Skip to main content

Losartan Potassium

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

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).

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Smith RD, Sweet CS, Goldberg A, et al. Losartan potassium (Cozaar™): a nonpeptide antagonist of angiotensin II. Drugs Today 1995; 31(7): 463–98

    CAS  Google Scholar 

  2. 2.

    Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993 Jun; 45: 205–51

    PubMed  CAS  Google Scholar 

  3. 3.

    Garrison JC, Peach MJ. Chapter 31. Renin and angiotensin. In: Gilman AG et al., editors. The pharmacological basis of therapeutics. New York: McGraw Hill Inc., 1992: 749–58

    Google Scholar 

  4. 4.

    Cody RJ. The clinical potential of renin inhibitors and angiotensin antagonists. Drugs 1994 Apr; 47: 586–98

    PubMed  CAS  Google Scholar 

  5. 5.

    Timmermans PBMWM, Wong PC, Chiu AT, et al. The preclinical basis of the therapeutic evaluation of losartan. J Hypertens 1995; 13 Suppl. 1: S1–13

    CAS  Google Scholar 

  6. 6.

    Chiu AT, Herblin WF, McCall DE, et al. Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989; 165(1): 196–203

    PubMed  CAS  Google Scholar 

  7. 7.

    Tsutsumi K, Viswanathan M, Stromberg C, et al. Type-1 and type-2 angiotensin II receptors in fetal rat brain. Eur J Pharmacol 1991 May 30; 198: 89–92

    PubMed  CAS  Google Scholar 

  8. 8.

    Whitebread S, Mele M, Kamber B, et al. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun 1989 Aug 30; 163: 284–91

    PubMed  CAS  Google Scholar 

  9. 9.

    Furuta H, Guo D-F, Inagami T. Molecular cloning and sequencing of the gene encoding human angiotensin II type 1 receptor. Biochem Biophys Res Commun 1992; 183(1): 8–13

    PubMed  CAS  Google Scholar 

  10. 10.

    Iwai N, Inagami T. Identification of two subtypes in the rat type I angiotensin II receptor. FEBS Lett 1992 Feb; 298(23): 257–60

    PubMed  CAS  Google Scholar 

  11. 11.

    Sasamura H, Hein L, Krieger JE, et al. Cloning, characterization, and expression of two angiotensin receptor (AT-1) isoforms from the mouse genome. Biochem Biophys Res Commun 1992 Feb; 185: 253–9

    PubMed  CAS  Google Scholar 

  12. 12.

    Timmermans PBMWM, Smith RD. Angiotensin II receptor subtypes: selective antagonists and functional correlates. Eur Heart J 1994 Dec; 15 Suppl. D: 79–87

    PubMed  CAS  Google Scholar 

  13. 13.

    Muñoz-García R, Maeso R, Rodrigo E, et al. Acute renal excretory actions of losartan in spontaneously hypertensive rats: role of AT2 receptors, prostaglandins, kinins and nitric oxide. J Hypertens 1995; 13: 1779–84

    PubMed  Google Scholar 

  14. 14.

    Johnston CI. Angiotensin receptor antagonists: focus on losartan. Lancet 1995 Nov 5; 346: 1403–7

    PubMed  CAS  Google Scholar 

  15. 15.

    Chai SY, Zhuo J, Mendelsohn FA. Localization of components of the renin-angiotensin system and site of action of inhibitors. Arzneimittelforschung 1993 Feb; 43: 214–21

    PubMed  CAS  Google Scholar 

  16. 16.

    Chiu AT, McCall DE, Ardecky RJ, et al. Angiotensin II receptor subtypes and their selective nonpeptide ligands. Receptor 1990–91 Winter; 1: 33–40

    PubMed  CAS  Google Scholar 

  17. 17.

    Regitz-Zagrosek V, Auch-Schelk W, Hess B, et al. Modulation of AngII receptors by chronic treatment with cyclosporin A, an ACE-inhibitor and AT1-blocker in rats [abstract no. 1055]. Eur Heart J 1996 Aug; 16 Abstract Suppl.: 182

  18. 18.

    Chiu AT, McCall DE, Price WA, et al. Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 735, an orally active antihypertensive agent. J Pharmacol Exp Ther 1990 Feb; 252: 711–8

    PubMed  CAS  Google Scholar 

  19. 19.

    Sachinidis A, Ko Y, Weisser P, et al. EXP3174, a metabolite of losartan (MK 954, DuP 753) is more potent than losartan in blocking the angiotensin II-induced responses in vascular smooth muscle cells. J Hypertens 1993 Feb; 11: 155–62

    PubMed  CAS  Google Scholar 

  20. 20.

    Wong PC, Tarn SW, Herblin WF, et al. Further studies on the selectivity of DuP 753, a nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol 1991 Apr 17; 196: 201–3

    PubMed  CAS  Google Scholar 

  21. 21.

    Rhaleb N-E, Rouissi N, Nantel F, et al. DuP 753 is a specific antagonist for the angiotensin receptor. Hypertension 1991 Apr; 17: 480–4

    PubMed  CAS  Google Scholar 

  22. 22.

    Chiu AT, McCall DE, Aldrich PE, et al. [3H]DUP 753, a highly potent and specific radioligand for the angiotensin II-1 receptor subtype. Biochem Biophys Res Commun 1990 Nov 15; 172: 1195–202

    PubMed  CAS  Google Scholar 

  23. 23.

    Chiu AT, McCall DE, Price Jr WA, et al. In vitro pharmacology of DuP 753. Am J Hypertens 1991 Apr; 4 Suppl.: 282S–7S

    PubMed  CAS  Google Scholar 

  24. 24.

    Abdelrahman A, Pang CCY. Competitive antagonism of pressor responses to angiotensin II and angiotensin III by the angiotensin II-1 receptor ligand losartan. Can J Physiol Pharmacol 1992 May; 70: 716–9

    PubMed  CAS  Google Scholar 

  25. 25.

    Wong PC, Price WA, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 1990 Feb; 252: 719–25

    PubMed  CAS  Google Scholar 

  26. 26.

    Wong PC, Price WA, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists. XI. Pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 1990 Oct; 255: 211–7

    PubMed  CAS  Google Scholar 

  27. 27.

    Wong PC, Price WA, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists. IX. Antihypertensive activity in rats of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 1990 Feb; 252: 726–32

    PubMed  CAS  Google Scholar 

  28. 28.

    Cockcroft JR, Sciberras DG, Goldberg MR, et al. Comparison of angiotensin-converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm. J Cardiovasc Pharmacol 1993 Oct; 22: 579–84

    PubMed  CAS  Google Scholar 

  29. 29.

    Goldberg MR, de Mey C, Wroblewski JM, et al. Differential effects of oral losartan and enalapril on local venous and systemic pressor responses to angiotensin I and II in healthy men. Clin Pharmacol Ther 1996; 59(1): 72–82

    PubMed  CAS  Google Scholar 

  30. 30.

    Christen Y, Waeber B, Nussberger J. Dose-response relationships following oral administration of DuP 753 to normal humans. Am J Hypertens 1991 Apr; 4 Suppl.: 350S–3S

    PubMed  CAS  Google Scholar 

  31. 31.

    Munafo A, Christen Y, Nussberger J, et al. Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist. Clin Pharmacol Ther 1992 May; 51: 513–21

    PubMed  CAS  Google Scholar 

  32. 32.

    Burnier M, Rutschmann B, Nussberger J, et al. Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects. Hypertension 1993 Sep; 22: 339–47

    PubMed  CAS  Google Scholar 

  33. 33.

    Azizi M, Chatellier G, Thanh-Tarn G, et al. Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation 1995; 92: 825–34

    PubMed  CAS  Google Scholar 

  34. 34.

    Goldberg MR, Tanaka W, Barchowsky A, et al. Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers. Hypertension 1993 May; 21; 704–13

    PubMed  CAS  Google Scholar 

  35. 35.

    Doig JK, MacFadyen RJ, Sweet CS. Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. J Cardiovasc Pharmacol 1993 May; 21: 732–8

    PubMed  CAS  Google Scholar 

  36. 36.

    Goldberg MR, Bradstreet TE, McWilliams 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

    PubMed  CAS  Google Scholar 

  37. 37.

    Grossman E, Peleg E, Carroll J, et al. Hemodynamic and humoral effects of the angiotensin II antagonist losartan in essential hypertension. Am J Hypertens 1994 Dec; 7: 1041–4

    PubMed  CAS  Google Scholar 

  38. 38.

    Smith MC, Barrows S, Meibohm A, et al. The effects of angiotensin II receptor blockade with losartan on systemic blood pressure and renal and extrarenal prostaglandin synthesis in women with essential hypertension. Am J Hypertens 1995; 8: 1177–83

    PubMed  CAS  Google Scholar 

  39. 39.

    Opsahl JA, Goldberg MR, Katz SA. Effect of acute and chronic losartan therapy on active and inactive renin and active renin glycoforms. Am J Hypertens 1995; 8: 1090–8

    PubMed  CAS  Google Scholar 

  40. 40.

    Wong PC, Price JWA, Chiu AT, et al. Hypotensive action of DuP 753, an angiotensin II antagonist, in spontaneously hypertensive rats: nonpeptide angiotensin II receptor antagonists: X. Hypertension 1990 May; 15: 459–68

    PubMed  CAS  Google Scholar 

  41. 41.

    Gradman AH, Arcuri KE, Goldberg AI, et al. Arandomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension 1995 Jun; 25: 1345–50

    PubMed  CAS  Google Scholar 

  42. 42.

    Arcuri K, Harm S, Nelson E, et al. Efficacy and safety of concomitant losartan (L) hydrochlorothiazide (H) therapy in patients with essential hypertension [abstract no. 148]. Am J Hypertens 1994; 7 (4 Pt 2): 110A

    Google Scholar 

  43. 43.

    Meredith PA. Trough/peak ratios of antihypertensive agents. Drugs 1994 Nov; 48(5): 661–6

    Google Scholar 

  44. 44.

    Weber MA, Byyny RL, Pratt JH, et al. Blood pressure effects of the angiotensin II receptor blocker, losartan. Arch Intern Med 1995 Feb 27; 155: 405–11

    PubMed  CAS  Google Scholar 

  45. 45.

    Stapff M, Dueck KD, Richard F, et al. Evaluation of the antihypertensive efficacy of losartan, an angiotensin II antagonist, compared to captopril using 24h ABPM [abstract no. 806]. Seventh European Meeting on Hypertension, 1995: 183.

  46. 46.

    Goldberg MR, Staub T, Ermlich S, et al. First-dose effects of losartan vs captopril in thiazide-treated hypertensive patients [abstract]. Clin Pharmacol Ther In press

  47. 47.

    Otsuka K, Tsukiyama H. Hemodynamic effects of MK-954 (losartan potassium), an angiotensin II receptor antagonist, in patients with essential hypertension [in Japanese]. Rinsho Iyaku 1995; 11(1): 165–74

    Google Scholar 

  48. 48.

    Cody RJ, Hunnicutt M, Sinnathamby S, et al. The long term systemic and ventricular hemodynamic response to losartan is comparable to enalapril, in pressure overload ventricular dysfunction [abstract]. Clin Res 1994 Oct; 42: 351A

    Google Scholar 

  49. 49.

    Caviezel B, Girerd X, Laloux B, et al. Effects of the selective AT1-receptor antagonist losartan on arterial compliance in hypertensives [abstract]. J Hypertens 1994 Mar; 12 Suppl. 3: S91

    Google Scholar 

  50. 50.

    Himmelmann A, Svensson A, Dahlöf B, et al. Atenolol versus losartan in hypertension–focus on left ventricular morphology [abstract]. J Hypertens 1994 Mar; 12 Suppl. 3: S98

    Google Scholar 

  51. 51.

    Mohabir R, Young SD, Strosberg AM. Role of angiotensin in pressure overload-induced hypertrophy in rats: effects of angiotensin-converting enzyme inhibitors, an AT1 receptor antagonist, and surgical reversal. J Cardiovasc Pharmacol 1994 Feb; 23: 291–9

    PubMed  CAS  Google Scholar 

  52. 52.

    Mizuno K, Tani M, Hashimoto S, et al. Effects of losartan, a nonpeptide angiotensin-II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats. Life Sci 1992; 51(5): 367–74

    PubMed  CAS  Google Scholar 

  53. 53.

    Nishimura N, Takase H, Morita T. Comparative effects of chronic treatment with losartan or captopril on myocardial and vascular hypertrophy in SHRs [abstract]. Jpn J Pharmacol 1994; 64 Suppl. 1: 330P

    Google Scholar 

  54. 54.

    Dostal DE, Baker KM. Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart. Mediation by the AT] receptor. Am J Hypertens 1992 May; 5 (5 Pt 1): 276–80

    PubMed  CAS  Google Scholar 

  55. 55.

    Ruzicka M, Yuan B, Leenen FHH. Effects of enalapril versus losartan on regression of volume overload-induced cardiac hypertrophy in rats. Circulation 1994 Jul; 90: 484–91

    PubMed  CAS  Google Scholar 

  56. 56.

    Bruckschlegel G, Jandeleit K, Holmer SR, et al. Effects of ACE inhibition and angiotensin II-type1 receptor antagonism on left ventricular hypertrophy in rats [abstract no. 503]. J Hypertens 1994; 12 Suppl. 3: S91

    Google Scholar 

  57. 57.

    Hunnicutt M, Alton ME, Haas GJ, et al. Attenuated development of left ventricular hypertrophy (LVH) with long term DUP753 in the spontaneously hypertensive rat [abstract no. 1122]. Am J Hypertens 1993 May; 6 (5 Pt 2): 28A

    Google Scholar 

  58. 58.

    Ishiye M, Umemura K, Uematsu T, et al. Effect of losartan, an angiotensin II receptor antagonist, on volume overload cardiac hypertrophy [abstract no. 0-130]. Jpn J Pharmacol 1992; 58 Suppl. 1: 100P

    Google Scholar 

  59. 59.

    de Simone G, Devereux RB, Camargo MJF, et al. Midwall left ventricular performance in salt-loaded Dahl rats: effect of AT1 angiotensin II inhibition. J Hypertens 1995; 13: 1808–12

    PubMed  CAS  Google Scholar 

  60. 60.

    Broten TP, Gibson RE, Cartwright ME, et al. Losartan and enalapril prevent cardiac hypertrophy and intramural coronary arterial hypertrophy and fibrosis in a low renin model of hypertension [abstract]. FASEB J 1994 Mar 15; 8 (Pt 1): 310

    Google Scholar 

  61. 61.

    Wilm C, Lues I, Schelling P. Regression of vascular hypertrophy in renal hypertensive rats treated with the angiotensin II antagonist losartan [abstract]. J Hypertens 1994 Mar; 12 Suppl. 3: S90

    Google Scholar 

  62. 62.

    Ling Q, Guo Z-G, Su Z, et al. Regression of cardiac hypertrophy and myosin isoenzyme patterns by losartan and captopril in renovascular hypertensive rats. Acta Pharmacol Sin 1994 May; 15(3): 206–10

    CAS  Google Scholar 

  63. 63.

    Nicoletti A, Heudes D, Hinglais N, et al. Left ventricular fibrosis in renovascular hypertensive rats. Hypertension 1995; 26: 101–11

    PubMed  CAS  Google Scholar 

  64. 64.

    Fornes P, Richer C, Vacher E, et al. Losartan’s protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 1993 Aug; 22: 305–13

    PubMed  CAS  Google Scholar 

  65. 65.

    Stier Jr CT, Adler LA, Levine S, et al. Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats. J Hypertens 1993 Apr; 11 Suppl. 3: S37–42

    CAS  Google Scholar 

  66. 66.

    Camargo MJ, von Lutterotti N, Campbell Jr WG, et al. Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade. J Hypertens 1993 Jan; 11: 31–40

    PubMed  CAS  Google Scholar 

  67. 67.

    von Lutterotti N, Camargo MJ, Campbell Jr WG, et al. Angiotensin II receptor antagonist delays renal damage and stroke in salt-loaded Dahl salt-sensitive rats. J Hypertens 1992 Sep; 10: 949–57

    Google Scholar 

  68. 68.

    Medina R, Cardona-Sanclemente LE, Born GVR. Effect of angiotensin II and losartan on the incorporation of human and rat low-density lipoprotein by organs of normotensive and hypertensive rats [abstract no. 1591]. Eur Heart J 1995 Aug; 16(6): 274

    Google Scholar 

  69. 69.

    Chabielska E, Pawlak R, Golatowski J, et al. Influence of losartan on platelet aggregation and venous thrombosis in rats [abstract no. 1658]. Thromb Haemost 1995 June; 73(6): 1332

    Google Scholar 

  70. 70.

    Tsunoda K, Abe K, Hagino T, et al. Hypotensive effect of losartan, a nonpeptide angiotensin II receptor antagonist, in essential hypertension. Am J Hypertens 1993 Jan; 6: 28–32

    PubMed  CAS  Google Scholar 

  71. 71.

    Fauvel JP, Laville M, Maakel N, et al. Effects of losartan on renal hemodynamic parameters in hypertensives [abstract]. J Hypertens 1994 Mar; 12 Suppl. 3: S93

    Google Scholar 

  72. 72.

    Erley CM, Bader B, Scheu M, et al. Renal hemodynamics in essential hypertensives treated with losartan. Clin Nephrol 1995 Jan; 43 Suppl. 1: S8–11

    PubMed  Google Scholar 

  73. 73.

    Chan JCN, Critchley JAJH, Tomlinson B, et al. Antihypertensive and anti-albuminuric effects of losartan potassium and felodipine-ER in Chinese elderly hypertensive patients with or without NIDDM. Am J Nephrol In press

  74. 74.

    Nakashima M, Uematsu T, Kosuge K. Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 1992 Mar; 42: 333–5

    PubMed  CAS  Google Scholar 

  75. 75.

    Shaw W, Keane W, Sica D, et al. Safety and antihypertensive effects of losartan (MK-954; DUP753) a new angiotensin II receptor antagonist, in patients with hypertension and renal disease [abstract]. Clin Pharmacol Ther 1993 Feb; 53: 140

    Google Scholar 

  76. 76.

    Gansevoort RT, de Zeeuw D, Shahinfar S, et al. Effects of the angiotensin II antagonist losartan in hypertensive patients with renal disease. J Hypertens 1994 Jul; 12 Suppl. 2: S37–42

    CAS  Google Scholar 

  77. 77.

    Campbell DJ, Kladis A, Valentijn AJ. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol 1995; 26(2): 233–40

    PubMed  CAS  Google Scholar 

  78. 78.

    Moan A, Hoieggen A, Eide I. Metabolic effects of antihypertensive treatment with the angiotensin II receptor antagonist losartan [abstract no. 551]. Seventh European Meeting on Hypertension, 1995.

  79. 79.

    Sami H, Laurel C, Anderson PW. Effects of losartan treatment in hypertensive patients [abstract]. J Invest Med 1995 Feb; 43 Suppl. 1: 199A

    Google Scholar 

  80. 80.

    de Zeeuw D, Gansevoort RT, Dullaart RPF, et al. Angiotensin II antagonism improves the lipoprotein profile in patients with nephrotic syndrome. J Hypertens 1995; 13 Suppl. 1: S53–8

    Google Scholar 

  81. 81.

    Moan A, Risanger T, Eide I. The effect of angiotensin II receptor blockade on insulin sensitivity and sympathetic nervous system activity in primary hypertension. Blood Press 1994 May; 3: 185–8

    PubMed  CAS  Google Scholar 

  82. 82.

    Barker JE, Bakhle YS, Piper PJ. The AT] receptor antagonist, losartan, inhibits contraction and enhances PGI2 release in human saphenous vein stimulated by angiotensin II [abstract no. 198P]. Br J Pharmacol 1995 Oct; 116

  83. 83.

    Sasaski M, Fujimura A, Harada K, et al. Effect of losartan, an angiotensin II receptor antagonist, on response of Cortisol and aldosterone to adrenocorticotrophic hormone. J Clin Pharmacol 1995 Aug; 35: 776–9

    Google Scholar 

  84. 84.

    Stearns RA, Miller RR, Doss GA, et al. The metabolism of DuP 753, a nonpeptide angiotensin II receptor antagonist, by rat, monkey, and human liver slices. Drug Metab Dispos 1992 Mar-Apr; 20: 281–7

    PubMed  CAS  Google Scholar 

  85. 85.

    Furtek CI, Lo M-W. Simultaneous determination of a novel angiotensin II receptor blocking agent, losartan, and its metabolite in human plasma and urine by high-performance liquid chromatography. J Chromatogr 1992 Jan 17; 573: 295–301

    PubMed  CAS  Google Scholar 

  86. 86.

    Lo M-W, Goldberg MR, McCrea JB, et al. Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Ther 1995 Dec; 58: 641–9

    PubMed  CAS  Google Scholar 

  87. 87.

    Ohtawa M, Takayama F, Saitoh K. Pharmacokinetics and biochemical efficacy after single and multiple oral administration of losartan, an orally active nonpeptide angiotensin II receptor antagonist, in humans. Br J Clin Pharmacol 1993 Mar; 35: 290–7

    PubMed  CAS  Google Scholar 

  88. 88.

    Merck & Co., Inc. Losartan potassium prescribing information. West Point, PA 19486, USA, April, 1995.

  89. 89.

    Christ DD. Human plasma protein binding of the angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174. J Clin Pharmacol 1995 May; 35: 515–20

    PubMed  CAS  Google Scholar 

  90. 90.

    Li ZH, Bains JS, Ferguson AV. Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat. Brain Res Bull 1993; 30(1–2): 33–9

    PubMed  CAS  Google Scholar 

  91. 91.

    Soldner A, Spahn-Langguth H, Mutschler E. Disposition profiles of losartan and EXP3174 in rat tissues and body fluids following single and multiple oral dosing [abstract no. 790]. Seventh European Meeting on Hypertension, 1995.

  92. 92.

    Bui JD, Kimura B, Phillips MI. Losartan potassium, a nonpeptide antagonist of angiotensin II, chronically administered p.o. does not readily cross the blood-brain barrier. Eur J Pharmacol 1992 Aug 14; 219: 147–51

    PubMed  CAS  Google Scholar 

  93. 93.

    Stevenson KM, Gibson KJ, Lumbers ER, et al. Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep. Br J Pharmacol 1995 Apr; 114: 1495–501

    PubMed  CAS  Google Scholar 

  94. 94.

    Sica DA, Lo M-W, Shaw WC, et al. The pharmacokinetics of losartan in renal insufficiency. J Hypertens 1995; 13 Suppl. 1: S49–52

    CAS  Google Scholar 

  95. 95.

    Stearns RA, Chakravarty PK, Chen R, et al. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes: role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos 1995 Feb; 23: 207–15

    PubMed  CAS  Google Scholar 

  96. 96.

    Yun C-H, Lee HS, Lee H, et al. Oxidation of the angiotensin II receptor antagonist losartan (DuP 753) in human liver microsomes: role of cytochrome P4503A(4) in formation of the active metabolite EXP3174. Drug Metab Dispos 1995 Feb; 23: 285–9

    PubMed  CAS  Google Scholar 

  97. 97.

    Goldberg MR, Lo M-W, Bradstreet TE, et al. Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist. Eur J Clin Pharmacol 1995; 49: 115–9

    PubMed  CAS  Google Scholar 

  98. 98.

    McCrea JB, Lo M-W, Furtek CI, et al. Ketoconazole does not affect the systemic conversion of losartan to E-3174 [abstract]. Clin Pharmacol Ther In press

  99. 99.

    Goldberg MR, Lo M-W, Deutsch PJ, et al. Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. Clin Pharmacol Ther In press; 59

  100. 100.

    Spielberg S, McCrea J, Cribb A, et al. A mutation in CYP2C9 is responsible for decreased metabolism of losartan [abstract]. Clin Pharmacol Ther In press

  101. 101.

    McCrea J, Lo M-W, Kong T, et al. A rare deficiency of the conversion of losartan to its active metabolite, E3174 [abstract]. Clin Pharmacol Ther In press

  102. 102.

    Kong A-NT, Tomasko L, Waldman SA, et al. Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1995; 35: 1008–15

    PubMed  CAS  Google Scholar 

  103. 103.

    De Smet M, Schoors DF, De Meyer G, et al. Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers. Br J Clin Pharmacol 1995 Dec; 40: 571–5

    PubMed  CAS  Google Scholar 

  104. 104.

    McCrea JB, Lo M-W, Tomasko L, et al. Absence of a pharmacokinetic interaction between losartan and hydrochlorothiazide. J Clin Pharmacol 1995; 35: 1200–6

    PubMed  CAS  Google Scholar 

  105. 105.

    Nelson E, Merrill D, Sweet C, et al. Efficacy and safety of oral MK-954 (DuP 753), an angiotensin antagonist, in essential hypertension [abstract]. J Hypertens 1991 Dec; 9 Suppl. 6: S468

    Google Scholar 

  106. 106.

    Tikkanen I, Omvik P, Jensen HÆ, et al. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. Hypertension 1995; 13: 1343–51

    CAS  Google Scholar 

  107. 107.

    Mallion J-M, Bradstreet DC, Makris L, et al. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with captopril in patients with mild to moderate essential hypertension. J Hypertens 1995; 13 Suppl. 1: S35–41

    CAS  Google Scholar 

  108. 108.

    Dahlöf 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

    PubMed  Google Scholar 

  109. 109.

    Chan JCN, Critchley JAJH, Lappe JT, et al. Randomised, double-blind, 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

    PubMed  CAS  Google Scholar 

  110. 110.

    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

    PubMed  CAS  Google Scholar 

  111. 111.

    Velivis M, Dai XC, Goldberg AI, et al. Safety and efficacy of losartan potassium/hydrochlorothiazide combination tablet in patients with severe hypertension [abstract]. Am J Hypertens 1995 Apr; 8 Pt 2: 192A

    Google Scholar 

  112. 112.

    Simpson RL, Morlin C, Toh J, et al. Efficacy and safety of losartan combined with hydrochlorothiazide in patients with mild to severe hypertension [abstract]. Am J Hypertens 1994 Apr; 7 (Pt 2): 37A

    Google Scholar 

  113. 113.

    MacKay JH, Arcuri KE, Goldberg AI, et al. Losartan and low-dose hydrochlorothiazide in patients with essential hypertension. Arch Intern Med 1994; 156: 278–85

    Google Scholar 

  114. 114.

    Soffer BA, Wright Jr JT, Pratt JH, et al. Effects of losartan on a background of hydrochlorothiazide in patients with hypertension. Hypertension 1995 July; 26(1): 112–7

    PubMed  CAS  Google Scholar 

  115. 115.

    Townsend R, Haggert B, Liss C, et al. Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in patients with essential hypertension. Clin Ther 1995; 17(5): 911–23

    PubMed  CAS  Google Scholar 

  116. 116.

    Gazdick LP, Maxwell M, Ruff D, et al. A double-blind, randomized, parallel, active-controlled study to evaluate the antihypertensive efficacy and safety of losartan in patients with severe hypertension [abstract]. Am J Hypertens 1994 Apr; 7 (Pt 2): 100A

    Google Scholar 

  117. 117.

    Schoenberger JA, The Losartan Research Group. Losartan with hydrochlorothiazide in the treatment of hypertension. J Hypertens 1995; 13 Suppl. 1: S43–7

    CAS  Google Scholar 

  118. 118.

    de Zeeuw D, Gansevoort RT, de Jong PE. Losartan in patients with renal insufficiency. Can J Cardiol 1995; 11 Suppl. F: 41F–4F

    PubMed  Google Scholar 

  119. 119.

    Yoshinaga K, Abe K, Iimura O, et al. Efficacy, safety and usefulness of MK-954 (losartan potassium), angiotensin II receptor antagonist, on essential hypertension in the long-term treatment [in Japanese]. Rinsho Iyaku 1995; 11(1): 175–207

    Google Scholar 

  120. 120.

    Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Am J Cardiol 1995 Apr 15; 75: 793–5

    PubMed  CAS  Google Scholar 

  121. 121.

    Ahmad S. Losartan and severe migraine [letter]. JAMA 1995 Oct 25; 274(16): 1266–7

    PubMed  CAS  Google Scholar 

  122. 122.

    Schlienger RG, Saxer M, Haefeli WE. Reversible ageusia associated with losartan [letter]. Lancet 1996 Feb 17; 347: 471–2

    PubMed  CAS  Google Scholar 

  123. 123.

    Acker CG, Greenberg A. Angioedema induced by the angiotensin II blocker losartan [letter]. N Engl J Med 1995 Dec 7; 333: 1572

    PubMed  CAS  Google Scholar 

  124. 124.

    Shand BI, Gilchrist NL, Nicholls MG, et al. Effect of losartan on haematology and haemorheology in elderly patients with essential hypertension: a pilot study. J Hum Hypertens 1995 Apr; 9: 233–5

    PubMed  CAS  Google Scholar 

  125. 125.

    Karlberg BE. Cough and inhibition of the renin-angiotensin system. J Hypertens Suppl 1993 Apr; 11: S49–52

    PubMed  CAS  Google Scholar 

  126. 126.

    Lacourcière Y, Lefebvre J. Modulation of the renin-angiotensinaldosterone system and cough. Can J Cardiol 1995; 11 Suppl. F: 33F–9F

    PubMed  Google Scholar 

  127. 127.

    Fletcher AE, Palmer AJ, Bulpitt CJ. Cough with angiotensin converting enzyme inhibitors: how much of a problem? J Hypertens 1994; 12 Suppl. 2: S43–7

    CAS  Google Scholar 

  128. 128.

    Lacourcière Y, Brunner H, Irwin R, et al. Effects of modulators of the renin-angiotensin-aldosterone system on cough. J Hypertens 1994 Dec; 12: 1387–93

    PubMed  Google Scholar 

  129. 129.

    Anon. Merck Cozaar cough advantage over ACE inhibitors labeling claim. FDC Rep Pink Sheet 1996 Jan 8

  130. 130.

    Merck & Co., Inc. Losartan potassium-hydrochlorothiazide prescribing information. West Point, PA, USA, April, 1995.

  131. 131.

    Wexler RR, Carini DJ, Duncia JV, et al. Rationale for the chemical development of angiotensin II receptor antagonists. Am J Hypertens 1992 Dec; 5 Suppl.: 209S–20S

    PubMed  CAS  Google Scholar 

  132. 132.

    Pitt B, Chang P, Timmermans PBMWWM. Angiotensin II receptor antagonists in heart failure: rationale and design of the Evaluation of Losartan in the Elderly (ELITE) trial. Cardiovasc Drugs Ther 1995; 9: 693–700

    PubMed  CAS  Google Scholar 

  133. 133.

    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

    PubMed  CAS  Google Scholar 

  134. 134.

    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

    Google Scholar 

  135. 135.

    Weber MA. Controversies in the diagnosis and treatment of hypertension: a personal review of JNC V. Am J Cardiol 1993; 72: 3H–9H

    PubMed  CAS  Google Scholar 

  136. 136.

    Elliott WJ. Controversies regarding the recommendations of the Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Comprehensive Therapy 1994; 20(3): 181–5

    PubMed  CAS  Google Scholar 

  137. 137.

    Edelman JM, Gazdick LP, Epstein RS, et al. Trial of Usual Care for Hypertension (TOUCH): an effectiveness study of newly treated hypertension comparing losartan potassium and usual care in a managed care setting. Am J Hypertens 1995 Apr; 8 (Pt 2): 79

    Google Scholar 

  138. 138.

    Shaw W, Snavely D. Safety and efficacy of losartan (DuP 753, MK 954) in hypertensive patients with renal impairment [abstract]. J Am Soc Nephrol 1994; 5: 567

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Karen L. Goa.

Additional information

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • Adis International Limited
  • Captopril
  • Enalapril
  • Atenolol
  • Losartan