Renin inhibitors Aliskiren Used in hypertension as monotherapy

Renin inhibitors Aliskiren • Used in hypertension as monotherapy or in combination therapy • Adverse effects; diarrhea, rash, anemia, hyperkalemia • Contraindicated in pregnancy and lactation

Ca++ channel blockers • Inhibit Ca++ influx in vascular smooth muscle, vasodilatation • Inhibit Ca++ influx in cardiac muscle, impairs excitation-contraction coupling, cardiac contractility is decreased • Do not depress skeletal muscle (which uses intracellular Ca++ pool) • Nimodipine has high affinity to cerebral blood vessels (used after subarachnoidal hemorrhage)

Ca++ channel blockers • Their vasodilator effect is significant at arterioles, less at venules • Used as monotherapy in mild and moderate hypertension • More effective in in hypertensive patients with low renin, low plasma Ca++ levels and salt sensitive patients • More efective in old patients and afroamerican race

Ca++ channel blockers • Dihydropyridines: amlodipine, felodipine, isradipine, nikardipine, nifedipine, nizoldipine, nimodipine • Benzothiazepines: Diltiazem • Phenylalkilamines: verapamil

Ca++ channel blockers • Dihydropyridines have less cardiodepressant effect, either maintains or mildly increases CO • Verapamil has cardiodepressant effect, decreases CO and HR • Oral-short acting nifedipine for hypertension emergency

Ca++ channel blockers Toxic effects: • Cardiac depression, bradycardia, AV block, cardiac arrest, HF • Edema at ankle (with hydropyridines) • The patients using beta blockers are more sensitive to cardiodepressant effect of Ca++ channel blockers (concomitant use of verapamil with beta blockers is contrindicated!)

Beta blockers • BP is decreased due to reduced CO • More efficient in patients with high renin activity

Beta blockers • • • Propranolol Metoprolol Atenolol Nadolol Carteolol Betaxolol Bisoprolol Acebutolol Pindolol Carvedilol Labetalol Nebivolol

Beta blockers • Metoprolol ve atenolol, cardioselective • The most used beta blockers • Advantageous in patients with asthma, diabetes or peripheral vascular disease • Betaxolol and bisoprolol are also selective beta 1 AR blocker

Beta blockers • Pindolol, acebutolol ve penbutolol: partial agonist (intrinsic sympathomimetic activity) • Decrease vascular resistance, the decrease in CO and HR is less than others • Could be particularly useful in patients with bradyaritmia or peripheral artery disease

Beta blockers • Labetalol, carvedilol and nebivolol; both beta blocker and vasodilatory effect • Labetalol; decreases PVR, no effect on CO or HR. Used in hypertensive emergency and pheochromacytoma as it has both alpha and beta blocker effect

Beta blockers • Carvedilol, nonselective beta blocker and vasodilator. Useful in HF and hypertension • Nebivolol, beta 1 AR selective blocker and vasodilator. Decreases PVR (NO mediated? ) • Esmolol, very short half life (9 -10 min), iv infusion. Intraoperative-postoperative hypertension treatment, hypertension emergency

Alpha 1 blockers • Vasodilatation • Reflex tachycardia is uncommon • More efective when combined with beta blocker and diuretics • Advers effects; first dose phenomenon, headache, dizziness, palpitations, lassitude • Used also in benign prostatic hyperplasia

Alpha 1 blockers • Prazosin • Terazosine • Doxazosine

Drugs that alter SNS function Centrally acting sympathoplegic drugs: • Methyldopa • Clonidine Adrenergic neuron blockers: • Guanethidine • Reserpine

Methyldopa; • First choice for hypertension in pregnancy • Has role in NE synthesis pathway. Coverted to alpha-methyl norepinephrine. This molecule is agonist of presynaptic alpha 2 ARs. • Decreases PVR, HR and CO • At the beginning of the treatment, sedation • In the chronic stage, mental lassitude, mental concentration difficulties (infrequently depression, nightmares, vertigo) • Could cause lactation (because of increased prolactin secretion)

Clonidine; • stimulates presinaptic alpha 2 ARs, decerases NE release, decreased HR and CO • Adverse effects, dry mouth and sedation • Should not be given to patients with mental depression • Concomitant use with TCAs inhibits the effect of clonidine • Sudden withdrawn of the drug could cause hypertensive crisis

Guanethidine; • Inhibits NE release from sympathomimetic nerve endings • Transported across the nerve membrane, concentrated in vesicles, replaces NE, causes depletion of NE • Adverse effects; postural hypotension and hypotension after exercise (particularly at the high doses) • Could cause hypertensive crisis in patients with pheochromacytoma • Its antihypertensive effect is decreased if used with TCAs

Reserpine; • Blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines • Results in depletion of NE, dopamine and serotonin in central and peripheral neurons • Decreases PVR and CO • Used at low doses in mild hypertension • Adverse effects; sedation, mental depression and extrapyramidal effects resembling Parkinson’s disease

Vazodilators • • Hydralazine Minoxidil Sodium Nitroprusside Diazoxide

Vasodilators • Relaxes smooth muscle of arterioles, decreases PVR • Nitrates and sodium nitroprusside relax both arteries and veins

Vasodilators Hydralazine relaxes only arteries Not efective (tachycardia occurs) Used in severe hypertension Adverse effects; headache, nausea, anorexia, palpitation, sweating and flushing • Angina or ischemic arythmia may be provoked in patients with ischemic heart disease • •

Vasodilators • Minoxidil, opens the K+ channels on the membrane of smooth muscle • Relaxes only arterioles • Tachycardia, palipitation, angina, edema • Headache, sweating, hypertrichosis • Also used in baldness

Vasodilators • Sodium nitroprusside, parenteral use (iv infusion • Hypertensive emergency • Vasodilatation both on arteries and veins • Activates GC, increased c. GMP, relaxation on vascular smooth muscle

Vasodilators • • • Diazoxide, parenteral use Effective and long acting Opens K+ channels, relaxes arterioles Used in hypertensive emergency Could cause hypotension (MI and stroke risk!) Inhibits insulin secretion from pancreas, used in the treatment of hypoglycemia secondary to insulinoma

Hypertensive emergency • Sodium nitroprusside (i. v. infusion) , first choice • Nifedipine, labetolol ve captopril

Preeclampsia: BP increase in pregnacy (30/15 mm. Hg compared to values before pregnancy) Or Diasolic pressure> 110 mm. Hg and proteinuria

Methyldopa, first choice Ca++ Ch bl. , labetolol or hydralazine

Dual Angiotensin Receptor–Neprilysin Inhibitors NEP (Neprilysin) hydrolyzes atrial natriuretic peptide, brain natriuretic peptide (BNP), C-type natriuretic peptide and, possibly, urodilatin The effects of NEP inhibition; Short term; vasodilation, enhanced diuresis, natriuresis and reduced sympathetic tone and aldosterone Long term; the induction of anti-inflammatory, antifibrotic, and antihypertrophic effects on cardiomyocytes or cardiac fibroblasts in vitro Dual neprilysin–angiotensin-converting enzyme inhibition with the first representative; omapatrilat lowered BP strongly enough for use in the treatment of patients with hypertension Increase in the risk of angioedema!!! Emerging Drug Classes and Their Potential Use in Hypertension Michel Azizi, Patrick Rossignol, Jean-S. bastien Hulot, Hypertension. 2019; 74: 1075 -1083.

Dual Angiotensin Receptor–Neprilysin Inhibitors Developing dual ARNIs (angiotensin receptor–neprilysin inhibitors); The prototype is LCZ 696, a single molecule synthesized by the co-crystallization of an ARB (angiotensin receptor blocker), valsartan, and the NEPi prodrug sacubitril (1: 1 molar ratio). Valsartan/sacubitril is approved for the treatment of heart failure with reduced ejection fraction (HFr. EF)

Soluble Guanylate Cyclase Stimulators Vericiguat soluble guanylate cyclase (s. GC) stimulator, thereby targeting the NO-s. GC-cyclic guanosine monophosphate (c. GMP) pathway

Nonsteroidal Dihydropyridine-Based Mineralocorticoid Receptor Antagonists Increased risk of hyperkalemia and worsening renal function with steroidal MRA (mineralocorticoid receptor antagonists), spironolactone and eplerenone, limited use Development of nonsteroidal dihydropyridine-based third- and fourth-generation MRA; dihydronaphthyridine finerenone (BAY 94 -8862) Aldosterone Synthase Inhibitors MRAs can cause reactive increases in components of the RAAS, particularly aldosterone Reducing the production of aldosterone, a new class of anti-aldosterone agents, an aldosterone synthase inhibitor (ASI), LCI 699 Emerging Drug Classes and Their Potential Use in Hypertension Michel Azizi, Patrick Rossignol, Jean-S. bastien Hulot, Hypertension. 2019; 74: 1075 -1083.

Activators of the Angiotensin-Converting Enzyme 2/ Angiotensin(1– 7)/ MAS Receptor Axis ACE 2 activators Ang (1– 7) analogs AT 2 receptor agonists, peptide and nonpeptide activators of the Mas receptor, and alamandine complexed with cyclodextrin Ferreira A J, Murça T M, Fraga-Silva R A, Castro C H, Raizada M K and Santos R A 2012 New cardiovascular and pulmonary therapeutic strategies based on the Angiotensin-converting enzyme 2/angiotensin-(1 -7)/mas receptor axis Int. J. Hypertens. 147825. Jiang F, Yang J, Zhang Y, Dong M, Wang S, Zhang Q, Liu F F, Zhang K and Zhang C 2014 Angiotensin-converting enzyme 2 and angiotensin 1 -7: novel therapeutic targets Nat. Rev. Cardiol. 11 413– 26

Centrally Acting Aminopeptidase A Inhibitors Existence of a functional RAS in the brain, controlling cardiovascular functions, and body fluid homeostasis An orally active prodrug of EC 33 (RB 150/QGC 001, firabastat) Inhibits brain APA activity, blocking the formation of brain angiotensin III (Marc Y, Llorens-Cortes C. The role of the brain renin-angiotensin system in hypertension: implications for new treatment. Prog Neurobiol. 2011; 95: 89– 103. )

Endothelin Receptor Antagonists The selective endothelin receptor antagonist, darusentan, a placebo corrected reduction in BP of ~ 11/6 and ~ 18/11 mm. Hg in phase II and III trials in participants with resistant hypertension (Black HR, Bakris GL, Weber MA, Weiss R, Shahawy. ME, Marple R, et al. Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo- controlled dose-ranging study. J Clin Hypertens (Greenwich). 2007; 9(10): 760– 9. Weber MA, Black H, Bakris G, Krum. H, Linas S, Weiss R, et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment -resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 374(9699): 1423– 31. ) A phase III placebo-controlled trial for selective ETA receptor antagonist aprocitentan (PRECISION study Clinical. Trials. gov NCT 03541174) the SONAR study for selective ETA receptor antagonist, atrosentan (Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa- Rotter R, Hou FF, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019; 393(10184): 1937– 47. ) Azzam O, Kiuchi MG, Ho JK, Matthews VB, Gavidia LML, Nolde JM, Carnagarin R, Schlaich MP. New Molecules for Treating Resistant Hypertension: a Clinical Perspective. Curr Hypertens Rep. 2019 Sep 10; 21(10): 80.

Natriuretic Peptide Receptor Agonists Inhibit degradation of endogenous natriuretic peptides for the treatment of HF and refractory or resistant hypertension. Synthetic natriuretic peptide receptor A (NPR-A) agonist PL-3994 (Sica D, Jordan R, Fischkoff SA. Phase IIa study of the NPR-A agonist, PL-3994, in healthy adult volunteers with controlled hypertension. J Card Fail. 2009; 15(6): S 67. ) Vasoactive Intestinal Peptide Receptor Agonists More selective and longer-acting analogue of VIP (PB 1046) dose-dependent effect on BP (Phase. Bio Pharmaceuticals Inc. 2015. PB 1046 (Vasomera™) in: clinical development pipeline. Available from: http: //phasebio. com/clinicaldevelopment-pipeline/vasomera/. Accessed 5 Jun 2019. )

Dopamine β-Hydroxylase Inhibitors Affect the final step of noradrenaline biosynthesis Novel, peripherally selective DβH inhibitor, BIA 5 -453, renamed as Etamicastat (Beliaev A, Learmonth DA, Soares-da-Silva P. Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethionebased inhibitors of dopamine beta-hydroxylase. J Med Chem. 2006; 49(3): 1191– 7. ) Azzam O, Kiuchi MG, Ho JK, Matthews VB, Gavidia LML, Nolde JM, Carnagarin R, Schlaich MP. New Molecules for Treating Resistant Hypertension: a Clinical Perspective. Curr Hypertens Rep. 2019 Sep 10; 21(10): 80.

Intestinal Na+/H+ Exchanger 3 (NHE 3) Inhibitor Highly selective NHE 3 inhibitor, Tenapanor Well-tolerated and reducing intestinal sodium absorption in two phase I studies (Rosenbaum DP, Yan A, Jacobs JW. Pharmacodynamics, safety, and tolerability of the NHE 3 inhibitor tenapanor: two trials in healthy volunteers. Clin Drug Investig. 2018; 38(4): 341– 51. ) Azzam O, Kiuchi MG, Ho JK, Matthews VB, Gavidia LML, Nolde JM, Carnagarin R, Schlaich MP. New Molecules for Treating Resistant Hypertension: a Clinical Perspective. Curr Hypertens Rep. 2019 Sep 10; 21(10): 80.

Sodium-Glucose Cotransporter 2 Inhibitors Oral hypoglycemic agents, increase the urinary elimination of glucose Several mechanisms for the antihypertensive actions of SGLT 2 inhibitors; modest diuretic effects, weight loss, and direct vascular effects leading to decreased arterial stiffness and vascular resistance (Sternlicht H, Bakris GL. Blood pressure lowering and Sodium-Glucose Co-transporter 2 inhibitors (SGLT 2 is): more than osmotic diuresis. Curr Hypertens Rep. 2019; 21: 12. ) Azzam O, Kiuchi MG, Ho JK, Matthews VB, Gavidia LML, Nolde JM, Carnagarin R, Schlaich MP. New Molecules for Treating Resistant Hypertension: a Clinical Perspective. Curr Hypertens Rep. 2019 Sep 10; 21(10): 80.

Vaccines Recent studies; AT 1 receptor vaccine ATRQβ-001 ATR 12181 (Chen X, Qiu Z, Yang S, Ding D, Chen F, Zhou Y, et al. Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals. Hypertension. 2013; 61(2): 408– 16. Li LD, Tian M, Liao YH, Zhou ZH, Wei F, Zhu F, et al. Effect of active immunization against angiotensin II type 1 (AT 1) receptor on hypertension & arterial remodelling in spontaneously hypertensive ats (SHR). Indian J Med Res. 2014; 139(4): 619– 24. )

Molecules Listed as Under Development B 244, undergoing a phase II study in patients with elevated blood pressure (Clinical. Trials. gov NCT 02998840) RMJH-111 b (magnesium citrate), a phase I/II safety and tolerability in subjects with essential hypertension, results have not been reported (Clinical. Trials. gov NCT 02822222). SP 20203, BAY s. GCstim and IT-103, in the development pipeline as of 2018 (Business Wire. 2018. Resistant Hypertension Drug Development Pipeline Study, H 1 2018 - Research. And. Markets. com. 9 June 2019]; Available from: https: //www. businesswire. com/ news/home/20180612006405/en/Resistant-Hypertension-Drug-Development-Pipeline-Study-H 1. Accessed 10 Jun 2019. Azzam O, Kiuchi MG, Ho JK, Matthews VB, Gavidia LML, Nolde JM, Carnagarin R, Schlaich MP. New Molecules for Treating Resistant Hypertension: a Clinical Perspective. Curr Hypertens Rep. 2019 Sep 10; 21(10): 80.

FDA Approved Drugs Byvalson (nebivolol and valsartan); Allergan; For the treatment of hypertension, Approved June 2016 Opsumit (macitentan); Actelion Pharmaceuticals; For the treatment of pulmonary arterial hypertension, Approved October 2013 Edarbi (azilsartan medoxomil); Takeda; For the treatment of hypertension, Approved February 2011 Edarbyclor (azilsartan medoxomil and chlorthalidone); Takeda; For the treatment of hypertension, Approved December of 2011 Amturnide (aliskiren + amlodipine + hydrochlorothiazide); Novartis; For the treatment of uncontrolled hypertension, Approved December 2010 Tekamlo (aliskiren + amlodipine); Novartis; For the treatment of hypertension, Approved August 2010