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 andInteractions of ARBs. Examples of ARBs with their structures. SAR of ARBs. Dosage/Administration and Pharmacokinetics ofARBs.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 ofmyocardial 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,sleeplessnessHypertension or hypotension (depending in part on the extent of cardiacdamage), tachycardia and arrhythmias.Recent clinical research indicates that the symptoms may be verydifferent between men and women. Chest pain is less common in women.Instead, their most common symptoms are weakness, fatigue anddyspnea( Lippincott W., et al.,2011).

BRIEF PATHOPHYSIOLOGY OF MYOCARDIAL INFARCTION

MI most commonly occurs when a coronary artery becomesoccluded following the rupture of an atherosclerotic plaque,which then leads to the formation of a blood clot (coronarythrombosis). This event can also trigger coronary vasospasm.If a vessel becomes completely occluded, the myocardiumnormally supplied by that vessel will become ischemic andhypoxic.Without sufficient oxygen, the tissue dies.The damaged tissue is initially comprised of a necrotic coresurrounded by a marginal (or border) zone that can eitherrecover normal function or become irreversibly damaged.The hypoxic tissue within the border zone may become a sitefor generating arrhythmias.

EFFECTS OF MYOCARDIAL INFARCTIONWhen myocardial infarction occurs, it leads to the following effects in differentparts of the body which includes:

Neurohumoral (Release of neurotransmitters)↑ circulating catecholaminesSympathetic 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 RemodelingInhibit sympathetic activityInhibit 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 themwith 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 bloodpressure, but was an enzyme which catalyzed the formation ofthe 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 receptorantagonists and initially, the main focus was on angiotensinpeptide analogues.

BRIEF HISTORY OF ARBs CON’T

Saralasin and other Ang II analogues were potent Ang IIreceptor blockers but the main problem was a lack of oralbioavailability(Adam, M. , 2005).

In the early 1980s it was noted that a series of imidazole-5-acetic acid derivatives diminished blood pressure responses toAng II in rats.

However, it was seen that their structures would have tomimic more closely the pharmacophore of Ang II. Structuralmodifications were made and the orally active, potent andselective nonpeptide AT1 receptor blocker losartan wasdeveloped.

In 1995 losartan was approved for clinical use in the UnitedStates 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 systemthat regulates blood pressure and water (fluid) balance.

The system can be activated when there is a loss of bloodvolume or a drop in blood pressure (such as in hemorrhage ordehydration). This loss of pressure is interpreted bybaroreceptors in the carotid sinus. In alternative fashion, adecrease in filtrate flow rate due to renal hypoperfusion willstimulate the macula densa to signal the juxtaglomerular cells torelease renin.

RAAS CONT.... The release of renin is followed by the following process:

Renin cleaves a zymogen, an inactive peptide, calledangiotensinogen release by the liver, converting it intoangiotensin I(inactive decapeptide).

Angiotensin I is then converted to angiotensin II ( activeoctapeptide) by angiotensin-converting enzyme (ACE)which is thought to be found mainly in lung capillaries.One study in 1992 found ACE in all blood vesselendothelial cells.( Rogerson FM et al., 1992).

Angiotensin II is the major bioactive product of therenin-angiotensin system (RAAS).

STRUCTURE OF ANGIOTENSIN II

Arginine

Leucine

Tyrosine

Isoleucine

Histidine

Proline

PhenylalanineAspartic acid

CARDIOVASCULAR EFFECTS OF ANGIOTENSIN IIWhen angiotensin II is formed, it acts via it receptors foundon different part of the body to cause different effects.ANGIOTENSIN II RECEPTORS AND THEIR LOCATION INTHE BODYThe 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 thatcauses blood vessels to constrict, resulting inincreased blood pressure.

Angiotensin II also stimulates the secretion of thehormone aldosterone from the adrenal cortex.

Aldosterone causes the tubules of the kidneys toincrease the reabsorption of sodium and water intothe blood. This increases the volume of fluid in thebody, which also increases blood pressure.

CARDIOVASCULAR EFFECTS OF ANGIOTENSIN II CON’T

Angiotensin II also acts on the posterior pituitary gland tocause the release of ADH which also increase the reabsorption of water along the collecting duct increasing fluidvolume and subsequently increase in blood pressure.

If the renin-angiotensin-aldosterone system is abnormallyactive, blood pressure will be too high.

There are many drugs that interrupt different steps in thissystem to lower blood pressure. These drugs are one of themain 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 reductionin 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 ,ejectionfraction and signs and symptoms of heart failure and hencequality of life of the patient.

Post myocardial infarction as they found to improve survival inclinically stable patients with signs , symptoms or radiologicalevidence of left ventricular failure and/ or with left ventricularsystolic dysfunction.

CONTRAINDICATIONS OF ARBsARBs 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 ARBsThese includes: Hypotension.

Acute renal failure.

Hyperkalemia .

Problems during pregnancy.

Dizziness , weakness and syncope

Headache, or cold or flu-like symptoms.

INTERACTIONS OF ARBSThe concomitant use of ARBs with other RAAS blockers likeACEIs can cause increased incidence of hypotension,hyperkalaemia and changes in renal function compared tomonotherapy.

The concomitant use of ARBs with NSAIDS including COX-2inhibitors leads to attenuation of antihypertensive effects andincreased risk of worsening of renal function.

With diuretics(especially potassium sparing diuretics) whichcan cause severe hypotension due to high fluid volumedepletion and also severe hyperkalaemia.

Cyclosporine which can cause severe hyperkalaemia.Potassium supplements leading to an additive hyperkalaemiceffect.

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 PharmacophoreThere are three functional groups that are the mostimportant parts for the bioactivity of ARBs.

The first one is the imidazole ring that binds to amino acidsin helix 7 (Asn295).

STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T

The second group is the biphenyl-methyl group that binds to amino acids in bothhelices 6 and 7 (Phe301, Phe300, Trp253 and His256).

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 thecase with telmisartan.

Telmisartan

Losartan

STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T

Most of the ARBs have the same pharmacophore so the difference in theirbiochemical and physiological effects is mostly due to different substituents.

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

An acidic group like tetrazole, CO2H or NHSO2CF3 at the 1-position of thebiphenyl-methyl group will bind to a basic position in the receptor and arerequired for potent antagonistic activity (Yanagiasawa H. et al., 1996).

LosartanTelmisartan

STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T

In valsartan, the imidazole ring of losartan has been replaced with an acylated amino acid.

Several substituents have been tried at the 4- and 5- positions on the imidazole ring.

The chloro and hydroxymethyl groups connected to these positions inlosartan are probably not of much importance in receptor binding since theother ARBs do not possess these functional groups and have comparable orbetter binding affinities than losartan.

ValsartanLosartan

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 groupthat mimics more closely the phenolic moiety of Tyr4 group of Ang II.

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

Telmisartan has a carboxylic acid at the 2-position of the biphenyl-methylgroup and is more potent than the tetrazole analogue (Aulakh GK et al., 2007).

Eprosartan

Losartan

Telmisartan

STRUCTURE ACTIVITY RELATIONSHIP OF ARBs CON’T

It has been reported that imidazoles that have hydroxymethyl and carboxygroups at the 4- and 5 position, possessed potent antagonistic activity, causedby the hydrogen bonding and hydrophilicity of the hydroxymethyl group(Yanagiasawa H. et al., 1996).

It has also been reported that a hydroxy group in the 4-position on theimidazole ring, plays an important role in the binding affinity andcompensates for the disadvantage of lipophilicity of the bulky alkyl group(Yanagiasawa H. et al., 1996).

OlmesartanLosartan

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 substituentof the 4-position on the imidazole ring. Furthermore, theionizable group is favorable for the binding affinity (YanagiasawaH. et al., 1996).

Candesartan and olmesartan have the highest affinity for theAT1 receptors, followed by irbesartan and eprosartan. Valsartan,telmisartan and EXP 3174 have similar affinities that are aboutten-fold less than that of candesartan. Losartan has the leastaffinity.

STRUCTURES OF NAMED ARBs

CandesartanEprosartan

IrbesartanTelmisartan

Valsartan Losartan Olmesartan

DOSAGE/ADMINISTRATION AND PHARMACOKINETICS OF ARBs

Drug Dose

Equivalence

(mg)

T1/2

(hrs)

Protein

binding

(%)

Bioavailability

(%)

Renal/hepatic

clearance (%)

Food effects Daily

dosage(mg)

Losartan

( Cozaar)

50 2 98.7 33 10/90 Minimal 50-100

EXP3174 - 6-9 99.8 - 50/50 - -

Candesartan

(Atacand)

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

Valsartan

(Diovan)

80 6 95 25 30/70

40-50%

decreased

by

80-320

Irbesartan

(Avapro)

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

Telmisartan

(Micardis)

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

Eprosartan

(Teveten)

600 5 98 13 30/70 No 400-800

Olmesartan

(Olmetec)

20 14-16 >99 29 40/60 No 10-40

DOSAGE/ADMINISTRATION AND PHARMACOKINETICS OF ARBs CON’T

ARBs have a large therapeutic index and therefore their (mostlylow) oral bioavailability does not appear to be of clinicalsignificance (Farsang C. et al., 2006).

ARBs are highly plasma protein-bound and therefore oraladministration once a day should provide sufficientantihypertensive 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 inactiveester prodrugs that are completely hydrolyzed to their active formsby 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 theirprodrugs. The other ARBs do not have active metabolites (Aulakh GK, et al.,2007).

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

CYP2C9 is for example responsible for the metabolizing of losartan to EXP3174 and the slow metabolizing of valsartan and candesartan to their inactivemetabolites.

Telmisartan is, on the other hand, in part metabolized by glucuronidation andolmesartan is excreted as the unchanged drug (Kamiyama, E. et al., 2007).

Telmisartan is the only ARB that can cross the blood–brain barrier and cantherefore inhibit centrally mediated effects of Ang II, contributing to even betterblood 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 whereprescribing 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

Several new nonpeptide ARBs are undergoing clinical trials or are at pre-clinical stages of development. Among these are embusartan (BAY 10-6734 orBAY 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 thatbears an oxo moiety (C=O) fused to the imidazole ring and its affinity for theAT1 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 groupson other ARBs(Ogihara, T. et al., 2008).

Pratosartan

ARBs UNDER DEVELOPMENT CON’T

Other attributes of ARBs are also under investigation,such as the positive effects of telmisartan on lipid andglucose metabolism and losartan's effects of lowering uricacid levels (Ogihara, T. et al., 2008).

Such effects might lead to new indications for thesedrugs but further research is needed.

THE AVAILABLE ARBs IN THE HOSPITAL

ROSART (Losartan potassium tablet): By RANBAXYLABORATORIESLIMITED (INDIA).

o Tablet Strengths: 25mg and 50mg.

o Dosage: In hypertension the usual dose is 50 mg oncedaily. The dose may be increased, if necessary, to 100 mg dailyas a single dose or in two divided doses. An initial dose of25 mg once daily should be given to patients withintravascular fluid depletion.

o In diabetic nephropathy losartan is given in an initialdose of 50 mg once daily, increased to 100 mg once dailydepending on the blood pressure.

NOTES:

A lower starting dose is recommended in patients withmoderate to severe renal and hepatic insufficiency.

Co administration with cimetidine may increase the serumconcentration of ROSART.

Rifampin (Rifadin) reduces the blood levels of losartan,and fluconazole (Diflucan) reduces the conversion oflosartan to its active form. These effects could decrease theeffects 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 mgonce 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 patientsover 75 years, and in those with intravascular volume depletion; similardosage 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 12hours after the infarction in clinically stable patients, in an initial dose of20 mg twice daily; the dose may be doubled at intervals over the next fewweeks up to 160 mg twice daily if tolerated. A maximum dose of 80 mg twicedaily 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 perday.When clinically appropriate either 80mg/12.5mg or 160mg/12.5mg or320mg/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 inchildren below the age of 18 years.

Due to hydrochlorothiazide component, Co-Diovan should be usedwith particular caution in patients with severe hepatic impairment.

DISCUSSION. ARBs are modulators of the renin-angiotensin-aldosteronesystem(RAAS).

Their main uses are in the treatment of hypertension (high bloodpressure), 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 otherkinins, and are thus only rarely associated with the persistentdry cough and/or angioedema that limit ACE inhibitortherapy.

They are therefore used where the patient is intolerant ofACE inhibitor therapy.

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