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For Rational Drug Use and Disease Management
SEPTEMBER 16, 1996
VOLUME 8, NO. 6
ISSN 1172-0360
CONTENTS
New drugs and
therapeutics
1 Losartan potassium:
low incidence of cough
confirmed
5
Which drug for
stable angina?
9 Scabies still a
widespread problem in
many countries
Drug reactions and
interactions
11 Aplastic anaemia and
ocular chloramphenicol:
any link?
Drug economics and
quality of life
13 A place on the formulary
for SSRIs in the treatment
of depression
Losartan potassium: low incidence
of cough confirmed
Losartan potassium is the first of a new class of
antihypertensives, the angiotensin II antagonists. It has similar
properties to those of ACE inhibitors, but unlike these drugs it does
not appear to cause persistent cough.
Thus, losartan potassium has a particular niche for use in
patients with essential hypertension who cannot tolerate ACE
inhibitors because of persistent cough. An expanded role in the
treatment of hypertension is likely to require long-term outcomes
data and pharmacoeconomic analysis.
In addition, whether losartan potassium has similar benefits
to ACE inhibitors in congestive heart failure and nephropathy
awaits the results of ongoing s t u d i e s .
Losartan potassium was first reviewed in Drugs & Therapy Perspectives
in 1993 when it was in the clinical phase of development [1] The drug has
now been marketed in a number of countries; thus, this review will evaluate
the increasing body of clinical data on losartan potassium to consider
whether its potential advantages have been realised.
Losartan potassium was the first angiotensin II antagonist to reach the
market; other drugs of this type include valsartan (launched in Germany),
irbesartan (preregistration in Europe), and candesartan hexetil, eprosartan,
telmisartan and tasosartan (all phase III). Losartan potassium is compared
with enalapril in the Differential features table.
A new class of antihypertensive
Losartan potassium and its active metabolite E3174 inhibit the renin-angiotensin system more completely and more selectively than ACE inhibitors.[2] The drug acts specifically at the angiotensin II subtype 1 receptor
(ATi), which appears to account for all the known cardiovascular effects of
angiotensin II [2] It does not inhibit the AT2 receptor subtype, the function of
which has not yet been defined. [2]
INTERNATIONAL
† Losartan potassium has been launched for treating essential hypertension in Canada, Denmark,
France, Germany, Sweden, the UK and the US; it is not yet available in Australia.
Drugs & Therapy Perspectives
Editor: C. Rhoda Lee
Associate Editor: Alison J. Forbes
Editorial Secretary: Carol Milligan
Group Editorial Director: Rennie C. Heel
Publishing Director, Periodicals: Paul Chrisp
Research Editors:
Tracey Langsdale (Senior Editor);, Pauline Curel; Tracey Hale;
Gill Higgins; June Katz; Gillian Keating; Tamara Schwarz;
Theresa Szeto; Carlene Todd; Rachel Webber-Foster
Editors, Clinical Pharmacology and Therapeutics:
Sarah Edmonds (Senior Editor); Alan S, Beedle; Claire L. Berkahn;
Stephen G. Coleman; Richard Crampton; Katharine J, Palmer; Rosie
Stather
Editors, Drug Evaluations:
Donna McTavish (Senior Editor);, Julia A, Balfour; Paul Benfield;
Rex N. Brogden; Harriet M. Bryson; Allan Coukell; Rick Davis;
Christopher J. Dunn; Diana Faulds; Jane C. Gillis; Karen L. Goa; Malini
Haria; Wendy Jeal; Heather D. Langtry; Andrew P. Lea; Anthony
Markham; Stuart Noble; Caroline M, Perry; Greg L. Plosker; Caroline
M. Spencer; Antona Wagstaff; Michelle I. Wilde;
Lynda R. Wiseman
Pesident and Publisher: Graeme S. Avery.
International Editorial Board
D.R. Abernethy, Washington, DC, USA; C,P.A Alderman, Adelaide,
SA, Australia; C.D. Bayliff, London, Canada; EJ. Begg,
Christchurch, New Zealand; T, Bergan, Oslo, Norway;
G. Bianchi Porro, Milan, Italy; C, Brater, Indianapolis, IN, USA;
A.M. Breckenridge, Liverpool, UK; W.W. Busse, Madison, WI, USA;
S.G. Carruthers, London, Canada; G. Carstens, Hanover, Germany;
J.A. J.H. Critchley, Hong Kong;R.O. Day, Sydney, NSW, Australia;
C. Doreau, Paris, France; M.N.G. Dukes, Sorborg, Denmark; A.
Ebihara, Tochigi-ken, Japan; L. Ereshefsky, San Antonio, TX, USA;
S, Erill, Barcelona, Spain; S.Erush, Philadelphia, PA, USA; P. Fallet,
Paris, France; J. Feely, Dublin, Ireland; R.G. Finch, Nottingham,
UK; S. Frias, Madrid, Spain; W.H. Frishman, Bronx, NY, USA; S.T.
Garner, Nottingham, UK; D.J. Greenblatt, Boston, MA, USA; R.
Gugler, Karlsruhe, Germany; F.D. Hart, London, UK; D.A. Henry,
Newcastle,, NSW, Australia; I. Hindmarch, Godalming, UK; T.
Ishizaki, Tokyo, Japan;
R. Janknegt, Sittard, The Netherlands;
G.L.Kearns, Kansas City, MO, USA; J. Kenyon, Auckland, New
Zealand; S,K. Lam, Hong Kong; M. Levy, Jerusalem, Israel; W, J.
Louis, Heidelberg, Vic, Australia; H.I. Maibach, San Francisco, CA,
USA; G. Mancia, Monza, Italy; A. McLean, Melbourne, Vic,
Australia; P.A. Mitenko,
Nanaimo, Canada; D. Nash, Philadelphia, PA, USA; M.O. Nielsen,
Hurup, Denmark; P.L. Nielsen, Frederikshavn, Denmark; H.C. Neu,
New York, NY, USA; L.P. Opie, Cape Town, South Africa; M. Packer,
New York, NY, USA; R. Pauwels, Ghent, Belgium; P. Persson,
Stockholm, Sweden; M.M. Reidenberg, New York, NY, USA;
J. Schentag, Buffalo, NY, USA; D-R. Sohn, Chonan, Korea;
De K. Sommers, Pretoria, South Africa; N.ATerragno, Buenos
Aires, Argentina; M. Thomas, Vellorre, India; J-P. Tillement,
Creteil, France; G. Tognoni, Milan, Italy, J.H. Toogood, London,
Canada; C. Tugwell, London, UK; T. Uematsu, Gifu, Japan;
C.J. van Boxtel, Amsterdam, The Netherlands; R.E. Vestal, Boise, ID,
USA; H.B. Wong, Singapore
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Vol. 8, No. 6; September 16, 1996
In contrast, ACE inhibitors act earlier in the reninangiotensin system by blocking the formation of angiotensin II from angiotensin I by inhibiting ACE. Because
angiotensin II is also formed by other enzymes that are
not blocked by ACE inhibitors (e.g. cardiac chymase),
ACE inhibitors do not completely prevent the effects of
angiotensin II.[2] Moreover, inhibition of ACE also results
in accumulation of bradykinin, which has been implicated
in causing ACE inhibitor-associated cough.[ 2 ]
Whether angiotensin II antagonists are
'more than just ACE inhibitors without the
cough' remains to be seen
24-hour duration of action
Blood pressure reductions produced by once-daily
losartan potassium 50 to 100 mg/day persist throughout
24 hours as assessed by ambulatory blood pressure monitoring [2] The drug does not affect heart rate.
Single doses of losartan potassium and captopril (both
50mg) yielded similar quantitative effects on blood pressure, although the onset was a few hours later with
losartan potassium. [2]
The effect of losartan potassium on other haemodynamic or cardiac indices in patients with hypertension has
not been well documented. [2]
Other effects
In patients with hypertension, losartan potassium 100
mg/day increases plasma renin activity and plasma
angiotensin II levels and appears to decrease plasma
levels of aldosterone, at least in the short term.[5] Enalapril 20
mg/day increases plasma renin activity, but decreases
plasma angiotensin II levels [5]
Forearm vasodilator responses to bradykinin are not
altered by losartan potassium, whereas they are potentiated by enalapril[2]
In animal studies, angiotensin II receptor antagonists
have been shown to:
• prevent cerebrovascular infarcts
• increase survival in chronic heart failure
• slow progression of diabetes-related renal disease
• regress left ventricular hypertrophy. [2]
Preliminary data suggest losartan administration is
associated with regression of left ventricular hypertrophy
in patients,[2] but the other effects have yet to be demonstrated in humans,
Pharmacokinetocs
The bioavailability of losartan potassium is about
33%, indicating a considerable first-pass effect, and is
not altered significantly by the presence of food. [2] In
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most patients, about 14% of an oral dose of losartan
potassium is metabolised via hepatic carboxylation to the
active metabolite E3 174, which is more active than the
parent drug.[2]
However, in a very small proportion of patients
(<1%), enzymes responsible for metabolism to E3174
are deficient (<1% of a dose is converted); [2] these
patients may not respond adequately to the drug.
Pharmacokinetic studies using cimetidine and ketoconazole suggest that clinically significant interactions with
losartan potassium and CYP34A inhibitors are unlikely to
occur. [2] However, drugs that induce cytochrome P450
systems may hasten the metabolism of losartan potassium, the clinical relevance of which has not been determined. No significant drug interactions appear to occur
between losartan potassium and digoxin or warfarin. [2]
Clinical efficacy
Losartan potassium has demonstrated efficacy in the
treatment of hypertension in randomised, double-blind
studies, usually of 8 to 12 weeks' duration, involving
about 3700 patients [2]
As monotherapy . . .
Large dose-finding trials have shown the efficacy of
losartan potassium 50mg once-daily to be superior to that
of placebo and indistinguishable from that of the l00 mg
dose, [2] The drug has reduced diastolic blood pressure
(DBP) by about 8 to 13mm Hg in patients with mild to
moderate hypertension. [2]
Antihypertensive efficacy, as determined by trough
blood pressure values and percentage responders, has not
differed significantly between once-daily administration
of losartan potassium 50 to l00mg and enalapril 20mg, [7]
atenolol 50 to l00mg[8] or felodipine extended release (ER)
5 to l0mg[2] in comparative trials. Blood pressure
lowering was evident within 1 to 2 weeks of initiating
losartan potassium therapy and was maximal by 3 to 6
weeks. [2]
In the comparison with enalapril 20 mg/day, losartan
potassium 50 mg/day appeared to be less effective
according to an 'all patients treated' analysis (n = 399),
but similarly effective by a 'per protocol' analysis that
included only those patients who had a trough blood
pressure measurement between 22 and 26 hours after the
previous dose (n = 275). [7]
. . . and combined with hydrochlorothiazide
The combination of losartan potassium plus hydrochlorothiazide produces larger reductions in blood pressure than are seen with either drug alone. Compared with
losartan potassium or hydrochlorothiazide monotherapy,
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losartan potassium plus hydrochlorothiazide reduced
DBP by an additional 4 to 6mm Hg. [2]
During one 12-week noncomparative trial, severe hypertension was successfully managed in approximately 30% of
patients treated with losartan potassium 50 or 100 mg/day
plus hydrochlorothiazide 12.5 or 25 mg/day; another 22% of
patients were maintained on losartan potassium monotherapy and the remainder required the addition of atenolol
and/or a calcium antagonist.[2] Overall decreases in DBP
Vol. 8, No. 6; September 16, 1996
a frequency of 3.1% for losartan potassium, 2.6% for
placebo, and 8.8% for ACE inhibitors. [11]
In trials conducted specifically in patients with a history of ACE inhibitor-related cough, the incidence of
cough was similar for losartan potassium (17 to 29%),
placebo (35%) and hydrochlorothiazide recipients (25 to
34%), but was much less than in lisinopril recipients (62
to72%).[16,17]
Dosage and administration
for regimens containing losartan potassium were in the
magnitude of 19mm Hg in this population.
Good tolerability
Results from double-blind trials involving >2800 patients with hypertension who received losartan potassium
indicate that the drug is well tolerated.[11]
Although headache (14.1% of patients), upper respiratory tract infections (6.5%), dizziness (4.1%), asthenia/
fatigue (3.8%) and cough (3.1%) have been reported
during administration of losartan potassium monotherapy, dizziness was the only adverse event documented
more often with losartan potassium than with placebo
treatment.[11]
Orthostatic effects and first-dose hypotension can
occur with losartan potassium therapy (combined incidence of 0.5% with 25 or 50 mg/day and 2.2% with 100
mg/day).[11] Liver enzyme levels have risen to a minor extent
in 1.9% of losartan potassium-treated patients.[11]
Hyperkalaemia (serum potassium 5.5 mmol/L) was
documented in 1.5% of patients, none of whom required
discontinuation of losartan potassium therapy. Losartan
potassium appears to have a uricosuric effect.[2,7]
To date, there have been 2 reports of angioedema.[12,13]
1 report of severe migraine[14] and 1 report of reversible loss
of taste[15] developing during losartan potassium therapy.
Low incidence of cough confirmed
Clinical experience thus far has validated the expectation that losartan potassium would be associated with
minimal cough because it lacks apparent effects on
bradykinin.[2] Spontaneous reports of cough occurred at
Vol. 8, No. 6; September 16, 1996
The recommended initial and maintenance dosage of
losartan potassium as monotherapy in patients with essential hypertension is 50mg once daily. Some patients may
benefit from 100 mg/day. Losartan potassium may be
given with or without food.[2]
In patients at high risk of hypotension or volume depletion and in those with hepatic dysfunction, the i n i t i a l
dose should be 25mg.[2] No dosage adjustment is needed for
the elderly or patients with renal impairment. Losartan
potassium is not recommended for use in pregnant women
because of the risk of fetal morbidity/mortality.[2]
Treatment with the combination product containing
losartan potassium and hydrochlorothiazide is initiated at
a dosage of 50/12.5 mg/day which can be doubled if the
result is unsatisfactory. This therapy is not recommended
for use as initial treatment when monotherapy would suffice, for patients with hepatic impairment or for those
with creatinine clearance 30 ml/min [2]
Prescribing and formulary considerations
Guidelines for the pharmacological management of
hypertension in the US[18] and the UK[19] recommend
initiation of therapy with diuretics or -blockers - these
agents have been proven to reduce cardiovascular morbidity and mortality. [2] ACE inhibitors, 1-blockers and
calcium antagonists are positioned as 'alternative firstline' strategies in patients in whom diuretics and -blockers are ineffective, contraindicated or poorly tolerated [2]
The final position of losartan potassium among the
various classes of drugs available for the management of
hypertension awaits clarification from long-term outcomes data.
Several important features of the profile of losartan
potassium that require examination are:
• its effects, if any, on mortality in hypertension
• its potential for benefits on symptoms and mortality
in congestive heart failure
• its potential for renal benefits in diabetic nephropathy
• whether long-term unopposed angiotensin II block
ade, which exposes other angiotensin receptors to
increased circulatory angiotensin II, will produce
unwanted consequences
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• whether its lack of effect on bradykinin will mean that
it lacks some of the positive as well as the negative
effects of ACE inhibitors
• its cost effectiveness and effects on quality of life. [2]
A number of studies are underway including the Eval
uation of Losartan in the Elderly (ELITE) trial and the
Losartan Intervention For Endpoint in hypertension
(LIFE) trial. [2]
Pending long-term efficacy, tolerability and mortality
data, the drug is likely to be used primarily in patients
who are not well managed with, or are intolerant of, their
current therapy. [2]
References
1. Losartan potassium: a more direct approach to lowering BP. Drug Ther
Perspect 1993 Aug 30; 2 (4): 7-8
2. Goa KL, Wagstaff AJ. Losartan potassium: a review of its pharmacology,
clinical efficacy and tolerability in the management of hypertension. Drugs
1996 May; 51 (5): 820-45
3. British National Formulary No. 31. London: The Pharmaceutical Press,
1996 Mar
4. 1995 Physicians GenRx. St Louis, Missouri: Mosby-Year Book, Inc., 1995
5. Goldberg MR, Bradstreet TE, Mc Williams EJ, et al. Biochemical effects of
losartan, a nonpeptide angiotensin II receptor antagonist, on the
renin-angiotensin-aldosterone system in hypertensive patients.
Hypertension 1995 Jan; 25: 37-46
6. Timmermans PBMWM, Wong PC, Chiu AT, et al. Angiotensin II
receptors and angiotensin II receptor antagonists. Pharmacol Rev
1993; 45: 205
7. Tikkanen I, Omvik P, Jensen H/E, et al. Comparison of the angiotensin II
antagonist losartan with the angiolensin converting enzyme inhibitor
enalapril in patients with essential hypertension. J Hypertens 1995 Nov. 13:
1343-51
8. Dahlof B, Keller SE, Makris L, et al. Efficacy and tolerability of losartan
potassium and atenolol in patients with mild to moderate essential
hypertension. Am J Hypertens 1995 Jun; 8: 578-83
9. Chan JCN, Critchley JAJH, Lappe JT, et al. Randomised, doubleblind, parallel study of the anti-hypertensive efficacy and safety of
losartan potassium compared with felodipine ER in elderly patients with
mild to moderate hypertension. J Hum Hypertens 1995; 9:765-71
10. Dunlay MC, Fitzpatrick V, Chrysant S, et al. Losartan potassium as initial therapy
in patients with severe hypertension. J Hum Hypertens 1995; 9: 861-7
11. Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan
potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensinconverting enzyme inhibitors for the treatment of systemic
hypertension. Am J Cardiol 1995 Apr 15; 75: 793-5
12. Merck & Co., Inc. Losartan potassium prescribing information. West
Point, PA 19486, USA, April, 1995.
13. Acker CG, Greenberg A. Angioedema induced by the angiotensin II
blocker losartan [letter]. N Engl J Med 1995 Dec 7; 333: 1572
14. Ahmad S. Losartan and severe migraine [letter]. JAMA 1995 Oct 25; 274
(16): 1266-7
15. Schliengcr RG, Saxcr M, Haefeli WE. Reversible ageusia associated with
losartan [letter]. Lancet 1996 Feb 17; 347: 471-2
16. Lacourciére Y, Brunner H, Irwin R, et al. Effects of modulators of the
renin-angiolensin-aklosterone system on cough. J Hyperlens 1994 Dec;
12: 1387-93
17. Merck Cozaar cough advantage over ACE inhibitors labeling claim. FDC
Rep Pink Sheet 1996 Jan 8; T&G 2
18. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential
hypertension: report of the second working party of the British
Hypertension Society. BMJ 1993 April 10; 306: 983-7
1172-0360/96/00018-005/$01.00® Adis International Limited. All rights reserved
19. Joint National Committee on Detection Evaluation and Treatment of High
Blood Pressure. The fifth report of the Joint National Committee on
Detection, Evaluation, and Treatment of High Blood Pressure (JNC V).
Arch Intern Med 1993; 153: 154-83
Which drug for stable angina?
Drug treatment is the therapy of choice for patients
with chronic stable angina. [1] The 3 most commonly used
drug classes are nitrates, -blockers and calcium
antagonists; the choice between these will often depend
on what concurrent disease the patient has.
Angina
Angina is a symptomatic manifestation of ischaemic
heart disease, which is usually caused by severe atherosclerotic eccentric lesions of 1 or more of the coronary
arteries. Symptoms occur when myocardial oxygen
demand is greater than supply, and this is normally
provoked by exercise or stress. Angina is classified as
stable when the frequency of attacks remains reasonably
constant for a period of a least 1 month.[1]
Nitrates, calcium antagonists and -blockers
appear equally effective in preventing
angina attacks; choice is likely to depend on
concomitant disorders
Angina is a disease predominately of the elderly; 10
to 25% of the elderly population aged >70 years have
been reported as having angina compared with only 2%
of the population aged >30 years.[2] Because the population
is mostly elderly, the occurrence of patients with
coexisting medical conditions is high. [2]
Modification of risk factors
Risk factors for angina include smoking, obesity, diabetes mellitus, hypertension and hyperlipidaemia.[3] Thus,
counselling patients to help them reduce body weight (particularly by reducing dietary fat intake), to stop smoking,
and to take appropriate exercise is important. [1,4]
Moreover, appropriate treatment of diabetes mellitus,
hypertension, hyperlipidaemia and heart failure all
increase the survival rate in patients with angina. [2]
Improvement in angina can also be achieved by treating
exacerbating conditions such as anaemia and hyperthyroidism.[2]
Treatment for acute attacks
Acute attacks of angina are nearly always treated with
sublingual nitroglycerin (glyceryl trinitrate), which pro-
Vol. 8, No. 6; September 16, 1996