Hypertension is often difficult to treat effectively despite available drugs. Combination drug therapy is usually needed to control blood pressure, as monotherapy is only effective in 40-60% of patients. Using two drugs with different mechanisms of action can more effectively lower blood pressure than monotherapy alone. Common effective combinations include a diuretic paired with a renin-angiotensin system inhibitor, calcium channel blocker, or beta blocker. This helps control blood pressure through multiple pathways and limits side effects.

1. 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

2. Approximately 70% of Patients* in Europe Do NotApproximately 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

3. Hypertension in EgyptHypertension in Egypt
•Hypertension is a major healthHypertension is a major health problem inproblem in
Egypt with a prevalence rate ofEgypt with a prevalence rate of
26.3%26.3% among the adult populationamong the adult population
((>> 25 years)25 years)11
..
Only 8% of hypertensive EgyptiansOnly 8% of hypertensive Egyptians
have their blood pressurehave their blood pressure
controlledcontrolled11
..
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.

4. BP Differences of 10 mmHg Are Associated With Up to a 40% Effect onBP Differences of 10 mmHg Are Associated With Up to a 40% Effect 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

5. Tight Glucose ControlTight Glucose Control
Tight BP ControlTight BP Control
**P < 0.05P < 0.05
-50 -
-40 -
-30 -
0 - Stroke
Any DM
End Point DM Death
Microvascular
Complications
ReductioninRisk(%)
UKPDS. BMJ. 1998:317;703-712.
-20 -
-10 -
Tight BP Control vs. Tight GlucoseTight BP Control vs. Tight Glucose
ControlControl

6. 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 pressure
Staessen JA et al. Hypertension Research. 2005;28:385-407.
MRC2
MIDAS/NICS/VHAS
UKPDS C vs A
NORDIL INSIGHT
HOT L vs H
HOT M vs H MRC1
HEP
EWPHE
STOP1ATMH
PART2/SCAT
CAPPP
Syst-China
0.25
0.50
0.75
1.00
1.25
1.50
Syst-EurSTONE
UKPDS L vs H
RCT70-80
OddsRatio
(experimental/reference)
P=0.002
Cardiovascular Mortality
–5 0 5 10 15 20 25
Difference (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

7. Antihypertensive monotherapy isAntihypertensive monotherapy is
effective in only about 40-60% ofeffective in only about 40-60% of
hypertensive patients, irrespective ofhypertensive patients, irrespective of
the category of the agent that is used.the category of the agent that is used.
Therefore, there is frequently a need forTherefore, there is frequently a need for
the use of two medications withthe use of two medications with
different mechanisms of action.different mechanisms of action.
MonotherapyMonotherapy

8. 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 AgentsMultiple 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.

9. So combine

10. G
G
A
Z
Z
A
G
H
A
Z
Z
A WHY?

11. ‫؟‬‫؟‬Why combination therapyWhy combination therapy
))11((Multiple mechanisms involved in theMultiple mechanisms involved in the
pathogenesis of hypertensionpathogenesis of hypertension
))22((Effectiveness of monotherapy limited byEffectiveness of monotherapy limited by
stimulation of counter-regulatory mechanismsstimulation of counter-regulatory mechanisms
))33((Effective BP control seen in only 50% ofEffective BP control seen in only 50% of
patients on monotherapy; combination therapypatients on monotherapy; combination therapy
results in a much higher responder rate (>80%results in a much higher responder rate (>80%((
))44((BP goals difficult to attain with monotherapy inBP goals difficult to attain with monotherapy in
patients with diabetes or target organ damagepatients with diabetes or target organ damage

12. Sympathetic nervous system
Renin-angiotensin system
Total body sodium
Patient 1Patient 2 Patient 3
B. Waeber, March 2007, with kind permission
Blood Pressure has Multiple RegulatoryBlood Pressure has Multiple Regulatory
PathwaysPathways

13. WHEN TOWHEN TO
COMBINECOMBINE??

14. Current Guidelines Acknowledge that Combination TherapyCurrent 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 achievedAlthough effective BP control can be achieved
in most patients who are hypertensive, thein most patients who are hypertensive, the
majority will require two or moremajority will require two or more
antihypertensive drugs.”antihypertensive drugs.”
• ESH/ESC guidelines stateESH/ESC guidelines state22
::
““Regardless of the drug employed, monotherapyRegardless of the drug employed, monotherapy
allows to achieve BP target in only a limitedallows to achieve BP target in only a limited
number of hypertensive patients. Use of morenumber of hypertensive patients. Use of more
than one agent is necessary to achieve targetthan one agent is necessary to achieve target
BP in the majority of patients.”BP in the majority of patients.”1
Chobanian et al. Hypertension 2003;42:1206–52
2
Mancia et al. J Hypertens 2007:25:1105−87
ESH = European Society of Hypertension
ESC = European Society of Cardiology
JNC = Joint National Committee

15. • JNC 7 guidelines stateJNC 7 guidelines state22
::
““When BP is more than 20 mmHg above systolicWhen BP is more than 20 mmHg above systolic
goal or 10 mmHg above diastolic goal,goal or 10 mmHg above diastolic goal,
consideration should be given to initiate therapyconsideration should be given to initiate therapy
with 2 drugs...”with 2 drugs...”
• ESH/ESC guidelines stateESH/ESC guidelines state22
::
““A combination of two drugs at low doses shouldA combination of two drugs at low doses should
be preferred as first step treatment when initialbe preferred as first step treatment when initial
BP is in the grade 2 or 3 range or totalBP is in the grade 2 or 3 range or total
cardiovascular risk is high or very high.”cardiovascular risk is high or very high.”
1
Chobanian et al. Hypertension 2003;42:1206–52
2
Mancia et al. J Hypertens 2007:25:1105−87
ESH = European Society of Hypertension
ESC = European Society of Cardiology
JNC = Joint National Committee

16. American Heart AssociationAmerican Heart Association
““Starting with combination therapy may beStarting with combination therapy may be
the best way to get hypertensive patientsthe best way to get hypertensive patients’’
blood pressure down to goal levelsblood pressure down to goal levels..””

17. Drug combinationDrug combination
• Fixed dose combinationFixed dose combination
Single preparations containing two or moreSingle preparations containing two or more
active agents,active agents,
BUTBUT
• DRUG THERAPY COMBINATIONDRUG THERAPY COMBINATION
is two or more drugs are administered separatelyis two or more drugs are administered separately
for a combined effectfor a combined effect..

18. Advantages of fixed-doseAdvantages of fixed-dose
combination therapycombination therapy
– (1)Better blood pressure control(1)Better blood pressure control
– (2)Lesser incidence of individual(2)Lesser incidence of individual
drugdrug’’s side-effectss side-effects
– (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(7)Early normalization of BP may
greatly motivate the patientsgreatly motivate the patients
– (8)(8) Recommended by guidelinesRecommended by guidelines

19. • Single-dose combinationSingle-dose combination
antihypertension therapy is anantihypertension therapy is an
important option that combinesimportant option that combines
efficacyefficacy of blood pressureof blood pressure
reduction and areduction and a low side effectlow side effect
profile withprofile with convenientconvenient once-dailyonce-daily
dosing to enhancedosing to enhance compliancecompliance..

20. • Drawbacks of Fixed-Dose CombinationsDrawbacks of Fixed-Dose Combinations
Dosage 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

21. TYPES OF DRUGTYPES OF DRUG
COMBINATIONCOMBINATION

22. • The use of antihypertensive combinationsThe use of antihypertensive combinations
started in thestarted in the 19601960s with hydrochlorothiazides with hydrochlorothiazide
(HCTZ) combined with triamterene.(HCTZ) combined with triamterene.

23. • The majority of currently available fixed-The majority of currently available fixed-
dose combinations are diuretic-baseddose combinations are diuretic-based
• Combinations may be individualizedCombinations may be individualized
according to the presence ofaccording to the presence of comorbiditiescomorbidities
like diabetes mellitus, CRF, HF, thyroidlike diabetes mellitus, CRF, HF, thyroid
disorders and fordisorders and for special groupsspecial groups likelike
elderly and pregnant femaleselderly and pregnant females

24. Diuretics-------Diuretics-------
why?why?

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

26. • (2) Because diuretics blunt the(2) Because diuretics blunt the
sodium- and water-retaining effectssodium- and water-retaining effects
of many other antihypertensiveof many other antihypertensive
drugsdrugs
• (3) The JNC VI states clearly, "If a(3) The JNC VI states clearly, "If a
diuretic is not chosen as the firstdiuretic is not chosen as the first
drug, it is usually indicated as adrug, it is usually indicated as a
second-step agent because itssecond-step agent because its
addition will enhance the effects ofaddition will enhance the effects of
other agentsother agents

27. • But the higher diuretic dosages used in the largeBut the higher diuretic dosages used in the large
trials cause relative hypokalemia, as well astrials cause relative hypokalemia, as well as
increased serum lipid levels, insulin resistanceincreased serum lipid levels, insulin resistance
and uric acid levels.and uric acid levels.
• These adverse metabolic effects counteract theThese adverse metabolic effects counteract the
positive cardiovascular benefits of bloodpositive cardiovascular benefits of blood
pressure reduction.pressure reduction.
• Such effects do not occur when diuretics areSuch effects do not occur when diuretics are
administered in a low dosage, such as 6.25 oradministered in a low dosage, such as 6.25 or
12.5 mg per day of hydrochlorothiazide12.5 mg per day of hydrochlorothiazide..

28. K sparingK sparing­­thiazide(K losing)thiazide(K losing)
diuretic combinationsdiuretic combinations
• have been in use for more than 20 years.have been in use for more than 20 years.
• Current combinations includeCurrent combinations include
(1)spironolactone-hydrochlorothiazide(1)spironolactone-hydrochlorothiazide
(Aldactazide),(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.

29. Potassium-Sparing andPotassium-Sparing and
Thiazide DiureticsThiazide Diuretics
reduce the risk of adverse metabolicreduce the risk of adverse metabolic
effects.effects.
• it does decrease the incidence ofit does decrease the incidence of
thiazide-induced hypokalemia without anthiazide-induced hypokalemia without an
increased risk of hyperkalemiaincreased risk of hyperkalemia
• However, this does not obviate the needHowever, this does not obviate the need
for serial monitoring of serum electrolytefor serial monitoring of serum electrolyte
levels.levels.

30. Adverse metabolic effects wereAdverse metabolic effects were
observed only for regimensobserved only for regimens
containing hydrochlorothiazide in acontaining hydrochlorothiazide in a
dosage of 25 mg per day.dosage of 25 mg per day.
• decrease Serum potassiumdecrease Serum potassium
• increase Serum glucoseincrease Serum glucose

31. DiureticsDiuretics
and Betaand Beta
BlockersBlockers

32. Beta blockers cause retention ofBeta blockers cause retention of
sodium and water.sodium and water.
• Diuretics can cause mild volumeDiuretics can cause mild volume
reduction that leads to an increase inreduction that leads to an increase in
renin secretion by the kidney.renin secretion by the kidney.
• combining beta blockers withcombining beta blockers with
diuretics is twofold:diuretics is twofold:
• ))1) beta blockers blunt the increase1) beta blockers blunt the increase
in the plasma renin level that isin the plasma renin level that is
induced by diuretics.induced by diuretics.
• (2) diuretics decrease the sodium(2) diuretics decrease the sodium
and water retention that is caused byand water retention that is caused by
beta blockersbeta blockers

33. • (3)diuretics and beta blockers are(3)diuretics and beta blockers are
shown to decrease the incidence ofshown to decrease the incidence of
stroke and congestive heart failure instroke and congestive heart failure in
patients with hypertensionpatients with hypertension..
• ))4)4) The combination of a beta blocker and aThe combination of a beta blocker and a
diuretic produces additive effects compared withdiuretic produces additive effects compared with
monotherapy using either agent alonemonotherapy using either agent alone

34. Beta blockers and diureticsBeta blockers and diuretics
• Atenolol and chlorthalidoneAtenolol and chlorthalidone
• Atenolol and chlorthalidone andAtenolol and chlorthalidone and
hydrochlorothiazide.hydrochlorothiazide.
• Bisoprolol and hydrochlorothiazideBisoprolol and hydrochlorothiazide
• Metoprolol and hydrochlorothiazideMetoprolol and hydrochlorothiazide
• Nadolol and bendroflumethazideNadolol and bendroflumethazide
• Propranolol and hydrochlorothiazidePropranolol and hydrochlorothiazide
• Timolol and hydrochlorothiazideTimolol and hydrochlorothiazide

35. Diuretics &Diuretics &
ACEACE
InhibitorsInhibitors

36. • (1)By causing volume and sodium(1)By causing volume and sodium
depletion, thiazide diuretics stimulate thedepletion, thiazide diuretics stimulate the
production of renin and angiotensin.production of renin and angiotensin.
-------- counteracts some ofcounteracts some of
antihypertensive effects of the thiazideantihypertensive effects of the thiazide
diuretics.diuretics.
• ))2) ACE inhibitors interfere with the2) ACE inhibitors interfere with the
conversion of angiotensin I toconversion of angiotensin I to
angiotensin II and thereby decreaseangiotensin II and thereby decrease
angiotensin II levels.angiotensin II levels.
• These effects lead to decreased sodiumThese effects lead to decreased sodium
retention and an enhancedretention and an enhanced
antihypertensive effectantihypertensive effect ..

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

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

39. ExammplesExammples::
• Hydrochlorothiazide+captoprilHydrochlorothiazide+captopril
• Hydrochlorothiazide+lisinoprilHydrochlorothiazide+lisinopril
• Hydrochlorothiazide+ramiprilHydrochlorothiazide+ramipril
• Hydrochlorothiazide+enalaprilHydrochlorothiazide+enalapril
• Hydrochlorothiazide+perindoprilHydrochlorothiazide+perindopril
• Hydrochlorothiazide+benaziprilHydrochlorothiazide+benazipril

40. •Diuretics &Diuretics &
Angiotensin-IIAngiotensin-II
AntagonistsAntagonists

41. In patients for whom ACEIn patients for whom ACE
inhibitorinhibitor­­ diuretic combinationsdiuretic combinations
are indicated but not toleratedare indicated but not tolerated
because of cough-----because of cough-----useuse
Diuretics and ARBsDiuretics and ARBs

42. Angiotensin-II AntagonistsAngiotensin-II Antagonists
and Diureticsand Diuretics
• diuretic -diuretic -volume depletion withvolume depletion with
increase renin level-increase renin level-increaseincrease
angiotensinangiotensin
• . Angiotensin-II receptor. Angiotensin-II receptor
antagonists work by blockingantagonists work by blocking
specific angiotensin II receptorsspecific angiotensin II receptors
selectively inhibiting the vasoactiveselectively inhibiting the vasoactive
properties of angiotensin IIproperties of angiotensin II ..

43. ExamplesExamples------------
• Hydrochlorothiazide+losartanHydrochlorothiazide+losartan
• Hydrochlorothiazide+valsartanHydrochlorothiazide+valsartan
• Hydrochlorothiazide+irbesartan----etc….Hydrochlorothiazide+irbesartan----etc….

44. •Calcium ChannelCalcium Channel
BlockersBlockers&&
•ACE InhibitorsACE Inhibitors

45. Calcium Channel BlockersCalcium Channel Blockers
and ACE Inhibitorsand ACE Inhibitors
• Although calcium antagonists exertAlthough calcium antagonists exert
much of their antihypertensivemuch of their antihypertensive
effect through a vasodilatoryeffect through a vasodilatory
action-----action-----
they also have diuretic andthey also have diuretic and
natriuretic propertiesnatriuretic properties

46. Value of cominationValue of comination----:----:
• .. (1)ACE inhibitors blunt the(1)ACE inhibitors blunt the
stimulation of the renin-angiotensin-stimulation of the renin-angiotensin-
aldosterone axis that may resultaldosterone axis that may result
from this diuretic effect.from this diuretic effect.
• (2)ACEI also inhibit the central(2)ACEI also inhibit the central
sympathetic stimulation that maysympathetic stimulation that may
result from vasodilatationresult from vasodilatation

47. • (3)ACE inhibitors and calcium channel(3)ACE inhibitors and calcium channel
blockers work effectively in combinationblockers work effectively in combination
to lower blood pressure.to lower blood pressure.
• (4) also work together to favorably(4) also work together to favorably
influence target-organ diseaseinfluence target-organ disease
independent of their effect on bloodindependent 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 ofto decrease mediators of

48. • (6)Calcium channel blocker(6)Calcium channel blocker ­­ACE inhibitorACE inhibitor
combinations may result in fewer orcombinations may result in fewer or
milder side effects than occur with eithermilder side effects than occur with either
agent alone.agent alone.
The addition of an ACE inhibitor to aThe addition of an ACE inhibitor to a
dihydropyridine calcium antagonistdihydropyridine calcium antagonist
significantly reduces the incidence ofsignificantly 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, anprominent metabolic side effects, an
advantage in patients with diabetes andadvantage in patients with diabetes and
renal diseaserenal disease..

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

50. ExamplesExamples::
• Amlodipine + lisinoprilAmlodipine + lisinopril
• Amlodipine + trandoprilAmlodipine + trandopril
• Amlodipine + perindoprilAmlodipine + perindopril
• Verapamil+trandoprilVerapamil+trandopril

51. •Calcium ChannelCalcium Channel
BlockersBlockers&&
•Beta BlockersBeta Blockers

52. CCB-BB combination in
hypertension : Mechanism of action
Peripheral Resistance Cardiac Output
Sodium & fluid
Retention
Aldosterone
Angiotensin II
Angiotensin I
Angiotensinogen
Muscle
contraction
Ca++
influx
Renin
Kidney
Ca
antagonist
Heart
BLOOD PRESSURE
B-
blockerl
x

53. • Tachycardia induced byTachycardia induced by
amlodipine or nifedipine -----amlodipine or nifedipine -----
is neutralized by bradycardia of b-is neutralized by bradycardia of b-
blockersblockers

54. • But----------do not combine 2 drugs with:But----------do not combine 2 drugs with:
Negative inotropic effects.Negative inotropic effects.
Negative chronotropic effects.Negative chronotropic effects.

55. Ca antagonist&
A.R.Bs.A.R.Bs.

56. ARBARB
VasodilationVasodilation
Blocks theBlocks the
vasoconstrictor andvasoconstrictor and
aldosteronealdosterone
secreting effects ofsecreting effects of
angiotensin IIangiotensin II
Reverses sodiumReverses sodium
and water retentionand water retention
by decreasingby decreasing
aldosteronealdosterone
secretionsecretion
Highly effective inHighly effective in
high-renin patientshigh-renin patients
Ca antagonist
))11((Blood pressureBlood pressure
VasodilationVasodilation
Reduces Ca-influx inReduces Ca-influx in
vascular smoothvascular smooth
muscle cellsmuscle cells
Highly effective inHighly effective in
low-renin patientslow-renin patients

57. ARBARB
Neutral effect onNeutral effect on
lipid profilelipid profile
Improves insulinImproves insulin
sensitivitysensitivity
Ca antagonist
Neutral effect onNeutral effect on
lipid profilelipid profile
Favourable effectsFavourable effects
on glucoseon glucose
metabolismmetabolism

58. 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
ARB
Inhibits angiotensin II-
induced stimulation &
proliferation of SMCs
Restores and preserves
endothelial function by
increasing NITRIC OXIDE
which is an endogenous
vasodilator

59. Intraglomerular effects of AMLODIPINE and LOSARTAN
Vasodilatory effects
Dihydropyridine
calcium antagonist
e.g. amlodipine
Angiotensin II receptor
antagonist - losartan
Efferent vesselAfferent vessel
Effect on mesangial cells:
anti-proliferative effect of
AMLODIPINE and LOSARTAN
Dihydropyridine
calcium antagonist
e.g. amlodipine
Intraglomerular pressure ↓ ↓
Albuminuria ↓ ↓
Mesangial matrix ↓ ↓
Angiotensin II receptor
antagonist losartan

60. MiscellaneousMiscellaneous
cominationscominations

61. • (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

62. • (5) aliskiren/amlodipine/hydrochlorothiazide(5) aliskiren/amlodipine/hydrochlorothiazide
FDA in the US has approved it with no restrictionsFDA in the US has approved it with no restrictions
except that it should not be used for initial therapy.except that it should not be used for initial therapy.
Aliskiren(direct renin inhibitor )alone or in combination hasAliskiren(direct renin inhibitor )alone or in combination has
not been shown to improve clinical outcomes.not been shown to improve clinical outcomes.

63. . .
(6)NO donor drugs (. Isosorbid mononitrate)(6)NO donor drugs (. Isosorbid mononitrate)
andand
phosphodiesterasephosphodiesterase inhibitors (sildenafil)inhibitors (sildenafil)
have antihypertensive propertieshave antihypertensive properties and theand the
combination can markedly reduce bloodcombination can markedly reduce blood
pressurepressure in resistant hypertensionin resistant hypertension

64. Combination of more thanCombination of more than
2 drugs2 drugs
• Few patients may require a third or fourth drug toFew patients may require a third or fourth drug to
adequately manage BP.adequately manage BP.
• Preference should be given to the selection of an agentPreference should be given to the selection of an agent
from a different class than the initial 2 drugs in thefrom a different class than the initial 2 drugs in the
combination therapy.combination therapy.
• Addition of the third drug may be in the form ofAddition of the third drug may be in the form of
spironolactone (requires the assessment of renalspironolactone (requires the assessment of renal
functions and potassium), minoxidil, hydralazine,functions and potassium), minoxidil, hydralazine,
carvedilol and rest of the drugs depending on thecarvedilol and rest of the drugs depending on the
specific conditions being treated.specific conditions being treated.
• Centrally acting drugs should be the last option due toCentrally acting drugs should be the last option due to
potential side effectspotential side effects..

65. Concept of "PolypillConcept of "Polypill
• It is generally accepted that reducing the pill burdenIt 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 preventPolypill has been thought as a single daily pill to prevent
CVD by simultaneously reducing four risk factors (LDLCVD by simultaneously reducing four risk factors (LDL
cholesterol, BP, platelet function, and serumcholesterol, BP, platelet function, and serum
homocysteine).homocysteine).
• It usually is composed of a statin, three pressure-It usually is composed of a statin, three pressure-
lowering drugs, each at half of its standard dose, aspirin,lowering drugs, each at half of its standard dose, aspirin,
75 mg, and folic acid.75 mg, and folic acid.
• The polypill was suggested to reduce ischemic heartThe polypill was suggested to reduce ischemic heart
disease by 88% and stroke by 80% if taken by everyonedisease by 88% and stroke by 80% if taken by everyone

66. BUTBUT----------------
• The polypill provides fix combination ofThe polypill provides fix combination of
substances, possibly resulting in undertreatmentsubstances, possibly resulting in undertreatment
of the main condition(s) and overtreatment ofof the main condition(s) and overtreatment of
secondary conditions.secondary conditions.
• It also neglects differences in metabolism due toIt also neglects differences in metabolism due to
age, race and sex.age, race and sex.
• Even after some studies showing itsEven after some studies showing its
effectiveness the idea is still under investigationeffectiveness the idea is still under investigation
and needs to be studied furtherand needs to be studied further

67. Suggested guidelines for the use of fixed-doseSuggested guidelines for the use of fixed-dose
combinationscombinations
Coexisting conditionCoexisting conditionFirst choiceFirst choice
Ischaemic 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 hypertensivesElderly hypertensivesAmlodipine + LosartanAmlodipine + Losartan
Amlodipine + LisinoprilAmlodipine + Lisinopril

68. Suggested guidelines for the use of fixed-doseSuggested guidelines for the use of fixed-dose
combinations (contdcombinations (contd.(.(
Coexisting conditionCoexisting conditionFirst choiceFirst choice
Peripheral 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 renalRenal insufficiency (not due to renalAmlodipine + LisinoprilAmlodipine + Lisinopril
artery stenosis)artery stenosis)Amlodipine + LosartanAmlodipine + Losartan

69. Initial TherapyInitial TherapyIndicationIndication
Thiazide diuretic, ACEIThiazide diuretic, ACEI
ACEI, ARBACEI, ARB
Thiazide diuretic, BB, ACEI, ARB,Thiazide diuretic, BB, ACEI, ARB,
CCBCCB
Recurrent strokeRecurrent stroke
preventionprevention
Chronic kidneyChronic kidney
diseasedisease
DiabetesDiabetes

70. Initial TherapyInitial TherapyIndicationIndication
Thiazide diuretic, BB, ACEI, CCBThiazide diuretic, BB, ACEI, CCB
BB, ACEI, aldosterone antagonistBB, ACEI, aldosterone antagonist
Thiazide diuretic, BB, ACEI, ARB,Thiazide diuretic, BB, ACEI, ARB,
aldosterone antagonistaldosterone antagonist
High CAD riskHigh CAD risk
Post-myocardialPost-myocardial
infarctioninfarction
Heart failureHeart failure

71. conclusionconclusion
• When combining drugs, use first-lineWhen combining drugs, use first-line
therapies.therapies.
• Choice of combination therapy dependsChoice of combination therapy depends
upon the risk factors, presence ofupon the risk factors, presence of
comorbidities like diabetes, renalcomorbidities like diabetes, renal
dysfunction and the adverse effects anddysfunction and the adverse effects and
tailored according to individual patienttailored according to individual patient..

72. ConclusionConclusion
Thiazide-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

73. • Caution should be exercised in combining a nonCaution should be exercised in combining a non
dihydropyridine CCB and a beta blocker to reducedihydropyridine 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 KMonitor creatinine and potassium when combining K
sparing diuretics, ACE inhibitors and/or angiotensinsparing diuretics, ACE inhibitors and/or angiotensin
receptor blockers.receptor blockers.
• If a diuretic is not used as first or second lineIf a diuretic is not used as first or second line
therapy, triple dose therapy should include atherapy, triple dose therapy should include a
diuretic, when not contraindicated.diuretic, when not contraindicated.
ConclusionConclusion

74. ConclusionConclusion
• More than one agent is necessary to achieve target BP in theMore than one agent is necessary to achieve target BP in the
majority of patientsmajority of patients
• Treatment can be initiated with monotherapy or a combinationTreatment can be initiated with monotherapy or a combination
of two drugs at low dosesof two drugs at low doses
– Drug dose or number of drugs may be increased if necessaryDrug dose or number of drugs may be increased if necessary
• A combination of two drugs at low doses preferred 1st stepA combination of two drugs at low doses preferred 1st step
whenwhen
– 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 treatment/favorFixed combinations of two drugs simplify treatment/favor
compliancecompliance
Task Force of ESH/ESC. J Hypertens 2007;25:1105–87

75. ConclusionConclusion
• ““When BP is more than 20 mmHg aboveWhen BP is more than 20 mmHg above
systolic goal or 10 mmHg above diastolicsystolic goal or 10 mmHg above diastolic
goal, consideration should be given togoal, consideration should be given to
initiate therapyinitiate therapy with 2 drugs, either aswith 2 drugs, either as
separate prescriptions or in fixed-doseseparate prescriptions or in fixed-dose
combinations”combinations”
Chobanian et al. JAMA 2003;289:2560–72

76. *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 ofAdvantages of Single-Pill Versus Free Combinations of
Two Antihypertensive DrugsTwo Antihypertensive Drugs
Single pill Free
Simplicity of treatment + –
Compliance + –
Efficacy + +
Tolerability +* –
Price + –
Flexibility +** ++

77. 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.

78. Thank