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Losartan

A Review of its Use, with Special Focus on Elderly Patients

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Summary

Abstract

Losartan is an orally active, nonpeptide, selective angiotensin subtype 1 (AT1) receptor antagonist. It provides a more specific and complete blockade of the actions of angiotensin II than renin or ACE inhibitors.

Short term (up to 12 weeks’ duration) clinical trials have shown losartan to be as effective at lowering blood pressure (BP) [causes a decrease in BP ≤26/20mm Hg] in elderly patients with hypertension as recommended dosages of captopril, atenolol, enalapril, felodipine and nifedipine. In patients with isolated systolic hypertension (ISH) the efficacy of losartan was similar to that of atenolol. The addition of hydrochlorothiazide to losartan therapy provides greater antihypertensive efficacy, equivalent to that seen with captopril plus hydrochlorothiazide. Preliminary evidence also indicates that losartan therapy contributes to the regression of left ventricular hypertrophy associated with chronic hypertension.

Exercise capacity is increased by losartan in patients with either asymptomatic or symptomatic heart failure. Results from the Losartan Heart Failure Survival or ELITE II (Evaluation of Losartan in the Elderly II) study indicate that there was no statistically significant difference between losartan and captopril in reducing overall deaths or in reducing sudden cardiac death and/or resuscitated cardiac arrest in patients with heart failure.

Other than ELITE II, little conclusive long term mortality and morbidity data exist for losartan. Additional long term trials to evaluate the survival benefits of losartan in elderly patients with hypertension, renal disease or after an acute myocardial infarction are currently in progress.

In elderly patients with hypertension, the incidence of treatment-related adverse events associated with once daily losartan (alone or in combination with hydrochlorothiazide) [19 to 27%] was similar to felodipine (23%) and nifedipine (21%), however, losartan tended to be better tolerated than captopril (11 vs 16%). Losartan was also better tolerated than atenolol in patients with ISH (10.4 vs 23%). In patients with heart failure the renal tolerability of losartan was similar to that of captopril, but losartan was associated with a lower withdrawal rate because of adverse events. No dosage adjustment is required in elderly or in patients with mild to moderate renal dysfunction, and the risk of first-dose hypotension is low.

Conclusions: comparative data have shown losartan to be as effective as other antihypertensive agents in the treatment of elderly patients with hypertension. Treatment with losartan is therefore an option for first-line therapy in all patients with hypertension, particularly those who are not well managed with or who are intolerant of their current therapy. Morbidity and mortality data from the Losartan Heart Failure Survival (ELITE II) study show that losartan has potential in the treatment of heart failure.

Pharmacodynamic Properties

Losartan is an orally active, nonpeptide, selective angiotensin subtype 1 (AT1) receptor antagonist. It provides a more specific and complete blockade of the actions of angiotensin II than renin or ACE inhibitors.

The active parent losartan is converted into an active metabolite E3174, which is 15 to 20 times more potent at blocking the angiotensin receptor subtype 1 (AT1). Losartan preserves renal function and reduces proteinuria. Preliminary evidence indicates that losartan therapy contributes to the regression of left ventricular hypertrophy associated with chronic hypertension. It has beneficial effects on left ventricular mass index, systemic vascular resistance, BP, pulomonary capillary wedge pressure, heart rate and cardiac index. In patients with heart failure, losartan had a more gradual effect on BP than captopril. In contrast to captopril, losartan had no negative effects on QT dispersion in patients with heart failure. Unlike ACE inhibitors, losartan appears to have no effect on haematology (haemoglobin and plasma erythropoietin levels) and haemorheology. It improves baroreceptor function in elderly patients with hypertension.

Pharmacokinetic Properties

After oral administration losartan is rapidly absorbed, reaching peak plasma concentrations within an hour, while plasma concentrations of the active metabolite E3174 peak approximately 4 hours after administration. The drug undergoes significant first pass metabolism with about 14% of the dose converted into E3174. The pharmacokinetic properties of losartan are similar in volunteers and patients with heart failure and there appears to be no clinically significant accumulation of the drug in these patients.

Renal impairment did not alter the pharmacokinetic properties of losartan. However, in patients with alcoholic liver cirrhosis, plasma concentrations of losartan and E3714 were increased and the dosage should be adjusted for such patients.

Losartan did not interact with single-dose warfarin, digoxin or hydrochlorothiazide. Drugs that affect the cytochrome P450 system have the potential to affect the pharmcokinetics of losartan.

Therapeutic Efficacy

Studies (generally of 12 weeks’ duration) in elderly patients indicate that the antihypertensive efficacy of losartan 50 or 100mg once daily (causes a decrease in BP of ≤26/20mm Hg) is similar to that of other antihypertensive agents, including once daily enalapril 10 or 20mg, captopril 50 or 100mg, nifedipine gastrointestinal system (GITS) 30 to 90mg and felodopine extended release 5 or 10mg. In addition, once daily losartan 50mg and atenolol 50mg had similar antihypertensive efficacy in patients with isolated systolic hypertension. The addition of hydrochlorothiazide 12.5 or 25mg to losartan produces additional BP decreases. A fixed combination of losartan 50mg/hydrochlorothiazide 12.5mg was as effective at reducing BP as captopril 50mg/hydrochlorothiazide 25mg.

Fewer patients with mild to moderate hypertension required switching to alternative therapy with a systematic losartan-based regimen than with usual care in a community-based study. The losartan regimen included losartan 50mg, losartan 50mg plus hydrchlorothiazide 12.5 or 25mg, followed by any other additional therapy (except angiotensin II antagonists) as required for adequate blood pressure control.

Losartan had a more favourable effect on quality of life than enalapril in elderly patients with hypertension. However, the drug had a similar effect on quality of life to nifedipine GITS, although the total number of adverse events reported with nifedipine GITS was greater than in losartan recipients.

Despite the promising results of the Losartan Heart Failure (ELITE I) study which showed a significant 32% reduction in the risk of death or admission to hospital for heart failure compared with captopril-treated patients, the Losartan Heart Failure Survival (ELITE II) study found no significant difference in all cause mortality between the 2 treatments. In addition, no differences were observed in sudden death, heart failure mortality, myocardial infarction, stroke or noncardiovascular death between the 2 groups. However, confirming the results of the Losartan Heart Failure (ELITE I) study, losartan was better tolerated than captopril. In this initial study, losartan and captopril produced similar improvements in quality of life after 48 weeks, although more captopril-treated patients withdrew from the study because of adverse reactions.

In patients with asymptomatic left ventricular dysfunction, losartan increased exercise tolerance, and reduced and delayed peak systolic BP during exercise. Losartan also improved exercise tolerance (including exercise time, oxygen consumption and ejection fraction) in patients with symptomatic heart failure to a similar extent to enalapril. Short term studies have indicated that the addition of losartan to an ACE inhibitor may provide additional benefits in patients with severe heart failure not sufficiently controlled by their current regimen.

Tolerability

Losartan 50 or 100mg, alone or in combination with low dose hydrochlorothiazide was well tolerated in elderly patients with hypertension. Headache, asthenia, oedema and upper respiratory tract infections were the most commonly reported adverse events occurring in approximately 5 to 10% of patients. The incidence of treatment-related adverse events in patients treated with losartan (19 to 27%) was similar to that in recipients of felodipine 5 or 10mg (23%) and nifedipine (21%), however, losartan tended to be better tolerated than captopril (11 vs 16%). Importantly, the incidence of cough was significantly (p < 0.05) lower with losartan/hydrochlorothiazide than with captopril/hydrochlorothiazide. Losartan was better tolerated than atenolol in patients with ISH (10.4 vs 23%). There were also significantly less withdrawals because of adverse events in losartan-treated patients than in those receiving atenolol (1.5 vs 7.2%).

In the Losartan Heart Failure (ELITE I) study the renal tolerability of losartan was similar to that of captopril in patients with heart failure after 48 weeks’ treatment (incidence of persistent increases in serum creatinine ≥26.5 μmol/L 10.5% each). However, there were more withdrawals from treatment among captopril recipients than those on losartan (20.8 vs 12.2%). Losartan was also better tolerated than captopril in the Losartan Heart Failure Survival (ELITE II) study and a higher number of patients treated with captopril withdrew because of adverse events than those on losartan.

Dosage and Administration

The recommended starting and maintenance dosage of losartan is 50mg once daily in patients with essential hypertension. If patients are not responding to losartan monotherapy a stepwise titration may be used to once daily losartan 50mg in fixed combination with hydrochlorothiazide 12.5mg and, if required, once daily losartan 100mg plus hydrochlorothiazide 25mg. A starting dosage of 25mg daily should be used in patients with severe renal dysfunction (creatinine clearance <1.2 L/h (20 ml/min)] or on dialysis and in those who have intravascular volume depletion or hepatic impairment. However, no dosage adjustment is required in elderly or in patients with mild to moderate renal dysfunction.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Kerryn L. Simpson & Karen J. McClellan

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  1. Kerryn L. Simpson
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  2. Karen J. McClellan
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Correspondence to Kerryn L. Simpson.

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Simpson, K.L., McClellan, K.J. Losartan. Drugs & Aging 16, 227–250 (2000). https://doi.org/10.2165/00002512-200016030-00006

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