Resistant hypertension

1. Resistant Hypertension
Which medications; and which doses?
Dr. Sahar Gamal El-Din
National Heart Institute

2. © 2008, American Heart Association. All rights reserved.
• Blood pressure remaining above goal in spite
of concurrent use of 3 antihypertensive agents of
different classes.
• Ideally, 1 of the 3 agents should be a diuretic
& all agents should be prescribed at optimal dose
amounts.
Resistant Hypertension

3. Definition Highlights
• Use of diuretic recommended but not required
before diagnosing resistant hypertension.
• Doses should be optimal but not necessarily
maximal before diagnosing resistant
hypertension.
• Controlled resistant hypertension: high blood
pressure controlled but with use of 4 of more
agents should be considered resistant.

4. Treatment of Resistant Hypertension
Pharmacologic Recommendations
• Withdrawal or down titration of interfering
substances as possible
• Optimize existing drugs
• Maximize diuretic therapy.
• Combination therapy.Combination therapy.
• Dosing schedule

5. Interfering Substances
•Many exogenous substances can
interfere with BP control by directly
raising BP, interfering with the
mechanisms of antihypertensive
drugs, or both.

6. • Non-Narcotic Analgesics
- Non-steroidal anti-inflammatory agents
including aspirin
- Selective COX-2 inhibitors
• Sympathomimetic agents
- Decongestants
- Diet pills
- Cocaine
• Stimulants
-Methylphenidate,dexmethylphenidate,
- amphetamine, methamphetamine,
dextroamphetamine.

7. • NSAIDs, should be avoided or withdrawn in
patients with resistant hypertension. However,
as this is often clinically difficult, the lowest
effective dose should be used with subsequent
down titration whenever possible.
• When initiating treatment with these agents,
blood pressure should be monitored closely
while recognizing that adjustments to the
antihypertensive regimen may become
necessary.

8. • Like other nonnarcotic analgesics,
acetaminophen is associated with an increased
risk of developing hypertension, although
when compared with ibuprofen it was less
likely to worsen blood pressure control in
treated subjects.
• Therefore, if analgesics are necessary,
acetaminophen may be preferable to NSAIDs
in subjects with resistant hypertension,
recognizing, however, that acetaminophen will
provide little if any antiinflammatory benefit.
Hypertension. 2005;46:500–507.

9. Diuretic therapyDiuretic therapy
• A 2008 scientific statement by the American
Heart Association provided treatment
recommendations for resistant hypertension.
• A primary recommendation is to maximize
diuretic therapy, because fluid retention is a
major cause of resistant hypertension.

10. Maximize diuretic therapy
• This can be accomplished by using :
• The preferred thiazide (chlorthalidone).
• Using a loop diuretic in patients with chronic
kidney disease (CKD).
• Adding an aldosterone antagonist
(spironolactone or eplerenone).

11. • Hydrochlorothiazide 12.5mg is (often)
ineffective dose, but doctors are sometimes
unwlling to increase it.
• The most effective thiazide(-like)
anytihypertensive drug is chlorthalidone which
is dosed at 12.5 or 25mg .
• Daily 12.5mg chlorthalidone is approximately
equipotent with 25mg hydrochlorothiazide.

12. • Chlorthalidone has other advantages
over the other drugs though including a
much longer ½ life, with the largest
difference occurring overnight.
• In contrast to hydrochlorothiazide,
chlorthalidone is available in very few fixed-
dose combinations and so its use will generally
require separate dosing.

14. • In patients with underlying chronic kidney
disease (creatinine clearance 30 mL/min), loop
diuretics may be necessary for effective volume
and blood pressure control.
• Furosemide is relatively short acting and
usually requires at least twice-daily dosing.
• Alternatively, loop diuretics with a longer
duration of action, such as torsemide, can be
used.

15. • Diuretics are often inappropriately stopped if a
patient develops hypokalemia.
• Potassium supplementation should always be
an adjunct to diuretic therapy.
• Potassium itself is a potent vasodilator and,
given as a supplement, has been shown to
reduce stroke risk in rats.

16. Adding an aldosterone antagonist
• Spironolactone is a mineralocorticoid receptor
antagonist that was shown to lower BP
effectively in both general hypertensive
patients and patients with primary
aldosteronism , as proved by a number of
small, uncontrolled trials that showed the
positive effect of small doses of spironolactone
in lowering BP in patients with resistant
arterial hypertension
J Hypertens. 2007;25:891– 894.

17. Addition of Spironolactone in Patients
With Resistant HTN (ASPIRANT)
• A randomized, double-Blind, placebo-controlled Trial,
117 patients were randomly assigned to receive
spironolactone or a placebo as an add-on to their
antihypertensive medication, by the method of
simple randomization.
• Analyses were done with 111 patients (55 in the
spironolactone and 56 in the placebo groups). At
8 weeks, the primary end points, a difference in
mean fall of BP on daytime ambulatory BP
monitoring (ABPM), between the groups was 5.4
mm Hg for systolic BP (P0.024) and 1.0 mm Hg
for diastolic BP (P0.358).

18. • The APBM nighttime systolic, 24-hour ABPM
systolic, and office systolic BP values were
significantly decreased by spironolactone
(difference of 8.6, 9.8, and 6.5 mm Hg; P0.011,
0.004, and 0.011), whereas the fall of the
respective diastolic BP values was not
significant (3.0, 1.0, and 2.5 mm Hg; P0.079,
0.405, and 0.079).
• The adverse events in both groups were
comparable. In conclusion, spironolactone is an
effective drug for lowering systolic BP in
patients with resistant arterial hypertension.
Hypertension. 2011;57:1069-1075.

20. • When using spironolactone, careful attention
must be paid to potassium levels, especially in
patients who also are taking an ACE inhibitor
or ARB.
• Spironolactone can cause gynecomastia in men.
• Eplerenone is an alternative
• aldosterone antagonist that does not cause
gynecomastia.

21. Combination TherapyCombination Therapy
• An abundance of studies demonstrate additive
antihypertensive benefit by combining 2
agents of different classes. This is particularly
true of thiazide diuretics, which significantly
improve blood pressure control when used in
combination with most if not all other classes
of agents.

22. Combination Therapy (JNC – VII)Combination Therapy (JNC – VII)
• ACE inhibitors and calcium channel blockersACE inhibitors and calcium channel blockers
(CCBs).(CCBs).
• ACE inhibitors and diureticsACE inhibitors and diuretics
• ARBs and diuretics.ARBs and diuretics.
• Beta blockers and diuretics.Beta blockers and diuretics.
• Centrally acting drug and diuretic.Centrally acting drug and diuretic.
• Diuretic and diuretic: e.g. amiloride andDiuretic and diuretic: e.g. amiloride and
hydrochlorothiazide.hydrochlorothiazide.

23. • Beyond studies of 2-drug combinations, there
is little data assessing the efficacy of specific
combinations of 3 or more drugs.
• Accordingly, recommendation of specific
multidrug combinations is largely empiric .
• Intuitively, it seems most appropriate to
continue to combine agents of different
mechanisms of action. In that regard, a triple
drug regimen of an ACE inhibitor or ARB,
calcium channel blocker, and a thiazide
diuretic is effective and generally well
tolerated.
• This triple regimen can be accomplished with 2
pills with use of various fixed-dose
combinations.

24. • Although α-β-antagonists are indicated in
the setting of coronary heart disease or
congestive heart failure, combined
antagonists, because of their dual
combination of action, may be more
effective antihypertensives, although head
to-head comparisons of maximal doses are
lacking.
• Centrally acting agents are effective
antihypertensive agents but have a higher
incidence of adverse effects and lack
outcome data.

25. • Lastly, potent vasodilators such as
hydralazine or minoxidil can be very
effective, particularly at higher doses,
but adverse effects are common. With
minoxidil especially, reflexive increases
in heart rate and fluid retention occur
such that concomitant use of a β -blocker
and a loop diuretic is generally
necessary.

26. • Ultimately, combinations of 3 or more drugs
must be tailored on an individual basis taking
into consideration prior benefit, history of
adverse events, contributing factors, including
concomitant disease processes such as CKD or
diabetes, and patient financial limitations.
• Treatment recommendations in this setting
cannot be overly standardized, particularly
when going beyond 3 drugs.

27. • Recent reports have suggested that the
combined use of an ACE inhibitor and ARB or
a dihydropyridine and non-dihydropyridine
calcium channel blocker provides significant
additional antihypertensive benefit compared
with monotherapy with the different agents.
• These studies, however, have not generally
used maximal doses of either of the combined
agents, so it is not possible to know whether
the additional blood pressure reduction is
really unique to the combination or simply a
titration effect. Accordingly, it is premature
from a purely blood pressure perspective to
recommend the use of same-class combinations
over use of agents from different classes.

28. Some “Wrong” Combinations
Beta blocker + ACE-inhibitor
Beta blocker + ARB
ACE inhibitor + ARB
Some “Right” Combinations
Thiazide + ACE inhibitor
Calcium channel blocker + ACE inhibitor
Beta blocker + alpha blocker

29. Practical Approach to combination therapy
(allow minimum of 2 weeks between dose adjustments)
Thiazide ½ dose (eg chlorthalidone 12.5mg)
↓
Not at target
add ACE-inhibitor ½ dose (eg ramipril 2.5mg)
↓
Not at target
Up thiazide to full dose (chlorthalidone 25mg)
↓
Not at target
Up ACE-inhibitor to full dose (ramipril 5mg)
↓
Not at target
Add CCB ½ dose (eg amlodipine 5mg)
↓
Not at target
Up CCB to full dose (eg amlodipine 10mg)

30. Dosing
• A recent cross-sectional analysis of ambulatory
blood pressure control indicated that patients
taking at least one of their hypertensive agents
at bedtime had better 24-hour mean blood
pressure control and, in particular, lower
nighttime systolic and diastolic blood pressure
values.
• This latter difference may be particularly
relevant as recent studies have suggested that
nighttime blood pressure levels better predict
cardiovascular risk than do daytime values
Hypertension.2005;46:1053–1059.

31. • It may be that twice-daily dosing of
nondiuretic blood pressure medications will
improve control rates in patients with resistant
hypertension.
• This potential benefit, however, would have to
be reconciled with reductions in adherence that
would likely occur with use of less convenient
and potentially more expensive dosing
regimens.
Hypertension. 2005;45:240 –245.

32. Encourage Adherence to Therapy
• it is important to keep the medication regimen
as simple as possible.
• A once-daily regimen improves patients’
adherence to antihypertensive medications.
• Fixed-dose combination pills, also may
improve adherence.

33. Pharmacologic principles
• Suboptimal dosing regimens or inappropriate
antihypertensive drug combinations are most
common causes of true resistant hypertension.
• As volume expansion is a frequent pathogenic
finding in these patients, an appropriate
diuretic to decrease volume overload remains a
cornerstone of therapy

34. • Dual renin-angiotensin system blockade is not
recommended for patients with true resistant
hypertension
• Ultimately, patient characteristics (age,
pathogenetic mechanisms involved, and
concomitant disease) will determine the best
combination of agents needed to achieve the
blood pressure goal.

35. Controlled Resistant Hypertension
• Such patients are at increased risk of reversible
and/or secondary causes of hypertension.
• Consider adjustment of the treatment regimen
to maintain blood pressure control but with use of
fewer medications and/or with use of a regimen
that minimizes adverse effects. In this regard,
patient preference will be an important
consideration.

36. Experimental drug therapy
• Endothelin receptor antagonists are currently
under investigation for the treatment of
resistant hypertension.
• The protein endothelin-1 (ET-1) is a potent
vasoconstrictor (30–50 times more potent than
angiotensin II and norepinephrine) and has a
long duration of action.
• ET-1 binds to two receptors with opposing
effects:
• ET-A promotes vasoconstriction, and
• ET-B promotes vasodilation and clears ET-1.

37. • Darusentan, a selective blocker of ET-A,was
tested in the phase III DORADO trial, which
was discontinued because the initial results
did not meet primary outcome measures.
• Initial findings had indicated that it might not
be as useful as hoped. Side effects included
headache, flushing, and edema.
Cl e v e l a n d c l i n i c j o u r n a l o f m e d i c i n e v o l . 8 0 . f e b r u a ry 2 0 1 3