What Are the Common Losartan Side Effects?

Angiotensin receptor blockers are a class of hypertension treatment drugs. Reduce blood pressure by blocking the Ang II effect. Now widely used in clinical. It is mainly used for the treatment of clinical hypertension and other heart and kidney diseases.

Chinese name: Angiotensin II receptor antagonist
Abbreviation: ARBs

Action intensity: 15 20 times
Country: Italy

Angiotensin receptor antagonist angiotensin

In RAS, the angiotensinogen (Ang) of tetradecapeptide under the action of renin, the peptide chain between two isoleucines is broken to produce angiotensin I (AngI), AngI is angiotensin-converting enzyme, etc. Under the action of enzymes, the phenylalanine and histidine interpeptide chains are broken to produce physiologically active AngII (octapeptide).

AngII is a potent vasoconstrictor, the most important active hormone in RAS, and plays a major role in the physiology and pathology of hypertension. AngII can cause arterioles to contract and increase vascular resistance; regulate aldosterone secretion (increased release), enhance water and sodium reabsorption, and increase blood volume; it can also cause cardiac output to increase; AngII can also cause catecholamine Rise, increase the release of norepinephrine at the end of sympathetic nerves, and at the same time, hyperplasia of smooth muscle cells. ^[1]

Angiotensin receptor

The biological effects of AngII are mediated by receptors. As determined by radioligand law, there are at least two types of AngII receptors (AT1, AT2), and possibly AT3, AT4 and other types, all of which are species and Tissue-specific. ^[1]

Angiotensin receptor antagonist angiotensin receptor antagonist

AngII receptor antagonists currently on the market are all targeting AT1 type receptors. AT1 antagonist inhibits AngII-mediated vasoconstriction, renal tubular sodium, and water reabsorption; inhibits RAS regulation of baroreceptor reflexes, improves sensitivity, inhibits sympathetic nerve excitation, and mediates central and peripheral sympathetic nerve Pressure effect.

The AT1 receptor antagonists used in clinical practice are non-peptide drugs and can be divided into two categories based on their structure: (1) biphenyltetrazoles, including losartan, valsartan, irbesar Irbesartan, candesartan cilexetil, and tasosartan. (2) Non-biphenyltetrazoles, including eprosartan and telmisartan. The above compounds have the following structural characteristics: (1) a tertiary substituted N as the core, a lone electron pair on N may form a hydrogen bond as a hydrogen acceptor; (2) a substituent on N is a lipophilic aromatic ring Except for Eprosartan being a benzene ring, the rest are biphenyl substituted; (3) There is an ionic acidic group on the aromatic ring, such as tetrazolium or a carboxylic acid, which may form an ionic bond with the acceptor; ( 4) The other two substituents on N may be non-cyclic (such as valsartan) or cyclic. One of the substituents is lipophilic, and one of the substituents contains a heteroatom such as O or N that can serve as a hydrogen acceptor. ^[1]

Other effects of angiotensin II receptor antagonists

Protect kidney function and delay the progression of kidney disease

It is now recognized that AT plays an important role in the deterioration of hypertensive renal damage, especially diabetic nephropathy. AT-mediated contraction of the glomerular arterioles leads to glomerular capillary hypertension and damage to the kidney through other mechanisms, including Elevated glomerular pressure and increased mesangial macromolecular inflow stimulated the expansion of cytokines and mesangial matrix. AT also increased proteinuria. Therefore, the application of AT1 receptor subtype antagonists has obvious renal protective effects, especially to reverse the deterioration of diabetic nephropathy. Inhibition of AT can relax the glomerular ventricular arterioles, reduce glomerular capillary pressure, reduce proteinuria and delay the progression of renal disease. According to a recent 4-week comparative study of losartan and amlodipine on hypertension with kidney damage, the former reduces urinary protein excretion in patients with renal damage, and total protein and albumin excretion is reduced by 25%, while the latter has no such effect ( P <0.01) [18]. Some people collectively analyze about 1,100 patients with diabetes and non-diabetic proteinuria. Various antihypertensive drugs have similar antihypertensive effects, and the protein-lowering proteinuria is the largest in ACEI, which can decrease by about 40%. Only 10% of the agents, etc., thought that the effect of ACEI is caused by bradykinin accumulation and inhibition of RAS. The authors explored this hypothesis, using lisinopril 100 & nbs p; mg / d and infusion of bradykinin antagonist or exogenous AT in animal models, and found that the addition of bradykinin antagonist had no effect on blood pressure and proteinuria However, adding AT increased blood pressure and proteinuria to pre-treatment levels, suggesting that inhibition of AT, not bradykinin, can control this type of proteinuria. Take placebo losartan 50 mg / d 100 mg / d placebo enalapril 10 mg / d 20 mg / d placebo for 7 consecutive 4-week periods. The antihypertensive effect of low and high dose losartan is the same, but the proteinuria-lowering effect is reduced by 30% at 4 weeks at 50 mg / d, and> 40% at 4 weeks at 100 mg / d. Proteinuria returned to pre-treatment levels. Losartan and enalapril have similar anti-proteinuria and antihypertensive effects and renal hemodynamic effects [effective renal plasma flow, filtration fraction, and glomerular filtration rate (GFR)]. The two drugs support losartan Tan clinical improvement of blood pressure, renal hemodynamics and proteinuria is similar to ACEI, which is caused by inhibiting AT. Therefore, a large-scale focused trial of 1500 patients with non-insulin-dependent diabetes mellitus (RENAAL) with losartan is underway. The results will clarify the renal protective effect of losartan on renal insufficiency. There is also research on the relationship between angiotensin-converting enzyme (ACE) phenotype and satanoids. Type DD has less decrease in urine protein after using ACEI than patients with ID or type II, and even some patients have worsening microproteinuria, but ID or type II Patients were relieved after using ACEI [18]. This difference is considered to be the highest level of ACE in patients with type DD, and the use of ACEI is not sufficient to completely inhibit its activity, while the saltans may be more effective. In a study of renal hemodynamic effects in normal people and patients with impaired renal function and in patients with hypertension taking losartan on renal function and nephrotic syndrome with or without renal impairment, losartan found that When the pressure drops, the effective renal blood flow can increase without affecting GFR [19]. These good effects on renal hemodynamics are also one of the basis for the RENAAL test.

Reverse effects of left ventricular hypertrophy and vascular remodeling

Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular disease, and saltans have a significant effect on reducing LVH. The effect of valsartan on left ventricular hypertrophy was reported at the 8th European Hypertension Conference held in Italy in 1997. Valsartan 80 mg / d and aminoacidan 50 were determined by echocardiography for patients with hypertension with LVH. Compared with mg / d, after 4 weeks of treatment, DBP was still> 95 mm Hg, and after doubling the drug, DBP was still> 95 mm Hg and chlorothiazide was added. 30% of patients in each group were treated with diuretics. After 3 and 8 months of echocardiography, left ventricular mass index analysis (LVMI) was performed in 58 of 69 randomized patients. Results The average LVMI in the valsartan group (29 patients) decreased by 10 g / mm2, which was 8% lower than the baseline. . Obviously, AT participates in LVH formation, and AT1 receptor subtype antagonists block AT, which can reverse LVH.

Regarding the role of vascular remodeling in hypertension and atherosclerosis, according to recent cell and molecular studies, it has been clear that AT regulates many key steps in the formation of atherosclerosis, which may regulate the interaction between leukocytes and endothelial cells. Many adhesion molecules such as E-selectin and vascular adhesion molecule (VCAM-1) promote the adhesion of leukocytes and monocytes to the luminal surface of endothelial cells, which is considered to be the first step in the formation of hypertension or atherosclerotic vascular lesions. AT stimulates the expression of adhesion molecules in cultured endothelial cells, which also suggests that peptides can promote the adhesion of leukocytes to the vessel wall. Therefore, not only ACEI, AT1 receptor subtype antagonists can also change the structure and function of arteries in patients with hypertension and atherosclerosis, which may have important significance for the prevention and treatment of vascular remodeling, but more research is needed.

AT1 receptor subtype antagonists also have an impact on fibrinolytic function. If the plasminogen activator inhibitor 1 (PAI-1) is increased and the fibrinolytic capacity is decreased, the risk of coronary heart disease may be increased. It has been found that some patients are genetically prone to elevated plasma PAI-1. Patients with PAI-14G homozygotes and 4G / 5G heterozygotes have increased levels of plasma PAI-1, which increases the risk of myocardial infarction. Patients with 5G homozygotes have low levels of PAI-1 and low risk of myocardial infarction. Because the production and secretion of endothelial PAI-1 are regulated by ATII, the production and secretion of tissue-type plasminogen activator is regulated by bradykinin. Endothelial ACE promotes thrombosis by degrading bradykinin and converting AT1 to ATII through bidirectional action. Therefore, ACEI and AT1 receptor subtype antagonists can enhance fibrinolytic function and reduce thrombosis through two-way inhibition [9]. In addition, losartan is used on ventricular muscles of pretreated Dutch pigs to reduce reperfusion arrhythmia, suggesting an endogenous antiarrhythmic effect, degrading uric acid, and inhibiting thromboxane (TX) A2. But candesartan cannot inhibit TXA2-induced platelet aggregation [8]. These preliminary studies may also have application value in preventing thromboembolism in cardiovascular disease.

In summary, ATreceptor antagonists (AT1 receptor subtype antagonists), as a new class of antihypertensive drugs, may have broad prospects in the prevention and treatment of heart failure, kidney disease and many cardio-renal vascular diseases. Recently, the WHO / ISH1999 guidelines for hypertension have included ATII receptor antagonists as one of the six major classes of drugs for the treatment of hypertension [20]. However, there are still many problems, such as whether it is better than ACE I, whether it is complementary to ACEI, and the advantages and disadvantages of long-term application, which needs to be solved from the long-term practice of basic theory and large-scale clinical multicenter. Many ongoing large-scale international randomized trials such as LIFE, ELITE-, VALUE, RENAAL, etc. may help to determine the role of AT1 receptor subtype antagonists in the prevention and treatment of cardiovascular disease.

Basic properties of angiotensin receptor antagonist

AT II stimulation causes many physiological reactions in the body to maintain blood pressure and kidney function. It plays a major role in the pathogenesis of hypertension, arterial disease, cardiac hypertrophy, heart failure, diabetes, and kidney disease. Angiotensin-converting enzyme inhibitors (ACEI) partially block the formation of AT, which has a significant therapeutic effect on the above-mentioned cardiovascular diseases, but a small number of patients are intolerable due to dry cough, which has led to the development of completely blocking the effects of AT AT receptor antagonists have shown a new and broad prospect for the prevention and treatment of cardiovascular disease. In particular, the appearance of telmisartan really maintained for 24 hours and reached a stable blood concentration after taking it for one month. Even if the drug was stopped suddenly, it would not rebound.

There are more than 10 AT1 receptor subtype antagonists that have been used in clinical or clinical trials. The earliest and most studied and applied is losartan, followed by valsartan. The preclinical pharmacological effects of various AT1 receptor subtype antagonists are generally similar. The specificity of blocking AT1 is the same, but the strength of antagonizing AT1, the ratio of selective action AT1 and AT2, and the chemically active substances are different. According to the testing conditions, the intensity ratio of selective blocking of the AT1 receptor subtype is greater than that of the AT2 receptor subtype. Each of the sartans is more than 10,000 times, and valsartan is the strongest. Body subtype affinity is 3000 times stronger [6]. Some are chemically active, some are metabolites. Losartan is characterized in that the mother and its metabolites E ~ 3174 are active and the E ~ 3174 aT1 receptor subtype has 10 times stronger affinity than the mother, and the elimination half-life (t1 / 2) is also significantly longer than the mother [7].

Clinical application of angiotensin receptor antagonist

Satans have been widely used in the prevention and treatment of clinical hypertension and other cardio-renal diseases in foreign countries. The most widely used domestic drugs are losartan and valsartan.

After evidence-based medical analysis, the effects of 9 ARBs on blood pressure reduction in 13451 subjects for 7 weeks were concluded, and the results were not significant : systolic blood pressure 8 mmHg and diastolic blood pressure 5 mmHg. Most of the antihypertensive effect (about 70%) comes from the lowest recommended dose. The antihypertensive effects of various ARBs are similar.

Angiotensin receptor antagonist hypertension

There have been many studies on the treatment of hypertension with losartan [7-10]. However, in multiple placebo-controlled studies, losartan at 50 to 100 mg / d for 4 to 12 weeks has a significant antihypertensive effect on mild to moderate hypertension. By 1996, more than 3,700 people were treated. It is effective to use diastolic blood pressure (DBP) <90 mm Hg (1 mm Hg = 0.133 kPa) or DBP 90 mm Hg and decrease 10 mm Hg at the end of the test. The effective rate of patients with 6.4 mm Hg was 41% to 54%, and the blood pressure decreased by 9.1 to 19.0 / 9.1 to 14.0 mm at the end of the week. The effective rate was 50% to 76% [7]. For patients with severe hypertension, some patients can still maintain the effect after 12 weeks of treatment, but most need to use diuretics or other antihypertensive drugs.

The antihypertensive magnitude and effectiveness of losartan have also been compared with many standard antihypertensive drugs, including -blocker aminopyranolol, diuretic chlorothiazide (dihydrogram urine plug), and calcium antagonist sustained release fee. Lodipine, controlled-release nifedipine (Baixintong), amlodipine, angiotensin-converting enzyme inhibitors enalapril, lisinopril, etc., the magnitude of blood pressure reduction is roughly the same as these standard blood pressure drugs. For example, with losartan at 50 to 100 mg / d, DBP decreases by an average of 8 to 13 mm Hg at 8 to 12 weeks, and the other antihypertensive drugs mentioned above are 10 to 14 mm Hg [11]. In a group of 132 elderly patients with hypertension, losartan reduced DBP by an average of 13 mm Hg, compared with 14 mm Hg in slow-release felodipine [12]. DBP decreased slightly better in the felodipine group at 6 weeks of treatment. At 12 weeks, there was no difference between the two groups. The antihypertensive response rate was 69% in the losartan group and 76% in the felodipine group, with a P value of> 0.05 [12]. A study of the antihypertensive effect and drug tolerance of double-blind losartan and amlodipine in 898 patients with mild to moderate hypertension in Sweden, Finland, and Australia participated in 63 centers for 12 weeks. The losartan 50 100 mg / d group was similar to the losartan 50 mg / d + chlorothiazine 12.5 mg group and the amlodipine 5 10 mg / d group; however, life was assessed by the psychiatric sensory score (PGWB). The quality of losartan was significantly improved in the two groups, but less in the amlodipine group; the incidence of drug-related side effects, especially ankle edema and other discomforts, increased from 8.4% and 23.3% at baseline to 30.6% ( P <0.001) and 33.1% (P = 0.002), while the losartan group had no significant difference from its baseline value, but dizziness increased slightly in the losartan group while standing, but not in the amlodipine group. Unknown [9]. In a study comparing losartan and enalapril in 400 patients with hypertension, there was no significant difference between the measured blood pressure trough, the magnitude of the antihypertensive effect, and the effective rate. The antihypertensive effect of losartan is in the treatment 1 Appears within the week. In another group of 576 patients with hypertension, a randomized double-blind parallel controlled comparison of losartan and enalapril, losartan 150 mg / d or enalapril 20 mg / d, within 1 to 2 weeks of treatment The blood pressure dropped significantly, and the maximum blood pressure decreased 3 to 6 weeks after the increase [13]. Losartan has the largest antihypertensive effect from 50 to 100 mg / d, and no significant antihypertensive effect was seen at <50 mg / d. Similarly, when comparing losartan with amidanil in the treatment of patients with mild to moderate hypertension, it was observed that the antihypertensive effect of losartan reached a plateau at 6 weeks and no further blood pressure drop at 12 weeks.

For the treatment of severe hypertension, losartan is often combined with chlorothiazide or other antihypertensive drugs. In a study of 179 patients with severe hypertension, at 50 weeks of losartan at 22 weeks, 22% can still maintain the antihypertensive effect alone, and 30% need to use chlorothiazide (2.5-25 mg / d). 46% need to add felodipine or aminooxamine or both, and 2% to other drugs. Blood pressure decreased by 26/19 mm Hg in all patients. Similar to another study of 131 patients (31% in black) treated for 12 weeks, DBP decreased by 18 mm Hg. Taking losartan 50 mg / d and chlorothiazine 12.5 mg / d capsules can control blood pressure in 1/3 patients, but Most need to be added to felodipine [7].

Valsartan has also compared the treatment of mild to moderate hypertension with a variety of other antihypertensive drugs, most of which are ACEI (such as enalapril, lisinopril), chlorothiazide, amlodipine, and aminoacid And another AT1 receptor subtype antagonist, losartan. In the short-term treatment of 8 to 12 weeks, the antihypertensive effect of valsartan is the same as that of ACEI, which is slightly inferior to lisinopril, but has no statistical significance. In the long-term treatment for up to 1 year (65 years of age in patients with hypertension), valsartan or lisinopril has the same effective rate and magnitude of blood pressure reduction in both groups. If the blood pressure control of valsartan alone is not good, 25% to 35% of diuretics need to be added. Valsartan and ACEI groups are roughly similar in the three trials. Compared with amlodipine, valsartan has the same antihypertensive range and effective rate. If valsartan alone does not control blood pressure well, amlodipine does not have more blood pressure control [6]. Patients started with a hypotensive blood pressure drop of amlodipine, and after doubling the dose, 28.6% of patients in the valsartan group and 33.7% of patients in the amlodipine group were randomized. Other antihypertensive drugs were needed to control blood pressure satisfactorily. .

Comparison of the antihypertensive effects of two sartans losartan and valsartan [14], valsartan 80-160 mg / d in 545 cases, losartan 50-100 mg / d in 534 cases, placebo group 269 example. At the end of the 8-week period, the blood pressure reduction in the three groups was 14/11, 13/10, and 5/5 mm hg. The difference between the two satans and the placebo group was significant, and the two groups were similar (P = 0.129). ); Effectiveness (DBP <90 mm Hg or decrease 10 mm Hg) The three groups were 61.6%, 54.5% and 29.3%, respectively. Side effects of sartans: 2085 cases of losartan and 535 cases of placebo in a double-blind study for 2 weeks, drug-related side effects (15.3% of losartan group, 15.5% of placebo group) and patient withdrawal rate: losartan It was 2.3% in the tank group and 3.7% in the placebo group. There was no significant difference between the two groups. The side effects of the drug were headache (4.2%), weakness or fatigue (2%), and dizziness. The losartan group was more than the placebo group, the former was 2.4% and the latter was 1.3%. Of the 306 patients treated with long-term losartan (1 year), the common side effects were headache 3.6%, dizziness 2.9%, and weakness or fatigue 2.6%. Sudden discontinuation of drug without rebound phenomenon, occasionally increased liver function and hyperkalemia. Compared with 12 weeks of ACEI treatment, cough incidence was 3.1% in the losartan group (2085 patients) and 8.8% in ACEI (enalapril, captopril, or lisinopril, 239), and placebo Group 2.6%, apparently the incidence of cough was very low in the losartan group. In a group of patients with cough-sensitive hypertension, the incidence of cough was 17% to 29% in the losartan group, similar to 35% in the placebo group and 25% to 34% in the chlorothiazide group, which was significantly lower than that of lisinop The profit group is 62% to 72%. Other side effects: fatigue in the ACEI group was 6.7%, which was higher than 3.8% in the losartan group or 3.9% in the placebo group, but the incidence of headache was reversed, with 14.1% in the losartan group, 10.9% in ACEI, and 17.0% in the placebo group. [7]. Compared with calcium antagonists (losartan and extended-release felodipine), headache and edema in the elderly were 9.0% and 6.7% in the losartan group, compared with 14.0% in the felodipine group and 8.0 in the losartan group. % And 1.0% in the Felodipine group. Compared with beta-blockers, the losartan group had fewer side effects than aminoacid, the former was 17.0%, the latter was 27.0%, and the side effects were related to discontinuation, the former was 2.2%, and the latter was 6.9% [7].

Valsartan 40 to 160 mg / d 2 in 316 cases had a headache and dizziness and fatigue increased by about 1% compared with 888 cases of placebo. The difference was not statistically significant. Compared with lisinopril, dry cough in the valsartan group was significantly reduced (P <0.001). For mild to moderate patients prone to ACEI dry cough, valsartan 80 mg / d for 6 weeks, lisinopril 10 mg / d or chlorothiazide 25 mg / d, the incidence of dry cough was 21.4%, 71.1%, and 19.0%, respectively. . Among 2316 patients, 7.1% of patients discontinued valsartan due to side effects, which was similar to 8.5% of 333 patients in the ACEI group and 10.5% of 888 patients in the placebo group. There was no significant increase in the incidence or type of side effects in the long-term treatment control study for 1 to 2 years. Some biochemical abnormalities are less than in the ACEI group, and bilirubin doubled in 6.0% in the valsartan group and 12.9% in the ACEI; serum creatinine increased by> 50%, 0.8% in the valsartan group, and 1.6% in ACEI; blood potassium The increase was> 20%, 4.4% in the valsartan group, and 6.4% in the ACEI group [6]. Losartan was also well tolerated in 2606 patients with mild to moderate hypertension. The incidence of headache was the most common, 16.7% in the placebo group (641 patients) and 12.3% in the irbesartan group (1965 patients). 3.3% discontinued treatment due to headache, upper respiratory tract infection, musculoskeletal pain, dizziness, and fatigue compared to 4.5% in the placebo group. In a comparison study with enalapril, the incidence of dry cough between losartan and enalapril was 10% to 17%, but there was no statistical difference [15].

Angiotensin receptor antagonist heart failure

Studies have shown that blocking the action of the renin-angiotensin system (RAS) is of great significance in the treatment of heart failure. Therefore, there are trials of AT1 receptor subtype antagonists for the treatment of heart failure. According to Crozier et al. [16] Hemodynamic studies of 134 patients with heart failure treated with different doses of losartan (2.5, 10, 25, and 50 mg / d), compared with the placebo group, the pulmonary capillaries after 12 weeks of medication Vascular pressure decreased significantly (P <0.05). The best reduction in blood pressure and vascular resistance was in the losartan 50 mg / d group. The 2.5 mg / d and 10 mg / d groups were not effective. Heart rate and cardiac output were also significant after 12 weeks. The effect was significant in the 25-50 mg / d group. According to Pitt et al. [17] reported 722 patients with heart failure over 65 years of age who were followed up for more than 1 year, comparing the effect of losartan and captopril on mortality (ELITE-1), resulting in death and / or hospitalization for heart failure Losartan group was 9.4%, Captopril group was 13.2%, risk decreased by 32%, P = 0.075). The decrease in risk was mainly due to a reduction in the mortality rate for various reasons. The mortality rate in the losartan group was 4.8%, the captopril group was 8.7%, and the risk was reduced by 46% (P = 0.035). Losartan's explanation over captopril may be due to the fact that losartan blocks AT more effectively at the AT1 receptor level. Because AT has various harmful effects on the heart, including increasing sympathetic nerve activity, promoting the deterioration of endothelial function, fibrosis, and myocardial hypertrophy, antagonizing some of these effects may be related to the clinical effects in ELITE-1. In addition, Dahlof pointed out that AT2 receptor expression increases during heart failure, and the clinical benefit of losartan may be due to the loss of antagonism of the AT2 receptor subtype. The reduction in sudden death in the losartan group in the ELIITE-1 trial may also be related to other effects such as the antiarrhythmic effect of losartan. In order to verify this assumption, a larger ELITE-II trial, which has included 1,000 international clinical trials, has also begun.