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Losartan Potassium

A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Management of Hypertension

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An Erratum to this article was published on 01 October 1996

Abstract

Synopsis

Losartan potassium is an orally active, nonpeptide angiotensin II (AII) receptor antagonist. It is the first of a new class of drugs to be introduced for clinical use in hypertension. This novel agent binds competitively and selectively to the AII subtype 1 (AT1) receptor, thereby blocking All-induced physiological effects. An active metabolite, E3174, contributes substantially to its antihypertensive effect, which persists throughout 24 hours after once-daily administration.

In patients with mild to moderate hypertension, losartan potassium 50 to 100mg once daily as monotherapy lowers blood pressure to a similar degree to enalapril, atenolol and felodipine extended release (ER). Losartan potassium combined with hydrochlorothiazide reduces blood pressure further than either drug given separately. About one-third of patients with severe hypertension have responded to the combination product. Losartan potassium appears to be effective in elderly patients.

Losartan potassium is very well tolerated. In clinical trials, dizziness was the only drug-related event reported more frequently with losartan potassium monotherapy than with placebo. First-dose hypotension is uncommon. An aspect of the drug’ tolerability profile which may prove to be particularly advantageous is that it is associated with a similar incidence of cough to placebo in patients with a history of ACE inhibitor—related cough. Additionally, clinically relevant adverse metabolic effects or laboratory abnormalities have not been documented during losartan potassium therapy and renal function is preserved in patients with or without renal insufficiency. The adverse effect profile of the losartan potassium-hydrochlorothiazide combination resembles those for losartan potassium monotherapy and placebo. Long term tolerability data are limited (<2 years) but support the very good tolerability profile in shorter studies.

Elements of the drug’s profile yet to be assessed or reported fully in the literature include long term efficacy, potential to favourably influence cardiovascular and renovascular systems (and ultimately mortality) in patients with hypertension and, lastly, cost effectiveness and influence on quality of life.

In summary, losartan potassium is the first AT1 receptor antagonist to become available for the management of hypertension and, as such, it is an important new antihypertensive agent. Pending long term data as outlined above, it is likely to find initial use in patients with mild to severe hypertension who are unresponsive to, or intolerant of, their current therapy. However, with its novel mechanism of action, good efficacy and favourable tolerability profile, losartan potassium is well placed to claim a prominent position in the management of patients with essential hypertension in the future.

Pharmacodynamic Properties

The action of angiotensin II (AII) at the AII subtype 1 receptor (AT1) is critical to cardiovascular homeostasis: physiological consequences pertinent to hypertension include vasoconstriction, sodium/fluid retention, increased sympathetic activity and cellular growth. Losartan potassium binds selectively, competitively and with high affinity to the AT1 receptor, thereby blocking the activity of AII. It has no clinically relevant affinity for any other pharmacological receptor at the concentrations tested.

The active metabolite E3174 is a noncompetitive antagonist which binds to the AT1 receptor with 10-fold greater affinity than its parent compound. E3174 is about 15 to 20 times more potent in inhibiting AII-induced pressor and contractile responses, as shown in vitro and in vivo. Neither losartan potassium nor E3174 possess any agonist activity at the AT1 receptor.

In patients with hypertension, losartan potassium increases plasma renin activity and plasma AII levels and appears to decrease plasma levels of aldosterone, at least in the short term. Forearm vasodilator responses to bradykinin are not altered by losartan potassium. Blood pressure decreases produced by once-daily losartan potassium persist throughout 24 hours and heart rate is unchanged. Single doses of losartan potassium and captopril (both 50mg) yielded similar quantitative effects on blood pressure, although the onset was slower in the first 3 hours with losartan potassium. The influence of pretreatment plasma renin activity on the antihypertensive effect of losartan potassium has not been determined, and its influence on other haemodynamic or cardiac indices in patients with hypertension has not been well reported.

Preliminary data obtained in a few patients and evidence from numerous animal studies suggest that losartan potassium causes regression of left ventricular hypertrophy (LVH); a large clinical study using losartan potassium is under way to determine whether any clinical benefits are associated with LVH regression. Losartan potassium improved mortality rates in animals prone to stroke and prevented fibrinoid necrosis of other end-organs, including the heart, in various animal models.

Renal function is preserved during losartan potassium administration in patients with hypertension with or without renal dysfunction. A uricosuric effect for losartan potassium demonstrable in healthy individuals has been observed in some but not all studies of patients with hypertension. Losartan potassium decreased proteinuria [including that associated with renal failure or with non-insulin-dependent diabetes mellitus (NIDDM)] in limited investigations. Plasma levels of lipids/lipoproteins and prostaglandins are unchanged during losartan potassium administration in patients without other concomitant diseases, as are plasma norepinephrine levels and insulin sensitivity in patients without NIDDM.

Pharmacokinetic Properties

The bioavailability of losartan potassium is about 33%, indicating a considerable first-pass effect, and is not altered significantly by the presence of food. In most patients about 14% of an oral dose of losartan potassium is metabolised via hepatic carboxylation to the active metabolite E3174. However, in a very small proportion of patients (<1%), enzymes responsible for metabolism to E3174 are deficient (<1 % of a dose is converted). Time to achieve peak plasma concentration is about 1 hour for losartan potassium and 3 to 4 hours for E3174. Blockade of pressor response correlates more closely with plasma concentrations of the metabolite than with those of the parent drug. The volume of distribution is about 34L for losartan potassium and 12L for E3174: both compounds are >98% bound to plasma proteins. The kinetics of losartan potassium and E3174 are not influenced by multiple-dose administration.

At about 4 hours (in Japanese) and 6 hours (in Western individuals), the terminal elimination half-life of E3174 is longer than that of losartan potassium (2 hours). The pharmacokinetic properties of losartan potassium and E3174 are not affected by renal dysfunction to any clinically important extent. In contrast, in patients with hepatic dysfunction, plasma drug concentration of both agents is increased and plasma clearance is reduced, necessitating dosage adjustment.

Pharmacokinetic studies using cimetidine and ketoconazole suggest that clinically significant interactions with losartan potassium and cytochrome P450 (CYP) 34A inhibitors are unlikely to eventuate. However, drugs that induce CYP systems may hasten the metabolism of losartan potassium. No significant drug interactions occur between losartan potassium and warfarin, digoxin or hydrochlorothiazide.

Clinical Efficacy

Losartan potassium is an effective treatment for hypertension. Large dose-finding trials have shown losartan potassium 50mg daily as monotherapy to be superior to placebo and indistinguishable from the 100mg dose. The drug has reduced diastolic blood pressure (DBP) by about 8 to 13mm Hg in patients with mild to moderate hypertension, as shown by several well-designed comparative trials lasting 8 to 12 weeks. Antihypertensive efficacy as determined by trough blood pressure values and percentage responders has not differed significantly between losartan potassium and enalapril, atenolol or felodipine extended release (ER) in comparative trials. Blood pressure lowering is evident within 1 week of initiating losartan potassium therapy and is maximal by 6 weeks.

Approximately 30% of patients with severe hypertension have had their condition managed with losartan potassium plus hydrochlorothiazide 12.5 or 25mg during 12-week noncomparative trials, with another 22% maintained on losartan potassium monotherapy in 1 trial and the remainder requiring the addition of atenolol and/or a calcium channel blocker. Overall decreases in DBP for regimens containing losartan potassium were in the magnitude of 18mm Hg in this population. Compared with losartan potassium or hydrochlorothiazide monotherapy, losartan potassium plus hydrochlorothiazide reduced DBP by an additional 4 to 6mm Hg. Polydrug regimens incorporating losartan potassium were as effective as similar strategies using enalapril.

Elderly patients have responded as well to losartan potassium as to felodipine ER. Published evidence for the efficacy of losartan potassium in other special patient groups is scant, as are long term efficacy data.

Tolerability

Results from double-blind trials involving a total of >2800 patients with hypertension who received losartan potassium indicate that the drug is very well tolerated. Although headache (14.1 %), 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, these are ‘all events’ regardless of causality. Dizziness was found to be the only drug-related event documented more often with losartan potassium than with placebo in the clinical trials database. Orthostatic effects and first-dose hypotension are uncommon (<-0.5% with <-50mg). There have been rare reports of patients developing angioedema, migraine or ageusia during losartan potassium therapy.

Cough, which can limit treatment with ACE inhibitors, is seldom experienced during losartan potassium therapy and its incidence is similar to that for placebo. Spontaneous reports of cough occurred at a frequency of 3.1% for losartan potassium vs 2.6% for placebo. In trials conducted specifically in patients with a history of ACE inhibitor-related cough, its incidence was similar for losartan potassium (17 to 29%), placebo (35%) and hydrochlorothiazide (25 to 34%) but was much less than with lisinopril (62 to 72%).

Comparisons without a placebo control showed that oedema was more common with felodipine ER (14%) and dizziness (7.4%) and insomnia (4.4%) were more frequent with atenolol compared with losartan potassium. Liver enzyme levels have risen to a minor extent in a few losartan potassium-treated patients, but this rarely necessitates treatment withdrawal. The incidence of drug-related adverse events and drug withdrawal using losartan potassium plus hydrochlorothiazide resembled that for losartan potassium alone and for placebo in clinical trials.

Dosage and Administration

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. In patients at high risk of hypotension or volume depletion and those with hepatic dysfunction, the initial dose should be 25mg. 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.

Japanese patients may receive losartan potassium 25mg daily.

The combination product containing losartan potassium and hydrochlorothiazide is started at a dosage of 50mg/12.5mg 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 <-1.8 L/h (30 ml/min).

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    Karen L. Goa & Antona J. Wagstaff

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Various sections of the manuscript reviewed by: J. Chan, Department of Clinical Pharmacology, The Chinese University of Hong Kong, Hong Kong; N.L. Gilchrist, Older Persons Health Division, The Princess Margaret Hospital, Christchurch, New Zealand; E. Grossman, Hypertension Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel; A. Himmelmann, Department of Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, Sweden; S.E. Kjeldsen, Department of Internal Medicine, Ullevaal University Hospital, Oslo, Norway; Y. Lacourciére, Hypertension Research Unit, Centre Hospitalier de l’Université Laval, Sante-Foy, Québec, Canada; J. Lefebvre, Hypertension Research Unit, Centre Hospitalier de l’Université Laval, Sante-Foy, Québec, Canada; M. Nakashima, Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu City, Japan; J.H. Pratt, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; L. Ramsay, University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, England; J.M. Ritter, Department of Clinical Pharmacology, Guy’s Hospital, London, England; C.T. Stier Jr, Department of Pharmacology, New York Medical College, Valhalla, New York, USA; K. Sugimoto, Department of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan; K. Yoshinaga, Tohuku Rosai Hospital, Sendai, Japan

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259151.

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Goa, K.L., Wagstaff, A.J. Losartan Potassium. Drugs 51, 820–845 (1996). https://doi.org/10.2165/00003495-199651050-00008

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