Journal of Human Hypertension (2000) 14, Suppl 1, S69–S72  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh II receptor antagonists in arterial hypertension

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

Angiotensin II receptor antagonists (AT-1) represent a a thiazide diuretic is added, 60 to 70% of patients are new group of orally active antihypertensive agents. Acti- controlled. The efficacy is similar to angiotensin- vation on AT-1 receptor leads to vasoconstriction, converting enzyme inhibitors, diuretics, calcium antag- stimulation of the release of catecholamines and anti- onists and beta-blocking agents. Tolerability has been diuretic hormone with production of thirst, and promote reported to be very good. AT-1 receptor antagonists growth of vascular and cardiac muscle; these effects would be a drug of choice in otherwise well-controlled are blocked by AT-1 antagonist agents. The first chemi- hypertensive patients treated with angiotensin- cally useful, orally active AT-1 receptor antagonist was converting enzyme inhibitors who developed cough or , followed by other agents currently in clinical angioedema. The final position in the antihypertensive use, such as: , , , telmisar- therapy in this special population and other clinical situ- tan, , and many others under investigation. ations, such as left ventricular hypertrophy, heart fail- AT-1 receptor antagonists are effective in reducing high ure, diabetes mellitus and renal disease, has to be blood pressure in hypertensive patients. Monotherapy determined in large prospective clinical trials, some of in mild to moderate hypertension controls blood press- which are now being conducted. Journal of Human Hyper- ure in 40 to 50% of these patients; when a low dose of tension (2000) 14, Suppl 1, S69–S72.

Keywords: angiotensin II receptor antagonist; AT-1 receptor; AT-2 receptor; losartan

Introduction the advantage in having a very low incidence of such side effects. However the place of this class of Saralasin was the first receptor antagonist of angio- antihypertensive action remains to be defined. tensin II available for clinical use more than 20 years ago.1,2 Saralasin is a peptide analogue of angiotensin II with partial agonist effect, and can only be used Angiotensin II receptors intravenously; it has a very short duration of action. Angiotensin II exerts its effects by stimulating some When salarasin is used there is an initial increase in specific receptors on the membrane of several arterial blood pressure, due to its partial agonist organs. Radioligand studies have characterised sev- effect, but prevents the increment of blood pressure eral angiotensin II receptors, mainly type I and type when angiotensin II is administrated. II (AT-1 and AT-2 receptor). Activation of AT-1 Furukawa et al3 was the first to synthesise an imi- receptor leads to vasoconstriction, stimulation of the dazole derivative that was found to be a selective release of catecholamines and antidiuretic hormone angiotensin II receptor competitive antagonist, and and production of thirst; also promoting growth after chemical modifications, orally active agent.4 effects in vascular and cardiac muscle,9 all these Losantan was the first orally active, and long-acting effects are blocked by AT-1 antagonists. Activation receptor antagonist developed and in use in the of AT-2 receptors tends to have opposite reaction treatment of hypertension,5,6 followed by valsartan, basically cardio-protective effects by inhibitory irbesartan, eprosartan, candesartan, effects on growth mechanisms at vascular and car- and others.7 diac level. Blockade of -angiotensin system is effi- AT-2 receptors are expressed during the intrauter- cacious and a safe way to reduce blood pressure as ine life but not during adult life; however in patho- a treatment of patients with hypertension and heart logical situations, such as myocardial infarction, left failure, mainly by the inhibition of angiotensin- ventricular hypertrophy and in vascular neointimal converting enzyme (ACE). The main side effects proliferation, the AT-2 receptors are re-expressed; observed with ACE inhibitors is cough and angio- in those conditions AT-2 receptor stimulation may edema, which is seen in 5 to 10% of patients produce some protection in the heart and vessels. treated.8 Angiotensin II receptor antagonists have When AT-1 receptor antagonists block AT-1 receptors, actions of AT-1 receptors are inhibited but angiotensin II produce stimulatory effect on AT- 10 Correspondence: Dr Rafael Herna´ndez Herna´ndez, Clinical Phar- 2 receptors. macology Unit, School of Medicine, Universidad Centroccidental Actions mediated by AT-1 and AT-2 receptors are Lisandro Alvarado, Ave. Libertador, Barquisimeto, Venezuela summarised in Table 1. Angiotensin II receptor antagonists in arterial hypertension R Herna´ndez Herna´ndez et al S70 Table 1 Actions mediated by AT-1 and AT-2 receptors antagonists increase plasma renin activity and angiotensin II levels either in acute administration Angiotensin II Angiotensin II or multiple dose administration;16,17 but the press- AT-1 Receptor AT-2 Receptor ure effect of angiotensin II is blocked. Whereas ACE inhibitors reduce plasma level of angiotensin II and ¼ Vasoconstriction ¼ Stimulation of apoptosis ¼ Aldosterone production and ¼ Antiproliferative effect increase bradykinin levels. release ¼ Embriogenic differentiation The efficacy in reducing blood pressure with the ¼ Sodium tubular Reabsortion and development use of AT-1 receptor antagonists is equivalent to ¼ Hypertrophy of heart ¼ Endothelial cells growing other well established antihypertensive agents. ¼ Proliferation of Smooth ¼ Vasodilatation muscle in vascular tree When losartan (50 to 100 mg daily) is compared to ¼ Catecholamines secretion and felodipine (5 to 10 mg daily, losartan was less effec- Potentiation (central and tive after 6 weeks of treatment but equally effective periphery) after 12 weeks of therapy).18 ¼ Vasopressin release The efficacy of losartan (50 to 100 mg once daily) ¼ Thirst ¼ Renal vasoconstriction and has been compared to atenolol (50 to 100 mg once reduction of renal blood flow daily), and (20 mg once daily). The blood ¼ Inhibition of renin release pressure lowering effect of losartan was comparable to enalapril and atenolol. On ambulatory blood pressure monitoring losartan showed antihyperten- sive effect over a period of 24 h without affecting the Other angiotensin II receptors have been body’s circadian rhythm.19,20 11 described such as AT-3 ant AT-4; in rats and mice, Several studies have compared the blood pressure AT-1 receptor is also composed of two subtypes: lowering effects of AT-1 receptor antagonist against 12 AT-1A and AT-1B; these receptors have to be enalapril; candesartan cilexitil,21 eprosartan22 and characterised pharmacologically and determinate its irbesartan23 lower systolic and diastolic blood press- relevance in man during physiological and patho- ure to the same extent to that of enalapril. physiological conditions. When diuretics were added to an AT-1 receptor antagonist, a better response is achieved. The AT-1 antagonists addition of hydrochorothiazide to losartan produce a dose-related reduction in blood pressure after a The first chemically useful, orally active AT-1 recep- treatment of 12 weeks.19 In a double-blind study 189 tor antagonist was losartan, followed by other agents patients were enrolled to compare valsartan + HCTZ 5,6 currently in clinical use or under investigation. (12.5 mg) and Enalapril + HCTZ (12.5 mg), which Table 2 summarises the AT-1 receptor antagonist after 8 weeks of treatment controlled blood pressure either in clinical use or under development: in about 64% of the patients in both group of treat- The AT-1 receptor antagonists reduce blood press- ments.24 ure by decreasing systemic vascular resistance; heart Losartan has been shown to exert a uricosuric 13–15 rate and cardiac output are not modified. effect in normotensive and hypertensive subjects, Reduction in systemic vascular resistance are due which could be an advantage when losartan is com- to inhibition of the direct vasoconstrictive effect of bined with a thiazide diuretic.20 angiotensin II, reductions in the sympathetic ner- vous system activity, in the release of aldosterone and in the reabsortion of sodium, are mediated by angiotensin II. It has also been described as sensitis- Effect on left ventricular hypertrophy ing in baroreceptors, the stimulation of prostacyclin release, and at long-term reduction in the proliferat- ACE inhibitors are particularly effective in reducing ive effect (antiproliferative effect).7 and perhaps preventing left ventricular hypertrophy In volunteers the administration of AT-1 receptor in hypertensive patients mediated by several mech- anisms, such as the reduction of circulating angio- Table 2 Angiotensin II receptor antagonists tensin II and aldosterone and increment of bradyki- nin.25,26 Losartan and other AT-1 receptor Agent Established oral dose Manufacturer antagonists reduce left ventricular hypertrophy in spontaneously hypertensive rats;27 even at dosages Losartan 50–100 mg daily DuPond-Merck that do not affect either blood pressure or the circul- Eprosartan 150–350 mg daily SmithKline Beecham ating renin-angiotensin system.28 Thu¨ rmann PA et Irbesartan 10–50 mg daily Sanofi al29 in a double-blind randomised trial on 69 pre- Telmisartan 40–80 mg daily Boeringer Ingelheim viously untreated hypertensive patients comparing Candesartan 5–10 mg daily Takeda – Astra Valsartan 80–160 mg daily Novartis valsartan (80 to 160 mg daily) to atenolol (50 to ZD-8731a Zeneca 100 mg daily) over 8 months, found that valsartan SC-52458 Searle reduced left ventricular mass index to a higher LR-B/081 Lusofarmaco extent than atenolol with similar reduction in sys- YM-358 Yamanouchi GR 117289C Glaxo tolic and diastolic blood pressure. Further docu- Zolarsartana mentation of the effects on left ventricular hyper- trophy and long-term benefit and risk reduction will aDevelopment suspended. have to be evaluated in other trials.

Journal of Human Hypertension Angiotensin II receptor antagonists in arterial hypertension R Herna´ndez Herna´ndez et al S71 Table 3 Summary of pharmacokinetic parameters of AT-1 receptor antagonists in clinical use

Agent Active metabolite Bioavailability (%) Food effect Half-life (hours) Protein bound (%)

Losartan EXP-3174 33% Minimal 6–9 98.7 Eprosartan None 13% Minimal 5–9 98 Irbesartan None 60–80 None 11–15 90 Telmisartan None 30–60 Minimal 24 Ͼ98 Candesartan Candesartan 15 None 9 Ͼ90 Cilexetil Valsartan None 25 Important 6 95

Adapted from Brunner.30

Pharmacokinetic system can cause foetal and neonatal morbidity and death when administered to pregnant women, any All AT-1 receptors antagonists studied to-date of the AT-1 receptor antagonists should not be used essentially seem to share the same pharmacodyn- during pregnancy and should be discontinued as amic characteristics, but these agents differ in their soon as possible when pregnancy is detected. pharmacokinetic characteristics in relation to absorption, bioavailability, metabolism, elimination, duration of action and half-life. Conclusions Table 3 summarises the pharmacokinetics of some AT-1 receptor antagonists are a new class of drugs AT-1 receptor antagonists in clinical use. Only two used to treat hypertensive patients. They are effec- agents have active metabolites, losartan and candes- tive in reducing systolic and diastolic blood press- artan cilexitil, which contribute to the duration of ure in mild to moderate hypertension in about 40% action of those agents. Drugs with higher bioavail- of treated patients when they are used in monother- ability are irbesartan and telmisartan; these drugs apy; but its efficacy increment to 60 to 70% when also have the longest half-life. All AT-1 antagonists 30 used in combination with low dose diuretic agent. are highly protein-bound. Blood pressure is reduced with about equal efficacy compared to ACE-inhibitors, beta-blockers and cal- Side effects cium channel blockers when these drugs are used 31 in monotherapy. Goldberg et al reported data on the safety and tol- AT-1 receptor antagonists could be used in combi- erability of losartan in 2900 hypertensive patients nation with most other antihypertensive agents in treated in double-blind clinical trials. Headache more severe hypertension. (14.1%), upper respiratory infection (6.5%), dizzi- AT-1 receptor antagonists are an important option ness (14.1%), asthenia/fatigue (3.8%), and cough for the treatment of hypertension, especially in (3.1%) were the clinical side effects most often patients who have been using ACE inhibitors and reported in patients treated with losartan; and the who present with cough or angioedema. Tolerability frequency reported during the placebo were 17.2%, has been reported to be excellent with the use of AT- 5.6%, 2.4%, 3.9% and 2.6% respectively. The inci- 1 receptor antagonists. dence of cough is similar to diuretic or placebo in The place in the antihypertensive therapy in a contrast with an ACE inhibitor (8.8%). special population and different clinical conditions, Dizziness, upper respiratory tract infection, back such as left ventricular hypertrophy, associated pain, sinusitis, diarrhoea and pharyngitis have been heart failure, diabetes, and renal disease, has to be reported to be 1 to 2% higher than placebo with dif- 32 determined in a further large prospective clinical ferent agents. trial. Chan P et al33 compared the incidence of cough with the ACE inhibitor , and the diuretic metolazone, with losartan in elderly hypertensive References patients with previous histories of ACE inhibitor 1 Streeten DH, Anderson GH Jr, Dalakos TH. Angioten- induced cough, in a randomised, double-blind, sin II blockade: its clinical significance. Am J Med parallel group comparison of each drug during 10 1976; 60: 817–824. weeks in 84 patients. The incidence of cough with 2 Brunner HR, Gavras H, Laragh JH. Specific inhibition losartan (18%) was significantly lower than lisino- of the renin-angiotensin system: a key to understand- pril (97%), and similar to that for metolazone (21%). ing blood pressure regulation. Prog Cardiovasc Dis Eprosartan, in a trial including 243 patients with 1974; 17: 87–98. mild to moderate hypertension, controlled blood 3 Furukawa Y, Kishimoto S, Hishikawa K. Takeda pressure in 42%, with a dosage of 600 mg daily the Chemical Industries Ltd. Hypotensive imidazole-5 total number of adverse events was similar in the acetic acid derivatives. US Patent 4 355 040, July 20, 34 1982. eprosartan and placebo groups. 4 Wexeler RR et al. Rationale for the chemical develop- AT-1 receptor antagonists do not modify glucose ment of angiotensin II receptor antagonists. Am J Hyp- tolerance with either cholesterol or triglycerides ertens 1992; 5: 209S–220S. levels. 5 Chuiu AT et al. Non peptide angiotensin II receptor Drugs that act directly on the renin-angiotensin antagonists, VIII: characterization of functional antag-

Journal of Human Hypertension Angiotensin II receptor antagonists in arterial hypertension R Herna´ndez Herna´ndez et al S72 onism displayed by DuP-753, an orally active antihy- 21 Gavras I, Gavras H. Effects of eprosartan versus enalap- pertensive agent. J Pharmacol Exp Ther 1990; 252: ril in hypertensive patients on the rennin angiotensin- 711–718. aldosterone system and safety parameters; results from 6 Gansevoort RT et al. Effects of the angiotensin II antag- a 26 week, double-blind, multicenter study. Curr Med onists losartan in hypertensive patients with renal dis- Res Opin 1999; 15: 15–24. ease. J Hypertens 1994; 12: S37–S42. 22 Zanchetti A. Candesartan cilexitil and enalapril are of 7 de Gasparro M, Bottari S, Levens NR. Characteristics of equivalent efficacy in patients with mild to moderate angiotensin II receptor and their role in cell and organ hypertension. J Hum Hypertens 1997; 11 (Suppl 2): physiology. In: Laragh JH, Brenner BM (eds). Hyper- S57–S59. tension: Pathophysiology, Diagnosis and Management. 23 Pouleur HG. Clinical overview of irbesartan: a new Second edition. Raven Press Ltd, New York, 1995, pp angiotensin II receptor antagonist. Am J Hypertens 1695–1720. 1997; 10 (Suppl): 318S–324S. 8 Israelli ZH, Hall WD. Cough and angioneurotic edema 24 Mallion JM et al. Valsartan, a new angiotensin II antag- associated with angiotensin-converting enzyme inhibi- onist; blood pressure reduction in essential hyperten- tors therapy: a review of the literature and pathophysi- sion compared with an angiotensin converting enzyme ology. Ann Intern Med 1992; 117: 234–242. inhibitor, enalapril. Blood Press Monit 1997; 2: 179– 9 Timmermans PBMW et al. Angiotensin II receptors 184. and functional correlates. Am J Hypertens 1992; 5: 25 Dahlo¨f B, Pennert K, Hansson L. Reversal of left ven- 221S–234S. tricular hypertrophy in hypertensive patients: a meta- 10 Dzau VJ, Mukoyama M, Pratt RE. Molecular biology of analysis of 109 treatment studies. Am J Hypertens angiotensin receptors: target for drug research. J Hy- 1992; 5: 95–110. pertens 1994; 12: S1–S5. 26 Cruickshank JM et al. Reversibility of left ventricular 11 Sasamura H et al. Cloning, characterization and expre- hypertrophy by differing types of antihypertensive sio´n of two antiotensin receptors (AT-1) isoforms from therapy. J Hum Hypertens 1992; 6: 85–90. the mouse genome. Biochem Biophys Res Commun 27 Mizuno K et al. Effects of losartan, a non-peptide angi- 1992; 351: 253–259. otensin II receptor antagonist, on cardiac hypertrophy 12 de Gasparo M et al. Proposed update of angiotensin and the tissue angiotensin II content in spontaneously receptor nomenclature. Hypertension 1995; 25: 924– hypertensive rats. Life Sci 1992; 51: 367–374. 927. 28 Bunkenburg B et al. Receptor-mediated effects of angi- 13 Wong PC et al. Non-peptide angiotensin II receptor otensin II on growth of vascular smooth muscle cells antagonists: studies with EXP9270 and DuP 753. from spontaneously hypertensive rats. Hypertension Hypertension 1990; 15: 823–834. 1992; 20: 746–754. 14 Markahm A, Goa KL. Valsartan. A review of its phar- 29 Thu¨rmann PA et al. Influence of the angiotensin II macology and therapeutic use in essential hyperten- antagonist valsartan on left ventricular hypertrophy in sion. Drug 1997; 54: 299–311. patients with essential hypertension. Circulation 1998; 15 Ruilope L. Human pharmacokinetic/pharmacodynamic 98: 2037–2042. profile of irbesartan: a new potent angiotensin II recep- 30 Brunner HR. The new angiotensin II receptor antagon- tor antagonist. J Hypertens Suppl 1997; 15: S15–S20. ist, irbesartan: Pharmacokinetic and pharmacodyn- 16 Criscione L et al. Valsartan: preclinical and clinical amic considerations. Am J Hypertens 1997; 10 (Suppl): profile of an antihypertensive angiotensin II antagon- 311S–317S. ist. Cardiovasc Drug Res 1995; 13: 230–250. 31 Goldberg AI, Dunlay MC, Sweet CS. Safety and toler- 17 Weber MA. Comparison of type I angiotensin II recep- ability of losartan potassium, an angiotensin II recep- tor blockers and angiotensin-converting enzyme tor antagonist, compared with hyrochrolothiazide, inhibitors in the treatment of hypertension. J Hyper- atenolol, felodipine AR and angiotensin-converting tens 1997; 15 (Suppl 5): S32–S36. enzyme inhibitors for the treatment of systemic hyper- 18 Chan JCN et al. A randomized, double blind, parallel tension. Am J Cardiol 1995; 75: 793–795. study of the antihypertensive efficacy and safety of los- 32 Physician Desk Reference 52 edition. Medical Eco- artan potassium compared to felodipine ER in elderly nomics Data, 1999. patients with mild to moderate hypertension. J Hum 33 Chan P et al. Double-blind comparison of losartan, lisi- Hypertens 1995; 9: 765–771. nopril, and metolazone in elderly hypertensive 19 Mallion JM, Goldberg AI. Global efficacy and toler- patients with previous angiotensin-converting enzyme ability of losartan, an angiotensin II subtype 1-receptor inhibitor-induced cough. J Clin Pharmacol 1997; 37: antagonist, in the treatment of hypertension. Blood 253–257. Press Suppl 1996; 2: 82–86. 34 Gradman AH et al. Assesment of once-daily eprosar- 20 Soffer BA et al. Effects of losartan on a blackground tan, an angiotensin II antagonist, in patients with sys- of hydrochlorothiazide in patients with hypertension. temic hypertension, Eprosartan Study Group. Clin Hypertension 1995; 26: 112–117. Ther 1999; 21: 442–453.

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