Recent advances in Hypertension Management Speaker: Dr.Rachana Menon
Jun 22, 2015
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