recent advances in treatment of htn
TRANSCRIPT
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Recent advances in treatment of Hypertension
- Dr. Chandini Rao Moderator: Dr. Nicole Pereira
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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
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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
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JNC criteria for diagnosis of HTN
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• 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.
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Treatment
Life style modification - 1st line
salt restriction - DASH diet (Dietary Approaches to Stop Hypertension) smoking cessation weight loss physical exercise relaxation techniques limited alcohol consumption
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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
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Drug therapy
Anti-hypertensives –
1. Drugs acting on RAAS2. Calcium channel blockers3. Diuretics4. Sympatholytics5. Adrenergic blockers6. Vasodilators
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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
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Drugs inhibiting RAAS
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Direct Renin inhibitorsDRI
1st generation
Peptide analogues of renin
2nd generationPeptide mimetics – CGP2928RemikirenEnalkirenZankiren
3rd generation
Aliskiren
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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
SPP676SPP1148
SPP1234 SPP800
Phase I
Pre-clinical phases
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ACE inhibitors
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Current status
• Stage 1: w/o comorbidities – 1st 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
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Angiotensin Receptor Blockers
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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
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Newer drugsAzilsartan 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
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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
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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 trial
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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
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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 IIADHThrombinCKs 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)
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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)
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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
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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
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Anti-Aldosterone agentsMechanism of action:
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MR antagonistsSpironolactone• 1st 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 toleratedEplerenone - more selective, but less potent with short T1/2Canerenone – 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
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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
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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
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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- 4th/5th line therapy in resistant HTN- More selective agents are required
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Drugs activating Counter-regulatory RAAS pathwayAT2 R agonistsACE 2 activatorsAng (1-7) analogsNonpeptide activators of the Mas RAlamandine
(complexed with cyclodextrin)
AT2 R• Vasodilatation• Antiproliferative
action• Fetal tissue
development• Apoptosis
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AT2 Receptor agonists
• Compound 21 (C21) – - 1st 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
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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)
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Ang (1-7) analogues• Peptide analogues - NorLeu3-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
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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
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Alamandine (complexed with cyclodextrin)
• Ala1-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
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Centrally acting Aminopeptidase Inhibitiors
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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
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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
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Calcium channel blockers
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• 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
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Clevidipine (Cleviprex)
• 3rd 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
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Combined L-type & T-type Ca+ channel blocking action
• Newly developed DHP CCBs - Manidipine, 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
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Ca2+
NE
Pure L-type Ca2+
channel blockers like nifedipine,
amlodipine
Ca2+
Vessels Vessels Heart Kidneyα1 adrenoceptors
β1 adrenoceptors
α1 & β1 adrenoceptors
•Vasoconstriction
Vasoconstriction
•↑ Cardiac contraction•↑ Heart rate
• ↓ Renal blood flow• Renin secretion
L-type Ca2+
channels
N-type Ca2+ channelsCilnidipine
Norepinephrine
Combined L- & N-type calcium channel blocking action:Cilnidipine (4th gen CCB)
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ACHIEVE ONE CLEAREDCARTER
Cilnidipine od 24 hr BP controlAs effective as traditional CCBs
Indian studyESC 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)
Current status• 1st line drug for HTN (as alt to Thiazides) • Combination therapy
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Diuretics
LOOP DIURETICSTHIAZIDESTHIAZIDE-LIKE AGENTSPOTASSIUM-SPARING DIURETICS
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LOOP DIURETICS –FurosemideBumetanideTorsemideEthacrynic acid
THIAZIDE DIURETICS –HydrochlorothiazideChlorthiazideTrichlormethiazideBenzthiazideHydroflumethiazideEpitizideMethychlorthiazideBendroflumethazidePolythiazide
THIAZIDE-LIKE DIURETICS –ChlorthalidoneIndapamideMetolazoneXipamide
POTASSIUM-SPARING DIURETICS –SpironolactoneAmilorideTriamtereneEplerenone
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Current status
Thiazides Loop K+ - sparing1st 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) – 1st line drug in resistant HTN
• Indapamide – best thiazide-type diuretic to be considered for HTN
• Spironolactone most effective add-on drug for resistant HTN.
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β blockers
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Newer generation beta blockers(3rd gen beta blockers)
• Vasodilating 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 β1 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
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Natriuretic Peptide Receptor Agonists• ANP & BNP Natriuretic, 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
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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
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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
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Dopamine β-hydroxylase inhibitor • DβH - catalyzes hydroxylation of dopamine noradrenaline sympathetic activation BP
• 1st, 2nd & early 3rd generations DβH inhibitors (Disulfiram, 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
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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)
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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
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Drugs under trial for HTN
Class Drug PhaseDRI SPP636 IIa
ACEI MC-4232 III
Dual ACE/NEP inhibitor FasidotrilIlepatril
IIIIIb
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 & DIZErhACE2
PreclinicalPhase I
Ang(1-7) analogues CGEN-856Encapsulated Ang (1–7)
PreclinicalPreclinical
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Drugs under trial (contd)
Class Drug PhaseNon-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 TadalafilKD027 II
Vaccines x Ang II: x AT1 R:
AngQbATRQB-001 & ATR12181
IIPreclinical
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Newly approved drugs
Class Drug
DRI Akiskiren
ARB Azilsartan medoxomil
CCBs: L-type blockersCombined L- & T- type blockers
Combined L- & N-type blockers
ClevidipineManidipine, Nilvadipine, Benidipine, Efonidipine & Benzimidazole mibefradilCilnidipine
Β blockers: 3rd gen Carvedilol & Nebivolol
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Combination RxDual 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 + diureticMetoprolol + HCTZ(Lopressor HCTZ)Thiazide + K-sparing diureticHCTZ + Triamterene (Maxzide)
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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 (4th agent) - if serum K+ level </= 4.5 mmol/L
• BP still high – Vasodilating β blockers (5th agent) sympatholytics or direct vasodilators
• Newer drug Rx - under trial
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Interventional treatments
1. Renal denervation2. Baroreflex activation Rx3. Carotid body ablation4. A-V fistula5. Neurovascular decompression6. Renal artery stenting
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References1) Goodman & Gilman2) Progress in medicine – Pritam Gupta3) New Approaches in the Treatment of Hypertension - Suzanne Oparil, Roland
E. Schmieder. Circulation research http://circres.ahajournals.org4) Aldosterone synthase inhibitors in hypertension: current status and future
possibilities – Milan Hargovan & Albert Ferro. JRSM Cardiovascular disease www.ncbi.nlm.nih.gov/pmc/articles/PMC3930157/5) ACE Inhibitors: A Comprehensive Review – Pradeep K Arora, Ashish Chauhan https://www.researchgate.net/publication/2368750206) 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/