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About the Compendium of Therapeutic ChoicesThe Compendium of Therapeutic Choices, formerly Therapeutic Choices, is a trusted Canadian source for evidence-based treatment information for all health care practitioners involved in therapeutic decision-making. Practical, bottom-line, clinical information covering more than 200 common medical conditions is referenced and organized in a concise format by therapeutic condition. More than 72 chapters cover drug therapy during pregnancy and breastfeeding. The content is based on the best available evidence, subject to a rigorous peer review process.

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490 Cardiovascular Disorders

Cardiovascular Disorders

Chapter 39HypertensionNorm R.C. Campbell, MD, FRCPCPaul Gibson, MD, FRCPC andRoss T. Tsuyuki, PharmD, MSc, FCSHP, FACC

Goals of Therapy■ Reduce the risk of premature cardiac, cerebrovascular, renal and other vascular morbidity andmortality

■ 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 arebelow these thresholds.

Investigations■ History:– duration of hypertension, usual level of blood pressure and any sudden change in severityof hypertension

– history of antihypertensive drug use, reason for changing therapy, effectiveness, side effectsand 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 sodiumintake, 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/urinarysymptoms or a past history of renal disease

Table 1: Blood Pressure Targets in Treated Patients1

Setting Target SBP/DBP (mm Hg)

Homea

Chapter 39: Hypertension 491

Table 2: Drugs and Other Exogenous Factors That Can Induce or AggravateHypertension1

Alcohol (excessive use) 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 andurgencies. This includes patients with hypertension that is compromising vital organ function(encephalopathy, cardiac, or rapidly decreasing renal function), hypertension and a major arterydissection, or those with DBP ≥130 mm Hg

– hypertension may be diagnosed in 2 ofce visits if blood pressure averages ≥180/110 mm Hg, orif it averages ≥140/90 mm Hg in the presence of diabetes, renal disease, atheroscleroticcardiovascular disease or cerebrovascular disease

– the diagnosis may be arrived at after 2 visits if home or ambulatory blood pressure measurementis used

– the diagnosis may require 3 visits if the blood pressure averages between 160/100 mm Hg and180/110 mmHg. However, 5 or more visits may be required to establish the diagnosis if the initialblood pressure average is between 140/90 mm Hg and 160/100 mm Hg and there is no targetorgan dysfunction. Attention to the details of measuring blood pressure is essential to makinga valid diagnosis. Automated blood pressure measurements (using an approved monitor) inthe ofce is recommended.

– home measurement of blood pressure can aid in the diagnosis of hypertension, identify white coatand masked hypertension, improve blood pressure control and improve medication adherencein 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)

Compendium of Therapeutic Choices. Copyright © 2014 Canadian Pharmacists Association. All rights reserved.


492 Cardiovascular DisordersTable 3: Hypertensive Patients Requiring Additional Laboratory Testing1

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 orchanges in abdominal pressure• Incidentally discovered adrenal adenoma• MEN 2A or 2B; von Recklinghausen's neurobromatosis or von Hippel-Lindau disease

Pheochromocytoma

• Spontaneous hypokalemia• Profound diuretic-induced hypokalemia (K+ 55 or

Chapter 39: Hypertension 493■ Sodium intake of 1500 mg (65 mmol) per day for those aged 19–50 years, 1300 mg (56 mmol) perday 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,

494 Cardiovascular DisordersBeta-blockersBeta-blockers are rst-line therapy in patients who are younger than 60 years, or who have stableangina, heart failure or a history of MI. Beta-blockers are also useful in patients who have migraineheadaches, tachycardia or essential tremor. However, beta-blockers are not as effective as angiotensinII receptor blockers (ARBs), calcium channel blockers (CCBs) or diuretics as initial therapy forprimary prevention of cardiovascular events in patients over the age of 60 years. In addition, they maybe 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 thissystem 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 patientswith hypertension. However, some inhibitors of the RAAS do provide additional benets in certainpatients, 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 classesshould not be prescribed in women of child-bearing potential unless the risks are carefully weighed andadequate 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 withuncomplicated hypertension and for patients with diabetes, ischemic heart disease, recent MI, heartfailure or chronic kidney disease.

Angiotensin II Receptor Blockers

ARBs are rst-line agents for patients with uncomplicated hypertension, for patients with diabetesor ischemic heart disease. They are good alternatives when ACE inhibitors are specically indicatedbut not tolerated.

Direct Renin Inhibitors

Aliskiren, the rst direct renin inhibitor, prevents renin from converting angiotensinogen to angiotensinI. The drug has a long duration of action and lowers blood pressure to the same extent as drugs fromother antihypertensive classes. Until data become available on the effect of aliskiren on cardiovascularevents the drug should be used only when rst-line therapies cannot be used.

Long-acting Calcium Channel BlockersLong-acting dihydropyridine CCBs can be used as rst-line agents but in practice they are generallyused in combination therapy. Short-acting formulations of these agents have caused an increase incardiovascular events in randomized controlled trials and should not be used. Elderly patients withisolated systolic hypertension and black patients are particularly responsive to CCBs.

Other Antihypertensive DrugsIn general, other classes of antihypertensive drugs should not be prescribed unless there are specicindications (Table 5), contraindications or intolerance to rst-line therapy, or a requirement foradditional blood pressure lowering in combination with rst-line antihypertensive drugs.

Combination TherapyAbout 50% of patients will require more than one antihypertensive agent to achieve blood pressuretargets. If the goal blood pressure is not achieved with moderate doses of a suitable rst-line drug, add,

Copyright © 2014 Canadian Pharmacists Association. All rights reserved. Compendium of Therapeutic Choices.


Chapter 39: Hypertension 495rather than substitute, a second drug. Combining 2 drugs from different classes yields a 5 times greaterincremental 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 preventingcardiovascular events. The Canadian Hypertension Education Program (CHEP) recommendsconsideration of an ACE inhibitor with amlodipine in high-risk patients whose blood pressure requires2 or more medications for control.9 CHEP recommends initiating therapy with a combination of2 rst-line agents if a patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended target.1Use of a diuretic is desirable in combination with all other drug classes. In contrast, any combinationof a beta-blocker, ACE inhibitor and/or an ARB has less than additive antihypertensive effects whencombined in a 2-drug regimen. These combinations should be avoided unless there is a specicindication, for example, use of an ACE inhibitor and a beta-blocker in post-MI patients or in thosewith heart failure (Table 5).

All possible combinations of rst-line agents are rational choices to lower blood pressure when 3 or 4drugs are required, with the exception of the simultaneous prescription of ACE inhibitors and ARBs. Acombination of ACE inhibitor plus ARB may further lower blood pressure but is associated with moreadverse effects (e.g., hyperkalemia, renal impairment) and no clear benet in terms of cardiovascularevents.10 This combination is generally not recommended for the treatment of hypertension, though itmay be appropriate in some medical circumstances such as refractory heart failure.

AdherenceMedication adherence should be assessed at each visit. Poor adherence to therapy is a major cause ofpoor blood pressure control. Patients may admit to poor adherence when questioned in a nonthreateningmanner, 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 withpatient information pamphlets (available at www.hypertension.ca in the Public section)

■ Include family or social support in lifestyle modication■ Use a simplied regimen of long-acting, once-daily drugs, and prescribe formulations that contain 2drugs 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 theirtoothbrush 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 ofce 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.



496 Cardiovascular Disorders■ Consider assessing adherence with an electronic pill dispenser■ Advise home-monitoring of adherence with pill counts and marking on a calendar when theprescription needs renewing

■ Consider regular telephone contact with the patient if feasible

Resistant HypertensionMany patients with hypertension require multiple drugs for blood pressure control. In those withresistant 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, considerthe 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 comfortableprescribing.

Hypertensive EmergenciesIt 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 withfacilities to continuously monitor blood pressure. In stabilizing patients for transfer, the use ofintermediate-acting drugs (e.g., felodipine) with close blood pressure monitoring is generally safer thanusing short-acting drugs that can rapidly produce hypotension with complications.

Choices during Pregnancy and BreastfeedingHypertension and PregnancyInform women with pre-existing hypertension who are of child-bearing potential, particularly thosewho are considering pregnancy, that they are at an increased risk for adverse pregnancy outcomesincluding: intrauterine growth restriction; placental abruption; preterm delivery and the attendantneonatal risks of prematurity; and particularly a heightened risk of preeclampsia, with a crude risk ofabout 20–25% (varying with the severity and duration of the pre-existing hypertension). Enhancedsurveillance is required during pregnancy to monitor for these complications. Prior to conception, orimmediately upon recognition of an unplanned pregnancy, review the choice of antihypertensivemedication for these women.

ManagementWhile there remains a dearth of high quality data on the effects of many common antihypertensivemedications on the developing fetus, international guidelines11,12,13 have reached some consensusregarding a list of “preferred” medications for use in pregnancy, as well as a few “avoid” and “mustavoid” drugs. Medications widely considered “rst-line” for the management of hypertension inpregnancy include: methyldopa (250 mg BID to 1000 mg TID), labetalol (100 mg BID to 800mg TID) and nifedipine XL (30 mg OD to 60 mg BID). These medications are preferred as theyhave evidence and/or a strong clinical record of safe and effective use in pregnancy,14,15 as well asan 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 dataregarding the use of nondihydropyridine calcium channel blockers16,17 and alpha-blockers inpregnancy 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 withfetal intrauterine growth restriction (IUGR).18 The other beta-blockers, in contrast, are only weaklyassociated with IUGR and have been used widely in pregnancy for various indications. Thiazides andloop 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



Chapter 39: Hypertension 497thereby impair uteroplacental perfusion and fetal growth.17 Available data do not support an adverseeffect on perinatal outcome,12 however, and these medications may therefore be considered orcontinued in women felt to have volume-dependent hypertension (renal impairment). They shouldbe avoided in settings in which uteroplacental perfusion is already reduced (preeclampsia or IUGR).Spironolactone should not be used at all in pregnancy, due to its anti-androgenic effects.19

ACE inhibitors have been clearly shown to be fetotoxic when taken during the second and thirdtrimesters,20 leading to oligohydramnios, IUGR, fetal/neonatal renal failure and other growtheffects. First trimester exposure has also been shown to lead to teratogenic effects, mainly to thefetal cardiovascular and central nervous system.21 Discontinue these drugs prior to conception, orimmediately upon discovery of an unplanned pregnancy. The data regarding the risk of fetal harm fromARBs22 and direct renin inhibitors23 are less robust (mainly animal data), but they appear to havesimilar harmful effects and should be avoided just as strictly as ACE inhibitors during pregnancy.

Most women with pre-existing hypertension, particularly those with long-standing, difcult-to-controlhypertension or end-organ damage, should be followed throughout pregnancy by a specialist inobstetrics and gynecology. These clinicians are skilled at ongoing maternal management as well asappropriate monitoring of fetal growth and well being. Women with difcult-to-control hypertension orother medical issues benet from assessment and follow-up with a hypertension specialist or obstetricmedicine physician during their pregnancy.

Hypertension and BreastfeedingFollowing the completion of a pregnancy, many women require ongoing antihypertensive therapy. Thechoice of antihypertensive agent may be inuenced by whether or not the woman is breastfeeding hernewborn child, as all oral medications appear in breast milk to some degree.24 Breastfeeding womenmay safely continue treatment with any “pregnancy-preferred” drug. Most other antihypertensivemedications may also be safely utilized, but a few choices to avoid in these women include diuretics(which may suppress lactation), atenolol and other beta-blockers with low serum protein-binding(which concentrate in breast milk), as well as long-acting ACE inhibitors and those for which there islittle or no lactation data (ramipril, lisinopril, cilazapril and perindopril).

A discussion of general principles on the use of medications in these special populations can befound in Appendix II and Appendix III. Other specialized reference sources are also provided inthese appendices.

Therapeutic Tips■ Prescribe a lower starting dose of antihypertensive drugs in elderly patients.■ Recent onset of hypertension or change in blood pressure control suggests an identiable orsecondary cause, such as drugs known to exacerbate hypertension or new onset of signicantrenal artery stenosis.

■ Many drugs ineffective as monotherapy for hypertension are effective components in a rationalcombination regimen.

■ Consider concurrent cardiovascular risk factors and disease states when prescribing therapy (Table5).

■ Cardiovascular risk can vary 10-fold in persons with the same blood pressure. Assess globalcardiovascular risk in all hypertensive patients using a risk form, chart or computer program (seeChapter 37, Figure 2 as an example).

■ Blood pressure measurements taken at home correlate better with cardiovascular outcomes thanofce-based measurements.25,26 Recommend monitors endorsed by the Canadian HypertensionSociety and train patients to use the proper technique. To allay anxiety, caution patients that some



Chapter 39: Hypertension 497thereby impair uteroplacental perfusion and fetal growth.17 Available data do not support an adverseeffect on perinatal outcome,12 however, and these medications may therefore be considered orcontinued in women felt to have volume-dependent hypertension (renal impairment). They shouldbe avoided in settings in which uteroplacental perfusion is already reduced (preeclampsia or IUGR).Spironolactone should not be used at all in pregnancy, due to its anti-androgenic effects.19

ACE inhibitors have been clearly shown to be fetotoxic when taken during the second and thirdtrimesters,20 leading to oligohydramnios, IUGR, fetal/neonatal renal failure and other growtheffects. First trimester exposure has also been shown to lead to teratogenic effects, mainly to thefetal cardiovascular and central nervous system.21 Discontinue these drugs prior to conception, orimmediately upon discovery of an unplanned pregnancy. The data regarding the risk of fetal harm fromARBs22 and direct renin inhibitors23 are less robust (mainly animal data), but they appear to havesimilar harmful effects and should be avoided just as strictly as ACE inhibitors during pregnancy.

Most women with pre-existing hypertension, particularly those with long-standing, difcult-to-controlhypertension or end-organ damage, should be followed throughout pregnancy by a specialist inobstetrics and gynecology. These clinicians are skilled at ongoing maternal management as well asappropriate monitoring of fetal growth and well being. Women with difcult-to-control hypertension orother medical issues benet from assessment and follow-up with a hypertension specialist or obstetricmedicine physician during their pregnancy.

Hypertension and BreastfeedingFollowing the completion of a pregnancy, many women require ongoing antihypertensive therapy. Thechoice of antihypertensive agent may be inuenced by whether or not the woman is breastfeeding hernewborn child, as all oral medications appear in breast milk to some degree.24 Breastfeeding womenmay safely continue treatment with any “pregnancy-preferred” drug. Most other antihypertensivemedications may also be safely utilized, but a few choices to avoid in these women include diuretics(which may suppress lactation), atenolol and other beta-blockers with low serum protein-binding(which concentrate in breast milk), as well as long-acting ACE inhibitors and those for which there islittle or no lactation data (ramipril, lisinopril, cilazapril and perindopril).

A discussion of general principles on the use of medications in these special populations can befound in Appendix II and Appendix III. Other specialized reference sources are also provided inthese appendices.

Therapeutic Tips■ Prescribe a lower starting dose of antihypertensive drugs in elderly patients.■ Recent onset of hypertension or change in blood pressure control suggests an identiable orsecondary cause, such as drugs known to exacerbate hypertension or new onset of signicantrenal artery stenosis.

■ Many drugs ineffective as monotherapy for hypertension are effective components in a rationalcombination regimen.

■ Consider concurrent cardiovascular risk factors and disease states when prescribing therapy (Table5).

■ Cardiovascular risk can vary 10-fold in persons with the same blood pressure. Assess globalcardiovascular risk in all hypertensive patients using a risk form, chart or computer program (seeChapter 37, Figure 2 as an example).

■ Blood pressure measurements taken at home correlate better with cardiovascular outcomes thanofce-based measurements.25,26 Recommend monitors endorsed by the Canadian HypertensionSociety and train patients to use the proper technique. To allay anxiety, caution patients that some


498 Cardiovascular Disordersvariation throughout the day is normal. Patient instructions for selecting and using home bloodpressure 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 managingtheir sodium and caloric intake.

■ A team approach to hypertension management is more effective than usual care. In patients withhypertension and diabetes, joint care by a family physician, community pharmacist and nurseresulted in an approximately 6 mm Hg greater reduction in SBP over 6 months, compared withusual physician-based care.27



Chapter

39:Hypertension

499Table 5: Individualization of Antihypertensive Therapy1

Category (BP Targets) Risk Factor/Disease Initial Therapy Second-line Therapy Notes/Cautions

Hypertension withoutother compellingindications(Target SBP/DBP

500Cardiovascular

Disorders

Table 5: Individualization of Antihypertensive Therapy1 (cont'd)Category (BP Targets) Risk Factor/Disease Initial Therapy Second-line Therapy Notes/Cautions

Heart failure ACE inhibitor and beta-blocker(ARB if ACE inhibitor nottolerated)Aldosterone antagonist in patientswith a recent cardiovascularhospitalization, acute MI, elevatedBNP, elevated NT-proBNP, orNYHA class II to IV symptoms

ARB added to ACE inhibitorHydralazine/isosorbidedinitrate combined if black,or if ACE inhibitor and ARBcontraindicated or not toleratedThiazide or loop diuretic asadditive therapyDihydropyridine CCB (exceptnifedipine)

Titrate doses of ACE inhibitors and ARBs to those usedin clinical trials.Monitor serum K+ and SCr with the combination of ACEinhibitor, ARB or aldosterone antagonist.

Left ventricularhypertrophy

ACE inhibitor, ARB, long-actingCCB or thiazide diuretic

Combination of additionalagents

Hydralazine and minoxidil should not be used.

Past stroke or TIA ACE inhibitor/diuretic combination Combination of additionalagents

Hypertension should not be treated in acute stroke unlessBP extremely elevated.Combination of an ACE inhibitor with an ARB is specicallynot recommended.

Nondiabetic chronickidney disease(Target SBP/DBP

Chapter

39:Hypertension

501Table 6: Drugs Used for HypertensionClass Drug Dose Adverse Effects Drug Interactions Comments Costa

ACE Inhibitors benazeprilLotensin, generics

Initial: 10 mg/dayUsual: 20 mg/dayMaximum: 40 mg/dayOnce daily or divided BIDpo

Dry cough, hyperkalemia.Unusual: angioedema.Can precipitate renal failurein renovascular disease,volume depletion or thosereceiving NSAIDs.

Marked increase in serumK+ in patients receivingK+ supplements and/orK+-sparing diuretics.Reduced hypotensive effectwith NSAIDs and increasedrisk of renal dysfunction.Elevated Li+ levels (potentialtoxicity).

Contraindicated inpregnancy—cautionwhen prescribingto women ofchild-bearingpotential.5,6 Use lower(50%) initial doses ifon diuretics (increasedrisk of hypotension withhypovolemia).Hyperkalemia usuallyoccurs only in thoseon K+ supplements ordrugs that cause K+retention, those withrenal impairment ordiabetics with highserum K+ levels. AssessSCr and K+ after a fewdays, then regularly.

$$

captoprilgenerics

Initial: 25 mg/dayUsual: 75 mg/dayMaximum: 150 mg/dayDivided BID or TID po

See benazepril. See benazepril. See benazepril. $$

cilazaprilInhibace, generics

Initial: 2.5 mg/dayUsual: 2.5–5 mg/dayMaximum: 10 mg/dayOnce daily or divided BIDpo

See benazepril. See benazepril. See benazepril. $

enalaprilVasotec, generics

Initial: 5 mg/dayUsual: 10–40 mg/dayMaximum: 40 mg/dayOnce daily or divided BIDpo


(cont'd)

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502Cardiovascular

Disorders

Table 6: Drugs Used for Hypertension (cont'd)Class Drug Dose Adverse Effects Drug Interactions Comments Costa

fosinoprilgenerics



lisinoprilPrinivil, Zestril,generics

Initial: 10 mg/dayUsual: 20 mg/dayMaximum: 40 mg/dayOnce daily po


perindoprilCoversyl, generics

Initial: 4 mg/dayMaximum: 8 mg/dayOnce daily or divided BIDpo


quinaprilAccupril, generics



ramiprilAltace, generics

Initial: 2.5 mg/dayUsual: 10 mg/dayMaximum: 20 mg/dayOnce daily or divided BIDpo


trandolaprilMavik

Initial: 1 mg/dayMaximum: 4 mg/dayOnce daily po


Alpha1-adrenergicAntagonists

doxazosinCardura, generics

Initial: 1 mg/dayUsual: 1–8 mg/dayMaximum: 16 mg/dayOnce daily po

Orthostatic hypotension,headache, drowsiness,palpitations, nasalcongestion.Syncope usually occurs atthe start of therapy, with rapiddose titration or on addition ofother agents. Titrate slowly.If interrupted for severaldays, restart at initial dose.

Caution when adding otherhypotensive drugs, maycause syncope.

Not for initial therapy. $

Copyright©2014

Canadian


Compendium



Chapter

39:Hypertension

503Class Drug Dose Adverse Effects Drug Interactions Comments Costa

prazosingenerics

Initial: 0.5 mg withp.m. meal (day 1),then 0.5 mg BID-TID po× 3 days and graduallyincrease as requiredMaximum: 20 mg/day

See doxazosin. See doxazosin. Not for initial therapy. $-$$

terazosinHytrin, generics

Initial: 1 mg QHS poUsual: 1–5 mg/dayMaximum: 20 mg/dayOnce daily or divided BIDpo

See doxazosin. See doxazosin.Verapamil increases serumconcentrations of terazosin.

Not for initial therapy. $

Angiotensin ReceptorBlockers (ARB)

azilsartanEdarbi


Hyperkalemia.Can precipitate renal failure insusceptible patients (bilateralrenovascular disease, thosewith volume depletion or withconcurrent NSAID use).Angioedema has beenreported, but a causalassociation has not beenestablished.

Marked increase in serumK+ in patients receivingK+ supplements and/orK+-sparing diuretics.May elevate Li+ levels(monitor Li+ levels, adjustdose).

Contraindicated inpregnancy—cautionwhen prescribingto women ofchild-bearingpotential.7Use lower initial dosesin patients who arevolume depleted or ondiuretics (increasedrisk of hypotension inhypovolemia).Hyperkalemia usuallyoccurs only in thoseon K+ supplements ordrugs that cause K+retention, those withrenal impairment ordiabetics with highserum K+ levels. AssessSCr and K+ after a fewdays, then regularly.

$$

candesartanAtacand, generics

Initial: 8 mg/dayUsual: 8–16 mg/dayOnce daily po

See azilsartan. See azilsartan. See azilsartan. $

eprosartanTeveten


See azilsartan. See azilsartan. See azilsartan. $$

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acistsAssociation.Allrightsreserved.


504Cardiovascular

Disorders


irbesartanAvapro, generics



losartanCozaar, generics

Initial: 50 mg/dayUsual: 25–100 mg/dayMaximum: 100 mg/dayOnce daily or divided BIDpo


olmesartanOlmetec


See azilsartan. See azilsartan. See azilsartan. $$

telmisartanMicardis, generics

Initial: 80 mg/dayUsual: 80 mg/dayOnce daily po


valsartanDiovan, generics



Beta1-adrenergicAntagonists,nonselective

nadololgenerics


Fatigue, bradycardia,decreased exercise capacity,headache, impotence, vividdreams.Less common:hyperglycemia, depression,heart failure, heart block.

Bradycardia with digoxin ornondihydropyridine CCBs.Cardiodepressant effectswith nondihydropyridineCCBs and amiodarone.

Beta-blockers shouldnot be used as initialtherapy in patients aged>60 y unless specicallyindicated.Avoid in patients withasthma.28

Avoid abrupt withdrawal(may precipitate reboundhypertension andischemia). Taperthe dose beforediscontinuation.Avoid in patients withsevere PAD.Contraindicated inpatients with 2nd or3rd degree heart blockin the absence of apacemaker.

$$

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Chapter39:Hypertension

505

Class Drug Dose Adverse Effects Drug Interactions Comments Costa

propranolol,controlled releaseInderal-LA

Initial: 80 mg/dayUsual: 320 mg/dayMaximum: 480 mg/daySR (once dailypo) formulationrecommended

See nadolol. See nadolol.CYP2D6 inhibitors increaselevels of propranolol.Propranolol increases serumlevels of rizatriptan.

See nadolol.Propranolol is morelikely to cause CNSside effects (insomnia,depression, vividdreams) than otheragents because ofgreater lipid solubility.

$$$$

timololgenerics

Initial: 5 mg BIDUsual: 20 mg BIDMaximum: 30 mg BID po

See nadolol. See nadolol. See nadolol. $$

Beta1-adrenergicAntagonists,β1-selective

atenololTenormin, generics


See nadolol.Fewer non-cardiac effectsdue to cardioselectivity.

See nadolol. See nadolol. $

bisoprololSandoz Bisoprolol,generics



See nadolol. See nadolol. $

metoprolol,Lopresor, generics

Initial: 50 mg/dayUsual: 100–200 mg/dayMaximum: 400 mg/dayGive regular formulationsBID po; SR formulationsonce daily po


See nadolol.CYP2D6 inhibitors increaselevels of metoprolol.

See nadolol. $

nebivololBystolic



See nadolol.CYP2D6 inhibitors increaselevels of nebivolol.

See nadolol. $$

Beta1-adrenergicAntagonists,nonselectivewith intrinsicsympathomimeticactivity (ISA)

pindololVisken, generics

Initial: 5 mg BID poUsual: 15 mg BID poMaximum: 60 mg/day

See nadolol. See nadolol. See nadolol.Agents with ISA haveless effect on restingheart rate than thosewithout ISA.

$$

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CompendiumofTherapeuticChoices.

Copyright©2014CanadianPharmacistsAssociation.Allrightsreserved.


506Cardiovascular

Disorders


Beta1-adrenergicAntagonists,β1-selective with ISA

acebutololSectral, generics



See nadolol. See nadolol.Agents with ISA haveless effect on restingheart rate than thosewithout ISA.

$

Beta1-adrenergicAntagonists withalpha1-blocking activity

labetalolTrandate, generics

Initial: 50 mg BID poUsual: 200 mg BID poMaximum: 1200 mg/day

See nadolol.Edema, dizziness and nasalcongestion and posturalhypotension due to alpha1antagonism.

See nadolol. See nadolol. $$

Calcium ChannelBlockers,dihydropyridine

amlodipineNorvasc, generics

Initial: 2.5 mg/dayMaximum: 10 mg/dayOnce daily po

Ankle edema, ushing,headache and palpitations.

CYP3A4 substrate (manypotential interactions).Strong inhibitors includeazole antifungals, proteaseinhibitors, macrolides andquinidine.Grapefruit juice mayincrease serumconcentrations.

$

felodipinePlendil, generics

Initial: 2.5 mg/dayUsual: 10 mg/dayMaximum: 20 mg/dayOnce daily po

See amlodipine. See amlodipine. Grapefruit juice causesmarked elevations infelodipine serum levelsand adverse events.

$$

nifedipine, extendedreleaseAdalat XL, generics


See amlodipine. See amlodipine. Do not use short-actingnifedipine formulationsfor treatment of essentialhypertension.

$$

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Canadian


Compendium



Chapter

39:Hypertension


Calcium ChannelBlockers,nondihydropyridine

diltiazemCardizem CD,Tiazac, Tiazac XC,generics

Initial: 120 mg/dayUsual: 240–360 mg/dayMaximum: 360 mg/dayGive CD or XCformulation once daily po,SR formulation dividedBID po

Headache, dizziness,bradycardia, heart block,new onset or worsening ofheart failure.

See amlodipine.Nondihydropyridinesinhibit the metabolismof carbamazepine,cyclosporine, lovastatin,simvastatin.Rifampin inducesmetabolism ofnondihydropyridines.Additive negative inotropiceffects with amiodarone,beta-blockers and digoxin.

Caution in patients withheart failure, or 2nd or3rd degree heart blockwithout a functioningpacemaker.

$$

verapamilIsoptin SR, generics

Initial: 80 mg TID poMaximum:160 mg TID poSR (once daily or dividedBID po): Initial: 180mg/day; Usual: 180–480mg/day; Maximum: 480mg/day

See diltiazem.Constipation.

See amlodipine.See diltiazem.Verapamil increases digoxinlevels by 50–75% within 1wk (monitor levels).

See diltiazem. $-$$

Centrally ActingAntihypertensiveAgents

methyldopagenerics

Initial: 500 mg/dayUsual: 2000 mg/dayMaximum: 3000 mg/dayDivided BID or TID po

Drowsiness, dry mouth, nasalcongestion, depression,orthostatic hypotension,palpitations, sexualdysfunction, sodium andwater retention.

Iron salts reduce absorption(separate administration).Additive hypotension withlevodopa.May exacerbate Li+ adverseevents without increasing Li+levels.

Positive Coombs' testis common, but usuallyunimportant; hemolyticanemia is rare.Drug fever with or withoutan inuenza-like illness;hepatic disorders haveoccurred.

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Direct Renin Inhibitors aliskirenRasilez


Diarrhea. The incidence ofdry cough and hyperkalemiais low compared with ACEinhibitors.

Avoid combining with anACE inhibitor or ARB inpatients with signicant renalimpairment.

May take 4 wk torealize maximumantihypertensive effect.Effect on cardiovascularoutcomes not yetestablished.Limited data inpatients with greaterthan moderate renaldysfunction.Avoid use in pregnancy.

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Copyright©

2014Canadian



508Cardiovascular

Disorders


Diuretics hydrochlorothiazide

generics

Initial: 12.5 mg/dayUsual: 25 mg/dayOnce daily po

Hypotension, weakness,muscle cramps, impotence.Hypokalemia, hyponatremia,hyperuricemia,hyperglycemia,hyperlipidemia.Rare: azotemia, blooddyscrasias, allergic reactions(potential cross sensitivitywith other sulfonamidederivatives), photosensitivity,fatigue.

Li+ excretion reduced(monitor Li+ levels, adjustdose).NSAIDs reduce hypotensiveefcacy.Diuretic-inducedhypokalemia increasesthe risk of digoxin toxicity.Reduced efcacy ofantihyperglycemic agents.

Particularly effective inISH, the elderly andblack patients.Monitor SCr and K+.Consider alternativesin patients withor predisposed toarrhythmias.Can exacerbate gout anddiabetes (biochemicalabnormalities are lessfrequent at low doses).Ineffective in patientswith ClCr

Chapter

39:Hypertension


ACE Inhibitor/Calcium ChannelBlocker Combinations

trandolapril/vera-pamilbTarka

Trandolapril 1–4 mg/dayplus verapamil 180–480mg/day. Once daily ordivided BID poc

See benazepril.See diltiazem.Constipation.

See benazepril.See amlodipine.Inhibits metabolismof carbamazepine,cyclosporine, lovastatin,simvastatin.Rifampin increasesmetabolism of verapamil.Additive negative inotropiceffects with amiodarone,beta-blockers, digoxin.Verapamil increases digoxinlevels by 50–75% within 1wk (monitor levels).

See benazepril.See diltiazem.

$$$

ACE Inhibitor/Diuretic Combinations

cilazapril/hy-drochlorothiazidebInhibace Plus,generics

5/12.5 mg once daily poc See benazepril.See hydrochlorothiazide.

See benazepril.See hydrochlorothiazide.


$

enalapril/hy-drochlorothiazidebVaseretic, generics

5/12.5 mg or 10/25 mgonce daily poc




$$

lisinopril/hy-drochlorothiazidebPrinzide, Zestoretic,generics

10/12.5 mg, 20/12.5 mgor 20/25 once daily poc




$-$$

perindopril/inda-pamidebCoversyl Plus,Coversyl Plus LD

4/1.25 mg once daily poc See benazepril.See hydrochlorothiazide.



$$

quinapril/hy-drochlorothiazidebAccuretic, generics

10/12.5 mg, 20/12.5 mgor 20/25 mg once dailypoc




$-$$

ramipril/hy-drochlorothiazidebAltace HCT, generics

2.5/12.5 mg, 5/12.5 mg,10/12.5 mg, 5/25 mg or10/25 mg once daily poc




$

ARB/Diuretic Combinations

azilsartan/chlorthali-donebEdarbyclor

40/12.5 mg, 40/25 mg or80/12.5 mg once daily po

See azilsartan.See hydrochlorothiazide.



$$

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Compendium


Copyright©2014

CanadianPharm

acistsAssociation.Allrightsreserved.


510Cardiovascular

Disorders


candesartan/hy-drochlorothiazidebAtacand Plus,generics

16/12.5 mg once daily poc See azilsartan.See hydrochlorothiazide.



$

eprosartan/hy-drochlorothiazidebTeveten Plus

600/12.5 mg once dailypoc




$$

irbesartan/hy-drochlorothiazidebAvalide, generics

150/12.5 mg or 300/12.5mg once daily poc




$

losartan/hy-drochlorothiazidebHyzaar, Hyzaar DS,generics





$

olmesartan/hy-drochlorothiazidebOlmetec Plus





$$

telmisartan/hy-drochlorothiazidebMicardis Plus,generics





$

valsartan/hy-drochlorothiazidebDiovan-HCT,generics





$

Beta1-adrenergicAntagonist/Diuretic Combinations

atenolol/chlorthali-donebTenoretic, generics

50/25 mg, or 100/25 mgonce daily poc

See nadolol.See hydrochlorothiazide.



$

pindolol/hy-drochlorothiazidebViskazide

10/25 mg or 10/50 mgonce daily poc




$$

Calcium ChannelBlocker/Anti-plateletCombinations

nifedipine XL/ASAAdalat XL Plus

nifedipine 20 mg, 30 mgor 60 mg with ASA 81 mgonce daily po

See amlodipine.Bleeding, gastric intolerance.

See amlodipine.Increased bleeding risk withanticoagulants.

See nifedipine. $-$$

Copyright©2014

Canadian


Compendium




Chapter

39:Hypertension


Calcium ChannelBlocker/ARB Combinations

amlodipine/telmisar-tanbTwynsta

5/40 mg, 5/80 mg, 10/40mg or 10/80 mg oncedaily poc

See amlodipine.See azilsartan.

See amlodipine.See azilsartan.

See azilsartan. $$

Calcium ChannelBlocker/HMG-CoA ReductaseInhibitor Combinations

amlodipine/atorvas-tatinCaduet, generics

Amlodipine 5 or 10 mgplus atorvastatin 10, 20,40 or 80 mg once dailypoc

See amlodipine.Adverse effects ofatorvastatin includeconstipation, atulence,dyspepsia, abdominal painand myalgia.

See amlodipine.Amlodipine and atorvastatinare both substrates ofCYP3A4.

For patients withhypertension andan indication for anHMG-CoA inhibitor.

$-$$

Direct Renin Inhibitor/Diuretic Combinations

aliskiren/hydrochlor-othiazideRasilez HCT

150/12.5 mg,150/25 mg,300/12.5 mgor 300/25 mgonce daily poc

See aliskiren.See hydrochlorothiazide.



$$

Diuretic Combinations hydrochloroth-iazide/amiloride(50/5)generics

One-half tablet once dailypo

See hydrochlorothiazide. See hydrochlorothiazide.May exacerbateACE inhibitor-inducedhyperkalemia.

See hydrochlorothiazide.Lower incidence ofhypokalemia than withhydrochlorothiazidealone.

$

hydrochlorothiazide/triamterene (25/50)generics

Initial: One-half tabletUsual: 1 tabletOnce daily po

See hydrochlorothiazide. See hydrochloroth-iazide/amiloride.

See hydrochloroth-iazide/amiloride.

$

hydrochlorothiazid-e/spironolactone(25/25)Aldactazide,generics

Initial: One-half tabletUsual: 1 tabletOnce daily po

See hydrochlorothiazide.Gynecomastia in men andbreast tenderness in women.



$

a Cost of 30-day supply of usual dose of drug; includes drug cost only.b 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.c 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 antidepressantLegend: $


512 Cardiovascular DisordersSuggested Readings

Adrogue HJ, Madias NE. Sodium and potassium in the pathogenesis of hypertension. N Engl J Med2007;356(19):1966-78.

Canadian recommendations on the management of hypertension are updated annually. A summary ofthe important and new recommendations can be found at www.hypertension.ca/ in the Professionalsection and is also broadly published in multidisciplinary journals annually.

References1. 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 Cardiol2002;18(6):657-61.

3. ALLHAT Ofcers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatmentto Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitoror 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 JMed 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 Teratol2005;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 participantsfrom 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 PatientsLiving 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 ONTARGETstudy): 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 GynaecolCan 2008;30(3 Suppl):S1-48.

12. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of theAmerican 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

pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens 1998;16(7):971-5.26. 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

blood pressure management in patients with diabetes mellitus: Study of Cardiovascular Risk Intervention by Pharmacists-Hypertension(SCRIP-HTN). Arch Intern Med 2008;168(21):2355-61.

28. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev2005;(4):CD003566.


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