Losartan

Observational studies

Losartan 2.5–100 mg has been studied in 175 hypertensive children aged 6–16 years [ ]. There were non-severe adverse events in 14; headache was the most common. In a comparison of losartan and nebivolol, headache was a common symptom in patients taking losartan; there were no serious adverse events [ ].

Respiratory

In contrast to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists are not usually associated with cough and are recommended as effective antihypertensive drugs to use in patients who develop a cough in response to an ACE inhibitor.

For example, in a comparison of candesartan, nifedipine, and manidipine for 6 months in 60 patients, including five with a history of ACE inhibitor-induced cough, no patient complained of persistent cough [ ]. An unusual case of losartan-induced cough has been described, with resolution after substitution with enalapril [ ].

• A 23-year-old non-smoking white woman who had not taken an ACE inhibitor and had no prior respiratory illnesses developed hypertension, proteinuria, and hyperlipidemia. She was treated with losartan, hydrochlorothiazide, furosemide, and simvastatin and after 3 days developed a dry irritating cough, which persisted for 2 weeks. The angiotensin II receptor antagonist was withdrawn and enalapril was substituted, after which the cough resolved within 1 week. The patient was not re-challenged with losartan.

Theoretically, adverse reactions that are due to the accumulation of bradykinin, substance P, and prostaglandins, such as cough, should not occur with angiotensin II receptor antagonists, as this class has no effect on angiotensin-converting enzyme. It is therefore difficult to understand this unusual pattern of adverse events, and although the authors defined the relationship between the losartan and cough as “probable”, it should be noted that although the symptom did not recur after 6 months of follow-up the patient was also found to have systemic lupus erythematosus during this time.

Nervous system

An isolated case of migraine occurring after a single dose of losartan was reported [ ]. The temporal association during challenge and rechallenge, although in unblinded conditions, argues for a possible causal relation.

A probable association between losartan and worsening of symptoms in Parkinson’s disease has been reported [ ]. The description of worsening falls, freezing episodes, and bradykinesia, both during a challenge and re-challenge with losartan was fairly convincing. The authors also pointed to experimental evidence that suggests that angiotensin facilitates the striatal release of dopamine, supporting a possible deleterious effects of angiotensin II receptor antagonists in Parkinson’s disease.

Worsening of Parkinson’s disease symptoms has been attributed to losartan [ ].

• A 65-year-old man with Parkinson’s disease and hypertension stabilized on a levodopa/carbidopa combination took losartan 50 mg/day instead of ramipril in order to gain better control of hypertension. His symptoms worsened, with bradykinesia, several falls, and freezing episodes. The symptoms improved after withdrawal for 48 hours but re-emerged after rechallenge with a lower dose (25 mg/day).

This adverse event was considered as a probable effect of losartan using the Naranjo classification.

Sensory systems

There have been reports of taste disturbance in patients taking ACE inhibitors, tentatively attributed to chelation of metal ions. However, no mechanism for taste loss due to angiotensin-II receptor blockers has been proposed. Reversible loss of taste discrimination has been reported with losartan [ ]. In two cases dysgeusia occurred some time after switching from an ACE inhibitor to losartan (1 week in one case and 3 months in the other). In both cases the dysgeusia disappeared after withdrawal of losartan (timing not reported in one case, 1 week after in the other) [ ]. The authors referred to previously reported cases, one with losartan [ ] and one with valsartan [ ], and to a personal communication from the manufacturer of 12 other cases within a large safety monitoring program.

Electrolyte balance

Severe hyperkalemia (8.4 mmol/l), which required hemodialysis, occurred in an 84-year-old woman taking losartan 50 mg/day and spironolactone 25 mg/day for hypertension and severe mitral insufficiency [ ].

Metal metabolism

Zinc, magnesium, and nitric oxide have been studied in a prospective observational study in patients with hypertension taking losartan alone and in combination with hydrochlorothiazide [ ]. Losartan caused zinc deficiency with increased urinary zinc excretion, an effect that was exacerbated by co-administration of hydrochlorothiazide. There were no effects on magnesium or nitric oxide. Zinc deficiency can aggravate hypertension and is also reported to be responsible for some adverse drug effects, such as dysgeusia.

Hematologic

Losartan has been used after renal transplantation to control both blood pressure and post-transplant erythrocytosis. The interaction between the renin–angiotensin system and erythropoietic mechanisms is complex, and after transplantation ACE inhibition can cause anemia without erythrocytosis. Anemia in hemodialysis [ ] and mainly in renal transplant patients has been reported [ ]. In a prospective controlled study renal transplant patients taking losartan had a significant fall in hemoglobin concentration compared with controls [ ]. The suggested mechanism is by an action on erythropoietin, similar to that of ACE inhibitors, which produce the same adverse effect. However, in a small uncontrolled but prospective study, losartan given for 3 months to 15 patients on chronic hemodialysis with anemia, neither altered plasma erythropoietin concentrations nor aggravated the anemia [ ]. In those taking losartan there was no need for higher doses of co-administered r-Hu Epo in order to correct anemia, in contrast to controls.