brief discussion on updates of ARB

1. ARB UPDATES
Dr. Shanjida Sultana
MO,Cardiology
NHFH&RI

2. INTRODUCTION
• Angiotensin Receptor Blockers(ARB) also known as
Angiotensin II Receptor Antagonists,AT-1 Receptor
Antagonists or Sartans are a group of pharmaceuticals
which modulate the renin-angiotensin aldosterone system.
• In early 1980s it was noted that a series of imidazole 5-
acetic acid derivatives diminished blood pressure
responses to Ang II in rats. Based on that finding & further
research a nonpeptide AT receptor blocker Losartan was
developed.
• In 1995 Losartan was approved for clinical use in the
United States and since then six additional ARBs have been
approved.

3. Angiotensin Receptors
• Specific angiotensin receptors have been discovered, grouped
and abbreviated as – AT1 and AT2
• They are present on the surface of the target cells
• Most of the physiological actions of angiotensin are mediated
via AT1 receptor
• Losartan is the specific AT1 blocker

4. DIFFERENCE BETWEEN AT1 & AT2
RECEPTORS
 All the adverse effects of angiotensin II is mediated by AT1
receptors.
 Vasoconstriction
 Sodium retention
 Cell growth promotion & connective tissue deposition
 LDL-C transport increased
 Increased efferent arteriolar constriction & thus increasing
intra glomerular pressure. This increases proteinuria.
 On the other hand when the same angiotensin II stimulates
AT2 receptors the exactly opposite & beneficial effects occurs.

5. Potential pathogenic properties of
Angiotensin II
 HEART
• Myocardial Hypertrophy
• Interstitial fibrosis
 CORONARY ARTERIES
• Endothelial dysfunction
• Coronary constriction via release of norepinephrine.
• Increased oxidative stress.
• Promotion of inflamatory response & Atheroma.
• Promotion of LDL cholesterol uptake.

6.  Kidneys
• Increased intraglomeruler pressure.
• Increased protein leak.
• Glomeruler growth & fibrosis.
• Increased sodium reabsorption.
 Adrenals
• Increased formation of aldosterone.
 Coagulation system
• Increased fibrinogen level.

8. Pharmacokinetics
• All ARBs are well absorbed after oral administration but
differ slightly in metabolism and pharmacokinetics.
• All of the ARBs, except for telmisartan and olmesartan, are
metabolized in some way by the cytochrome P450 enzyme ,
in liver.
• Telmisartan is metabolized by glucuronidation and
olmesartan is excreted as the unchanged drug. Telmisartan is
the only ARB that can cross the blood–brain barrier and can
therefore inhibit centrally mediated effects of Ang II,
contributing to even better blood pressure control .

10. Indications of ARBs
• Hypertension
• Chronic heart failure
• Diabetic Nephropathy
• Stroke

11. Use in Hypertension
• ARB reduce BP with an astonishing lack of side effects in
comparison to ACEi.
• Already regarded as 1st line therapy in hypertension by
the European Guidelines.
Justifiable use of ARBs in HTN are
• Losartan (LIFE)
• Valsartan (VALUE & JiKei Heart)
• Eprosartan (MOSES).

12. Comparison of ARBs Versus ACE inhibitors Relevant to Use in
Hypertension
Property ARB ACE Inhibitor
•Major site of block
•Major claims,
basic science
•Side effects
•Compelling indications,
modified
from JNC 7
AT-1 receptor
More complete AT-1 block,
AT-2 activity increased;
latter may be beneficial
(not certain)
Generally similar to
placebo; cough
unusual; angioedema
very rare but reported
Heart failure, diabetes,
chronic renal disease,
recurrent stroke
Converting enzyme
Block of two receptors:
AT-1, AT-2. Inhibition of
breakdown of protective
Bradykinin
Dry cough; angioedema
higher in black (1.6%)
than nonblack patients
(0.6%), enalapril data
from OCTAVE24
As for ARB plus post-MI,
high coronary risk,
recurrent stroke (with
diuretic)

13. Property ARB ACE Inhibitor
•Major clinical
claims in
Hypertension
•Outcome trials
(death, stroke,
coronary events,
etc.)
Equal BP reduction to
ACE-inhibitors, little or
no cough, excellent
tolerability, well tested
in LVH and in diabetic
Nephropathy
LIFE (losartan better than
atenolol, stroke less,
deaths less in diabetics);
VALUE (valsartan
vs amlodipine; about
equal); JIKEI-heart
(valsartan)
Well tolerated, years of
experience especially
in CHF, good quality of
life; used in coronary
prevention trials (HOPE,
EUROPA, PEACE)
Enalapril >diuretic,
Diuretic >lisinopril in
ALLHAT

14. Use in Chronic Heart Failure
• ARBs are reasonable alternative for use in heart failure, (ACEi
intolerant patients )
• Justification of using ARB in HF is-
1.Benefits of ARBs are bought almost without any costly side
effects.
2.The adverse effects of major renin-angiotensin activation in heart
failure are mediated by the stimulation of angiotensin II via AT-1
receptor, which the ARBs specifically block.
3.There are other non ACE paths for the generation of pathogenic
angiotensin II.

15. • Recommendation in AHA and ACC,2009: Use of ARBs
is recommended in patients with current or previous
symptoms of heart failure and reduced LVEF who
have an intolerance to ACEi

17. Use in Chronic Renal Disease, Including Diabetic
Nephropathy
• ARBs have better supporting documentation for
benefits in type-2 diabetes.
• On the other hand, in type 1 diabetes, the ACE
inhibitors have better evidence of benefit.
• In proteinuric renal disease, with or without
diabetes, ARBs and ACE inhibitors similarly reduced
proteinuria.
• A dual approach, targeting both BP and albuminuria,
is required.

18. Fewer Cases of New Diabetes
• In HTN, losartan was associated with fewer cases of new
diabetes than atenolol,
• candesartan was associated with fewer cases than
hydrochlorothiazide (HCTZ),
• valsartan was associated with fewer cases than amlodipine.
• In the NAVIGATOR study of patients with impaired glucose
tolerance and CVD or risk factors, administration of valsartan up
to 160 mg daily for 5 years, plus lifestyle modification, reduced
the incidence of diabetes by 14% without reducing the rate of
CV events.

19. Use in Stroke
• More than 25 years ago Brown hypothesized that
angiotensin II could protect against strokes . Three recent
trials support the Brown hypothesis.
• First, in PROGRESS an ACE inhibitor reduced BP but not
repeat stroke unless combined with a diuretic.
• Second, an ARB, eprosartan, reduced repeat stroke better
than a CCBs.
• Third, losartan gave better protection from stroke in
patients with LVH than atenolol in the LIFE study.

21. Nonissues with ARBs: Myocardial Infarction
and Cancer
• The ARB-MI paradox refers to the theoretical and
unexpected proposal that ARBs may increase the risk
of MI.
• But, there was controversy about the effects on MI of
ARBs versus ACE inhibitors

22. • The controversy has been settled by the large and
comprehensive analysis based on 37 randomized
clinical trials including 147,020 participants with a
total follow-up of 485,166 patient years. This study
firmly refutes the claim that ARBs increase the risk of
MI .
• ARBs reduce the risk of stroke, heart failure, and
new-onset diabetes.
• Another nonissue is the proposal that ARBs are
associated with an increased incidence of cancer.

23. Combinations of ACE Inhibitor–ARB
Therapy
• In heart failure
1. Addition of ARB, candesartan or valsartan to ACE-
inhibitor therapy is associated with improved outcomes
in CHF.
2. In patients with LV systolic dysfunction who remain
symptomatic on ACE inhibitors and beta-blockers, ARBs
can give added benefit as an alternative to the addition
of third-line aldosterone blockers.

24. • In stroke, Combined ACE inhibitor–ARB therapy provides
CV protection in high-risk persons.
• The ONTARGET study tested the effects on highrisk
persons of ramipril 10 mg daily compared with telmisartan
80 mg daily and with the combination..
• Telmisartan was not superior to ramipril, despite
telmisartan 80 mg reducing BP better over 24 hr than
ramipril 10 mg.
• The combination produced unchanged CV outcomes,
although it resulted in increased hypotension, syncope,
and renal dysfunction. Thus this combination is not the
gold standard .

25. Comparison of ARBs and ACE Inhibitors in Heart Failure, CV
Prevention, and Stroke
Property ARB ACE Inhibitor
•HF
•Post-MI: Major
studies
Valsartan reduces hospitalization;
candesartan for class 2-4 HF where EF
≤ 40% to reduce CV deaths and
hospitalization; may be added to ACEI
VALIANT, valsartan noninferior to
captopril in postinfarct heart failure.
Yes, several but not all.
Several large studies, definite
protection including LV
dysfunction.

26. Property ARB ACE Inhibitor
•Diabetic
nephropathy:
Major claims
•Nondiabetic renal
disease
•Prevention of CV
complications (MI,
heart failure, stroke,
or CV death)
•Prevention of
Stroke
Renoprotective in type 2
diabetes independently
of hypertension; slows progress
of microalbuminuria.
Decreases proteinuria.
ONTARGET evaluates
telmisartan vs ramipril vs
combination in HOPE-like study.
TRANSCEND compares
telmisartan with placebo.
LIFE, less stroke in LVH
treated by losartan usually
with diuretic versus atenolol;
less repeat stroke with
Eprosartan in MOSES.
Renoprotective in type 1 diabetes
independently of hypertension; slows
development of microalbuminuria in
diabetics.
Better outcome, REIN,AASK.
HOPE, reduction of this primary end-
point by 22%; EUROPA, reduction of
MI and combined endpoints.
PROGRESS, less repeat stroke with
perindopril only if with diuretic.

27. Adverse effects
• Hyperkalaemia due to potassium retention mediated
by reduction of aldosterone.
• Impairment of renal function. Caution if bilateral
renal artery stenosis suspected.
• Dizziness and syncope. Rare but may be precipitated
by volume depletion.
• Angioedema – very rare.

28. Losartan (Cozaar)
• The prototype ARB.
• Numerous clinical studies to support its efficacy in BP
reduction, diabetic nephropathy and LVH .
• For hypertension, the standard start-up dose is 50 mg once
daily, with an increase to 100 mg if needed.
• As with all the ARBs, a dose increase is usually less
effective than the addition of a low-dose diuretic in
achieving greater BP control.
• When there is volume depletion or liver disease , the
starting dose should be only 25 mg.

29. • In diabetic nephropathy, in the RENAAL study, losartan (50-
100 mg daily) reduced ESRD and proteinuria.
• In heart failure, losartan 50 mg daily was disappointing,
whereas a higher dose (150 mg daily) gave positive results.

30. Irbesartan (Avapro)
• Terminal half-life of 11-15 hr
• Dose: 150-300 mg once daily
• In important studies on type 2 diabetic nephropathy,
irbesartan reduced the rate of progression of
microalbuminuria to overt proteinuria.
• In the ACTIVE I study on 9000 high-risk patients with atrial
fibrillation, irbesartan was added to prior therapy, including
an ACE inhibitor in 60%. Irbesartan did not reduce CV
events, yet hospitalization was reduced .

31. Telmisartan (Micardis)
• A very long half life of 24 hr
• 40 to 80 mg once daily .
• In the main ONTARGET study, 25,620 participants were
randomly assigned to ramipril 10 mg a day , telmisartan 80
mg a day , or the combination of both drugs. Telmisartan
and ramipril had equal outcomes in patients judged to be
at high CVD.

32. • In the ONTARGET renal study, telmisartan gave equal
renoprotection to ramipril, but the combination of
these two agents increased major adverse renal
outcomes despite decreasing proteinuria.
• In the combined TRANSCEND and ONTARGET
populations, in patients at high vascular risk,
telmisartan reduced new-onset electrocardiographic
LVH by 37%.

33. Dose: Oral; 80-320 mg once daily.
• no active metabolite.
• In the VALIANT trial, valsartan up to 160 mg twice daily was as
effective as captopril up to 50 mg thrice daily in patients at
high risk for fatal and nonfatal CV events after MI.
• Valsartan Antihypertensive Long-term Use Evaluation. VALUE:
( Valsartan vs Amlodipine)
Pt with HTN & high cardiovascular risk factors
showed no significant mortality benefit
but incidence of fatal & non fatal MI was reduced.

34. Other agents
• Eprosartan (Teveten)
• Olmesartan (Benicar)

35. ACE Inhibitors and ARBs: Shared Contraindications and
Cautions
• Pregnancy all trimesters.
• Severe renal failure (caution if creatinine . 2.5-3 mg/dL, 220-
265 mmol/L)
• Hyperkalemia requires caution or cessation.
• Bilateral renal artery stenosis or equivalent lesions.
• Preexisting hypotension.
• Severe aortic stenosis or obstructive cardiomyopathy.
• Often less effective in black subjects without added diuretic.

36. Newer ARB
• Azilsartan medoxomil:
Compared with olmesartan 40 mg daily, azilsartan 80
mg reduced mean systolic blood pressure (SBP) by an
additional 2.1 mm Hg

37. ARBs under development
Several new nonpeptide ARBs are undergoing clinical
trials or are at pre-clinical stages of development.
 Embusartan
 Fonsartan
 Pratosartan
Pratosartan has affinity for the AT1receptor about 7
times higher than losartan.