxin (0.5 mg)
digoxin pharmacokinetics did not change significantly. The disposition of oral or intravenous talinolol
was unaffected by digoxin. Presumably the slow talinolol absorption caused the half-life to be
increased by one hour after oral administration as compared to intravenous administration (10.2 +/1.2 versus 11.2 +/- 0.9 hours; p less than 0.05) (Westphal et al, 2000).
The digoxin-talinolol drug interaction may be dosage form dependent and may not involve Pglycoprotein as the main cause for this interaction (Chiou et al, 2001). The dosage forms of digoxin
determine it oral bioavailability. Theoretically, for P-glycoprotein to exert its efflux effect, the fraction of
dose absorbed should increase and the time to reach peak plasma concentrations should decrease
with an increase in dose. The P-glycoprotein efflux pump does not appear to play a significant role in
retarding oral absorption of digoxin. Also, talinolol may have resulted in the observed increase in
bioavailability compared with the control study since it may have caused an increase of in vivo
dissolution rate of digoxin from the administered tablets. Further, clinical studies are needed to
confirm this above hypothesis.
Carvedilol increased serum concentrations of digoxin in children; dose may need to be reduced to
avoid toxicity. Eight children who received digoxin for ventricular failure secondary to complex
congenital heart disease were observed for any pharmacokinetic interactions before and after the
addition of carvedilol. The children ranged in age between 2 weeks and 7.8 years, and the carvedilol
daily dose was titrated according to clinical response. The clearance of digoxin was calculated before
and after at least 4 days of unchanged dose of carvedilol. In one child, there were 2 episodes of
discontinuation, resulting in a decrease of the apparent clearance of digoxin and then a rebound of
clearance when the drug was stopped. Carvedilol dose ranged from 0.1 mg/kg/day to 1.02
mg/kg/day. GFR did not change significantly before and after administration of carvedilol. There was
a mean two-fold decrease in the clearance of digoxin (from 153.0 +/- 92.3 mL/min/1.73 meters
squared to 80.6 +/- 23.9 mL/min/1.73 meters squared, p equal to 0.056), and the ratio of digoxin
clearance to the GFR decreased from 1.8 +/- 0.60 to 1.00 +/- 0.24 (p equal to 0.002). Multiple
regression analysis with age, initial ratio, and carvedilol dose confirmed univariate analysis, with the
initial ratio the significant factor (p equal to 0.05), whereas dose (p equal to 0.78) and age (p equal to
0.5) were not significant. The author concluded that the interaction between carvedilol and digoxin is
enhanced in children possibly because of a higher expression of the P-glycoprotein pump
(Ratnapalan et al, 2003).

Reference(s):
Chiou W, Ma C, Chung S et al: An alternative hypothesis to involvement of intestinal P-glycoprotein
as the cause for digoxin oral bioavailability enhancement by talinolol (letter). lin Pharmacol Ther
2001; 70:79-80.
Lowenthal DT, Porter S, Saris SD et al: Clinical pharmacology, pharmacodynamics and interactions
with esmolol. Am J Cardiol 1985; 56:14F-18F.
Ratnapalan S, Griffiths K, Moldovan Costei A et al: Digoxin-carvedilol interactions in children. J
Pediatr 2003; 142:572-574.
Rynne MV: Timolol toxicity: ophthalmic medication complicating systemic disease. J Maine Med
Assoc 1980; 71:82.
Singh S, Saini RK, DiMarco J et al: Efficacy and safety of sotalol in digitalized patients with chronic
atrial fibrillation. Am J Cardiol 1991; 68:1227-1230.
Wermeling DP, Field CJ, Smith DA et al: Effects of long-term oral carvedilol on the steady-state
pharmacokinetics of oral digoxin in patients with mild to moderate hypertension. Pharmacotherapy
1994; 14:600-606.
Westphal K, Weinbrenner A, Giessmann T et al: Oral bioavailability of digoxin is enhanced by
talinolol: evidence for involvement of intestinal P-glycoprotein. Clin Pharmacol Ther 2000; 68(1):6-12.
Copyright 1974-2007 Thomson MICROMEDEX. All Rights Reserved.

ASPIRIN SPIRONOLACTONE
Warning: Concurrent use of ASPIRIN and SPIRONOLACTONE may result in decreased
spironolactone effectiveness.

Clinical Management: Avoid aspirin doses of greater than 650 mg daily in adults receiving
spironolactone.

Onset: Rapid
Severity: Moderate
Documentation: Fair
Probable Mechanism: altered renin effect
Summary: Aspirin can decrease the effectiveness of diuretics like furosemide or spironolactone,
but not that of thiazides. The mechanism of this interaction may be related to the interactions of the
drugs with the renin-angiotensin system (Karsh, 1990).

Literature:
Although aspirin has been reported to interfere with the diuretic action of spironolactone due to
inhibition of intrarenal prostaglandins, aspirin does not alter the effect of spironolactone on blood
pressure, serum electrolytes, urea nitrogen, or plasma renin activity in hypertensive patients (Prod
Info Aldactone, 1992).

Antagonism of the diuretic effect of spironolactone by aspirin was first reported by (Elliott, 1962). The
inhibitory effect of aspirin on spironolactone natriuresis was investigated in 10 normal volunteer male
physicians (Tweeddale & Ogilvie, 1973). On the study days, patients received 1 mg of fludrocortisone
to provide constant mineralocorticoid stimulus against which the effects of spironolactone
administration could be assessed. In randomized, crossover design, patients received placebo or
spironolactone in a single dose of 25 mg, 50 mg, and 100 mg. A second phase of the study involved
patients receiving 25 mg of spironolactone four times daily for one week. When aspirin was
administered, it was given as a single PO 600 mg dose. The results of this investigation
demonstrated that, in normal patients receiving fludrocortisone, aspirin administration reduced the
effect of spironolactone. The mean sodium content of the overnight urine was decreased by 30%.
Six patients age 23 to 28 years were administered a single oral dose of 50 mg of spironolactone
concomitantly with aspirin. It was determined that the aspirin significantly decreased the urinary
excretion and fractional excretion of canrenone, the principal metabolite of spironolactone. It was
reported that aspirin slightly reduced the pharmacological activity of spironolactone (Ramsay et al,
1976).

Reference(s):
Elliott HC: Reduced adrenocortical steroid excretion rates in man following aspirin administration.
Metabolism 1962; 11:1015-1018.
Karsh J: Adverse reactions and interactions with aspirin. Considerations in the treatment of the
elderly patient. Drug Saf 1990; 5:317-327.
Product Information: Aldactone(R), spironolactone. G.D. Searle & Co., Chicago, IL, 1992.
Ramsay L, Shelton J, Harrison I et al: Spironolactone and potassium canrenoate in normal man. Clin
Pharmacol Ther 1976; 20:167-177.
Tweeddale MG & Ogilvie RI: Antagonism of spironolactone-induced natriuresis by aspirin in man. N
Engl J Med 1973; 289:198.
Copyright 1974-2007 Thomson MICROMEDEX. All Rights Reserved.