Recent advances in Hypertension Management

Speaker: Dr.Rachana Menon

Contents

Definition Pathophysiology Management of Hypertension Newer Antihypertensives Hypertensive Emergency Recent guildelines

Hypertension

Rise of blood pressure above the normal level is called hypertension

COPVR

Hypertension (Contd.)

European Society of Hypertension

European Society of Cardiology

World Health Organization-International Society of

Hypertension

British hypertensive society

Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure

(JNC 8)

SBP is ≥150 mm Hg DBP is ≥90 mm Hg

Why to treat HTN?

2014 GUIDELINES-

JNC 8

Antihypertensives

• Diuretics– Thiazide– Loop diuretics– Aldosterone antagonists– K-sparing

• Adrenergic inhibitors– Peripheral agents– Central (α-agonists)– alpha -blockers– beta-blockers– Alpha+beta-blockers

• Direct Vasodilators

• Calcium channel blockers– Dihydropyridine

– Non dihydropyridine

• ACE-inhibitors

• Angiotensin-II blockers

Historical Perspective

1898 – Tiegerstedt and Bergman

1934 – Goldblatt and his colleagues

1940 – Braun-Menéndez - Angiotensionogen

1950s – Two forms of angiotensin were recognized

1970s – The formation of AngI or blocked AngII receptors

RATE LIMITING STEP

What causes Renin release

HypotensionHypovolemia Strech Receptors

Sympathetic tone

AT 1 Receptor AT 2 Receptor

Vasoconstriction Vasodilation

Cell growth & Proliferation Anti-growth

Promotes Reabsorption of Na & Water Natriuresis

Produces Free radicalsProduces Nitric oxide (Vasodilation)

Induces growth factors , Endothelin and Plasminogen Activator Inhibitor 1(PAI-1)

Preprorenin >>> prorenin >>> renin

The (Pro) Renin Receptor

ORGAN DAMAGE

Compelling Indications for Certain Drug Classes

 Recommended Drugs

Compelling Indication

Diuretic ACEI BB ARB CCBAldoANT

Heart failure ₀ ₀ ₀ ₀   ₀

Post-MI   ₀ ₀     ₀

High coronary disease risk

₀ ₀ ₀   ₀  

Diabetes ₀ ₀ ₀ ₀ ₀  

Chronic kidney disease

  ₀   ₀    

Recurrent stroke prevention

₀ ₀        

Newer agents Structure Pharmacokinetics

Adverse effects

Dose

Lisinopril Carboxy 30% BAt1/2 ~12 h

5-40 mg

Benazepril Ester 37% BAt1/2 11 h

5-80 mg

Fosinopril phosphinate BA 36%t1/2 11.5 h

10-80 mg

Trandolapril Ester 10% BAbiphasic elimination kinetics t1/2 11 h

1-8 mg

Quinapril Esterases t1/2 25 h 5-80 mg

Moexipril Esterases ~13- BAt1/2

12 h

7.5-30 mg

Perindopril Esterases ~35% BA 2-16 mg

CoughHypotensionHyperkalemiaAngiodema

ACE Inhibitors – Clinical Summary

Normalise BP in ~50% of patients with mild to moderate HTN.

Left Ventricular Systolic Dysfunction Acute Myocardial Infarction DM and RF

Antacids – BA

Capsaicin – WORSEN Cough

NSAIDs - response to ACE inhibitors

K+-sparing diuretics and K+ supplements may exacerbate

hyperkalemia

plasma levels of digoxin /lithium

Hypersensitivity reactions to allopurinol.

Newer ARB – AZILSARTAN

AT1 receptor anatagonist

Azilsartan medoxomil – pro drug Hydrolyzed to the active moiety azilsartan, a BA 60% t½

12 hours The other major metabolite, M-II, is formed via CYP2C9 40 or 80 mg once daily

2011, FDA approved- Mild/ Moderate Htn

Therapeutic Uses of AngII Receptor Antagonists

ARB’s Indication Dose Clinical trial

Irbesartan Diabetic nephropathy/ AF

300 mg IDNT (2003)

Losartan Diabetic nephropathy/ Stroke/ HF/ Portal HTN

40/80 mg ELITE study LIFE (1998)

Valsartan HF/ Htn/ Post MI 80/160 mg ValHeFt(2001)

Telmisartan Htn/HF 40/80 mg ONTARGET (2008)

Candesartan PreHtn/ HF 4,8,16,32 mg

CHARM-Additive(2007)

Direct Renin Inhibitors

LMW non-peptide that is a potent competitive inhibitor of renin

ALISKIREN

Direct Renin Inhibitors (Contd.)

U.S. FDA in 2007 for the treatment of hypertension

150 or 300 mg/day – Monotherapy/ FDC

t1/2 is 20-45 hours., BA poor, Fatty meal

Metabolism- CYP3A4

Elimination is mostly as unchanged drug in faeces

Marketing stopped after

July 2012

AVOID66

Type 2 diabetes with

hypertension and proteinuria

Allkiren (150 → 300 mg) + losartan (100 mg)

Placebo + losartan (100 mg)

24 weeks

PrimaryChange in UACRSecondaryProportion of patients with ≥ 50% reduction in UACR

Change in BP

 

ALOFT67

Stable heart failure and raised BNP

levels (> 100 pg/ml)

Allkiren (150 mg) + standard therapy (including ACE inhibitor or ARB, and beta-blocker

Placebo + Standard therapy

12 weeks

PrimarySafety and tolerabilitySecondaryChange in BNPChange in NT-proBNPChange in plasma aldosterone

ALLAY80

Overweight with hypertension and LV hypertrophy

465

Allskiren (150 → 300 mg)

Losartan (50 → 100 mg)

Allkiren/losartan (150 → 300/50 → 100 mg)

36 weeks

PrimaryChange in LV mass indexSecondaryProportion of patients with ≥ 50% reduction in UACR

Change in BP

 

AGELESS85

65 years of age, with systolic

hypertension (140 to < 180 mmHg

912

Allskiren (150 → 300 mg) + optional HCT and amlodipine

Rampiril (5 → 10 mg) + optional HCT and amlodipine

36 weeks

PrimaryChange in SBP at Week 12 (i.e. monotherapy phase)SecondaryChange in BP at study endpointSafety and tolerability

DIRECT RENIN INHIBITORS UNDER TRIAL

SPP635 – Mild to Moderate Hypertension-2006

- Phase II Study to Investigate the Efficacy and Safety

of SPP635 in Diabetic and Hypertensive Patients With

Albuminuria

SPP1148 – Preclinical trial 2007

SPP800 A – Preclinical trial 2008

AT2 RECEPTOR AGONIST

• Nonpeptidic, orally active AT2R agonists

• Potential novel class of drugsPromising target

-HTN

-STROKE

-MYOCARDIAL FIBROSIS

Calcium Channel Blockers

DIHYDROPYRIDINES

SHORT ACTING• Nifedipine Nicardipine Nimodipine  

INTERMEDIATE ACTING • Nisoldipine Nitrendipine Isradipine Lacidipine Clinidipine

Lercanidipine

LONG ACTING • Felodipine Benidipine

NON DIHYDROPYRIDINE

SHORT ACTING • Verapamil Diltiazem

LONG ACTING • Bepridil

Calcium channel blockers

Manidipine Nilvadipine BenidipineEfonidipineMibefradil

T + L TYPE Ca channel blockers

2nd generation

Newer Calcium channel Blockers

CLINIDIPINE MEBUDIPINE DIBUDIPINE AZELNIDIPINE

Superior Endothelia function

Urinary protein excretion -GFR

LDL , Vasodilation- Efonidipine

Vasodilatory edema. –Mibefradil

Azelnidipine – 3rd generation

Azelnidipine is the newest Ca2+ channel blocker

Ltype channel

Noninferiority against amlodipine in phase III clinical

trials. –Mid to Moderate HTN

No increase in HR –LVDF

Long duration of action – 24hrs

Headache and hot facial flushes

Diabetic patients-CMMI

ATHEROSCLEROSISANTI OXIDANT

CLINIDIPINE – 4th Generation

Alone or in combination with other drugs

DOC- elderly with isolated systolic hypertension

Angina pectoris

Treatment of supraventricular

arrhythmias

- Atrial Flutter

- Atrial Fibrillation

- Paroxysmal SVT

Other uses

Clevidipine Inhibits L-type calcium channels in a voltage-dependent

manner  rapid and dose dependent Arterial vasodilation and lesser effects on venodilation highly plasma protein bound Metabolism-Hydrolysis Half-life i-15 minutes  IV formulation – lipid emulsion

AF and sinus tachycardia – ADR

Escape trialVelocity trial

Post-CABG patients

Protection – MI/ renal changes

Hypertension crisis

Advantages

Current status in elderly

Preferred in elderly hypertensives

They have stroke prevention potential next to ACE

inhibitors in reducing albuminuria

Slowing disease progression in hypertensive / diabetic

nephropathy

Cyclosporin induced hypertension in renal transplant

Adrenergic inhibitors

Drug MOA Kinetics ADR Clinical trial

Nebevilol10 mg

Β1-antagonist endothelial NO-mediated vasodilator activity

Highly protein-boundt ½- 10.3 hourExtensive first pass metabolism

headache, dizziness, fatigue, nasopharyngitis

Metabolic syndrome

Celiprolol β1 antagonist(weak)vasodilating-NO production

BA- 30%. unmetobolized. excretion is renal.

Same

Bucindolol HDL

β1,2 -non-selective α1 - weak

Well absorbed after oral. protein bound (87%), t1/2 of ~8 hMetabolism- liver

Same BEST-survival benefit

Carvedilol-Anti inflammatoryAntioxidantMembrane stabilizing activityVasodilation

β1,2 - α1 - ANTAGONIST

95% protein bound t1/2 is 7metabolism by the liver

Hypotension-higer doses

COPERNICUS-reduces mortality / attenuates MIcimetidine, quinidine,

fluoxetine, and paroxetine

Alpha antagonist

Prasozin

Terasozin

Doxazosin

Phentolamine

Phenoxybenzamine

HTN CRISIS

•Diagnosis and treatment of

pheochromocytoma

•Clonidine withdrawal

syndrome

•Cheese reaction

Postural hypotension

Combination with beta blocker

Diuretics

Epelerenone

Spironilactone

Amiloride

Thaizides

Eplerenone Greater selectivity for the MR.

Bind to mineralocorticoid receptors and blunt

aldosterone activity

Currently approved for use only in hypertension

Experimental effects of eplerenone on aldosterone-associated cardiovascular and renal dysfunction

Blockade in vivo of renal effects of hormone

Reduced vascular inflammation and fibrosis

Reduced post-MI fibrosis (but not healing)

Reduced renal damage in experimental models of hypertension

Eplerenone (Contd.)

Metabolized via the CYP3A4 pathway half-life -4 to 6 hours Hypertension trials- EPHESUS trial RALES trial T ½ - 5hrs .Good BA 25- 50mg

 Heart failure secondary to myocardial infarction

Characteristics Spironolactone Eplerenone

Clinical indication

Severe (NYHA class III-IV) CHF with LV systolic dysfunctionEssential hypertensionPrimary hyperaldosteronism

Severe (NYHA class III-IV) CHF after myocardial infarctionEssential hypertension

Receptor binding affinity (aldosterone = 1)

1.1 X 10-1 5.1 X 10-3

Sex-steroid receptor cross-reactivity

Yes Minimal

Metabolism HepaticCytochrome P450, isoenzyme CYP3A4

Conversion to metbolites for effect

Yes No

Half-life, h 1.4 4 to 6Excretion Renal and bile Renal and GI

AdministrationWith food to maximize absorption

With or without food

Recommended dose, mg/dHypertension, 50 - 100; CHF, 25 - 200

Hypertension, 50 - 100; CHF, 25 -50

Drug interactions

Potentiate hyperkalemiaACE - INSAIDsPotentiate hypotension

Hypertension, 50 - 100; CHF, 25 -50Potentiate hyperkalemiaACE - INSAIDsCYP3A4 inducers decrease

Side effects

NarcoticsIncrease digoxin levelsHyperkalemiaGynecomastia, breast tendernessErectile dysfunctionDysmenorrhea, amenorrhea

HyperkalemiaAbdominal pain, diarrhea

Spironolactone and Amloride

Synthetic steroid that acts as a competitive antagonist to

aldosterone.

Several days before full therapeutic effect is achieved.

Highly protein bound

10 hrs

Long DOA

21 hrs

Diarrhoea/skin rash/ hypotension

.

Hyperkalemia – ADR

In Resistant Hypertension

Aldosterone excess may be a more common cause

Low-dose spironolactone

Eplerenone

FDC combination with THAIZIDE

Factors increasing the risk of hyperkalaemia during aldosterone blockade

1. Diminished renal function

2. Combined therapy with beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and direct renin inhibitors

3. Adjunct therapy with non-steroidal anti-inflammatory drugs

4. Ageing

5. Potassium supplements

A, B, C, D approach

Endothelins

21-AA peptide isolated from cultured porcine aortic

endothelial cells, first reported in 1988

Potent vasoconstrictor peptide

Endothelial cells

Endothelin Receptors

ET a G protein couple

receptor Primary

vasoconstrictor Mitogenesis Vascular smooth

cells

ET b G protein couple

receptor Vasodilator Inhibit growth factor

ET-1 as a key mediator in endothelial maintainance of tone and structure

IP3/PLC

PLA 2-PG I synthase

Constriction of afferent and efferent

arterioles decrease GFR

Preventing tubular reabsorption of sodium

and water (ETB)

Mitogenic effect on mesangial cells

Positive chronotropic and inotropic effects

Increased afterload / baroreceptor mediated

decrease in HR.

Mitogenic effect on cardiac myocytes

Stimulates ACE and aldosterone release

PULMONARY VASCULAR BED- Vasoconstriction through

vascular smooth muscle cell 

SYSTEMIC HYPERTENSION

Preclinical data on hypertension have been

underscored by clinical studies in humans with essential

hypertension

Nonselective ET-receptor antagonist bosentan

Selective ETA-receptor antagonist darusentan

Bosentan

Non-selective ET-1 receptor antagonist Vasodilatory effects Pulmonary hypertension and CHF 5 -8 h. BA- 50% hepatic metabolism followed

by biliary excretion  300-500 mg

Longer half life

Darusentan

• Selective ETA receptor antagonist

• 10, 50, 100, 150, and 300 mg

• orally bioavailable

• t1/2 12.5 hours

• Metabolized in the liver and excreted via the bile• Resistant Hypertension

Increase in heartrate, facial flush, Facial edema

Vasopeptidase Inhibitors

Omapatrilat

Sampatrilat

Fasidotrilat

Gemopratilat

SYNERGISTIC ACTION

Characteristics of selected vasopeptidase inhibitors under clinical development

Substance Dose Comments/Status

Sampatrilat 30mg/kgProduced sustained reductions in blood pressure in African-Americans.Currently under clinical development after reformulation to improve bioavailability

GemopatrilatAntihypertensive actions, good oral efficacy. Phase I/II clinical trials for hypertension

MDL-100240High affinity inhibotor of both ACE and neutral endopeptidase; antihypertensive and natriuretic. Under clinical investigation for hypertension and congestive heart failure

Fasidotril 10mg/kgModerate antihypertensive effects. Natriuretic in animal experiments. Improved survival of rats after myocardial infarction. Phase II clinical trials for renovascular hypertension

Z-13752APhase I/II clinical evaluation for hypertension. Reduced severity of consequences of coronary artery occlusion in animal experiments

Omapatrilat 10 mgMost advanced stage of clinical development OVERTURE and OCTAVE study recently completed

 angiotensin receptor neprilysin inhibitor 

Recent trials

OVERTURE trial

OCTAVE study

OPERA trial

AngiodemaCough

Hypotension

Potential benefits of vasopeptidase inhibitors

Reduction in BP through increase in natriuretic peptide

activity and decrease in Ang II

Prevention of compensatory rise in aldosterone secretion

Broad spectrum of action in hypertension

Preservation of renal blood flow and GFR- diuresis

Reduction in pre-load and afterload in congestive heart

failure

Vaccine-based strategies

Two antihypertensive vaccines were developed:

PMD3117 against Ang I and Cyt006 against Ang II

lower (-9/-4 mm Hg) blood pressure

Week 0, 4, and 12 or 0, 2, 4, 6, and 10

Seems feasible and preventive employment against CV

diseases

Renalase system

• Vasoactive kidney-related proteins

• novel catecholamine peptidase .• Renalase deficiency increases SBP and DBP

Knock-out MOUSE MODEL – Down regulation of renalase

• Supplementation with recombinant renalase - Dahl salt-sensitive rats and rats with chronic kidney disease.

Kidneys-Urinary catecholamines

Gene therapy

Overexpression of ACE2 and AT2R delivered in viral vectors reduced cardiac remodelling.

Exciting, but more safe and reliable methods of nucleic acid transfer re required.

Renal sympathetic denervation• Resistant hypertension• The Rheosw Pivotal Trial- electrical activation of the

carotid baroreflex

Hypertension Polypill

5-mg Amlodipine/160-mg Valsartan/12.5-mg HCTHZ

Maximum of 10/320/25.

Dietary changes

Modest restriction of Na+ intake to 2 g daily.

Diet high in fruits and vegetables and low-fat dairy

products lowers blood

Alcohol

Cardio exercise

Yoga/ meditation/Music

Gestational Hypertersion

• Definitive Treatment = Delivery

• Major indication for antihypertensive therapy is prevention of stroke.

– Diastolic pressure ≥105-110 mmHg or systolic pressure ≥160

mmHg

• Choice of drug therapy:

– Acute – IV labetalol, IV hydralazine, SR Nifedipine

– Long-term – Oral methyldopa or labetalol

• Medical Management

• Acute Therapy = IV Labetalol, IV Hydralazine, SR Nifedipine

• Expectant Therapy = Oral Labetalol, Methyldopa, Nifedipine

• Eclampsia prevention = MgSO4

• ACE inhibitors

• Angiotensin receptor antagonists

Labetalol orally in dose of 100-400 mg every 8-12hrly.

Methyl dopa 250mg-500mg 6-8 hrly.Nifedipine 10-20mg bd - tds

Hypertension Urgency and Emergency

Hypertension Guidelines

Hypertension Guidelines Date

JNC

JNC 7 2003

JNC 8 - Expected Release Date 2012 (TBC)

NICE Guidelines

NICE Guidelines 2011

ESC/ESH Hypertension Guidelines

ESC Guideline 2007

Reappraisal of 2007 Hypertension Guidelines Sep-09

Compelling Indications

Compelling Indication

Initial Therapy Clinical Trial Basis

Heart failureTHIAZ, BB, ACEI, ARB, ALDO ANT

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT,

RALES

Post myocardial infarction

BB, ACEI, ALDO ANT

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

High CAD risk

THIAZ, BB, ACE, CCB

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

Compelling Indications

Compelling Indication

Initial Therapy Options Clinical Trial Basis

Diabetes THIAZ, BB, ACE, ARB, CCBNKF-ADA Guideline,

UKPDS, ALLHAT

Chronic Kidney Disease

ACEI, ARBNKF Guideline, Captopril

Trial, RENAAL, IDNT, REIN, AASK

Recurrent Stroke Prevention

THIAZ, ACEI PROGRESS

JNC 8 REPORT

60 years, initiate pharmacologic treatment

(SBP)150mmHg or (DBP)90mmHg

>60years,achieved SBP <140mmHg)treatment iswell tolerated .Noadverse effectsSBP< 140

Dose need not be adjusted

<60 years, DBP -90mmHg Initiate treatment

18 years with CKD Initiate treatment –SBP<140mmHg and DBP<90mmHg

18years with DM Initiate treatment –SBP<140mmHg and DBP<90mmHg

nonblack population, including those with diabetes

thiazide-type diuretic, CCB

ACEI/angiotensin receptor blocker

black population with/ out DM thiazide-type diuretic or CCB

aged18 years with CKD ACEI or ARB

Maintain goal BP.

Not achieved- increase the dose of the initial drug or add thiazide-

type diuretic,CCB,ACEI, or ARB.

Should continue to assess BP

Not achieved with 2, add and titrate a third drug

Do not use an ACEI and ARB together in the same patient.

Not achieved - other classes can be used.

Referral to a hypertension specialist- GOAL not

achieved/CKD/DM/HF

2014 Hypertension Guideline

Critical question and review criteria defined by expert panel with

input from methodology team

Initial systematic review by methodologists restricted to RCT

evidence

2014 Hypertension Guideline

Definition of hypertension and prehyerptension not

addressed, but thresholds for pharmalogic treatment

were defined

Similar treatment goals defined for all hypertensive

populations except when evidence review supports

different goals for a particular population

Lifestyle modifications recommended

2014 Hypertension Guideline

Recommended selection among 4 specific medication

classes (ACEI or ARB, CCB or diuretics) and doses based

on RCT evidence

Recommended specific medication classes based on evidence

review for racial, CKD, and diabetic subgroups

Panel created a table of drugs and doses used in the outcome

trials