 Ade Yohana S.

 Marco Stanley
 Adi Haratua  Metha Vionari D.
 Ahmad Ismail D.  Michael Khosasih
 Anthony Tias  Misfa Noca Manda M.
 Calson  Muhammad Asro
 Dara Yunita  Muhammad Yunus
 Dewi Sri Hartati  Natalia Manangap S.
 Edo Kusda Pratama  Naurati Lova
 Eunike Perbina br S.  Putri Maal C.B.
 Hady Wiraputra  Rohani Purba
 Handy Pramana P.  Siti Erliana Siagian
 Hartian Lubis  Vivian Loletta
 Jansen B.L.  Yusnawati
 Junensi Monika H.
 Group Drug

Potassium-depleting diuretics

Carbonic anhydrase Acetazolamide, Diclofenamide (Dichlorphenamide),

inhibitors Methazolamide

Bumetanide, Etacrynic acid, Furosemide, Piretanide,

Loop diuretics
Torasemide

Altizide, Bemetizide, Bendroflumethiazide, Benzthiazide,

Butizide, Chlorothiazide, Chlortalidone, Clopamide,
Thiazides and related Cyclopenthiazide, Cyclothiazide, Epitizide,
diuretics Hydrochlorothiazide, Hydroflumethiazide, Indapamide,
Mefruside, Methyclothiazide, Metolazone, Polythiazide,
Teclothiazide, Trichlormethiazide, Xipamide

Potassium-sparing diuretics

Aldosterone inhibitors Eplerenone, Potassium canrenoate, Spironolactone

Other Amiloride, Triamterene

 Obat A Obat B Mekanisme Efek Solusi

Increased FUROSEMIDE
Furosemid Reduced oral Furosemide
Phenytoin* (eg, doses may be needed in
e*
Lasix)
(eg,
Dilantin)
absorption
FUROSEMIDE
of
↓ patients receiving
PHENYTOIN

An increase in the
Observe for
free (active)
exaggerated diuresis
fraction of LOOP
from a LOOP DIURETIC
DIURETICS as a
during concurrent
result of their
Furosemid Furosemide clofibrate use. If an
Clofibrate* (eg, displacement from
e*
Lasix)
(eg,
Atromid-S) protein binding ↑ excessive
response
diuretic
occurs,
sites by
consider lowering the
CLOFIBRATE has
dose of one or both
been proposed
drugs, or discontinue
but not
CLOFIBRATE.
established.
 Obat A Obat B Mekanisme Efek Solusi

Inhibitor CYP3A4
Decrease
Eplerenone
Eplerenone ↑
(Cimetidine) metabolism.
Adjust the dose
Eplerenone
accordingly
Increase
Inducer CYP3A4
(Dexamethasone) Eplerenone Eplerenone ↓
metabolism.

Monitor plasma
lithium levels and
Thiazide
Diuretics
Lithium*
Eskalith)
(eg, Decreased renal
LITHIUM clearance. Lithium ↑ observe the patient
for symptoms of
toxicity. Adjust the
dose accordingly.
1. Ahmad S. Renal insensitivity to frusemide caused by chronic
anticonvulsant therapy. BMJ (1974) 3, 657–9.
2. Fine A, Henderson JS, Morgan DR, Tilstone WJ. Malabsorption of
frusemide caused by phenytoin. BMJ (1977) 2, 1061–2.
3. Srivastava RC, Bhise SB, Sood R, Rao MNA. On the reduced furosemide
response in the presence of diphenylhydantoin. Colloids and Surfaces
(1986) 19, 83–8.

The observation that dependent oedema in a group of epileptics was higher

than expected, and that the response to diuretic treatment seemed to be
reduced, prompted further study. In 30 patients taking phenytoin 200 to
400 mg daily with phenobarbital 60 to 180 mg daily the maximal diuresis
in response to furosemide 20 or 40 mg occurred after 3 to 4 hours instead
of the usual 2 hours, and the total diuresis was reduced by 32% for the
20-mg dose and 49% for the 40-mg dose. When intravenous furosemide
20 mg was given, the total diuresis was reduced by 50%. Some of the
patients were also taking carbamazepine, pheneturide, ethosuximide,
diazepam or chlordiazepoxide.1

Another study in 5 healthy subjects given phenytoin 100 mg three times

daily for 10 days found that the maximum serum levels of furosemide
20 mg, given orally or intravenously, were reduced by 50%.2
1. Ahmad S. Renal insensitivity to frusemide caused by chronic
anticonvulsant therapy. BMJ (1974) 3, 657–9.
2. Fine A, Henderson JS, Morgan DR, Tilstone WJ. Malabsorption of
frusemide caused by phenytoin. BMJ (1977) 2, 1061–2.
3. Srivastava RC, Bhise SB, Sood R, Rao MNA. On the reduced furosemide
response in the presence of diphenylhydantoin. Colloids and Surfaces
(1986) 19, 83–8.

Mechanism
Not fully understood. One suggestion is that the phenytoin causes changes
in the jejunal sodium pump activity, which reduces the absorption of the
furosemide,2 but this is not the whole story because an interaction also
occurs when furosemide is given intravenously.1 Another suggestion, based
on in vitro evidence, is that the phenytoin generates a ‘liquid membrane,’
which blocks the transport of the furosemide to its active site.3

Importance and management

Information is limited but the interaction is established. A reduced diuretic
response should be expected in the presence of phenytoin. A dosage
increase may be needed.
 Obat A Obat B Mekanisme Efek Solusi

profound
Carefully titrate with small or
Both groups diuresis and
intermittent doses. Monitor
Loop Thiazide have serious
patients for dehydration and
Diuretics Diuretics synergistic electrolyte
electrolyte abnormalities at
effects abnormalities.
the start of combined therapy.

Do not use this combination

POTASSIUM- without documented evidence
SPARING that a patient has clinical
DIURETICS will symptoms of hypokalemia
Additive,
Potassium Potassium increase unresponsive to either agent
synergistic or
-Sparing Preparatio potassium alone.
summation
Diuretics ns retention and If the combination is required,
interactions.
can produce the patient should have strict
severe dietary counseling and close
hyperkalemia. monitoring of serum
potassium concentrations.
 Obat A Obat B Mekanisme Efek Solusi

Opposing or
Based on
antagonistic interactions
Loop currently
ACETAMINOPHEN may
Loop
Diuretics
Acetaminophen
*(eg, Tylenol)
decrease renal Diuretics ↓ available clinical
data, no special
prostaglandin excretion
precautions are
and decrease plasma
needed.
renin activity.

Nondepol. Potensiasi:
Muscle Nondepol. Monitor the
Relaxants LOOP DIURETICS may Muscle patient for
Atracurium potentiate or antagonize neuromuscular
Loop
(Tracrium) the actions of Relaxants ↑ blockade and
Gallamine NONDEPOLARIZING respiratory
Diuretics
(Flaxedil) MUSCLE RELAXANTS, Antagonis: depression.
Tubocurarine*P perhaps dependent on Nondepol. Provide life
ancuronium* dosage. Muscle support when
(Pavulon)
Relaxants ↓ necessary.
 Greenblatt DJ, Koch-Weser J. Adverse reactions to spironolactone. A
report from the Boston Collaborative Drug Surveillance Program. Clin
Pharmacol Ther (1973) 14, 136–7.
 Simborg DN. Medication prescribing on a university medical service
— the incidence of drug combinations with potential adverse
interactions. Johns Hopkins Med J (1976) 139, 23–6.
 Kalbian VV. Iatrogenic hyperkalemic paralysis with
electrocardiographic changes. South Med J (1974) 67, 342–5.
 McCaughan D. Hazards of non-prescription potassium supplements.
Lancet (1984) i, 513–14.
 Yap V, Patel A, Thomsen J. Hyperkalemia with cardiac arrhythmia.
Induction by salt substitutes, spironolactone, and azotemia. JAMA
(1976) 236, 2775–6.
 O’Reilly MV, Murnaghan DP, Williams MB. Transvenous pacemaker
failure induced by hyperkalemia. JAMA (1974) 228, 336–7.
 In a retrospective analysis of hospitalised patients who
had received spironolactone, hyperkalaemia had
developed in 5.7% of patients taking spironolactone alone
and in 15.4% of those also taking a potassium chloride
supplement. The incidence was 42% in those with severe
azotaemia given spironolactone and potassium chloride.1
 A retrospective survey of another group of 25 patients
taking spironolactone and oral potassium chloride
supplements found that half of them had developed
hyperkalaemia.2
◦ Another patient developed severe hyperkalaemia and cardiotoxicity as a
result of treatment with spironolactone and a potassium supplement.3
◦ Three patients taking furosemide and spironolactone became
hyperkalaemic4,5 because they took potassium-containing salt substitutes
(No Salt in one case4).
◦ Two developed cardiac arrhythmias.5
◦ The pacemaker of a patient failed because of hyperkalaemia caused by the
concurrent use of triamterene/hydrochlorothiazide (Dyazide) and
potassium chloride (Slow-K).6
Mechanism
The effects of these potassium-sparing diuretics and potassium
compounds are additive, which can result in hyperkalaemia.

Importance and management

The interaction with spironolactone is established and of clinical
importance. A case has also been reported with triamterene; amiloride
and eplerenone would be expected to behave similarly.
Avoid potassium compounds in patients taking potassium-sparing
diuretics except in cases of marked potassium depletion and where the
effects can be closely monitored.
Warn patients about the risks of salt substitutes containing potassium,
which may increase the potassium intake by 50 to 60 mmol daily.5
The signs and symptoms of hyperkalaemia include muscular weakness,
fatigue, paraesthesia, flaccid paralysis of the extremities, bradycardia,
shock and ECG abnormalities, which may develop slowly and
insidiously.
 Obat A Obat B Mekanisme Efek Solusi

This is a theoretical
Possible interaction, but be aware
pharmacodynamic of the potential for
interaction involving hypokalaemia in patients
Potassium
additive loss of potassium who are taking
-
Aloes and water by Hypokalemia potassium-depleting
depleting
anthraquinone-containing diuretics and who
diuretics
substances and regularly use, or abuse,
potassium-depleting anthraquinone-
diuretics. containing substances
such as aloes.

Little understood. The

changes in furosemide Absorpsi
Potassium More study is required
-
Senna
absorptive
may be
permeability
caused by Furosemide ↑ before any clinical
depleting recommendations can be
interference with P
diuretics made.
glycoprotein or other Hypokalemia
transporter proteins.
 Obat A Obat B Mekanisme Efek Solusi

Evidence appears to be limited

to this one clinical study.
Although hawthorn extract
Additive caused a reduction in diastolic
blood blood pressure in patients,
pressure- many of whom were taking
Diuretics Hawthorn lowering Hypotension antihypertensives, the effect
effects was small.
might As such, it is unlikely that
occur. clinically important
hypotension would occur if
hawthorn is added to existing
antihypertensive treatment.
 Obat A Obat B Mekanisme Efek Solusi

It is probably not
Liquorice may cause fluid
appropriate for
retention and therefore
patients taking
reduce the effects of
Loop dan Hypertension antihypertensive
antihypertensives.
Thiazide Liquorice & drugs to be treated
Diuretics Hypokalaemia with liquorice,
Additive hypokalemia may
especially if their
also occur with loop and
hypertension is not
thiazide diuretics.
well controlled.

Ingestion of liquorice inhibits 11β-hydroxysteroid dehydrogenase type 2, thereby

preventing the inactivation of cortisol to cortisone. This results in mineralocorticoid
effects including sodium and water retention (leading to hypertension) and
hypokalaemia. This effect would oppose the effects of drugs used to lower blood
pressure.

In addition, the potassium-depleting effect of liquorice would be expected to be

additive with loop and thiazide diuretics. The mineralocorticoid effect of liquorice is
due to the content of glycyrrhetinic acid (a metabolite of glycyrrhizic acid), and
therefore deglycyrrhizinated liquorice would not have this effect.
 Becker BN, Greene J, Evanson J, Chidsey J, Stone WJ. Ginseng-induced
diuretic resistance. JAMA (1996) 276, 606–7.
 Sweetman SC, ed. Martindale: The complete drug reference. 35th ed.
London: Pharmaceutical Press; 2007. p. 2097.
A 63-year-old man was hospitalised for hypertension and oedema 10
days after adding ginseng containing germanium to his usual treatment
with cyclophosphamide and furosemide. He gained almost 13 kg in
weight. After treatment with intravenous furosemide he was discharged
and again took ginseng with germanium.
This time he gained 12 kg in weight over 14 days, despite an increase in
the dose of furosemide from 80 to 240 mg twice daily. The weight gain
and oedema again resolved when the ginseng and germanium was
withdrawn and he was given intravenous furosemide. The authors
suggest that germanium was responsible for this interaction.1

This is an isolated report, and its general significance is unclear.

However, note that it has been said that the use of germanium should
be discouraged due to its potential to cause renal toxicity.2