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Journal of Human (2002) 16 (Suppl 1), S93–S99  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh II antagonists role in arterial hypertension

R Herna´ndez-Herna´ndez1, B Sosa-Canache1, M Velasco2, MJ Armas-Herna´ndez1, MC Armas-Padilla1 and R Cammarata1 1Clinical Unit, Center of Biomedical Research, School of , Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Venezuela; 2Clinical Pharmacology Unit, Vargas Medical School, Central University of Venezuela, Caracas, Venezuela

Angiotensin II receptor blockers represent a class of with low incidence of side effects even at long term use. effective and well tolerated orally active antihyperten- Monotherapy in mild-to-moderate hypertension controls sive . of AT1 receptors leads to in 40 to 50% of these patients; when a , stimulation of the release of cat- low dose of is added, 60–70% of echolamines and antidiuretic and promote patients are controlled. The efficacy is similar to angio- growth of vascular and . AT1 receptor tensin-converting (ACE) inhibitors, , blockers antagonise all those effects. was the antagonists and beta-blocking agents. AT1 first of this class marketed, shortly followed by val- receptor blockers are specially indicated in patients with sartan, , , , hypertension who are being treated with ACE inhibitors and others on current investigation. All these drugs and developed side effects such as, cough or angio- have the common properties of blockading the AT1 . The final position in the antihypertensive ther- receptor thereby relaxing vascular , apy in this special population and other clinical situ- increase salt , decrease cellular hypertrophy ations, such as left ventricular hypertrophy, and induce antihypertensive effect without modifying failure, mellitus and renal disease, has to be or . Most of the AT1 receptor determined in large prospective clinical trials, some of blockers in use controlled during the which are now being conducted and seem promising. 24 h with a once-daily dose, without evidence of produc- Journal of Human Hypertension (2002) 16 (Suppl 1), S93– ing tolerance to the antihypertensive effect and being S99. DOI: 10.1038/sj/jhh/1001352

Keywords: angiotensin II ; AT1 receptor; AT2 receptor; losartan

Introduction Salarasin was the first receptor antagonist of angiotensin II available for clinical use more than The -angiotensin system is integrally involved 20 years ago.4,5 Salarasin is a analogue of in maintaining the healthy body’s haemodynamic angiotensin II with partial effect, and can status. Angiotensin II is the prime effector molecule only be used intravenously; it has a very short dur- of the renin-angiotensin- system, ation of action. When is used there is an inducing vasoconstriction, promotion of initial increase in arterial blood pressure due to its in vascular and myocardial tissue, activation of the effect, but prevents the increment of sympathetic and producing blood pressure when angiotensin II is administrated. and fluid retention. Most of these cardiovascular Furukawa et al6 was the first to synthesise an imi- effects of angiotensin II are mediated by AT1 recep- dazole derivative that was found to be a selective tors. Selective blockade of the AT1 receptor not only angiotensin II receptor competitive antagonist, and inhibits vasoconstriction and vascular hypertrophy, after chemical modifications, orally active agent.7 but also could lead to a compensatory increase in Losartan was the first orally active and long-acting angiotensin II levels. These increased concen- receptor antagonist developed and in use in the trations of angiotensin II may confer additional treatment of hypertension,8,9 followed by , pharmacological benefits by stimulating the AT2 irbesartan, eprosartan, candesartan, telmisartan receptor subtype, which has been reported to and others.10 mediate antiproliferative actions on cardiac and vas- 1–3 Blockade of renin-angiotensin system is effi- cular smooth muscle. cacious and a safe way to reduce blood pressure as treatment of patients with hypertension, mainly by the inhibition of angiotensin-converting enzyme Correspondence: Dr Rafael Herna´ndez-Herna´ndez, Clinical Phar- macology Unit, School of Medicine, Universidad Centroccidental (ACE). The main side effects observed with ACE Lisandro Alvarado. Barquisimeto, Venezuela. PO Box 516 inhibitors are cough and , which are E-mail: rhernanȰcantv.net seen in 5 to 10% of patients treated with this drug Angiotensin II receptor antagonists role in arterial hypertension R Herna´ndez-Herna´ndez et al

S94 11 21–24 class. AT1 receptor blockers have the advantage in AT2 receptor. The effect of the AT1 receptor having a very low incidence of such side effects. antagonists might be a result of the blockade of the However the place of this class of antihypertensive AT1 receptor and stimulation of the AT2 receptor, action remains to be defined. because increased might act preferen- tially on the AT2 receptor when the AT1 receptor is 25 Angiotensin II receptors blocked. It may be possible that the AT2 receptor plays a role in the pathogenesis and remodelling of Angiotensin II (AII) exerts its effects by stimulating cardiovascular diseases, further understanding of some specific receptors on the membrane of several AT2 receptors could contribute to new therapeutic organs. Radioligand studies have characterised sev- strategies for and hyperten- eral angiotensin II receptors, mainly type I and type sion. II (AT1 and AT2 receptors). Activation of AT1 recep- Actions mediated by AT1 and AT2 receptors are tors leads to vasoconstriction, stimulation of the summarised in Table 1. Other angiotensin II recep- 26 release of and antidiuretic hormone tors have been described such as AT3 and AT4 in and production of thirst; also promoting growth rats and mice; AT1 receptor is also composed of two 12 27 effects in vascular and cardiac muscle, all these subtypes: AT1A and AT1B; these receptors have to effects are blocked by AT1 antagonists. Several AT1 be characterised pharmacologically and in patho- receptor antagonists are now available for clinical physiological conditions. use. Experimental studies have shown interesting differences in their binding properties and the AT receptor antagonists pattern of inhibition of contractile responses to 1 13–15 angiotensin II in isolated blood vessels. In The first chemically useful, orally active AT1 recep- human subcutaneous resistance the AT1 tor antagonist was losartan, followed by other agents receptor antagonists, candesartan, losartan and los- currently in clinical use or under investigation.8,9 artan’s metabolite EXP-3174, reduce the maximal They have a high affinity of AT1 receptor subtype contractile response to AII suggestive of non-com- without exerting agonistic effects and do not bind to petitive . In the case of losartan the con- the AT2 receptor when given at the recommended centration-response curve also appears to be dis- clinical doses. Likewise, specific inhibitors of the 28,29 placed by higher concentrations of AII, giving the AT2 receptor do not bind to the AT1 receptor. overall appearance of mixed competitive and non- Table 2 summarises the AT1 receptor antagonists competitive antagonism.13 These observations differ either in clinical use or under development. from those obtained in rabbit and rat vessels where The AT1 receptor antagonist reduce blood press- losartan appears to behave as a competitive antagon- ure by decreasing systemic ; heart ist16,17 in contrast with candesartan which acts in a rate and cardiac output are not modified.30–32 non-competitive manner.18 Eprosartan differs from Reduction in systemic vascular resistance are due other agents in its class in that it is a non-biphenyl, to inhibition of the direct vasoconstrictive effect of non-tetrazole, competitive angiotensin II receptor antagonist with a high affinity for AT subtype. In 1 Table 1 Actions mediated by AT and AT receptor addition, eprosartan also differs from other angio- 1 2 tensin II receptor antagonists by providing com- Angiotensin II Angiotensin II bined inhibition of both the renin-angiotensin sys- AT1 Receptor AT2 Receptor tem and the sympathetic nervous system, as 19,20 demonstrated in pithed rats. Vasoconstriction Vasodilatation via In contrast to the AT1 subtype, the physiological and nitric oxide role of the AT2 receptor has long remained an Aldosterone production and Antiproliferative effect enigma. This subtype is highly expressed in fetal release tissues, whereas its expression is dramatically Sodium tubular reabsortion Embriogenic differentiation and decrease after birth, being restricted to a few organs development such as brain, adrenal, heart, myometrium and Hypertrophy of heart Stimulation of ovary. The AT receptors are re-expressed during 2 Proliferation of smooth muscle Endothelial cells growing stressful situations in the adult animal, after cardiac in vascular tree and vascular injury (such as , Catecholamines secretion and left ventricular hypertrophy and in vascular neo- potentiation (central and intimal proliferation), also nerve crush and during periphery) wound healing, obstruction and sodium release depletion. This suggests a role for this receptor in tissue remodelling, growth and/or development. A Thirst major step towards the understanding of AT2 recep- Renal vasoconstriction and tor functions has recently been provided by the gen- reduction of renal blood flow eration of genetically engineered animals either Inhibition of renin release lacking or over-expressing the gene encoding the

Journal of Human Hypertension Angiotensin II receptor antagonists role in arterial hypertension R Herna´ndez-Herna´ndez et al S95 Table 2 Angiotensin II receptor antagonists results showed that eprosartan reduced seated sys- tolic blood pressure by 29 mm Hg in comparison Agent Established oral dose Manufacturer with a reduction of 21 mm Hg in those taking enala- pril (P Ͻ 0.05).41 Losartan 50–100 mg daily DuPond-Merk When diuretics were added to an AT receptor Eprosartan 150–350 mg daily SmithKline Beecham 1 Irbesartan 150–450 mg daily Sanofi antagonist, a better response is achieved. The Telmisartan 40–160 mg daily Boeringer Ingelheim addition of hydrochorothiazide to losartan produces Candesartan 5–10 mg daily Takeda-Astra a dose-related reduction in blood pressure after a Valsartan 80–160 mg daily Novartis treatment of 12 weeks.36 In a double-blind study 189 SC-52458 Searle patients were enroled to compare valsartan + HCTZ LRB/081 Lusofarmaco + YM-358 Yamanouchi (12.5 mg) and HCTZ (12.5 mg), which GR 117289 Glaxo after 8 weeks of treatment controlled blood pressure Zolarsartan in about 64% of the patients in both group of treat- ments.42 Losartan has been shown to exert a uricosuric effect in normotensive and hypertensive subjects, angiotensin II, reductions in the sympathetic ner- which could be an advantage when losartan is com- vous system activity, in the release of aldosterone bined with a thiazide diuretic.37 At 4 h after single and in the re-absorption of sodium, are mediated by doses of 100 mg of losartan, serum levels angiotensin II. It has also been described as sensitis- were reduced by approximately 20% and urinary ing in , the stimulation of prostacyclin excretion of uric acid was increased.43 This urico- release, and at long-term reduction in the proliferat- suric effect was maintained after administration of ive effect (antiproliferative effect).10 losartan once daily for 7 days. The clinical signifi- In volunteers the administration of AT1 receptor cance of the uricosuric effect remains to be estab- antagonists increase and lished; however, is a special indication when angiotensin II levels either in acute administration patient has or goat. or multiple dose administration;33,34 but the press- ure effect of angiotensin II is blocked. Whereas, ACE Pharmacokinetic inhibitors reduce plasma level of angiotensin II increasing bradykinin levels. Angiotensin AT1 receptors antagonists in clinical The efficacy in reducing blood pressure with the use essentially seem to share about the same pharm- use of AT1 receptor antagonists is equivalent to acodynamic characteristics with only very few other well established antihypertensive agents. differences; but these agents differ in their pharma- When losartan (50 to 100 mg daily) is compared to cokinetic characteristics in terms of oral bioavail- (5 to 10 mg daily, losartan was less effec- ability, rate of absorption, metabolism, route and tive after 6 weeks of treatment but equally effective rate of elimination, duration of action and half-life. after 12 weeks of therapy).35 Table 3 summarises the pharmacokinetic of some The efficacy of losartan (50 to 100 mg once daily) AT1 receptor antagonists in current use. Losartan has been compared to (50 to 100 mg once undergoes extensive first-pass metab- daily), and enalapril (20 mg once daily). The blood olism and is converted into EXP3174 in the pressure lowering effect of losartan was comparable .44,45 Peak concentrations of losartan are achi- to enalapril and atenolol. On ambulatory blood eved by 1 h after administration, whereas EXP3174 pressure losartan showed antihyperten- reaches peak levels at 3.5 h; both losartan and EXP sive effect over a period of 24 h without affecting the 3174 are active, as antihypertensive and AT1 recep- body’s circadian rhythm.36,37 tor blocker, in fact EXP 3174 prolong the antihyper- Several studies have compared the blood pressure tensive effect. On the other hand, candesartan cilex- lowering effects of AT1 receptor antagonists against etil is a pro-drug that is converted to active drugs in enalapril; candesartan cilexitil,38 eprosartan39 and vivo. After oral administration, in contrast, candes- irbesartan40 lower systolic and diastolic blood press- artan cilexetil is fully converted into candesartan by ure to the same extent to that of enalapril. cleavage of the cilexetil moiety in the gastrointes- In a study of severe hypertensive patients, epros- tinal tract during absorption and achieves peak artan has been shown to be as effective as enalapril plasma concentrations at 4 h.46 Candesartan cilexetil in lowering diastolic blood pressure and superior to is not detected in plasma after oral administration. 41 enalapril in reducing systolic blood pressure. In a The other AT1 receptor antagonists (irbesartan, val- 10-week, randomised, multicentre, double-blind, sartan, eprosartan, and telmisartan) are neither pro- parallel-group trial, 118 patients (78% aged Ͻ65 drugs nor active without bioconversion. After oral у years and 22% aged 65 years) with severe hyper- administration AT1 receptor antagonists are rapidly tension (diastolic blood pressure у115 mm Hg and absorbed (time for peak plasma levels: 0.5–4 h) but р125 mm Hg) were randomly assigned to receive they have a wide range of (from a low either eprosartan (400–800 mg per day, given twice of 13% for eprosartan to a high of 60–80% for daily) or enalapril (10–40 mg once daily). The irbesartan); food does not influence the bioavail-

Journal of Human Hypertension Angiotensin II receptor antagonists role in arterial hypertension R Herna´ndez-Herna´ndez et al S96 Table 3 Summary of pharmacokinetic parameter AT1 receptor antagonists in clinical use

Agent Active Biovailability Food Elimination half-life bound Major route of metabolite (%) effect (h) (%) elimination

Losartan EXP-3174 33 Minimal 2 h for losartan; 98.7 Biliary excretion 6–9 h for its active (70–80%) metabolitea Valsartan None 25 Import 6 95 Bilary excretion (70–80%) Irbesartan None 60–80 None 11–15 90 Bilary excretion (70–80%) Eprosartan None 13 Minimal 5–9 98 Kidneys Telmisartan None 40–60 Minimal 24 Ͼ98 Biliary excretion (Ͻ90%) Candesartan Candesartan 15 None 9 Ͼ90 Renal (40%) and cilexetilb biliary (40%)

aLosartan’s active metabolite, EXP-3174, comprises two-thirds of active drug. bCandesartan cilexetil, the prodrug, is completely converted to candesartan during gastrointestinal absorption.

ability, except for valsartan (reduction in 40–50%) untreated hypertensive patients comparing valsar- and eprosartan.46 tan (80 to 160 mg daily) with atenolol (50 to 100 mg AT1 receptor antagonists are highly bound to daily) over 8 months, found that valsartan reduced plasma , ranging from 90% with irbesartan left ventricular mass index to a higher extent than to more than 99% with candesartan and EXP3174. atenolol with similar reduction in systolic and dias- Despite the high protein binding, these agents tolic blood pressure. Further documentation of the achieve pharmacologically significant concen- effects on left ventricular hypertrophy and long-term trations at the receptor, as evident by their ability to benefit and risk reduction will have to be evaluated antagonise angiotensin II mediated effects.45,47 in other trials. The elimination characteristics of the AT1 recep- tor antagonists differ in term of both half-life and Side effects route. Losartan has an elimination half-life of 2 h, suggesting that it is a short-acting agent, but its The AT1 receptor antagonists have low incidence of metabolite EXP3174 has an elimination of 6 to 9 h, adverse effects even in the elderly. The adverse comparable to those of valsartan and eprosartan. In effects profile seems to be similar of control. comparison, candesartan cilexetil (9 h), irbesartan Goldberg et al56 reported data on the safety and tol- (11–15 h) and telmisartan (24 h) are longer act- erability of losartan in 2900 hypertensive patients 48,49 ing. The major route of elimination of the AT1 treated in double-blind clinical trials. Headache receptor antagonists is unrelated to half-life. (14.1%), upper respiratory infection (6.5%), dizzi- Losartan, valsartan, and irbesartan primarily ness (14.1%), asthenia/fatigue (3.8%), and cough undergo biliary excretion, with 70% to 80% of the (3.1%) were the clinical side effects most often dose eliminated in faeces, whereas eprosartan is reported in patients treated with losartan; and the almost exclusively eliminated by the kidneys.50 In frequency reported during the placebo were 17.2%, contrast, candesartan cilexetil undergoes both renal 5.6%, 2.4%, 3.9% and 2.6% respectively. The inci- and biliary elimination, with approximately 60% dence of cough is similar to diuretic or placebo in excreted in the and 40% in the faeces. contrast with an ACE inhibitor with an average inci- dence of 8.8%.57 58 Effect on left ventricular hypertrophy Chan P et al compared the incidence of cough with the ACE inhibitor , and the diuretic ACE inhibitors are particularly effective in reducing metolazone, with losartan in elderly hypertensive and perhaps preventing left ventricular hypertrophy patient with previous histories of ACE inhibitor- in hypertensive patients mediated by several induced cough, in a randomised, double-blind, par- mechanisms, such as the reduction of circulating allel group comparison of each drug during 10 angiotensin II and aldosterone and increment of bra- weeks in 84 patients. The incidence of cough with 51,52 dykinin. Losartan and other AT1 antagonists losartan (18%) was significantly lower than lisino- reduce left ventricular hypertrophy in spon- pril (97%), and similar to that for metolazone (21%). taneously hypertensive rats;53 even at dosages that , upper respiratory tract infection, back do not effect either blood pressure or the circulating pain, sinusitis, diarrhoea and pharyngitis have been renin-angiotensin system.54 Thu¨ rmann PA et al55 in reported to be 1 to 2% higher that placebo with dif- a double-blind randomised trial on 69 previously ferent agents.57

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Journal of Human Hypertension