Hypertension today is a triple paradox which is :

Easy to diagnose OFTEN remains undetected

Simple to treat OFTEN remains untreated

Despite availability of potent drugs, treatment OFTEN is ineffective

Approximately 70% of Patients* in Europe Do Not Approximately 70% of Patients* in Europe Do Not Reach BP GoalReach BP Goal

Wolf-Maier et al. Hypertension 2004;43:10–17

*Treated for hypertension

BP goal is <140/90 mmHg

60 79 70 81 72

0

20

40

60

80

100

BP goal achieved BP goal not achievedPatients)%(

England Sweden Germany Spain Italy

Hypertension in EgyptHypertension in Egypt

•Hypertension is a major health Hypertension is a major health problem in Egypt problem in Egypt with a prevalence rate of with a prevalence rate of 26.3%26.3% among among

the adult population (the adult population (>> 25 years) 25 years)11..

Only 8% of hypertensive Egyptians Only 8% of hypertensive Egyptians have their blood pressure controlledhave their blood pressure controlled11 . .

1 -Ibrahim MM, Rizk H, Apple LJ, et al. For the NHP investigation team. Hypertension, prevalence, awareness, treatment and control in Egypt .Results from the Egyptian National hypertension Project (NHP). Hypertension 1995; 26:880 .

BP Differences of 10 mmHg Are Associated With Up to a 40% Effect BP Differences of 10 mmHg Are Associated With Up to a 40% Effect on on

CV RiskCV Risk • Meta-analysis of 61 prospective, observational studies

• 1 million adults

• 12.7 million person-years

Lewington S et al. Lancet. 2002;360:1903–1913.

10 mmHg decrease in mean SBP 40% reduction

in risk of stroke mortality

30% reduction in risk of IHD mortality

Tight Glucose ControlTight Glucose Control

Tight BP ControlTight BP Control

**P < 0.05P < 0.05-50 -

-40 -

-30 -

0 - StrokeAny DM

End Point DM DeathMicrovascular

Complications

Red

uctio

n in

Ris

k (%

)

UKPDS. BMJ. 1998:317;703-712.

-20 -

-10 -

Tight BP Control vs. Tight Tight BP Control vs. Tight Glucose ControlGlucose Control

Importance of Lowering BPImportance of Lowering BP (Data from Multiple Clinical Trials Measuring the Impact of (Data from Multiple Clinical Trials Measuring the Impact of

Hypertensive Therapy on Cardiovascular MortalityHypertensive Therapy on Cardiovascular Mortality))

Greater differences in BP reduction mean greater reductions in the risk of cardiovascular mortality.

BP, blood pressureStaessen JA et al. Hypertension Research. 2005;28:385-407.

MRC2

MIDAS/NICS/VHAS

UKPDS C vs A

NORDIL INSIGHTHOT L vs H

HOT M vs H MRC1

HEPEWPHE

STOP1ATMHPART2/SCAT

CAPPP

Syst-China

0.25

0.50

0.75

1.00

1.25

1.50

Syst-EurSTONE

UKPDS L vs HRCT70-80

Od

ds

Rat

io (

exp

erim

enta

l/re

fere

nce

)

P=0.002

Cardiovascular Mortality

–5 0 5 10 15 20 25Difference (reference treatment minus experimental treatment) in Systolic BP (mmHg)

actively controlled trials.

placebo-controlled studies or trials with an untreated control group.

Negative values indicate tighter BP control on reference treatment.

HOPE

SHEP

STOP2/ACEIs

STOP2/CCBs

Antihypertensive monotherapy is effective in Antihypertensive monotherapy is effective in

only about 40-60% of hypertensive patients, only about 40-60% of hypertensive patients,

irrespective of the category of the agent that irrespective of the category of the agent that

is used. Therefore, there is frequently a need is used. Therefore, there is frequently a need

for the use of two medications with different for the use of two medications with different

mechanisms of action.mechanisms of action.

MonotherapyMonotherapy

Target BP )mm Hg(Number of antihypertensive agents

1Trial 2 3 4

AASK MAP <92

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

IDNT SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

Multiple Antihypertensive Agents Multiple Antihypertensive Agents Are Needed to Achieve Target BPAre Needed to Achieve Target BP

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Cushman WC et al. J Clin Hypertens. 2002;4:393-405.

So combine

GGAZZA

GHAZZA WHY?

Why combination therapyWhy combination therapy؟؟((11))Multiple mechanisms involved in the Multiple mechanisms involved in the

pathogenesis of hypertensionpathogenesis of hypertension

((22))Effectiveness of monotherapy limited by Effectiveness of monotherapy limited by stimulation of counter-regulatory stimulation of counter-regulatory mechanismsmechanisms

((33))Effective BP control seen in only 50% of Effective BP control seen in only 50% of patients on monotherapy; combination patients on monotherapy; combination therapy results in a much higher therapy results in a much higher responder rate (>80%)responder rate (>80%)

((44))BP goals difficult to attain with BP goals difficult to attain with monotherapy in patients with diabetes or monotherapy in patients with diabetes or target organ damagetarget organ damage

Sympathetic nervous systemRenin-angiotensin system

Total body sodium

Patient 1 Patient 2 Patient 3

B. Waeber, March 2007, with kind permission

Blood Pressure has Multiple Regulatory Blood Pressure has Multiple Regulatory PathwaysPathways

WHEN TO WHEN TO COMBINECOMBINE??

Current Guidelines Acknowledge that Combination Therapy Current Guidelines Acknowledge that Combination Therapy is Required by the Majority of Patients to Reach BP Goalis Required by the Majority of Patients to Reach BP Goal

• JNC 7 guidelines stateJNC 7 guidelines state11::““Although effective BP control can be achieved Although effective BP control can be achieved in most patients who are hypertensive, the in most patients who are hypertensive, the majority will require two or more majority will require two or more antihypertensive drugs.”antihypertensive drugs.”

• ESH/ESC guidelines stateESH/ESC guidelines state22::““Regardless of the drug employed, Regardless of the drug employed, monotherapy allows to achieve BP target in monotherapy allows to achieve BP target in only a limited number of hypertensive patients. only a limited number of hypertensive patients. Use of more than one agent is necessary to Use of more than one agent is necessary to achieve target BP in the majority of patients.”achieve target BP in the majority of patients.”

1Chobanian et al. Hypertension 2003;42:1206–522Mancia et al. J Hypertens 2007:25:110587

ESH = European Society of HypertensionESC = European Society of CardiologyJNC = Joint National Committee

• JNC 7 guidelines stateJNC 7 guidelines state22::““When BP is more than 20 mmHg above systolic goal When BP is more than 20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with 2 drugs...”should be given to initiate therapy with 2 drugs...”

• ESH/ESC guidelines stateESH/ESC guidelines state22::““A combination of two drugs at low doses should be A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is the grade 2 or 3 range or total cardiovascular risk is high or very high.”high or very high.”

1Chobanian et al. Hypertension 2003;42:1206–52 2Mancia et al. J Hypertens 2007:25:110587

ESH = European Society of HypertensionESC = European Society of CardiologyJNC = Joint National Committee

American Heart AssociationAmerican Heart Association

““Starting with combination therapy Starting with combination therapy may be the best way to get may be the best way to get hypertensive patientshypertensive patients’’ blood pressure blood pressure

down to goal levelsdown to goal levels..””

Drug combinationDrug combination

• Fixed dose combinationFixed dose combination Single preparations containing two or Single preparations containing two or

more active agents, more active agents,

BUTBUT

• DRUG THERAPY COMBINATION DRUG THERAPY COMBINATION is two or more drugs are administered is two or more drugs are administered

separately for a combined effectseparately for a combined effect. .

Advantages of fixed-doseAdvantages of fixed-dosecombination therapycombination therapy

– (1)Better blood pressure control(1)Better blood pressure control

– (2)Lesser incidence of individual drug(2)Lesser incidence of individual drug ’’s side-s side-

effectseffects

– (3)Neutralisation of side-effects(3)Neutralisation of side-effects

– (4)Increased patient compliance(4)Increased patient compliance

– (5)Modification of risk factors(5)Modification of risk factors

– (6)Lesser cost of therapy(6)Lesser cost of therapy

– (7)Early normalization of BP may greatly (7)Early normalization of BP may greatly

motivate the patientsmotivate the patients

– (8)(8) Recommended by guidelines Recommended by guidelines

–

•Single-dose combination Single-dose combination antihypertension therapy is an antihypertension therapy is an important option that combines important option that combines efficacyefficacy of blood pressure of blood pressure reduction and a reduction and a low side effectlow side effect profile with profile with convenientconvenient once-daily once-daily dosing to enhance dosing to enhance compliancecompliance..

• Drawbacks of Fixed-Dose Drawbacks of Fixed-Dose CombinationsCombinationsDosage flexibility is lostDosage flexibility is lost

Can be overcome by: Can be overcome by:

(1) multiple combinations of the two (1) multiple combinations of the two ingredientsingredients

(2)Wide dose ranges(2)Wide dose ranges

TYPES OF DRUG TYPES OF DRUG COMBINATIONCOMBINATION

• The use of antihypertensive combinations The use of antihypertensive combinations

started in the started in the 19601960s with s with hydrochlorothiazide (HCTZ) combined with hydrochlorothiazide (HCTZ) combined with triamterene.triamterene.

• The majority of currently available The majority of currently available fixed-dose combinations are diuretic-fixed-dose combinations are diuretic-basedbased

• Combinations may be individualized Combinations may be individualized according to the presence ofaccording to the presence of comorbiditiescomorbidities like diabetes mellitus, like diabetes mellitus, CRF, HF, thyroid disorders and for CRF, HF, thyroid disorders and for special groupsspecial groups like elderly and like elderly and pregnant femalespregnant females

Diuretics-------Diuretics-------why?why?

• (1) In long-term trials, diuretics have (1) In long-term trials, diuretics have been shown to reduce the incidence been shown to reduce the incidence of stroke, congestive heart failure, of stroke, congestive heart failure, coronary artery disease and total coronary artery disease and total mortality from cardiovascular mortality from cardiovascular diseasedisease. .

• (2) Because diuretics blunt the (2) Because diuretics blunt the sodium- and water-retaining sodium- and water-retaining effects of many other effects of many other antihypertensive drugsantihypertensive drugs

• (3) The JNC VI states clearly, "If a (3) The JNC VI states clearly, "If a

diuretic is not chosen as the first diuretic is not chosen as the first drug, it is usually indicated as a drug, it is usually indicated as a second-step agent because its second-step agent because its addition will enhance the effects addition will enhance the effects of other agentsof other agents

• But the higher diuretic dosages used in the But the higher diuretic dosages used in the large trials cause relative hypokalemia, as large trials cause relative hypokalemia, as well as increased serum lipid levels, insulin well as increased serum lipid levels, insulin resistance and uric acid levels. resistance and uric acid levels.

• These adverse metabolic effects counteract These adverse metabolic effects counteract the positive cardiovascular benefits of blood the positive cardiovascular benefits of blood pressure reduction. pressure reduction.

• Such effects do not occur when diuretics are Such effects do not occur when diuretics are administered in a low dosage, such as 6.25 administered in a low dosage, such as 6.25 or 12.5 mg per day of hydrochlorothiazideor 12.5 mg per day of hydrochlorothiazide. .

K sparingK sparing thiazide(K losing) thiazide(K losing) diuretic combinationsdiuretic combinations• have been in use for more than 20 have been in use for more than 20

years. years.

• Current combinations include Current combinations include (1)spironolactone-(1)spironolactone-hydrochlorothiazide (Aldactazide),hydrochlorothiazide (Aldactazide),

• (2) triamterene-hydrochlorothiazide (2) triamterene-hydrochlorothiazide (Dyazide, Maxzide) and (Dyazide, Maxzide) and

• (3)amiloride-hydrochlorothiazide (3)amiloride-hydrochlorothiazide (Moduretic).(Moduretic).

• (4) spironolactone-furosemide. (4) spironolactone-furosemide.

Potassium-Sparing and Potassium-Sparing and Thiazide DiureticsThiazide Diuretics

reduce the risk of adverse metabolic reduce the risk of adverse metabolic effects.effects.

• it does decrease the incidence of it does decrease the incidence of thiazide-induced hypokalemia without thiazide-induced hypokalemia without an increased risk of hyperkalemiaan increased risk of hyperkalemia

• However, this does not obviate the However, this does not obviate the need for serial monitoring of serum need for serial monitoring of serum electrolyte levels. electrolyte levels.

Adverse metabolic effects were Adverse metabolic effects were observed only for regimens observed only for regimens containing hydrochlorothiazide containing hydrochlorothiazide in a dosage of 25 mg per day.in a dosage of 25 mg per day.

• decrease Serum potassiumdecrease Serum potassium

• increase Serum glucoseincrease Serum glucose

Diuretics Diuretics and Beta and Beta BlockersBlockers

Beta blockers cause retention of Beta blockers cause retention of sodium and water. sodium and water.

• Diuretics can cause mild volume Diuretics can cause mild volume reduction that leads to an increase in reduction that leads to an increase in renin secretion by the kidney.renin secretion by the kidney.

• combining beta blockers with diuretics combining beta blockers with diuretics is twofold:is twofold:

• ))1) beta blockers blunt the increase in 1) beta blockers blunt the increase in the plasma renin level that is induced the plasma renin level that is induced by diuretics.by diuretics.

• (2) diuretics decrease the sodium and (2) diuretics decrease the sodium and water retention that is caused by beta water retention that is caused by beta blockersblockers

•(3)diuretics and beta blockers are (3)diuretics and beta blockers are shown to decrease the incidence of shown to decrease the incidence of stroke and congestive heart failure stroke and congestive heart failure in patients with hypertensionin patients with hypertension..

•))4) 4) The combination of a beta blocker and a The combination of a beta blocker and a diuretic produces additive effects compared diuretic produces additive effects compared with monotherapy using either agent alonewith monotherapy using either agent alone

Beta blockers and Beta blockers and diureticsdiuretics

• Atenolol and chlorthalidoneAtenolol and chlorthalidone

• Atenolol and chlorthalidone and Atenolol and chlorthalidone and hydrochlorothiazide.hydrochlorothiazide.

• Bisoprolol and hydrochlorothiazideBisoprolol and hydrochlorothiazide

• Metoprolol and hydrochlorothiazide Metoprolol and hydrochlorothiazide

• Nadolol and bendroflumethazide Nadolol and bendroflumethazide

• Propranolol and hydrochlorothiazide Propranolol and hydrochlorothiazide

• Timolol and hydrochlorothiazide Timolol and hydrochlorothiazide

Diuretics & Diuretics & ACE ACE InhibitorsInhibitors

• (1)By causing volume and sodium (1)By causing volume and sodium depletion, thiazide diuretics stimulate depletion, thiazide diuretics stimulate the production of renin and the production of renin and angiotensin. ----angiotensin. ---- counteracts some counteracts some of antihypertensive effects of the of antihypertensive effects of the thiazide diuretics.thiazide diuretics.

• ))2) ACE inhibitors interfere with the 2) ACE inhibitors interfere with the conversion of angiotensin I to conversion of angiotensin I to angiotensin II and thereby decrease angiotensin II and thereby decrease angiotensin II levels.angiotensin II levels.

• These effects lead to decreased These effects lead to decreased sodium retention and an enhanced sodium retention and an enhanced antihypertensive effectantihypertensive effect..

• (3)Synergism between ACE (3)Synergism between ACE inhibitors and diuretics is inhibitors and diuretics is especially prominent in black especially prominent in black patients, a population in whom patients, a population in whom monotherapy with ACE inhibitors monotherapy with ACE inhibitors has been shown to be less has been shown to be less effective than it is in white effective than it is in white patients. patients.

• (4)Studies have shown that ACE (4)Studies have shown that ACE inhibitorinhibitor diuretic combinations diuretic combinations achieve blood pressure control in achieve blood pressure control in approximately 80 percent of approximately 80 percent of patientspatients. .

ExammplesExammples::

• Hydrochlorothiazide+captoprilHydrochlorothiazide+captopril

• Hydrochlorothiazide+lisinoprilHydrochlorothiazide+lisinopril

• Hydrochlorothiazide+ramiprilHydrochlorothiazide+ramipril

• Hydrochlorothiazide+enalaprilHydrochlorothiazide+enalapril

• Hydrochlorothiazide+perindoprilHydrochlorothiazide+perindopril

• Hydrochlorothiazide+benaziprilHydrochlorothiazide+benazipril

•Diuretics & Diuretics & Angiotensin-II Angiotensin-II AntagonistsAntagonists

In patients for whom ACE In patients for whom ACE inhibitorinhibitor diuretic diuretic combinations are indicated combinations are indicated but not tolerated because of but not tolerated because of cough-----cough-----useuse

Diuretics and ARBsDiuretics and ARBs

Angiotensin-II Antagonists Angiotensin-II Antagonists and Diureticsand Diuretics

• diuretic -diuretic -volume depletion with volume depletion with increase renin level-increase renin level-increase increase angiotensinangiotensin

• . Angiotensin-II receptor . Angiotensin-II receptor antagonists work by blocking antagonists work by blocking specific angiotensin II receptors specific angiotensin II receptors selectively inhibiting the vasoactive selectively inhibiting the vasoactive properties of angiotensin IIproperties of angiotensin II..

ExamplesExamples------------

• Hydrochlorothiazide+losartanHydrochlorothiazide+losartan

• Hydrochlorothiazide+valsartanHydrochlorothiazide+valsartan

• Hydrochlorothiazide+irbesartan----Hydrochlorothiazide+irbesartan----etc….etc….

•Calcium Channel Calcium Channel BlockersBlockers& &

• ACE InhibitorsACE Inhibitors

Calcium Channel Blockers Calcium Channel Blockers and ACE Inhibitorsand ACE Inhibitors

• Although calcium antagonists Although calcium antagonists exert much of their exert much of their antihypertensive effect through antihypertensive effect through a vasodilatory action-----a vasodilatory action-----

they also have diuretic and they also have diuretic and natriuretic propertiesnatriuretic properties

Value of cominationValue of comination:----:----

• . . (1)ACE inhibitors blunt the (1)ACE inhibitors blunt the stimulation of the renin-stimulation of the renin-angiotensin-aldosterone axis that angiotensin-aldosterone axis that may result from this diuretic effect. may result from this diuretic effect.

• (2)ACEI also inhibit the central (2)ACEI also inhibit the central sympathetic stimulation that may sympathetic stimulation that may result from vasodilatationresult from vasodilatation

• (3)ACE inhibitors and calcium channel (3)ACE inhibitors and calcium channel blockers work effectively in combination to blockers work effectively in combination to lower blood pressure.lower blood pressure.

• (4) also work together to favorably (4) also work together to favorably influence target-organ disease influence target-organ disease independent of their effect on blood independent of their effect on blood pressure.pressure.

• ))5) Together they appear to5) Together they appear to

a have renal-protective effect,a have renal-protective effect,

to promote reduction of LV massto promote reduction of LV mass

to decrease mediators of vascular dsto decrease mediators of vascular ds

• (6)Calcium channel blocker(6)Calcium channel blocker ACE inhibitor ACE inhibitor combinations may result in fewer or milder combinations may result in fewer or milder side effects than occur with either agent side effects than occur with either agent alone. alone.

The addition of an ACE inhibitor to a The addition of an ACE inhibitor to a dihydropyridine calcium antagonist dihydropyridine calcium antagonist significantly reduces the incidence of significantly reduces the incidence of peripheral edema and reflex tachycardia. peripheral edema and reflex tachycardia.

• (7)Neither class of medications has (7)Neither class of medications has prominent metabolic side effects, an prominent metabolic side effects, an advantage in patients with diabetes and advantage in patients with diabetes and renal diseaserenal disease..

• Results from the ACCOMPLISH study Results from the ACCOMPLISH study (Avoiding Cardiovascular Events (Avoiding Cardiovascular Events Through Combination Therapy in Through Combination Therapy in Patients Living with Systolic Patients Living with Systolic Hypertension) suggest that patients Hypertension) suggest that patients receiving an ACEI plus a calcium-receiving an ACEI plus a calcium-channel blocker (CCB) do better than channel blocker (CCB) do better than patients receiving an ACEI and a patients receiving an ACEI and a diureticdiuretic

ExamplesExamples::

• Amlodipine + lisinoprilAmlodipine + lisinopril

• Amlodipine + trandoprilAmlodipine + trandopril

• Amlodipine + perindoprilAmlodipine + perindopril

• Verapamil+trandoprilVerapamil+trandopril

•Calcium Channel Calcium Channel BlockersBlockers & &

•Beta BlockersBeta Blockers

CCB-BB combination in hypertension : Mechanism of action

Peripheral Resistance Cardiac Output

Sodium & fluid Retention

Aldosterone

Angiotensin II

Angiotensin I

Angiotensinogen

Beta stimulation

Muscle contraction

Ca++ influx

Renin

Kidney

Ca antagonist

Heart

BLOOD PRESSURE

B-blockerl

x

•Tachycardia induced by Tachycardia induced by amlodipine or nifedipine -----amlodipine or nifedipine -----

is neutralized by bradycardia is neutralized by bradycardia of b-blockersof b-blockers

• But----------do not combine 2 drugs But----------do not combine 2 drugs with:with:

Negative inotropic effects.Negative inotropic effects.

Negative chronotropic effects.Negative chronotropic effects.

Ca antagonist&

A.R.Bs.A.R.Bs.

ARBARB

VasodilationVasodilation

Blocks the Blocks the vasoconstrictor and vasoconstrictor and

aldosterone aldosterone secreting effects of secreting effects of

angiotensin IIangiotensin II

Reverses sodium Reverses sodium and water and water retentionretention

by decreasing by decreasing aldosterone aldosterone

secretionsecretion

Highly effective in Highly effective in high-renin patientshigh-renin patients

Ca antagonist))11((Blood Blood

pressurepressureVasodilationVasodilation

Reduces Ca-influx Reduces Ca-influx in vascular smooth in vascular smooth

muscle cellsmuscle cells

Highly effective in Highly effective in low-renin patientslow-renin patients

ARBARB

Neutral effect on Neutral effect on lipid profilelipid profile

Improves insulin Improves insulin sensitivitysensitivity

Ca antagonist

Neutral effect on Neutral effect on lipid profilelipid profile

Favourable effects Favourable effects on glucose on glucose

metabolismmetabolism

Ca antagonist

(2)Atherosclerosis

Suppresses proliferation & migration of SMCs

Prevents excessive secretion of connective tissue

Inhibits LDL oxidation

Normalises elevated serum insulin and triglyceride concentrations

Restores and preserves endothelial function

ARB

Inhibits angiotensin II-induced stimulation & proliferation of SMCs

Restores and preserves endothelial function by increasing NITRIC OXIDE which is an endogenous vasodilator

In t r a g l o m e r u l a r e f f e c t s o f A M L O D I P IN E a n d L O S A R T A N

V a s o d i l a t o r y e f f e c t sD ih y d r o p y r id i n e

c a lc iu m a n t a g o n is te . g . a m l o d ip i n e

A n g i o t e n s in I I r e c e p t o ra n t a g o n is t - l o s a r t a n

E f f e r e n t v e s s e lA f f e r e n t v e s s e l

E f f e c t o n m e s a n g i a l c e l l s :a n t i - p r o l i f e r a t i v e e f f e c t o f

A M L O D I P IN E a n d L O S A R T A N

D i h y d r o p y r i d i n ec a lc iu m a n t a g o n i s t

e . g . a m l o d i p i n e

In t r a g l o m e r u l a r p r e s s u r e A l b u m i n u r i a M e s a n g i a l m a t r i x

A n g i o t e n s i n I I r e c e p t o ra n t a g o n is t l o s a r t a n

Miscellaneous Miscellaneous cominationscominations

• (1)Clonidine and chlorthalidone(1)Clonidine and chlorthalidone

• (2)Hydralazine and hydrochlorothiazide (2)Hydralazine and hydrochlorothiazide

• (3)Methyldopa and hydrochlorothiazide (3)Methyldopa and hydrochlorothiazide

• (4)Prazosin and polythiazide(4)Prazosin and polythiazide

• (5) aliskiren/amlodipine/hydrochlorothiazide (5) aliskiren/amlodipine/hydrochlorothiazide FDA in the US has approved it with no FDA in the US has approved it with no

restrictions except that it should not be used for restrictions except that it should not be used for initial therapy.initial therapy.

   Aliskiren(direct renin inhibitor )alone or in Aliskiren(direct renin inhibitor )alone or in combination has not been shown to improve combination has not been shown to improve clinical outcomes.clinical outcomes.  

. .

(6)NO donor drugs (. Isosorbid (6)NO donor drugs (. Isosorbid mononitrate) andmononitrate) and

phosphodiesterasephosphodiesterase inhibitors inhibitors (sildenafil)(sildenafil)

have antihypertensive propertieshave antihypertensive properties and and the combination can markedly the combination can markedly reduce blood pressurereduce blood pressure in resistant in resistant hypertensionhypertension

Combination of more Combination of more than 2 drugsthan 2 drugs

• Few patients may require a third or fourth drug to Few patients may require a third or fourth drug to adequately manage BP.adequately manage BP.

• Preference should be given to the selection of an Preference should be given to the selection of an agent from a different class than the initial 2 agent from a different class than the initial 2 drugs in the combination therapy.drugs in the combination therapy.

• Addition of the third drug may be in the form of Addition of the third drug may be in the form of spironolactone (requires the assessment of renal spironolactone (requires the assessment of renal functions and potassium), minoxidil, hydralazine, functions and potassium), minoxidil, hydralazine, carvedilol and rest of the drugs depending on the carvedilol and rest of the drugs depending on the specific conditions being treated. specific conditions being treated.

• Centrally acting drugs should be the last option Centrally acting drugs should be the last option due to potential side effectsdue to potential side effects. .

Concept of "PolypillConcept of "Polypill

• It is generally accepted that reducing the pill burden It is generally accepted that reducing the pill burden improves adherence and/or compliance to therapy,improves adherence and/or compliance to therapy,

• . Wald and Law introduced the term "polypill" in 2003.. Wald and Law introduced the term "polypill" in 2003.

• Polypill has been thought as a single daily pill to prevent Polypill has been thought as a single daily pill to prevent CVD by simultaneously reducing four risk factors (LDL CVD by simultaneously reducing four risk factors (LDL cholesterol, BP, platelet function, and serum homocysteine). cholesterol, BP, platelet function, and serum homocysteine).

• It usually is composed of a statin, three pressure-lowering It usually is composed of a statin, three pressure-lowering drugs, each at half of its standard dose, aspirin, 75 mg, and drugs, each at half of its standard dose, aspirin, 75 mg, and folic acid. folic acid.

• The polypill was suggested to reduce ischemic heart disease The polypill was suggested to reduce ischemic heart disease by 88% and stroke by 80% if taken by everyone over 55 by 88% and stroke by 80% if taken by everyone over 55 years of ageyears of age]. ].

BUTBUT----------------

• The polypill provides fix combination of The polypill provides fix combination of substances, possibly resulting in substances, possibly resulting in undertreatment of the main condition(s) and undertreatment of the main condition(s) and overtreatment of secondary conditions. overtreatment of secondary conditions.

• It also neglects differences in metabolism It also neglects differences in metabolism due to age, race and sex. due to age, race and sex.

• Even after some studies showing its Even after some studies showing its effectiveness the idea is still under effectiveness the idea is still under investigation and needs to be studied furtherinvestigation and needs to be studied further

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

Coexisting conditionCoexisting conditionFirst choiceFirst choiceIschaemic heart diseaseIschaemic heart diseaseAmlodipine + AtenololAmlodipine + Atenolol

DiabetesDiabetesAmlodipine + LisinoprilAmlodipine + Lisinopril

Amlodipine + LosartanAmlodipine + Losartan

HyperlipidemiaHyperlipidemiaAmlodipine + LisinoprilAmlodipine + Lisinopril

Amlodipine + LosartanAmlodipine + Losartan

Congestive heart failureCongestive heart failureLisinopril + HCTZLisinopril + HCTZ

Losartan + HCTZLosartan + HCTZ

TachycardiaTachycardiaAmlodipine + AtenololAmlodipine + Atenolol

BradycardiaBradycardiaAmlodipine + LisinoprilAmlodipine + Lisinopril

Amlodipine + LosartanAmlodipine + Losartan

Asthma/COPDAsthma/COPDAmlodipine + LosartanAmlodipine + Losartan

Amlodipine + LisinoprilAmlodipine + Lisinopril

Elderly hypertensives Elderly hypertensives Amlodipine + LosartanAmlodipine + Losartan

Amlodipine + LisinoprilAmlodipine + Lisinopril

Lisinopril/Losartan + HCTZLisinopril/Losartan + HCTZ

Suggested guidelines for the use of fixed-Suggested guidelines for the use of fixed-dose combinations (contd.)dose combinations (contd.)

Coexisting conditionCoexisting conditionFirst choiceFirst choicePeripheral vascular diseasePeripheral vascular diseaseAmlodipine + LisinoprilAmlodipine + Lisinopril

Amlodipine + LosartanAmlodipine + Losartan

Losartan + HCTZLosartan + HCTZ

Lisinopril + HCTZLisinopril + HCTZ

GoutGoutAmlodipine + LisinoprilAmlodipine + Lisinopril

Amlodipine + LosartanAmlodipine + Losartan

Amlodipine + AtenololAmlodipine + Atenolol

AnxietyAnxietyAmlodipine + AtenololAmlodipine + Atenolol

DepressionDepressionAmlodipine + LisinoprilAmlodipine + Lisinopril

Amlodipine + LosartanAmlodipine + Losartan

Lisinopril + HCTZLisinopril + HCTZ

Losartan + HCTZLosartan + HCTZ

Renal insufficiency (not due to renal Renal insufficiency (not due to renal Amlodipine + LisinoprilAmlodipine + Lisinopril

artery stenosis)artery stenosis)Amlodipine + LosartanAmlodipine + Losartan

Initial TherapyInitial TherapyIndicationIndication

Thiazide diuretic, ACEIThiazide diuretic, ACEI

ACEI, ARBACEI, ARB

Thiazide diuretic, BB, ACEI, Thiazide diuretic, BB, ACEI, ARB, CCBARB, CCB

Recurrent stroke Recurrent stroke preventionprevention

Chronic kidney Chronic kidney diseasedisease

DiabetesDiabetes

Initial TherapyInitial TherapyIndicationIndication

Thiazide diuretic, BB, ACEI, Thiazide diuretic, BB, ACEI, CCBCCB

BB, ACEI, aldosterone BB, ACEI, aldosterone antagonistantagonist

Thiazide diuretic, BB, ACEI, Thiazide diuretic, BB, ACEI, ARB, aldosterone antagonistARB, aldosterone antagonist

High CAD riskHigh CAD risk

Post-myocardialPost-myocardialinfarctioninfarction

Heart failureHeart failure

conclusionconclusion

• When combining drugs, use first-line When combining drugs, use first-line therapies.therapies.

• Choice of combination therapy Choice of combination therapy depends upon the risk factors, depends upon the risk factors, presence of comorbidities like presence of comorbidities like diabetes, renal dysfunction and the diabetes, renal dysfunction and the adverse effects and tailored adverse effects and tailored according to individual patientaccording to individual patient..

ConclusionConclusionThiazide-type diuretics should be initial drug therapy for most hypertensive patients, alone or combined with other medications

If BP is >160/100 mmHg, therapy should probably started with two medications, one of which should be a thiazide-type diuretic

• Caution should be exercised in combining a non Caution should be exercised in combining a non dihydropyridine CCB and a beta blocker to reduce dihydropyridine CCB and a beta blocker to reduce the risk of bradycardia or heart block.the risk of bradycardia or heart block.

• Monitor creatinine and potassium when combining Monitor creatinine and potassium when combining K sparing diuretics, ACE inhibitors and/or K sparing diuretics, ACE inhibitors and/or angiotensin receptor blockers.angiotensin receptor blockers.

• If a diuretic is not used as first or second line If a diuretic is not used as first or second line therapy, triple dose therapy should include a therapy, triple dose therapy should include a diuretic, when not contraindicated.diuretic, when not contraindicated.

ConclusionConclusion

ConclusionConclusion• More than one agent is necessary to achieve target More than one agent is necessary to achieve target

BP in the majority of patientsBP in the majority of patients

• Treatment can be initiated with monotherapy or a Treatment can be initiated with monotherapy or a combination of two drugs at low dosescombination of two drugs at low doses– Drug dose or number of drugs may be increased if Drug dose or number of drugs may be increased if

necessarynecessary

• A combination of two drugs at low doses preferred 1st A combination of two drugs at low doses preferred 1st step whenstep when– Initial BP in grade 2–3 rangeInitial BP in grade 2–3 range– Total CV risk high/very highTotal CV risk high/very high

• Fixed combinations of two drugs simplify Fixed combinations of two drugs simplify treatment/favor compliancetreatment/favor compliance

Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

ConclusionConclusion• ““When BP is more than 20 mmHg When BP is more than 20 mmHg

above systolic goal or 10 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration above diastolic goal, consideration should be given to should be given to initiate therapy initiate therapy with 2 drugs, either as separate with 2 drugs, either as separate prescriptions or in fixed-dose prescriptions or in fixed-dose combinations”combinations”

Chobanian et al. JAMA 2003;289:2560–72

*Lower doses generally used in single-pill combinations**An increasing number of single-pill combinations are becoming available with a range of doses

= +potential advantage

*Lower doses generally used in single-pill combinations**An increasing number of single-pill combinations are becoming available with a range of doses

= +potential advantage

Advantages of Single-Pill Versus Free Combinations of Advantages of Single-Pill Versus Free Combinations of Two Antihypertensive DrugsTwo Antihypertensive Drugs

Single pillFree

Simplicity of treatment+–

Compliance+–

Efficacy++

Tolerability +*–

Price+–

Flexibility +**++

JNC VII on Combination TherapyJNC VII on Combination Therapy

•“Failure to titrate or combine medications, despite knowing the patient is not at goal BP, represents clinical inertia and must be overcome.”

JNC VII. JAMA. 2003.

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