BY PHARM.

SALLAU Manasseh

IN THE DEPARTMENT OF CLINICAL PHARMACY

FEDERAL TEACHING HOSPITAL GOMBE.

 OUTLINES
 The concept of myocardial infarction.
Definition of ARBs /Brief history.
Mechanism of action of ARBs/RAAS.
Indications, Contraindications, Side effects and
Interactions of ARBs.
 Examples of ARBs with their structures.
 SAR of ARBs.
 Dosage/Administration and Pharmacokinetics of
ARBs.
ARBs combination and ARBs under development.
Examples of available ARBs in the hospital.
Discussion.
Conclusion.
 MYOCARDIAL INFARCTION
 DEFINITION

Myocardial infarction ("heart attack") is the irreversible damage of

myocardial tissue caused by prolonged ischemia and hypoxia.

 SIGNS AND SYMPTOMS OF MYOCARDIAL INFARCTION

Myocardial infarction produces clinical symptoms that include:

Intense chest pain that may radiate into the neck, jaw or arms (i.e.,
referred pain)
A sense of substernal heaviness, shortness of breath (dyspnea)
Fatigue, fainting (syncope), nausea, sweating (diaphoresis), anxiety,
sleeplessness
Hypertension or hypotension (depending in part on the extent of cardiac
damage), tachycardia and arrhythmias.
Recent clinical research indicates that the symptoms may be very
different between men and women. Chest pain is less common in women.
Instead, their most common symptoms are weakness, fatigue and
dyspnea( Lippincott W., et al.,2011).
 BRIEF PATHOPHYSIOLOGY OF MYOCARDIAL
INFARCTION
 MI most commonly occurs when a coronary artery becomes
occluded following the rupture of an atherosclerotic plaque,
which then leads to the formation of a blood clot (coronary
thrombosis). This event can also trigger coronary vasospasm.
If a vessel becomes completely occluded, the myocardium
normally supplied by that vessel will become ischemic and
hypoxic.
 Without sufficient oxygen, the tissue dies.
The damaged tissue is initially comprised of a necrotic core
surrounded by a marginal (or border) zone that can either
recover normal function or become irreversibly damaged.
The hypoxic tissue within the border zone may become a site
for generating arrhythmias.
 EFFECTS OF MYOCARDIAL INFARCTION
When myocardial infarction occurs, it leads to the following effects in different
parts of the body which includes:

Neurohumoral (Release of neurotransmitters)

↑ circulating catecholamines
Sympathetic activation
↑ angiotensin II and ↑ aldosterone
↑ arginine vasopressin (ADH)

Cardiopulmonary
 Sytolic/diastolic dysfunction
 Decreased cardiac output (↓ stroke volume)
 Tachycardia
 Arrhythmias
 Pulmonary congestion/edema
 Dyspnea

Systemic Vasculature
 ↑ Systemic vascular resistance
 ↑ Blood volume
↑ Systemic edema
 RATIONALE FOR DRUG THERAPY IN MI
Improve Myocardial Oxygen Supply/Demand Ratio

This can be achieved in two broad ways:

 Restore coronary blood flow

• Dilate coronaries (inhibit vasospasm)
• Coronary thrombolysis
• Inhibit coagulation and platelet function

Decreased myocardial oxygen consumption

↓ Heart rate
↓ Contractility
↓ After load
↓ Preload
 RATIONALE FOR DRUG THERAPY IN MI CON’T

Pain Management
 Analgesics

 Control Heart Rhythm

 Suppress arrhythmias

Inhibit Cardiac Remodeling

Inhibit sympathetic activity
Inhibit cardiac effects of angiotensin II
 WHAT ARE ARBs?
Angiotensin receptor blockers (ARBs) , also known as,
angiotensin II receptor antagonists, angiotensin II type 1
(AT1) receptor antagonists or sartans, are a group of
pharmaceuticals that modulate the renin-angiotensin-
aldosterone system (RAAS).
Their main uses are in the treatment of hypertension (high
blood pressure), diabetic nephropathy (kidney damage due
to diabetes) and congestive heart failure. Furthermore , they
are of clinical benefits when use in patients with myocardial
infarction.
 BRIEF HISTORY OF ARBs.
 In 1898, the Physiologist Robert Tigerstedt and his student,
Per Bergman, experimented with rabbits by injecting them
with kidney extracts.

 Their results suggested that the kidneys produced a protein,

which they named renin, that caused a rise in blood pressure.

 In 1939, renin was found not to cause the rise in blood

pressure, but was an enzyme which catalyzed the formation of
the substances that were responsible, namely, angiotensin I
(Ang I) and Ang II (Van Epps, et al., 2005).

 Attempts had been made to develop useful Ang II receptor

antagonists and initially, the main focus was on angiotensin
peptide analogues.
 BRIEF HISTORY OF ARBs CON’T
 Saralasin and other Ang II analogues were potent Ang II
receptor blockers but the main problem was a lack of oral
bioavailability(Adam, M. , 2005).

In the early 1980s it was noted that a series of imidazole-5-

acetic acid derivatives diminished blood pressure responses to
Ang II in rats.

However, it was seen that their structures would have to

mimic more closely the pharmacophore of Ang II. Structural
modifications were made and the orally active, potent and
selective nonpeptide AT1 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.
 MECHANISM OF ACTION OF ARBs/RAAS
 Since ARBs are modulators of the renin-angiotensin-
aldosterone system(RAAS).

Understanding how the RAAS works will help us to

understand how the ARBs act to elicits their function.
 THE RENIN-ANGIOTENSIN-
ALDOSTERONE SYSTEM(RAAS)
 The renin-angiotensin system (RAS) or the renin-
angiotensin-aldosterone system (RAAS) is a hormone system
that regulates blood pressure and water (fluid) balance.

 The system can be activated when there is a loss of blood

volume or a drop in blood pressure (such as in hemorrhage or
dehydration). This loss of pressure is interpreted by
baroreceptors in the carotid sinus. In alternative fashion, a
decrease in filtrate flow rate due to renal hypoperfusion will
stimulate the macula densa to signal the juxtaglomerular cells to
release renin.
 RAAS CONT....
 The release of renin is followed by the following process:

Renin cleaves a zymogen, an inactive peptide, called

angiotensinogen release by the liver, converting it into
angiotensin I(inactive decapeptide).

Angiotensin I is then converted to angiotensin II ( active

octapeptide) by angiotensin-converting enzyme (ACE)
which is thought to be found mainly in lung capillaries.
One study in 1992 found ACE in all blood vessel
endothelial cells.( Rogerson FM et al., 1992).

Angiotensin II is the major bioactive product of the

renin-angiotensin system (RAAS).
 STRUCTURE OF ANGIOTENSIN II

Isoleucine
Leucine
Proline

Aspartic acid Phenylalanine

Tyrosine
Histidine
Arginine
 CARDIOVASCULAR EFFECTS OF ANGIOTENSIN II
When angiotensin II is formed, it acts via it receptors found
on different part of the body to cause different effects.
ANGIOTENSIN II RECEPTORS AND THEIR LOCATION IN
THE BODY
The actions of Ang II are mediated by angiotensin receptors,
AT1 and AT2.
Two more angiotensin receptors have been described, AT3
and AT4, but their role is still unknown (Dihn, D.T. et al.,
2001).
AT1 receptors are mainly found in the heart, adrenal glands,
brain, liver and kidneys. Their main role is to regulate blood
pressure as well as fluid and electrolyte balance.
AT2 receptors are highly expressed in the developing fetus
but they decline rapidly after birth (Dihn, D.T. et al., 2001).
 Most of the known actions of Ang II are mediated through
the AT1 receptors.
 CARDIOVASCULAR EFFECTS OF ANGIOTENSIN II CON’T

Angiotensin II is a potent vaso-active peptide that

causes blood vessels to constrict, resulting in
increased blood pressure.

 Angiotensin II also stimulates the secretion of the

hormone aldosterone from the adrenal cortex.

Aldosterone causes the tubules of the kidneys to

increase the reabsorption of sodium and water into
the blood. This increases the volume of fluid in the
body, which also increases blood pressure.
 CARDIOVASCULAR EFFECTS OF
ANGIOTENSIN II CON’T
Angiotensin II also acts on the posterior pituitary gland to
cause the release of ADH which also increase the re
absorption of water along the collecting duct increasing fluid
volume and subsequently increase in blood pressure.

If the renin-angiotensin-aldosterone system is abnormally

active, blood pressure will be too high.

There are many drugs that interrupt different steps in this

system to lower blood pressure. These drugs are one of the
main ways to control high blood pressure (hypertension),
heart failure, kidney failure, and harmful effects of diabetes.
 MECHANISM OF ACTION OF ARBs CON’T
 These substances (ARBs) are AT1-receptor antagonists; that
is, they block the activation of angiotensin II type 1
(AT1)receptors. Blockage of AT1 receptors directly causes
vasodilatation, reduces secretion of vasopressin(ADH) , and
reduces production and secretion of aldosterone, among other
actions.

 These combined effects above reduces blood pressure.

MECHANISM OF ACTION OF ARBs CON’T
 INDICATIONS OF ARBs
 Hypertension.

Heart failure:

 They are found to improve morbidity primarily via reduction

in hospitalization for heart failure patients.
 They are also found to slow the progression of heart failure.
 They are also found to improve NYHA functional class ,ejection
fraction and signs and symptoms of heart failure and hence
quality of life of the patient.

Post myocardial infarction as they found to improve survival in

clinically stable patients with signs , symptoms or radiological
evidence of left ventricular failure and/ or with left ventricular
systolic dysfunction.
 CONTRAINDICATIONS OF ARBs
ARBs are contraindicated in pregnancy because they cause
congenital malformations, still births and neonatal death.

Patients with bilateral renal artery stenosis may experience

renal failure if ARBs are administered and so should be avoided.

Patients that are hypersensitive to any of the ARBs.

 SIDE EFFECTS OF ARBs
These includes:
 Hypotension.

 Acute renal failure.

 Hyperkalemia .

 Problems during pregnancy.

Dizziness , weakness and syncope

Headache, or cold or flu-like symptoms.

 INTERACTIONS OF ARBS
The concomitant use of ARBs with other RAAS blockers like
ACEIs can cause increased incidence of hypotension,
hyperkalaemia and changes in renal function compared to
monotherapy.

The concomitant use of ARBs with NSAIDS including COX-2

inhibitors leads to attenuation of antihypertensive effects and
increased risk of worsening of renal function.

With diuretics(especially potassium sparing diuretics) which

can cause severe hypotension due to high fluid volume
depletion and also severe hyperkalaemia.

Cyclosporine which can cause severe hyperkalaemia.

Potassium supplements leading to an additive hyperkalaemic
effect.
 EXAMPLES OF ARBs AND THEIR
TRADE NAMES
Candesartan (Atacand).

Eprosartan (Teveten).

Irbesartan (Avapro).

Telmisartan (Micardis).

Valsartan (Diovan).

Losartan (Cozaar).

Olmesartan (Benicar or Olmetec).

BINDING POCKETS AND RECEPTOR BINDING OF
ARBs

Losartan receptor binding

 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs
Pharmacophore
There are three functional groups that are the most
important parts for the bioactivity of ARBs.

The first one is the imidazole ring that binds to amino acids
in helix 7 (Asn295).
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T
The second group is the biphenyl-methyl group that binds to amino acids in both
helices 6 and 7 (Phe301, Phe300, Trp253 and His256).

Losartan

The third one is the tetrazole group that interacts with amino acids in helices 4 and 5
(Arg167 and Lys199)

NOTE:
The tetrazole group has been successfully replaced by a carboxylic acid group as is the
case with telmisartan.

Telmisartan
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T
Most of the ARBs have the same pharmacophore so the difference in their
biochemical and physiological effects is mostly due to different substituents.

Lipophilic substituents like the linear alkyl group at the 2-position on the
imidazole ring together with the biphenyl-methyl group, associate with
hydrophobic pockets of the receptor.

Losartan
Telmisartan

An acidic group like tetrazole, CO2H or NHSO2CF3 at the 1-position of the
biphenyl-methyl group will bind to a basic position in the receptor and are
required for potent antagonistic activity (Yanagiasawa H. et al., 1996).
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T
In valsartan, the imidazole ring of losartan has been replaced with an
acylated amino acid.

Losartan Valsartan

Several substituents have been tried at the 4- and 5- positions on the

imidazole ring.

The chloro and hydroxymethyl groups connected to these positions in

losartan are probably not of much importance in receptor binding since the
other ARBs do not possess these functional groups and have comparable or
better binding affinities than losartan.
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T

 Irbesartan has a carbonyl group at the 5-position, functioning as

a hydrogen bond acceptor in place of the hydroxymethyl group of
losartan, resulting in a longer binding to the receptor.

Irbesartan Losartan
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T

 The structure of eprosartan is the one that differs most from the other ARBs,
the usual biphenyl-methyl group has been replaced by a carboxy benzyl group
that mimics more closely the phenolic moiety of Tyr4 group of Ang II.

Eprosartan

Losartan
This change results in a stronger binding to the receptor but the biochemical
and physiological effects are not significantly improved (Aulakh GK et al., 2007).

Telmisartan has a carboxylic acid at the 2-position of the biphenyl-methyl

group and is more potent than the tetrazole analogue (Aulakh GK et al., 2007).

Telmisartan
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T
It has been reported that imidazoles that have hydroxymethyl and carboxy
groups at the 4- and 5 position, possessed potent antagonistic activity, caused
by the hydrogen bonding and hydrophilicity of the hydroxymethyl group
(Yanagiasawa H. et al., 1996).

Losartan
Olmesartan

 It has also been reported that a hydroxy group in the 4-position on the
imidazole ring, plays an important role in the binding affinity and
compensates for the disadvantage of lipophilicity of the bulky alkyl group
(Yanagiasawa H. et al., 1996).
 STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T
 These results show that a medium-sized hydroxy alkyl group,
such as CHMeOH and CMe2OH, is favorable for the substituent
of the 4-position on the imidazole ring. Furthermore, the
ionizable group is favorable for the binding affinity (Yanagiasawa
H. et al., 1996).

Candesartan and olmesartan have the highest affinity for the

AT1 receptors, followed by irbesartan and eprosartan. Valsartan,
telmisartan and EXP 3174 have similar affinities that are about
ten-fold less than that of candesartan. Losartan has the least
affinity.
 STRUCTURES OF NAMED ARBs

Candesartan Telmisartan
Irbesartan
Eprosartan

Losartan Olmesartan
Valsartan
 DOSAGE/ADMINISTRATION AND PHARMACOKINETICS OF
ARBs
Drug Dose T1/2 Protein Bioavailability Renal/hepatic Food effects Daily
Equivalence (hrs) binding (%) clearance (%) dosage(mg)
(mg) (%)
Losartan 50 2 98.7 33 10/90 Minimal 50-100
( Cozaar)
EXP3174 - 6-9 99.8 - 50/50 - -

Candesartan 8 9 >99 15 60/40 No 4-32

(Atacand)

40-50%
Valsartan 80 6 95 25 30/70 decreased 80-320
(Diovan) by

Irbesartan 150 11-15 90-95 70 1/99 No 150-300

(Avapro)

Telmisartan 40 24 >99 42-58 1/99 No 40-80

(Micardis)

Eprosartan 600 5 98 13 30/70 No 400-800

(Teveten)
Olmesartan 20 14-16 >99 29 40/60 No 10-40
(Olmetec)
 DOSAGE/ADMINISTRATION AND PHARMACOKINETICS OF ARBs
CON’T
 ARBs have a large therapeutic index and therefore their (mostly
low) oral bioavailability does not appear to be of clinical
significance (Farsang C. et al., 2006).

ARBs are highly plasma protein-bound and therefore oral

administration once a day should provide sufficient
antihypertensive effects (Aulakh GK, et al., 2007).

Around 14% of orally ingested losartan is metabolized to its 5-

carboxylic acid metabolite EXP 3174.

Candesartan cilexetil and olmesartan medoxomil are inactive

ester prodrugs that are completely hydrolyzed to their active forms
by esterases during absorption from the gastrointestinal tract.
 DOSAGE/ADMINISTRATION AND PHARMACOKINETICS OF
ARBs CON’T
These three metabolites are more potent AT1 receptor antagonists than their
prodrugs. The other ARBs do not have active metabolites (Aulakh GK, et al.,
2007).

All of the ARBs, except for telmisartan and olmesartan, are metabolized in
some way by the cytochrome P450 (CYP) enzyme 2C9, that is found in the
human liver.

CYP2C9 is for example responsible for the metabolizing of losartan to EXP

3174 and the slow metabolizing of valsartan and candesartan to their inactive
metabolites.

Telmisartan is, on the other hand, in part metabolized by glucuronidation and

olmesartan is excreted as the unchanged drug (Kamiyama, E. et al., 2007).

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 (Aulakh GK, et al., 2007).
 ARBs COMBINATION

ARBs are usually combined with thiazide diuretics (hydrochlorothiazide)

to form a single combined regimen for better compliance in a case where
prescribing the two drugs is of clinical benefits.

 EXAMPLES OF SUCH COMBINATIONS ARE:

Irbesartan+Hydrochlorthiazide ( CoAprovel).

Losartan+Hydrochlorthiazide ( Cozaar Comp).

Olmesartan +Hydrochlorthiazide (Olmetec Plus).

Telmisartan+Hydrochlorthiazide (Micardis Plus).

Valsartan+Hydrochlorthiazide (Co-Diovan).
 ARBs UNDER DEVELOPMENT

Pratosartan

 Several new nonpeptide ARBs are undergoing clinical trials or are at pre-
clinical stages of development. Among these are embusartan (BAY 10-6734 or
BAY 10-6734), KRH-594, fonsartan (HR 720) and pratosartan (KT3-671).
(Aulakh GK. Et al., 2007).

Pratosartan, for example, has a novel structure: a seven-membered ring that

bears an oxo moiety (C=O) fused to the imidazole ring and its affinity for the
AT1 receptor is about 7 times higher than losartan's (Aulakh GK. Et al., 2007).

The purpose of the oxo group is similar to that of the carboxylic acid groups
on other ARBs(Ogihara, T. et al., 2008).
 ARBs UNDER DEVELOPMENT CON’T

 Other attributes of ARBs are also under investigation,

such as the positive effects of telmisartan on lipid and
glucose metabolism and losartan's effects of lowering uric
acid levels (Ogihara, T. et al., 2008).

Such effects might lead to new indications for these

drugs but further research is needed.
 THE AVAILABLE ARBs IN THE HOSPITAL

 ROSART (Losartan potassium tablet): By RANBAXY

LABORATORIES
LIMITED (INDIA).

o Tablet Strengths: 25mg and 50mg.

o Dosage: In hypertension the usual dose is 50 mg once

daily. The dose may be increased, if necessary, to 100 mg daily
as a single dose or in two divided doses. An initial dose of
25 mg once daily should be given to patients with
intravascular fluid depletion.

o In diabetic nephropathy losartan is given in an initial

dose of 50 mg once daily, increased to 100 mg once daily
depending on the blood pressure.
 NOTES:

 A lower starting dose is recommended in patients with

moderate to severe renal and hepatic insufficiency.

 Co administration with cimetidine may increase the serum

concentration of ROSART.

 Rifampin (Rifadin) reduces the blood levels of losartan,

and fluconazole (Diflucan) reduces the conversion of
losartan to its active form. These effects could decrease the
effects of ROSART.
DIOVAN( Valsartan): By NORVATIS.

oTablet Strengths: 80 mg and 160 mg.

o Dosage: In hypertension, valsartan is given in an initial dose of 80 mg

once daily. This may be increased, if necessary, to 160 mg once daily,
although doses of up to 320 mg once daily have been used.
o A lower initial dose of 40 mg once daily may be used in elderly patients
over 75 years, and in those with intravascular volume depletion; similar
dosage reductions have been suggested in hepatic or renal impairment.

o In heart failure, valsartan is given in an initial dose of 40 mg twice daily.

The dose should be increased, as tolerated, to 160 mg twice daily.

o Following myocardial infarction, valsartan may be started as early as 12

hours after the infarction in clinically stable patients, in an initial dose of
20 mg twice daily; the dose may be doubled at intervals over the next few
weeks up to 160 mg twice daily if tolerated. A maximum dose of 80 mg twice
daily is recommended in hepatic impairment.
 THE AVAILABLE ARB COMBINATION IN THE HOSPITAL
 CO-DIOVAN (Valsartan+Hydrochlorothiazide ): By NOVARTIS.
Tablet strengths: 80mg/12.5mg, 160mg/12.5mg.

o Dosage: The recommended dose of Co-Diovan is 1 coated tablet per

day.
When clinically appropriate either 80mg/12.5mg or 160mg/12.5mg or
320mg/12.5 may be used.

o When necessary 160mg/25mg or 320mg/25mg may be used.

The maximum daily dose is 320mg/25mg.

NOTES:
The safety and efficacy of Co-Diovan have not been established in
children below the age of 18 years.

Due to hydrochlorothiazide component, Co-Diovan should be used

with particular caution in patients with severe hepatic impairment.
 DISCUSSION.
 ARBs are modulators of the renin-angiotensin-aldosterone
system(RAAS).

 Their main uses are in the treatment of hypertension (high blood

pressure), diabetic nephropathy (kidney damage due to diabetes). However,
they are of clinical benefits when use in patients with myocardial infarction.

 Several new nonpeptide ARBs are undergoing clinical trials or are at pre-
clinical stages of development. Among these are embusartan (BAY 10-6734),
KRH-594, fonsartan (HR 720) and pratosartan (KT3-671). (Aulakh GK. Et
al., 2007).

 Angiotensin II, through AT1 receptor stimulation, is a major stress

hormone and, because (ARBs) block these receptors, in addition to their
eliciting anti-hypertensive effects, may be considered for the treatment of
stress-related disorders (Pavel J., et al 2008).
 CONCLUSION

 ARBs do not inhibit the breakdown of bradykinin or other

kinins, and are thus only rarely associated with the persistent
dry cough and/or angioedema that limit ACE inhibitor
therapy.

They are therefore used where the patient is intolerant of

ACE inhibitor therapy.
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