Side Effects and Contraindications of Losartan

Losartan is among the best-tolerated antihypertensive drugs: in clinical studies the rate of discontinuation due to side effects was close to placebo. However, «well tolerated» does not mean «safe for everyone». The editorial team has systematized the adverse reactions of losartan, explained their mechanism, and listed the situations in which the drug is contraindicated or requires special caution.

General tolerability profile

In controlled studies of arterial hypertension, the most frequent complaints on losartan were dizziness, upper respiratory tract symptoms, nasal congestion, and back pain. Most of them occurred at a frequency close to placebo and rarely became a reason for discontinuation.

Such good tolerability is explained by the selectivity of the mechanism. Losartan blocks only the AT1 receptors and does not affect bradykinin, so a dry cough — a typical problem of ACE inhibitors — occurs much less often. It is precisely for this reason that losartan is often prescribed to patients who do not tolerate ACE inhibitors because of cough.

At the same time, most of the important side effects of losartan are not «allergies» or «toxicity» but the natural consequences of blocking the renin-angiotensin system. They are predictable: an excessive drop in blood pressure, potassium retention, a change in filtration in the kidneys. Knowing the mechanism, they can be detected and prevented in time.

We will separately mention the history of 2018–2019, when a number of batches of sartans, including losartan, were recalled from the market in Europe and the US because of detected nitrosamine impurities. This was a problem of the substance manufacturing technology at individual producers, not a property of the molecule itself; regulators introduced new requirements for controlling such impurities.

Hypotension and dizziness

An excessive drop in blood pressure is most likely at the beginning of treatment and in people whose renin-angiotensin system is especially strongly activated. Typical examples are dehydration, a strict salt-free diet, taking high doses of diuretics, diarrhea or vomiting, and prolonged physical exertion in the heat.

In such states, the body «holds» blood pressure specifically at the expense of angiotensin II. When its action is blocked, blood pressure can drop sharply. This manifests as dizziness on standing up, weakness, darkening of vision, and in severe cases — fainting.

The prescribing information recommends correcting the water-salt balance before starting treatment or beginning with a lower dose in such patients. Elderly people and those taking several antihypertensive agents should get out of bed slowly, especially in the first days of intake.

For people who train, training in the heat and significant sweat loss are relevant. Dizziness during or after exercise against the background of taking losartan is a reason to stop, restore fluid, and inform the doctor, not to «tough it out».

Potassium and kidneys: the main laboratory risks

Aldosterone, the production of which is stimulated by angiotensin II, causes the kidneys to excrete potassium. Blocking the AT1 receptors reduces the effect of aldosterone, so potassium is retained in the body. In most people with normal kidney function the changes are insignificant, but in certain groups hyperkalemia can become dangerous.

In the RENAAL study (Brenner et al., 2001), which included patients with diabetic nephropathy, hyperkalemia was registered more often in the losartan group than in the placebo group. The risk increases with chronic kidney disease, diabetes mellitus, heart failure, and also with the simultaneous intake of potassium preparations, potassium-sparing diuretics, and salt substitutes with potassium.

Severe hyperkalemia is dangerous because of heart rhythm disturbances. Its symptoms are nonspecific — weakness, muscle fatigue, a feeling of interruptions in the work of the heart — so one cannot rely on how one feels. It is precisely for this reason that doctors monitor the blood potassium level after the start of treatment.

As for the kidneys: at the beginning of intake, creatinine may rise somewhat because of a decrease in pressure in the glomeruli. A moderate increase is usually acceptable, but a significant rise requires an assessment of the causes. An especially dangerous situation is bilateral renal artery stenosis, in which filtration depends on angiotensin II, and a blockade can cause acute renal failure.

Rare but serious reactions

Angioedema — swelling of the face, lips, tongue, larynx — occurs rarely on losartan, less often than on ACE inhibitors. However, it is possible and potentially dangerous if it affects the airways. In people in whom such edema has already occurred on an ACE inhibitor, sartans are prescribed with caution.

Any swelling of the tongue or throat, difficulty swallowing or breathing is a reason to call an ambulance immediately. After such an episode, the drug is not resumed without a doctor’s decision.

In the post-marketing period, isolated cases of liver dysfunction, changes in blood parameters, and allergic skin reactions have been reported. The causal relationship in rare cases is not always unambiguous, but if jaundice, a rash, or unusual symptoms appear, you should consult a doctor.

Losartan, like other blood pressure medications, may affect the ability to drive a car at the beginning of treatment because of dizziness. This is especially important in the first days and after a dose increase.

Contraindications and special groups

The main contraindication is pregnancy. Drugs that act on the renin-angiotensin system in the 2nd–3rd trimesters impair the development of the fetal kidneys, cause oligohydramnios, skull anomalies, and can lead to fetal death. In the FDA prescribing information this is placed in a «black box». For women planning a pregnancy, the doctor selects a different drug in advance.

Other contraindications and precautions:

• hypersensitivity to losartan or excipients;
• concomitant use of aliskiren in patients with diabetes mellitus or reduced kidney function;
• combination with ACE inhibitors (dual RAAS blockade) — not recommended by the guidelines;
• severe hepatic insufficiency; in mild and moderate — caution and a lower starting dose per the prescribing information;
• bilateral renal artery stenosis or stenosis of the artery of a single kidney;
• the breastfeeding period.

The inappropriateness of dual RAAS blockade is confirmed by the ONTARGET and VA NEPHRON-D studies: the combination of drugs acting on this system did not improve outcomes but increased the frequency of hyperkalemia, hypotension, and acute kidney injury.

Losartan is not prescribed to people with normal blood pressure «for prevention» without medical indications. In a healthy person, even a standard dose can cause hypotension, especially in combination with intense exertion and fluid loss.

Editorial conclusions

Losartan is generally well tolerated, and its main side effects — hypotension, hyperkalemia, changes in kidney function — follow directly from the mechanism of action and are predictable.

The risks increase with dehydration, kidney diseases, and the intake of potassium preparations and anti-inflammatory agents. An absolute contraindication is pregnancy.

Regular monitoring of blood pressure, potassium, and creatinine, and honest information to the doctor about all medications and supplements, make it possible to avoid most problems.

On this topic we recommend «Losartan: Mechanism of Action», «Interaction of Losartan with Other Drugs», and «Why Athletes Need Losartan».

References

1. U.S. Food and Drug Administration. Cozaar (losartan potassium) tablets: prescribing information. Organon.
2. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy (RENAAL). N Engl J Med. 2001;345(12):861–869.
3. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–1559.
4. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy (VA NEPHRON-D). N Engl J Med. 2013;369(20):1892–1903.
5. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension. J Hypertens. 2023;41(12):1874–2071.
6. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet. 2000;355(9204):637–645.