Lau Yik Hoe

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 RAAS overview
 ARB overview
 Indications
 Contraindications
 Drug information
 ACEI and ARB differences
 ARB in Type 2 Diabetic Nephropathy
 ARB in CV disorders
 Conclusion
 References

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 ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE

Cardiac & Vascular Vasoconstriction

Hypertrophy Direct Renal
Sodium Retention

↑ Cardiac Aldosterone
Contractility Angiotensin Secretion
II

Sympathetic ↑ Thirst
Facilitation:
ADH Release
Central
Nerve terminal
(ganglionic ?)
All known physiologic effects are mediated
by the angiotensin II type 1 receptor
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 Angiotensin receptor blockers block receptors that
angiotensin II binds to, particularly angiotensin II type 1
receptors.

 Affinify for type 1 receptors are much higher than type 2

receptors

 Inhibits angiotensin II induced vasoconstriction and salt and

water retention.

 BLOOD PRESSURE IS SUBSEQUENTLY LOWERED

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Mechanism of Action

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Indication Hypertension Diabetic LV
Nephropathy Hypertroph
y
Valsartan (x)

Irbesartan (x) (essential) (x)

Telmisartan (x)

Losartan (x) (x)(for HTN) (x)(for HTN)

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 Valsartan Telmisartan Losartan Irbesartan

Dosage (HTN) 80 or 160 40 - 80 mg daily 50mg od – 150 mg to 300 mg

mg od. Max (blue book) 100mg od daily.
320 mg od 20 - 80mg (CPG
HPT08)

Dosage 50mg od – 150 mg to 300 mg

(diabetic 100mg od daily
nephropathy)

ARBs are also given in combination with HCT to give an additive

effect on BP lowering.

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 ADEC Category D

 Crosses placenta and interferes with fetal renal

hemodynamics.

 Induces decline in GFR in fetal kidneys which may then lead

sequentially to decrease in urine production &
oligohydramnios.

 Developmental abnormalities such as limb contractures, lung

hypoplasia, and cranial ossification deficits leading to
craniofacial deformation.

 Kidney function in most infants return to normal after birth but

persistent renal insufficiency can occur as well.

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 Circulating and intrarenal angiotensin II constricts efferent arteriole
more than afferent arteriole within the kidney, which helps to maintain
glomerular capillary pressure and filtration.

 Removing this constriction by blocking angiotensin II receptors on the

efferent arteriole can cause an abrupt fall in glomerular filtration rate.

 Further reduction blood flow to the kidneys and reduction of GFR.

 Can cause oliguria, progressive azotemia and ACUTE RENAL FAILURE

 * Not contraindicated in blue book (Precaution), contraindicated in CPG

of HPT 2008

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 Well tolerated

 Dizziness : associated with 1st dose hypotensive effect (2-4%)

 Diabetic nephropathy patients may experience chest and back pain

 Hyperkalaemia : especially with renal dysfunction, DM, K+ supplements

 Fatigue

 Headache

 Cough, angioedema (rare)

 Nausea and diarrhoea (as always..)

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 Losartan + Ketoconazole
◦ Due to inhibition of formation of losartan active metabolite.

 Losartan + rifampicin
◦ Due to increased losartan metabolism, decreasing concentration and
affecting BP control

 ARB + potassium salt/supplement/K+ sparing diuretics.

◦ Use cautiously in patients with renal dysfunction, and potassium levels
should be monitored.
◦ Elevate potassium concentrations
◦ Can cause HYPERKALAEMIA.

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(1) Angiotensin converting enzyme (ACE) is a kininase.

 Degrades inflammatory mediator, bradykinin.

 ACE inhibition increases kinin, causing pro-inflammatory

effects including the infamous “cough”.

 ARBs do not inhibit ACE, and therefore ensures normal

breakdown of bradykinin. Kinin levels remain normal,
reducing the risk of cough. (Katzung 9 Edition)
th

 This explains why less cough side effects are seen with
Angiotensin receptor blockers.

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(2) ACE inhibitors, by decreasing angiotensin II production,
reduce the effect of both AT1 and AT2 receptors

 Only the former are inhibited by the angiotensin II receptor

blockers.

 Chronic stimulation of the AT2 receptor may be beneficial

 Studies show that AT2 receptor stimulation counteracts the

effect of AT1, though not significant in effect. (UptoDate)

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(3) In the heart, brain, and perhaps the blood vessels, the
production of angiotensin II may be catalyzed by enzymes
other than angiotensin converting enzyme, such as chymase.

 ACE inhibitors have no effect on these other enzymes.

 Additional angiotensin II still produced.

 Angiotensin II receptor antagonists overcomes this problem.

Act on the receptors that angiotensin II binds to, and not
inhibition of angiotensin II.

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 Proven efficacy
◦ Two major trials have demonstrated a clear benefit in terms of
renoprotection with ARBs in patients with nephropathy due to type 2
diabetes.

 Irbesartan Diabetic Nephropathy Trial (IDNT)

◦ in treating patients with both Type 2 diabetes and proteinuria for 3
years, irbesartan reduced rates of doubling of serum creatinine 23%
better than amlodipine.

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 In the RENAAL trial..
◦ comparison between losartan (50mg titrating to 100mg) and placebo
was done

◦ both in addition to conventional antihypertensive therapy

◦ Compared to placebo, losartan reduced the incidence of a doubling of

the plasma creatinine and end-stage renal disease by 16 percent after 3
years

◦ These benefits were again not associated with differences in blood

pressure levels between the groups.

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 ARB in Type 2 Diabetes and
Nephropathy Summary

 Good blood pressure control in earlier studies has proven

critical to slow the progression of nephropathy in type 2
diabetes

 New guidelines for good blood pressure control are:

◦ <130/80 mmHg (CPG HPT 08)
◦ <125/75 mmHg for patients with renal insufficiency with greater than
1 g/d of proteinuria/24 hours (JNC VII)

 ARBs now are indicated for the treatment of type 2

diabetes with nephropathy

www.hypertensiononline.org
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 Primary Endpoint: Average
Composite of doubling of Duration
serum creatinine, end stage
renal disease, or death

RENAAL Losartan 50-100 mg ↓ 16% (p=0.02) 3.4 yrs

(n=1,514) vs placebo*

IDNT Irbesartan 150-300mg vs ↓ 20% (p=0.02) 2.6 yrs

(n=1,715) placebo*

Irbesartan 150-300 mg
vs Amlodipine* ↓ 23% (p=0.006)

*In combination with conventional antihypertensive therapy (excluding ACE inhibitors)

RENAAL=The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan
IDNT=The Irbesartan in Diabetic Nephropathy Trial
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860.
www.hypertensiononline.org
 Effects of angiotensin II on cardiac muscle

◦ Induces hypertrophy, correlating with increased protein synthesis in

heart.

◦ Involved in maladaptive remodelling. Stimulates collagen synthesis 

fibrosis & inadequate remodelling.

Deterioration of cardiac performance.

 ARBs have been shown to reduce morbidity. (CPG HPT 08)

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
VALIANT
◦ comparison between Valsartan and Captopril.
◦ Patients were at high risk of cardiovascular events and were post-MI.
◦ Similar efficacy.

 Val-HeFT
◦ Comparison between Valsartan and placebo
◦ Summary:
◦ Diovan reduced endpoint mortality and HF morbidity
◦ Reduced HF hospitalisations, reversed LV remodelling
◦ Improved HF signs and symptoms.

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 Subgroup without ACE inhibitor background
therapy
1.000
0.914
Event-free probability

DIOVAN (n=185)
0.829
0.743
0.657 44%
risk
0.571 reduction*

0.486 Placebo
0 (n=181)
0 3 6 9 12 15 18 21 24 27
Time since randomisation (months)
*p<0.001 for morbidity/mortality; 33% relative risk (RR; p=0.017) for
all-cause mortality
Val-HeFT: Valsartan in Heart Failure Trial
Maggioni et al. J Am Coll Cardiol 2002;40:1414–21
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Patients aged 55–80 years with BP 160–200/95–115 mmHg and LVH
Treatment titrated to <140/90 mmHg
4.8 years of follow-up
30 13% risk reduction*
27.9
(p=0.021)
events per 1,000 patient-

23.8
Death, MI and stroke

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10
years

0 Atenolol-based Losartan-based
(n=4,588) (n=4,605)
BP at end of study: 145/81 mmHg 144/81 mmHg
*RR 0.87, 95% CI: 0.77–0.98
LVH = left ventricular hypertrophy
LIFE = Losartan Intervention For Endpoint Dahlöf et al. Lancet 2002;359:995–100323
 ARBs are primarily known for their antihypertensive action
but there is much about what they can do which is still
being investigated.

 They are seen as a much improved version of ACE

inhibitors, however ACE inhibitors are still generally
preferred due to more extensive studies as compared to
ARBs

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 (1) Wong, M, Staszewsky, L, Latini, R, et al. Valsartan benefits left ventricular
structure and function in heart failure: Val-HeFT echocardiographic study. J Am
Coll Cardiol 2002; 40:970.
 (2) Fogari et.al. A Double Blind Crossover Study of Antihypertensive Efficacy of
Angiotensin II Antagonists and their Activation of The Renin-Angiotensin
System. 2000; 61:10
 (3) Chobanian, AV, Bakris, GL, Black, HR, et al. The Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure: The JNC 7 Report. JAMA 2003; 289:2560
 (4)  Cohn, JN, Tognoni, G. Valsartan Heart Failure Trial Investigators. A
Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic
Heart Failure. N Engl J Med 2001; 345:1667.
 (5)  Pitt, B, Poole-Wilson, PA, Segal, R, et al. Effect of Losartan Compared With
Captopril on Mortality in Patients With Symptomatic Heart Failure: Randomised
Trial - The Losartan Heart Failure Survival Study ELITE II. Lancet, 2000,
355:1582.
 (6) Brenner BM, Cooper ME, de Zeeuw D, Keane WK, Mitch WE, Parving HH,
Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, et al.: Effects of losartan on
renal ands cardiovascular outcomes in patients with type 2 diabetes
and nephropathy. N Engl J Med 2001, 345:861-869.
 (7) UptoDate
 (8)

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