Recent advances in treatment of htn

Dr. Chandini Rao

1. Recent advances in treatment of Hypertension - Dr. Chandini Rao Moderator: Dr. Nicole Pereira

2. Introduction Drug therapy for HTN Drugs acting on RAAS - DRIs - ACEIs - ARBs - Vasoactive peptides - Vaccines against RAAS CCBs Diuretics Beta blockers Misc drugs Combination Rx Rx of Resistant HTN Contents

3. Intro - Hypertension is the most common modifiable risk factor for cardiovascular events. 50% of global adult population (60-69 yrs ) Prevalence further increased beyond age 70 Major risk factor for stroke, MI, heart failure, CKD etc Sustained increase in BP >/= 140/90 mmHg, based on an average >/= 2 seated BP readings during each of >/= 2 OPD visits

4. JNC criteria for diagnosis of HTN

5. Essential hypertension – no known cause (>90%) – hereditary component Secondary hypertension – secondary to an underlying cause (<10%) - chronic kidney disease, endocrine disorders, drugs, diet etc Control of BP leads to a reduction in events – Approximately 50% reduction in heart failure – Approximately 40% reduction in stroke – Approximately 20-25% reduction in MI Persistent/untreated HTN  LVH, coronary artery disease, HF, atrial fibrillation, renal insufficiency etc.

6. Treatment Life style modification - 1 st line salt restriction - DASH diet ( Dietary Approaches to Stop Hypertension ) smoking cessation weight loss physical exercise relaxation techniques limited alcohol consumption

7. DASH diet 2000-calorie-a-day diet: Daily & weekly eating plan goals Low in Na+ : Standard DASH diet – upto 2300mg/day Lower Na+ DASH diet – upto 1500mg/day Eating vegetables, fruits, and whole grains Including fat-free or low-fat dairy products, fish (salmon, tuna), poultry, nuts & vegetable oils. (high saturated fatty foods to be avoided) Limiting sugar-sweetened beverages and sweets . Limiting caffeine & alcohol Prevention of osteoporosis, cancer, stroke, diabetes

8. Drug therapy Anti- hypertensives – Drugs acting on RAAS 2. Calcium channel blockers 3. Diuretics Sympatholytics Adrenergic blockers Vasodilators

9. Resistant HTN – - 10-15 % of general hypertensive population - Uncontrolled BP on >/= 3 antihypertensive drugs of different classes , including a non-potassium sparing diuretic, at optimal doses, OR requiring >/= 4 drugs to achieve control Refractory HTN – 0.5% of hypertensive patients Uncontrolled BP on >/= 5 drugs Newer therapies – high-risk patients - treat HTN & co-morbidities

10. Drugs inhibiting RAAS

11. Direct Renin inhibitors

12. Current status Aliskiren – as effective as ACEI/ARBs in lowering BP (ALLAY, ALOFT & AVOID trials ). FDA – Combinations of aliskiren with ACEI/ARBs to be avoided in diabetic patients with renal impairment - combination with hydrochlorothiazide approved SPP635 – completed Phase IIa SPP676 SPP1148 SPP1234 SPP800 Phase I Pre-clinical phases

13. ACE inhibitors

14. Current status Stage 1: w/o comorbidities – 1 st line drugs (if thiazides are not being used) DOC for HTN a/w DM, LVH, CCF, post-MI, CAD, CKD, CVA Stage 2 : in combination with thiazides Drugs of the future: MC-4232 – combination of MC-1 and lisinopril MC-1: naturally occurring metabolite of vitamin B6  damage to the heart caused by ischemia Phase II trial ( MATCHED )  promising safety & efficacy profile (co-existing T2 DM & HTN) Phase III trial  

15. Angiotensin Receptor Blockers

16. Current status - Similar to ACEIs - As an alternative to ACEIs – intolerance to ACEIs - Important option in patients with concurrent disorders – heart failure, stroke, DM Losartan Candesartan Irbesartan Valsartan Telmisartan Eprosartan Olmesartan medoxomil

17. Newer drugs Azilsartan medoxomil Developed by Takeda – ‘ Edarbi ’ Prodrug  Azilsartan Approved by FDA (Feb’11) - treatment of essential HTN in adults. Approved in India in 2017. 3 major trials (24 wks duration) – @20, 40 or 80 mg doses  BP, with OD administration - better anti-hypertensive efficacy than olmesartan & valsartan - well-tolerated; headache & dizziness - better patient compliance Further studies required  

18. Dual ACE/NEP Inhibitors Neural endopeptidase (NEP) or Neprilysin - therapeutic target for HTN & other forms of CVD - degrades Natriuretic peptides (ANP, BNP), Angiotensin I, II endothelin , bradykinin etc Potentiation of ANP + attenuation of angiotensin II (NEP inhibition) (ACE inhibition) Natriuresis , Vasodilation, RAAS inhibition , Reduced sympathetic drive , Antiproliferative and antihypertrophic effects on the heart and vessels Control of BP Vasoactive peptides

19. Dual ACE/NEP inhibitors Sampatril - Halted in Phase II Omapatril ( OCTAVE, OVERTURE trials) – failed in Phase III Gemopatril – preclinical Mixanpril – preclinical Fasidotril – Phase III CGS30440 – preclinical Ilepatril – Phase IIb RAVEL – 1 tria l

20. Dual ARB/ NEP inhibitor LCZ696 ( Entresto ) – AHU377 ( Sacubitril ) + Valsartan (1:1) Currently approved for Rx of HF, not yet approved for HTN (off label) PARAMOUNT (Phase II trial) LCZ696 vs Valsartan Greater in SBP than valsartan PARADIGM ( Phase III trial) LCZ696 vs Enalapril Greater in symptoms, physical limitations & cardiac death due to HF PARAMETER LCZ696 vs Olmesartan Greater in BP, pulse pressure & arterial stiffness in elderly

21. Dual Angiotensin (AT1) receptor/ Endothelin inhibition & NEP/ Endothelin Converting Enzyme (ECE) inhibition Big ET-1 (39 AA precursor) Endothelin (ET-1) Endothelin -converting enzyme (ECE) Ang II ADH Thrombin CKs etc Most potent vasoconstrictor Vascular diseases of several organ systems Antagonists - Rx of PAH ( Ambrisentan & Macitentan – recently approved) Rx of Sys HTN? ( Darusentan , TBC3711 trials)

22. ET-1 antagonism in Rx of Systemic HTN ET-1 R antagonist + ARB ECE inhibitor + NEP inhibitor Dual ET-1 R/ARB blocker PS433540 ( Sparsentan ) – Phase II trial for stage 1-2 HTN (200, 400 & 800mg) - BP compared to placebo & also to Irbesartan (in Phase III trial for Rx of FSGS)  

23. Dual ECE/NEP inhibitor (only preclinical data available) Daglutril (SLV-306) – prodrug oral administration  KC-12615 (active metabolite) Diabetic rat - BP, proteinuria & prevent nephrosclerosis as effectively as the captopril. - safe & well-tolerated Heart failure patients (multicentre RCT) - pulmonary and right atrial pressures without affecting systemic arterial pressure, cardiac output, or heart rate Others - SLV336 and SLV338  

24. Aldosterone Mineralocorticoid Receptor (MR) - principal effector - Cortical collecting duct Na+ & water reabsorption & K+ loss  BP MRs in extra-adrenal tissues (heart & blood vessels)  HTN & CVD Aldosterone inhibition  additive effect to Ang II inhibition  

25. Anti-Aldosterone agents Mechanism of action:

26. MR antagonists Spironolactone 1 st MR antagonist Current status – Add-on drug in Resistant HTN - Rx of HF - Primary & Secondary aldosteronism Lack of specificity (also binds to progesterone & androgen Rs ) - not well tolerated Eplerenone - more selective, but less potent with short T1/2 Canerenone – active metabolite of spironolactone, limited use Non-steroidal MR antagonists Finerenone (BAY94-8662) – more selective to MR - greater in BP vs Eplerenone - under phase III trials for Rx of CHF & CKD  

27. Aldosterone Synthase Inhibitors Aldosterone synthase – - catalyses the final three rate-limiting steps of aldosterone synthesis - CYP11B2 gene Preclinical studies of aldosterone synthase inhibition – Fadrozole & FAD286 – tested preclinically in rats - inhibit aldosterone synthase & BP - urine & plasma aldosterone levels (FAD286) - atherosclerosis - lack specificity; also inhibits 11-β-hydroxylase  inhibition of cortisol synthesis  

28. Clinical studies of aldosterone synthase inhibition – LCI699 – Greater selectivity for inhibition of CYP11B2 (> CYP11B1) - less influence on cortisol 1st orally active aldosterone synthase inhibitor tested in humans . 4 Phase II trials - Lack of selectivity @ higher doses (>3mg) – unlikely to supplant MR blockers clinically. Pyridyl - or isoquinolinyl -substituted indolines and indoles - recently synthesized - More selective than LCI699 for CYP11B2 - currently tested as Rx for mineralocorticoid-dependent CVD & renal disease

29. Disadv of aldosterone synthase inhibitors hyperkalemia and hyponatraemia . long-term effect on kidney function is not known . Current status of Aldosterone blockers – Rx of HTN: used less in most countries 4 th /5 th line therapy in resistant HTN More selective agents are required  

30. Drugs activating Counter-regulatory RAAS pathway AT2 R agonists ACE 2 activators Ang (1-7) analogs Nonpeptide activators of the Mas R Alamandine ( complexed with cyclodextrin ) AT2 R Vasodilatation Antiproliferative action Fetal tissue development Apoptosis

31. AT2 Receptor agonists Compound 21 (C21) – - 1 st orally available, specific, and selective AT2 R agonist - Anti-inflammatory , antifibrotic and antiapoptotic properties - Anti-inflammatory Rx & TGF-β guided immunosuppression  innovative strategy for the Rx of high BP - Effect on the vascular wall C21 + ARB in HTN rats  collagen content in vessels & improved their elastic properties (w/o additional effect on BP) - also improved MI - Other effects: Renoprotective Neuroprotective - Preclinical phase  

32. ACE2 agonists XNT & DIZE – small molecule ACE2 activators - BP, improve myocardial function, and reverse myocardial and perivascular fibrosis in the SHR Recomb human ACE2 (rhACE2) - BP in SHR - slow the progression of diabetic nephropathy - Phase I study – suppression of circulating Ang II levels after a single iv injection of rhACE2 with no effect on BP (& no major a/e)  

33. Ang (1-7) analogues Peptide analogues - NorLeu 3 -Ang 1–7, CGEN-856 Cyclic analogue – PanCyte CGEN-856 - BP in SHR Other peptide analogues – tested for pulmonary hypertension and pulmonary diseases Encapsulated Ang ( 1–7 ) – - hydroxyl-propyl‑β- cyclodextrin encapsulation - BP , HR & myocardial hypertrophy in SHR - inflammation in carotid atherosclerotic plaques - ameliorated type 2 diabetes - expected to enter the clinical phase of development soon  

34. Non-peptide Mas Receptor agonist AVE-0991 Very promising experimental data only available nonpeptide Mas receptor agonist Besides blood pressure-lowering effects, AVE-0991 seems to exert blood pressure-independent renoprotective effects as well Preclinical phase

35. Alamandine ( complexed with cyclodextrin ) Ala 1 -Ang(1–7 ) - novel member of the Ang peptide family Isolated from human plasma and rat heart Alamandine is similar in structure to Ang (1–7)  Antihypertensive , antifibrotic , and central cardiovascular effects Mas-related G-protein-coupled receptor Alamandine /HPβCD – Alamandine / β - cyclodextrin inclusion complex

36. Centrally acting Aminopeptidase Inhibitiors

37. APA inhibitor RB150 Crosses BBB Block Ang III formation Diuresis & sympathetic tone BP Combination with systemic RAAS inhibitor (ACEI)  potentiated RB-150 induced BP & CVD disease risk. Phase I  

38. Vaccines against RAAS AngQb x Ang II derived peptide - Phase 1a: Ang II–specific antibodies in all subjects - Phase IIa : 2 doses of AngQb  significantly mean ambulatory daytime & early morning BP (high-dose group) - mild a/e - T1/2: 4 months need for daily dosing of anti- htn medications - adherence. ATRQB-001 & ATR12181 - x AT1 R  

39. Calcium channel blockers

40. L-type - main targets of CCBs - cardiac, smooth muscles & endocrine cells T-type – neurons & endocrine cells - pacemaker cells, atrial cells and purkinje fibers N-/P-/R type – brain, neuron & pituitary gland

41. Clevidipine ( Cleviprex ) 3 rd gen (L-type) CCB Approved as IV infusion for acute pre-op & post-op HTN in adult cardiac surgery patients. Easily titratable – rapid onset & short duration of action 3 large Phase III: - more effective than NTG or sodium nitroprusside ( peri -op) & as effective as IV Nicardipine (post-op) - acute severe HTN Safe & well-tolerated in cardiac surgery

42. Combined L-type & T-type Ca + channel blocking action Newly developed DHP CCBs - M anidipine , Nilvadipine , Benidipine , Efonidipine & Benzimidazole mibefradil Greater efficacy than classical L-type CCBs in controlling BP Adv – vasodilatory properties - minimum reflex tachycardia - renal protection - very less risk of edema ( compared to L-type CCBs) Mibefradil More desirable profile - as part of combination therapy Further study required to asses risk/benefit ratio

43. Ca 2+ NE Pure L-type Ca 2+ channel blockers like nifedipine , amlodipine Ca 2+ Vessels Vessels Heart Kidney α 1 adrenoceptors β 1 adrenoceptors α 1 & β 1 adrenoceptors Vasoconstriction Vasoconstriction ↑ Cardiac contraction ↑ Heart rate ↓ Renal blood flow Renin secretion L-type Ca 2+ channels N-type Ca 2+ channels Cilnidipine Norepinephrine Combined L- & N-type calcium channel blocking action: Cilnidipine (4 th gen CCB)

44. ACHIEVE ONE CLEARED CARTER Cilnidipine od 24 hr BP control As effective as traditional CCBs Indian study ESC 2014 Cilnidipine vs Amlodipine Cilnidipine – greater in BP & prevention of ankle edema CLEARED Cilnidipine Reno protective effects in DM proteinuria in DM patients (compared to Amlodipine) ACHIEVE ONE CLEARED CARTER Cilnidipine od 24 hr BP control As effective as traditional CCBs Indian study ESC 2014 Cilnidipine vs Amlodipine CLEARED Cilnidipine Reno protective effects in DM Current status 1st line drug for HTN (as alt to Thiazides) Combination therapy

45. Diuretics LOOP DIURETICS THIAZIDES THIAZIDE-LIKE AGENTS POTASSIUM-SPARING DIURETICS

46. LOOP DIURETICS – Furosemide Bumetanide Torsemide Ethacrynic acid THIAZIDE DIURETICS – Hydrochlorothiazide Chlorthiazide Trichlormethiazide Benzthiazide Hydroflumethiazide Epitizide Methychlorthiazide Bendroflumethazide Polythiazide THIAZIDE-LIKE DIURETICS – Chlorthalidone Indapamide Metolazone Xipamide POTASSIUM-SPARING DIURETICS – Spironolactone Amiloride Triamterene Eplerenone

47. Current status Thiazides Loop K+ - sparing 1 st choice in Rx of essential HTN ( esp in elderly) Severe HTN associated with CRF, CCF Used with thiazides to prevent K+ loss Most of the outcome trials favour CTD over HCTZ (HDFP, MRFIT, SHEP, ALLHAT) – 1 st line drug in resistant HTN Indapamide – best thiazide-type diuretic to be considered for HTN Spironolactone most effective add-on drug for resistant HTN.

48. β blockers

49. Newer generation beta blockers (3 rd gen beta blockers) V asodilating effects Carvedilol – most evidence for morbidity & mortality in HF & acute MI patients Adv – better tolerated - do not risk of DM, atherogenic dylipidemia or weight gain Nebivolol – Recently approved β 1 selective blocker with NO enhancing effects Superior therapeutic profile formation of atherosclerosis – benefit in HF SENIORS trial (in HF Rx) - mortality & morbidity irrespective of LVEF  

50. Natriuretic Peptide Receptor Agonists ANP & BNP  N atriuretic , vasodilatant , and antiproliferative effects via NPR-A Rx of HTN, heart failure, stroke PL3994, MK-7145 & MK-8150 - clinical phase of development for HTN PL3994 Phase I trial: single SC dose  natriuresis & diuresis  in BP (compared to placebo) Phase II trial ( ≥1 antihypertensive medications): synergistic action with ACEI  as an adjunct to standard therapy in patients with refractory or resistant HTN or HF  

51. Vasoactive Intestinal Peptide Receptor Agonist VIP - neuropeptide with vasodilator and positive inotropic / chronotropic properties - mediated via the VPAC1 and VPAC 2 Vasomera (PB1046) - a stable long-acting form of VIP, selective for VPAC2 - BP and improves inotropic and lusitropic properties of the heart in animal models - safe and well-tolerated after single SC or IV injections (Phase I) - SC Vasomera : once weekly dosing regimen  chronic use in the home setting . - Phase II  

52. Intestinal Na+/H+ exchanger 3 inhibitor Na + /H +  exchangers – NHE2, NHE3, and NHE8 - apical regions of the enterocyte - transport Na+ from the intestinal lumen into enterocytes Tenapanor - selectively inhibits NHE3 - BP & urinary sodium excretion in rat models. - may be a useful alternative or adjunct to dietary Na+ reduction or diuretics in the Rx of HTN - Phase I  

53. Dopamine β -hydroxylase inhibitor D β H - catalyzes hydroxylation of dopamine  noradrenaline  sympathetic activation  BP 1st, 2 nd & early 3rd generations DβH inhibitors ( D isulfiram , Fusaric acid, and Nepicastat )  CNS a/e not clinically used Etamicastat (BIA 5–453) - potent and reversible inhibitor of DβH - selective for peripheral DβH (orally) - BP & prolonged survival in animal models - significantly lowered 24-hr ambulatory BP in HTN patients  

54. Soluble epoxide hydrolase inhibitors Soluble epoxide hydrolase (s-EH) – catalyzes the conversion of multiple lipid epoxides to the corresponding dihydroxy lipids . Inhibitors of s-EH  BP, cardiac hypertrophy prevent atherosclerosis & aneurysm insulin resistance, in animal models AR9281 – potent & selective inhibitor of s-EH - BP improve vascular function, renal damage & improve glycemic parameters in rat models - RCT in healthy volunteers: BP (further studies needed)  

55. Phosphodiesterase inhibitors Rx of PAH for years - PDE-3 I ( Cilostazol ) PDE-5I (Sildenafil, vardenalfil , tadalafil ) Not shown significant results in improving sys HTN Tadalafil - Pleiotropic CV effects - under trial for exceptional cases of resistant hypertension KD027 (PDE-5 I) - Phase II studies for hypertension treatment

56. Drugs under trial for HTN Class Drug Phase DRI SPP636 IIa ACEI MC-4232 III Dual ACE/NEP inhibitor Fasidotril Ilepatril III IIb Dual ARB/NEP inhibitor LCZ696 ( Entresto ) III Dual ET-1/NEP inhibitor PS433540 ( Sparsentan ) II Dual ECE/NEP inhibitor Daglutril (SLV-306) II Anti-aldosterone agents Finerenone III AT2 R agonist C21 Preclinical ACE2 agonists XNT & DIZE rhACE2 Preclinical Phase I Ang (1-7) analogues CGEN-856 Encapsulated Ang (1–7) Preclinical Preclinical

57. Drugs under trial ( contd ) Class Drug Phase Non-peptide Mas Receptor agonist AVE-0991 Preclinical Alamandine Alamandine /HPβCD Preclinical APA inhibitor RB 150 Preclinical Natriuretic Peptide Receptor Agonists PL-3994 II VIP R agonist Vasomera II Intestinal Na+/H+ exchanger 3 inhibitor Tenapanor I Dopamine β -hydroxylase inhibitor Etamicastat I PDE inhibitors Tadalafil KD027 II Vaccines x Ang II: x AT1 R: AngQb ATRQB-001 & ATR12181 II Preclinical

58. Newly approved drugs Class Drug DRI Akiskiren ARB Azilsartan medoxomil CCBs: L-type blockers Combined L- & T- type blockers Combined L- & N-type blockers Clevidipine Manidipine , Nilvadipine , Benidipine , Efonidipine & Benzimidazole mibefradil Cilnidipine Β blockers: 3 rd gen Carvedilol & Nebivolol

59. Combination Rx Dual combinations Preferred - ACEI or ARB + DHP CCB ACEI or ARB + diuretic Recently approved – RAAS inhibitor + CCB Olmesartan + Amlodipine ( Azor ) RAAS inhibitor + Diuretic Azilsartan + Chlorthalidone ( Edarbycyclor ) Triple combinations – VAL+AML+HCTZ OM+AML+HCTZ (TRINITY trial) ALI+AML+HCTZ blocker + diuretic Metoprolol + HCTZ (Lopressor HCTZ) Thiazide + K-sparing diuretic HCTZ + Triamterene ( Maxzide )  

60. Rx of Resistant HTN Patients already on 3 anti- htn drugs: ACEI/ARBs + CCB + Thiazide diuretic Chlorthalidone (twice as potent as HCTZ) - initial Rx Add-on drugs : MR antagonists – Spironolactone (4 th agent) - if serum K+ level </= 4.5 mmol /L BP still high – Vasodilating β blockers (5 th agent) sympatholytics or direct vasodilators Newer drug Rx - under trial

61. Interventional treatments Renal denervation Baroreflex activation Rx Carotid body ablation A-V fistula Neurovascular decompression Renal artery stenting

62. References Goodman & Gilman Progress in medicine – Pritam Gupta New Approaches in the Treatment of Hypertension - Suzanne Oparil, Roland E. Schmieder. Circulation research http:// circres.ahajournals.org Aldosterone synthase inhibitors in hypertension: current status and future possibilities – Milan Hargovan & Albert Ferro. JRSM Cardiovascular disease www.ncbi.nlm.nih.gov/pmc/articles/PMC3930157 / ACE Inhibitors: A Comprehensive Review – Pradeep K Arora, Ashish Chauhan https :// www.researchgate.net/publication/236875020 6) New Developments in the Pharmacological Treatment of Hypertension: Dead- End or a Glimmer at the Horizon ? – Ludovit , Romana , Fedor . Current Hypertension reports. www.ncbi.nlm.nih.gov/pmc/articles/PMC4412646 / 7) Current perspectives on combination therapy in the management of hypertension – Samir, Houssam , Bassem . Integrated blood pressure control. www.ncbi.nlm.nih.gov/pmc/articles/PMC3699293 /