Review Articles Significant beneficial effect of AT-1 receptor blockers (sartans) in stroke Marwan S. Al-Nimer, MD, PhD. ABSTRACT Neurosciences 2012; Vol. 17 (1): 6-15 From the Department of Pharmacology, College of Medicine, .Al-Mustansiriya University, Baghdad, Iraq يعد ارتفاع ضغط الدم من أكثر عوامل اخلطر املسببة للسكتة ,Address correspondence and reprint request to: Prof. Marwan S. Al-Nimer الدماغية والتي ميكن السيطرة عليها، كما تعد العﻻقة بني Professor of Pharmacology, Department of Pharmacology, College of ضغط الدم والوفاة الناجتة عن السكتة الدماغية خطية وقوية. 2 Medicine, Al-Mustansiriya University, PO Box 14132, Baghdad, Iraq. Tel. +964 5591530. E-mail: [email protected] تعد مركبات سارتان التي تثبط فعالية هرمون أجنيوتنسني- من خﻻل تثبيط مستقبﻻت هرمون أجنيوتنسني من اﻷدوية السليمة في معاجلة ارتفاع ضغط الدم، كما أن لها تأثيرات مضادة rterial blood pressure and cardiac output are لﻻلتهاب من خﻻل عملها في تثبيط احملركات اخللوية. تلعب Acontrolled by the renin angiotensin aldosterone هذه التأثيرات دوراً في تقليل اﻷذى الذي يلحق بالدماغ عقب system (RAAS) via regulation of the blood volume السكتة الدماغية، وحتسن من عواقب السكتة الدماغية بتحسينها and peripheral systemic vascular resistance.1 Renin للوظائف اﻹدراكية للدماغ. تعد هذه املركبات سليمة في معاجلة is a proteolytic enzyme, primarily released from السكتة الدماغية بسبب ارتفاع ضغط الدم كما أن فوائدها تتعدى juxtaglomerular cells into the circulation, acting upon a حتكمها بارتفاع ضغط الدم فحسب. وتعمل هذه املركبات على circulating alpha-2 globulin substrate angiotensinogen تكوين أوعية دموية حديثة املنشأ وبذلك حتمي الدماغ من خﻻل to form the decapeptide angiotensin I (Ang I). In حمايتها لﻷوعية الدموية وحتسينها ﻹعادة تشكيل منشأ اﻷوعية ,the vascular endothelium, particularly in the lungs الدموية. لقد قمنا في هذا املقال مبناقشة التأثيرات املفيدة لهذه angiotensin-converting enzyme (ACE) cleaves off املركبات في معاجلة السكتة الدماغية مع اﻷخذ بعني اﻻعتبار ,amino acids from Ang I to form the octapeptide 2 لنتائج التجارب والدراسات السريرية. angiotensin II (Ang II) (Figure 1). Other tissues in the Hypertension is the most important controllable and body, heart, brain, and blood vessels also can form modifiable risk factor for stroke. The relationship Ang II. Angiotensin II is a powerful dipsogen acting between blood pressure and stroke mortality is as an endocrine, autocrine, paracrine, and intracrine strong and linear. Angiotensin receptor blockers hormone. It acts on angiotensin receptors (ATR), a class (sartans) are competitive pharmacological antagonists of G protein coupled receptors.2 The subclass receptor of angiotensin II receptors, and some of them are approved for use in the treatment of hypertension. AT1R is mainly expressed in vascular smooth muscle, These drugs also show anti-inflammatory effects by liver, kidneys, lung, adrenal cortex, pituitary gland, reducing the cytokine levels. The anti-inflammatory and brain. The AT2R is expressed in fetal tissues, adult effects of sartans play a role in reducing cerebral injury brain, adrenal gland (zona granulose), ovary, uterus, following stroke, and improve the outcome of stroke endothelium and heart.2 The affinity of Ang II to AT1R in terms of improving cognitive function. In humans, and AT2R is similar. sartans are safe in hypertensive acute stroke patients Activation of AT1R by Ang II leads to:3,4 1. and may offer advantages independent of blood Increased peripheral vascular resistance (as a result pressure control. Sartans promote neovascularization and thereby provide long-term cerebro-protection in of vasoconstriction) and thereby increased arterial terms of vascular protection and enhancement of early blood pressure. 2. Enhanced sympathetic adrenergic angiogenic remodeling. In this review, the beneficial function via facilitation of the release of norepinephrine effects of sartans in the management of stroke are from sympathetic nerve endings and inhibition of discussed, considering the results of experimental and norepinephrine uptake by terminal nerve endings. 3. clinical studies. Cardiac and vascular cell proliferation (hypertrophy) 4. Increased cardiac contractility and thereby increased 6 Sartans and stroke ... Al-Nimer thereby disturb fetal growth and development, inhibition of neointima formation, and differentiation of neuronal cells.8,9 The ARBs are similar in action and side effects (Table 1). They differ in how they are eliminated from the body and the extent to which they are distributed throughout the body. Some ARBs need to be converted to an active form (prodrug) in the body before they can lower blood pressure (BP). Some of them lower BP better than others, for example, irbesartan and candesartan reduced BP better than losartan. The main uses of ARBs include: treatment of systemic hypertension, treatment of heart failure, prevention of renal failure in diabetes mellitus and hypertension, reduction in the risk of stroke in hypertension and cardiomegaly, prevention of the recurrence of atrial fibrillation, and treatment of diabetic nephropathy. The ARBs do not inhibit bradykinin metabolism or enhance prostaglandin Figure 1 - The renin-angiotensin aldosterone system. ACE - angiotensin synthesis (Figure 1). Therefore, cough occurs much less converting enzyme, AT-I - angiotensin-I, AT-II - angiotensin-II often with those agents than with ACEIs. Also, ARBs do not adversely affect lipid profile or cause rebound hypertension after discontinuation. More than 10 drugs cardiac output. 5. Decreased renal blood flow. 6. related to ARBs were launched and in addition to the Synthesis and release of aldosterone, and thereby causing differences in the pharmacokinetics Table( 2), they also sodium, and water retention. 7. Release of vasopressin show differences in pharmacodynamics and indications. (antidiuretic hormone) from the posterior pituitary Among these drugs: gland, which increases fluid retention by the kidneys. Losartan. This was the first AT1R antagonist 8. Stimulation of the thirst center within the brain. 9. introduced in 1995 with the empirical formula Increased extracellular matrix formation. C H ClN O. Its affinity for AT1R is around 1000 4 22 23 6 Activation of AT2R by Ang II leads to: 1. Decreased times greater than its affinity for AT2R. It is well cell growth. 2. Fetal tissue development. 3. Modulation tolerated, and as efficacious as enalapril and nifedipine of extracellular matrix. 4. Cell differentiation. 5. for lowing BP.10,11 The duration of its activity for a dose is Neuronal regeneration. 6. Apoptosis. 7. Vasodilation. 24 hours. It undergoes significant first pass metabolism 5,6 Drugs that act on the RAAS include: 1. to produce 5-carboxylic acid metabolite (EXP3174), Angiotensin converting enzyme inhibitors (ACEIs): which is a long acting non-competitive antagonist at they are classified, based on molecular structure, into: a) Sulfhydryl containing agents: for example, captopril, and zofenopril. b) Dicarboxylate containing agents: for Table 1 - List of sartan drugs, mechanism of action, and adverse example, enalapril, ramipril, quinapril, perindopril, reactions. lisinopril, and benazepril. c) Phosphonate containing Sarcosine-8-isoleucine angiotensin II Irbesartan agents: for example, fosinopril. 2. Angiotensin receptor Abitesartan Losartan potassium blockers (ARBs). 3. Renin inhibitors: for example, Azilsartan kamedoxomil Losartan aliskiren, remikiren, and enalkiren. 4. Aldosterone Azilsartan medoxomil Milfasartan Azilsartan Olmesartan medoxomil antagonists: for example, spironolactone, eplerenone, Candesartan cilexetil Olmesartan canrenone, prorenone, and mexrenone. Candesartan Pomisartan The purpose of this review is to highlight the Elisartan Pratosartan Elisartan Ripisartan beneficial effects of ARBs in the prevention and Embusartan Saprisartan potassium management of stroke, taking into consideration their Enoltasosartan Saprisartan anti-inflammatory effect. Eprosartan mesylate Tasosartan Eprosartan Telmisartan The ARBs are competitive pharmacological Fimasartan Valsartan antagonists of angiotensin II receptors (ATII). Most of Forasartan Zolasartan the described actions of ATII, such as vasoconstriction, Mechanism of action: to block AT1 receptors stimulation of cellular proliferation, and facilitation of sympathetic transmission are mediated by ATI receptors Adverse reactions: Dizziness, headache, hyperkalemia, first dose and blocked by ARBs.7 The ARBs may block ATII and hypotension, myalgia, insomnia Neurosciences 2012; Vol. 17 (1) Sartans and stroke ... Al-Nimer AT1R and contributes to the pharmacological effects of it inhibits sympathetic noradrenaline production. The losartan. It shows nephroprotective effects, due to its bioavailability is approximately 13% after a 300 mg oral down-regulation of transforming growth factor (TGF- dose. Food delays absorption, and causes non-clinically b) type I and type II receptors in the kidney. significant variable changes (<25%) in peak plasma Valsartan. This is a non-peptide orally active concentration (Cmax) and area under the plasma concentration–time curve. Administration of eprosartan compound with the empirical formula C24H29N5O3 and its affinity for AT1R is around 20000 times greater during the second and third trimesters can cause fetal than its affinity for AT2R. It is as effective as enalapril, and neonatal morbidity and mortality (neonatal skull lisinopril, and amlodipine in the treatment of mild- hypoplasia, oligohydramnios, deterioration in fetal moderate hypertension.12-14 Also, it is prescribed for renal function, fetal limb contractures,