hypertension 1

HypertensionHypertensionAn OverviewAn Overview

Dr. Devendra Khandke MDDr. Devendra Khandke MD

Head- Medical ServicesHead- Medical Services

Alembic LimitedAlembic Limited

What Is Blood Pressure ?What Is Blood Pressure ?

Blood pressure is the amount of Blood pressure is the amount of force on the walls of the arteries as force on the walls of the arteries as the blood circulates around the the blood circulates around the body.body.

BLOOD PRESSUREBLOOD PRESSURE

Systolic Blood pressure:Systolic Blood pressure:

- Pressure during systole- Pressure during systole

- The reading is higher- The reading is higher

Diastolic Blood pressure: Diastolic Blood pressure:

- Pressure during diastole- Pressure during diastole

- The reading is lower- The reading is lower

Blood PressureBlood Pressure

BP = pressure exerted on the vessel wall by BP = pressure exerted on the vessel wall by bloodblood

BP = BP = cardiac output ( CO)cardiac output ( CO) x x PVR PVR

where CO iswhere CO is

CO = stroke volume x Heart rateCO = stroke volume x Heart rate

BP = ( BP = ( SVSV X X HRHR ) X ) X PVRPVR

BLOOD PRESSUREBLOOD PRESSURE Peripheral Vascular Resistance depends on :Peripheral Vascular Resistance depends on :

- Lumen diameter of peripheral - Lumen diameter of peripheral arteriolesarterioles

- - dilatation of peripheral arterioles dilatation of peripheral arterioles decreases PVR & lowers BPdecreases PVR & lowers BP

- - Contraction of peripheral arterioles Contraction of peripheral arterioles increases PVR & BPincreases PVR & BP

BP:Diurnal variation

Blood PressureBlood Pressure

Two physiological systems which mainly controlTwo physiological systems which mainly control

blood pressure :blood pressure :

Sympathetic (SNS)Sympathetic (SNS) Autonomic Nervous SystemAutonomic Nervous System

(ANS)(ANS)

ParasympatheticParasympathetic

Renin-Angiotensin – Aldosterone – System Renin-Angiotensin – Aldosterone – System

(RAAS)(RAAS)

ANS:NeurotransmittersANS:Neurotransmitters

Sympathetic nervous sys:Sympathetic nervous sys:– NorepinephrineNorepinephrine– Epinephrine-released from adrenal Epinephrine-released from adrenal

medullamedulla

Parasympathetic nervous sys:Parasympathetic nervous sys:– AcetylcholineAcetylcholine

Blood PressureBlood PressureRole of SNS :Role of SNS : Neurotransmitters - Epinephrine Neurotransmitters - Epinephrine

(adrenaline) (adrenaline) Norepinephrine Norepinephrine (nor-adrenaline)(nor-adrenaline)

Adrenoceptors/ Adrenergic receptors - Adrenoceptors/ Adrenergic receptors - 11 (alpha) (alpha) 22

ββ11

ββ (Beta) (Beta)

ββ22

Main effect of Main effect of -adrenoceptors-adrenoceptors

OrganOrgan ReceptorReceptor Effect of Effect of stimulationstimulation

Blood vessels Blood vessels arterioles :arterioles :

1 Constriction – Constriction – increase in increase in PVRPVR

Main response mediated by Main response mediated by ββ-adrenoceptors-adrenoceptors

OrganOrgan β-ADRENOCEPTORSUBTYPE

RESPONSE TO STIMULATION

Heart β1 Increase in heart rate, and force of contraction

Kidney β1 Stimulation of renin release

Blood Vessels β2 Dilatation

Lung β2 Bronchodilatation

Glycogenolysis β1 (heart)β2 (skeletalmuscle, liver)

Promotes Glycogenolysis

Lipolysis (adipocytes)

β1 > β2 Promotes lipolysis

Sympathetic Nervous SystemSympathetic Nervous System SNS stimulation Release of neurotransmitters SNS stimulation Release of neurotransmitters

(Norepinephrine & (Norepinephrine & epinephrine)epinephrine)

They Combine with receptors (alpha & beta)They Combine with receptors (alpha & beta)

• Alpha receptors of blood vesselsAlpha receptors of blood vessels : :

vasoconstriction PVRvasoconstriction PVR

• Beta receptors of heartBeta receptors of heart : :

increase in heart rate, increase in force ofincrease in heart rate, increase in force of contraction contraction

Effect of SNS stimulationEffect of SNS stimulation

Heart rate (HR) Heart rate (HR) Cardiac Cardiac Force of contractionForce of contraction output output

Vasoconstriction - PVRVasoconstriction - PVR

Increase in BP

RAASRAAS

RENINAngiotensinogen Angiotensin I (Liver)

Angiotensin Converting

Enzyme Angiotensin II ( Active )

Major Actions: Major Actions: seen after combing with seen after combing with AT1 receptorsAT1 receptors

Most potent Vasoconstrictor-Most potent Vasoconstrictor-

- - Increase in PVRIncrease in PVR

Stimulates release of Aldosterone Stimulates release of Aldosterone

- - Sodium & Water retentionSodium & Water retention

Stimulates sympathetic Nervous Stimulates sympathetic Nervous

systemsystem

Angiotensin IIAngiotensin II

HypertensionHypertension

JNC-7JNC-7

Causes of HypertensionCauses of Hypertension Primary / Essential hypertension:Primary / Essential hypertension:

- No- No identifiable causeidentifiable cause– Most common causeMost common cause– Accounts for 93 % of cases Accounts for 93 % of cases

Secondary Hypertension:Secondary Hypertension:

(Due to other diseases)(Due to other diseases)– Renal HypertensionRenal Hypertension– Endocrine Hypertension etc.Endocrine Hypertension etc.

Harmful effects of High Blood PressureHarmful effects of High Blood Pressure

Hardening of the arteries-Hardening of the arteries-atherosclerosisatherosclerosis

StrokeStroke

Heart attackHeart attack

Kidney damage-kidney failureKidney damage-kidney failure

BlindnessBlindness

Target Organ Damage:Target Organ Damage:

HeartHeart - - CHF, MI CHF, MI

BrainBrain -- Stroke, Stroke,

Kidney - Renal failureKidney - Renal failure

Eyes -Eyes - Hypertensive RetinopathyHypertensive Retinopathy

Blood vessels Blood vessels - Atherosclerosis- Atherosclerosis

Complications of uncontrolled hypertensionComplications of uncontrolled hypertension


Important risk factor:Important risk factor:

- Myocardial infarction- Myocardial infarction

- Heart failure- Heart failure

- Stroke- Stroke

- Renal failure- Renal failure

Hypertension: MortalityHypertension: Mortality


A. Uncomplicated hypertension :A. Uncomplicated hypertension :

– Usually no symptomsUsually no symptoms

B. Complicated hypertension : B. Complicated hypertension :

Target organ damageTarget organ damageHeadacheHeadacheConfusionConfusionSevere shortness of breath etc.Severe shortness of breath etc.

Benefits of lowering BPBenefits of lowering BP

Condition Percent reductionStroke 34-40%

MI 20-25 %Heart Failure 50%

Goals of therapyGoals of therapy

BP < 140/90 mmHgBP < 140/90 mmHg

In diabetics or in patients with In diabetics or in patients with chronic renal disease:chronic renal disease:

<130/80 mmHg<130/80 mmHg

ISH : SBP in persons>50 years:ISH : SBP in persons>50 years: <140 mmHg<140 mmHg

Hypertension - ManagementHypertension - Management

Non- drug therapyNon- drug therapy

Drug therapyDrug therapy

Lifestyle modifications for Lifestyle modifications for hypertension controlhypertension control

Used as definitive or adjunctive therapy.Used as definitive or adjunctive therapy. Manage weight.Manage weight. Limit daily alcohol intake to Limit daily alcohol intake to 1 ounce of 1 ounce of

ethanol.ethanol. Engage in physical activity regularly.Engage in physical activity regularly. Reduce daily sodium intake to <2.3 grams of Reduce daily sodium intake to <2.3 grams of

sodium or <6 grams of sodium chloride.sodium or <6 grams of sodium chloride. Maintain adequate potassium, calcium, and Maintain adequate potassium, calcium, and

magnesium intake.magnesium intake. Stop smoking. Stop smoking. Reduce saturated fat and cholesterol intake.Reduce saturated fat and cholesterol intake.

Hypertension - ManagementHypertension - Management

Non - Pharmacological approach :Non - Pharmacological approach :

1. Relaxation techniques :1. Relaxation techniques :

Yoga, Meditation etcYoga, Meditation etc

2. 2. Regular ExerciseRegular Exercise

Lifestyle ModificationLifestyle Modification

ModificationModification Approximate SBP Approximate SBP reductionreduction(range)(range)

Weight reductionWeight reduction 5–20 mmHg/10 kg weight loss5–20 mmHg/10 kg weight loss

Adopt DASH eating planAdopt DASH eating plan 8–14 mmHg8–14 mmHg

Dietary sodium reductionDietary sodium reduction 2–8 mmHg2–8 mmHg

Physical activityPhysical activity 4–9 mmHg4–9 mmHg

Moderation of alcohol Moderation of alcohol consumptionconsumption

2–4 mmHg2–4 mmHg

Ideal Antihypertensive drugIdeal Antihypertensive drug

Good efficacy-should provide Good efficacy-should provide 24-hr control24-hr control

of BP with once daily doseof BP with once daily dose

Minimal or no serum glucose imbalanceMinimal or no serum glucose imbalance

Minimal or no electrolyte imbalanceMinimal or no electrolyte imbalance

Minimal or no lipid profile imbalanceMinimal or no lipid profile imbalance

Improve quality of life Improve quality of life

- Physical activity, sleep, sexual - Physical activity, sleep, sexual

functions.functions.

Dosage complianceDosage compliance

Major AntihypertensivesMajor Antihypertensives

1. Diuretics: Hydrochlorothiazide1. Diuretics: Hydrochlorothiazide

2. Beta blockers : Atenolol,nebivolol,metoprolol2. Beta blockers : Atenolol,nebivolol,metoprolol

3.3. ACE inhibitors :ACE inhibitors :

- Enalapril, Lisinopril, Ramipril etc- Enalapril, Lisinopril, Ramipril etc

4. AT1 receptor antagonists:4. AT1 receptor antagonists:

- Losartan,valsartan,telmisartan etc- Losartan,valsartan,telmisartan etc

5.5. Calcium antagonists : Calcium antagonists :

- Amlodipine, Nifedipine, Diltiazem- Amlodipine, Nifedipine, Diltiazem

6.6. Alpha blockers :Alpha blockers :

- - Prazosin,terazosin,doxazosinPrazosin,terazosin,doxazosin

DiureticsDiuretics Act onAct on kidneyskidneys-Increase excretion of -Increase excretion of

sodium & watersodium & water

Reduce Blood Volume Reduce Blood Volume [ Preload ][ Preload ]

• Reduce BP

Thiazide DiureticsThiazide Diuretics

First-line treatment in mildFirst-line treatment in mild

( Stage 1 ) hypertension( Stage 1 ) hypertension

Often used in combination with other Often used in combination with other

antihypertensive agents -antihypertensive agents -

e.g. ACEIs, ATe.g. ACEIs, AT11 lockers, lockers,

beta blockersbeta blockers

DiureticsDiuretics

IndicationsIndications


Heart failureHeart failure

Beta BlockersBeta Blockers Mode of actionMode of action

Block Beta receptors present in heart :Block Beta receptors present in heart :

Decrease CO-decrease heart rate & force of Decrease CO-decrease heart rate & force of

contraction-contraction-negative chronotropic & negative chronotropic &

negative inotropic effectsnegative inotropic effects

Decrease in Renin release from the KidneysDecrease in Renin release from the Kidneys

Central action - reduction in Sympathetic Central action - reduction in Sympathetic

tonetone

Beta blockersBeta blockersClassification :Classification :

1.1.Non-selective:Non-selective:

Block both Block both beta1beta1 & & beta2beta2 receptors receptors

(Propranolol )(Propranolol )

2.2.Cardio-selectiveCardio-selective::

Block only beta1 receptors Block only beta1 receptors (Atenolol,Metoprolol,Nebivolol )(Atenolol,Metoprolol,Nebivolol )

3. 3. Combined beta & alpha blockerCombined beta & alpha blocker::

Block both beta1 & beta2 + alpha1 receptors Block both beta1 & beta2 + alpha1 receptors

( ( carvedilolcarvedilol ) )

Beta BlockersBeta Blockers IndicationsIndications

HypertensionHypertension AnginaAngina Post-MIPost-MI

Beta BlockersBeta Blockers

Side effectsSide effectsBradycardiaBradycardiaAV block- not safe in heart blockAV block- not safe in heart blockFatigueFatigueBronchospasm- not safe in Bronchospasm- not safe in asthmaasthma

Loss of LibidoLoss of LibidoImpotenceImpotenceDyslipidemiaDyslipidemia

Calcium AntagonistsCalcium Antagonists Also called calcium channel blockers-Dialate Also called calcium channel blockers-Dialate

arterioles- decrease PVR & BParterioles- decrease PVR & BP 3 groups:3 groups:

1.1.Dihydropyridine derivatives:Dihydropyridine derivatives: Nifedipine,felodipine,amlodipine etcNifedipine,felodipine,amlodipine etc

22.Benzothiazepines: Diltiazem.Benzothiazepines: Diltiazem

3.3.Phenylalkylamines:Phenylalkylamines: VerapamilVerapamil

CCBsCCBs block the L type calcium channels block the L type calcium channels present within blood vessels- present within blood vessels- prevent entry prevent entry of calcium ions into vascular smooth muscle of calcium ions into vascular smooth muscle fibersfibers

– relaxing large and small arteries and relaxing large and small arteries and

reducing peripheral resistancereducing peripheral resistance( PVR )( PVR )

– Reduce force of contraction of Reduce force of contraction of myocardiummyocardium

Calcium Antagonists

Calcium Channel BlockersCalcium Channel Blockers

IndicationsIndications

– HypertensionHypertension

– AnginaAngina

CCBs are commonly used to treat hypertension CCBs are commonly used to treat hypertension because:because:

– Very well tolerated,compliance is high, Very well tolerated,compliance is high,

– They don’t have any adverse effect on quality They don’t have any adverse effect on quality of lifeof life

– Do not alter carbohydrate or lipid MetabolismDo not alter carbohydrate or lipid Metabolism

– often used in combination with beta-blocker often used in combination with beta-blocker therapy therapy

Calcium antagonists

Contraindications:Contraindications:– Acute MIAcute MI– Heart failureHeart failure

Averse Drug Reactions:Averse Drug Reactions:– FlushingFlushing– HeadacheHeadache– Ankle oedemaAnkle oedema– Reflex tachycardiaReflex tachycardia

Calcium antagonists

ACE InhibitorsACE Inhibitors Inhibit Angiotensin Converting Inhibit Angiotensin Converting

EnzymeEnzyme

Decrease formation of angiotensin IIDecrease formation of angiotensin II

- - decrease afterload & preloaddecrease afterload & preload

Lower BPLower BP

Examples:Examples: CaptoprilCaptoprilEnalaprilEnalaprilLisinoprilLisinoprilBenazeprilBenazeprilPerindoprilPerindoprilRamiprilRamipril

ACE InhibitorsACE Inhibitors

Indications:Indications:


Heart failureHeart failure

Post MIPost MI

Diabetic NephropathyDiabetic Nephropathy


Adverse effects:Adverse effects:

HyperkalemiaHyperkalemia Dry coughDry cough

Less common:Less common: RashRash


Contraindications :Contraindications :

Bilateral renal artery Bilateral renal artery

stenosisstenosis

Severe renal failureSevere renal failure

PregnancyPregnancy

lactationlactation


Block the ATBlock the AT1 1 receptors receptors

Reduce afterload & preloadReduce afterload & preload

e.g. Losartan, candesartan, valsartan,e.g. Losartan, candesartan, valsartan,

telmisartan etctelmisartan etc

Better tolerated than ACE inhibitors-Better tolerated than ACE inhibitors-

- do not produce dry cough- do not produce dry cough

Angiotensin-II Receptor BlockersAngiotensin-II Receptor Blockers

Diabetic hypertensiveDiabetic hypertensive

70 % of Type 2 diabetics have hypertension70 % of Type 2 diabetics have hypertension

Co-existing diabetes & hypertension Co-existing diabetes & hypertension increases risk of renal diseaseincreases risk of renal disease Target BP : <130/80 mmHgTarget BP : <130/80 mmHg Drugs of choiceDrugs of choice: ACEIs,ARBs,CCBs: ACEIs,ARBs,CCBs

Benefits : Benefits : Greater reduction in cardiovascular Greater reduction in cardiovascular events e.g. MI, deathevents e.g. MI, death Slower decline in renal functionSlower decline in renal function

Hypertension with heart failureHypertension with heart failure

ACE-I or ARBACE-I or ARB

Add diuretic if- not controlled or water retentionAdd diuretic if- not controlled or water retention

Additional therapy: carvedilol or MetoprololAdditional therapy: carvedilol or Metoprolol

Smoking Beta-blocker

The benefits of treatingsmokers with beta-blockers

remain uncertainin the absence

of a specific indicationlike angina or post-MI

Treatment of Hypertension With Treatment of Hypertension With Associated Risk Factors Associated Risk Factors

Drug of choice : CCB

Treatment of Hypertension Treatment of Hypertension

with Airways Diseases*with Airways Diseases*

Airway disease*

Standard HTN treatment.If thiazide, add

potassium-sparing diuretic

Beta-blocker

Calcium channel blocker

All Beta-blockers arecontraindicated if asthma

or bronchial hyperreactivity

* Asthma, COPD

Hypertension with IHD/ CADHypertension with IHD/ CAD

Stable angina

Post - MI

Beta blocker or CCB

Beta blocker or ACE-I

Isolated Systolic Hypertension :Isolated Systolic Hypertension :

Most common type of hypertension seen in the Most common type of hypertension seen in the

elderlyelderly

Prevalence:Prevalence: 5% in populations aged 60-69yrs 5% in populations aged 60-69yrs

10% in populations aged 70-79 yr.10% in populations aged 70-79 yr.

Cause:Cause: Rigidity & loss of elasticity of large Rigidity & loss of elasticity of large

arteries.arteries.

Isolated Systolic hypertension ( ISH)Isolated Systolic hypertension ( ISH)

Systolic BP > 140 mm HgSystolic BP > 140 mm Hg

Diastolic BP < 90 mm HgDiastolic BP < 90 mm Hg

Common in elderlyCommon in elderly

Increased risk of MI,stroke & Increased risk of MI,stroke &

cardiovascular mortalitycardiovascular mortality

Treatment:Treatment: Calcium channel blockers Calcium channel blockers

DiureticsDiuretics

Initial Drug Choices

Without Compelling indication: Thiazide-Type Diuretics (or ACEI, ARB, BB, CCB)

Treatment ofTreatment ofHypertensionHypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB,

or combination.

Without Compelling Indications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Algorithm for Treatment of HypertensionAlgorithm for Treatment of Hypertension


2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)


2-drug combination for most

(usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Guidelines: Hypertension Prevention Guidelines: Hypertension Prevention and Management -- JNC 7and Management -- JNC 7

For patients 50 and older, elevated systolic BP is a For patients 50 and older, elevated systolic BP is a better indicator of cardiovascular risk than elevated better indicator of cardiovascular risk than elevated diastolic BPdiastolic BP

Normal BP is defined as SBP <120 mm Hg and DBP <80 Normal BP is defined as SBP <120 mm Hg and DBP <80 mm Hgmm Hg

Within the BP range of 115/75 to 185/115 mm Hg, each Within the BP range of 115/75 to 185/115 mm Hg, each increment of 20/10 mm Hg doubles cardiovascular riskincrement of 20/10 mm Hg doubles cardiovascular risk

Lifestyle modification for all patients with Lifestyle modification for all patients with prehypertension and drug therapy only for prehypertension and drug therapy only for prehypertensive patients with "compelling indications" prehypertensive patients with "compelling indications" (heart failure, prior MI, high CHD risk, diabetes, chronic (heart failure, prior MI, high CHD risk, diabetes, chronic kidney disease, prevention of recurrent stroke)kidney disease, prevention of recurrent stroke)


BP-control target is <140/<90 mm Hg, except in BP-control target is <140/<90 mm Hg, except in patients with diabetes or renal disease, whose target patients with diabetes or renal disease, whose target is <130/<80 mm Hgis <130/<80 mm Hg

Prevention and treatment should begin with multiple Prevention and treatment should begin with multiple lifestyle modificationslifestyle modifications

Thiazide-type diuretics -- either alone or in Thiazide-type diuretics -- either alone or in combination with ACE inhibitors, angiotensin-receptor combination with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, or calcium-channel blockers -- blockers, beta-blockers, or calcium-channel blockers -- should be initial drug therapy for most patients with should be initial drug therapy for most patients with uncomplicated hypertension uncomplicated hypertension

Hypertensive patients with compelling indications start Hypertensive patients with compelling indications start with another drug class, specific to the compelling with another drug class, specific to the compelling conditioncondition


Most hypertensive patients will require at least 2 BP-Most hypertensive patients will require at least 2 BP-lowering medications to achieve BP goals. lowering medications to achieve BP goals.

If a patient is more than 20/10 mm Hg above goal, the If a patient is more than 20/10 mm Hg above goal, the authors recommend that clinicians consider initiating authors recommend that clinicians consider initiating therapy with 2 drugs.therapy with 2 drugs.

Because adherence to antihypertensive treatment is Because adherence to antihypertensive treatment is generally poor, a clearly articulated, patient-centered generally poor, a clearly articulated, patient-centered BP-control approach with diligent monitoring is BP-control approach with diligent monitoring is importantimportant

Renin –Angiotensin – Aldosterone Renin –Angiotensin – Aldosterone System (RAAS)System (RAAS)

Plays an essential role in regulation of Plays an essential role in regulation of

blood pressure, blood volume, blood pressure, blood volume,

electrolyte balance and glomerular electrolyte balance and glomerular

filtration rate (GFR)filtration rate (GFR)

RAASRAASAngiotensinogenAngiotensinogen

Renin(kidney)Renin(kidney)

Angiotensin IAngiotensin I

Non ACE ACENon ACE ACE PathwayPathway


ATAT11 receptors AT receptors AT22 receptors receptors

Vasoconstriction Aldosterone Stimulation Cell Vasoconstriction Aldosterone Stimulation Cell growthgrowth

(PVR)(PVR) release of SNS release of SNS salt & watersalt & water retention retention (preload)(preload)

RAASRAAS

RAASRAAS Renin Renin

– An enzyme synthesized and released by the An enzyme synthesized and released by the

juxtaglomerular cells of the kidneysjuxtaglomerular cells of the kidneys

– Acts on Acts on AngiotensinogenAngiotensinogen

– Converts angiotensinogen to Angiotensin IConverts angiotensinogen to Angiotensin I

AngiotensinogenAngiotensinogen Angiotensin - I Renin

RAASRAAS

Angiotensin IAngiotensin I Angiotensin II (A II) ACE

Functions of ACE:

Conversion of Angiotensin I to Angiotensin II

Degradation of bradykinin

Bradykinin Inactive ingredientsACE

RAASRAAS

Angiotensin II is highly active Angiotensin II is highly active

Produces a number of effects in different Produces a number of effects in different

parts of the body after combining with parts of the body after combining with

Angiotensin II receptorAngiotensin II receptor

ATAT11 and AT and AT22 receptors receptors

RAASRAAS

ATAT11 receptors: receptors:

– Responsible for virtually all the known Responsible for virtually all the known

actions of Angiotensin II actions of Angiotensin II

ATAT11 receptors are present in the receptors are present in the

– blood vesselsblood vessels

– adrenal glandadrenal gland

– heartheart

– kidney kidney

– brain & brain &

– liverliver

RAASRAAS Vasoconstriction:Vasoconstriction:

– Angiotensin II is the most potent Angiotensin II is the most potent

vasoconstrictor in the body vasoconstrictor in the body

– Produces constriction of arterioles as Produces constriction of arterioles as

well as veinswell as veins

– Constriction of peripheral arterioles Constriction of peripheral arterioles

results in increased Peripheral results in increased Peripheral

Vascular Resistance (PVR)Vascular Resistance (PVR)

RAASRAAS Aldosterone releaseAldosterone release


Aldosterone release from adrenal glandAldosterone release from adrenal gland

Retention of sodium & waterRetention of sodium & water

Increase in blood volume (Preload)Increase in blood volume (Preload)

RAASRAAS

– Stimulation of sympathetic nervous Stimulation of sympathetic nervous system, which leads to increased release system, which leads to increased release of norepinephrineof norepinephrine

– Stimulates the release of antidiuretic Stimulates the release of antidiuretic hormone, ADH from the posterior pituitary, hormone, ADH from the posterior pituitary, which increases fluid retention by the which increases fluid retention by the kidneyskidneys

– Stimulates thirst centers within the brain Stimulates thirst centers within the brain

Aldosterone release

RAASRAAS

Trophic action (Proliferative action):Trophic action (Proliferative action):

– Angiotensin II leads to proliferation of Angiotensin II leads to proliferation of

cardiac myocytes cardiac hypertrophy cardiac myocytes cardiac hypertrophy

vascular smooth muscle cells vascular vascular smooth muscle cells vascular

hypertrophyhypertrophy

RAASRAAS

RAASRAAS Inappropriately elevated levels of angiotensin II have Inappropriately elevated levels of angiotensin II have

following adverse effects:following adverse effects:

– Constriction of peripheral arterioles leads to Constriction of peripheral arterioles leads to increased PVR (afterload)increased PVR (afterload)

– Angiotensin II leads to aldosterone secretion from Angiotensin II leads to aldosterone secretion from adrenal cortexadrenal cortex

– Aldosterone causes sodium & water retention in the Aldosterone causes sodium & water retention in the body, thus increasing blood volume (preload)body, thus increasing blood volume (preload)

RAASRAAS Inappropriately elevated levels of angiotensin II have Inappropriately elevated levels of angiotensin II have

following adverse effects:following adverse effects:

– Angiotensin II stimulates sympathetic nervous Angiotensin II stimulates sympathetic nervous system results in increased blood levels of system results in increased blood levels of norepinephrine & epinephrinenorepinephrine & epinephrine

– Angiotensin II has trophic action on the heart, Angiotensin II has trophic action on the heart, kidneys & blood vesselskidneys & blood vessels

RAASRAAS

Excessive activation of the RAAS Excessive activation of the RAAS

plays an important role in the plays an important role in the

pathophysiology of hypertension, pathophysiology of hypertension,

heart failure & diabetic heart failure & diabetic

nephropathynephropathy

RAASRAAS

All these actions of angiotensin II All these actions of angiotensin II

are seen after it has combined are seen after it has combined

with ATwith AT11 receptors receptors

RAASRAAS

Harmful effects of angiotensin II can be Harmful effects of angiotensin II can be

prevented by two different ways :prevented by two different ways :

– By decreasing formation of angiotensin II By decreasing formation of angiotensin II

from angiotensin I- through inhibition of ACE from angiotensin I- through inhibition of ACE

– By blocking the ATBy blocking the AT11 receptors - As a result receptors - As a result

angiotensin II is not in a position to combine angiotensin II is not in a position to combine

with ATwith AT11 receptors receptors

RAAS - InhibitionRAAS - Inhibition

Two different groups of drugs that Two different groups of drugs that

inhibit the RAAS are:inhibit the RAAS are:

– ACE inhibitors e.g. Enalapril, Lisinopril, ACE inhibitors e.g. Enalapril, Lisinopril,

Ramipril Ramipril

– ATAT11 receptor blockers (ARBs) e.g. receptor blockers (ARBs) e.g.

Losartan, Valsartan, Telmisartan Losartan, Valsartan, Telmisartan

RAAS - InhibitionRAAS - Inhibition

PARAMETERPARAMETER ACE INHIBITORSACE INHIBITORS AT1RECEPTOR BLOCKERSAT1RECEPTOR BLOCKERS

Inhibition of RAASInhibition of RAAS Incomplete ( Partial)Incomplete ( Partial) CompleteComplete

Effect on blood levels of Effect on blood levels of AIIAII

DecreasedDecreased No changeNo change

Effect on blood levels of Effect on blood levels of bradykininbradykinin

IncreasedIncreased No changeNo change

TolerabilityTolerability PoorPoor(Dry cough, (Dry cough, angioedema)angioedema)

BetterBetter( No dry cough)( No dry cough)

Tellzy Tellzy (Telmisartan 20, 40, 80 mg (Telmisartan 20, 40, 80 mg

tablets)tablets)

Novel ATNovel AT11 receptor receptor antagonistantagonist

Tellzy Tellzy

DescriptionDescription

TELLZY (telmisartan) is an TELLZY (telmisartan) is an

angiotensin II receptor antagonist angiotensin II receptor antagonist

that is highly selective for Type1 that is highly selective for Type1

angiotensin II receptorsangiotensin II receptors

TelmisartanTelmisartan

Mechanism Of actionMechanism Of action

Telmisartan prevents the effects of angiotensin II by Telmisartan prevents the effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATselectively blocking the binding of angiotensin II to the AT11 receptors in many tissues, such as receptors in many tissues, such as – vascular smooth musclevascular smooth muscle– adrenal glandadrenal gland

Its action is therefore independent of the pathways for Its action is therefore independent of the pathways for angiotensin II synthesisangiotensin II synthesis

Telmisartan produces more complete inhibition of RAAS as Telmisartan produces more complete inhibition of RAAS as compared to ACE inhibitorscompared to ACE inhibitors


Mechanism Of actionMechanism Of action

Highly selective ATHighly selective AT11 receptor blocker receptor blocker

High affinity for ATHigh affinity for AT11 receptors receptors

Prevents binding of Angiotensin II with ATPrevents binding of Angiotensin II with AT11 receptors receptors

Blocks action of angiotensin II

Lowers PVR and preload- lowering of BP

TelmisartanTelmisartan Anti-hypertensive action: Anti-hypertensive action:

– Following once daily administration of telmisartan, Following once daily administration of telmisartan,

the magnitude of blood pressure reduction from the magnitude of blood pressure reduction from

baseline was approximately (SBP/DBP) baseline was approximately (SBP/DBP)

– 6-8/6 mmHg for 20 mg6-8/6 mmHg for 20 mg

– 9-13/6-8 mmHg for 40 mg9-13/6-8 mmHg for 40 mg

– 12-13/7-8 mmHg for 80 mg12-13/7-8 mmHg for 80 mg


There were no changes in the heart rate of There were no changes in the heart rate of

patients treated with telmisartanpatients treated with telmisartan

Unlike dihydropyridine CCBs, telmisartan Unlike dihydropyridine CCBs, telmisartan

doesn’t produce reflex tachycardia doesn’t produce reflex tachycardia


Additional Beneficial Metabolic effects: Additional Beneficial Metabolic effects:

– Telmisartan is a partial agonist of PPAR – γ (perioxisome Telmisartan is a partial agonist of PPAR – γ (perioxisome

proliferators activated receptor γ), that plays a role in the proliferators activated receptor γ), that plays a role in the

regulation of carbohydrate and lipid metabolismregulation of carbohydrate and lipid metabolism

Improves insulin sensitivityImproves insulin sensitivity

Decreases adipocyte cell sizeDecreases adipocyte cell size

Decrease hepatic fat storageDecrease hepatic fat storage


Telmisartan treatment results in improvements in Telmisartan treatment results in improvements in

lipid profiles and insulin sensitivity in lipid profiles and insulin sensitivity in

hypertensive patients with co-existing type 2 hypertensive patients with co-existing type 2

diabetesdiabetes


PharmacokineticsPharmacokinetics

– Rapidly absorbed ( TRapidly absorbed ( Tmaxmax :1hr) :1hr)

– Bioavailability : 50%Bioavailability : 50%

– Steady state achieved within : 5-7 daysSteady state achieved within : 5-7 days

– Metabolized in liver- inactive metabolitesMetabolized in liver- inactive metabolites

– Mean elimination half life: 24 hrsMean elimination half life: 24 hrs

– Main route of excretion: feaces ( > 90 %)Main route of excretion: feaces ( > 90 %)

Long Terminal Half LifeLong Terminal Half Life

Pharmacokinetic evaluation of telmisartan in mild Pharmacokinetic evaluation of telmisartan in mild to-moderate hypertensive patients showed a to-moderate hypertensive patients showed a terminal half life of ~ 24 hterminal half life of ~ 24 h

Long terminal half-life supports a once-daily Long terminal half-life supports a once-daily dosing regimen and suggests that drug dosing regimen and suggests that drug concentrations do not decline below therapeutic concentrations do not decline below therapeutic levels even if a dose is delayedlevels even if a dose is delayed

Expert Opin. Pharmacother. (2008) 9(8):1397-1406

9

5-9

11-15

2.5-910-15

24

9

0 5 10 15 20 25

Telmisartan has long half life : 24 hours

Valsartan

Telmisartan

Olmesartan

Losartan

Irbesartan

Eprosartan

Candesartan

Goodman & Gilman p 812-813 11th edition

Telmisartan- Unique propertiesTelmisartan- Unique properties

Greater affinity (>3,000 fold) for the ATGreater affinity (>3,000 fold) for the AT11

receptors than for the ATreceptors than for the AT22 receptors receptors

Highly lipophilic in nature therefore it has Highly lipophilic in nature therefore it has

better tissue penetration & it provides greater better tissue penetration & it provides greater

inhibition of tissue RAASinhibition of tissue RAAS


Longer elimination half lifeLonger elimination half life

After binding with ATAfter binding with AT11 receptors, it dissociates very slowly receptors, it dissociates very slowly

[dissociation half-life 5.9 hours] ensures prolonged [dissociation half-life 5.9 hours] ensures prolonged

antihypertensive action of telmisartanantihypertensive action of telmisartan

As a result once daily dose of telmisartan provides 24 hrs As a result once daily dose of telmisartan provides 24 hrs

control of blood pressurecontrol of blood pressure

BP control is sustained through out the 24 hour dosage BP control is sustained through out the 24 hour dosage

interval, including during the last 6 hours of the periodinterval, including during the last 6 hours of the period


Highly lipophilic- better tissue penetration- Highly lipophilic- better tissue penetration-

better inhibition of tissue RAS.better inhibition of tissue RAS.

Slow dissociation from ATSlow dissociation from AT11 receptors receptors

Long elimination half life :24 hrsLong elimination half life :24 hrs

24 hrs blood pressure lowering effect


ADDITIONAL BENEFICIAL METABOLIC EFFECTS:ADDITIONAL BENEFICIAL METABOLIC EFFECTS:

Majority of the patients with hypertension have other Majority of the patients with hypertension have other features of the metabolic syndrome like:features of the metabolic syndrome like:

– Abdominal ObesityAbdominal Obesity– DyslipidemiaDyslipidemia– Insulin resistanceInsulin resistance

Telmisartan treatment results in improvements in lipid Telmisartan treatment results in improvements in lipid profiles and insulin sensitivity in hypertensive patients with profiles and insulin sensitivity in hypertensive patients with co-existing type 2 diabetesco-existing type 2 diabetes


High Trough to Peak Ratio – better control of BPHigh Trough to Peak Ratio – better control of BP

The patients on telmisartan experienced greater The patients on telmisartan experienced greater

regression of LVHregression of LVH

Mean treatment compliance rate was 98.6 to 99.9 %Mean treatment compliance rate was 98.6 to 99.9 %

Telmisartan- AdvantagesTelmisartan- Advantages

Longer elimination half-life of 24 hrsLonger elimination half-life of 24 hrs

High affinity towards ATHigh affinity towards AT11 receptor (telmisartan > receptor (telmisartan >

olmesartan > candesartan olmesartan > candesartan >> valsaratan valsaratan >> losartan) losartan)

Very slow dissociation rateVery slow dissociation rate

These unique properties of Telmisartan ensure

improved 24- hr control of blood pressure as

compared to other ARBs

Telmisartan- AdvantagesTelmisartan- Advantages

Unlike other once a day ARBs, which fall short of

providing good antihypertensive action for 4 to 6

hours before the next morning dose is

administrated, Telmisartan has demonstrated better

BP lowering effect in predosing hours

24-hour action of Telmisartan covers the early

morning risk- hours, when the need for the BP

control is the greatest

TellzyTellzy INDICATIONSINDICATIONS

– TELLZY (telmisartan) is indicated for the treatment of TELLZY (telmisartan) is indicated for the treatment of hypertensionhypertension

– US FDA has approved it for the reduction of the risk US FDA has approved it for the reduction of the risk of myocardial infarction (heart attack), stroke, or of myocardial infarction (heart attack), stroke, or death from cardiovascular (CV) causes in patients 55 death from cardiovascular (CV) causes in patients 55 years of age or older at high risk of developing major years of age or older at high risk of developing major CV events who are unable to take ACE inhibitorsCV events who are unable to take ACE inhibitors

– European Commission has approved telmisartan for European Commission has approved telmisartan for the reduction of cardiovascular morbidity in patients the reduction of cardiovascular morbidity in patients with: with: I. manifest atherothrombotic cardiovascular disease I. manifest atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or (history of coronary heart disease, stroke, or peripheral arterial disease) or, peripheral arterial disease) or, II. type 2 diabetes mellitus with documented target II. type 2 diabetes mellitus with documented target organ damage.organ damage.

Telmisartan is the first treatment in its class to be approved for this indication.

TellzyTellzy

DOSAGE AND ADMINISTRATIONDOSAGE AND ADMINISTRATION

– Usual starting dose of Telmisartan tablets is 20 mg once a dayUsual starting dose of Telmisartan tablets is 20 mg once a day

– If required, its dose may be increased to 40mg after 2-4 wksIf required, its dose may be increased to 40mg after 2-4 wks

– Maximum antihypertensive effect is generally attained 4 to 8 Maximum antihypertensive effect is generally attained 4 to 8

weeks after the start of therapyweeks after the start of therapy

– Maximum recommended dose is 80mg/ dayMaximum recommended dose is 80mg/ day

– When additional blood pressure reduction beyond that achieved When additional blood pressure reduction beyond that achieved

with 80 mg Telmisartan is required, a diuretic with 80 mg Telmisartan is required, a diuretic

(Hydrochlorothiazide) may be added(Hydrochlorothiazide) may be added

TellzyTellzy

DOSAGE AND ADMINISTRATIONDOSAGE AND ADMINISTRATION

– No dose adjustment required in elderly or in renal No dose adjustment required in elderly or in renal

impairmentimpairment

– Use with caution in hepatic dysfunction- dose Use with caution in hepatic dysfunction- dose

should not exceed 40 mg /dayshould not exceed 40 mg /day

– Safety and efficacy not proven in childrenSafety and efficacy not proven in children

TellzyTellzy SAFETY PROFILESAFETY PROFILE

– Tolerability profile similar to placeboTolerability profile similar to placebo

– Mild and transient side effects- Mild and transient side effects-

headache,giddiness and fatigueheadache,giddiness and fatigue

– Better tolerated than ACE inhibitorsBetter tolerated than ACE inhibitors

lower incidence of coughlower incidence of cough

– Better tolerated than Amlodipine-Better tolerated than Amlodipine-

No Edema,flushing or reflex tachycardia.No Edema,flushing or reflex tachycardia.

TellzyTellzyDRUG INTERACTIONSDRUG INTERACTIONS

Not metabolized by cytochrome PNot metabolized by cytochrome P450 450 enzymes - Very low enzymes - Very low

potential for drug interactionspotential for drug interactions

Telmisartan does not alter kinetics of:Telmisartan does not alter kinetics of:

– AmlodipineAmlodipine

– GlibenclamideGlibenclamide

– WarfarinWarfarin

– HydrochlorothaizideHydrochlorothaizide

– SimvastatinSimvastatin

May increase serum digoxin levelsMay increase serum digoxin levels

TellzyTellzyPRECAUTIONSPRECAUTIONS

Similar to other ATSimilar to other AT11 blockers & ACE inhibitors: blockers & ACE inhibitors:

Use with caution in patients with-Use with caution in patients with-

Liver dysfunctionLiver dysfunction

Dehydration (Hypovolemia)Dehydration (Hypovolemia)

TellzyTellzy

CONTRA-INDICATIONSCONTRA-INDICATIONS

HypersensitivityHypersensitivity

PregnancyPregnancy

Bilateral renal artery stenosis- may lead to acute Bilateral renal artery stenosis- may lead to acute

renal failurerenal failure

Cardiovascular End Cardiovascular End Organ ProtectionOrgan Protection

MethodsMethods– Patients underwent double-blind randomizationPatients underwent double-blind randomization

8576 assigned to 10 mg of ramipril per day8576 assigned to 10 mg of ramipril per day 8542 assigned to 80 mg of telmisartan per day8542 assigned to 80 mg of telmisartan per day 8502 assigned to both drugs (combination therapy)8502 assigned to both drugs (combination therapy)

– Primary composite outcome –Primary composite outcome – death from cardiovascular causesdeath from cardiovascular causes myocardial infarctionmyocardial infarction StrokeStroke hospitalization for heart failure.hospitalization for heart failure.

ONTARGET ONTARGET TrialTrial

ONTARGETONTARGET

Blood Pressure Control:Blood Pressure Control:

Mean blood pressure was lower in both the Mean blood pressure was lower in both the

telmisartan group (a 0.9/0.6 mm Hg greater telmisartan group (a 0.9/0.6 mm Hg greater

reduction) and the combination-therapy group (a reduction) and the combination-therapy group (a

2.4/1.4 mm Hg greater reduction) than in the ramipril 2.4/1.4 mm Hg greater reduction) than in the ramipril

group. group.

N Engl J Med 2008;358:1547-59

ONTARGETONTARGET

1.1%

4.2%

0.1% 0.3%

0

1

2

3

4

5

% o

f P

atie

nt s

uffe

ring

from

adv

erse

eff

ect

Cough Angioedema

Telmisartan Good Safety Profile :Incidence of Cough & Angioedema is Low

Telmisartan

Ramipril

As compared with the ramipril group,the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema(0.1% vs. 0.3%, P = 0.01)

N Engl J Med 2008;358:1547-59

ONTARGETONTARGET

Conclusion:Conclusion:

Telmisartan was equivalent to ramipril in patients Telmisartan was equivalent to ramipril in patients with vascular disease or highrisk diabetes and with vascular disease or highrisk diabetes and was associated was associated with less angioedema. with less angioedema.

N Engl J Med 2008;358:1547-59

The Telmisartan Randomised Assessment The Telmisartan Randomised Assessment Study in ACE iNtolerant subjects with Study in ACE iNtolerant subjects with

cardiovascular Disease (TRANSCEND) 1cardiovascular Disease (TRANSCEND) 1

BackgroundBackground ACE inhibitors reduce major cardiovascular ACE inhibitors reduce major cardiovascular

events but intolerant in 20% patientsevents but intolerant in 20% patients

Study assessed Telmisartan effectiveness Study assessed Telmisartan effectiveness in patients intolerant to ACE inhibitors with in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with cardiovascular disease or diabetes with end-organ damage end-organ damage

Lancet 2008; 372: 1174-1183

The Telmisartan Randomised Assessment The Telmisartan Randomised Assessment Study in ACE intolerant subjects with Study in ACE intolerant subjects with


Evaluation of patients:Evaluation of patients:

The primary outcome was the composite of The primary outcome was the composite of

cardiovascular death, myocardial infarction, cardiovascular death, myocardial infarction,

stroke, or hospitalisation for heart failure. stroke, or hospitalisation for heart failure.

Lancet 2008; 372: 1174-1183

The Telmisartan Randomised Assessment The Telmisartan Randomised Assessment Study in ACE intolerant subjects with Study in ACE intolerant subjects with


Patients: 5926 patients intolerant to ACE Patients: 5926 patients intolerant to ACE inhibitors were enrolled if they had inhibitors were enrolled if they had – Established coronary arteryEstablished coronary artery– Peripheral vascular or cerebrovascular diseasePeripheral vascular or cerebrovascular disease– Diabetes with end-organ damage. Diabetes with end-organ damage.

Treatment: Telmisartan 80 mg/day or placebo Treatment: Telmisartan 80 mg/day or placebo

Duration: 56 months. Duration: 56 months. Lancet 2008; 372: 1174-1183

ResultsResults

Mean blood pressure in Mean blood pressure in Telmisartan group lowerTelmisartan group lower than placebo through out the study period than placebo through out the study period

Primary Outcome:Primary Outcome:Fewer patients in the telmisartan Fewer patients in the telmisartan group experienced the primary composite outcomegroup experienced the primary composite outcome of cardiovascular death,myocardial infarction, stroke, of cardiovascular death,myocardial infarction, stroke, or hospitalisation for heart failure than did patients in or hospitalisation for heart failure than did patients in the placebo group( 15.7% vs 17% ) the placebo group( 15.7% vs 17% )

The Telmisartan Randomised Assessment The Telmisartan Randomised Assessment Study in ACE intolerant subjects with Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND)cardiovascular Disease (TRANSCEND)

Lancet 2008; 372: 1174-1183

The Telmisartan Randomised Assessment The Telmisartan Randomised Assessment Study in ACE intolerant subjects with Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND)cardiovascular Disease (TRANSCEND)

Hospitalized cardiovascular reason: Fewer patients Hospitalized cardiovascular reason: Fewer patients were hospitalised for cardiovascular reasons in the were hospitalised for cardiovascular reasons in the telmisartan group than in the placebo group ( 30.3% telmisartan group than in the placebo group ( 30.3% vs 33%, p =0.025)vs 33%, p =0.025)

Fewer permanent discontinuations in Telmisartan Fewer permanent discontinuations in Telmisartan group than in placebo group (21·6%group than in placebo group (21·6%vsvs 23·8% 23·8% p=0·055)p=0·055)

Lancet 2008; 372: 1174-1183

ConclusionConclusion– Telmisartan well tolerated in patients unable to Telmisartan well tolerated in patients unable to

tolerate ACE inhibitorstolerate ACE inhibitors

– Modestly reduced risk of composite outcome of Modestly reduced risk of composite outcome of cardiovascular death, myocardial infarction, or cardiovascular death, myocardial infarction, or strokestroke

The Telmisartan Randomised The Telmisartan Randomised Assessment Study in ACE intolerant Assessment Study in ACE intolerant subjects with cardiovascular Disease subjects with cardiovascular Disease

(TRANSCEND)(TRANSCEND)

1 Lancet 2008; 372: 1174-1183

TELMISARTAN TELMISARTAN VS. VS.

OTHER ANTI-HYPERTENSIVESOTHER ANTI-HYPERTENSIVES

Comparative Clinical Comparative Clinical TrialsTrials

Comparison with other ARBsComparison with other ARBs

Versus Losartan :Telmisartan monotherapy (40 or Versus Losartan :Telmisartan monotherapy (40 or 80mg OD) demonstrated superior anti-hypertensive 80mg OD) demonstrated superior anti-hypertensive efficacy to Losartan monotherapy (50mg or 100mg efficacy to Losartan monotherapy (50mg or 100mg OD)OD)

Versus Valsartan:Telmisartan monotherapy (40–Versus Valsartan:Telmisartan monotherapy (40–80mg OD) demonstrated better anti-hypertensive 80mg OD) demonstrated better anti-hypertensive efficacy than Valsartan monotherapy (80–160mg efficacy than Valsartan monotherapy (80–160mg once daily)once daily)

Drugs 2006;66(1) 51-83

ABPM comparison of telmisartan & ABPM comparison of telmisartan & losartan in mild to moderate losartan in mild to moderate

hypertensiveshypertensives

Aim: Anti-hypertensive efficacy & tolerability of Aim: Anti-hypertensive efficacy & tolerability of Telmisartan and Losartan compared with placebo Telmisartan and Losartan compared with placebo in a in a

6-week study6-week study

Patients: 223 patients with mild-to moderate Patients: 223 patients with mild-to moderate HypertensionHypertension

Treatment: Telmisartan 40 mg, telmisartan 80 Treatment: Telmisartan 40 mg, telmisartan 80 mg, losartan 50 mg, or placebomg, losartan 50 mg, or placebo

J Hum Hypertens. 1999 Oct;13(10):657-64.

Results: Results: – Ambulatory blood pressure monitoring (ABPM) after 6 Ambulatory blood pressure monitoring (ABPM) after 6

weeks showed all active treatments produced weeks showed all active treatments produced significant (P < 0.01) reductions from baseline in 24-significant (P < 0.01) reductions from baseline in 24-h mean SBP and DBP compared with placeboh mean SBP and DBP compared with placebo

– Reductions in SBP/DBP with Telmisartan 40 mg Reductions in SBP/DBP with Telmisartan 40 mg (10.7/6.8 mm Hg) and 80 mg (12.2/7. 1 mm Hg) were (10.7/6.8 mm Hg) and 80 mg (12.2/7. 1 mm Hg) were each significantly (P <0.05) greater than those each significantly (P <0.05) greater than those observed for Losartan 50 mg (6.0/3.7 mm Hg)observed for Losartan 50 mg (6.0/3.7 mm Hg)

– 24-h mean blood pressure control: Telmisartan 40 24-h mean blood pressure control: Telmisartan 40 mg and 80 mg were significantly (P< 0.05) better mg and 80 mg were significantly (P< 0.05) better than Losartan 50 mgthan Losartan 50 mg

J Hum Hypertens. 1999 Oct;13(10):657-64.



-10.7/6.8mm Hg

-12.2/7.1 mm Hg

-6/3.7 mm Hg

-14

-12

-10

-8

-6

-4

-2

0

Re

du

ctio

n in

Blo

od

Pre

ssu

re

Telmisartan more effective anti-hypertensive during 18-24 hour peroid after dosing( P<0.05)

Telmisartan 40mg

Telmisartan 80mg

Losartan 50mg

J Hum Hypertens. 1999 Oct;13(10):657-64





Conclusion: Conclusion: – Telmisartan 40 mg and 80 mg once Telmisartan 40 mg and 80 mg once

daily were effective and well tolerated in daily were effective and well tolerated in the treatment of mild-to-moderate the treatment of mild-to-moderate hypertension, producing sustained 24-h hypertension, producing sustained 24-h blood pressure control which compared blood pressure control which compared favorably with Losartan.favorably with Losartan.

Comparison of Telmisartan vs. Valsartan Comparison of Telmisartan vs. Valsartan in mild to moderate hypertension usingin mild to moderate hypertension usingambulatory blood pressure monitoringambulatory blood pressure monitoring

AIM: Efficacy for 24-hour control of blood pressure AIM: Efficacy for 24-hour control of blood pressure assessed using ambulatory blood pressure assessed using ambulatory blood pressure monitoring monitoring

Results : Mean changes in diastolic blood pressure Results : Mean changes in diastolic blood pressure for the last 6 hours before dosing and the nighttime for the last 6 hours before dosing and the nighttime period were significantly greater with Telmisartan period were significantly greater with Telmisartan than with Valsartan (p<0.01 for the last 6 hours than with Valsartan (p<0.01 for the last 6 hours before dosing; p<0.05 for the nighttime period)before dosing; p<0.05 for the nighttime period)

J Clin Hypertens (Greenwich). 2002 Jul-Aug;4(4 Suppl 1):26-3


Results :Results : Mean changes in systolic and diastolic blood Mean changes in systolic and diastolic blood

pressures for the 24-hour interval, the morning, and pressures for the 24-hour interval, the morning, and the daytime periods were significantly greater with the daytime periods were significantly greater with Telmisartan than with Valsartan (p<0.01)Telmisartan than with Valsartan (p<0.01)

The incidence of all adverse events and the most The incidence of all adverse events and the most common adverse events were comparable for common adverse events were comparable for patients receiving Telmisartan and patients patients receiving Telmisartan and patients receiving Valsartanreceiving Valsartan

Neither treatment was associated with coughNeither treatment was associated with coughJ Clin Hypertens (Greenwich). 2002 Jul-Aug;4(4 Suppl 1):26-31

Conclusion: Conclusion:

– Greater efficacy for Telmisartan than Valsartan Greater efficacy for Telmisartan than Valsartan in controlling blood pressure throughout the in controlling blood pressure throughout the 24-hour dosing interval,including the last 6 24-hour dosing interval,including the last 6 hours before dosinghours before dosing

– Two agents had similarly tolerabilityTwo agents had similarly tolerability

J Clin Hypertens (Greenwich). 2002 Jul-Aug;4(4 Suppl 1):26-31.


ParametersParameters TelmisartanTelmisartan OlmesartanOlmesartan

24 hr control of BP*24 hr control of BP* Complete 24 hr control of Complete 24 hr control of BP BP Covers early morning hourCovers early morning hour

Incomplete 24 hr control Incomplete 24 hr control of BPof BP

Trough Peak RatioTrough Peak Ratio 66 -100 %66 -100 % 60 -80%60 -80%

PPAR – γ Agonistic PPAR – γ Agonistic activityactivity

Present therefore Improves Present therefore Improves insulin sensitivity and lipid insulin sensitivity and lipid profileprofile

AbsentAbsent

LipophilicityLipophilicity More Lipophilic so better More Lipophilic so better tissue penetration and hence tissue penetration and hence better inhibition of tissue better inhibition of tissue RAAS RAAS

Less lipophilic so less Less lipophilic so less inhibition of tissue inhibition of tissue RAAS.RAAS.

Renal Insufficiency Renal Insufficiency No dosage adjustmentNo dosage adjustment 20 mg maximum in 20 mg maximum in severe diseasesevere disease

Telmisartan vs. OlmesartanTelmisartan vs. Olmesartan

Telmisartan vs. LosartanTelmisartan vs. LosartanParametersParameters TelmisartanTelmisartan LosartanLosartan

24 hr control of BP covers early 24 hr control of BP covers early morning hourmorning hour

Complete 24 hr control of BP Complete 24 hr control of BP Cover early morning hourCover early morning hour

Incomplete 24 hr control of Incomplete 24 hr control of BPBPMay not cover early morning May not cover early morning hourhour

Trough Peak RatioTrough Peak Ratio 66 -100 %66 -100 % 65%65%

PPAR – γ Agonistic activityPPAR – γ Agonistic activity Present therefore Improves Present therefore Improves insulin sensitivity and lipid insulin sensitivity and lipid profileprofile

AbsentAbsent

LipophilicityLipophilicity More Lipophilic so better More Lipophilic so better tissue penetration and hence tissue penetration and hence better inhibition of tissue better inhibition of tissue RAAS RAAS

Less lipophilic so less Less lipophilic so less inhibition of tissue RAAS.inhibition of tissue RAAS.

Drug InteractionsDrug Interactions LessLess MoreMore

IndicationsIndications HypertensionHypertension Hypertension, Diabetic Hypertension, Diabetic nephropathy in type 2 nephropathy in type 2 diabetes mellitus with diabetes mellitus with hypertension, stroke hypertension, stroke reduction with hypertension reduction with hypertension and left ventricular and left ventricular hypertrophy hypertrophy

Comparison vs ACE InhibitorsComparison vs ACE Inhibitors

Telmisartan has better tolerability profile as Telmisartan has better tolerability profile as compared to ACE inhibitorscompared to ACE inhibitors

Due to better Tolerability profile the patient Due to better Tolerability profile the patient compliance is bettercompliance is better

Therefore, Telmisartan may provide better long Therefore, Telmisartan may provide better long term blood pressure control than ACE inhibitors.term blood pressure control than ACE inhibitors.

J Int Med Res. 2002 Nov-Dec;30(6):543-52.

ABPM comparison of Telmisartan and ABPM comparison of Telmisartan and Enalapril in patients with mild-to-moderate Enalapril in patients with mild-to-moderate

hypertension (PROBE study)hypertension (PROBE study)

Patients: 522 patients with mild-to moderate Patients: 522 patients with mild-to moderate hypertensionhypertension

Treatment: Telmisartan 40/ 80 mg vs Enalapril Treatment: Telmisartan 40/ 80 mg vs Enalapril 10-20 mg once-daily 10-20 mg once-daily

Duration: Twelve week study in which Duration: Twelve week study in which ambulatory blood pressure monitoring (ABPM)ambulatory blood pressure monitoring (ABPM)

ABPM comparison of Telmisartan and ABPM comparison of Telmisartan and Enalapril in patients with mild-to-Enalapril in patients with mild-to-

moderate hypertension (PROBE study)moderate hypertension (PROBE study) Significantly greater proportion of patients achieved Significantly greater proportion of patients achieved

seated diastolic response with telmisartan than enalapril seated diastolic response with telmisartan than enalapril (59% versus 50%; P < 0.05)(59% versus 50%; P < 0.05)


59%

50%

44

46

48

50

52

54

56

58

60

% o

f P

atient show

ing D

iasto

lic

response

Telmisartan more effective in achieving Patient response in controlling Diastolic Blood Pressure(p<0.05)

Telmisartan

Enalapril

Results:Results:

Tolerability Profile:Compared with telmisartan, Tolerability Profile:Compared with telmisartan, enalapril was associated with a enalapril was associated with a higher incidence of higher incidence of coughcough (8.9% versus 0.8%) and (8.9% versus 0.8%) and hypotensionhypotension (3.9% (3.9% versus 1.1%)versus 1.1%)


Telmisartan may provide better long-term Telmisartan may provide better long-term compliance and consequently, better blood compliance and consequently, better blood pressure control than enalaprilpressure control than enalapril


ABPM comparison of Telmisartan and ABPM comparison of Telmisartan and Enalapril in patients with mild-to-moderate Enalapril in patients with mild-to-moderate

hypertension (PROBE study)hypertension (PROBE study)

Telmisartan vs. ACE inhibitorsTelmisartan vs. ACE inhibitors

Telmisartan produces more complete inhibition of Telmisartan produces more complete inhibition of

the RAASthe RAAS

Telmisartan therapy does not produce the side Telmisartan therapy does not produce the side

effect of dry cough ( 20-30% of patients develop effect of dry cough ( 20-30% of patients develop

dry cough with ACE inhibitors)dry cough with ACE inhibitors)

Telmisartan therapy provides better 24-hr control Telmisartan therapy provides better 24-hr control

of blood pressure than Enalaprilof blood pressure than Enalapril

Telmisartan is better tolerated than ACE inhibitorsTelmisartan is better tolerated than ACE inhibitors

Improved patient complianceImproved patient compliance

Versus Calcium Channel Blockers:Versus Calcium Channel Blockers:Comparison of efficacies & duration of Comparison of efficacies & duration of action of Telmisartan and Amlodipineaction of Telmisartan and Amlodipine

Patients: 234 patients with hypertensionPatients: 234 patients with hypertensionTreatment:Treatment:

40 mg Telmisartan increased to 80 and 120 mg as 40 mg Telmisartan increased to 80 and 120 mg as necessary for patients necessary for patients

5 mg Amlodipine titrated to 10 mg as necessary 5 mg Amlodipine titrated to 10 mg as necessary for patients for patients

Placebo (n = 81)Placebo (n = 81) 12 weeks of double-blind treatment12 weeks of double-blind treatment

Both drugs also significantly reduced 24 h mean Both drugs also significantly reduced 24 h mean systolic blood pressures and DBP compared with systolic blood pressures and DBP compared with placebo (P < 0.0001)placebo (P < 0.0001)

Blood Press Monit. 1998 Oct;3(5):295-302.

71%

55%

0

10

20

30

40

50

60

70

80

% p

atie

nts

with

Tw

enty

four

-hou

r m

ean

AB

PM

DB

P <

85

mm

Hg

Telmisartan effective in controlling Diastolic Blood pressure

Telmisartan

Amlodipine


Comparison of efficacies & duration of Comparison of efficacies & duration of action of Telmisartan and Amlodipineaction of Telmisartan and Amlodipine

Twenty four-hour mean ABPM DBP < 85 mmHg were observed in 71% of telmisartan patients and in 55% of patients administered amlodipine

Reductions in DBP with telmisartan greater (P < Reductions in DBP with telmisartan greater (P < 0.05) than with amlodipine during the night-time 0.05) than with amlodipine during the night-time interval and the last 4 h of the dosing periodinterval and the last 4 h of the dosing period

Both telmisartan and amlodipine well toleratedBoth telmisartan and amlodipine well tolerated– Drug-related edema occurred significantly more Drug-related edema occurred significantly more

commonly (P < 0.05) among the patients commonly (P < 0.05) among the patients administered amlodipine than it did among administered amlodipine than it did among patients administered either telmisartan or patients administered either telmisartan or placeboplacebo


Comparison of efficacies & duration of Comparison of efficacies & duration of action of Telmisartan and Amlodipineaction of Telmisartan and Amlodipine

Telmisartan vs. AmlodipineTelmisartan vs. Amlodipine

Telmisartan provides better control of blood pressure Telmisartan provides better control of blood pressure

than Amlodipine during the pre-dose interval ( 4-6 hrs than Amlodipine during the pre-dose interval ( 4-6 hrs

before the next morning dose)before the next morning dose)

Telmisartan is better tolerated than Amlodipine: Side Telmisartan is better tolerated than Amlodipine: Side

effect of pedal edema is seen frequently with effect of pedal edema is seen frequently with

AmlodipineAmlodipine

Telmisartan is preferred over Amlodipine in Telmisartan is preferred over Amlodipine in

hypertensive patients with diabetic nephropathy hypertensive patients with diabetic nephropathy

(proteinuria) & in patients with heart failure(proteinuria) & in patients with heart failure

Comparison of 26-week efficacy and Comparison of 26-week efficacy and tolerability of Telmisartan and Atenololtolerability of Telmisartan and Atenolol

Patients:Patients: 533 patients with mild- moderate 533 patients with mild- moderate hypertension hypertension

Duration:Duration: 26-week 26-week

Treatment :Treatment : - Telmisartan (40 mg titrated to 80 mg titrated - Telmisartan (40 mg titrated to 80 mg titrated to 120 mg) to 120 mg) - Atenolol (50 mg titrated to 100 mg) - Atenolol (50 mg titrated to 100 mg) - Hydrochlorothiazide (HCTZ) 12.5 or 25 mg was - Hydrochlorothiazide (HCTZ) 12.5 or 25 mg was added if neededadded if needed

Clin Ther. 2001 Jan;23(1):108-23.

80%

68%

60

65

70

75

80

% o

f Pat

ient

sho

wing

Re

duct

ion

of S

BP >

or

= 10

mm

Hg

Telmisartan more effective than Atenolol in Controlling Systolic Blood Pressure(p=0.003)

Telmisartan

Atenolol

Clin Ther. 2001 Jan;23(1):108-23.


Reduction from baseline in SBP of > or = 10 mm Hg achieved by 80% of Telmisartan-treated and 68% of Atenolol-treated patients (P = 0.003)


ResultResult

Final SBP/DBP reductions of 20.9/14.4 mm Hg for Final SBP/DBP reductions of 20.9/14.4 mm Hg for Telmisartan versus 16.7/13.3 mm Hg for AtenololTelmisartan versus 16.7/13.3 mm Hg for Atenolol

Difference in SBP was significant (P = 0.005)Difference in SBP was significant (P = 0.005)

Clin Ther. 2001 Jan;23(1):108-23.


Safety Profile:Safety Profile: Mild to moderate adverse events reported by 52.7% Mild to moderate adverse events reported by 52.7%

of patients given Telmisartan and 61.2% of patients of patients given Telmisartan and 61.2% of patients given Atenolol difference not statistically significantgiven Atenolol difference not statistically significant

Fatigue and male impotence more common in Fatigue and male impotence more common in atenolol-treated patients (3.4% and 4.0% resp)atenolol-treated patients (3.4% and 4.0% resp)

Conclusions: Conclusions: Telmisartan appears to be at least as effective as Telmisartan appears to be at least as effective as

Atenolol in the treatment of mild to moderate Atenolol in the treatment of mild to moderate hypertension and may be better tolerated. hypertension and may be better tolerated.

Clin Ther. 2001 Jan;23(1):108-23.

Telmisartan vs. AtenololTelmisartan vs. Atenolol

No adverse effect on lipid or carbohydrate metabolismNo adverse effect on lipid or carbohydrate metabolism

Safe in Bronchial asthma, heart block, bradycardiaSafe in Bronchial asthma, heart block, bradycardia

Better tolerated- No rebound hypertension, cold Better tolerated- No rebound hypertension, cold

extremities, fatigue, impotenceextremities, fatigue, impotence

Telmisartan in isolated systolic Telmisartan in isolated systolic hypertension (ARAMIS) Studyhypertension (ARAMIS) Study

Aim: Efficacy and safety of Telmisartan 20, 40 or Aim: Efficacy and safety of Telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or 80 mg versus hydrochlorothiazide 12.5 mg or placeboplacebo

Patients:1039 patients (age 36-84 years) with Patients:1039 patients (age 36-84 years) with isolated systolic hypertension (ISH) [seated SBP isolated systolic hypertension (ISH) [seated SBP 150-179 mmHg and seated diastolic blood 150-179 mmHg and seated diastolic blood pressure (DBP) < 90 mmHg] pressure (DBP) < 90 mmHg]

J Hypertens. 2004 May;22(5):1033-7.

Telmisartan in isolated systolic Telmisartan in isolated systolic hypertension (ARAMIS) Studyhypertension (ARAMIS) Study

Treatment :Once-daily treatment with Telmisartan 20, Treatment :Once-daily treatment with Telmisartan 20, 40 or 80 mg, hydrochlorothiazide 12.5 mg, or placebo40 or 80 mg, hydrochlorothiazide 12.5 mg, or placebo

Conclusion: Conclusion: – All doses of Telmisartan (20-80 mg) significantly All doses of Telmisartan (20-80 mg) significantly

superior to placebo in reducing SBP in patients with superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ 12.5 mgISH and clinically comparable to HCTZ 12.5 mg

– Tolerability of Telmisartan similar to placeboTolerability of Telmisartan similar to placebo

J Hypertens. 2004 May;22(5):1033-7.

In Combination with Other In Combination with Other Antihypertensive AgentsAntihypertensive Agents

Adjunctive therapy with Telmisartan Adjunctive therapy with Telmisartan calcium channel antagonistcalcium channel antagonist a β-blockera β-blocker a diuretic agenta diuretic agent

Was effective in controlling Blood PressureWas effective in controlling Blood Pressure

Drugs 2006; 66 (1)

Salient FeaturesSalient Features Once daily dose of Telmisartan provides better 24-hr Once daily dose of Telmisartan provides better 24-hr

control of blood pressure, even in the crucial early morning control of blood pressure, even in the crucial early morning

hours hours

Telmisartan provides better 24 hr control of blood pressure Telmisartan provides better 24 hr control of blood pressure

than Enalapril, Amlodipine, Losartan & Valsartanthan Enalapril, Amlodipine, Losartan & Valsartan

Adverse event rates are significantly lower than with other Adverse event rates are significantly lower than with other

classes of antihypertensive drugs including ACE inhibitorsclasses of antihypertensive drugs including ACE inhibitors

No dosage adjustment is required in renal insufficiency No dosage adjustment is required in renal insufficiency

patientspatients

Salient FeaturesSalient Features Telmisartan has very low potential for drug interactions Telmisartan has very low potential for drug interactions

Telmisartan displays favorable effects on Left ventricular Telmisartan displays favorable effects on Left ventricular hypertrophy and renal functionhypertrophy and renal function

Telmisartan improves the insulin sensitivity and lipid profile.Telmisartan improves the insulin sensitivity and lipid profile.

Telmisartan is particularly useful in following groups of Telmisartan is particularly useful in following groups of hypertensive patients:hypertensive patients:– A. Intolerance to ACE inhibitorA. Intolerance to ACE inhibitor– B. DiabeticsB. Diabetics– C. Patients with heart failureC. Patients with heart failure– D. ElderlyD. Elderly– E. Renal impairmentE. Renal impairment

Improved patient compliance due to once daily dosage & Improved patient compliance due to once daily dosage & excellent tolerabilityexcellent tolerability

Indications: HypertensionIndications: Hypertension Telmisartan is recommended for the treatment of Telmisartan is recommended for the treatment of

hypertension in adults, either as monotherapy or in hypertension in adults, either as monotherapy or in combination with other antihypertensive agentscombination with other antihypertensive agents

The dosage regimen of Telmisartan should be The dosage regimen of Telmisartan should be individualized for the patient, with the usual starting individualized for the patient, with the usual starting dose being 40mg once daily.dose being 40mg once daily.

If additional BP lowering beyond that achieved with If additional BP lowering beyond that achieved with Telmisartan 80mg once daily is required, then the Telmisartan 80mg once daily is required, then the addition of another antihypertensive agent may be addition of another antihypertensive agent may be considered. considered.

Telmisartan may be administered without regard to foodTelmisartan may be administered without regard to food

Drugs 2006; 66 (1)

Temisartan FDA IndicationsTemisartan FDA Indications

HypertensionHypertension– Indicated for treatment of hypertensionIndicated for treatment of hypertension

– May be used alone or in combination with May be used alone or in combination with other antihypertensive agentsother antihypertensive agents

Temisartan FDA IndicationsTemisartan FDA Indications

Cardiovascular Risk ReductionCardiovascular Risk Reduction– Indicated for risk reduction of myocardial Indicated for risk reduction of myocardial

infarction, stroke, or death from cardiovascular infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at causes in patients 55 years of age or older at high risk of developing major cardiovascular high risk of developing major cardiovascular events events who are unable to take ACE inhibitors.who are unable to take ACE inhibitors.

– High risk for cardiovascular events can be High risk for cardiovascular events can be evidenced by a history of coronary artery evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin dependent) with (insulin-dependent or non-insulin dependent) with evidence of end-organ damageevidence of end-organ damage

– Use of telmisartan with an ACE inhibitor is not Use of telmisartan with an ACE inhibitor is not recommendedrecommended

Place of Telmisartan in thePlace of Telmisartan in theManagement of HypertensionManagement of Hypertension

European Society of Hypertension/European European Society of Hypertension/European Society of Cardiology guidelines recommend the Society of Cardiology guidelines recommend the use of agents that provide 24-hour efficacy with a use of agents that provide 24-hour efficacy with a once-daily dose.once-daily dose.

Long acting drugs may offer advantages to short-Long acting drugs may offer advantages to short-acting agents for a number of reasons, including acting agents for a number of reasons, including greater compliance, sustained BP control, greater compliance, sustained BP control, maintenance of control regardless of missing a maintenance of control regardless of missing a dose and a reduced risk of cardiovascular events dose and a reduced risk of cardiovascular events during the early morning hours.during the early morning hours.

Drugs 2006; 66 (1)


Telmisartan is an AII receptor antagonist with a Telmisartan is an AII receptor antagonist with a long duration of action and shows no evidence of long duration of action and shows no evidence of drug accumulation after repeated administrationdrug accumulation after repeated administration

A T A T 1/21/2 of approximately 24 hours for Telmisartan of approximately 24 hours for Telmisartan considerably longer than that observed with other considerably longer than that observed with other agents in this class (all ≤15 hours), ensures that agents in this class (all ≤15 hours), ensures that it will provide consistent and sustained reductions it will provide consistent and sustained reductions in BP over 24 hoursin BP over 24 hours

Drugs 2006; 66 (1)

Place of Telmisartan in Management Place of Telmisartan in Management of Hypertensionof Hypertension

Clinical trials and the clinical practice setting indicates Clinical trials and the clinical practice setting indicates that Telmisartan, either as monotherapy or in that Telmisartan, either as monotherapy or in combination with other antihypertensive agents, is combination with other antihypertensive agents, is effective in a broad spectrum of hypertensive patients:effective in a broad spectrum of hypertensive patients:

– Including the elderly Including the elderly – Those with coexisting type 2 diabetesThose with coexisting type 2 diabetes– Metabolic syndrome Metabolic syndrome – Renal impairment. Renal impairment.

Drugs 2006; 66 (1)


Consistent antihypertensive efficacy during the Consistent antihypertensive efficacy during the entire 24-hour dosage interval and sustained BP-entire 24-hour dosage interval and sustained BP-lowering effect in the long term combined with its lowering effect in the long term combined with its favorable tolerability profilefavorable tolerability profile

Telmisartan is a valuable first-line treatment Telmisartan is a valuable first-line treatment option for the management of essential option for the management of essential hypertensionhypertension

Drugs 2006; 66 (1)

Tellzy-HTellzy-H

COMPOSITION:COMPOSITION:

Telmisartan…………..…… 40 mgTelmisartan…………..…… 40 mg

Hydrochlorothiazide …….. 12.5 mgHydrochlorothiazide …….. 12.5 mg

Extra- Cardiac Extra- Cardiac EffectsEffects

INNOVATION StudyINNOVATION StudyIncipient to Overt: Incipient to Overt:


Blocker, Telmisartan, Blocker, Telmisartan, Investigation onInvestigation on

Type 2 Diabetic NephropathyType 2 Diabetic Nephropathy

DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007

Prevention of Transition From Incipient Prevention of Transition From Incipient to Overt Nephropathy With Telmisartan to Overt Nephropathy With Telmisartan

in Patients With Type 2 Diabetesin Patients With Type 2 Diabetes

INNOVATION Study :INNOVATION Study :

First large-scale clinical study to investigate First large-scale clinical study to investigate

prevention of overt diabetic nephropathy using an prevention of overt diabetic nephropathy using an

ARB in normotensive and ARB in normotensive and hypertensive Japanese hypertensive Japanese

patients with type 2 diabetespatients with type 2 diabetes

Objective : Evaluate efficacy of Telmisartan in Objective : Evaluate efficacy of Telmisartan in

preventing transition from microalbuminuria to overt preventing transition from microalbuminuria to overt

nephropathy in Japanese patients nephropathy in Japanese patients


Prevention of Transition From Prevention of Transition From Incipient to Overt Nephropathy With Incipient to Overt Nephropathy With Telmisartan in Patients With Type 2 Telmisartan in Patients With Type 2

DiabetesDiabetesPatients: Patients: A total of 527 type 2 diabetes patients and A total of 527 type 2 diabetes patients and

urinary albumin-to-creatinine ratio (UACR) 100–urinary albumin-to-creatinine ratio (UACR) 100–

300mg/g and serum creatinine <1.5 mg/dl (men) and 300mg/g and serum creatinine <1.5 mg/dl (men) and

<1.3mg/dl (women) <1.3mg/dl (women)

Treatment :Treatment :

80 or 40 mg Telmisartan or placebo80 or 40 mg Telmisartan or placebo

The starting dose was 20 mg, titrated to 40 mg after 2 The starting dose was 20 mg, titrated to 40 mg after 2

weeks or to 80 mg after a further 2 weeksweeks or to 80 mg after a further 2 weeks


INNOVATION StudyINNOVATION Study

Evaluation:Evaluation: Primary efficacy end point: transition rate from Primary efficacy end point: transition rate from

incipient to overt nephropathy (UACR >300 mg/g incipient to overt nephropathy (UACR >300 mg/g and increase ≥30% from baseline at two and increase ≥30% from baseline at two consecutive 4-week visits)consecutive 4-week visits)

Secondary end point: microalbuminuria remission Secondary end point: microalbuminuria remission (UACR < 30 mg/g)(UACR < 30 mg/g)

Mean duration of follow-up was 1.3 yearsMean duration of follow-up was 1.3 years



16.7%22.6%

49.9%

0

10

20

30

40

50

% o

f In

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ien

t N

ep

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pa

thy

pa

tien

ts

con

vert

ed

to O

vert

Ne

ph

rop

ath

y

Telmisartan Prevents Transition from Incipient Nephropathy to Overt Nephropathy ( p <0.0001)

Telmisartan 80mg

Telmisartan 40mg

Placebo

Diabetes care, Volume 30, Number 6, June 2007

Transition rates to overt nephropathy: Telmisartan 80mg (n = 168) 16.7%, Telmisartan 40 mg (n= 172) 22.6%, and placebo (n . 174) 49.9% (both Telmisartan doses vs. placebo, P < 0.0001)


21.2%

12.8%

1.2%

0

5

10

15

20

25

% P

atie

nts

with

M

icro

alb

um

inu

ria

re

mm

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Telmisartan effective in Promoting Microalbuminuria remmision (p< 0.001)

Telmisartan 80mg

Telmisartan 40mg

Placebo




Patients with type 2 diabetes and microalbuminuria Patients with type 2 diabetes and microalbuminuria receiving 80 or 40 mg telmisartanreceiving 80 or 40 mg telmisartan– Superior renoprotection, demonstrated by lower Superior renoprotection, demonstrated by lower

transition rates to overt nephropathy, compared with transition rates to overt nephropathy, compared with placeboplacebo

Achievement of microalbuminuria remission was Achievement of microalbuminuria remission was superior with 80 or 40 mg telmisartan than with placebosuperior with 80 or 40 mg telmisartan than with placebo

Telmisartan reduced transition from incipient to overt Telmisartan reduced transition from incipient to overt nephropathy and induced remission of albuminuria in nephropathy and induced remission of albuminuria in Japanese type 2 diabetic patientsJapanese type 2 diabetic patients


Effects on Glucose Effects on Glucose MetabolismMetabolism

Effects on glucose metabolismEffects on glucose metabolism

Overactivity of the renin–angiotensin system is Overactivity of the renin–angiotensin system is likely to impair insulin signaling and contribute to likely to impair insulin signaling and contribute to insulin resistanceinsulin resistance

Inhibition of the renin–angiotensin system by Inhibition of the renin–angiotensin system by ARBs might be expected to reduce insulin ARBs might be expected to reduce insulin resistance, thereby improving glucose resistance, thereby improving glucose metabolism and metabolic syndrome metabolism and metabolic syndrome


Effects on glucose metabolismEffects on glucose metabolism

Effect on Glucose metabolism is proposed to be Effect on Glucose metabolism is proposed to be mediated through mediated through PPAR- γ activityPPAR- γ activity

Among ARBs, Telmisartan has the strongest Among ARBs, Telmisartan has the strongest ability to activate PPAR- γ in vitroability to activate PPAR- γ in vitro

PPAR- γ activation by Telmisartan occurs at PPAR- γ activation by Telmisartan occurs at clinically relevant concentrations of the drug clinically relevant concentrations of the drug


Metabolic effect of Telmisartan and Metabolic effect of Telmisartan and Losartan in hypertensiveLosartan in hypertensive

patients with metabolic syndromepatients with metabolic syndrome Background: Metabolic syndrome is a cluster of Background: Metabolic syndrome is a cluster of

common cardiovascular risk factors that includes common cardiovascular risk factors that includes hypertension, hypertriglyceredemia and insulin hypertension, hypertriglyceredemia and insulin resistance resistance

Hypertension and diabetes mellitus are frequent co-Hypertension and diabetes mellitus are frequent co-morbidities and, like metabolic syndrome, increase the morbidities and, like metabolic syndrome, increase the risk of cardiovascular events risk of cardiovascular events

Telmisartan, an antihypertensive agent with evidence of Telmisartan, an antihypertensive agent with evidence of partial peroxisome proliferator-activated receptor partial peroxisome proliferator-activated receptor activity gamma (PPAR γ) activity, may improve insulin activity gamma (PPAR γ) activity, may improve insulin sensitivity and lipid profile in patients with metabolic sensitivity and lipid profile in patients with metabolic syndromesyndrome

Cardiovascular Diabetology 2005, 4:6


patients with metabolic syndromepatients with metabolic syndrome

Methods: Methods: – 40 patients with metabolic syndrome received 40 patients with metabolic syndrome received

once-daily doses of Telmisartan 80 mg or once-daily doses of Telmisartan 80 mg or Losartan 50 mg for 3 months Losartan 50 mg for 3 months

– At baseline and end of treatment, fasting and At baseline and end of treatment, fasting and postprandial plasma glucose, insulin postprandial plasma glucose, insulin sensitivity, glycosylated haemoglobin (HBA 1c ) sensitivity, glycosylated haemoglobin (HBA 1c ) and 24-hour mean systolic and diastolic blood and 24-hour mean systolic and diastolic blood pressures were determinedpressures were determined



patients with metabolic syndromepatients with metabolic syndromeResults: Results:

Telmisartan, but not losartan, significantly (p < Telmisartan, but not losartan, significantly (p < 0.05) reduced free plasma glucose, free plasma 0.05) reduced free plasma glucose, free plasma insulin, homeostasis model assessment of insulin insulin, homeostasis model assessment of insulin resistance and HbA resistance and HbA ICIC

Plasma glucose and insulin were reduced during Plasma glucose and insulin were reduced during the oral glucose tolerance test by Telmisartan, but the oral glucose tolerance test by Telmisartan, but not by losartan not by losartan

Telmisartan also significantly reduced 24-hour Telmisartan also significantly reduced 24-hour mean systolic blood pressure (p < 0.05) and mean systolic blood pressure (p < 0.05) and diastolic blood pressure (p < 0.05) compared with diastolic blood pressure (p < 0.05) compared with losartanlosartan



Effect of Telmisartan and Losartan Effect of Telmisartan and Losartan during OGTT patients with metabolic during OGTT patients with metabolic

syndromesyndrome

Before treatment After treatment


patients with metabolic syndromepatients with metabolic syndrome


In addition to providing superior 24-hour blood In addition to providing superior 24-hour blood

pressure control, Telmisartan, unlike Losartan, pressure control, Telmisartan, unlike Losartan,

displayed insulin-sensitizing activity, which may be displayed insulin-sensitizing activity, which may be

explained by its partial PPARγ activityexplained by its partial PPARγ activity


Effects on Lipid Effects on Lipid MetabolismMetabolism

Effect of Telmisartan on Cholesterol Effect of Telmisartan on Cholesterol Levels in Patients with Hypertension - Levels in Patients with Hypertension -

Saga Telmisartan Aggressive Research Saga Telmisartan Aggressive Research (STAR)(STAR)

Patients :A total of 197 patients with a systolic blood Patients :A total of 197 patients with a systolic blood pressure of ≥140 or a diastolic blood pressure of pressure of ≥140 or a diastolic blood pressure of ≥90 mmHg were enrolled≥90 mmHg were enrolled

Treatment : Patients prescribed 20 to 80 mg/day of Treatment : Patients prescribed 20 to 80 mg/day of Telmisartan for 6 monthsTelmisartan for 6 months

Results: In all patients, both systolic and diastolic Results: In all patients, both systolic and diastolic blood pressures decreasedblood pressures decreased– Systolic : 159 to 135 mm Hg, p<0.0001 Systolic : 159 to 135 mm Hg, p<0.0001 – Diastolic: 87 to 75 mm Hg, p<0.0001Diastolic: 87 to 75 mm Hg, p<0.0001

Horm Metab Res 2007; 39(5): 372-376

Effect of Telmisartan on Cholesterol Effect of Telmisartan on Cholesterol Levels in Patients with Hypertension - Levels in Patients with Hypertension -

Saga Telmisartan Aggressive Research Saga Telmisartan Aggressive Research (STAR)(STAR)

Horm Metab Res 2007; 39(5): 372-376

EffectEffect of Telmisartan on Cholesterol of Telmisartan on Cholesterol Levels in Patients withLevels in Patients with

HypertensionHypertension - Saga Telmisartan - Saga Telmisartan Aggressive Research (STAR)Aggressive Research (STAR)

Effects of telmisartan on Effects of telmisartan on

total cholesterol reduction total cholesterol reduction

in patients with levels in patients with levels ≥ ≥ 220 mg/dl220 mg/dl

Horm Metab Res 2007; 39(5): 372-376

Effect of Telmisartan on Cholesterol Effect of Telmisartan on Cholesterol Levels in Patients withLevels in Patients with

Hypertension - Saga Telmisartan Hypertension - Saga Telmisartan Aggressive Research (STAR)Aggressive Research (STAR)

Patients receiving statins Patients receiving statins

Horm Metab Res 2007; 39(5): 372-376



In patients receiving In patients receiving telmisartan in exchange telmisartan in exchange for other ARBs with total for other ARBs with total cholesterol ≥ 220 mg/dl cholesterol ≥ 220 mg/dl

Horm Metab Res 2007; 39(5): 372-376



Fasting blood glucose (FBG) was decreased (158 to Fasting blood glucose (FBG) was decreased (158 to 138 mg/dl, p<0.05) in patients with FBG ≥110 mg/dl138 mg/dl, p<0.05) in patients with FBG ≥110 mg/dl

Conclusion:Conclusion:

Telmisartan may have favorable effects on lipid and Telmisartan may have favorable effects on lipid and glucose metabolism, in addition to lowering blood glucose metabolism, in addition to lowering blood pressurepressure

Profound effect of Telmisartan to lower cholesterol Profound effect of Telmisartan to lower cholesterol suggests a potential use in hypertensive patients suggests a potential use in hypertensive patients with dyslipidemiawith dyslipidemia

Horm Metab Res 2007; 39(5): 372-376

Telmisartan: Lipid Lowering MechanismTelmisartan: Lipid Lowering Mechanism

Hypertrigriceridaemia is often complicated in Hypertrigriceridaemia is often complicated in patients with Type 2 diabetes or insulin resistance. patients with Type 2 diabetes or insulin resistance.

PPARs – PPAR- α as well as PPAR- γ – play a role in PPARs – PPAR- α as well as PPAR- γ – play a role in intracellular lipid metabolism by upregulating the intracellular lipid metabolism by upregulating the expression of the enzyme involved in the expression of the enzyme involved in the conversion of fatty acid in acyl-CoA esters, fatty conversion of fatty acid in acyl-CoA esters, fatty acid entry into mitochondria, and peroxisomal and acid entry into mitochondria, and peroxisomal and mitochondrial fatty acid catabolismmitochondrial fatty acid catabolism

PPAR- γ activation of telmisartan may also PPAR- γ activation of telmisartan may also contribute to its hypotriglyceridaemic actioncontribute to its hypotriglyceridaemic action


Telmisartan: Reverse Telmisartan: Reverse Cholesterol TransportCholesterol Transport

Excessive cholesterol in non-hepatic peripheral Excessive cholesterol in non-hepatic peripheral cells triggers efflux of free cholesterol from these cells triggers efflux of free cholesterol from these cells to liver by binding to HDLcells to liver by binding to HDL

This reverse cholesterol transport, regulates This reverse cholesterol transport, regulates cholesterol catabolism and is mediated by the cholesterol catabolism and is mediated by the ATP-binding cassette (ABC) transporters ABCA1, ATP-binding cassette (ABC) transporters ABCA1, ABCG1, ABCG5 and ABCG8 ABCG1, ABCG5 and ABCG8


Telmisartan: Reverse Cholesterol Telmisartan: Reverse Cholesterol TransportTransport

ABCA1 is involved in HDL production and ABCA1 is involved in HDL production and mediates the cholesterol efflux from the mediates the cholesterol efflux from the periphery and its delivery to liverperiphery and its delivery to liver

Telmisartan induced ABCA1 gene expressionTelmisartan induced ABCA1 gene expression

Telmisartan may accelerate reverse cholesterol Telmisartan may accelerate reverse cholesterol transport through activation of ABCA1, leading to transport through activation of ABCA1, leading to total cholesterol and LDL-cholesterol loweringtotal cholesterol and LDL-cholesterol lowering


Telmisartan: Lipid Lowering Telmisartan: Lipid Lowering MechanismMechanism

Liver X receptor α (LXR α ) plays a crucial role in the Liver X receptor α (LXR α ) plays a crucial role in the regulation of regulation of cholesterol efflux from enterocytes back cholesterol efflux from enterocytes back into the intestinal lumeninto the intestinal lumen via ABCA1 and ABCG5/G8 via ABCA1 and ABCG5/G8

Both PPAR- α and PPAR- γ upregulate LXR α gene Both PPAR- α and PPAR- γ upregulate LXR α gene expressionexpression and may indirectly regulate ABCA1 and and may indirectly regulate ABCA1 and ABCG5/G8 , resulting in inhibition of intestinal ABCG5/G8 , resulting in inhibition of intestinal cholesterol absorption cholesterol absorption

Inhibition of net cholesterol absorption may be one of Inhibition of net cholesterol absorption may be one of the possible mechanisms by which Telmisartan the possible mechanisms by which Telmisartan lowers total cholesterol and LDL-cholesterol levels via lowers total cholesterol and LDL-cholesterol levels via its PPAR- γ –activating effectits PPAR- γ –activating effect


Overview : Mechanism of Cardiovascular Overview : Mechanism of Cardiovascular Protection by TelmisartanProtection by Telmisartan


ConclusionsConclusions

Telmisartan has Telmisartan has Anti-hypertensive action: Anti-hypertensive action: – highly selective for the AT1 receptorhighly selective for the AT1 receptor– long duration of action because of its long terminal long duration of action because of its long terminal

elimination half-lifeelimination half-life

Telmisartan- Unique property of activating PPAR- γ, Telmisartan- Unique property of activating PPAR- γ, improving insulin sensitivity and reducing triglyceride improving insulin sensitivity and reducing triglyceride levelslevels

Improves insulin sensitivityImproves insulin sensitivity

Decreases adipocyte cell sizeDecreases adipocyte cell size

Decrease hepatic fat storageDecrease hepatic fat storage

ConclusionsConclusions

Improvement in metabolic syndrome & reduction Improvement in metabolic syndrome & reduction of atherosclerosis riskof atherosclerosis risk

Decreased serum glucose and serum triglyceride Decreased serum glucose and serum triglyceride levels, and increased glucose uptake and GLUT4 levels, and increased glucose uptake and GLUT4 protein expressionprotein expression

Telmisartan associated:Telmisartan associated:– Significant reduction in left ventricular mass Significant reduction in left ventricular mass

indexindex– Posterior and septal wall thickness, in mild-to-Posterior and septal wall thickness, in mild-to-

moderate LVHmoderate LVH

ConclusionConclusion

Telmisartan valuable treatment option in the Telmisartan valuable treatment option in the management of hypertension and cardiovascular management of hypertension and cardiovascular riskrisk

Doctors and patients appreciate its excellent Doctors and patients appreciate its excellent safety profilesafety profile


The consistent antihypertensive efficacy during The consistent antihypertensive efficacy during

the entire 24 hr dosage interval and sustained the entire 24 hr dosage interval and sustained

BP lowering effect in the long term, combined BP lowering effect in the long term, combined

with its favorable tolerability profile, mean that with its favorable tolerability profile, mean that

telmisartan is a valuable first line treatment telmisartan is a valuable first line treatment

option for the management of essential option for the management of essential

hypertensionhypertension

Why combination therapy ?Why combination therapy ?

Multiple mechanisms involved in the pathogenesis Multiple mechanisms involved in the pathogenesis of hypertensionof hypertension

Effective BP control seen in only 50% of patients Effective BP control seen in only 50% of patients on monotherapy;on monotherapy;

BP goals difficult to attain with monotherapy in BP goals difficult to attain with monotherapy in patients with diabetes or target organ damagepatients with diabetes or target organ damage

combination therapy results in a much higher combination therapy results in a much higher responder rate (>80%)responder rate (>80%)

Hypertension: combination therapyHypertension: combination therapy

What is the need?What is the need?

JNC -7 recommends initiating combination therapy if:JNC -7 recommends initiating combination therapy if:

BP > 20/10 mm Hg above goal BPBP > 20/10 mm Hg above goal BP

( < 140/90)( < 140/90)

In diabetic hypertensivesIn diabetic hypertensives

In patients with chronic renal diseaseIn patients with chronic renal disease

Goal < 130/80

Combination therapy for hypertension Combination therapy for hypertension

With any single drug, not more than 25–50% of With any single drug, not more than 25–50% of hypertensives achieve adequate blood pressure controlhypertensives achieve adequate blood pressure control

J Hum. Hypertens 1995; 9:S33–S36J Hum. Hypertens 1995; 9:S33–S36

For patients not responding adequatelyto low doses of monotherapy

Increase the dose of drug. This, however, may lead to

increased side effects

Substitute with another drug from a different class

Add a second drug from a different class

(Combination therapy)

Add second drug from different class (Combination therapy)

If inadequate response obtained


Requirement of combination therapy:Requirement of combination therapy:

Both drugs must have Both drugs must have different mechanismsdifferent mechanisms of of

actionaction..

Combination should be Combination should be more effectivemore effective than than

monotherapy- additive/synergistic effectmonotherapy- additive/synergistic effect

Matching kinetics-Matching kinetics-

No adverse drug interactionsNo adverse drug interactions

No additive side effects.No additive side effects.


Beneficial combinations:Beneficial combinations:

Beta blocker + DiureticBeta blocker + Diuretic

ACEI /ARB + DiureticACEI /ARB + Diuretic

CCB + Beta blockerCCB + Beta blocker

CCB+ ACE-I /ARBCCB+ ACE-I /ARB

A or B + C or D


Benefits:Benefits:

Improved control of BP - Better target organ Improved control of BP - Better target organ

protection protection [response rate increase from 50% to 80%][response rate increase from 50% to 80%]

Better tolerated- Reduced side effects - Lower dose Better tolerated- Reduced side effects - Lower dose

of individual drugsof individual drugs

Improve patients compliance-Improve patients compliance- Reduced pill burdenReduced pill burden

EconomicalEconomical


Candidates:Candidates:

Stage 2 hypertensives: Stage 2 hypertensives: >>160/100160/100

Diabetic hypertensivesDiabetic hypertensives

Chronic renal diseaseChronic renal disease

Suggested guidelines for the use of Suggested guidelines for the use of fixed-dose combinationsfixed-dose combinations

Coexisting conditionCoexisting condition First choiceFirst choice

Ischaemic heart diseaseIschaemic heart disease Amlodipine + AtenololAmlodipine + Atenolol

DiabetesDiabetes Amlodipine +ACEI/ ARBAmlodipine +ACEI/ ARB

Congestive heart failureCongestive heart failure ACEI/ ARB + HCTZACEI/ ARB + HCTZ

TachycardiaTachycardia Amlodipine + Atenolol Amlodipine + Atenolol

Elderly hypertensivesElderly hypertensives Amlodipine + HCTZ Amlodipine + HCTZ ACEI/ ARB + HCTZACEI/ ARB + HCTZ

Renal insufficiencyRenal insufficiency (not due to renal (not due to renal Amlodipine + ACEI/ ARB Amlodipine + ACEI/ ARB artery stenosis)artery stenosis)

Combination TherapyCombination TherapyStrategy for improving efficacy Strategy for improving efficacy

and reducing side effectsand reducing side effects

Angiotensin II Receptor Blocker Angiotensin II Receptor Blocker (ARB)/Diuretic Combination(ARB)/Diuretic Combination

Diuretics ARBs

Fluid volume ( Preload)

Renin release

RAAS activation

PVR & preload via inhibition of action of AT II at the receptor level

RAAS suppression

Telmisartan/HydrochlorothiazideTelmisartan/HydrochlorothiazideParameterParameter TelmisartanTelmisartan HCTZHCTZ Tellzy-HTellzy-H

MOAMOA AT1 Receptor AT1 Receptor BlockerBlocker

DiureticDiuretic Complementary Complementary effecteffect

Pre load ( Blood Pre load ( Blood Volume)Volume)

DecreaseDecrease DecreaseDecrease Additive effectAdditive effect

After Load (PVR)After Load (PVR) DecreaseDecrease DecreaseDecrease Additive effectAdditive effect

RAASRAAS SuppressionSuppression ActivationActivation Neutral effectNeutral effect

DosingDosing ODOD ODOD ODOD

Telmisartan/HydrochlorothiazideTelmisartan/Hydrochlorothiazide

ParameterParameter TelmisartanTelmisartan HCTZHCTZ Tellzy-HTellzy-H

Renin LevelsRenin Levels DecreaseDecrease IncreaseIncrease No ChangeNo Change

Potassium Potassium LevelsLevels

IncreaseIncrease DecreaseDecrease No ChangeNo Change

• No Risk of Electrolytic imbalance

• Improved tolerability

Tellzy-HTellzy-H

Candidates:Candidates:

• Stage 2 hypertensives: Stage 2 hypertensives: >>160/100160/100

• Diabetic hypertensivesDiabetic hypertensives

• Chronic renal diseaseChronic renal disease

Tellzy-HTellzy-H

DoseDose : : one tablet daily in the morningone tablet daily in the morning– No dose adjustment required in:No dose adjustment required in: elderly or mild to moderate renal impairment elderly or mild to moderate renal impairment

– Use with caution in hepatic dysfunctionUse with caution in hepatic dysfunction

– Dose should not exceed 40 mg /day+ Dose should not exceed 40 mg /day+ 12.5mg/day12.5mg/day

– Not recommended in severe hepatic Not recommended in severe hepatic impairmentimpairment

Telmisartan/HydrochlorothiazideTelmisartan/Hydrochlorothiazide

Advantages :Advantages :

– Better blood pressure controlBetter blood pressure control

– Lesser incidence of individual drug’s side-effectsLesser incidence of individual drug’s side-effects

– Neutralisation of side-effectsNeutralisation of side-effects

– Improved patient compliance- Reduced pill Improved patient compliance- Reduced pill

burdenburden


The consistent antihypertensive efficacy during the The consistent antihypertensive efficacy during the

entire 24 hr dosage interval and sustained BP lowering entire 24 hr dosage interval and sustained BP lowering

effect in the long term, combined with its favorable effect in the long term, combined with its favorable

tolerability profile, mean that telmisartan is a valuable tolerability profile, mean that telmisartan is a valuable

first line treatment option for the management of first line treatment option for the management of

essential hypertensionessential hypertension

hypertension 1

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