1. health and fitness
2. therapy

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About the Compendium of
Therapeutic Choices
The Compendium of Therapeutic Choices, formerly Therapeutic Choices, is a
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Cardiovascular Disorders
Cardiovascular Disorders
Chapter 39
Hypertension
Norm R.C. Campbell, MD, FRCPC
Paul Gibson, MD, FRCPC and
Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC
Goals of Therapy
■
■
Reduce the risk of premature cardiac, cerebrovascular, renal and other vascular morbidity and
mortality
Achieve blood pressure targets in treated patients. The targets presented in Table 1 are maximums;
thus, the desired systolic blood pressure (SBP) and diastolic blood pressure (DBP) values are
below these thresholds.
Investigations
■
History:
– duration of hypertension, usual level of blood pressure and any sudden change in severity
of hypertension
– history of antihypertensive drug use, reason for changing therapy, effectiveness, side effects
and intolerance
– drugs that may cause hypertension (Table 2)
– drugs that may interact with antihypertensive drugs (those that induce or inhibit metabolism)
– adherence with lifestyle recommendations and drug therapy
– family history of hypertension, cardiovascular risk factors and premature cardiovascular disease
– personal history of cigarette and alcohol use, usual physical activity, usual diet and sodium
intake, current weight and recent weight change, waist circumference, diabetes and dyslipidemia
– cerebrovascular, cardiac and peripheral vascular symptoms to assess for target organ damage
– symptoms of secondary hypertension, which include, for example, pheochromocytoma
(hyperadrenergic symptoms), hyper- and hypothyroidism, Cushing's syndrome, renal/urinary
symptoms or a past history of renal disease
Table 1:
Blood Pressure Targets in Treated Patients1
Setting
Target SBP/DBP (mm Hg)
Homea
<135/85
Ofce
General patient population
<140/90
Isolated systolic hypertension
SBP <140
SBP <150 (if 80 y or older)
Diabetes mellitus
<130/80
Measured by a validated home blood pressure monitor.
Abbreviations: DBP = diastolic blood pressure; SBP = systolic blood pressure
a
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Compendium of Therapeutic Choices.
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Chapter 39: Hypertension
Table 2:
Drugs and Other Exogenous Factors That Can Induce or Aggravate
Hypertension1
Alcohol (excessive use)
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491
NSAIDs including COX–2 inhibitors
Calcineurin inhibitors, e.g., cyclosporine, tacrolimus
Oral contraceptive and sex hormones
Corticosteroids and anabolic steroids
Salt (sodium—high intake)
Erythropoietin and analogues
Selective serotonin reuptake inhibitors (SSRIs)
Licorice root
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Midodrine
Stimulants, including cocaine
MAO inhibitors
Vasoconstricting, sympathomimetic decongestants
Diagnosis:1
– the diagnosis of hypertension is immediate in the case of hypertensive emergencies and
urgencies. This includes patients with hypertension that is compromising vital organ function
(encephalopathy, cardiac, or rapidly decreasing renal function), hypertension and a major artery
dissection, or those with DBP ≥130 mm Hg
– hypertension may be diagnosed in 2 ofce visits if blood pressure averages ≥180/110 mm Hg, or
if it averages ≥140/90 mm Hg in the presence of diabetes, renal disease, atherosclerotic
cardiovascular disease or cerebrovascular disease
– the diagnosis may be arrived at after 2 visits if home or ambulatory blood pressure measurement
is used
– the diagnosis may require 3 visits if the blood pressure averages between 160/100 mm Hg and
180/110 mmHg. However, 5 or more visits may be required to establish the diagnosis if the initial
blood pressure average is between 140/90 mm Hg and 160/100 mm Hg and there is no target
organ dysfunction. Attention to the details of measuring blood pressure is essential to making
a valid diagnosis. Automated blood pressure measurements (using an approved monitor) in
the ofce is recommended.
– home measurement of blood pressure can aid in the diagnosis of hypertension, identify white coat
and masked hypertension, improve blood pressure control and improve medication adherence
in poorly adherent patients
Physical exam:
– fundi for hypertensive retinopathy
– bruits and peripheral pulses for vascular disease and renovascular hypertension
– edema and lung elds for signs of heart failure
– heart sounds (4th heart sound), sustained and displaced apex for left ventricular hypertrophy
– abdominal mass for polycystic kidneys and aortic aneurysm
– neurologic exam for cerebrovascular disease
Initial laboratory testing:
– serum potassium, sodium and creatinine
– urinalysis
– fasting glucose, total cholesterol, HDL-C, LDL-C, triglycerides
– standard 12-lead ECG
– select patients should have additional testing (Table 3)
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Cardiovascular Disorders
Hypertensive Patients Requiring Additional Laboratory Testing1
Table 3:
If these characteristics are present:
Check for:
• High serum creatinine (high normal in the elderly)
Renal disease
• Urinary albumin
Diabetes, renal disease
• Paroxysmal and/or severe sustained hypertension refractory to usual antihypertensive therapy
• Hypertension and symptoms suggestive of catecholamine excess (2 or more of headaches,
palpitations, sweating, etc.)
• Hypertension triggered by beta-blockers, monoamine oxidase inhibitors, micturition or
changes in abdominal pressure
• Incidentally discovered adrenal adenoma
• MEN 2A or 2B; von Recklinghausen's neurobromatosis or von Hippel-Lindau disease
Pheochromocytoma
•
•
•
•
Hyperaldosteronism
Spontaneous hypokalemia
Profound diuretic-induced hypokalemia (K+ <3 mmol/L)
Hypertension refractory to treatment with ≥3 drugs
Incidental adrenal adenoma
Two or more of:
• Sudden onset or worsening of hypertension in patients aged >55 or <30 y
• Abdominal bruit
• Uncontrolled hypertension despite use of ≥3 drugs
• Decreased renal function associated with use of an ACE inhibitor or ARB
• Overt atherosclerotic vascular disease
• Recurrent episodes of hypertension and ash pulmonary edema
Abbreviations:
Renovascular disease
ARB = angiotensin receptor blocker; MEN = multiple endocrine neoplasia
Table 4:
Effect of Lifestyle Changes on Blood Pressure in Adults with Hypertension
Change in Blood Pressure
(systolic/diastolic) mm Hg
Intervention
Recommendation
Reduction in sodium intake
Reduce by 1800 mg (78 mmol) per day
−5.8/−2.5
Weight loss
Reduce weight by 4.5 kg
−7.2/−5.9
Reduction in alcohol intake
Reduce by 2.7 drinks/day
−4.6/−2.3
Exercise
3 times/week
−10.3/−7.5
Dietary modication
DASH eating
plana
−11.4/−5.5
Available from: www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf.
Adapted with permission from Campbell N. Canadian Hypertension Education
Program. Brief overview of 2004 recommendations. Can Fam Physician 2004;50:1411-5.
a
Therapeutic Choices
Nonpharmacologic Choices
All individuals should be advised about a healthy lifestyle to prevent or control hypertension and
cardiovascular disease (Table 4).
■ Weight loss of 4 kg or more if overweight (target body mass index: 18.5–24.9 kg/m2; waist
circumference <102 cm in men and <88 cm in women).
■ Healthy diet—high in fresh fruits, vegetables, soluble bre and low-fat dairy
products, low in saturated fats and sodium, e.g., DASH eating plan available at
www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf.
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Compendium of Therapeutic Choices.
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Chapter 39: Hypertension
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493
Sodium intake of 1500 mg (65 mmol) per day for those aged 19–50 years, 1300 mg (56 mmol) per
day for those aged 51–70 years and 1200 mg (52 mmol) per day in those 71 years and older.
Regular, moderate intensity cardiorespiratory physical activity for 30–60 minutes on most days.
Low risk alcohol consumption (0 to 2 drinks/day, <9 drinks/week for women and <14 drinks/week
for men).
Smoke-free environment.
Pharmacologic Choices (Table 6)
If the average SBP/DBP is 140–159/90–99 mm Hg, treatment is recommended in the presence of either:
■ hypertensive target organ damage or
■ other independent risk factors for cardiovascular disease, e.g., cigarette smoking, dyslipidemia,
strong family history of premature cardiovascular disease, truncal obesity, sedentary lifestyle, males
older than 55 years, females older than 60 years.1 More than 90% of patients with hypertension
have other cardiovascular risks or overt cardiovascular disease so pharmacologic therapy is almost
always recommended.2
If the average SBP/DBP is 140–159/90–99 mm Hg and the individual does not have additional risk
factors, the short-term benets of pharmacotherapy are small; discuss the risks and benets of therapy
with the patient. Monitor blood pressure and other risk factors regardless of whether such a patient
chooses to begin drug therapy as generally the risks accumulate and blood pressure increases over time.
Consider low-dose ASA in patients over age 50 once blood pressure is controlled. Consider therapy for
dyslipidemia if the patient meets the current Canadian criteria (see Chapter 37).
In general, the reduction in cardiovascular risk depends more on the extent of the reduction in blood
pressure than on the specic blood pressure medication. Pharmacologic therapy should usually be
started with a low dose of the initial drug. Consider concurrent risk factors and disease states when
selecting initial therapy (Table 5). Dose titration to achieve goal blood pressure should be done every
4–8 weeks for all but those with severe hypertension or target organ damage or high cardiovascular
risk, for whom closer follow-up and more frequent dosage titration is required. Lack of control over
blood pressure is in most cases due to a failure to titrate therapy (adding drugs and/or increasing doses)
in response to high ofce readings. Greater condence in ofce readings can result from supplementing
with home blood pressure measurements or ambulatory 24-hour monitors. Generally, high ofce
readings should trigger a dosage increase, addition of another medication, investigations to identify the
cause of the high readings or a follow-up appointment within 2–8 weeks to reassess blood pressure.
Diuretics
Extensive evidence supports low-dose thiazide or related diuretics (e.g., indapamide) as rst-line
therapy for uncomplicated hypertension. They should generally be selected unless there are specic
indications for other drugs (see Table 5). Diuretics are inexpensive and well tolerated. They have
proven antihypertensive effectiveness in patients with isolated systolic hypertension, the elderly and
black patients.
Diuretics can cause hypokalemia that may be associated with adverse cardiovascular outcomes.
Consider alternative rst-line agents in those with or strongly predisposed to a serious arrhythmia,
for example, prolonged QT syndrome. Consider using a combination product to minimize the risk of
hypokalemia (hydrochlorothiazide plus a potassium-sparing diuretic—spironolactone, amiloride or
triamterene). Reserve the use of high doses (e.g., >25 mg/day of hydrochlorothiazide) for patients with
resistant hypertension unresponsive to treatment with multiple drugs or secondary to renal impairment.
Consider using a loop diuretic in patients with renal impairment. Diuretics may worsen dysglycemia,
although cardiovascular outcomes in patients with diabetes who are treated with diuretics are similar to
those treated with ACE inhibitors.3
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Cardiovascular Disorders
Beta-blockers
Beta-blockers are rst-line therapy in patients who are younger than 60 years, or who have stable
angina, heart failure or a history of MI. Beta-blockers are also useful in patients who have migraine
headaches, tachycardia or essential tremor. However, beta-blockers are not as effective as angiotensin
II receptor blockers (ARBs), calcium channel blockers (CCBs) or diuretics as initial therapy for
primary prevention of cardiovascular events in patients over the age of 60 years. In addition, they may
be ineffective in preventing cardiovascular events in people who smoke.4
Drugs that Act via the Renin Angiotensin Aldosterone System (RAAS)
The renin angiotensin aldosterone system (RAAS) plays a crucial role in modulating blood pressure,
kidney function, electrolyte balance and vascular and cardiac structure. Drugs that act directly on this
system include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists,
direct renin inhibitors and spironolactone. Antihypertensive drugs that stimulate the RAAS axis (e.g.,
diuretics) are as effective as those that block this system in preventing cardiovascular events in patients
with hypertension. However, some inhibitors of the RAAS do provide additional benets in certain
patients, including those with heart failure, diabetes and/or chronic kidney disease. ACE inhibitors,
ARBs and direct renin inhibitors are contraindicated in pregnant women.5,6,7 Drugs from these classes
should not be prescribed in women of child-bearing potential unless the risks are carefully weighed and
adequate measures are taken to prevent pregnancy (see Choices during Pregnancy and Breastfeeding).
Angiotensin-converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are rst-line agents for non-black patients with
uncomplicated hypertension and for patients with diabetes, ischemic heart disease, recent MI, heart
failure or chronic kidney disease.
Angiotensin II Receptor Blockers
ARBs are rst-line agents for patients with uncomplicated hypertension, for patients with diabetes
or ischemic heart disease. They are good alternatives when ACE inhibitors are specically indicated
but not tolerated.
Direct Renin Inhibitors
Aliskiren, the rst direct renin inhibitor, prevents renin from converting angiotensinogen to angiotensin
I. The drug has a long duration of action and lowers blood pressure to the same extent as drugs from
other antihypertensive classes. Until data become available on the effect of aliskiren on cardiovascular
events the drug should be used only when rst-line therapies cannot be used.
Long-acting Calcium Channel Blockers
Long-acting dihydropyridine CCBs can be used as rst-line agents but in practice they are generally
used in combination therapy. Short-acting formulations of these agents have caused an increase in
cardiovascular events in randomized controlled trials and should not be used. Elderly patients with
isolated systolic hypertension and black patients are particularly responsive to CCBs.
Other Antihypertensive Drugs
In general, other classes of antihypertensive drugs should not be prescribed unless there are specic
indications (Table 5), contraindications or intolerance to rst-line therapy, or a requirement for
additional blood pressure lowering in combination with rst-line antihypertensive drugs.
Combination Therapy
About 50% of patients will require more than one antihypertensive agent to achieve blood pressure
targets. If the goal blood pressure is not achieved with moderate doses of a suitable rst-line drug, add,
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Compendium of Therapeutic Choices.
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Chapter 39: Hypertension
495
rather than substitute, a second drug. Combining 2 drugs from different classes yields a 5 times greater
incremental reduction in blood pressure than doubling the dose of 1 drug [Evidence: SORT C*].8
In high-risk patients (hypertension with diabetes or known cardiovascular disease) an ACE inhibitor
(benazepril) with amlodipine was superior to an ACE inhibitor with a diuretic at preventing
cardiovascular events. The Canadian Hypertension Education Program (CHEP) recommends
consideration of an ACE inhibitor with amlodipine in high-risk patients whose blood pressure requires
2 or more medications for control.9 CHEP recommends initiating therapy with a combination of
2 rst-line agents if a patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended target.1
Use of a diuretic is desirable in combination with all other drug classes. In contrast, any combination
of a beta-blocker, ACE inhibitor and/or an ARB has less than additive antihypertensive effects when
combined in a 2-drug regimen. These combinations should be avoided unless there is a specic
indication, for example, use of an ACE inhibitor and a beta-blocker in post-MI patients or in those
with heart failure (Table 5).
All possible combinations of rst-line agents are rational choices to lower blood pressure when 3 or 4
drugs are required, with the exception of the simultaneous prescription of ACE inhibitors and ARBs. A
combination of ACE inhibitor plus ARB may further lower blood pressure but is associated with more
adverse effects (e.g., hyperkalemia, renal impairment) and no clear benet in terms of cardiovascular
events.10 This combination is generally not recommended for the treatment of hypertension, though it
may be appropriate in some medical circumstances such as refractory heart failure.
Adherence
Medication adherence should be assessed at each visit. Poor adherence to therapy is a major cause of
poor blood pressure control. Patients may admit to poor adherence when questioned in a nonthreatening
manner, or it may be indicated by:
■ Failure to keep scheduled appointments
■ Poor blood pressure control
■ Lack of secondary physiologic effects, e.g., decreased heart rate on beta-blocker
■ Failure to renew prescriptions on time
■ Lack of awareness of usual pill-taking routine and prescriptions
Poor adherence can be prevented. Routine care should include the following:
Ensure patients are well informed about hypertension and its treatment, preferably verbally and with
patient information pamphlets (available at www.hypertension.ca in the Public section)
■ Include family or social support in lifestyle modication
■ Use a simplied regimen of long-acting, once-daily drugs, and prescribe formulations that contain 2
drugs in combination when appropriate
■ Ensure the patient can afford the prescribed drugs
■ Advise the patient to establish a daily routine for pill-taking, e.g., putting their pills by their
toothbrush and taking them every morning prior to brushing
■
Treat poor adherence:
Determine the reason for poor adherence and tailor advice or interventions to the cause
■ Increase the frequency of ofce visits
■ Advise use of adherence-enhancing medication dispensers, e.g., dosette box
■ Advise self-measurement of blood pressure
■
* SORT (Strength of Recommendation Taxonomy) is a rating system (A, B or C) that addresses the quality of available evidence.
For more information consult How to Use Compendium of Therapeutic Choices on page xxv.
Compendium of Therapeutic Choices.
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Cardiovascular Disorders
Consider assessing adherence with an electronic pill dispenser
Advise home-monitoring of adherence with pill counts and marking on a calendar when the
prescription needs renewing
Consider regular telephone contact with the patient if feasible
Resistant Hypertension
Many patients with hypertension require multiple drugs for blood pressure control. In those with
resistant hypertension, investigate for a white coat effect, secondary hypertension, renal dysfunction,
poor adherence, and in those with a poor response to an adequate combination of medications, consider
the possibility of an “interfering lifestyle.” Refer (to a hypertension specialist, nephrologist or internist)
those who do not achieve blood pressure targets with medication regimens you feel comfortable
prescribing.
Hypertensive Emergencies
It is uncommon for elevated blood pressure alone, without new or progressive target organ damage,
to require emergency therapy. Refer true hypertensive emergencies to experienced centres with
facilities to continuously monitor blood pressure. In stabilizing patients for transfer, the use of
intermediate-acting drugs (e.g., felodipine) with close blood pressure monitoring is generally safer than
using short-acting drugs that can rapidly produce hypotension with complications.
Choices during Pregnancy and Breastfeeding
Hypertension and Pregnancy
Inform women with pre-existing hypertension who are of child-bearing potential, particularly those
who are considering pregnancy, that they are at an increased risk for adverse pregnancy outcomes
including: intrauterine growth restriction; placental abruption; preterm delivery and the attendant
neonatal risks of prematurity; and particularly a heightened risk of preeclampsia, with a crude risk of
about 20–25% (varying with the severity and duration of the pre-existing hypertension). Enhanced
surveillance is required during pregnancy to monitor for these complications. Prior to conception, or
immediately upon recognition of an unplanned pregnancy, review the choice of antihypertensive
medication for these women.
Management
While there remains a dearth of high quality data on the effects of many common antihypertensive
medications on the developing fetus, international guidelines11,12,13 have reached some consensus
regarding a list of “preferred” medications for use in pregnancy, as well as a few “avoid” and “must
avoid” drugs. Medications widely considered “rst-line” for the management of hypertension in
pregnancy include: methyldopa (250 mg BID to 1000 mg TID), labetalol (100 mg BID to 800
mg TID) and nifedipine XL (30 mg OD to 60 mg BID). These medications are preferred as they
have evidence and/or a strong clinical record of safe and effective use in pregnancy,14,15 as well as
an absence of demonstrated adverse effects on subsequent neonatal and childhood development.
Other antihypertensive medications considered appropriate for use in pregnancy include clonidine,
hydralazine and other beta-blockers (oxprenolol, pindolol, propranolol, metoprolol). The data
regarding the use of nondihydropyridine calcium channel blockers16,17 and alpha-blockers in
pregnancy is very limited, so these agents are typically deferred or exchanged for other preferred agents.
Avoid atenolol, as its use for the treatment of hypertension in pregnancy has been associated with
fetal intrauterine growth restriction (IUGR).18 The other beta-blockers, in contrast, are only weakly
associated with IUGR and have been used widely in pregnancy for various indications. Thiazides and
loop diuretics are other classes of medications which most experts caution to avoid during pregnancy.
These medications may prevent the physiologic volume expansion seen in normal pregnancy, and
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Compendium of Therapeutic Choices.
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Chapter 39: Hypertension
497
thereby impair uteroplacental perfusion and fetal growth.17 Available data do not support an adverse
39: Hypertension
497
effect on perinatal outcome,12 however, and these medicationsChapter
may therefore
be considered or
continued in women felt to have volume-dependent hypertension (renal impairment). They should
thereby
impair
uteroplacental
and fetal
growth.is17 already
Available
data do
not support an
be
avoided
in settings
in whichperfusion
uteroplacental
perfusion
reduced
(preeclampsia
or adverse
IUGR).
12 however,
effect
on perinatal
outcome,
these medications
may
therefore be considered
Spironolactone
should
not be
used at alland
in pregnancy,
due to its
anti-androgenic
effects.19 or
continued in women felt to have volume-dependent hypertension (renal impairment). They should
ACE
inhibitors
have in
been
clearly
shown to beperfusion
fetotoxiciswhen
taken
during(preeclampsia
the second and
be
avoided
in settings
which
uteroplacental
already
reduced
or third
IUGR).
20 leading to oligohydramnios, IUGR, fetal/neonatal renal failure and other growth
trimesters,
Spironolactone should not be used at all in pregnancy, due to its anti-androgenic effects.19
effects. First trimester exposure has also been shown to lead to teratogenic effects, mainly to the
21 Discontinue
ACE
inhibitors have
been
clearly
shownsystem.
to be fetotoxic
when these
takendrugs
duringprior
the to
second
and third
fetal cardiovascular
and
central
nervous
conception,
or
trimesters,20 leading
to oligohydramnios,
IUGR,
fetal/neonatal
renal
failure and
other
immediately
upon discovery
of an unplanned
pregnancy.
The data
regarding
the risk
ofgrowth
fetal harm from
effects.22 First
trimester
exposure
has 23also
shown (mainly
to lead to
teratogenic
effects,
ARBs
and direct
renin
inhibitors
arebeen
less robust
animal
data), but
theymainly
appear to
to the
have
21 Discontinue
fetal cardiovascular
andand
central
nervous
system.
priorduring
to conception,
or
similar
harmful effects
should
be avoided
just
as strictly as these
ACE drugs
inhibitors
pregnancy.
immediately upon discovery of an unplanned pregnancy. The data regarding the risk of fetal harm from
Most
with pre-existing
hypertension,
thoseanimal
with long-standing,
22 and direct
23 are lessparticularly
ARBswomen
renin inhibitors
robust (mainly
data), but theydifcult-to-control
appear to have
hypertension
or
end-organ
damage,
should
be
followed
throughout
pregnancy
a specialist
in
similar harmful effects and should be avoided just as strictly as ACE inhibitors by
during
pregnancy.
obstetrics and gynecology. These clinicians are skilled at ongoing maternal management as well as
Most
womenmonitoring
with pre-existing
hypertension,
particularly
those with difcult-to-control
long-standing, difcult-to-control
appropriate
of fetal growth
and well
being. Women
hypertension or
hypertension
end-organ
should beand
followed
throughout
pregnancy byspecialist
a specialist
in
other
medicalor
issues
benetdamage,
from assessment
follow-up
with a hypertension
or obstetric
obstetrics physician
and gynecology.
Thesepregnancy.
clinicians are skilled at ongoing maternal management as well as
medicine
during their
appropriate monitoring of fetal growth and well being. Women with difcult-to-control hypertension or
other
medical issues
benet
from assessment and follow-up with a hypertension specialist or obstetric
Hypertension
and
Breastfeeding
medicine physician during their pregnancy.
Following the completion of a pregnancy, many women require ongoing antihypertensive therapy. The
choice
of antihypertensive
agent may be inuenced by whether or not the woman is breastfeeding her
Hypertension
and Breastfeeding
newborn child, as all oral medications appear in breast milk to some degree.24 Breastfeeding women
Following
completion
of a pregnancy,
many women require drug.
ongoing
antihypertensive
therapy. The
may safelythe
continue
treatment
with any “pregnancy-preferred”
Most
other antihypertensive
choice
of antihypertensive
agentutilized,
may be but
inuenced
by whether
or not
the woman
is include
breastfeeding
her
medications
may also be safely
a few choices
to avoid
in these
women
diuretics
24 Breastfeeding
women
newbornmay
child,
as all oral
medications
appear
in breast
milk to some
withdegree.
low serum
protein-binding
(which
suppress
lactation),
atenolol
and other
beta-blockers
may
safely
continueintreatment
with as
any
“pregnancy-preferred”
drug. Mostand
other
antihypertensive
(which
concentrate
breast milk),
well
as long-acting ACE inhibitors
those
for which there is
medications
may also
be (ramipril,
safely utilized,
but acilazapril
few choices
avoid in these women include diuretics
little or no lactation
data
lisinopril,
andtoperindopril).
(which may suppress lactation), atenolol and other beta-blockers with low serum protein-binding
in inhibitors
these special
can be
A
discussion
of general
principles
of medications
(which
concentrate
in breast
milk),on
as the
welluse
as long-acting
ACE
and populations
those for which
there is
found
in
Appendix
II
and
Appendix
III.
Other
specialized
reference
sources
are
also
provided
in
little or no lactation data (ramipril, lisinopril, cilazapril and perindopril).
these appendices.
A discussion of general principles on the use of medications in these special populations can be
found in AppendixTips
II and Appendix III. Other specialized reference sources are also provided in
Therapeutic
these appendices.
■ Prescribe a lower starting dose of antihypertensive drugs in elderly patients.
■ Recent onset of hypertension or change in blood pressure control suggests an identiable or
Therapeutic Tips
secondary cause, such as drugs known to exacerbate hypertension or new onset of signicant
■ Prescribe a lower starting dose of antihypertensive drugs in elderly patients.
renal artery stenosis.
■ Recent onset of hypertension or change in blood pressure control suggests an identiable or
■ Many drugs ineffective as monotherapy for hypertension are effective components in a rational
secondary cause,
such as drugs known to exacerbate hypertension or new onset of signicant
combination
regimen.
renal artery stenosis.
■ Consider concurrent cardiovascular risk factors and disease states when prescribing therapy (Table
■ Many drugs ineffective as monotherapy for hypertension are effective components in a rational
5).
combination regimen.
■ Cardiovascular risk can vary 10-fold in persons with the same blood pressure. Assess global
■ Consider concurrent cardiovascular risk factors and disease states when prescribing therapy (Table
cardiovascular risk in all hypertensive patients using a risk form, chart or computer program (see
5).
Chapter 37, Figure 2 as an example).
persons
with the
same
blood
pressure. Assess
global
■
risk can vary 10-fold
■ Cardiovascular
Blood pressure measurements
taken atinhome
correlate
better
with
cardiovascular
outcomes
than
cardiovascular
risk
in
all
hypertensive
patients
using
a
risk
form,
chart
or
computer
program
(see
25,26
Recommend monitors endorsed by the Canadian Hypertension
ofce-based measurements.
Chapter
37, train
Figure
2 as antoexample).
Society and
patients
use the proper technique. To allay anxiety, caution patients that some
■ Blood pressure measurements taken at home correlate better with cardiovascular outcomes than
ofce-based measurements.25,26 Recommend monitors endorsed by the Canadian Hypertension
Society and train patients to use the proper technique. To allay anxiety, caution patients that some
Compendium of Therapeutic Choices.
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Compendium of Therapeutic Choices.
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
SAM PLE
498
■
■
CH AP TER
Cardiovascular Disorders
variation throughout the day is normal. Patient instructions for selecting and using home blood
pressure monitors can be found in the Public section of www.hypertension.ca.
Pharmacists and nurses can play an important role in hypertension screening, medication selection,
patient education, follow-up and adherence monitoring. Dietitians can assist patients in managing
their sodium and caloric intake.
A team approach to hypertension management is more effective than usual care. In patients with
hypertension and diabetes, joint care by a family physician, community pharmacist and nurse
resulted in an approximately 6 mm Hg greater reduction in SBP over 6 months, compared with
usual physician-based care.27
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Compendium of Therapeutic Choices.
SA MP LE
Compendium of Therapeutic Choices.
Table 5:
CH AP TER
Individualization of Antihypertensive Therapy1
Risk Factor/Disease Initial Therapy
Second-line Therapy
Notes/Cautions
Hypertension without
other compelling
indications
(Target SBP/DBP <140/90
mm Hg. If isolated systolic
hypertension and age ≥80
y, target SBP <150 mm
Hg)
Diastolic ± systolic
hypertension
Thiazide diuretic, beta-blocker,
ACE inhibitor, ARB or long-acting
CCB
Consider ASA and statins in
select patients
Consider initiating therapy with a
combination of rst-line drugs if
SBP is ≥20 mm Hg or DBP is ≥10
mm Hg above target
Combinations of rst-line
drugs
Beta-blockers are not recommended as initial therapy in
patients over 60 years of age.
Avoid hypokalemia in those who are prescribed diuretics
as monotherapy by using K+-sparing agents.
ACE inhibitors are not recommended as initial therapy
in black patients.
ACE inhibitors, ARBs and direct renin inhibitors are
teratogenic. Marked caution is required if prescribing to
women of child-bearing potential.
Combination of an ACE inhibitor with an ARB is not
recommended.
Isolated systolic
hypertension
without other
compelling
indications
Thiazide diuretic, ARB or
long-acting dihydropyridine CCB
Combinations of rst-line
drugs
See diastolic ± systolic hypertension above.
Diabetes mellitus
with albuminuria,
renal disease,
CVD or additional
cardiovascular risk
factors
ACE inhibitor or ARB
Addition of a dihydropyridine
CCB is preferred over thiazide
diuretics
A loop diuretic could be considered in hypertensive CKD
patients with extracellular uid volume overload.
Diabetes mellitus
not included in the
above category
ACE inhibitor, ARB, long-acting
dihydropyridine CCB or thiazide
diuretic
Combine rst-line drugs
If combination with ACE
inhibitor is being considered,
a dihydropyridine CCB is
preferable to thiazide diuretics
Albuminuria is dened as an albumin to creatinine ratio
(ACR) >2 mg/mmol in men and >2.8 mg/mmol in women.
Coronary artery
disease
ACE inhibitor or ARB (except in
low-risk patients); beta-blocker for
patients with stable angina
Long-acting CCB
When combination
therapy is being used for
high-risk patients, an ACE
inhibitor/dihydropyridine CCB
is preferred
Avoid short-acting nifedipine.
Combination of an ACE inhibitor with an ARB is specically
not recommended.
Recent MI
Beta-blocker and ACE inhibitor
(ARB if ACE inhibitor not
tolerated)
Long-acting CCB
Non-dihydropyridine CCBs should not be used in the
presence of concomitant heart failure.
Diabetes mellitus
(Target SBP/DBP <130/80
mm Hg)
Cardiovascular and
cerebrovascular
disease
(Target SBP/DBP <140/90
mm Hg)
499
(cont'd)
Chapter 39: Hypertension
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Category (BP Targets)
SA MP LE
500
Individualization of Antihypertensive Therapy1 (cont'd)
Category (BP Targets)
Nondiabetic chronic
kidney disease
(Target SBP/DBP <140/90
mm Hg)
Other conditions
(Target SBP/DBP <140/90
mm Hg)
Compendium of Therapeutic Choices.
Risk Factor/Disease Initial Therapy
Second-line Therapy
Notes/Cautions
Heart failure
ACE inhibitor and beta-blocker
(ARB if ACE inhibitor not
tolerated)
Aldosterone antagonist in patients
with a recent cardiovascular
hospitalization, acute MI, elevated
BNP, elevated NT-proBNP, or
NYHA class II to IV symptoms
ARB added to ACE inhibitor
Hydralazine/isosorbide
dinitrate combined if black,
or if ACE inhibitor and ARB
contraindicated or not tolerated
Thiazide or loop diuretic as
additive therapy
Dihydropyridine CCB (except
nifedipine)
Titrate doses of ACE inhibitors and ARBs to those used
in clinical trials.
Monitor serum K+ and SCr with the combination of ACE
inhibitor, ARB or aldosterone antagonist.
Left ventricular
hypertrophy
ACE inhibitor, ARB, long-acting
CCB or thiazide diuretic
Combination of additional
agents
Hydralazine and minoxidil should not be used.
Past stroke or TIA
ACE inhibitor/diuretic combination
Combination of additional
agents
Hypertension should not be treated in acute stroke unless
BP extremely elevated.
Combination of an ACE inhibitor with an ARB is specically
not recommended.
Nondiabetic chronic
kidney disease with
proteinuria
ACE inhibitor (ARB if ACE
inhibitor not tolerated) diuretics as
additive therapy
Combinations of additional
agents
Carefully monitor serum K+ and SCr in patients on an ACE
inhibitor or an ARB.
Combination of an ACE inhibitor with an ARB is specically
not recommended in patients with chronic kidney disease
without proteinuria.
Renovascular
disease
Does not affect initial treatment
recommendations
Combinations of additional
agents
Avoid ACE inhibitors or ARBs in patients with bilateral
renal artery stenosis or unilateral disease with a solitary
kidney.
Peripheral arterial
disease
Does not affect initial treatment
recommendations
Combinations of additional
agents
Avoid beta-blockers in patients with severe disease.
Dyslipidemia
Does not affect initial treatment
recommendations
Combinations of additional
agents
Overall vascular
protection
Statin therapy for patients with
hypertension and 3 or more
cardiovascular risk factors or with
atherosclerotic disease
Low-dose ASA in patients over 50
y with controlled blood pressure
Exercise caution if blood pressure is not controlled.
Adapted with permission from Canadian Hypertension Education Program.
Abbreviations: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; BNP = brain natriuretic peptide; CCB = calcium channel blocker; CKD = chronic kidney disease; CVD = cardiovascular
disease; MI = myocardial infarction; NT-proBNP = N-terminal-proBNP; NYHA = New York Heart Association; SCr = serum creatinine; TIA = transient ischemic attack
Cardiovascular Disorders
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Table 5:
CH AP TER
SA MP LE
Compendium of Therapeutic Choices.
Table 6:
CH AP TER
Drugs Used for Hypertension
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
ACE Inhibitors
benazepril
Lotensin, generics
Initial: 10 mg/day
Usual: 20 mg/day
Maximum: 40 mg/day
Once daily or divided BID
po
Dry cough, hyperkalemia.
Unusual: angioedema.
Can precipitate renal failure
in renovascular disease,
volume depletion or those
receiving NSAIDs.
Marked increase in serum
K+ in patients receiving
K+ supplements and/or
K+-sparing diuretics.
Reduced hypotensive effect
with NSAIDs and increased
risk of renal dysfunction.
Elevated Li+ levels (potential
toxicity).
Contraindicated in
pregnancy—caution
when prescribing
to women of
child-bearing
potential.5,6 Use lower
(50%) initial doses if
on diuretics (increased
risk of hypotension with
hypovolemia).
Hyperkalemia usually
occurs only in those
on K+ supplements or
drugs that cause K+
retention, those with
renal impairment or
diabetics with high
serum K+ levels. Assess
SCr and K+ after a few
days, then regularly.
$$
captopril
generics
Initial: 25 mg/day
Usual: 75 mg/day
Maximum: 150 mg/day
Divided BID or TID po
See benazepril.
See benazepril.
See benazepril.
$$
cilazapril
Inhibace, generics
Initial: 2.5 mg/day
Usual: 2.5–5 mg/day
Maximum: 10 mg/day
Once daily or divided BID
po
See benazepril.
See benazepril.
See benazepril.
$
enalapril
Vasotec, generics
Initial: 5 mg/day
Usual: 10–40 mg/day
Maximum: 40 mg/day
Once daily or divided BID
po
See benazepril.
See benazepril.
See benazepril.
$
Chapter 39: Hypertension
(cont'd)
501
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Class
SA MP LE
502
Drugs Used for Hypertension (cont'd)
Class
Compendium of Therapeutic Choices.
Alpha1-adrenergic
Antagonists
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
fosinopril
generics
Initial: 10 mg/day
Usual: 20 mg/day
Maximum: 40 mg/day
Once daily or divided BID
po
See benazepril.
See benazepril.
See benazepril.
$
lisinopril
Prinivil, Zestril,
generics
Initial: 10 mg/day
Usual: 20 mg/day
Maximum: 40 mg/day
Once daily po
See benazepril.
See benazepril.
See benazepril.
$
perindopril
Coversyl, generics
Initial: 4 mg/day
Maximum: 8 mg/day
Once daily or divided BID
po
See benazepril.
See benazepril.
See benazepril.
$$
quinapril
Accupril, generics
Initial: 10 mg/day
Maximum: 40 mg/day
Once daily or divided BID
po
See benazepril.
See benazepril.
See benazepril.
$$
ramipril
Altace, generics
Initial: 2.5 mg/day
Usual: 10 mg/day
Maximum: 20 mg/day
Once daily or divided BID
po
See benazepril.
See benazepril.
See benazepril.
$
trandolapril
Mavik
Initial: 1 mg/day
Maximum: 4 mg/day
Once daily po
See benazepril.
See benazepril.
See benazepril.
$$
doxazosin
Cardura, generics
Initial: 1 mg/day
Usual: 1–8 mg/day
Maximum: 16 mg/day
Once daily po
Orthostatic hypotension,
headache, drowsiness,
palpitations, nasal
congestion.
Syncope usually occurs at
the start of therapy, with rapid
dose titration or on addition of
other agents. Titrate slowly.
If interrupted for several
days, restart at initial dose.
Caution when adding other
hypotensive drugs, may
cause syncope.
Not for initial therapy.
$
Cardiovascular Disorders
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Table 6:
CH AP TER
SA MP LE
Compendium of Therapeutic Choices.
Class
Angiotensin Receptor
Blockers (ARB)
CH AP TER
Dose
Adverse Effects
Drug Interactions
Comments
Costa
prazosin
generics
Initial: 0.5 mg with
p.m. meal (day 1),
then 0.5 mg BID-TID po
× 3 days and gradually
increase as required
Maximum: 20 mg/day
See doxazosin.
See doxazosin.
Not for initial therapy.
$-$$
terazosin
Hytrin, generics
Initial: 1 mg QHS po
Usual: 1–5 mg/day
Maximum: 20 mg/day
Once daily or divided BID
po
See doxazosin.
See doxazosin.
Verapamil increases serum
concentrations of terazosin.
Not for initial therapy.
$
azilsartan
Edarbi
Initial: 40 mg/day
Maximum: 80 mg/day
Once daily po
Hyperkalemia.
Can precipitate renal failure in
susceptible patients (bilateral
renovascular disease, those
with volume depletion or with
concurrent NSAID use).
Angioedema has been
reported, but a causal
association has not been
established.
Marked increase in serum
K+ in patients receiving
K+ supplements and/or
K+-sparing diuretics.
May elevate Li+ levels
(monitor Li+ levels, adjust
dose).
Contraindicated in
pregnancy—caution
when prescribing
to women of
child-bearing
potential.7
Use lower initial doses
in patients who are
volume depleted or on
diuretics (increased
risk of hypotension in
hypovolemia).
Hyperkalemia usually
occurs only in those
on K+ supplements or
drugs that cause K+
retention, those with
renal impairment or
diabetics with high
serum K+ levels. Assess
SCr and K+ after a few
days, then regularly.
$$
candesartan
Atacand, generics
Initial: 8 mg/day
Usual: 8–16 mg/day
Once daily po
See azilsartan.
See azilsartan.
See azilsartan.
$
eprosartan
Teveten
Initial: 600 mg/day
Maximum: 800 mg/day
Once daily or divided BID
po
See azilsartan.
See azilsartan.
See azilsartan.
$$
503
(cont'd)
Chapter 39: Hypertension
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Drug
SA MP LE
504
Drugs Used for Hypertension (cont'd)
Class
Beta1-adrenergic
Antagonists,
nonselective
Compendium of Therapeutic Choices.
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
irbesartan
Avapro, generics
Initial: 150 mg/day
Usual: 150–300 mg/day
Once daily po
See azilsartan.
See azilsartan.
See azilsartan.
$
losartan
Cozaar, generics
Initial: 50 mg/day
Usual: 25–100 mg/day
Maximum: 100 mg/day
Once daily or divided BID
po
See azilsartan.
See azilsartan.
See azilsartan.
$
olmesartan
Olmetec
Initial: 20 mg/day
Maximum: 40 mg/day
Once daily po
See azilsartan.
See azilsartan.
See azilsartan.
$$
telmisartan
Micardis, generics
Initial: 80 mg/day
Usual: 80 mg/day
Once daily po
See azilsartan.
See azilsartan.
See azilsartan.
$
valsartan
Diovan, generics
Initial: 80 mg/day
Usual: 80–320 mg/day
Once daily po
See azilsartan.
See azilsartan.
See azilsartan.
$
nadolol
generics
Initial: 20 mg/day
Usual: 160 mg/day
Maximum: 320 mg/day
Once daily po
Fatigue, bradycardia,
decreased exercise capacity,
headache, impotence, vivid
dreams.
Less common:
hyperglycemia, depression,
heart failure, heart block.
Bradycardia with digoxin or
nondihydropyridine CCBs.
Cardiodepressant effects
with nondihydropyridine
CCBs and amiodarone.
Beta-blockers should
not be used as initial
therapy in patients aged
>60 y unless specically
indicated.
Avoid in patients with
asthma.28
Avoid abrupt withdrawal
(may precipitate rebound
hypertension and
ischemia). Taper
the dose before
discontinuation.
Avoid in patients with
severe PAD.
Contraindicated in
patients with 2nd or
3rd degree heart block
in the absence of a
pacemaker.
$$
Cardiovascular Disorders
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Table 6:
CH AP TER
SA MP LE
Compendium of Therapeutic Choices.
Class
Beta1-adrenergic
Antagonists,
β1-selective
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Beta1-adrenergic
Antagonists,
nonselective
with intrinsic
sympathomimetic
activity (ISA)
CH AP TER
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
propranolol,
controlled release
Inderal-LA
Initial: 80 mg/day
Usual: 320 mg/day
Maximum: 480 mg/day
SR (once daily
po) formulation
recommended
See nadolol.
See nadolol.
CYP2D6 inhibitors increase
levels of propranolol.
Propranolol increases serum
levels of rizatriptan.
See nadolol.
Propranolol is more
likely to cause CNS
side effects (insomnia,
depression, vivid
dreams) than other
agents because of
greater lipid solubility.
$$$$
timolol
generics
Initial: 5 mg BID
Usual: 20 mg BID
Maximum: 30 mg BID po
See nadolol.
See nadolol.
See nadolol.
$$
atenolol
Tenormin, generics
Initial: 25 mg/day
Usual: 50 mg/day
Maximum: 100 mg/day
Once daily or divided BID
po
See nadolol.
Fewer non-cardiac effects
due to cardioselectivity.
See nadolol.
See nadolol.
$
bisoprolol
Sandoz Bisoprolol,
generics
Initial: 5 mg/day
Usual: 10 mg/day
Maximum: 20 mg/day
Once daily po
See nadolol.
Fewer non-cardiac effects
due to cardioselectivity.
See nadolol.
See nadolol.
$
metoprolol,
Lopresor, generics
Initial: 50 mg/day
Usual: 100–200 mg/day
Maximum: 400 mg/day
Give regular formulations
BID po; SR formulations
once daily po
See nadolol.
Fewer non-cardiac effects
due to cardioselectivity.
See nadolol.
CYP2D6 inhibitors increase
levels of metoprolol.
See nadolol.
$
nebivolol
Bystolic
Initial: 5 mg/day
Usual: 10 mg/day
Maximum: 20 mg/day
Once daily po
See nadolol.
Fewer non-cardiac effects
due to cardioselectivity.
See nadolol.
CYP2D6 inhibitors increase
levels of nebivolol.
See nadolol.
$$
pindolol
Visken, generics
Initial: 5 mg BID po
Usual: 15 mg BID po
Maximum: 60 mg/day
See nadolol.
See nadolol.
See nadolol.
Agents with ISA have
less effect on resting
heart rate than those
without ISA.
$$
(cont'd)
SA MP LE
506
Drugs Used for Hypertension (cont'd)
Class
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
Beta1-adrenergic
Antagonists,
β1-selective with ISA
acebutolol
Sectral, generics
Initial: 100 mg/day
Usual: 400 mg/day
Maximum: 800 mg/day
Once daily or divided BID
po
See nadolol.
Fewer non-cardiac effects
due to cardioselectivity.
See nadolol.
See nadolol.
Agents with ISA have
less effect on resting
heart rate than those
without ISA.
$
Beta1-adrenergic
Antagonists with
alpha1-blocking activity
labetalol
Trandate, generics
Initial: 50 mg BID po
Usual: 200 mg BID po
Maximum: 1200 mg/day
See nadolol.
Edema, dizziness and nasal
congestion and postural
hypotension due to alpha1
antagonism.
See nadolol.
See nadolol.
$$
Calcium Channel
Blockers,
dihydropyridine
amlodipine
Norvasc, generics
Initial: 2.5 mg/day
Maximum: 10 mg/day
Once daily po
Ankle edema, ushing,
headache and palpitations.
CYP3A4 substrate (many
potential interactions).
Strong inhibitors include
azole antifungals, protease
inhibitors, macrolides and
quinidine.
Grapefruit juice may
increase serum
concentrations.
felodipine
Plendil, generics
Initial: 2.5 mg/day
Usual: 10 mg/day
Maximum: 20 mg/day
Once daily po
See amlodipine.
See amlodipine.
Grapefruit juice causes
marked elevations in
felodipine serum levels
and adverse events.
$$
nifedipine, extended
release
Adalat XL, generics
Initial: 30 mg/day
Usual: 60 mg/day
Maximum: 120 mg/day
Once daily po
See amlodipine.
See amlodipine.
Do not use short-acting
nifedipine formulations
for treatment of essential
hypertension.
$$
$
Cardiovascular Disorders
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Table 6:
CH AP TER
Compendium of Therapeutic Choices.
SA MP LE
CH AP TER
Compendium of Therapeutic Choices.
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
Calcium Channel
Blockers,
nondihydropyridine
diltiazem
Cardizem CD,
Tiazac, Tiazac XC,
generics
Initial: 120 mg/day
Usual: 240–360 mg/day
Maximum: 360 mg/day
Give CD or XC
formulation once daily po,
SR formulation divided
BID po
Headache, dizziness,
bradycardia, heart block,
new onset or worsening of
heart failure.
See amlodipine.
Nondihydropyridines
inhibit the metabolism
of carbamazepine,
cyclosporine, lovastatin,
simvastatin.
Rifampin induces
metabolism of
nondihydropyridines.
Additive negative inotropic
effects with amiodarone,
beta-blockers and digoxin.
Caution in patients with
heart failure, or 2nd or
3rd degree heart block
without a functioning
pacemaker.
$$
verapamil
Isoptin SR, generics
Initial: 80 mg TID po
Maximum:160 mg TID po
SR (once daily or divided
BID po): Initial: 180
mg/day; Usual: 180–480
mg/day; Maximum: 480
mg/day
See diltiazem.
Constipation.
See amlodipine.
See diltiazem.
Verapamil increases digoxin
levels by 50–75% within 1
wk (monitor levels).
See diltiazem.
$-$$
Centrally Acting
Antihypertensive
Agents
methyldopa
generics
Initial: 500 mg/day
Usual: 2000 mg/day
Maximum: 3000 mg/day
Divided BID or TID po
Drowsiness, dry mouth, nasal
congestion, depression,
orthostatic hypotension,
palpitations, sexual
dysfunction, sodium and
water retention.
Iron salts reduce absorption
(separate administration).
Additive hypotension with
levodopa.
May exacerbate Li+ adverse
events without increasing Li+
levels.
Positive Coombs' test
is common, but usually
unimportant; hemolytic
anemia is rare.
Drug fever with or without
an inuenza-like illness;
hepatic disorders have
occurred.
$$
Direct Renin Inhibitors
aliskiren
Rasilez
Initial: 150 mg/day
Maximum: 300 mg/day
Once daily po
Diarrhea. The incidence of
dry cough and hyperkalemia
is low compared with ACE
inhibitors.
Avoid combining with an
ACE inhibitor or ARB in
patients with signicant renal
impairment.
May take 4 wk to
realize maximum
antihypertensive effect.
Effect on cardiovascular
outcomes not yet
established.
Limited data in
patients with greater
than moderate renal
dysfunction.
Avoid use in pregnancy.
$$
Chapter 39: Hypertension
(cont'd)
507
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Class
SA MP LE
Class
Drugs Used for Hypertension (cont'd)
Drug
Compendium of Therapeutic Choices.
Dose
Adverse Effects
Drug Interactions
Comments
Costa
Initial: 12.5 mg/day
Usual: 25 mg/day
Once daily po
Hypotension, weakness,
muscle cramps, impotence.
Hypokalemia, hyponatremia,
hyperuricemia,
hyperglycemia,
hyperlipidemia.
Rare: azotemia, blood
dyscrasias, allergic reactions
(potential cross sensitivity
with other sulfonamide
derivatives), photosensitivity,
fatigue.
Li+
excretion reduced
(monitor Li+ levels, adjust
dose).
NSAIDs reduce hypotensive
efcacy.
Diuretic-induced
hypokalemia increases
the risk of digoxin toxicity.
Reduced efcacy of
antihyperglycemic agents.
Particularly effective in
ISH, the elderly and
black patients.
Monitor SCr and K+.
Consider alternatives
in patients with
or predisposed to
arrhythmias.
Can exacerbate gout and
diabetes (biochemical
abnormalities are less
frequent at low doses).
Ineffective in patients
with ClCr <30 to 40
mL/min.
$
chlorthalidone
generics
Initial: 12.5 mg/day
Usual: 12.5–25 mg/day
Once daily po
See hydrochlorothiazide.
See hydrochlorothiazide.
Lowest available tablet
strength is 50 mg. Tablet
(or “pill”) splitters, widely
available in pharmacies,
can be used to derive
a dose of 12.5 mg (¼
tablet) with reasonable
accuracy.
See hydrochlorothiazide.
$
indapamide
Lozide, generics
Initial: 1.25 mg/day
Usual: 2.5 mg/day
Once daily po
See hydrochlorothiazide.
See hydrochlorothiazide.
See hydrochlorothiazide.
$
metolazone
Zaroxolyn
Initial: 2.5 mg/day
Usual: 5 mg/day
Maximum: 10 mg/day
Once daily po
See hydrochlorothiazide.
See hydrochlorothiazide.
See hydrochlorothiazide.
Metolazone is effective in
patients with moderate to
severe renal dysfunction.
$
hydrochlorothiazide
generics
Cardiovascular Disorders
Diuretics
508
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Table 6:
CH AP TER
SA MP LE
CH AP TER
Compendium of Therapeutic Choices.
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
ACE Inhibitor/
Calcium Channel
Blocker Combinations
trandolapril/verapamilb
Tarka
Trandolapril 1–4 mg/day
plus verapamil 180–480
mg/day. Once daily or
divided BID poc
See benazepril.
See diltiazem.
Constipation.
See benazepril.
See amlodipine.
Inhibits metabolism
of carbamazepine,
cyclosporine, lovastatin,
simvastatin.
Rifampin increases
metabolism of verapamil.
Additive negative inotropic
effects with amiodarone,
beta-blockers, digoxin.
Verapamil increases digoxin
levels by 50–75% within 1
wk (monitor levels).
See benazepril.
See diltiazem.
$$$
ACE Inhibitor/
Diuretic Combinations
cilazapril/hydrochlorothiazideb
Inhibace Plus,
generics
5/12.5 mg once daily poc
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
$
enalapril/hydrochlorothiazideb
Vaseretic, generics
5/12.5 mg or 10/25 mg
once daily poc
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
$$
lisinopril/hydrochlorothiazideb
Prinzide, Zestoretic,
generics
10/12.5 mg, 20/12.5 mg
or 20/25 once daily poc
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
$-$$
perindopril/indapamideb
Coversyl Plus,
Coversyl Plus LD
4/1.25 mg once daily poc
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
$$
quinapril/hydrochlorothiazideb
Accuretic, generics
10/12.5 mg, 20/12.5 mg
or 20/25 mg once daily
poc
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
$-$$
ramipril/hydrochlorothiazideb
Altace HCT, generics
2.5/12.5 mg, 5/12.5 mg,
10/12.5 mg, 5/25 mg or
10/25 mg once daily poc
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
See benazepril.
See hydrochlorothiazide.
$
azilsartan/chlorthalidoneb
Edarbyclor
40/12.5 mg, 40/25 mg or
80/12.5 mg once daily po
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$$
ARB/
Diuretic Combinations
509
(cont'd)
Chapter 39: Hypertension
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Class
SA MP LE
510
Drugs Used for Hypertension (cont'd)
Class
Compendium of Therapeutic Choices.
Beta1-adrenergic
Antagonist/
Diuretic Combinations
Calcium Channel
Blocker/
Anti-platelet
Combinations
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
candesartan/hydrochlorothiazideb
Atacand Plus,
generics
16/12.5 mg once daily poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$
eprosartan/hydrochlorothiazideb
Teveten Plus
600/12.5 mg once daily
poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$$
irbesartan/hydrochlorothiazideb
Avalide, generics
150/12.5 mg or 300/12.5
mg once daily poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$
losartan/hydrochlorothiazideb
Hyzaar, Hyzaar DS,
generics
50/12.5 mg or 100/25 mg
once daily poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$
olmesartan/hydrochlorothiazideb
Olmetec Plus
20/12.5 mg, 40/12.5 mg
or 40/25 mg once daily
poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$$
telmisartan/hydrochlorothiazideb
Micardis Plus,
generics
80/12.5 mg or 80/25 mg
once daily poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$
valsartan/hydrochlorothiazideb
Diovan-HCT,
generics
80/12.5 mg, 160/12.5 mg
or 160/25 mg once daily
poc
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
See azilsartan.
See hydrochlorothiazide.
$
atenolol/chlorthalidoneb
Tenoretic, generics
50/25 mg, or 100/25 mg
once daily poc
See nadolol.
See hydrochlorothiazide.
See nadolol.
See hydrochlorothiazide.
See nadolol.
See hydrochlorothiazide.
$
pindolol/hydrochlorothiazideb
Viskazide
10/25 mg or 10/50 mg
once daily poc
See nadolol.
See hydrochlorothiazide.
See nadolol.
See hydrochlorothiazide.
See nadolol.
See hydrochlorothiazide.
$$
nifedipine XL/ASA
Adalat XL Plus
nifedipine 20 mg, 30 mg
or 60 mg with ASA 81 mg
once daily po
See amlodipine.
Bleeding, gastric intolerance.
See amlodipine.
Increased bleeding risk with
anticoagulants.
See nifedipine.
$-$$
Cardiovascular Disorders
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Table 6:
CH AP TER
SA MP LE
CH AP TER
Compendium of Therapeutic Choices.
Drug
Dose
Adverse Effects
Drug Interactions
Comments
Costa
Calcium Channel
Blocker/
ARB Combinations
amlodipine/telmisartanb
Twynsta
5/40 mg, 5/80 mg, 10/40
mg or 10/80 mg once
daily poc
See amlodipine.
See azilsartan.
See amlodipine.
See azilsartan.
See azilsartan.
$$
Calcium Channel
Blocker/
HMG-CoA Reductase
Inhibitor Combinations
amlodipine/atorvastatin
Caduet, generics
Amlodipine 5 or 10 mg
plus atorvastatin 10, 20,
40 or 80 mg once daily
poc
See amlodipine.
Adverse effects of
atorvastatin include
constipation, atulence,
dyspepsia, abdominal pain
and myalgia.
See amlodipine.
Amlodipine and atorvastatin
are both substrates of
CYP3A4.
For patients with
hypertension and
an indication for an
HMG-CoA inhibitor.
$-$$
Direct Renin Inhibitor/
Diuretic Combinations
aliskiren/hydrochlorothiazide
Rasilez HCT
150/12.5 mg,
150/25 mg,
300/12.5 mg
or 300/25 mg
once daily poc
See aliskiren.
See hydrochlorothiazide.
See aliskiren.
See hydrochlorothiazide.
See aliskiren.
See hydrochlorothiazide.
$$
Diuretic Combinations
hydrochlorothiazide/amiloride
(50/5)
generics
One-half tablet once daily
po
See hydrochlorothiazide.
See hydrochlorothiazide.
May exacerbate
ACE inhibitor-induced
hyperkalemia.
See hydrochlorothiazide.
Lower incidence of
hypokalemia than with
hydrochlorothiazide
alone.
$
hydrochlorothiazide/
triamterene (25/50)
generics
Initial: One-half tablet
Usual: 1 tablet
Once daily po
See hydrochlorothiazide.
See hydrochlorothiazide/amiloride.
See hydrochlorothiazide/amiloride.
$
hydrochlorothiazide/spironolactone
(25/25)
Aldactazide,
generics
Initial: One-half tablet
Usual: 1 tablet
Once daily po
See hydrochlorothiazide.
Gynecomastia in men and
breast tenderness in women.
See hydrochlorothiazide/amiloride.
See hydrochlorothiazide/amiloride.
$
Cost of 30-day supply of usual dose of drug; includes drug cost only.
The Canadian Hypertension Education Program recommends initiating therapy with a combination of two rst-line agents if a patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended target.
It is generally recommended that the dose of each component is titrated before starting a combination product.
Dosage adjustment may be required in renal impairment; see Appendix I.
Abbreviations: CV = cardiovascular; IR = immediate-release; ISA = intrinsic sympathomimetic activity; ISH = isolated systolic hypertension; PAD = peripheral arterial disease; SCr = serum creatinine; SR =
slow-release; TCA = tricyclic antidepressant
Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$$ $40–60 $$$$ $60–80
a
b
c
Chapter 39: Hypertension
511
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Class
SAM PLE
512
CH AP TER
Cardiovascular Disorders
Suggested Readings
Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med
2007;356(19):1966-78.
Canadian recommendations on the management of hypertension are updated annually. A summary of
the important and new recommendations can be found at www.hypertension.ca/ in the Professional
section and is also broadly published in multidisciplinary journals annually.
References
1. Hypertension Canada. Canadian Hypertension Education Program (CHEP). 2014 CHEP recommendations. Available from:
hypertension.ca/en/chep. Accessed April 24, 2014.
2. Khan N, Chockalingam A, Campbell NR. Lack of control of high blood pressure and treatment recommendations in Canada. Can J Cardiol
2002;18(6):657-61.
3. ALLHAT Ofcers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor
or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA 2002;288(23):2981-97.
4. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed)
1985;291(6488):97-104.
5. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after rst-trimester exposure to ACE inhibitors. N Engl J
Med 2006;354(23):2443-51.
6. Friedman JM. ACE inhibitors and congenital anomalies. N Engl J Med 2006;354(23):2498-500.
7. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol
2005;73(2):123-30.
8. Wald DS, Law M, Morris JK et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants
from 42 trials. Am J Med 2009;122(3):290-300.
9. Weber MA, Bakris GL, Dahlof B et al. Baseline characteristics in the Avoiding Cardiovascular events through Combination therapy in Patients
Living with Systolic Hypertension (ACCOMPLISH) trial: a hypertensive population at high cardiovascular risk. Blood Press 2007;16(1):13-9.
10. Mann JF, Schmieder RE, McQueen M et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET
study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372(9638):547-53.
11. Magee LA, Helewa M, Moutquin JM et al. Diagnosis, evaluation, and management of hypertensive disorders of pregnancy. J Obstet Gynaecol
Can 2008;30(3 Suppl):S1-48.
12. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the
American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122(5):1122-31.
13. U.K. National Institute for Health and Care Excellence (NICE). Clinical guidelines. Hypertension in pregnancy (CG107). Available from:
www.nice.org.uk/guidance/CG107.
14. Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008;51(4):960-9.
15. Magee LA. Drugs in pregnancy. Antihypertensives. Best Pract Res Clin Obstet Gynaecol 2001;15(6):827-45.
16. Magee LA, Schick B, Donnenfeld AE et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicentre cohort
study. Am J Obstet Gynecol 1996;174(3):823-8.
17. Papatsonis DN, Lok CA, Bos JM et al. Calcium channel blockers in the management of preterm labor and hypertension in pregnancy. Eur
J Obstet Gynecol Reprod Biol 2001;97(2):122-40.
18. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during pregnancy. BMJ 1990;301(6752):587-9.
19. Groves TD, Corenblum B. Spironolactone therapy during human pregnancy. Am J Obstet Gynecol 1995;172(5):1655-6.
20. Shotan A, Widerhorn J, Hurst A et al. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence,
potential mechanisms, and recommendations for use. Am J Med 1994;96(5):451-6.
21. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after rst trimester exposure to ACE inhibitors. N Engl J
Med 2006;354(23):2443-51.
22. Lambot MA, Vermeylen D, Noel JC. Angiotensin-II-receptor inhibitors in pregnancy. Lancet 2001;357(9268):1619-20.
23. Cheng JW. Aliskiren: renin inhibitor for hypertension management. Clin Ther 2008;30(1):31-47.
24. Beardmore KS, Morris JM, Gallery ED. Excretion of antihypertensive medication into human breast milk: a systematic review. Hypertens
Pregnancy 2002;21(1):85-95.
25. Ohkubo T, Imai Y, Tsuji I et al. Home blood pressure measurement has a stronger predictive power for mortality than does screening blood
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26. Ohkubo T, Asayam K, Kikuya M et al. How many times should blood pressure be measured at home for better prediction of stroke risk?
Ten-year follow-up results from the Ohasama study. J Hypertens 2004;22(6):1099-104.
27. McLean DL, McAlister FA, Johnson JA et al. A randomized trial of the effect of community pharmacist and nurse care on improving
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2005;(4):CD003566.
Copyright © 2014 Canadian Pharmacists Association. All rights reserved.
Compendium of Therapeutic Choices.
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