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Spotlight on Antihypertensives
Contact Hours: 2.0 First Published: April 2, 2012 Course Expires: April 2, 2015
Copyright © 2012 by RN.com All Rights Reserved
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Acknowledgments RN.com acknowledges the valuable contributions of … Darrell Hulisz, RPh, PharmD is an Associate Professor of Family Medicine & Community Health in the School of Medicine at Case Western Reserve University, Cleveland, OH. He also holds a clinical faculty appointment at Ohio Northern University, College of Pharmacy. Dr. ("Darrell") Hulisz received his BS in Pharmacy from the University of Toledo & Doctor of Pharmacy from the Medical University of South Carolina. Darrell has published over 70 papers in the medical and pharmacy literature, has lectured extensively both locally and nationally and has served as an investigator in several clinical trials. He has made numerous appearances on local television and radio programs, and has been quoted in magazines such as "Newsweek", "Parenting”, and “USA Weekend”. He also serves on several national advisory panels and is an author for WebMD’s Medscape.com and a speaker/author for AMN Healthcare's RxSchool.com. Darrell currently practices as a clinical pharmacist with University Hospitals, Case Medical Center, Family Medicine Residency Program, where he works in consultation with family physicians, both on inpatient and outpatient services. Darrell has been the recipient of multiple teaching awards. He also completed a federal, multi‐agency faculty development fellowship to further his expertise in the field of addiction medicine. He also served as a co‐investigator for a multidisciplinary chronic pain study funded by the Macy Foundation. He was recently awarded a federal grant as a co‐investigator to develop leadership and advocacy in urban health and community health within a multidisciplinary team. Katherine Salay is a Pharmacy Intern & a Doctor of Pharmacy Candidate (May 2012) at Ohio Northern University. Some of her achievements include six publications, mostly for Ohio Northern University's student journal, The Pharmacy and Wellness Review, and a poster presentation at the Ohio Pharmacists Association Annual Conference. She is a member of two honor societies, Rho Chi and Phi Kappa Phi. Katherine was a four‐year letter winner in softball at Ohio Northern University, and was named to ESPN The Magazine's All‐District Academic Team. Upon receiving her PharmD, Katherine plans to continue training in Post‐Graduate Pharmacy Practice residency in Ohio.
Disclaimer RN.com strives to keep its content fair and unbiased. The authors, planning committee, and reviewers have no conflicts of interest in relation to this course. Conflict of Interest is defined as circumstances a conflict of interest that an individual may have, which could possibly affect Education content about products or services of a commercial interest with which he/she has a financial relationship. There is no commercial support being used for this course. Participants are advised that the accredited status of RN.com does not imply endorsement by the provider or ANCC of any commercial products mentioned in this course. There is no "off label" usage of drugs or products discussed in this course. You may find that both generic and trade names are used in courses produced by RN.com. The use of trade names does not indicate any preference of one trade named agent or company over another. Trade names are provided to enhance recognition of agents described in the course. Note: All dosages given are for adults unless otherwise stated. The information on medications contained in this course is not meant to be prescriptive or all‐encompassing. You are encouraged to consult with physicians and pharmacists about all medication issues for your patients. Purpose The purpose of this continuing education course is to provide an overview of the role of the renin‐angiotensin‐aldosterone system (RAAS) in the pathogenesis of hypertension. This will facilitate a comprehensive understanding of the pharmacology of RAAS drugs, including angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and direct renin inhibitors (DRIs). This is an intermediate to advanced pharmacology course, suitable for APRNs and RNs wanting an in‐depth review of antihypertensive pharmacology.
Learning Objectives After successful completion of this course, you will be able to:
1. Describe the epidemiology of hypertension with respect to prevalence and associated risks.
2. Explain the role of the renin‐angiotensin‐aldosterone system (RAAS) in the pathogenesis of hypertension.
3. Understand the mechanisms of actions of RAAS drugs, such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and direct renin inhibitors (DRIs).
4. Compare and contrast individual members of RAAS drugs with respect to dosing and precautions.
5. Identify clinical scenarios where a RAAS may be preferred or contraindicated using a case study.
Epidemiology of Hypertension According to the most recent data from the American Heart Association, 33.5% of Americans have hypertension, as defined as a blood pressure that exceeds 140/90 mm Hg. This statistic has gradually increased and amounts to an estimated 76 million US adults. At present, the prevalence of hypertension is approximately equal in men and women. Some ethnic minorities have higher rates, such as African Americans at 44% (Roger, et al., 2012).
Hypertension & Cardiovascular Disease The relationship between hypertension and the risk of cardiovascular disease (CVD), such as stroke, myocardial infarction, and heart failure is continuous and consistent. Aggressive blood pressure lowering is associated with a:
• 35‐40% decrease in stroke • 20‐25% decrease in myocardial infarction • 50% decrease in heart failure
(Chobanian, et al., 2003; ALLHAT Collaborative Research Group 2002) Individuals who are normotensive at age 55 have a 90% lifetime risk for developing hypertension. Each increment of 20/10 mmHg doubles the risk of cardiovascular disease (CVD) across the entire blood pressure range, starting from 115/75 mmHg (Chobanian, et al., 2003; ALLHAT Collaborative Research Group 2002). Those with a systolic BP between 120–139 mmHg or DBP 80–89 mmHg should be considered pre‐hypertensive and require health‐promoting lifestyle modifications to prevent CVD (Chobanian, et al., 2003). What Cause Hypertension? What exactly causes hypertension remains a mystery. The disorder can be classified as either essential, where the exact cause is unknown, or secondary, where a cause can be identified. Several factors may play a role in the development of hypertension. Risk factors such as being sedentary, obesity, smoking, stress, poor nutrition, hypokalemia, excessive alcohol intake and genetic factors probably contribute to the development essential hypertension.
Hypertension remains one of the most
important, potentially modifiable,
independent risk factors for CVD.
What Causes Secondary Hypertension? Secondary hypertension results from identifiable causes such as sleep apnea, hyperthyroidism, Cushing’s disease, kidney disease, and/or pheochromocytoma (tumor of the adrenal glands). Examples of drugs that may increase blood pressure include NSAIDS drugs (e.g. ibuprofen), corticosteroids (e.g. prednisone), estrogens, tacrolimus, cyclosporine, amphetamines, cocaine, ginseng, and pseudoephedrine (Hulisz, 2008). The Importance of Blood Pressure Control There is an overwhelming amount of evidence that proves cause and effect with respect to poorly controlled hypertension. Patients with high blood pressure are clearly at increased risk for:
• Stroke (also known as cerebrovascular accident, or CVA) • Heart failure • Heart attack (myocardial infarction) • Chronic kidney disease
Thus, aggressive and appropriate blood pressure control is essential at decreasing the risk of these diseases (Chobanian, et al., 2003).
Risk Factors for Hypertension While uncontrolled, undertreated, or undiagnosed hypertension leads to the development of CVD, the following risk factors are also associated with CVD and must be addressed in patients with hypertension (Chobanian, et al., 2003):
• Cigarette smoking • Obesity (Body Mass index or BMI >30 kg/m2) • Physical inactivity • Dyslipidemia • Diabetes mellitus • Renal insufficiency • Age (older than 55 for men, 65 for women) • Family history of premature CVD, where premature is defined as men under age
55 or women under age 65 years of age. Hypertension Treatment Overview Nurses should maintain awareness that lifestyle modification is the cornerstone of initial management of hypertension and should include measures to reduce intake of sodium (salt), saturated fats, sugars, red meat, alcohol, caffeine, and nicotine. Nurses can promote healthy nutrition by recommending the DASH diet eating plan to hypertensive patients. The DASH eating plan, developed by the National Heart, Lung, and Blood Institute (NHLBI), follows heart healthy guidelines to limit saturated fat and cholesterol. It focuses on increasing the intake of food rich in nutrients that are expected to lower blood pressure, mainly minerals (like potassium, calcium, and magnesium), protein, and fiber. The diet encourages the consumption of whole grains, fruits, vegetables, and fat‐free or low‐fat milk and milk products (NHLBI, 2006). It is recommended that 2.3 grams of sodium per day be the upper limit for management of hypertension and that potassium intake increased in most patients to 4.7 grams daily. This should be achieved through increased intake of potassium‐rich fruits and vegetables. Males should consume no more than one or two alcoholic drinks per day, where one drink is considered 12oz of beer, 5oz of wine, or 1.5oz of 80‐proof liquor (Appel, 2006).
Initiating Pharmacological Management of Hypertension Lifestyle modification is continued after decisions are made to initiate medications. A thiazide diuretic has traditionally been considered the first‐line hypertensive in the absence of compelling indications that would favor a different agent (Bui, 2010, Chobanian, et al., 2003). However, over 75% of patients require two or more medications to achieve optimal blood pressure goals (Sarafidis, Bakris, 2008). Not all patients with hypertension are aware of their condition and receiving treatment. Only 48% of those that they are aware that they have hypertension have their condition controlled (Roger, et al., 2012). Blood Pressure Goals Regardless if patients are treated with lifestyle modifications alone, or with drug therapy, their blood pressure should be lowered to <140/90 mmHg, or <130/80 mmHg in those with diabetes or chronic kidney disease (Chobanian, et al., 2003). Once blood pressure goals are met, follow‐up visits are done at 3‐ to 6‐month intervals. Co‐morbidities, such as heart failure, diabetes, high cholesterol, and the need for laboratory tests will influence the frequency of visits. Usually there are no symptoms of hypertension, so nurses should explain the consequences of poorly controlled blood pressure, along with the benefits of good control in an attempt to improve long‐term medication adherence.
Benefits of Lifestyle Modification for Hypertension Modification Approximate Systolic BP Reduction (range) Weight reduction 5‐20 mmHg/10 kg weight loss Adopt DASH eating plan 8‐14 mmHg Dietary sodium reduction 2‐8 mmHg Physical activity 4‐9 mmHg Moderation of alcohol consumption 2‐4 mmHg Chobanian, et al., 2003 Concurrent Medical Conditions for RAAS Drugs in Hypertension Angiotensin Converting Enzyme Inhibitors (ACE inhibitors) and Angiotensin II Receptor Blockers (ARBs) are preferred drugs as initial therapy in patient with hypertension who also have the following conditions:*
• Heart failure • Post myocardial infarction • Patients at high risk for coronary artery disease • Diabetes • Chronic kidney disease (with stable renal function) • Recurrent stroke prevention
* For most conditions, an ACEI inhibitor is preferred over an ARB. (Chobanian, et al., 2003, Rosendorff, 2007) What are the RAAS Drugs? RAAS is the renin‐angiotensin‐aldosterone system (discussed in more detail later). While several drugs indirectly affect RAAS, the following drugs more directly work here, and are the focus of this module:
• Angiotensin‐converting enzyme inhibitors (ACEI) • Angiotensin receptor blockers (ARBs) • Direct renin inhibitors
Renin‐Angiotensin‐Aldosterone System (RAAS) The RAAS is a group of hormones that act together to regulate blood pressure. It is called a system because each hormone influences the others and all are necessary for the whole to function correctly. This complex endogenous (internal) system acts on the kidneys to that ultimately controls arterial blood pressure (BP,) by regulating levels of:
• Sodium • Potassium • Blood volume
RAAS alters blood pressure by impacting vascular tone and sympathetic nervous system activity to affect vascular tone, and is mainly controlled by the kidney. The RAAS is the site of action for many antihypertensives, including angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors. (Saseen et al, 2011).
Image Source: Rad, A. (2006) Under the GNU Free Documentation License.
A Closer Look at Renin Renin is a hormone and an enzyme that controls the conversion of angiotensinogen to angiotensin I, and is stored in the juxtaglomerular cells, which are located in blood vessels within the kidney. The release of renin is influenced by many factors, both within the kidney, such as kidney perfusion pressure, catecholamines levels, and angiotensin II. Renin is also released in response to sodium, chloride, and potassium. For example, renin release is stimulated by:
• Decreased kidney arterial pressure and blood pressure • Decreased sodium, chloride, and blood volume
(Saseen et al, 2011) A Closer Look at Angiotensin • Once angiotensinogen is converted to angiotensin I by renin, angiotensin I is converted to
angiotensin II by Angiotensin Converting Enzyme (ACE). This conversion occurs mostly in the blood vessels.
• Angiotensin II is a strong hormone that acts directly on blood vessels to increase blood pressure. It also has another important function ‐ stimulating the release of aldosterone.
• Angiotensin II exerts its effects in various tissues by binding to specific receptor subtypes, AT1 and AT2.
o AT1 receptors are located in the brain, kidney, myocardium, peripheral vasculature, and adrenal glands; stimulation influences kidney and cardiovascular function, including BP regulation.
o AT2 receptors are located in adrenal medulla, uterus, and brain; have no influence on BP regulation (Saseen et al, 2011).
The Effect of Angiotensin II on Blood Pressure • Angiotensin II elevates BP by directly causing peripheral vasoconstriction, initiating the
release of catecholamines from the adrenal medulla, and increasing sympathetic nervous system activity.
• Angiotensin II also increases fluid volume effects, by activating resulting from aldosterone synthesis and release from the adrenal cortex. Aldosterone then acts on the kidneys to reabsorb sodium and water. This results in increased plasma volume, total peripheral resistance, and elevated BP.
• Antihypertensive medications, such as ACEIs, ARBs and DRIs block the activity of the RAAS, to lower blood pressure (Saseen et al, 2011).
Review of Efficacy of RAAS Drugs for Treating Hypertension Summary of the ALLHAT Trial (The ALLHAT Collaborative Research Group, 2002) The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
• The ALLHAT study is the largest, randomized, double‐blind, multi‐center clinical hypertension trial ever conducted.
• A major aim was to determine whether occurrence of fatal CHD or nonfatal MI is lower for high‐risk hypertensive patients treated with newer agents (CCB, ACEI, alpha‐blocker) compared with a diuretic.
• The study enrolled 42,418 high‐risk hypertensive patients ≥ 55 years of age. (The ALLHAT Collaborative Research Group, 2002)
Overall Conclusions from the ALLHAT Trial
• Lisinopril (representing ACEI) was about equivalent to chlorthalidone (representing thiazide‐type diuretics) in preventing major coronary events or increasing overall survival.
• Chlorthalidone was superior to lisinopril in preventing aggregate CV events, principally stroke, HF, angina, and urgent coronary vessel surgery.
• Total cholesterol was 1‐2 mg/dL higher in the chlorthalidone group, as compared to amlodipine and lisinopril.
• Fasting glucose was 5 mg/dL higher in the chlorthalidone than in the lisinopril group. • About 6‐8% more of the participants in the lisinopril group than those in the
chlorthalidone group required additional antihypertensive drugs. • Mean systolic BP averaged about 2 mm Hg higher in the lisinopril than the
chlorthalidone group (4 mm Hg for blacks); but mean diastolic BPs were equivalent. • Results were generally consistent for most outcomes by age, gender, race, and diabetic
status.
ACEIs: Mechanism of Action By inhibiting ACE, these drugs prevent the conversion of angiotensin I to angiotensin II. Decreasing the production of angiotensin II results in:
• Vasodilatation (enlarging the opening of both arteries and veins) • Decreased aldosterone secretion, which leads to less sodium and water
reabsorption and less potassium excretion. The net effect is a reduced blood pressure (Saseen et al, 2011).
ACE Inhibitors Dosing Dosing:
• Most agents can be dosed once daily, although certain agents may require twice daily dosing.
• Because of the risk for hypotension (seen most common after the first few doses), initial dose should be reduced by 50% in those patients who are taking a diuretic, or are volume depleted, or in very elderly (Saseen et al, 2011).
• All ACEIs require dosage adjustment for renal impairment, except for fosinopril. • Note! See individual agents for specific dosages.
Generic availability: All ACE inhibitors are available as generic products (Micromedex®, 2012). ACE Inhibitors: Black Box Warning ACE inhibitors are contraindicated in pregnancy:
• [U.S. Boxed Warning]: Based on human data, ACE inhibitors can cause injury and death to the developing fetus when used in the second and third trimesters. ACE inhibitors should be discontinued as soon as possible once pregnancy is detected.
• ACE inhibitors have been associated with congenital malformations and fetopathy.
• Females of child‐bearing potential should be counseled on appropriate birth‐control measures before initiation of ACE inhibitor.
(Saseen et al, 2011)
Side Effects of ACE Inhibitors: Angioedema Angioedema is the rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is a rare (<1%) but serious side effect of ACE Inhibitors. It can occur at any time during treatment, but most often after the first dose. Patients should be made aware of symptoms before initiating treatment. Symptoms include:
• Lip and tongue swelling • Difficulty breathing • Edema around the larynx
African Americans and smokers are at higher risk. Contraindication: ACE inhibitors are contraindicated in any patient who has a history of angioedema, even if not related to previous treatment with an ACE inhibitor. Note! An ARB can be used in patients with a history of ACE inhibitor angioedema due to low cross‐reactivity (Saseen et al, 2011). Side Effects of ACE Inhibitors: Persistent Dry Cough Persistent dry, unproductive cough
• Another potential side effect of ACE Inhibitors is a persistent dry and unproductive cough, and is seen in up to 20% of patients. It usually develops during the first few months of treatment, and results from an increase in bradykinin. ACE itself is the enzyme normally responsible for bradykinin degradation (Saseen et al, 2011).
• The ACEI cough does not require a change in therapy. It should be considered if patients find it bothersome and if it affects compliance.
• Upon discontinuation of the ACEI, the cough should resolve in 1‐4 weeks. Other causes for cough should be excluded anytime a patient develops a cough while receiving an ACEI.
Angioedema may require urgent treatment with
epinephrine, steroids, antihistamines, and/or
intubation.
Side Effects of ACE Inhibitors: Hyperkalemia Elevated potassium (hyperkalemia) may occur with the use of ACE Inhibitors, due to decreased aldosterone levels. Risk factors for hyperkalemia can include:
• Chronic kidney disease • Diabetes mellitus • Concomitant drug therapy with potassium supplements, potassium‐sparing
diuretics, ARBs, or direct renin inhibitors Potassium levels should be monitored within 4 weeks of initiating treatment or increasing the dose and should be monitored extremely close in those patients with risk factors for hyperkalemia (Saseen et al, 2011). Side Effects of ACE Inhibitors: Declined Renal Function Small increases in serum creatinine (<1mg/dL) and decreases in glomerular filtration rate are expected to occur, because angiotensin II normally vasoconstricts the efferent arteriole of the kidney. If kidney function greatly worsens, the ACE inhibitor should be stopped or the dose reduced. Acute kidney failure occurs in <1% of patients; those with preexisting renal disease are at increased risk. Patients with bilateral renal artery stenosis or unilateral renal artery stenosis of a single functioning kidney are at increased risk due to their reliance on angiotensin II to maintain kidney function. ACE inhibitors should generally not be used in these patients (Saseen et al, 2011).
Note: Concomitant use with NSAIDs may cause a further decline in renal
function; NSAIDS also can elevate BP and decrease the effectiveness of ACE
inhibitors.
ACE Inhibitors: Side Effects & Monitoring Common side effects of ACE Inhibitors may include:
• Hypotension • Syncope • Dizziness • Headache • Hyperkalemia • Cough • Abnormal renal function tests
Severe side effects may include:
• Hypotension • Angioedema • Agranulocytosis • Neutropenia • Cholestatic jaundice, • Acute kidney failure
Monitoring should include observation and documentation of:
• Blood pressure • Renal and liver function • Serum potassium • WBC in those with renal disease and collagen vascular disease
Benazepril (Lotensin®) Pharmacology: prodrug; carboxyl ligand Dosing:
• Initial: 10mg daily • Usual range: 20‐80mg/day divided daily /BID • Renal impairment (CrCl<30 mL/min): Initial 5mg/day, maximum 40mg/day • Dialysis: Moderately dialyzable; administer post‐dialysis or administer
supplemental dose of 25‐35% Clinical pearl: If patient’s BPs are high at end of daily dosing interval, consider using BID dosing Micromedex Drugdex, 2012
Captopril (Capoten®) Pharmacology: sulfhydryl ligand, short duration of action Dosing:
• Initial: 12.5‐25mg BID‐TID • Usual range: 25‐100mg BID‐TID, maximum 150mg TID • Renal impairment:
o CrCl 10‐50 mL/min: Administer 75% of normal dose o CrCl <10 mL/min: Administer 50% of normal dose
• Dialysis: Moderately dialyzable; administer post‐dialysis or administer supplemental dose of 25‐35%
Clinical pearls
• The dose should be titrated upwards by 12.5‐25mg per dose at 1‐2 week intervals.
• The drug should be taken 1 hour before meals as food decreases its bioavailability.
• This drug can be compounded into an oral solution. • There is an increased risk of rash/hypersensitivity with other ACE inhibitors due
to sulfhydryl group; this risk is increased when taken with allopurinol. • A rare incidence of neutropenia exists, especially in those with renal impairment
and collagen vascular disease.
Enalapril (Vasotec®) Pharmacology: Enalapril is a prodrug that must be converted in the liver to be active. Dosing:
• Initial: 2.5‐5mg daily • Usual range: 2.5‐40mg/day divided daily /BID • Renal impairment (CrCl<30mL/min): Initial 2.5mg/day • Dialysis: Moderately dialyzable; administer 2.5mg on dialysis days & normal dose
based on BP on non‐dialysis days Clinical pearls:
• If a patient’s BP is high at end of daily dosing interval, consider using BID dosing. • Rifampin may result in decreased effectiveness of enalapril. • This drug is available for injection, useful for hypertensive urgency or emergency. • Can be compounded into oral solution for patients who cannot swallow, or have
an NG tube. Fosinopril (Monopril®) Pharmacology: prodrug, longer‐acting than enalapril Dosing:
• Initial: 10mg daily • Usual range: 20‐40mg daily, maximum 80mg/day • Hepatic impairment: A decreased initial dose is recommended, then monitor
closely and dose according to blood pressure response and tolerability. Clinical pearls:
• Does not require dosage adjustment for renal impairment. • There is a potential assay interference when checking digoxin levels. This may
result in false low digoxin levels.
Lisinopril (Prinivil®, Zestril®) Pharmacology: carboxyl ligand Dosing:
• Initial: 10mg daily • Usual range: 10‐40mg daily • Renal impairment (CrCl<30mL/min or creatinine >3mg/dL): Initial 5mg daily • Dialysis: Initial 2.5mg daily
Clinical pearl: If patient’s BP is high at end of dosing interval, consider increasing the dose to extend the duration of effect. Moexipril (Univasc®) Pharmacology: Moexipril is a prodrug, thus it needs to be converted in the body first in order to be active. Dosing:
• Initial: 7.5mg daily • Usual range: 7.5‐30mg/day divided daily /BID, maximum 60mg/day • Renal impairment (CrCl<40mL/min): Initial 3.75mg daily, maximum 15mg/day • Hepatic impairment: Consider decreasing dose
Clinical pearls:
• If patient’s BP is high at end of daily dosing interval, consider using BID dosing. • Should be taken 1 hour before meals as food decreases its bioavailability. • While these ACEIs & others may be said to be less likely to cause a cough, there
is no compelling evidence for this.
Perindopril (Aceon®) Pharmacology: prodrug; carboxyl ligand Dosing:
• Initial: 4mg daily • Usual range: 4‐8mg/day divided daily /BID, maximum 16mg/day • Renal impairment:
o CrCl>30mL/min: Initial 2mg daily, maximum 8mg/day o CrCl<30mL/min: No data on safety/efficacy
Clinical pearl: Titrate dose upwards at 1‐2 week intervals Quinapril (Accupril®) Pharmacology: prodrug, carboxyl ligand Dosing:
• Initial: 10‐20mg daily • Usual range: 10‐80mg/day divided daily /BID • Renal impairment:
o CrCl 30‐60mL/min: Initial 5mg daily o CrCl<30mL/min: Initial 2.5mg daily
Clinical pearls:
• If patient’s BP is high at end of daily dosing interval, consider using BID dosing. • Titrate dose upwards at intervals of at least 2 weeks. • Quinapril may reduce the absorption of tetracyclines.
Ramipril (Altace) Pharmacology: Ramipril is also a prodrug that must be converted / activated first. Dosing:
• Initial: 2.5‐5mg daily • Usual range: 2.5‐20mg/day divided daily /BID, maximum 20mg/day • Renal impairment (CrCl<40mL/min): administer 25% of the normal dose
Clinical pearls:
• If patient’s BP is high at end of daily dosing interval, consider using BID dosing (Allen, 2002).
• Available in capsule form; contents of capsule may be mixed with water, apple juice, or applesauce.
• Ramipril is one of most long‐acting ACEIs. Trandolapril (Mavik®) Pharmacology: Also a prodrug that is long‐acting Dosing:
• Initial: 1mg daily, 2mg daily in African Americans • Usual range: 2‐4mg daily • Renal impairment (CrCl<30mL/min): Initial dose is 0.5mg daily • Hepatic impairment (cirrhosis): Initial dose is 0.5mg daily
Clinical pearls:
• Titrate dose upwards at intervals of at least 1 week • Consider BID dosing if BP is uncontrolled at 4mg daily
Angiotensin Receptor Blockers: ARBs Mechanism of action: ARBs directly block angiotensin II AT1 receptors resulting in:
• Vasodilatation (leading to decreased blood pressure) • Decreased aldosterone secretion, which leads to:
o Less sodium and water reabsorption o Less potassium excretion o Lower blood pressure
Note! ARBs do not block degradation of bradykinin, unlike ACEIs which increase bradykinin. Thus, the likelihood of drug‐induced cough is minimal (Saseen et al, 2011). ARBs: Dosing Dosing:
• Most agents can be dosed once daily, although certain agents may require twice daily dosing.
• Consider lower initial doses (~50% normal dose) for volume‐depleted (dehydrated) patients.
• There are no published, empiric dosage adjustments for patients with renal impairment, although caution must be used and serum creatinine monitored.
• Only losartan requires a dosage adjustment for hepatic impairment, but caution may need to be used with other ARBs in liver failure.
ARBs: Administration & Generic Availability Administration: All agents can be taken without regards to meals. Generic Availability: Only losartan and eprosartan are available as generic products at this time.
ARBs: Black Box Warning and Precautions Refer to ACE inhibitor slides for information on the following as information is applicable to both:
• [U.S. Boxed Warning]: Pregnancy • Precautions:
o Hyperkalemia o Declined renal function
ARBs: Side Effects & Monitoring Side effects:
• Common side effects of ARBs include dizziness, hypotension, fatigue, diarrhea, abdominal pain, and abnormal renal function tests
• Rare, but potentially severe side effects include hyperkalemia, hypotension, renal failure, and neutropenia.
• Much less likely than ACE Inhibitors to cause cough and angioedema. Monitoring:
• Patients receiving ARBs should be monitored for blood pressure, changes in kidney and liver function, and an increase in serum potassium.
Azilsartan (Edarbi®) Dosing: Initial dose is 80mg daily and usually does not require titrating unless there is a clinical indication. Clinical pearls:
• Available in both 40mg and 80mg tablets. • Concurrent use with lithium may result in increased lithium levels (Lexi‐Drugs,
2012).
Candesartan (Atacand®) Dosing:
• Initial: 16mg daily • Usual range: 8‐32mg/day divided daily /BID, maximum: 32mg/day
Clinical pearl:
• If patient’s BP is high at end of daily dosing interval, consider using BID dosing Eprosartan (Teveten®) Dosing:
• Initial: 600mg daily • Usual range: 400‐800mg/day divided daily /BID • Renal impairment: Maximum 600mg/day
Clinical pearls:
• If patient’s BP is high at end of daily dosing interval, consider using BID dosing. • Recently available in a generic formulation.
Irbesartan (Avapro®) Dosing:
• Initial: 150mg daily • Usual range: 150‐300mg daily
Clinical pearls: • Available in 3 different strengths: 75mg, 150mg and 300mg tablets • Also FDA approved to treat diabetic nephropathy in patients with Type 2
diabetes
Losartan (Cozaar®) Dosing:
• Initial: 50mg daily • Usual range: 25‐100mg/day divided daily /BID • Hepatic impairment: Initial: 25mg daily
Clinical pearl:
• If patient’s BP is high at end of daily dosing interval, consider using BID dosing. Olmesartan (Benicar®) Dosing:
• Initial: 20mg daily • Usual range: 20‐40mg daily
Clinical pearl:
• Titrate dose upwards to 40mg daily only if response to 20mg daily is inadequate after 2 weeks
Telmisartan (Micardis®) Dosing:
• Initial: 40mg daily • Usual range: 20‐80mg daily
Clinical pearls:
• Available in 20mg, 40mg, and 80mg tablets • This drug may also decrease lithium clearance, which may result in increased
lithium levels (Lexi‐Drugs 2012)
Valsartan (Diovan®) Dosing:
• Initial: 80‐160mg daily • Usual range: 80‐320mg daily, maximum 320mg/day
Clinical pearls:
• Different strengths available make this drug easier to titrate up or down. Tablets available include 40mg, 80mg, 160mg and 320mg.
• Valsartan is also FDA‐approved for heart failure treatment. Direct Renin Inhibitor: Aliskiren (Tekturna®) Aliskiren is the first and only direct renin inhibitor available in the US, and is FDA‐approved for treatment of hypertension. This drug works by directly inhibiting renin; thus, it inhibits the conversion of angiotensinogen to angiotensin I. Unlike ACEIs & ARBs which indirectly increases blood levels of renin, aliskiren reduces renin, as well as angiotensin I, and angiotensin II by directly inhibiting renin release. These reductions occur whether or not aliskiren is used as monotherapy or concomitantly with other antihypertensive agents.
Although this drug is classified as a Category C drug in 1st trimester and Category D in 2nd trimester pregnancy, it is considered contraindicated in
pregnancy.
Absorbtion of Aliskiren (Tekturna®) High fat‐content food decreases the extent of total drug absorption significantly, thus it should not be given with fatty meals. Side effects include:
• Rash • Diarrhea • Increased CK enzyme • Cough (1.1%) • Angioedema (0.06%) • Hypotension
Contraindications of Aliskiren (Tekturna®) The contraindications are similar to ACEIs & ARBs, and include a history of hereditary, idiopathic, or ACEI‐induced angioedema, bilateral renal artery stenosis, pregnancy, and renal failure. The dose is 150 mg once daily; and may be increased to 300 mg/day based on clinical response. Aliskiren is available in both 150mg and 300mg tablets. RAAS Drugs + Diuretic Combinations
Combination Brand Name Available Doses Benazepril/HCTZ* Lotensin® 5/6.25, 10/12.5, 20/12.5, 20/25 Captopril/HCTZ Capozide® 25/15, 25/25, 50/15, 50/25 Enalapril/HCTZ Vaseretic® 5/12.5, 10/25 Fosinopril/HCTZ Monopril‐HCT® 10/12.5, 20/12.5 Lisinopril/HCTZ Prinzide®, Zestoretic® 10/12.5, 20/12.5, 20/25 Moexipril/HCTZ Uniretic® 7.5/12.5, 15/25 Quinapril/HCTZ Accuretic® 10/12.5, 20/12.5, 20/25
*hydrocholorothiazide
ARB/HCTZ
Combination Brand Name Available Doses Candesartan/HCTZ Atacand HCT® 600/12.5, 600/25
Eprosartan/HCTZ Teveten HCT® 16/12.5, 32/12.5 Irbesartan/HCTZ Avalide® 75/12.5, 150/12.5, 300/12.5 Losartan/HCTZ Hyzaar® 50/12.5, 100/25
Olmesartan/HCTZ Benicar HCT® 20/12.5, 40/12.5, 40/25 Telmisartan/HCTZ Micardis HCT® 40/12.5, 80/12.5 Valsartan/HCTZ Diovan HCT® 80/12.5, 160/12.5
Renin Inhibitor/HCTZ
Combination Brand Name Available Doses Aliskiren/HCTZ Tekturna HCT® 150/12.5, 150/25, 300/12.5, 300/25
Case Study: Introduction BB is a 39 Year old female with a history of hypertension who states her BPs at home have been “running a bit high.” BB has some complaints of mild fluid retention (puffy eyes & hands), and her BP is 176/98. On review of her medical history, it was noted that her blood pressure was previously well‐controlled. On examination, BB’s pulse is 80bpm, and her respiratory rate is 28.
Case Study: Medications & History Medications:
• HCTZ 25mg daily, no signs or symptoms of heart failure • Ibuprofen 400mg PRN for headache.
Past medical & social history: Hypertension, tension‐type headaches, BB is newly sexually‐active with one male partner and has regular periods. She drinks 3‐4 beers daily, exercises on the weekends, and smokes 1 pack of cigarettes daily and denies recreational drug use. She uses no natural products or supplements. Case Study: Assessing Lack of BP Control As the intake nurse, what might you consider or do to help explain BB’s lack of adequate blood pressure control?
1. Verify BB’s adherence to hydrochlorothiazide. 2. Repeat BB’s blood pressure. 3. Ask if she recently smoked a cigarette. 4. Inquire about how much and how often she is taking ibuprofen. 5. Ask about BB’s sodium (salt intake) and caloric intake. 6. Ask if there is any change that she may be, or may become pregnant.
Case Study: Counseling How might you counsel BB to improve her blood pressure control?
1. After probing for her tension headaches, it is advisable for BB to discontinue ibuprofen and change to acetaminophen since ibuprofen can worsen BP control. The ibuprofen is also a likely reason for her puffy eyes and hands.
2. Increase exercise and/or activity level as tolerated to a more regular, sustained, and aerobic form of exercise.
3. After taking a diet history, recommend reduction of intake of sodium (salt), saturated fats, sugars, red meat, and eat more fruits and vegetables, if necessary.
4. Assess BB’s readiness for change with respect to smoking cessation and alcohol intake reduction.
Case Study: Selection of Drug & Education Would an ACEI or ARB be an appropriate choice for BB to improve her blood pressure control and what general counsel should she receive?
1. Both drug classes are contraindicated in pregnancy, so this may not be the best choice if BB is not using birth control. However, if she is unable to conceive (e.g., post‐tubal ligation, using reliable birth control, etc.), then an ACEI would be acceptable.
2. If BB receives an ACEI, a once daily generic ACEI would be preferred (e.g., ramipril, lisinopril, etc.) and added onto her diuretic (hydrochlorothiazide).
3. Clinical Pearl: Giving a single drug, combination product that is generically available is a cost‐effective strategy (e.g., lisinopril plus HCTZ).
4. BB should be cautioned about the development of a dry cough and angioedema (swelling of the lips, tongue, and/or face).
Conclusion The nurse plays a significant role in managing and educating the hypertensive patient. By exploring the basic tenants of the renin‐angiotensin‐aldosterone system (RAAS), a better understanding of the pharmacology of antihypertensive agents can be achieved. Knowledge of drug classes, modes of action, and possible side effects can assist the nurse in anticipating potential complications and educating the hypertensive patient on following a healthy lifestyle to minimize the risk of complications of high blood pressure.
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References ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. (2002). 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, 288(23), 2981‐2997. Appel, L.J., Brands, M.W., Daniels, S.R., Karanja, N., Elmer, P.J., Sacks, F.M. (2006) Dietary Approaches to Prevent and Treat Hypertension: A Scientific Statement from the American Heart Association. Hypertension, 47, 296‐308. Bui, Q. (2010). Cochrane for Clinicians: Putting Evidence Into Practice. First‐Line Treatment for Hypertension. American Family Physician, 81(11), 1333‐35. Chobanian, A.V., Bakris, G.L., Black, H.R., Cushman, W.C., Green, L.A., Izzo, J.L, et al. and the National High Blood Pressure Education Program Coordinating Committee. (2003). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA, May 21; 289, 2560‐72. Hulisz, D., Lagzdins, M. (2008). Drug‐Induced Hypertension. US Pharmacist, 33(9), HS11‐HS20. Lexi‐Comp, Lexi‐Drugs Online®. Retrieved February 18, 2010, retrieved from http://online.lexi.com/ Hudson, OH: Lexi‐Comp, Inc. Micromedex® Healthcare Drugdex. Retrieved February 18, 2012 from http://www.thomsonhc.com Greenwood Village, CO: Thomson Healthcare. National Heart, Lung & Blood Institute (NHLBI). (2006).Your Guide To Lowering Your Blood Pressure With DASH. Retrieved March 28, 2012 from: http://www.nhlbi.nih.gov/health/public/heart/hbp/dash/new_dash.pdf Ong, K.L., Cheung, B.M.Y., Man, Y.B., Lau, C.P., Lam, K.S.L. (2007). Prevalence, Awareness, Treatment, and Control of Hypertension Among United States Adults 1999–2004. Hypertension, 9, 69‐75. Roger, V.L., Go, A.S., Lloyd‐Jones, D.M., Benjamin, E.J., Berry, J.D., Borden, W.B.; et al., (2012). AHA Statistical Update Heart Disease and Stroke Statistics—2012 Update. A Report from the American Heart Association. Circulation, 125, e2‐e220. Rosendorff, C., Black, H.R., Cannon, C.P., et al. (2007). Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation, 115, 2761–2788. Sarafidis, P.A., Bakris, G.L. (2008). State of Hypertension Management in the United States: Confluence of Risk Factors and the Prevalence of Resistant Hypertension. J Clin Hypertens, 10(2), 130‐139. Saseen J.J., Maclaughlin E.J. (2011). Chapter 19. Hypertension. In J.T. DiPiro, R.L. Talbert, G.C. Yee, G.R. Matzke, B.G. Wells, L.M. Posey (Eds), Pharmacotherapy: A Pathophysiologic Approach, 8e. Retrieved February 21, 2012. The National Heart, Lung & Blood Institute (2004). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure – Reference Card. Retrieved from: http://www.nhlbi.nih.gov/guidelines/hypertension/phycard.pdf
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