Cardiology

1. ARBUPDATES
Dr. Shanjida Sultana
MO,Cardiology
NHFH&RI

2. INTRODUCTION
Blockers(ARB) also known as• Angiotensin Receptor
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 wasnoted that aseries of imidazole 5-
acetic acid derivatives diminished blood pressure
responses to AngII in rats. Basedon that finding &further
research anonpeptide ATreceptor blocker Losartan was
developed.
• In 1995 Losartan wasapproved for clinical usein the
United Statesand since then six additional ARBshave been
approved.

3. Angiotensin Receptors
• Specific angiotensin receptors havebeen discovered,grouped
and abbreviated as–AT1andAT2
• Theyare present on the surface of the target cells
• Most of the physiological actions of angiotensin are mediated
viaAT1receptor
• Losartan is the specificAT1blocker

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-Ctransport increased
Increased efferent arteriolar constriction & thus increasing
intra glomerular pressure. This increasesproteinuria.
Onthe other hand when the sameangiotensin II stimulates AT2
receptors the exactly opposite & beneficial effectsoccurs.

5. Potential pathogenic properties of
Angiotensin II
 HEART
• Myocardial Hypertrophy
• Interstitial fibrosis
 CORONARYARTERIES
• Endothelial dysfunction
• Coronary constriction via release ofnorepinephrine.
• Increased oxidative stress.
• Promotion of inflamatory response &Atheroma.
• Promotion of LDLcholesteroluptake.

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 ARBsare well absorbed after oral administrationbut
differ slightly in metabolism andpharmacokinetics.
• 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 asthe unchanged drug. Telmisartanis
the only ARBthat cancrossthe blood–brain barrier and can
therefore inhibit centrally mediated effects of AngII,
contributing to even betterblood pressure control .

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

11. Use in Hypertension
• ARBreduce BPwith an astonishing lack of side effects in
comparison to ACEi.
• Already regarded as1st line therapy in hypertension by
the EuropeanGuidelines.
Justifiable useof ARBsin HTNare
• Losartan (LIFE)
• Valsartan (VALUE& JiKei Heart)
• Eprosartan (MOSES).

12. Comparison of ARBs Versus ACE inhibitors Relevant to Use in
Hypertension
•Major claims,
basic science
•Sideeffects
•Compelling indications,
modified
from JNC7
More completeAT-1block,
AT-2activity 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
Property ARB ACEInhibitor
•Major site of block AT-1receptor 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
Asfor ARBplus post-MI,
high coronary risk,
recurrent stroke (with
diuretic)

13. Property ARB ACEInhibitor
•Major clinical
claims in
Hypertension
•Outcome trials
(death, stroke,
coronary events,
etc.)
Equal BPreduction to
ACE-inhibitors, little or
no cough, excellent
tolerability, well tested
in LVHand in diabetic
Nephropathy
LIFE(losartan better than
atenolol, stroke less,
deaths lessin diabetics);
VALUE(valsartan
vsamlodipine; about
equal); JIKEI-heart
(valsartan)
Well tolerated, yearsof
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 usein heartfailure, (ACEi
intolerant patients)
• Justification of using ARBin HFis-
1. Benefits of ARBsare bought almost without any costly
side effects.
2. Theadverse effects of major renin-angiotensin activation in
heart failure are mediated by the stimulation of angiotensin II
via AT-1 receptor, which the ARBsspecifically block.
3. There are other non ACEpaths for the generation of
pathogenic angiotensin II.

15. • Recommendation in AHAandACC,2009:Useof ARBs
is recommended in patients with current orprevious
symptoms of heart failure and reduced LVEFwho
have an intolerance to ACEi

17. Use in Chronic Renal Disease, Including Diabetic
Nephropathy
• ARBshave better supporting documentation for
benefits in type-2 diabetes.
• Onthe other hand, in type 1 diabetes, theACE
inhibitors have better evidence of benefit.
• In proteinuric renal disease, with or without
diabetes,ARBsandACEinhibitors similarly reduced
proteinuria.
• Adual approach, targeting both BPand albuminuria,
is required.

18. Fewer Cases of New Diabetes
• In HTN,losartan wasassociated with fewer casesof new
diabetes than atenolol,
• candesartan wasassociated with fewer casesthan
hydrochlorothiazide (HCTZ),
• valsartan wasassociated with fewer casesthanamlodipine.
• In the NAVIGATORstudy of patients with impaired glucose
tolerance and CVDor risk factors, administration of valsartanup
to 160 mg daily for 5 years, plus lifestyle modification, reduced
the incidence of diabetes by 14%without reducing the rate of
CVevents.

19. Use in Stroke
• More than 25 years agoBrown hypothesized that
angiotensin II could protect against strokes . Threerecent
trials support the Brownhypothesis.
• First, in PROGRESSanACEinhibitor reduced BPbut not
repeat stroke unless combined with adiuretic.
• Second,anARB,eprosartan, reduced repeat stroke better
than aCCBs.
• Third, losartan gavebetter protection from strokein
patients with LVHthan atenolol in the LIFEstudy.

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
ARBsversusACEinhibitors

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 ARBsincrease 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 heartfailure
1. Addition of ARB,candesartan or valsartan to ACE-
inhibitor therapy is associated with improvedoutcomes
in CHF.
2. In patients with LVsystolic dysfunction who remain
symptomatic on ACEinhibitors and beta-blockers,ARBs
cangive added benefit asan alternative to the addition
of third-line aldosteroneblockers.

24. • In stroke, CombinedACEinhibitor–ARB therapyprovides
CV protection in high-riskpersons.
• TheONTARGETstudy tested the effects on highrisk
persons of ramipril 10 mg daily compared withtelmisartan
80 mgdaily and with thecombination..
• Telmisartan wasnot superior to ramipril, despite
telmisartan 80 mg reducing BPbetter over 24 hrthan
ramipril 10mg.
• Thecombination produced unchanged CVoutcomes,
although itresulted 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
•Post-MI:Major
studies
VALIANT,valsartan noninferior to
captopril in postinfarct heartfailure.
Property ARB ACEInhibitor
•HF Valsartan reduces hospitalization; Yes,several but not all.
candesartan for class2-4 HFwhere EF
≤ 40% to reduce CV deaths and
hospitalization; may be added to ACEI
Several large studies, definite
protection including LV
dysfunction.

26. Property ARB ACEInhibitor
•Diabetic
nephropathy:
Major claims
•Nondiabetic renal
disease
•Prevention of CV
complications (MI,
heart failure, stroke,
or CVdeath)
•Prevention of
Stroke
Renoprotective in type2
diabetes independently
of hypertension; slowsprogress
of microalbuminuria.
Decreasesproteinuria.
ONTARGETevaluates
telmisartan vsramipril vs
combination in HOPE-likestudy.
TRANSCENDcompares
telmisartan with placebo.
LIFE,lessstroke in LVH
treated by losartan usually
with diuretic versusatenolol;
lessrepeat 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 combinedendpoints.
PROGRESS,lessrepeat stroke with
perindopril only if with diuretic.

27. Adverse effects
• Hyperkalaemia due to potassium retentionmediated
by reduction of aldosterone.
• Impairment of renal function. Caution if bilateral
renal artery stenosissuspected.
• Dizziness and syncope. Rarebut may beprecipitated
by volume depletion.
• Angioedema – very rare.

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

29. • In diabetic nephropathy, in the RENAALstudy, losartan (50-
100 mg daily) reduced ESRDand proteinuria.
• In heart failure,losartan 50 mg daily was disappointing,
whereas ahigher dose (150 mg daily) gavepositive results.

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

31. Telmisartan (Micardis)
• Avery long half life of 24hr
• 40 to 80 mg once daily .
• In the main ONTARGETstudy, 25,620 participants were
randomly assigned to ramipril 10 mg aday , telmisartan80
mg aday , or the combination of both drugs. Telmisartan
and ramipril had equal outcomes in patients judged to be
at high CVD.

32. • In the ONTARGETrenal study, telmisartan gaveequal
renoprotection to ramipril, but the combination of
these two agents increased major adverse renal
outcomes despite decreasing proteinuria.
• In the combined TRANSCENDand ONTARGET
populations, in patients at high vascular risk,
telmisartan reduced new-onset electrocardiographic
LVHby37%.

33. Dose: Oral; 80-320 mg oncedaily.
• no active metabolite.
• In the VALIANTtrial, valsartan up to160 mg twice daily wasas
effective ascaptopril up to 50 mg thrice daily in patients at
high risk for fatal and nonfatal CVevents afterMI.
• Valsartan Antihypertensive Long-term Use Evaluation. VALUE:
( Valsartan vsAmlodipine)
Pt with HTN& high cardiovascular risk factors
showed no significant mortalitybenefit
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
•Pregnancyall trimesters.
•Severerenal failure (caution if creatinine . 2.5-3 mg/dL,220-
265 mmol/L)
• Hyperkalemia requires caution or cessation.
•Bilateral renal artery stenosis or equivalentlesions.
•Preexisting hypotension.
• Severeaortic stenosis or obstructive cardiomyopathy.
•Often lesseffective in black subjects without addeddiuretic.

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 ARBsare undergoing clinical
trials or are at pre-clinical stagesofdevelopment.
 Embusartan
 Fonsartan
 Pratosartan
Pratosartan hasaffinity for the AT1receptor about 7
times higher than losartan.