1. Martin Štěrba, PharmD., PhD. Associate professor Department of Pharmacology Faculty of Medicine in Hradec Kralove 2015 Drugs affecting RAAS

2. Overview of drugs affecting RAAS Angiotensin converting enzyme inhibitors (ACE-I) Inhibit conversion of ATI to ATII AT 1 -blockers (ARBs) antagonists of AT-II on AT 1 receptor  -blockers Inhibit renin secretion Direct inhibitors of renin activity Inhibit conversion angiotensinogen to ATI

3. RAAS (renin-angiotensin-aldosterone system): 1.Plasmatic endocrine cascade 2.Local tissue RAAS (heart, vessels, kidneys...) Plasmatic RAAS a)Renin Synthetized as preprorenin in juxtaglomelular cells (kidney) Then cleaved to prorenin (still inactive) and finally to active renin a protease catalyzing conversion of angiotensinogen (synthetized in the liver and secreted into the circulation) to AT-I Renin secretion is induced (to activate RAAS) by Drop in BP in vas afferens (renal vascular receptor) Drop in Na + concentrations in distal tubule (macula densa) Increased sympathetic activity - NA and adrenalin bind  1 -receptors b) Angiotensin I (AT-I) – small to none its own physiological effects Renin-angiotensin-aldosterone system

4. Angiotensin-converting enzyme (ACE) mainly bound to endothelial membrane (mainly in pulmonary circulation) limited solubilized plasmatic fraction Responsible for AT-I to AT-II conversion bradykinine breakdown Overexpressed after MI Drives cardiac pathological remodeling → ventricular dilation ACE2 enzyme ACE homologue Responsible for conversion of AT-I to AT1-9 (may be converted further to AT1-7) AT-II to AT1-7 (which induce vasodilation and tissue protection)

5. Very short plasma half-life (max. 1 min) Hydrolyzed by plasmatic peptidases (angiotensinases) Effects Vasoconstriction ( esp. arteries ) ↑ BP (small to none bradycardia, re-set baroreceptors) facilitation of peripheral NOR neurotransmission Aldosterone secretion (zona glomerulosa, adrenal cortex)  ↑ Na + retention Tissue remodeling vascular smooth muscle proliferation, fibroblast activation, proliferation and collagen synthesis and deposition cardiomyocyte hypertrophy and apoptosis Central effects thirst center activation increased sympathetic tonus ADH and ACTH-secretion Angiotensin II (ATII)

6. Membrane GPCR receptors AT 1 -R Vascular smooth muscle, cardiomyocytes, fibroblasts…. Mediate most important of AT-II effects Density is dynamically controlled – depends on AT-II In prolonged stimulation: myocyte & cardiac hypertrophy increased collagen synthesis (replacement and interstitial fibrosis)  remodeling of the heart and vessel AT 2 R The effects are more complex, but generally opposing AT 1 R – antiproliferative effect, antifibrotic, NO production, vasodilation In adults: brain, kidney, heart – fibroblasts, interstitial cells Upregulated in hypertension, MI, HF, vascular injury, atherosclerosis Target for protective AT1-7AT-II-receptors

7. Aldosterone release Proteinuria GFR Angiotensin-II plays a central role in organ damage AT-II AT 1 receptor Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis* LV hypertrophy Fibrosis Remodelling Apoptosis Stroke DEATH *Preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate Hypertension Heart failure MI Renal failure

8. Schema of plasmic RAAS cascade angiotensinogen angiotensin I angiotensin II renin ACE liver kidney lungs AT 1 receptor AT 2 receptor Increase in PVR Cardiovascular remodeling Kidney dysfunction tissues effect

9. Schema angiotensinogen angiotensin I angiotenzin II AT 1 -receptors AT 2 -receptors Alternative pathways renin ACE (lungh and tissue) bradykinin Inactive fragments

10. Rank among kinins (tissue hormones) acting mainly at the site of production Effects (B 2 -receptors) Vasodilation! Increase in cell permeability Increase diuresis ACE also act to INACTIVATE bradykinin ! Bradykinin

11. angiotensin- converting enzyme Angiotensin I (inactive) Angiotensin II (active vasoconstrictor) Bradykinin (active vasodilator) Inactive metabolites ACE inhibitors Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

12. NEW CONCEPT OF OPOSING ANGIOTENSIN LIGANDS AND RECEPTORS: ACE vs ACE2 and AT1R vs AT2R/MasR Tracey A. Gaspari et al. Hypertension. 2012;60:17-19 Copyright © American Heart Association, Inc. All rights reserved.

13. Angiotensin converting enzyme inhibitors (ACE-I) Inhibit conversion of AT-I to AT-II  inhibit activation of the pathophysiologically important part of RAAS Induce vasodilation ↓ AT-II vasoconstriction + ↑ bradykinin vasodilaton without significant tachycardia ↓ preload, ↓ filling heart pressures and ↓ cardiac dilation ↓ afterload – in HF ↑ CO NaCl excretion (natriuretic effect) Inhibit pathological remodeling of the heart and vessels and may induce their regression back to normal Does not inhibit alternative (ACE-independent) pathways The block of AT-II effects the pathway is not complete – esp. in the tissues The effects are NOT directly linked to the renin plasma concentrations

14. PK differences are more significant than PD differences Well absorbed, captopril on empty stomach C max a T 1/2 are different in each drug ( captopril ↓ t 1/2 ) Majority = prodrugs ( ↑ BAV) Eliminated mainly by kidney (fosinopril also by liver ), decrease the dose in kidney function impairment (usually not necessary in fosinopril) ACE-I Pharmacokinetics

15. 1. Direct acting: captopril lisinopril (derived from enalaprilate) 2. Prodrugs (higher BAV): enalapril – enalaprilate perindopril – perindoprilate trandolapril, ramipril, quinapril, fosinopril… ACEI classification (-prils)

16. ACE inhibitors duration of action DrugDuration of effect (hours) Short-acting:captopril 6-8 Intermediate- acting: enalapril 12 quinapril Long-acting: perindopril 24 lisinopril spirapril ramipril Angiotensin-converting enzyme inhibitors (ACEI)

17. Chronic heart failure Decrease overall and cardiovascular mortality (x digoxin) Decrease progression of LV dysfunction Inhibit and reverse pathological remodeling of the heart and vessels Improve symptoms Chronic arterial hypertension Effective control of BP (both hypertensive crisis & chronic hypertension) Prevent and may regress pathological remodeling of the heart & vessels After MI Prevent pathological myocardial remodeling and progression into HF and LV dilation + decreased re-infarction Diabetic nephropathy decrease proteinuria and stabilize the renal function complex improvement in renal hemodynamic: mainly dilatation of both the afferent and efferent renal arterioles →↓ intraglomerular pressure, ↓proteinuria and glomerulosclerosis Prevention of atrial fibrillations?! ACE inhibitors: clinical indications

18. First dose hypotension Esp. in hypovolemia (intensive diuretic treatment) Dose titration! Dry cough bradykinin - 5-10 (20) % patients PGI-mediated, but NSAID not recommended Angioneurotic edema (bradykinin) Hyperkalemia Cave ! - combination with K + sparring diuretics ! Useful combination with diuretics Teratogenicity (severe malformations, particularly 2 nd -3 rd trimester) Oligohydramnios ( ↓ amniotic fluid ), fetal and neonatal renal failure, bone defects … MONITORING: BP, K+, urea, creatinine and proteinuria ACE inhibitors: adverse effects

19. Contraindication: Pregnancy (and PIH) – less dangerous in 1 st trimester Angioneurotic edema after any ACEI Bilateral stenosis of renal artery (or stenosis of renal a. in single kidney) intrarenal perfusion pressure is already reduced and GFR largely depends on AT- II-maintained vasoconstriction of vas efferens a severe fall of GFR may occur after ACE-I treatment Cardiogenic shock and hypotension (e.g. after MI) Hyperkalemia Interactions: K + sparing diuretics,  -blockers, NSAIDs, diuretics and other hypotensive agents. ACE inhibitors contraindications and interactions

20. PHARMACODYNAMICS Mostly non-competitive AT 1 receptors - Semi-irreversible binding to the receptor (insurmontable effect), - losartant is competitive, but its metabolite is non-competitive AT 2 receptors are still available to high amount of AT II (no feedback regulation of to renin) ARBs - AT 1 receptor blockers: sartans

21. losartan, candesartan, irbesartan, valsartan, olmesartan Pharmacodynamics – similar as in ACE-I Little to no effect on bradykinin (pros and contras) No chance to bypass by alternative pathways as in ACE-I Pharmacokinetics: Lipophilic compounds - Good BAV and high plasma protein binding Liver metabolism (first-pass effect) Adverse effect: relatively well tolerable, much less risk of dry cough and angioedema then in ACE-I otherwise roughly similar to ACE-I Indication: an alternative to ACE-I namely in hypertension – majority of the effect in 2 weeks, max. in 4-6 weeks. heart failure and chronic kidney disease – seems to provide similar benefits as ACE-I, but still rather second line drugs after ACE-I Contraindication: pregnancy, lactation ARBs: sartans

22. NEW CONCEPT OF OPOSING ANGIOTENSIN LIGANDS AND RECEPTORS: ACE vs ACE2 and AT1R vs AT2R/MasR Tracey A. Gaspari et al. Hypertension. 2012;60:17-19 Copyright © American Heart Association, Inc. All rights reserved.

23. Direct renin inhibitors Introduced relativity recently Inhibit enzymatic activity of renin ↓ ATI-production Aliskiren Indication hypertension (only combination treatment) inferior to ACE-I an ARBs Therapeutic value? Combination aliskiren + ACE-I/ARBs Since 2012 contraindicated in diabetics and in kidney dysfunction Due to the increased risk of renal impairment, hyperkalemia and hypotension