Transcript Slide 1

Principals of prescription and
drug therapy in Hypertension
Dr. Firouzeh Moeinzadeh
Nephrologist
Scopes of this presentation
• 1) Problems in HTN treatment
• 2) Antihypertensive drugs
• 3) Recommendations in treatments
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Reasons for Poor Control
• Systolic BP levels are more difficult to bring
under control even under the best of
circumstances, with fewer than half of
patients enrolled in controlled trials having
their systolics brought to 140 mm Hg or lower,
whereas 80% of diastolics were brought to 90
mm Hg or lower
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Problems with physician
• Many practitioners do not recognize their
shortcomings. They often underestimate the
level of their patient's cardiovascular risk and,
even though they are unwilling to intensify
therapy to the levels recommended in
guidelines, they usually perceive their level of
adherence to guidelines as being much better
than it is.
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• Hypertension “experts” have contributed to
practitioners' problems by promoting
conflicting positions, often at the same time:
diuretics are bad—no, they are good;
β-blockers are good—no, they are bad;
calcium channel blockers (CCBs) are bad—no,
they are good, and so on.
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Problems with Patients
• Failure to identify and deal with patients' differing
perceptions about their disease and beliefs about both
the benefits and the problems of therapy.
• The largely asymptomatic nature of hypertension,
making it difficult for patients to forego immediate
pleasures (salt, calories, money, etc.) for distant,
unrecognized benefits, even more so if therapy makes
them feel worse.
• Competing problems such as poverty, psychological
depression, or more immediately threatening diseases
such as diabetes.
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• Inability to access and maintain contact with a health
care system that is affordable, available, and
appropriate to their long-term needs.
• Real and imaginary concerns about the safety of
lifelong medication. In the past, many people were
willing to take whatever they were prescribed with full
confidence in their physician, but there are fewer
today. The delayed recognition that a NSAID prescribed
by physicians to patients was responsible for heart
attacks surely will further damage the patient-doctor
relationship.
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Problems with the Therapy
• Difficulty in changing unhealthy lifestyles, in
particular weight gain from too many calories and
too little physical activity.
• The high cost of most new, patent-protected
medications. When available, generic agents that
are equally efficacious are more likely to be
taken.
• The prescription of two or more doses per day
when long-acting once-a-day options are
available. Even worse is one daily dose of drugs,
e.g. atenolol, which lack a 24 hour effect.
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• Side effects of antihypertensive drugs, some not
predicted such as impotence with diuretics.
• Even less obvious but perhaps more critical, the
sympathetic nervous system may be chronically
activated when the BP is lowered.
• Interactions with other medications and
substances, NSAIDs the most common, grapefruit
juice likely the least recognizable , herbal
remedies perhaps the most dangerous .
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• Difficulty in assessment of adherence. Although
there are multiple ways to assess the degree of
patients' pill taking, few have been found to be
accurate.
• Variable responses to any dose of any
medication. The starting and usual doses are
determined by trials in only a limited number of
usually uncomplicated patients. In practice, many
patients respond either more or less to any drug.
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Guidelines to Improve Maintenance of
Antihypertensive Therapy
• Involve the patient in decision making to the
extent desired.
• Articulate the goal of therapy: to reduce BP to
near normotension with few or no side effects.
• Be alert for signs of inadequate intake of
medications, e.g., absence of BP response or
expected effects, e.g., bradycardia with β-blocker.
• Recognize and manage depression
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• Maintain contact with the patient
• Keep care inexpensive and simple
• Prescribe according to pharmacologic
principles
– Add one drug at a time
– Start with small doses, aiming for 5- to 10-mm Hg
reductions at each step, unless more rapid
response is indicated
– Have medication taken immediately on awakening
in the morning. If morning surge of BP (above
160/100) persists, give at least some drugs at 6
p.m. or at bedtime
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Timing of Dosing
• The time of day to take one-a-day
antihypertensive medications needs to be more
carefully considered.
• Early morning has usually been recommended
but there are two potential problems:
– The pills may not exert a full 24-hour effect, as shown
for atenolol; solution for the first problem is twofold:
first, ensure full 24-hour control by having the patient
measure early a.m. BP at home; second, choose
intrinsically long-acting medications: metoprolol XL
rather than atenolol, amlodipine rather than
felodipine
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– second, an even greater effect may be needed in
the early morning, before today's therapy has
kicked in, to keep the pressure from surging in the
immediate postarising time, thereby contributing
to the “morning surge” of cardiovascular
catastrophes: The solution seems as obvious but
has never been definitely proven, i.e., take
medications later in the day or even at bedtime.
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Follow-up Visits
• To achieve and maintain target BP with the lowest
possible dosage of medication requires ongoing patient
follow-up, preferably with home BPM, and may involve
multiple dosage adjustments.
• Most patients should be seen within 1 to 2 months
after the initiation of therapy to:
–
–
–
–
–
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determine the adequacy of BP control
the degree of patient cooperation in taking pills
the need for more therapy
the presence of adverse effects.
Evaluation of target organ damage, other major risk
factors, and laboratory test abnormalities.
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• Once the BP is stabilized, follow-up at 3- to 6month intervals (depending on the patient's
status) is generally appropriate.
• In most patients, particularly the elderly and
patients with orthostatic symptoms,
monitoring should include BP measurement in
the supine position and after standing for up
to 5 minutes, to recognize postural
hypotension
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Reduction or Discontinuation of Therapy
• Once a good response has occurred and has been
maintained for a year or longer, medications may be
reduced or discontinued.
• In one research from 6,200 hypertensives who had
been successfully controlled, only 18% were able to
remain normotensive after stopping therapy.
• The characteristics that make withdrawal more likely to
be successful were lower levels of BP before and after
therapy, fewer and lower doses of medication needed
to control hypertension, and patient's willingness to
follow lifestyle modifications.
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Antihypertensive drugs
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Diuretics
• Among the first orally effective drugs to
become available, diuretics are being used
even more frequently because their
effectiveness has been reiterated and, with
lower doses, their side effects minimized.
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• Treatment is usually initiated with a thiazide
diuretic (acting at, the distal convoluted
tubule).
• If renal function is significantly impaired (i.e.,
serum creatinine exceeding 1.5 mg/dL) or in
overload setting ( like heart failure), a loop
diuretic likely will be needed.
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• The thiazide diuretics act by inhibiting sodium
and chloride cotransport .
• Plasma and extracellular fluid volume are
thereby shrunken, and cardiac output falls.
• Within 3-9 days: balance between Na intake
and excretion + decreased body fluid volume.
• With chronic use (4-6 weeks), plasma volume
returns partially toward normal but, at the
same time, peripheral resistance decreases.
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• The full antihypertensive effect of low doses
of diuretic may not become apparent in 4
weeks, so patience is advised when low doses
are prescribed
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Resistance to Diuretics
1) Excessive dietary sodium intake.
2) For those with renal impairment (i.e., serum
creatinine >1.5 mg/dL or GFR <30
mL/minute), thiazides likely will not work.
3) Food affects the absorption and
bioavailability of different diuretics to
variable degrees, so the drugs should be
taken in a uniform pattern in terms of the
time of day and food ingestion.
4) NSAIDs may blunt the effect of most diuretics
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• With low doses, thiazides have little effect on
the blood lipid profile.
• However, higher doses may induce significant
effects on fat distribution which in turn may
be associated with insulin resistance.
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•
•
•
•
Effects of low dose:
No significant hypokalaemia
Low incidence of arrhythmia
Lower incidence of hyperglycaemia,
hyperlipidemia and hyperuricaemia
• Reduction in MI incidence
• Reduction in mortality and morbidity
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Drug
Usual starting dose
(mg/day)
Dosage forms(mg)
Usual dosage range
(mg/day)
Max. dose (mg/day)
dosing frequency
Diuretics
Hydrochlorothiazide
Tab (50)
12.5
12.5-25
50
Daily
Amiloride/HCTZ
Tab (5/50)
-
1 Tab, daily
-
Daily
Triamterene/HCTZ
Tab (50/25)
1 Tab, daily
1-2 Tab, daily
2 Tab, daily
Daily to BID
Furosemide
Tab (40)
Inj(10 mg/mL;
2,4 mL)
Oral:20-40mg/dose
20-80
-
Daily toBID*
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α-Adrenergic Blockers
• Specific alpha-1 blockers like prazosin and
terazosin are used, BUT NOT AS FIRST LINE.
• Postural hypotension developing in 30 to 90
minutes may be seen particularly in volumedepleted patients given the shorter-acting
prazosin.
• The problem generally can be avoided by
initiating therapy with a small dose and ensuring
that the patient is not volume-depleted as a
result of diuretic therapy.
• Urinary incontinence in women.
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α1-Blockers
Drug
Dosage
forms(mg)
Usual starting
dose (mg/day)
Usual dosage
range (mg/day)
Max. dose
(mg/day)
dosing frequency
Prazosin
Tab (1 , 5)
2 mg, at bedtime
2-20
20
BID to TID
Terazosin
Tab(2 , 5)
1 mg, at bedtime
1-20
20
Daily to BID*
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Beta-adrenergic blockers
• Non selective: Propranolol , labetolol
• Cardioselective: Metoprolol, atenolol
• All beta-blockers similar antihypertensive effects,
irrespective of additional properties.
• Initially: reduction in CO and remains lower
chronically.
• Peripheral resistance, on the other hand,
usually rises acutely but falls toward, if not to,
normal with time
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Side Effects
•
•
•
•
•
•
•
•
•
Fatigue
Diminished exercise ability
Weight gain
Worsening of insulin sensitivity
New onset of diabetes
Rise in serum triglycerides, fall in HDL-cholesterol
Slight rise in serum potassium
Increased rate of suicide
Worsening of psoriasis
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special problems
1) Insulin-taking diabetics who are prone to
hypoglycemia: If these patients become
hypoglycemic, β-blockade delays the return
of the blood sugar. The only symptom of
hypoglycemia may be sweating
2) Coronary patients.
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Carvedilol
• This “third” generation nonselective β-blocker
with only one-tenth as much α-blocking
activity has been used mainly for treatment of
heart failure. It is also approved for the
treatment of hypertension.
• In doses starting at 6.25 mg twice a day and
proceeding up to 25 mg b.i.d, carvedilol is
equal to 50 up to 200 mg of metoprolol b.i.d.
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• Unlike traditional β-blockers, carvedilol does
not worsen insulin sensitivity or have as much
of an adverse effect on lipids.
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β-Blockers
Drug
Atenolol
Dosage
forms(mg)
Tab (50 , 100)
Usual starting
dose (mg/day)
25
ImmediateMetoprolol
release tab (50)
50
tartrate
Inj (1 mg/mL; 5
mL)
Metoprolol
Extended-release
succinate
tab (47.5 , 95 ,
47.5
(MetoHEXAL®) 190)
Propranolol
Tab (10 , 20 , 40)
Inj (1 mg/mL)
40
Usual dosage
range (mg/day)
Max. dose
(mg/day)
dosing frequency
25-100
100*
Daily to BID
100-400
400
BID
47.5-190
190
Daily
40-160
160
BID
* Doses >100 mg are unlikely to produce any further benefit.
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Calcium Channel Blockers
1. Dihydropyridines (DHPs) are predominantly
vasodilators
 1◦ generation: Nifedipin
 2nd generation: Amlodipine(amlober®)
2. Non-dihydropyridines: Diltiazem, Verapamil
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• In hypertensive patients with renal damage, as
manifested by proteinuria, DHP-CCBs do not
reduce proteinuria, whereas verapamil and
diltiazem do about as well as ACEIs.
• DHP-CCBs should only be added to an ACEI or
ARB if needed to control hypertension in
patients with renal insufficiency.
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CCBs and salt
• CCBs have a mild natriuretic effect more obvious
in the presence of a higher sodium diet so that
the BP would fall more. With a low sodium
intake, this natriuretic effect would not be as
pronounced, so the BP would diminish less.
• Dietary sodium restriction may reduce (but not
abolish) the antihypertensive effect of CCBs,
whereas high sodium intake may enhance (or not
diminish) their efficacy.
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Side effects
• Headaches, flushing, local ankle edema due to:
vasodilation. Reduce with slow-release and
longer-acting formulations.
• Dependent edema is related to localized
vasodilation and not generalized fluid retention
and is not prevented or relieved by diuretics.
• If the pedal edema is bothersome, either a nonDHP-CCB should be substituted or the DHP-CCB
combined with an ACEI to reduce the edema.
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• Gingival hyperplasia
• Eye pain, possibly due to ocular vasodilation
with nifedipine.
• Cutaneous reactions,rarely
• Impotence seems, rarely
• Gynecomastia
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• A problem noted with most other classes of
antihypertensive drugs—interference from
NSAIDs—is usually not seen with CCBs.
• Nifedipine but not with amlodipine: an
increased plasma level and duration of action
when taken along with large amounts of
grapefruit juice or Seville orange juice.
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• Reduce the risk of coronary disease equally, stroke
more, but heart failure less, than other
antihypertensive therapies while having similar effects
on overall mortality.
• A long-acting, second-generation DHP seems the best
choice, because it will maintain better BP control in the
critical early morning hours and on through the next
day if the patient misses a daily dose.
• Rate-slowing CCBs, verapamil or diltiazem, may be
preferable with concomitant tachyarrhythmias or
heavy proteinuria.
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Calcium Channel Blockers (CCBs)
Non-Dihydropyridines**
Drug
Diltiazem
(Cardizem®)
Dosage
forms(mg)
Usual starting
dose (mg/day)
Usual dosage
range (mg/day)
Max. dose
(mg/day)
dosing frequency
Sustained-release
Cap. (120)
120-240
180-420
480
Daily
Amlodipine
Tab (5 , 10)
2.5
2.5-10
10
Daily
Amlodipine/
Atorvastatin
Tab (5/10 , 5/20)
-
-
-
-
Nifedipine***
(Adalat LA®)
Sustained-release
tab(30)
30-60
30-90
90-120
Daily
Dihydropyridines
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Angiotensin Converting Enzyme (ACE)
Inhibitors
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Captopril, lisinopril., enalapril,
ramipril..
• An immediate fall in BP occurs in
approximately 70% of patients given captopril,
and the decrease is sometimes rather
precipitous.
• Such a dramatic fall is more likely in those
with high renin levels.
• Black or elderly hypertensives, with lower
renin levels as a group, respond less well to
ACEIs than do white or younger patients.
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• An initial decline of 25% to 30% in renal
function after starting ACEI therapy in patients
with mild to moderate renal insufficiency was
found to be associated with a better long-term
renoprotection , presumably reflecting a
beneficial dilation of efferent arterioles which
reduces intraglomerular pressure and
filtration
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Benefits
•
•
•
•
•
•
No postural hypotension
Safe in asthmatics and diabetics
Prevention of K+ loss
Renal perfusion well maintained
Reverse LVH
No hyperuraecemia or deleterious effect on
plasma lipid profile
• No rebound hypertension
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Adverse reactions: especially in
Captopril
• Cough in 20% cases
• Hyperkalemia in renal failure patients with K+ sparing
diuretics, NSAID and beta blockers
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: CHF and bilateral renal artery
stenosis
• Angioedema: swelling of lips, mouth, nose .
• Rashes, urticaria
• Foetopathic: hypoplasia of organs, growth retardation
• Neutripenia
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Angiotensin Receptor Blockers (ARBs)
• Losartan(Losaver®) is the specific AT1 blocker
• Valsartan ( Valsacor®)
• Absorption not affected by food but unlike
ACEIs its bioavailability is low
– Do not enter brain
• Adverse effects:
– Foetopathic like ACEIs
– Rare 1st dose effect hypotension
– Low dysgeusia and dry cough
– Lower incidence of angioedema
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Drug
Usual starting dose
(mg/day)
Dosage forms(mg)
Usual dosage range
(mg/day)
Max. dose (mg/day)
dosing frequency
Angiotensin Converting Enzyme Inhibitors (ACEIs)
Captopril
Tab (25 , 50)
25
50-100
150-200
BID to TID
Enalapril
Tab (5,20)
5
10-40
40
Daily to BID
Lisinopril
Tab (5 , 10 , 20)
10
20-40
40
Daily
* Starting dose may be decreased 50% if patient is volume depleted, in acute heart failure exacerbation, or very elderly (≥ 75 year).
** In patients with CHF, target dose could be 50 mg, TID.
Angiotensin Receptor Blockers (ARBs)
Losartan
Tab (25 , 50)
50
25-100
100
Daily to BID
Losartan/HCTZ
Tab (50/12.5)
-
-
-
-
Telmisartan
(Micardis®)
Tab (80)
40
20-80
80
Daily
Telmisartan/HCTZ
(Micardis plus®)
Tab (80/12.5)
-
-
-
-
Valsartan
Tab , Cap (80 , 160)
40-80
80-320
320
Daily
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Starting dose may be decreased 50% if patient is volume depleted, very elderly (≥ 75 year), or taking a diuretic.
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Case 1
• A 65 year-old man visited in office for high
blood pressure. His BP is 145/85 mmHg within
3 sessions of visits.
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Recommendation 1
• In the general population aged 60 years or
older, initiate pharmacologic treatment to
lower BP at SBP of ≥150 mmHg or DBP of ≥
90mmHg .
• Treat to a goal SBP <150mmHg and goal DBP<
90mmHg.
• This case dose not need to drug therapy.
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Case 2
• A new case of hypertension of 45 year-old
woman visits in office. Her BP is 150/90 mmHg
within 2 weeks ago. After complete evaluation
her hypertension is essential HTN.
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Recommendation 2,3
• In the general population younger than 60
years, initiate pharmacologic treatment to
lower BP at SBP of ≥ 140 mmHg and DBP of ≥
90 mm Hg.
• Treat to a goal SBP < 140 mmHg and DBP of <
90mmHg.
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Case 3
• A new case of hypertension of 28 year-old
woman visits in office. Her BP is 150/90 mmHg
within 2 weeks ago. After complete evaluation
her hypertension is essential HTN.
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• In adults younger than 30 years, there are no
good- or fair quality RCTs that assessed the
benefits of treating elevated DBP on health
outcomes.
• In the absence of such evidence, it is the
panel’s opinion that in adults younger than 30
years, the DBP threshold and goal should be
the same as in adults 30 through 59 years of
age.
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• Initiation of antihypertensive treatment at a
DBP threshold of 90 mmHg or higher and
treatment to a DBP goal of lower than 90mm
Hg reduces cerebrovascular events, heart
failure, and overall mortality
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Life style modification
Modification
Approximate SBP reduction
(range
Weight reduction
5–20 mmHg/10 kg weight loss
Dietary sodium reduction
2–8 mmHg
Physical activity
4–9 mmHg
Moderation of alcohol
consumption
2–4 mmHg
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Drug therapy:
• Thiazide-type diuretic,
• Calcium channel blocker (CCB)
• Angiotensin-converting enzyme inhibitor
(ACEI)
• Angiotensin receptor blocker (ARB).
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• The panel did not recommend β-blockers for
the initial treatment of hypertension because
in one study use of β-blockers resulted in a
higher rate of the primary composite outcome
of cardiovascular death, myocardial infarction,
or stroke compared to use of an ARB, a finding
that was driven largely by an increase in
stroke.
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• α-Blockers were not recommended as firstline therapy because in one study initial
treatment with an α-blocker resulted in worse
cerebrovascular, heart failure, and combined
cardiovascular outcomes than initial
treatment with a diuretic.
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Case 4
• A 25 year-old woman is evaluate for paleness
and malaise from 6 months ago. In laboratory
findings, she had Hb= 8.9mg/dL, serum Cr=
3.2mg/dL. In renal ultrasonography, her
kidneys were 7.8 and 8.4 cm. She did not
receive any antihypertensive drugs. She had
BP= 150/90 mmHg in 2 weeks ago.
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Recommendation 4
• In the population aged 18 years with chronic
kidney disease (CKD), initiate pharmacologic
treatment to lower BP at SBP 140mmHg or
DBP 90 mmHg and treat to goal
SBP<140mmHg and goal DBP<90mmHg
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Recommendation 8
• In the population aged 18 years or older with
CKD and hypertension, initial (or add-on)
antihypertensive treatment should include an
ACEI or ARB to improve kidney outcomes. This
applies to all CKD patients with hypertension
regardless of race or diabetes status.
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• Recommendation8applies toadults aged 18 years
or older with CKD, but there is no evidence to
support renin-angiotensin system inhibitor
treatment in those older than 75 years.
• Although treatment with an ACEI or ARB may be
beneficial in those older than 75 years, use of a
thiazide-type diuretic or CCB is also an option for
individuals with CKD in this age group.
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• Attention to rising serum Cr and hyperkalemia
after initiating ACEI/ARB especially in CKD
patients.
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Case 5
• A 55 year-old man visits in routine check up
due to diabetes mellitus. He had DM for 5
years and receive only Glibenclamide and
metformine. His BP was 150/85mmHg in last 3
months.
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Recommendation 5
• In the general nonblack population, including
those with diabetes, initial antihypertensive
treatment should include a thiazide-type
diuretic, calcium channel blocker (CCB),
angiotensin-converting enzyme inhibitor
(ACEI), or angiotensin receptor blocker (ARB).
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• Similar to those for the general population,
this recommendation applies to those with
diabetes because trials including participants
with diabetes showed no differences in major
cardiovascular or cerebrovascular outcomes
from those in the general population.
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• Any of these 4 classes would be good choices
as add-on agents.
• This recommendation is specific for thiazidetype diuretics, which include thiazide diuretics
, chlorthalidone, and indapamide; it does not
include loop or potassium- sparing diuretics.
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Recommendation 6
• In the general nonblack population, including
those with diabetes, initial antihypertensive
treatment should include a thiazide-type
diuretic, calcium channel blocker (CCB),
angiotensin-converting enzyme inhibitor
(ACEI), or angiotensin receptor blocker (ARB
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Recommendation 7
• In the general black population, including
those with diabetes, initial antihypertensive
• treatment should include a thiazide-type
diuretic or CCB.
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Recommendation 9-1
• The main objective of hypertension treatment is
to attain and maintain goal BP.
• If goal BP is not reached within a month of
treatment, increase the dose of the initial drug or
add a second drug from one of the classes in
recommendation 6 (thiazide-type diuretic, CCB,
ACEI, or ARB).
• The clinician should continue to assess BP and
adjust the treatment regimen until goal BP is
reached.
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Recommendation 9-2
• If goal BP cannot be reached with 2 drugs, add
and titrate a third drug from the list provided.
• Do not use an ACEI and an ARB together in the
same patient.
• If goal BP cannot be reached using only the
drugs in recommendation 6 because of a
contraindication or the need to use more than
3 drugs to reach goal BP, antihypertensive
drugs from other classes can be used.
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Recommendation 9-3
• Referral to a hypertension specialist may be
indicated for patients in whom goal BP can not
be attained using the above strategy or for the
management of complicated patients for
whom additional clinical consultation is
needed
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Thanks
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