ANTIHYPERTENSIVE MEDICATIONS

Dana Bartlett, RN, BSN, MSN, MA, CSPI

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevier, Lippincott, and Thieme. He has written widely on the subject of toxicology and was a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Rocky Mountain Poison Control Center.

ABSTRACT

The use of antihypertensive medications is a well accepted treatment for heart disease and stroke, poor function of the kidney and peripheral vascular systems. The medications help to lower blood pressure and to enhance patient health outcomes by slowing cardiovascular disease outcomes. The classes of drugs used to treat hypertension and cardiovascular disease, and specifically the effectiveness of antihypertensive medication in certain medical conditions and populations, and in the setting of certain lifestyle practices, is discussed.

1

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 2.5 hours.

Statement of Learning Need

Antihypertensive medications are abundant, often are used in combination treatment, and health clinicians have a wide variety of medications to currently select from when treating a cardiovascular and hypertensive condition. The newer and older antihypertensive medications differ slightly in chemical structure but produce nearly identical effects. Clinicians are better able to individualize patient use of a drug to better control elevated blood pressure, and to avoid medication side effects. In addition, treatment of co- occurring conditions is possible, such as hypertension and congestive heart failure.

2

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Course Purpose

To inform health clinicians of the indications, uses, contraindications and potential side effects of antihypertensive medication.

Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, RN, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – All have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

3

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

1. Which of the following act as competitive antagonists that reduce the release of norepinephrine and lower blood pressure?

a. Alpha1 blockers b. Vasodilators c. Alpha2 agonists d. Non-steroidal anti-inflammatory drugs (NSAIDs)

2. Benign prostatic hyperplasia may be treated with the following medication(s):

a. Prazosin b. Metolazone c. Doxazosin, terazosin d. Guanfacine, methyldopa

3. For doxazosin, the 24-hour maximum dose is ___ mg.

a. 10 b. 8 c. 25 d. 16

4. The maximum dose of prazosin is 20 mg a day in divided doses, although some patients may need and tolerate up to ___ mg a day.

a. 40 b. 50 c. 25 d. 30

5. Terazosin should begin with ___ mg a day, given at bedtime.

a. 8 b. 4 c. 7 d. 1

4

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

Introduction

Antihypertensive medications are used to treat heart disease and stroke, as well as comorbid conditions of the kidneys and peripheral vascular system. The use of an antihypertensive medication lowers blood pressure and improves health outcomes of patients by slowing disease outcomes caused by cardiovascular morbidity. The classes of drugs used to treat hypertension and cardiovascular disease is discussed in the following sections. Additionally, the effectiveness of antihypertensive medication in certain medical conditions and populations, and in the setting of certain lifestyle practices, is discussed.

Alpha1-adrenergic Blocking Medication

Alpha1‐adrenergic‐blocking drugs help to reduce blood pressure. When combined with most drug classes, they not only lower the blood pressure but also improve plasma lipid profiles. They are also used for other conditions as well, such as anxiety disorders and benign prostatic hypertrophy. There are significant side effects and patients prescribed an alpha1-adrenergic blocking

(alpha1 blocker, for short) should be closely monitored.

Category

● Alpha1 blocker

● Antihypertensive

Uses

● Benign prostatic hyperplasia (Doxazosin, terazosin)

● Hypertension (Doxazosin, prazosin, terazosin)

5

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Mechanism of Action

The alpha1 blockers act as competitive antagonists at postsynaptic alpha1 adrenergic receptors, reducing the release of norepinephrine. This decreases systemic vascular resistance (SVR) and lowers blood pressure.

Available Forms

● Doxazosin: 1 mg, 2 mg, 4, and 8 mg tablets, generic and brand name Cardura. Extended release 24-hour tablet: Cardura XL, 4 mg and 8 mg

● Prazosin: 1 mg, 2 mg, and 5 mg capsules, generic and brand name Minipress.

● Terazosin: Generic capsules, 1 mg, 2 mg, 5 mg, and 10 mg.

Dosing

Doxazosin:

Begin with 1 mg a day, titrate by doubling the daily dose; the 24-hour maximum dose is 16 mg. For Cardura XL, the starting dose is 4 mg. If needed after 3-4 weeks the dose can be increased to a maximum of 8 mg.1

Prazosin:

The initial dose should be 1 mg two-three times a day. The dosage can be gradually increased to a maximum of 20 mg a day in divided doses, although some patients may need and can tolerate 40 mg a day. Some patients only require twice a day dosing.2

Terazosin:

Begin with 1 mg a day, given at bedtime. Slowly increase the dose until the desired blood pressure level has been reached; the maximum 24-hour dose

6

nursece4less.com nursece4less.com nursece4less.com nursece4less.com is 20 mg. If the patient’s blood pressure is significantly decreased two to four hours after a dose, the total daily amount can be divided into two doses.3

Dosing Adjustments: Geriatric Patients

Doxazosin:

There are no recommendations about specific doses of doxazosin that should be used to treat geriatric patients. However, the prescribing information does note that for extended release Cardura the incidence of hypotension (a common adverse effect of the drug) appears to be related to age and is more prevalent in people aged 70 and older.1

Prazosin:

Use the adult dosing recommendations for geriatric patients.

Terazosin:

There are no recommendations about specific doses of terazosin that should be used to treat geriatric patients. However, the prescribing information states that terazosin was listed in the 2015 Beers Criteria as a medication that could be potentially harmful in patients 65 years and older because of the risk for orthostatic hypotension.3

The Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, commonly called the Beers Criteria, is a list produced by the American Geriatrics Society. The Beers Criteria (named after one of its founders, Dr. Mark Beers) identifies medications that should be avoided in older adults or used with caution and close monitoring because of the risk of harmful adverse effects.4

7

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Orthostatic hypotension is defined as an abnormal decrease in blood pressure after moving from a lying to a standing position. After five minutes of being supine blood pressure is measured after the patient has been standing quietly for two to five minutes. At that point orthostatic hypotension is present if the systolic blood pressure has decreased ≥ 20 mmHg, the diastolic blood pressure has decrease ≥10 mm Hg, or both.5 Elderly patients are more likely to have orthostatic hypotension, probably because of decreased baroreceptor sensitivity.5

Dosing Adjustments: Hepatic Impairment

Doxazosin:

The prescribing information for Cardura states that as the drug is extensively metabolized by the liver, Cardura could be problematic for patients who have hepatic impairment; Cardura should not be used for patients who have severe hepatic impairment (Child-Pugh class C), and Cardura should be used cautiously for patients who have mild or moderate hepatic impairment (Child-Pugh call A or B) and these patients should have their blood pressure monitored. The Child-Pugh classification system measures albumin, bilirubin, and prothrombin time and assesses the severity of ascites and hepatic encephalopathy, assigns a point score to each, and the total score can be used to determine the one-year survival rate in patients with cirrhosis. It is often used to categorize a patient’s level of hepatic impairment.

Prazosin:

There are no recommendations for specific doses of prazosin that are appropriate and/or needed if a patient has hepatic impairment.

Terazosin:

8

nursece4less.com nursece4less.com nursece4less.com nursece4less.com There are no recommendations for specific doses of terazosin that are appropriate and/or needed if a patient has hepatic impairment.

Dosing Adjustment: Renal Impairment

There are no recommendations for specific doses of doxazosin, prazosin, and terazosin that are appropriate and/or needed if a patient has renal impairment.

Contraindications

Hypersensitivity to the drug or any components of the product. Also, hypersensitivity to any of the other quinazolines is contraindicated; for example, a patient who is hypersensitive to doxazosin should not take prazosin or terazosin.

Doxazosin:

Extended release doxazosin should not be used to treat hypertension,and it should not be taken by women.

Warnings

These warnings apply to doxazosin, prazosin, and terazosin. Warnings that are specific to each drug will be discussed separately. Warnings that apply to the use of these drugs for benign prostatic hypertrophy (BPH) will not be covered.

Central Nervous System:

All the alpha1 blockers can cause central nervous system (CNS) depression. Cardiovascular Disease:

9

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Doxazosin can negatively affect myocardial function, and if a patient has heart failure, angina pectoris, or has had an acute myocardial infarction in the past six months, doxazosin should be used cautiously. If a patient develops angina pectoris, he or she should discontinue taking the drug. The warnings for prazosin and terazosin state that these drugs can worsen heart failure.

Floppy Iris Syndrome:

Prescribing information for the alpha1 blockers states that intraoperative floppy iris syndrome has occurred during cataract surgery in some patients who were or had been treated with alpha1 blockers. The prescribing information also states that stopping therapy with the alpha1 blockers, before cataract surgery is likely not necessary, and that floppy iris syndrome can happen years after a patient has stopped taking an alpha1 blocker.

Orthostatic Hypotension:

The alpha1 blockers doxazosin, prazosin, and terazosin can cause orthostatic hypotension and syncope. This adverse effect usually develops shortly after taking a dose, sometimes within 30-90 minutes, but it can be delayed, as well. Increasing the dose, interruptions in taking the drug, and beginning treatment with another antihypertensive while taking an alpha1 blocker may also cause orthostatic hypotension.

Phosphodiesterase Inhibitors:

Taking one of these alpha1 blockers and a phosphodiesterase inhibitor at the same time can lower blood pressure and cause symptomatic hypotension.

Priapism:

10

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Priapism is a rare, potentially dangerous adverse effect of these alpha1 blockers.

Other:

Cardura has been associated with decreased white blood cell (WBC) count and mean neutrophil count. These effects were seen during clinical trials, the WBC and neutrophil count returned to normal after the patients stopped taking the drug, and no patients became symptomatic.

Adverse Reactions

Doxazosin:

During clinical trials using doxazosin as an antihypertensive, the following adverse reactions occurred in > 1% of the patients: Dizziness (19%), fatigue (12%), somnolence (5%), rhinitis (3%), polyuria (2%). Adverse effects that occurred in < 1% more often in patients receiving Cardura versus patients receiving placebo were edema, epistaxis, hot flushes, hypotension, and vertigo. Adverse effects reported from post-marketing use of Cardura are shown in the following table.

Cardiovascular Bradycardia Gastrointestinal Vomiting Hematologic Leukopenia, thrombocytopenia Hepatic/biliary Cholestasis, cholestatic hepatitis Immune system Allergic reaction Musculoskeletal Muscle cramps, muscle weakness Neurologic Hypoesthesia Renal Frequency, hematuria, micturition disorder, nocturia Reproductive Gynecomastia, priapism Respiratory Bronchospasm, aggravated Miscellaneous Urticaria Prazosin:

11

nursece4less.com nursece4less.com nursece4less.com nursece4less.com During clinical trials, the most common adverse effects of prazosin were dizziness (10.3%), headache (7.8%), drowsiness (7.6%), lack of energy (6.9%), weakness (6.5%), palpitations (5.3%). Adverse effects that occurred during clinical trials and post marketing use of prazosin are shown in the following tables.

Adverse effects occurring in 1%-4% of patients in clinical trials Cardiovascular Orthostatic hypotension, syncope Dermatologic Rash EENT Blurred vision, dry mouth, epistaxis, nasal congestion, reddened sclera Gastrointestinal Constipation, diarrhea, and vomiting Genitourinary Urinary frequency Respiratory Dyspnea Miscellaneous Edema

Adverse effects occurring in <1% of patients in clinical trials Cardiovascular Tachycardia Dermatologic Alopecia, lichen planus, pruritus EENT Tinnitus Gastrointestinal Abdominal discomfort/pain, pancreatitis Genitourinary Priapism, incontinence Hepatic Abnormal liver function tests Neurological Hallucinations, paresthesia Miscellaneous Arthralgia, diaphoresis, fever, positive ANA screen, worsening of narcolepsy. Lone instances of pigmentary mottling and serous retinopathy have been reported.

Adverse effects occurring in post-marketing use of prazosin Cardiovascular Angina pectoris, bradycardia, hypotension Dermatologic Urticaria EENT Eye pain Endocrine Gynecomastia Psychiatric Insomnia Vascular Vasculitis Miscellaneous Allergic reaction, asthenia, flushing malaise, pain

Terazosin:

12

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The most common adverse effects are dizziness (9% to 19%) and myasthenia (7% to 11%). Adverse effects that occurred to 1%-10% of patients are shown in the following table.

Cardiovascular Peripheral edema (1% to 6%), orthostatic hypotension (1% to 4%), palpitations (≤4%), tachycardia (≤2%), syncope (≤1%)

EENT Blurred vision (≤2%) Gastrointestinal Nausea (2% to 4%) Genitourinary Impotence (≤2%), Decreased libido (≤1%) Endocrine/metabolic Weight gain (≤1%) Musculoskeletal Limb pain (≤4%), back pain (≤2%) Neurologic Drowsiness (4% to 5%), paresthesia (≤3%), vertigo (1%)

Respiratory Nasal congestion (2% to 6%), dyspnea (2% to 3%), sinusitis (≤3%)

Adverse effects occurring in < 1% of patients during post-marketing use or from case reports are shown below.

Abdominal pain, anaphylaxis, anxiety, arthralgia, arthritis, arthropathy, atrial fibrillation, bronchitis, cardiac arrhythmia, chest pain, conjunctivitis, constipation, cough, diaphoresis, diarrhea, dyspepsia, epistaxis, facial edema, fever, flatulence, flu-like symptoms, gout, hypersensitivity reaction, insomnia, intraoperative floppy iris syndrome (IFIS), myalgia, neck pain, pharyngitis, polyuria, priapism, pruritus, rhinitis, shoulder pain, skin rash, thrombocytopenia, tinnitus, urinary incontinence, urinary tract infection, vasodilatation, visual disturbance, vomiting, and xerostomia.

Use During Breastfeeding

13

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Doxazosin:

The prescribing information for Cardura states that there is one case study that reported the presence of the drug in breast milk, but the information in this report was not enough to confirm the presence of Cardura in breast milk. There is no information on the effect of doxazosin on lactation or on nursing infants.

Prazosin:

The prescribing information for Minipress states that the drug can be excreted in small amounts in breast milk; prazosin should be used cautiously in nursing mothers.

Terazosin:

It is not known if terazosin is excreted in breast milk; the drug should be used cautiously in nursing mothers.

Use During Pregnancy

The potential of a drug to cause fetal harm has been categorized by a system developed by the Food and drug Administration (FDA). The system used five categories, A, B, C, D, and X. A drug would be considered category C if data from animal studies had shown adverse fetal effects, there were no well controlled studies in humans, and the potential benefits of the drug may outweigh the risk of its use during pregnancy: doxazosin, prazosin, and terazosin are all category C. This system has been replaced by the FDA’s Pregnancy and Lactation Labeling Rule (PLLR); information about the PLLR can be obtained at the following FDA web link: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor

14

nursece4less.com nursece4less.com nursece4less.com nursece4less.com mation/Guidances/UCM450636.pdf. The A-X system, however, is still widely used.

Doxazosin:

Doxazosin is a pregnancy risk category C drug. Animal studies have shown that doxazosin can cross the placenta; it does not cause fetal harm, but it has caused reduced fetal survival and delays in postnatal development. There is not enough human data to determine if Cardura may cause fetal harm or injury during delivery.

Hypertension during pregnancy can be harmful to the mother and the fetus, so prescribers and clinicians will have to evaluate the risks and benefits of administering Cardura to a pregnant woman.

Prazosin:

Prazosin is a pregnancy risk category C drug, and adverse effects have happened when prazosin was given to pregnant animals. Prazosin does cross the placenta. The use of prazosin during pregnancy has not caused adverse effects, but there is limited experience with the drug in this situation. The prescribing information for prazosin states that it is not known if the drug is safe to use during pregnancy, and prescribers and clinicians will have to evaluate the risks and benefits of administering prazosin to a pregnant woman.

Terazosin:

Terazosin is a pregnancy risk category C drug. Administration of terazosin to pregnant animals did not cause adverse effects. Prescribers will have to evaluate the risks and benefits of administering terazosin to a pregnant

15

nursece4less.com nursece4less.com nursece4less.com nursece4less.com woman, but the drug is not generally recommended to be used to treat hypertension in pregnant women.

Dietary Concerns

The alpha1 blockers can be taken with or without food.

Clinical Pearls: Alpha1 Blocking Medication

Drug prescribing information provides basic information like labeled uses, dosing, warnings, and adverse effects, and it provides guidelines for prescribing and/or administering. However, it can lack important details and background, and some of the information can be a bit confusing and may even seem to be somewhat contradictory. Drug prescribing information can also appear complicated and difficult to understand partly because the content is so dense.

This section on clinical pearls expands on what was covered in the above discussion of the basic pharmacology profile on alpha1 blocking medication. It includes relevant information based on the clinical observation or experience of medical experts related to the best use of a specific type and purpose of medication. These clinical pearls can be helpful in the treatment of specific clinical symptoms for which controlled data do not exist. An extensive search of the medical literature was done on alpha1 blocking medication, but some of these topics that has been published about the uses, benefits, risks, and adverse effects of alpha1 blocking medication is at times limited. If a topic covered in the basic pharmacology section is not mentioned here there is no information available or it has been adequately explained in that section.

Labeled Uses 16

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Doxazosin (the immediate release form only), prazosin, and terazosin have a labeled use for treating hypertension,1-3 but these drugs are seldom used for

6 this purpose. The current recommendations for the use of alpha1 blockers in hypertension and the background information that helps explain why these drugs are not a preferred choice for this purpose are discussed.

The Eight National Joint Committee (JNC-8) recommendations for the treatment of hypertension stated that α-blockers are “not recommended as first-line therapy because in one study initial treatment with an α-blocker resulted in worse cerebrovascular, heart failure, and combined cardiovascular outcomes than initial treatment with a diuretic.”7 The 2017 report from the American College of Cardiology on prevention, detection, evaluation, and management of high blood pressure stated that the alpha1 blockers are second-line agents, and they should only be used if blood pressure is not controlled by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) in combination with a calcium channel blocker (CCB), and a thiazide diuretic.8

A recent review (2017) on drug therapy for primary hypertension stated that the alpha1 blockers are not recommended as a monotherapy for the treatment of hypertension and particularly so if the patient has a high cardiovascular risk profile.9 An exception can be made if the patient has hypertension and benign prostatic hypertrophy.9

Alpha1 Blockers and Treatment of Hypertension

Safety and risk are the primary reasons that doxazosin, prazosin, and terazosin are considered a second-line treatment and a fourth choice for treating hypertension.8 Orthostatic hypotension is a common adverse effect of the alpha1 blockers, and orthostatic hypotension is more common in the

17

nursece4less.com nursece4less.com nursece4less.com nursece4less.com elderly, a group that is likely to be treated for hypertension. Additionally,

Mann (2017) stated that the alpha1 blockers should not be used if a patient has a high cardiovascular risk profile.9 No rationale for this recommendation was given but it would be reasonable to assume that it was concluded that doxazosin, prazosin, and terazosin could cause cardiovascular complications in this group. Given that many people who have hypertension do have a high cardiovascular risk profile, for example, concurrent pathologies like atherosclerosis, coronary artery disease, congestive heart failure, and left ventricular hypertrophy, it would seem prudent to avoid using alpha1 blockers in most hypertensive patients.

The alpha1 blockers can exacerbate heart failure. In 2016, the American Heart Association (AHA) published a scientific statement about drugs that

6 may cause or exacerbate heart failure, and the alpha1 blockers were mentioned as drugs that can do so. The evidence for this effect (and the rationale for the AHA’s statement and the JNC-8 recommendation) is primarily based on the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial. The ALLHAT trial used chlorthalidone or doxazosin to treat patients who had hypertension, and a secondary outcome of the trial was to determine the effectiveness of these medications at preventing cardiovascular disease (CVD), including heart failure.10 Patients who had been receiving doxazosin had an 80% higher risk for heart failure, as well as a significantly higher risk for other types of CVD disease.

There is research that has concluded that doxazosin does not exacerbate

11,12 heart failure, but the JNC-8 and the AHA both advise that alpha1 blockers exacerbate heart failure. Mechanism of Action

18

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Adrenergic receptors are part of the sympathetic nervous system. They are activated by the catecholamines epinephrine and norepinephrine, and there are alpha (α) and beta (β) receptors, which are further divided into α1 and α2 and β1 and β2 receptors. The α2 receptors are in presynaptic adrenergic and cholinergic nerve terminal and in the gastrointestinal tract. Stimulation of the α2 inhibits adenyl cyclase, decreasing the formation of cyclic adenosine monophosphate (cAMP), reducing the release of norepinephrine and thus producing an inhibitory effect.

The alpha1 adrenergic receptors are in the vascular smooth muscle in the skin, skeletal muscle, in sphincters in the gastrointestinal tract and the bladder, and in the iris. Stimulation of these receptors causes these tissues to constrict and in the vascular bed this increases blood pressure. Doxazosin, prazosin, and terazosin act as competitive antagonists at postsynaptic alpha1 adrenergic receptors, and this receptor blockade decreases systemic vascular resistance (SVR) and lowers blood pressure. Systemic vascular resistance is the resistance to blood flow that is created by the systemic vasculature, aside from the pulmonary vessels.

Dosing Adjustments: Geriatric Patients

The prescribing information states that terazosin was listed in the 2015 Beers Criteria as a medication that could be potentially harmful in patients 65 years and older because of the risk for orthostatic hypotension. Orthostatic hypotension is defined as an abnormal decrease in blood pressure after moving from a lying to a standing position. For most people, positional decrease in blood pressure is expected, as 0.5-1 liter of blood can pool in the lower extremities when someone moves from lying to standing. When this happens, the baroreceptor reflex increases sympathetic outflow, catecholamines bind to the alpha1 receptors, and the resulting

19

nursece4less.com nursece4less.com nursece4less.com nursece4less.com vasoconstriction increases SVR so that any change in blood pressure that occurs when changing positions is minimal and can be tolerated.

The alpha1 blockers interfere with this compensatory mechanism, and orthostatic hypotension is a common adverse effect of these drugs. Elderly patients may have decreased baroreceptor sensitivity,5 so doxazosin, prazosin, and terazosin should be used cautiously in this population.

Dosing Adjustments: Hepatic Impairment

Doxazosin:

The prescribing information for Cardura states: 1) the drug is extensively metabolized by the liver and hepatic impairment could increase exposure to the drug, 2) Cardura should not be used for patients who have severe hepatic impairment (Child-Pugh class C), and 3) Cardura should be used cautiously for patients who have mild or moderate hepatic impairment (Child-Pugh class A or B) and these patients should have their blood pressure closely monitored. One article was located that discussed hepatic impairment and doxazosin, a small study of 24 subjects that found an increased exposure to the drug in 12 patients with hepatic impairment/stable alcoholic cirrhosis.13 No articles were found that discussed hepatic impairment and its effect on prazosin and terazosin.

Warnings

Floppy Iris Syndrome:

Prescribing information for the alpha1 blockers states intraoperative floppy iris syndrome has occurred during cataract surgery in some patients who were or had been treated with alpha1 blockers. It is also stated that stopping

20

nursece4less.com nursece4less.com nursece4less.com nursece4less.com therapy with the alpha1 blockers before cataract surgery is likely not necessary.

Floppy iris syndrome is an intraoperative complication of cataract surgery. It is characterized by intraoperative pupillary constriction, a flaccid iris that billows through the surgical incision, and prolapse of the iris. The first description of floppy iris syndrome was by Chang and Campbell in 2005,14 and the authors concluded that alpha1 blockade caused relaxation of the dilator muscle of the iris, and this was the mechanism by which these drugs caused floppy iris syndrome.

Floppy iris syndrome occurs in approximately 2%-34.1% of all cataract surgeries,15-17 and it can cause significant intraoperative and postoperative complications. The alpha1 blockers doxazosin, prazosin, and terazosin have all been associated with intraoperative floppy iris syndrome,18,19 but it is not clear how much these drugs increase the risk for this complication. According to Jacobs (2017), surgeons usually don’t recommend that the patients stop taking alpha1 blockers before cataract surgery as this approach hasn’t been shown to prevent or decrease the severity of floppy iris syndrome.15

Phosphodiesterase Inhibitors:

Concurrent use of doxazosin, prazosin, or terazosin and a phosphodiesterase inhibitor can lower blood pressure and cause symptomatic hypotension. The phosphodiesterase type 5 (PDE-5) inhibitors avanafil, sildenafil, tadalafil, and vardenafil block the action of the PDE-5 enzyme. The PDE-5 enzyme inhibits the activity of the second messenger cyclic guanosine monophosphate (cGMP) and increased intracellular levels of cGMP causes vasodilation and possibly, hypotension.

21

nursece4less.com nursece4less.com nursece4less.com nursece4less.com There is abundant and conclusive evidence that concurrent use of doxazosin, prazosin, or terazosin and a PDE-5 inhibitor can cause hypotension,20-22 and the prescribing information for avanafil, sildenafil, tadalafil, and vardenafil affirm this risk. The prescribing information for these drugs states that patients taking an alpha1 blocker like doxazosin should be on a stable dose before beginning therapy with a PDE-5 inhibitor, the PDE-5 should be started at the lowest dose, and titration of the dose of either drug should be done slowly and cautiously.

Priapism:

Priapism is a rare, potentially dangerous adverse effect of these alpha1 blockers. The prescribing information for doxazosin, prazosin, and terazosin list priapism as an adverse effect that has been reported during post- marketing use and in case reports. There is little published information on alpha1 blocker-induced priapism - less than 20 articles about the topic (primarily case reports) were found in a literature search - and there is no data on the specific level of level of risk for this adverse effect.

There are adrenergic receptors in the arterial vessels of the penis, and blockade of the alpha receptors prevents detumescence and may cause

23 priapism. Priapism can happen after the first dose of an alpha1 blocker or after several weeks of taking the drug.23

Decreased WBC Count: Doxazosin

Cardura has been associated with decreased white blood cell (WBC) count and mean neutrophil count. These effects were seen during clinical trials, the WBC and neutrophil count returned to normal after the patients stopped taking the drug, and no patients became symptomatic. Use During Breastfeeding 22

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Doxazosin:

The prescribing information for Cardura notes that one case study reported the presence of the drug in breast milk, but the information in this report was not enough to confirm the presence of Cardura in breast milk. There prescribing information for Cardura also states that there is no information on doxazosin and lactation or on nursing infants.

The report mentioned in the Cardura prescribing information involved a 37- year-old woman who had taken 4 mg a day of doxazosin for two days.24 Doxazosin was detected in her breast milk, but the authors concluded that given these concentrations of the drug, a nursing infant would be exposed to an estimated relative infant dose of 0.06%-0.09%, levels that are well below the 10% cutoff point that is considered acceptable for a nursing infant. Versmissen, et al., (2016) reported on a 35-year-old woman who had been diagnosed as having a pheochromocytoma and had been taking doxazosin 4 mg a day.25 The patient delivered a healthy baby; placental transfer of doxazosin was confirmed and a 30 hour after the last dose was taken, doxazosin was not detected in the patient’s breast milk. The authors noted that given the doxazosin plasma half-life of 16-30 hours it would be likely that if doxazosin was transferred into breast milk, a detectable level of the drug would have been found. They concluded that transfer of doxazosin into breast milk is low.

LactMed is a database organized and maintained by the National library of Medicine that surveys and summarizes information that has been published on drugs and breastfeeding. The LactMed entry on doxazosin states that regarding the effect of doxazosin on breastfed infants or its effect on breast milk or lactation that “... published information was not found as of the revision date.26

23

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

Prazosin: The prescribing information for Minipress states that the drug can be excreted in small amounts in breast milk; prazosin should be used cautiously in nursing mothers. A literature search did not find any published information on prazosin and transfer of the drug to breast milk or its effects on lactation or a nursing infant. LactMed states that the manufacturer reported one mother taking prazosin excreted, at most, 3% of her dose in breast milk but no other details of this incident were available.27 LactMed also states that there is no relevant information about prazosin and breastfeeding, lactation, or the effects of the drug on a nursing infant.27

Terazosin:

It is not known if terazosin is excreted in breast milk; use the drug cautiously in nursing mothers. A literature search did not find any published information on prazosin and transfer of the drug to breast milk or its effects on lactation or a nursing infant. LactMed states that there is no relevant information about terazosin and breastfeeding, lactation, or the effects of the drug on a nursing infant.28

Overdose of Doxazosin, Prazosin, and Terazosin

There is very little information about doxazosin, prazosin, or terazosin overdose; it is mentioned in the prescribing information for Cardura and Minipress (one case in each) and < 10 case reports and one review article were located.29-35 Clinical effects seen after a vasodilator overdose include (but are not limited to dizziness, drowsiness, headache, and hypotension.

There is no established toxic dose.36 There is no antidote. Symptomatic patients should be treated with supportive care.36 24

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

Centrally-Acting Antihypertensives: Guanfacine and Methyldopa

Centrally-acting antihypertensives act to reduce sympathetic outflow and have been widely used, but some have become less popular because of difficult side effects. Individuals diagnosed with diabetes and/or renal disease often respond to centrally-acting antihypertensives because their hypertension tends to be sympathetically driven. Also certain drugs of this class are often used adjunctively with traditional heart failure therapy in the setting of hypertension. The centrally-acting antihypertensives can often cause fluid retention and then diuretic therapy is needed to reduce edema.

Guanfacine

Category

Alpha2 adrenergic agonist; anti-hypertensive

Uses

Hypertension, immediate release form only. Treatment of attention deficit hyperactivity disorder (ADHD), extended release form only. Extended release guanfacine can be used as monotherapy or as an adjunct to stimulant drugs.

Mechanism of Action

Guanfacine is a selective alpha2 agonist. Stimulation of the presynaptic alpha2 receptors in the brain decreases sympathetic outflow, lowering heart rate and decreasing vascular tone in the smooth muscles, resulting in vasodilation, lowered blood pressure, and decreased SVR.37 Lowering blood pressure with guanfacine does not cause reflex tachycardia.

25

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Available Forms

● Immediate release: 1 mg and 2 mg tablets, generic and brand name (Tenex).

● Extended release: Generic and brand name tablets, 1 mg, 2 mg, 3 mg, and 4 mg. The brand name is Intuniv.

Dosing

Dosing is usually 1 mg every night at bedtime. After several weeks and if the patient has tolerated the 1 mg dose, 2 mg once a night may be used. Doses > 3 mg greatly increase the risk for adverse effects.37 Nighttime dosing of guanfacine can lessen the sedating effects of guanfacine and may also align its reduction of sympathetic outflow with elevations of blood pressure that typically occur in the early morning.

Dosing: Geriatric Patients

Consider a lower starting dose and close observation of blood pressure for geriatric patients.

The Beers Criteria consider guanfacine a potentially inappropriate medication for patients > 65 years of age,38 and the Pharmacy Quality Alliance (PQA) considers guanfacine a high-risk medication for this patient population. According to the Beers Criteria, guanfacine can cause bradycardia, CNS depression, and orthostatic hypotension, its use in elderly patients should be avoided if possible, and it should not be used as a first-line antihypertensive for this patient population.38 Dosing: Hepatic impairment

26

nursece4less.com nursece4less.com nursece4less.com nursece4less.com There are no recommendations for specific doses of guanfacine that are appropriate/needed for patients who have hepatic impairment. However, the drug should be used cautiously if a patient has hepatic impairment.37

Guanfacine is metabolized by the liver and approximately 50% of the drug is hepatically cleared.37

Dosing: Renal Impairment

There are no recommendations for specific doses of guanfacine that are appropriate/needed for patients who have renal impairment. However, clearance of the drug is reduced in patients who have renal impairment and if the patient has renal impairment, it is recommended that the lower end of the dosing range be used.37

Contraindications

Hypersensitivity to the drug or to any component of the product.

Warnings

Cardiovascular:

Guanfacine can cause atrioventricular (AV) block, bradycardia, hypotension, orthostatic hypotension, sinus node dysfunction, and syncope. These effects are more likely to occur when the patient begins taking the drug, with higher doses, or when the patient is taking another sympatholytic drug (a drug that blocks activity of sympathetic branch of the autonomic nervous system) like

37 an alpha1 blocker or a beta-blocker. Guanfacine should be used cautiously if a patient has bradycardia, cardiovascular disease, dehydration, heart block, hypotension, severe coronary insufficiency, or syncope. Cerebrovascular Disease:

27

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Guanfacine should be used cautiously if a patient has a history of cerebrovascular disease.37

CNS Effects:

Drowsiness is a common adverse effect of guanfacine.

Dermatological:

Exfoliative skin rash and pruritus have been associated with guanfacine. If these conditions develop, the patient should stop taking the drug.37

Discontinuing Therapy:

Abruptly stopping therapy with guanfacine may cause rebound hypertension and can cause hypertensive encephalopathy. The dose should be tapered in decrements of ≤ 1mg a day over a period of three to seven days and blood pressure should be closely observed during this process.37

Adverse Effects

Adverse effects that could occur are listed below.

1) >10%:37

● CNS: Drowsiness (10%-57%, dose-related), headache (4%- 28%), fatigue (5%-22%), dizziness (4%-16%, dose related), insomnia (2%-13%) ● Gastrointestinal: Xerostomia (3%-54%, dose related), abdominal pain (≤ 8%-19%, dose related), decrease appetite (5%-15%), constipation (2%-15%, dose related)

2) 1% to 10%:37

28

nursece4less.com nursece4less.com nursece4less.com nursece4less.com ● Cardiovascular: Hypotension and orthostatic hypotension (≤1% to 9%; dose-related), bradycardia (2% to 5%), atrioventricular block (≥2%), sinus arrhythmia (≥2%), syncope (1% to ≥2%) ● CNS: Irritability (5% to 8%), lethargy (3% to 8%), anxiety (2% to 5%), nightmares (3% to 4%), agitation (≥2%), depression (≥2%) ● Dermatologic: Skin rash (2% to 3%), pruritus (2%) ● Endocrine/metabolic: Weight gain (≤2% to 3%) ● Gastrointestinal: Nausea (≤5% to 7%), vomiting (2% to 7%), diarrhea (2% to 6%), dyspepsia (≥2%), stomach pain (≥2%) ● Genitourinary: Impotence (≤3% to 7%), urinary incontinence (2% to 5%) ● Respiratory: Asthma (≥2%) ● Miscellaneous: Fever (8%), weakness (≤ 2%-7%)

3) Reported/Incidence not known:37

● Cardiovascular: Chest pain, hypertension ● CNS: Seizure ● Dermatologic: Pallor ● Genitourinary: Urinary frequency ● Hepatic: Increased serum ALT ● Miscellaneous: Hypersensitivity reaction

4) < 1%, Post-marketing information, or case reports:37 Abnormal LFTS, aggressive behavior (immediate release; children), alopecia, amnesia, arthralgia, blurred vision, cardiac fibrillation, cerebrovascular accident, confusion, conjunctivitis, decreased libido dermatitis, diaphoresis, dysgeusia, dysphagia, dyspnea, edema, sinus node dysfunction, AV block, exfoliative dermatitis, hallucination, hypertensive encephalopathy, hypokinesia, iritis, leg cramps, leg pain, malaise, mania (immediate release, children), myalgia, myocardial infarction, nervousness, nocturia, palpitations, paresis, paresthesia, purpura, Raynaud phenomenon, rebound hypertension, renal failure, rhinitis, tachycardia, tinnitus, tremor, vertigo, visual disturbances visual disturbance.

Use During Breastfeeding

29

nursece4less.com nursece4less.com nursece4less.com nursece4less.com There is no information about the excretion of guanfacine in breast milk, and guanfacine should be used cautiously in nursing mothers.37

Use During Pregnancy

Pregnancy risk category B: Animal reproduction studies have not shown risk to the fetus and there are no well-controlled studies in pregnant women. Animal studies, using doses that caused maternal toxicity, have caused adverse events.37

Untreated hypertension during pregnancy can be harmful to the mother and the fetus, but if a pregnant woman has hypertension guanfacine is not recommended.37

Pharmacological Pearls: Guanfacine

This section expands on the pharmacological profile and has in-depth information about guanfacine.

Uses

Hypertension:

Guanfacine immediate release has a labeled use for the treatment of high blood pressure, but a literature search did not find any articles published within the past 10 years that specifically discussed guanfacine and hypertension, and it appears that guanfacine is seldom used as an antihypertensive. Information from professional guidelines that directly or indirectly address the use of guanfacine as an antihypertensive is summarized below.

30

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The JNC-8 recommendations from 2014 do not mention guanfacine but they do state that there “... were no RCTs of good or fair quality comparing the following drug classes to the 4 recommended classes: ... central α2- adrenergic agonists (for example, clonidine) ... Therefore, these drug classes are not recommended as first-line therapy.”7

The clinical practice guidelines for the management of hypertension published by the American Society of Hypertension and the International Society of Hypertension state that if the standard three drug regimen of an ACE inhibitor or an ARB plus a CCB and a thiazide diuretic are not effective, a centrally acting drug can be added.39 The 2017 report from the American College of Cardiology/American Heart Association on prevention, detection, evaluation, and management of high blood pressure stated that “... centrally acting drugs like guanfacine are generally reserved as last-line because of significant CNS adverse effects, especially in older adults.”8

A recent (2017) review on the treatment of essential hypertension did not mention guanfacine as a first or second-line choice.9 In a review of the treatment of resistant hypertension, Calhoun, et al. (2017) wrote that guanfacine could be used for patients whose blood pressure was not controlled with the standard regimen, but other medications were mentioned as choices, as well, and there were no recommendations regarding when and for whom guanfacine should be prescribed.40

Dosing: Renal Impairment

There are no recommendations for specific doses of guanfacine that are appropriate/needed for patients who have renal impairment. However, clearance of the drug is reduced in patients who have renal impairment, and in these cases, it is recommended that the lower end of the dosing range be

31

nursece4less.com nursece4less.com nursece4less.com nursece4less.com used.37 Up to 75% of a dose of guanfacine is excreted by the kidneys as unchanged drug, and older references (1980-1989) state that total body clearance, renal clearance, and cumulative urinary excretion of guanfacine are decreased, and plasma levels are increased in patients who have renal impairment.41-43

Warnings

Cardiovascular:

Guanfacine can cause atrioventricular (AV) block, bradycardia, hypotension, orthostatic hypotension, sinus node dysfunction, and syncope. These effects are more likely to occur when the patient begins taking the drug, with higher doses, or when the patient is taking another sympatholytic drug (a drug that blocks activity of sympathetic branch of the autonomic nervous system) like

37 an alpha1 blocker or a beta-blocker.

A literature search did not find any information that discussed a cause and effect relationship between the use of guanfacine and AV block or sinus node dysfunction. The Lexicomp® Drug Interaction database states that concurrent use of guanfacine and a beta-blocker can enhance the AV blocking effects of the beta-blocker and may enhance sinus node dysfunction, but no supporting references are provided.44

Discontinuing Therapy:

Abruptly stopping therapy with guanfacine may cause rebound hypertension and can cause hypertensive encephalopathy. The dose should be tapered in decrements of ≤ 1mg a day for a period of three to seven days and blood pressure should be closely observed during this process.37

32

nursece4less.com nursece4less.com nursece4less.com nursece4less.com There appears to be little clinical experience with this adverse effect and a literature search found three articles (1980, 2007, and 2011) that briefly mentioned rebound hypertension from guanfacine discontinuation,45-47 and one of these was a small (35 subjects) phase 1 study that found no increase in systolic or diastolic blood pressure when guanfacine therapy was abruptly stopped.47 No information about guanfacine discontinuation and hypertensive encephalopathy was located.

Use During Breastfeeding

There is no information about the excretion of guanfacine in breast milk, and guanfacine should be used cautiously in nursing mothers.37 The LactMed database states that there is no relevant published information about the effects of guanfacine on the the nursing infant, on lactation, or whether the drug can be excreted in breast milk.48

Use During Pregnancy

Animal studies using doses of guanfacine that caused maternal toxicity have reported adverse events.37 A study done in 1980 used guanfacine to treat 30 women who had pre-eclamptic toxemia, and no delivery or postnatal complications or adverse effects to the infants occurred.49 A literature search did not locate any other published information about guanfacine and pregnancy.

Guanfacine Overdose

A literature search for guanfacine overdose/poisoning found six case reports, two mentions of the topic in the prescribing information for guanfacine, and a retrospective review of 870 cases.50-57 Reviewing the information, several points about guanfacine poisoning that are prominent are: 1) for a small

33

nursece4less.com nursece4less.com nursece4less.com nursece4less.com child, one or two tablets can cause significant effects, 2) profound CNS depression, bradycardia, hypotension, and respiratory depression are the most common clinical signs of guanfacine poisoning, 3) a brief and self- limited period of hypertension may occur shortly after the ingestion, and 4) hypotension caused by guanfacine overdose/poisoning can be very persistent, lasting > 24 hours, and the lowest blood pressure level may not occur for 16-30 hours after the ingestion.50-57

Any pediatric exposure to any amount of guanfacine is potentially dangerous and warrants referral to an emergency room. There is no antidote for guanfacine overdose. Bradycardia should be treated with atropine, hypotension should be treated with IV fluids and vasopressors, and respiratory depression should be treated with airway control measures and supplemental oxygen.57 Symptomatic patients should be admitted and be observed for 24 hours. Naloxone has been successful53 and unsuccessful50 at reversing the toxic effects of guanfacine poisoning.

Methyldopa

Category

Antihypertensive; alpha2 adrenergic agonist

Uses

● Management of hypertension.58

● Methyldopa is not recommended as a first-line drug antihypertensive.8

Mechanism of Action

Methyldopa decreases sympathetic outflow to the heart, kidneys and the

58 peripheral vasculature by stimulating alpha2 receptors in the brain. It is a

34

nursece4less.com nursece4less.com nursece4less.com nursece4less.com prodrug that is metabolized to its pharmacologically active form, alpha- methylnorepinephrine.

Available Forms

● Oral: Generic tablets 250 mg and 500 mg.

● IV solution: Generic, 250 mg/5 mL.

● The brand name form of methyldopa, Aldomet, is no longer manufactured.

Dosing

● Oral: 250 mg tablets, 2-3 times day. The dose can be increased as needed every 2 days to a maximum daily dose of 3000 mg; the usual dose for the treatment of hypertension is 250 mg to 1000 mg a day.8

● When methyldopa is used with other antihypertensives other than a thiazide diuretic, the initial dose should be ≤ 500 mg a day.58

● IV: 250 mg – 1000 mg every 6-8 hours to maximum of 1000 mg every 6 hours.58

● Between the second and third month of therapy with methyldopa patients may develop a tolerance to the drug. If this occurs prescribing a diuretic or increasing the methyldopa dose will usually bring the blood pressure under control.

Dosing Adjustment: Geriatric Patients

Adult dosing can be used for geriatric patients, but therapy should be started at the lower end of the dosing range. The Beers Criteria considers methyldopa to be a drug that is potentially unsafe for patients > 65 years of age.38 The PQA has identified methyldopa as a high-risk drug for patients > 65 years of age.58

35

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Dosing Adjustment: Hepatic Impairment

There are no recommendations for specific doses of methyldopa that are appropriate/needed for patients who have hepatic impairment. However, methyldopa is contraindicated if a patient has active hepatic disease.58

Dosing Adjustment: Renal Impairment

There are no manufacturers’ recommendations for specific doses of methyldopa that are appropriate/needed for patients who have renal impairment. However, the active metabolites of methyldopa can accumulate if the patient has renal impairment. A 2007 source made recommendations for reducing the dose of methyldopa based on creatinine clearance (CrCl):59

● CrCl > 50 mL/minute, administer the dose every eight hours

● CrCl 10-50 mL/minute, administer the dose every 10-12 hours

● CrCl < 10 mL/minute, administer the dose every 12-24 hours

Dosing adjustments may also be needed if the patient undergoes hemodialysis or peritoneal dialysis.58

Contraindications

● Hypersensitivity to the drug or any components of the product.

● Active hepatic disease, for example, acute hepatitis, acute cirrhosis.

● Hepatic disorders associated with methyldopa

● Concurrent use of MAO inhibitors.

Warnings

CNS:

Methyldopa may cause sedation during the beginning of therapy or when the dose is increased. 36

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

Cerebrovascular Disease:

There are rare reports of choreoathetotic movements happening to patients who have severe, bilateral cerebrovascular disease and are taking methyldopa. If these occur the patient should stop taking the drug.

Edema:

Methyldopa can cause edema and weight gain. If this adverse effect or signs of heart failure occur, the patient should stop taking the drug. Mild edema however, may only require use of a diuretic.

Hematologic:

Reversible granulocytopenia, thrombocytopenia, and hemolytic anemia have rarely been reported as adverse effects of methyldopa. Regarding hemolytic anemia, 10%-20% of patients taking methyldopa will have a positive Coombs test, and this usually happens between six to 12 months after the beginning of therapy. Scheduled, periodic measurements of the CBC are advised and if methyldopa-induced Coombs-positive anemia is detected, discontinue therapy with the drug and do not restart it.58 After stopping use of methyldopa it may be several weeks or months before the Coombs test result normalizes.

Hepatic:

Methyldopa is a rare cause of hepatic damage, including fatal hepatic necrosis.58 Discontinue use of the drug if the patient develops evidence of hepatic damage.

37

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Pheochromocytoma:

Methyldopa is not recommended for patients who have pheochromocytoma.

Adverse Effects

The frequency of the adverse effects caused by methyldopa is not known.58

● Cardiovascular: Bradycardia, cardiac failure, exacerbation of angina pectoris, myocarditis, orthostatic hypotension, paradoxical high blood pressure (IV), pericarditis, peripheral edema, prolonged carotid sinus syncope, vasculitis

● Central nervous system: Bell’s palsy, cerebrovascular insufficiency, choreoathetosis, decreased mental acuity, depression, dizziness, headache, nightmares, paresthesia, Parkinson’s disease, sedation

● Dermatologic: Skin rash, toxic epidermal necrolysis

● Endocrine/metabolic: Amenorrhea, decreased libido, gynecomastia, hyperprolactinemia

● Gastrointestinal: Abdominal distention, colitis, constipation, diarrhea, flatulence, glossalgia, melanoglossia, nausea, pancreatitis, sialadenitis, vomiting, xerostomia

● Genitourinary: Breast hypertrophy, impotence, lactation

● Hematologic/oncologic: Bone marrow depression, eosinophilia, granulocytopenia, hemolytic anemia, leukopenia, positive ANA titer, positive direct Coombs test, thrombocytopenia

● Hepatic: Abnormal hepatic function tests, hepatitis, jaundice

● Neuromuscular/skeletal: Arthralgia, lupus-like syndrome, myalgia, positive rheumatoid factor

● Renal: Increased blood urea nitrogen

● Respiratory: Nasal congestion

● Miscellaneous: Drug fever, positive lupus erythematosus (LE) cell preparation test, weakness, weight gain

38

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Use During Breastfeeding

Methyldopa is transferred into breast milk in low concentrations, < 1% of the weight-adjusted maternal dose.58 This means that the infant would be receiving < 1% of the mother’s dose and any amount of a drug in breast milk < 10% is generally considered safe.60 Nonetheless, manufacturers recommend caution when giving methyldopa to breastfeeding women.

Use During Pregnancy

Oral methyldopa is a pregnancy risk category B drug; the IV form is a pregnancy category C drug. Category B means that animal reproduction studies have not shown risk to the fetus and there are no well controlled studies in pregnant women. Category C means that animal studies have shown that the drug can cause fetal damage, there are no adequate, well — controlled research of the effects of the drug during human pregnancies, and the benefits of the drug may outweigh any risks.

Methyldopa crosses the placenta and appears in cord blood. Using oral methyldopa during pregnancy has not caused fetal harm and it may be beneficial for the fetus, as untreated maternal hypertension can cause harm to the fetus, the infant, and the mother. If a pregnant woman has chronic hypertension, methyldopa is one of the preferred drugs. IV methyldopa is not recommended for pregnant women.61

Clinical Pearls: Methyldopa

The following section expands on what was covered in the pharmacological profile.

39

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Uses

Hypertension:

Methyldopa has a labeled use for the treatment of high blood pressure. However, a literature search found only one article published within the past 10 years that specifically discussed methyldopa and hypertension,62 and it appears that methyldopa is seldom used as an antihypertensive;62,63 this may be because newer drugs have fewer side effects and there is comparatively less data about its effectiveness and its ability to reduce the incidence of the complications of hypertension.62,63 Information from professional guidelines that directly or indirectly discuss using methyldopa for treating high blood pressure topic is summarized below.

The JNC-8 recommendations from 2014 do not mention methyldopa but they do state that there “... were no RCTs of good or fair quality comparing the following drug classes to the 4 recommended classes: ... central α2- adrenergic agonists (for example, clonidine) ... therefore, these drug classes are not recommended as first-line therapy.”7

The clinical practice guidelines for the management of hypertension published by the American Society of Hypertension and the International Society of Hypertension state that if the standard three drug regimen of an ACE inhibitor or an ARB plus a CCB and a thiazide diuretic are not effective, a centrally acting drug can be added; methyldopa is not specifically mentioned.39 The 2017 report from the American College of Cardiology/American Heart Association on prevention, detection, evaluation, and management of high blood pressure stated that “... centrally acting drugs like methyldopa are generally reserved as last-line because of significant CNS adverse effects, especially in older adults.”8

40

nursece4less.com nursece4less.com nursece4less.com nursece4less.com A recent (2017) review on the treatment of essential hypertension did not mention guanfacine as a first or second-line choice.9 In a review of the treatment of resistant hypertension, Calhoun, et al. (2017) wrote that a centrally acting drug could be used for patients whose blood pressure was not controlled with the standard regimen, but other medications were mentioned as choices, as well, and methyldopa was not specifically mentioned.40

Hypertension and Pregnancy

Methyldopa has been used for many years to treat hypertension in pregnant women, the oral form is a pregnancy risk category B drug and authoritative sources, including the American College of Obstetricians and Gynecologists, state that methyldopa is safe for the fetus and for infants.58,61,64 More recent data is not as encouraging.

Fitton, et al. (2017) reviewed the literature on in-utero exposure to antihypertensives.65 The authors examined data from five studies involving methyldopa, and they concluded that: 1) methyldopa was associated with an increased risk of low birth weight, perinatal mortality, and preterm birth; 2) in the one study that was considered to excellent quality there was an increased risk for preterm birth (adjusted OR 4.2; 95% CI 3.2–5.5), perinatal death (adjusted OR 2.1; 95% CI 1.1–4.0), low birth weight (adjusted OR 3.8; 95% CI 2.9–4.9), intrauterine growth restriction (adjusted OR 4.3; 95% CI 2.8–6.6), and low Apgar scores (≤7) at 1 min (adjusted OR 2.0; 1.4–2.7) and 5 min (adjusted OR 2.8; 95% CI 1.5–5.4), in 99 514 women who had been exposed to methyldopa in the third trimester in 99 514 women, and the design of these five studies was such that it could not be determined if the adverse effects were caused by methyldopa or the ongoing effects in-utero effects of hypertension.

41

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Methyldopa may also may also cause hepatic injury during pregnancy (discussed in the next section).

Hoeltzenbein, et al. (2017) retrospectively reviewed 261 first trimester exposures to methyldopa and compared these cases to 526 pregnancies.66 The incidence in birth defects in the methyldopa group and the control group was not significantly different, 3.7% and 2.5%, respectively. However, the risk of preterm birth was significantly higher and the adjusted birth weight scores were significantly lower for the methyldopa group. The authors concluded that: “Further studies are needed to confirm its safety in the first trimester and clarify the influence of hypertension and methyldopa on preterm birth and intrauterine growth.”66

Dosing Adjustment: Hepatic Impairment

The prescribing information states that methyldopa may rarely cause hepatic damage, including acute hepatitis, acute cirrhosis, and fatal hepatic necrosis, and that abnormal hepatic function tests and jaundice are adverse effects of methyldopa.

Acute hepatitis, cholestatic liver injury, asymptomatic elevations of hepatic function tests, and fatal hepatic necrosis have been reported as adverse effects of methyldopa,67-72 and hepatitis is a well-documented adverse effect of methyldopa during pregnancy and the postpartum period.73-76 Evidence of significant liver damage may begin within several weeks of starting therapy with the drug, but an onset of months and years has been reported, as well.67,70,72,73,77 Several hundred cases of clinically apparent and/or significant liver injury caused by methyldopa have been reported,77 and transient and reversible elevations in serum transaminase levels (5-100 fold) occur in 5%-35% of all patients who chronically take methyldopa.77

42

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The true incidence of significant methyldopa-induced liver damage is not known: it has been reported to be between 1% - 10%73,76 and most of the literature describes hepatic injury from methyldopa using terms like rare or relatively uncommon.77 In most cases the liver injury is temporary and the patient fully recovers, but fatalities and chronic hepatitis have been reported.68,69,74,77 The pathologic mechanism of methyldopa-induced liver damage appears to be idiosyncratic and immune-mediated and related to metabolism of the drug.72 Methyldopa is a pro-drug, and in methyldopa- induced liver injury a derangement in CYP450 enzyme system metabolism of the pro-drug metabolite appears to stimulate an immune system reaction.72

Warnings

Cerebrovascular Disease:

There are rare reports of choreoathetotic movements happening to patients who have severe, bilateral cerebrovascular disease and are taking methyldopa. If these occur the patient should stop taking the drug. The author located three articles (one published in French, a translation was not available) describing movement disorders that were presumably caused by methyldopa, one involving a patient who had severe cerebrovascular disease and the second involving a patient who had chronic renal failure.78,79

Hematologic:

Reversible granulocytopenia, thrombocytopenia, and hemolytic anemia have rarely been reported adverse effects of methyldopa. Regarding hemolytic anemia, 10%-20% of patients taking methyldopa will have a positive Coombs test, and this usually happens between six to 12 months after the beginning of therapy. Scheduled, periodic measurements of the CBC are advised and if methyldopa-induced Coombs-positive anemia is detected,

43

nursece4less.com nursece4less.com nursece4less.com nursece4less.com discontinue therapy with the drug and do not restart.58 After stopping use of methyldopa it may be several weeks or months before the Coombs test result normalizes.

There are case reports of methyldopa causing, or its use being associated with agranulocytosis, neutropenia, and thrombocytopenia,80-85 but the scarcity of these incidents indicates that these effects are rare. Methyldopa- induced hemolytic anemia has been well described. This is an autoimmune- mediated adverse effect, and between 10%-20% of all patients who are chronically taking methyldopa will develop antibodies that target an autoantigen on red blood cells (RBCs)86,87 and 0.5%-1% will develop hemolytic anemia.86 The clinical course can be mild, but very low hemoglobin levels (for example, 5 g/dL) and death have been reported.85

The direct Coombs test, also known as the direct antibody test (DAT) can detect autoimmune antibodies that are binding to the RBC surfaces. The test will become positive several months after starting methyldopa therapy, and it may remain positive for years after the patient has stopped taking the methyldopa.85

Use During Breastfeeding

Methyldopa is transferred into breast milk in low concentrations, < 1% of the weight-adjusted maternal dose.58 This means that the infant would be receiving < 1% of the mother’s dose, and any amount of a drug in breast milk < 10% is generally considered safe.60 Nonetheless, manufacturers recommend caution when giving methyldopa to breastfeeding women.

The LactMed database summary of methyldopa states that: 1) low levels of methyldopa are found in breastmilk and these amounts are not expected to

44

nursece4less.com nursece4less.com nursece4less.com nursece4less.com cause harm to a nursing infant; 2) neither acute or long-term effects were seen in nursing infants whose mothers has been taking methyldopa, and 3) methyldopa has caused galactorrhea (excessive or inappropriate milk production).88

Methyldopa Overdose

Overdose with methyldopa typically causes bradycardia, CNS depression from mild to profound, and hypotension.89-91 There is limited data, but 2.5 grams to 75 grams have produced significant effects (with survival) and 25 grams caused death.89 There is no antidote and no specialized therapies that would be helpful; treat symptomatic patients with standard supportive care.89

Vasodilator Medications

Vasodilator medications are effectively used for hypertension and work by lowering total peripheral resistance. These drugs are often used in hypertensive crises and can be associated with significant adverse effects. Newer drugs are now used to manage hypertension that have fewer adverse effects and are better tolerated.

Hydralazine

Category

Antihypertensive; vasodilator

Labeled Uses

Management of moderate to severe hypertension.92 Mechanism of Action

45

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Hydralazine dilates arterioles and decreases SVR.92

Available Forms

● Oral tablets, generic; 10 mg, 25 mg, 50 mg, 100 mg

● IV solution, generic; 20 mg/mL

● Hydralazine 37.5 mg combined with isosorbide dinitrate 20 mg; brand name BilDil, no generic equivalent.

Dosing

Begin with 10 mg four times a day for two to four days. Increase the dose to 25 mg four times a day for the rest of the first week. Following that, increase the dose to 50 mg four times a day. The 24-hour maximum is 300 mg.92

Dosing Adjustments: Geriatric Patients

The adult dosing recommendations should be used. The Beers Criteria considers hydralazine to be potentially inappropriate for patients 65 years and older who have a history of syncope.38

Dosing Adjustments: Hepatic Impairment

There are no recommendations for specific doses of hydralazine that are appropriate/needed for patients who have hepatic impairment. Hydralazine is extensively metabolized by the liver.92

Dosing Adjustment: Renal Impairment

46

nursece4less.com nursece4less.com nursece4less.com nursece4less.com There are no recommendations for specific doses of hydralazine that are appropriate/needed for patients who have renal impairment. A 2007 source made recommendations for reducing the dose of hydralazine based on renal status.59 These recommendations assume the patient is taking 25 mg-50 mg every eight hours. For GFR ≥10 mL/minute, give the dose every eight hours, and for GFR <10 mL/minute, give the dose every eight to 16 hours. For intermittent hemodialysis, the dose should be given after dialysis, for peritoneal dialysis, the dose should be given every eight to 16 hours, and for continuous renal replacement therapy, the dose should be given every eight hours.

Contraindications

Hypersensitivity to the drug or any component of the product, coronary artery disease (CAD), and mitral valve rheumatic heart disease.

Warnings

Cardiovascular Disease:

Hydralazine is contraindicated in patients who have CAD, and it should be used cautiously if the patient has had a CVA or is likely to have CAD. Patients who have CAD, hypertension, and heart failure with reduced ejection fraction should not be given hydralazine unless a nitrate is used concomitantly.93

Drug-induced Lupus Syndrome:

Hydralazine can cause a lupus-like syndrome and glomerulonephritis. This is usually reversible but if the lupus-like syndrome occurs, the risk-benefit ratio of continuing versus stopping therapy with hydralazine must be considered. Hematologic:

47

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Agranulocytosis, decreased hemoglobin and RBC count, and purpura may occur with hydralazine use. If these occur therapy with the drug should be stopped.

Hypotension:

Orthostatic hypotension is possible.

Mitral Valve Disease: Hydralazine can increase pulmonary artery pressure in patients who have mitral valve disease.

Peripheral Neuritis:

Hydralazine has been associated with peripheral neuritis. If the patient develops signs and symptoms of this disorder, he/she should be treated with pyridoxine.

Renal Impairment:

Hydralazine should be used cautiously if the patient has renal impairment.

Tartrazine Sensitivity:

Hydralazine may contain tartrazine as an excipient, and this can cause allergic reactions in susceptible patients, particularly in patients who are hypersensitive to aspirin. (Note: Tartrazine is a synthetic yellow dye).

Adverse Reactions

48

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The frequency of the following adverse reactions listed in the following table has not been reported.

Cardiovascular: Angina pectoris, flushing, orthostatic hypotension, palpitations, paradoxical hypertension, peripheral edema, shock, tachycardia

Central nervous system: Anxiety, chills, depression, disorientation, dizziness, headache, increased intracranial pressure (IVP); in patient with pre-existing increased intracranial pressure), peripheral neuritis, psychotic reaction

Dermatologic: Diaphoresis, pruritus, skin rash, urticaria

Gastrointestinal: Anorexia, constipation, diarrhea, nausea, paralytic ileus, vomiting

Genitourinary: Dysuria, impotence

Hematologic/oncologic: Agranulocytosis, decreased hemoglobin, decreased RBC count, eosinophilia, hemolytic anemia, leukopenia

Neuromuscular/skeletal: Lupus-like syndrome, dose-related (See the following section of the module for more details), muscle cramps, rheumatoid arthritis, tremor, weakness

Ophthalmic: Conjunctivitis, lacrimation

Respiratory: Dyspnea, nasal congestion

Miscellaneous: Fever

<1%: post-marketing and/or case reports: Thrombocytopenia (IV)

Use During Breastfeeding

Hydralazine is excreted into breast milk, and the relative infant dose (RID) is 0.77% to 3%; this range was determined by using the highest amount of hydralazine found in breast milk and the infant oral dosing range of 0.7 to 3 mg/kg/day.92

49

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Breastfeeding is usually considered safe for a nursing infant if the RID is < 10%.94 However, it is recommended that hydralazine should be used cautiously during breastfeeding.92

Use During Pregnancy

Hydralazine is a pregnancy risk category C drug. It crosses the placenta and adverse effects have been observed in animal studies.92

Intravenous hydralazine is a first-line choice for treating acute onset, severe hypertension caused by preeclampsia or eclampsia in pregnant and postpartum women.92 Hydralazine is not recommended for the routine treatment of chronic hypertension in pregnant women.

Clinical Pearls: Hydralazine

This section of the module expands on the pharmacological profile and has in-depth information about hydralazine.

Uses

Hydralazine has a labeled use for treatment of moderate to severe hypertension. However, it is no longer prescribed as a long-term therapy for treating primary hypertension;7-9 and, it is primarily used for the treatment of hypertensive emergencies95 and the treatment of severe hypertension caused by preeclampsia96 and in the former, it would not be considered a first line choice.97

Regarding hypertensive emergencies, IV hydralazine is effective at lowering blood pressure, but it has a long duration of action, the hypotensive effect is unpredictable, and it can be potentially harmful if the patients has CAD or is at risk for an aortic dissection.95 Oral hydralazine can be and is used PRN for 50

nursece4less.com nursece4less.com nursece4less.com nursece4less.com treatment of acute elevations of blood pressure that are not considered hypertensive emergencies.97

Intravenous hydralazine has been used for many years to treat for severe hypertension caused by preeclampsia and for this purpose it has been shown to be effective and safe.98-100

Dosing Adjustments: Hepatic Impairment

There are no recommendations for specific doses of hydralazine that are appropriate/needed for patients who have hepatic impairment. Hydralazine is extensively metabolized by the liver.92

Liver injury from short-term and long-term use of hydralazine has been reported, including acute hepatitis, auto immune-like drug-induced liver injury, centrilobular necrosis, and cholestatic jaundice.101-106 These adverse effects have been reported to be uncommon and/or rare, some are clearly idiosyncratic reactions, some are immune system mediated, and depending on the specific mechanism of injury they can be reversible or can cause permanent injury.101,105,106

Dosing Adjustment: Renal Impairment

There are no recommendations for specific doses of hydralazine that are appropriate/needed for patients who have renal impairment, but the prescribing information warns that hydralazine should be used cautiously if a patient has advanced renal impairment, and a 2007 source made recommendations for reducing the dose of hydralazine based on renal status.59 A literature search did not locate any articles that discussed hydralazine and pre-existing renal impairment or the need to make dosing adjustments of hydralazine in patients who have renal impairment. 51

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Several authoritative reviews of the treatment of hypertension in patients who have chronic kidney disease did not mention hydralazine.107,108 Autoimmune renal damage caused by hydralazine has been well described, either as part of drug-induced lupus or as an autoimmune-induced vasculitis; drug-induced lupus will be discussed later in the module.

Contraindications

Coronary Artery Disease:

Hydralazine is contraindicated in patients who have coronary artery disease (CAD), and it should be used cautiously if the patient has had a CVA or is likely to have CAD. Patients who have CAD, hypertension, and heart failure with reduced ejection fraction should not be given hydralazine unless a nitrate is used concomitantly.93

The American Heart Association, the American College of Cardiology, and the American Society of Hypertension published a scientific statement on the treatment of hypertension in patients who have coronary artery disease. The statement indicated that because there is no evidence from randomized clinical trials “... to support the use of hydralazine without a nitrate in the treatment of primary hypertension and concerns that hydralazine may provoke angina, monotherapy with hydralazine in IHD (ischemic heart disease) is not recommended… Drugs to avoid in patients with hypertension and HF with reduced ejection fraction are non-dihydropyridine CCBs (such as verapamil and diltiazem), clonidine, moxonidine, and hydralazine without a nitrate.”93 The rationale for these recommendations appears to have come from the African-American Heart Failure Trial (A-heFT) in which a combination of hydralazine and isosorbide dinitrate significantly reduced the incidence of mortality (43% reduction) and the risk for hospitalization (39% reduction) caused by heart failure.109 52

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Nitrates alone are helpful for treating heart failure (HF), but their effectiveness as monotherapy is limited because patients develop nitrate tolerance and hydralazine both prevents and reverses nitrate tolerance.110

Mitral Valve Rheumatic Heart Disease:

Hydralazine can increase pulmonary artery pressure in patients who have mitral valve disease. The 2014 American College of Cardiology/American Heart Association guideline for management of patients with valvular disease states that vasodilator therapy is not recommended for asymptomatic, normotensive patients who have chronic, primary mitral regurgitation and normal systolic left ventricular function.111

Warnings

Drug-induced Lupus Syndrome:

Hydralazine can cause a lupus-like syndrome and glomerulonephritis. This is usually reversible, but if the lupus-like syndrome occurs the risk-benefit ratio of continuing versus stopping therapy with hydralazine must be considered. Lupus-like syndrome caused by hydralazine is a drug-induced autoimmune (DIA) condition,112 drug-induced lupus (DIL) is the most common type of DIA, and hydralazine is one the two most common causes of DIL (procainamide is the other), with an incidence of 5%-10%.112,113

Drug-induced lupus closely mimics the signs/symptoms and clinical findings of systemic lupus erythematosus (SLE), but there are some significant differences: SLE affects women to men in a 9:1 ratio, DIL affects men and women equally; DIL seldom causes a rash but a rash is a prominent sign of SLE; the kidneys are rarely affected by DIL but 30%-50% of patients with SLE will have renal issues, and; for the majority of patients DIL resolves

53

nursece4less.com nursece4less.com nursece4less.com nursece4less.com when therapy with the drug is stopped,113 but SLE is a chronic, incurable disease. Most patients who develop this adverse effect are female, white, and are taking a high dose of hydralazine, > 400 mg a day,112,114 and the signs and symptoms of usually begin after several months of therapy with the drug.112 Arthralgias (usually in the hands and subsequently in joints of the lower extremities) fever, and myalgias are typical; the central nervous system, and cardiac, pulmonary, and renal systems can also be affected, for example, cardiac tamponade, pneumonitis, and glomerulonephritis may occur, but these complications are rare or unusual.112,114

Use During Breastfeeding

Hydralazine is excreted into breast milk, and it is recommended that hydralazine should be used cautiously during breastfeeding.92 The LactMed summary on the use of hydralazine during breastfeeding states that the data and years of experience “... indicate that hydralazine is an acceptable antihypertensive in nursing mothers, even those nursing newborns.” One study of 10 women showed the daily dose of hydralazine in a nursing infant would be unlikely to exceed 25 mcg. Hydralazine has been measured in the serum of nursing infants when their mothers were taking the drug. There is no relevant information on hydralazine and lactation. No adverse effects were seen in an infant who breastfed for eight weeks and whose mother was taking hydralazine.115

Use During Pregnancy

The American Congress of Obstetrics and Gynecology recommends hydralazine as a first-line choice for treating acute onset severe hypertension caused by preeclampsia or eclampsia in pregnant women.116 Dosing recommendations are as follows: 1) If the patient’s blood pressure is severe (systolic blood pressure ≥ 160 mm Hg, diastolic blood pressure ≥ 110 mm Hg) for ≥15 54

nursece4less.com nursece4less.com nursece4less.com nursece4less.com minutes, the patient should be given 5 mg - 10 mg of hydralazine IV over two minutes. 2) Measure blood pressure 20 minutes after this dose and if it is still ≥ 160 mm Hg/110 mm Hg, give 10 mg of hydralazine IV over two minutes. 3) Re-measure the blood pressure 20 minutes after this dose and if severe hypertension persists, use labetalol; do not give more hydralazine.116

Hypotension is a possible adverse effect and the patient’s blood pressure should be monitored closely. The American Congress of Obstetrics and Gynecology recommends labetalol, methyldopa, or nifedipine to treat chronic hypertension in pregnant women.61 Hydralazine is not mentioned, and it can cause reflex tachycardia and fluid retention.96

Minoxidil

Category

Antihypertensive; direct-acting vasodilator

Uses (Systemic Form)

Treatment of symptomatic hypertension or hypertension that is associated with target organ damage and cannot be controlled with the maximum doses of two antihypertensives and a diuretic.117 Minoxidil is not recommended as an initial treatment for hypertension.8

Mechanism of Action

Relaxation of smooth muscle in arterioles, causing vasodilation.

Available Forms

Generic tablets, 2.5 mg and 10 mg. Dosing

55

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Start with 5 mg once a day and increase the dose in one to three divided doses,117 every three days or more; titrate every six hours to urgently lower blood pressure.8 Daily maximum dose is 100 mg;117 adjust the minoxidil dose if added to a pre-existing antihypertensive regimen. If supine diastolic blood pressure is reduced < 30 mm Hg, give one dose a day; if the supine diastolic blood pressure is reduced > 30 mm Hg, give the dose in two equal parts.117

Dosing Adjustments: Geriatric Patients

Start with 2.5 mg a day and gradually increase the dose as needed.118

Dosing Adjustments: Hepatic Impairment

There are no recommended dosing adjustments in the case of hepatic impairment. Minoxidil should be used cautiously and titrated slowly if the patient has hepatic disease.117

Dosing Adjustments: Renal Impairment

There are no recommended dosing adjustments in the case of renal impairment. Dosing adjustments may be needed if the patient has renal failure or requires hemodialysis.117

US Boxed Warning

Minoxidil can cause pericardial effusion and cardiac tamponade, and it can exacerbate angina pectoris. Minoxidil should only be used if the patient has not responded to the maximum doses of two other antihypertensive medications and a diuretic. Animal experiments have caused myocardial lesions and other adverse cardiac effects. Contraindications

56

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Hypersensitivity to the drug or any components of the product, and pheochromocytoma.

Additional Warnings

Cardiovascular:

Minoxidil can cause pericarditis, pericardial effusion, and cardiac tamponade. Patients who have renal impairment but are not being treated with hemodialysis may have a high risk for these effects. Minoxidil should be used cautiously if the patient has heart failure. A rapid drop in blood pressure from minoxidil in patients who have severe hypertension can cause a CVA, MI, syncope, and ischemia of eyes and ears with loss vision or hearing.

Patients who have poor circulation or cryoglobulinemia may develop ischemia of the affected organs. Minoxidil should be used cautiously in patients who have ischemic heart disease as it may cause reflex tachycardia, increasing myocardial oxygen demand and exacerbating angina pectoris. A beta-blocker may be helpful in preventing this adverse effect and a beta- blocker should be used concomitantly with minoxidil if there is no contraindication. Minoxidil should not be used for one month after an acute myocardial infarction (MI); reflex tachycardia can increase myocardial oxygen demand.

Minoxidil may worsen heart failure and/or increase adverse effects related to the disease, for example, angina and ventricular arrhythmias. It should used very cautiously if the patient has heart failure. Sodium and water retention that can cause edema are possible adverse effects, and the concomitant use of a loop diuretic is recommended. If the patient has malignant hypertension and minoxidil is prescribed, hospitalization is advised to ensure that blood pressure reduction is not done too quickly. Minoxidil should be used 57

nursece4less.com nursece4less.com nursece4less.com nursece4less.com cautiously and small doses considered in patients who have significant renal impairment.

Adverse Effects

Cardiovascular: ECG changes (T-wave changes 60%), edema (7% - 10%), pericardial effusion (3%). Frequency not reported, angina pectoris, cardiac failure, pericarditis, tachycardia

Dermatologic: Hypertrichosis (80%). Frequency not reported, bullous rash (rare), skin rash, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis

Endocrine/metabolic: Sodium and water retention

Gastrointestinal: Nausea, vomiting

Hematologic: Decreased hematocrit, hemoglobin, and RBC count (transient, from hemodilution), leukopenia (rare), thrombocytopenia (rare)

Hepatic: Ascites, increased serum alkaline phosphatase

Renal: Increased BUN and creatinine blood urea nitrogen (transient)

Respiratory: Pulmonary edema

Miscellaneous: <1%, post-marketing, and/or case reports: Breast tenderness (rare)

Use During Breastfeeding

There is one case report of minoxidil being excreted in breast milk. Minoxidil should be use cautiously during breastfeeding.

Use During Pregnancy

58

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Pregnancy risk category C. Hypertrichosis (excessive body hair) has been reported in neonates whose mother had been taking minoxidil. Adverse effects have been reported in animal studies.

Clinical Pearls: Minoxidil

This section of the module expands on the pharmacological profile and has in-depth information about hydralazine.

Uses

Hypertension:

The 2017 guidelines on the hypertension by the American College of Cardiology and the American Heart Association state that direct acting vasodilators are second-line agents for treatment of high blood pressure.8 These guidelines also note that minoxidil can cause sodium and water retention and reflex tachycardia and concomitant use of a beta-blocker and a loop diuretic is recommended; minoxidil can induce pericardial effusion; and, minoxidil is associated with hirsutism.8

The decision to use minoxidil as a second-line antihypertensive medication appears to be because of the incidence and severity of water and sodium retention, reflex tachycardia, pericardial effusion, and hirsutism.119-121

The primary use for minoxidil is for treatment of symptomatic hypertension or hypertension that is associated with target organ damage and cannot be controlled with the maximum doses of two antihypertensives and a diuretic,117 aka treatment resistant hypertension,40 although the evidence and the clinical experience that support this is sparse and primarily derived from old research that was published 25-30 years ago.119-121

59

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

A 2018 review of the treatment of resistant hypertension states that minoxidil should be used for male patients and only when a patient’s blood pressure is not controlled by a combination of an ACE inhibitor or an ARB, a CCB, and a diuretic.40

US Boxed Warning

Minoxidil can cause pericardial effusion and cardiac tamponade. Pericardial effusion, which progress to cardiac tamponade, has been reported as an adverse effect of minoxidil with an incidence of 3%-3.9%;121-123 the incidence of progression to cardiac tamponade has been reported to be 1%.124 This adverse effect may be more likely to occur if a patient has renal impairment or is receiving hemodialysis,117,121,122 and to patients who have connective tissue disease, fluid retention, heart failure, or uremic syndrome,121 but it has happened to patients without these risk factors and who have normal renal function.121,123

The mechanism of action by which minoxidil causes pericardial effusion is not known,123 and the occurrence of pericardial effusion could be (and has been) simply an association without a proven cause and effect relationship, or it may be simply an extension of minoxidil-induced fluid overload. Most cases resolve spontaneously and discontinuation of therapy with the drug is sufficient,123 but pericardial drainage may be needed,125 and fatalities have been reported.126

Minoxidil can exacerbate angina pectoris. Reflex tachycardia can exacerbate angina pectoris and cause myocardial ischemia,117,127 likely by increasing myocardial oxygen demand. This adverse effect is more likely to happen if a patient has ischemic heart disease, and it is common enough that the use of

60

nursece4less.com nursece4less.com nursece4less.com nursece4less.com a beta-blocker during therapy with minoxidil is considered mandatory.8,117 Minoxidil should only be used for patients who are nonresponse to the maximum doses of two other antihypertensive medication and a diuretic.

Dosage Adjustments: Geriatric Patients

The normal starting dose is 5 mg but for geriatric patients, start with 2.5 mg a day and gradually increase the dose as needed.118 The 2015 Beers Criteria states that vasodilators are potentially inappropriate for patients ≥ 65 years of age who have history of syncope as vasodilators can worsen this condition,38 and syncope is a common problem in the elderly.128 The incidence of minoxidil-associate syncope is not known; two web-based reviews of 4898 people taking minoxidil (not known how many were taking systemic versus topical) found an incidence of syncope of 2%.129

Dosing Adjustments: Hepatic Impairment

There are no recommended dosing adjustments for patients that have hepatic impairment, but the prescribing information recommends that minoxidil should be used cautiously and titrated slowly if the patient has hepatic disease.117 Minoxidil is extensively metabolized by the liver, and one article was found suggesting that for patients who have cirrhosis, longer dosing intervals of minoxidil may be needed.130

Dosing Adjustments: Renal Impairment

There are no recommended dosing adjustments in the case of renal impairment, but dosing adjustments may be needed if the patient has renal failure or requires hemodialysis.117 The information on minoxidil and patents who have renal impairment is scant. McComb, et al. (2016) wrote that minoxidil “... has traditionally been reserved for patients with severe,

61

nursece4less.com nursece4less.com nursece4less.com nursece4less.com refractory hypertension or renal insufficiency.”121 The authors do not explain this statement; they do have supporting references for it, but they are relatively old (1980, 1981, and 2004) and the information from one of these references cites studies that were done 20-35 years ago.127 McComb, et al., also indicated that minoxidil may help prevent the progression of kidney disease, but again the references that support this statement are not current. Sica (2004) noted that patients who have chronic kidney disease and malignant hypertension and are receiving minoxidil may develop an increase in GFR that is significant enough that hemodialysis is needed.127 Sica also wrote that “... GFR is often recoverable and discontinuation of dialysis possible if normal BP is established with minoxidil therapy.”127

Contraindications

Minoxidil may cause a release of catecholamines in patients who have pheochromocytoma.121

Warnings

Heart Failure: It is stated in the prescribing information that minoxidil should be used cautiously if the patient has heart failure. No explanation or rationale is provided for this recommendation, but fluid retention and tachycardia are common adverse effects of minoxidil and both can exacerbate heart failure.

Hearing Loss/Vision Loss:

A rapid drop in blood pressure from minoxidil in patients who have severe hypertension can cause a CVA, MI, syncope, and ischemia of eyes and ears with loss vision or hearing. A sudden and dramatic drop in blood pressure to the vasculature supplying the eyes and ears could cause hearing and vision

62

nursece4less.com nursece4less.com nursece4less.com nursece4less.com loss. No information or case reports documenting this adverse effect could be found.

Poor Circulation, Cryoglobulinemia:

Patients who have poor circulation or cryoglobulinemia may develop ischemia in the affected organs, and compromised circulation and hypotension (an adverse effect of minoxidil) together obviously have the potential to cause ischemia. Cryoglobulinemia cause the deposits of antigen- antibody complexes in small and medium-size arteries, causing inflammation and blocking blood flow through these vessels; this would another situation in which hypotension caused by minoxidil could be potentially injurious.

Sodium and Water Retention:

Sodium and water retention and a resulting edema are possible adverse effects of minoxidil. Sodium and water retention are caused by minoxidil increasing the activity of plasma renin and renin increasing the secretion of ADH and aldosterone; this effect and (possibly) increased capillary pressure caused by the peripheral arteriolar dilation can cause edema, hence the need for a loop diuretic.8,119-121

The incidence of fluid retention caused by minoxidil has been reported to be 20%.124 Reflex tachycardia, caused by a baroreceptor response that activates the peripheral sympathetic nervous system, can be managed by concomitant use of a beta-blocker. 8,118-120

Adverse Effects

Electrocardiogram Changes:

63

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The prescribing information states that T waves changes have been reported to occur in 60% of all patients taking minoxidil. Sica and Cohn, et al wrote that these electrocardiogram (ECG) changes have been seen in 90% of patients taking minoxidil, and T wave flattening, and inversion and ST segment depression can occur.120,127 The ECG changes are seen within the first few days of therapy, and the ECG changes should slowly resolve and although in this situation these drug-associated findings are not associated with cardiac damage, T wave and ST segment changes themselves can be a sign of ischemia and left ventricular hypertrophy.120,127

Hypertrichosis:

Hypertrichosis is defined as excessive growth of hair (hirsutism is defined as abnormal hairiness, especially an adult male pattern of hair distribution, in women). Hypertrichosis is considered a common adverse effect of minoxidil with a reported incidence of 80%,117,120,121 but it is not clear from the sources in the literature if this figure includes topical and systemic minoxidil. The excessive hair growth begins three to six weeks after the patient begins taking minoxidil, it is typically on the face and upper limbs and it may also involve the trunk and other areas of the body.120,121,127,128 The mechanism by which minoxidil causes hypertrichosis is not known.128

The condition is treated by bleaching, shaving, and discontinuation of therapy with the drug, and may take several months for the hair growth to stop and resolve.120,121 Hypertrichosis in newborns has been reported in mothers taking minoxidil.129

Use During Breastfeeding and Pregnancy

There is one case report of minoxidil being excreted in breast milk.130 The Lactmed summary of the use of minoxidil during breastfeeding states that 64

nursece4less.com nursece4less.com nursece4less.com nursece4less.com there is minimal information about minoxidil and breastfeeding, so this drug should be used cautiously during nursing. There is no relevant information on infant levels of minoxidil during breastfeeding and no relevant information on the effect of minoxidil on breastmilk or lactation.131

Minoxidil is pregnancy risk category C. Hypertrichosis (excessive body hair) has been reported in neonates whose mother had been taking minoxidil.129 A 23-year-old female used 2% minoxidil topical cream and an ultrasound examination at 22 weeks of her pregnancy showed significant fetal malformations and an abnormal placenta. A recent (2018) review of treating hypertension during pregnancy did not mention minoxidil.100

Vasodilator Overdose

Overdose with a vasodilator is very uncommon; a literature search found one case each of hydralazine and systemic minoxidil overdose 133,134 and six cases of overdose with topical minoxidil.135-140 There is no established toxic dose of either drug; a two-year-old child ingested 100 gm of minoxidil and only developed sinus tachycardia,134 and a 52-year old man ingested 60 mL of 2% topical minoxidil (1160 mg) and developed severe hypotension, tachycardia, and a non-Q-wave MI.137 The clinical effects of hydralazine and minoxidil overdose include hypotension and tachycardia,133-140 and these can be quite serious (systolic blood pressure <60 mm Hg) and require aggressive supportive care like intubation and IV vasopressors. There is no antidote for vasodilator overdose; symptomatic patients should be treated with standard therapies like airway management and supplemental oxygen, fluid resuscitation, and IV vasopressors.141 Summary

Second-line antihypertensive drugs (guanfacine, hydralazine, doxazosin, prazosin, terazosin, methyldopa, and minoxidil) used for the treatment of 65

nursece4less.com nursece4less.com nursece4less.com nursece4less.com hypertension were introduced many years ago. The need for frequent dosing and the adverse effect profiles of these drugs, however, along with the development and introduction of antihypertensives that are more effective, safer, and more versatile means that the centrally-acting agents, alpha blockers, and vasodilators are now seldom prescribed. There are specific situations like hypertensive emergencies or acute treatment of high blood pressure in pregnant women in which they may be used, but none of these drugs is used or recommended as a primary therapy for hypertension.

The most common adverse effect of these miscellaneous antihypertensives is hypotension. Orthostatic hypotension can also occur, as can syncope and the worsening of pre-existing cardiovascular conditions like angina pectoris and heart failure. All these drugs should be used cautiously for geriatric patients, during breastfeeding and, aside from methyldopa, they should be used cautiously during pregnancy. Caution is advised for many of these drugs in patients who have hepatic and/or renal impairment.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement. 1. Which of the following act as competitive antagonists that reduce the release of norepinephrine and lower blood pressure?

a. Alpha1 blockers b. Vasodilators 66

nursece4less.com nursece4less.com nursece4less.com nursece4less.com c. Alpha2 agonists d. Non-steroidal Anti-inflammatory Drugs (NSAIDs)

2. Benign prostatic hyperplasia may be treated with the following medication(s):

a. Prazosin b. Metolazone c. Doxazosin, terazosin d. Guanfacine, methyldopa

3. For doxazosin, the 24-hour maximum dose is ___ mg.

a. 10 b. 8 c. 25 d. 16

4. The maximum dose of prazosin is 20 mg a day in divided doses, although some patients may need and tolerate up to ___ mg a day.

a. 40 b. 50 c. 25 d. 30

5. Terazosin should begin with ___ mg a day, given at bedtime.

a. 8 b. 4 c. 7 d. 1

6. True or False: Moxidil may cause a release of catecholamines in patients who have pheochromocytoma.

a. True b. False

7. Sodium and water retention are caused by minoxidil may require a patient to also take a

a. vasoconstrictor. 67

nursece4less.com nursece4less.com nursece4less.com nursece4less.com b. non-steroidal anti-inflammatory drugs (NSAIDs). c. loop diuretic. d. beta-blocker.

8. Hydralazine is NOT recommended for the routine treatment of

a. women who are breastfeeding. b. acute onset, severe hypertension caused by preeclampsia or eclampsia in postpartum women. c. acute onset, severe hypertension caused by preeclampsia or eclampsia in pregnant women. d. chronic hypertension in pregnant women.

9. True or False: Hypertension is treated with Guanfacine, extended release form only.

a. True b. False

10. ______is a selective alpha2 agonist that decreases sympathetic outflow, lowering heart rate and decreasing vascular tone in the smooth muscles.

a. Methoxamine b. Phenylephrine c. Guanfacine d. Tetrahydrozoline

11. For Cardura XL, the starting dose is ___ mg.

a. 8 b. 12 c. 4 d. 6

12. ______decreases sympathetic outflow to the heart, kidneys and the peripheral vasculature by stimulating alpha2 receptors in the brain.

a. Nifedipine 68

nursece4less.com nursece4less.com nursece4less.com nursece4less.com b. Methyldopa c. Indapamide d. Pindolol

13. Methyldopa is contraindicated if a patient has active

a. hypertension. b. hepatic disease. c. cystic fibrosis. d. gastroesophageal reflux disease (GERD).

14. ______is an intraoperative complication of cataract surgery, characterized by intraoperative pupillary constriction.

a. Glaucoma b. CMV Retinitis c. Floppy iris syndrome d. Ocular hypertension

15. ______dilates arterioles and decreases systemic vascular resistance (SVR).

a. Chlorothiazide b. Hydralazine c. Fosinopril sodium d. Clonidine

CORRECT ANSWERS:

1. Which of the following act as competitive antagonists that reduce the release of norepinephrine and lower blood pressure? 69

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

a. Alpha1 blockers

“The alpha1 blockers act as competitive antagonists at postsynaptic alpha1 adrenergic receptors, reducing the release of norepinephrine. This decreases systemic vascular resistance (SVR) and lowers blood pressure.”

2. Benign prostatic hyperplasia may be treated with the following medication(s):

c. Doxazosin, terazosin

“Uses: 1: Benign prostatic hyperplasia (Doxazosin, terazosin) 2: Hypertension (Doxazosin, prazosin, terazosin)”

3. For doxazosin, the 24-hour maximum dose is ___ mg.

d. 16

“Doxazosin: Begin with 1 mg a day, titrate by doubling the daily dose; the 24-hour maximum dose is 16 mg.”

4. The maximum dose of prazosin is 20 mg a day in divided doses, although some patients may need and tolerate up to ___ mg a day.

a. 40

“The initial dose should be 1 mg two-three times a day. The dosage can be gradually increased to a maximum of 20 mg a day in divided dose, although some patients may need and can tolerate 40 mg a day. Some patients only require twice a day dosing.”

5. Terazosin should begin with ___ mg a day, given at bedtime.

d. 1

“Terazosin: Begin with 1 mg a day, given at bedtime. Slowly increase the dose until the desired blood pressure level has been reached; the maximum 24-hour dose is 20 mg.”

6. True or False: Minoxidil may cause a release of catecholamines in patients who have pheochromocytoma.

70

nursece4less.com nursece4less.com nursece4less.com nursece4less.com a. True

“Contraindications: Minoxidil may cause a release of catecholamines in patients who have pheochromocytoma.”

7. Sodium and water retention are caused by minoxidil may require a patient to also take a

c. loop diuretic.

“Sodium and water retention and a resulting edema are possible adverse effects of minoxidil. Sodium and water retention are caused by minoxidil increasing the activity of plasma renin (renin increases the secretion of ADH and aldosterone); this effect and (possibly) increased capillary pressure caused by the peripheral arteriolar dilation can cause edema, hence the need for a loop diuretic.”

8. Hydralazine is NOT recommended for the routine treatment of

d. chronic hypertension in pregnant women.

“Hydralazine is not recommended for the routine treatment of chronic hypertension in pregnant women.’”

9. True or False: Hypertension is treated with Guanfacine, extended release form only.

b. False

“Guanfacine ... Uses: Hypertension, immediate release form only.”

10. ______is a selective alpha2 agonist that decreases sympathetic outflow, lowering heart rate and decreasing vascular tone in the smooth muscles.

c. Guanfacine

“Guanfacine is a selective alpha2 agonist. Stimulation of the presynaptic alpha2 receptors in the brain decreases sympathetic outflow, lowering heart rate and decreasing vascular tone in the smooth muscles,...”

11. For Cardura XL, the starting dose is ___ mg.

71

nursece4less.com nursece4less.com nursece4less.com nursece4less.com c. 4

“For Cardura XL, the starting dose is 4 mg. if needed after 3-4 weeks the dose can be increased to a maximum of 8 mg.”

12. ______decreases sympathetic outflow to the heart, kidneys and the peripheral vasculature by stimulating alpha2 receptors in the brain.

b. Methyldopa

“Methyldopa decreases sympathetic outflow to the heart, kidneys and the peripheral vasculature by stimulating alpha2 receptors in the brain.”

13. Methyldopa is contraindicated if a patient has active

a. hepatic disease.

“Methyldopa is contraindicated if a patient has active hepatic disease.”

14. ______is an intraoperative complication of cataract surgery, characterized by intraoperative pupillary constriction.

c. Floppy iris syndrome

“Floppy iris syndrome is an intraoperative complication of cataract surgery. It is characterized by intraoperative pupillary constriction,...”

15. ______dilates arterioles and decreases systemic vascular resistance (SVR).

b. Hydralazine

“Hydralazine dilates arterioles and decreases SVR.”

72

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Reference Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Cardura (2016). [package insert]. New York, NY; Pfizer: 06/2016. Retrieved online from http://labeling.pfizer.com/ShowLabeling.aspx?id=538#section-8.1. 2. Minipress [package insert]. New York, NY; Pfizer: 09/2016. Retrieved online from http://labeling.pfizer.com/ShowLabeling.aspx?id=637. 3. UpToDate (2018). Terazosin. Retrieved online from https://www.uptodate.com/contents/terazosin-drug- information?search=Terazosin&source=search_result&selectedTitle=1 ~26&usage_type=default&display_rank=1. 4. Kim GJ, Lee KH, Kim JH. (2018). South Korean geriatrics on Beers Criteria medications at risk of adverse drug events. PLoS One. 2018 Mar 15;13(3):e0191376. doi: 10.1371/journal.pone.0191376. eCollection 2018. 5. Kauffman H. (2015). Mechanisms, causes, and evaluation of orthostatic hypotension. UpToDate. June 5, 2015. Retrieved online from https://www.uptodate.com/contents/mechanisms-causes-and- evaluation-of-orthostatic-hypotension. 6. Page RL 2nd, O'Bryant CL, Cheng D, et al; (2016). American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement from the American Heart Association [published correction appears in Circulation. 2016;134(12):e261]. Circulation. 2016;134(6): e32-e69. 7. James PA, Oparil S, Carter BL, et al. (2014). 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520. 8. Whelton PK, Carey RM, Aronow WS, et al. (2017). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice

73

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Guidelines. J Am Coll Cardiol. 2017 Nov 7. pii: S0735-1097(17)41519- 1. doi: 10.1016/j.jacc.2017.11.006. [Epub ahead of print] 9. Mann JFE. (2017). Choice of drug therapy in primary (essential) hypertension. UpToDate. December 18, 2017. Retrieved online from https://www.uptodate.com/contents/choice-of-drug-therapy-in- primary-essential-hypertension. 10. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. (2003). Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2003;42(3):239-246. 11. Chapman N, Chang CL, Dahlöf B, et al. (2008). Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial. Circulation. 2008;118(1):42-48. 12. Spoladore R, Roccaforte R, Fragasso G, et al. (2009). Safety and efficacy of doxazosin as an "add-on" antihypertensive therapy in mild to moderate heart failure patients. Acta Cardiol. 2009;;64(4):485-491. 13. Penenberg D, Chung M, Walmsley P, Vashi V. (2000). The effects of hepatic impairment on the pharmacokinetics of doxazosin. J Clin Pharmacol. 2000;40(1):67-73. 14. Chang DF, Campbell JR. (2005). Intraoperative floppy iris syndrome associated with tamsulosin. J. Cataract Refract. Surg. 2005;31(4), 664–673. 15. Jacobs DS. (2017). Cataracts in adults. UpToDate. August 30, 2017. Retrieved online from https://www.uptodate.com/contents/cataract-in- adults#!. 16. Kaczmarek IA, Prost ME, Wasyluk J. (2018). Clinical risk factors associated with intraoperative floppy iris syndrome: a prospective study. Int Ophthalmol. 2018 Mar 17. doi: 10.1007/s10792-018-0840- 3. [Epub ahead of print] 17. Vollman DE, Gonzalez-Gonzalez LA, Chomsky A, et al. (2014). Intraoperative floppy iris and prevalence of intraoperative complications: results from ophthalmic surgery outcomes database. Am J Ophthalmol. 2014; 157)6):1130-1135. 18. Chatziralli IP, Peponis V, Parikakis E, et al. (2016). Risk factors for intraoperative floppy iris syndrome: a prospective study. Eye (Lond). 2016;30(8):1039-1344. 19. Issa SA, Hadid OH, Baylis O, Dayan M. (2008). Alpha antagonists and intraoperative floppy iris syndrome: A spectrum. Clin Ophthalmol. 2008;2(4):735-741. 20. Khera M, Cunningham GR. (2018). Treatment of male sexual dysfunction. UpToDate. February 5, 2018. Retrieved online from

74

nursece4less.com nursece4less.com nursece4less.com nursece4less.com https://www.uptodate.com/contents/treatment-of-male-sexual- dysfunction. 21. Cunningham GR, Kadmon D. (2018). Medical treatment of benign prostatic hyperplasia. UpToDate. February 23, 2018. Retrieved online from https://www.uptodate.com/contents/medical-treatment-of- benign-prostatic-hyperplasia#!. 22. LexiComp® Drug Interaction. (2018). Retrieved online from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 23. Hammond KP, Nielsen C, Linnebur SA, et al. (2014). Priapism induced by boceprevir-CYP3A4 inhibition and α-adrenergic blockade: case report. Clin Infect Dis. 2014;58(1):e35-e38. 24. Jensen BP, Dalrymple JM, Begg EJ. (2013). Transfer of doxazosin into breast milk. J Hum Lact. 2013;29(2):150-153. 25. Versmissen J, Koch BC, Roofthooft DW et al. (2016). Doxazosin treatment of pheochromocytoma during pregnancy: Placental transfer and disposition in breast milk. Br J Clin Pharmacol. 2016;82(2):568- 569. 26. National Library of Medicine. TOXNET: LactMed. Doxazosin. Retrieved online from https://toxnet.nlm.nih.gov/cgi-bin/sis/search2. 27. National Library of Medicine. TOXNET: LactMed. Prazosin. Retrieved online from https://toxnet.nlm.nih.gov/cgi- bin/sis/search2/f?./temp/~j7pYu3:4 28. National Library of M\medicine. TOXNET: LactMed. Terazosin. Retrieved online from https://toxnet.nlm.nih.gov/cgi-bin/sis/search2. 29. Satar S, Sebe A, Avci A, Yesilagac H, Gokel Y. (2005). Acute intoxication with doxazosin. Hum Exp Toxicol. 2005;24(6):337-339. 30. Gokel Y, Dokur M, Paydaş S. (2000). Doxazosin overdosage. Am J Emerg Med. 2000;18(5):638-639. 31. Lip GY, Ferner RE. (1995). Poisoning with anti-hypertensive drugs: alpha-adrenoceptor antagonists. J Hum Hypertens. 1995;9(7):523- 526. 32. Seak CJ, Lin CC. (2008). Acute intoxication with terazosin. Am J Emerg Med. 2008;117.e5-e6. 33. McClean WJ. (1976). Letter: Prazosin overdose. Med J Aust. 1976;1(16):592. 34. Rygnestad TK, Dale O. (1983). Self-poisoning with prazosin. Acta Med Scand. 1983;213(2):1657-158. 35. Lenz K, Druml W, Kleinberger G, Laggner A, Schneeweiss B. (1985). Acute intoxication with prazosin: case report. Hum Toxicol. 1985;4(1):53-56. 36. IBM Micromedex. Poisindex.® Alpha-adrenergic blockers. Retrieved online from https//dhremoteaccess.dhha.org

75

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 37. Lexicomp (2018). Drug Information:Guanfacine. Retrieved online from https://www.uptodate.com/contents/guanfacine-drug- information?source=history_widget. 38. American Geriatrics Society 2015 Beers Criteria Expert Panel. (2015). American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246. 39. Weber MA, Schiffrin EL, White WB, et al. (2014). Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens. 2014;32(1):3-15. 40. Calhoun DA, Townsend RR. (2018). Treatment of resistant hypertension. UpToDate. February 27, 2018. Retrieved online from https://www.uptodate.com/contents/treatment-of-resistant- hypertension#!. 41. Carchman SH, Sica DA, Davis J, et al. (1989). Steady-state plasma levels and pharmacokinetics of guanfacine in patients with renal insufficiency. Nephron. 1989;53(1):18-23. 42. Kiechel JR. (1986). Pharmacokinetics of guanfacine in patients with impaired renal function and in some elderly patients. Am J Cardiol. 1986;57(9):18E-21E. 43. Kirch W, Köhler H, Braun W. (1980). Elimination of guanfacine in patients with normal and impaired renal function. Br J Clin Pharmacol. 1980;10 Suppl 1:33S-35S. 44. Lexicomp® Drug Interactions. (2018). Beta Blockers/Alpha2 Agonists. 2018. Retrieved online from https://www.uptodate.com/drug- interactions/?source=responsive_home#di-document. 45. Higuchi M, Overlack A, Stumpe KO. (1980). Evaluation of long-term treatment of essential hypertension with guanfacine. Br J Clin Pharmacol. 1980;10 Suppl 1:61S-64S. 46. Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management, Wolraich M, Brown L, et al. (2011). ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007- 1022. 47. Kisicki JC, Fiske K, Lyne A. (2007). Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years. Clin Ther. 2007;29(9):1967-1979. 48. National Library of Medicine. TOXNET: LactMed. Guanfacine. Retrieved online from https://toxnet.nlm.nih.gov/cgi-bin/sis/search2.

76

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 49. Philipp E. (1980). Guanfacine in the treatment of hypertension due to pre-eclamptic toxaemia in thirty women. Br J Clin Pharmacol. 1980;10 (Suppl 1):137S-140S. 50. Walton J, Byrum M, Shumaker A, Coury DL. (2014). Prolonged bradycardia and hypotension following guanfacine extended release overdose. J Child Adolesc Psychopharmacol. 2014;24(8):463-465. 51. Fontane E, Shiber J. (2013). A somnolent 2-year-old boy with a hyperactive brother. Pediatr Emerg Care. 2013;29(9):1033-1036. 52. Fein DM, Hafeez ZF, Cavagnaro C. (2013). An overdose of extended- release guanfacine. Pediatr Emerg Care. 2013;29(8):929-931. 53. Tsze DS, Dayan PS. (2012). Treatment of guanfacine toxicity with naloxone. Pediatr Emerg Care. 2012;28(10):1060–1061. 54. Minns AB, Clark RF, Schneir A. (2010). Guanfacine overdose resulting in initial hypertension and subsequent delayed, persistent orthostatic hypotension. Clin Toxicol (Phila). 2010;48(2):146-148. 55. Van Dyke MW, Bonace AL, Ellenhorn MJ. (1990). Guanfacine overdose in a pediatric patient. Vet Hum Toxicol. 1990;32(1):46–47. 56. McGrath JC, Klein-Schwartz W. (2002). Epidemiology and toxicity of pediatric guanfacine exposures. Ann Pharmacother. 2002; 36(11):1698-1703. 57. IBM Micormedex.® Poisindex. Guanfacine. Retrieved online from https//dhremoteaccess.dhha.org 58. Lexicomp (2018). Methyldopa. UptoDate. Retrieved online from https://www.uptodate.com/contents/methyldopa-drug- information?search=methyldopa&source=search_result&selectedTitle= 1~57&usage_type=default&display_rank=1#F195009. 59. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007. 60. Gardiner S. (2001). Drug Safety in Lactation. MEDSAFE. Retrieved online from http://www.medsafe.govt.nz/Profs/PUarticles/lactation.htm. 61. American College of Obstetricians and Gynecologists (ACOG) (2013). Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1131. 62. Mah GT, Tejani AM, Musini VM. (2009). Methyldopa for primary hypertension. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD003893. doi: 10.1002/14651858.CD003893.pub3. 63. McComb MN, Chao JY, Ng TM. (2016). Direct vasodilators and sympatholytic agents. J Cardiovasc Pharmacol Ther. 2016;21(1):3-19. 64. August P. (2018). Management of hypertension in pregnant and postpartum women. UpToDate. March 19, 2018. Retrieved online from

77

nursece4less.com nursece4less.com nursece4less.com nursece4less.com https://www.uptodate.com/contents/management-of-hypertension-in- pregnant-and-postpartum-women. 65. Fitton CA, Steiner MFC, Aucott L, et al. (2017). In-utero exposure to antihypertensive medication and neonatal and child health outcomes: a systematic review. J Hypertens. 2017;35(11):2123-2137. 66. Hoeltzenbein M, Beck E, Fietz AK, et al. (2017). Pregnancy outcome after first trimester use of methyldopa: A prospective cohort study. Hypertension. 2017;70(1):201-208. 67. Moses A, Zahger D, Amir G. (1989). Cholestatic liver injury after prolonged exposure to methyldopa. Digestion. 1989;42(1):57-60. 68. Bezahler GH. (1982). Fatal methyldopa-associated granulomatous hepatitis and myocarditis. Am J Med Sci. 1982;283(1):41-45. 69. Picaud A, Walter P, de Préville G, Nicolas P. (1990). Fatal toxic hepatitis in pregnancy. A discussion of the role of methyldopa. [Article in French]. J Gynecol Obstet Biol Reprod (Paris). 1990;19(2):192-196. 70. Seggie J, Saunders SJ, Kirsch RE, et al. (1979). Patterns of hepatic injury induced by methyldopa. S Afr Med J. 1979;55(3):75-83. 71. Toghill PJ, Smith PG, Benton P, Brown RC, Matthews HL. (1974). Methyldopa liver damage. Br Med J. 1974;3(5930):545-548. 72. Rodman JS, Deutsch DJ, Gutman SI. (1976). Methyldopa hepatitis. A report of six cases and review of the literature. Am J Med. 1976;60(7):941-948 73. Firoz T, Webber D, Rowe H. (2015). Drug-induced fulminant hepatic failure in pregnancy. Obstet Med. 2015;8(4):190-192. 74. Kashkooli S, Baraty B, Kalantar J. (2014). α-Methyldopa-induced hepatitis during the postpartum period. BMJ Case Rep. 2014 Feb 27;2014. pii: bcr2014203712. doi: 10.1136/bcr-2014-203712. 75. Slim R, Ben Salem C, Hmouda H, Bouraoui K. (2010). Hepatotoxicity of alpha-methyldopa in pregnancy. J Clin Pharm Ther. 2010;35(3):361-363. 76. Ozsvár Z, Solymossi Z, Monostory K. (2010). Methyldopa-induced acute reactive hepatitis in pregnancy, drug-metabolizing capacity of the liver. [Article in Hungarian]. Orv Hetil. 2010;151(11):457-461. 77. National Institutes of Health. (2018). LiverTox. Methyldopa. April 4, 2018. Retrieved online from https://livertox.nlm.nih.gov/Methyldopa.htm. 78. Neil EM, Waters AK. (1981). Generalized choreiform movements as a complication of methyldopa therapy in chronic renal failure. Postgrad Med J. 1981;57(673):732-733. 79. Yamadori A, Albert ML. (1972). Involuntary movement disorder caused by methyldopa. N Engl J Med. 1972;286(11):610. 80. Pai RG, Pai SM. (1988). Methyldopa-induced reversible immune thrombocytopenia. Am J Med. 1988 Jul;85(1):123

78

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 81. Polk OD, Kletter GG, Smith J, Castro O. (1982). Impaired clot retraction in thrombocytopenia due to methyldopa. South Med J. 1982 Mar;75(3):374-375. 82. Marcus GJ, Stevenson M, Brown T. (1975). Alpha-methyldopa-induced immune thrombocytopenia. Report of case. Am J Clin Pathol. 1975;64(1):113-115. 83. Clark KG. (1967). Haemolysis and agranulocytosis complicating treatment with methyldopa. Br Med J. 1967;4(5571):94. 84. Closs SP, Cummins D, Contreras M, Armitage SE. (1984). Neutropenia due to methyldopa antibodies. Lancet. 1984;1(8392):1479. 85. van der Klauw MM, Wilson JH, Stricker BH. (1998). Drug-associated agranulocytosis: 20 years of reporting in The Netherlands (1974- 1994). Am J Hematol. 1998;57(3):206-211. 86. Grigoriadis C, Tympa A, Liapis A, Hassiakos D, Bakas P. (2013). Alpha- methyldopa-induced autoimmune hemolytic anemia in the third trimester of pregnancy. Case Rep Obstet Gynecol. 2013;2013:150278. doi: 10.1155/2013/150278. Epub 2013 Sep 23. 87. Murphy WG, Kelton JG. (1988). Methyldopa-induced autoantibodies against red blood cells. Blood Rev. 1988;2(1):36–42 88. National Library of Medicine. TOXNET. LactMed: Methyldopa. Retrieved online from. https://toxnet.nlm.nih.gov/cgi- bin/sis/search2/f?./temp/~umjZmX:5. 89. IBM Micromedex.® Poisindex. Methyldopa. Retrieved online from https//dhremoteaccess.dhha.org. 90. Chan TY, Joynt GM. (2014). Prolonged profound hypotension complicating severe methyldopa overdose. Int J Clin Pharmacol Ther. 2014;52(7):628-30. 91. Shnaps Y, Almog S, Halkin H, Tirosh M. (1982). Methyldopa poisoning. J Toxicol Clin Toxicol. 1982;19(5):501-503. 92. Lexicomp (2018). Hydralazine. UpToDate. Retrieved online from https://www.uptodate.com/contents/hydralazine-drug- information?search=hydralazine&source=search_result&selectedTitle= 1~117&usage_type=default&display_rank=1#F179437. 93. Rosendorff C, Lackland DT, Allison M, et al; American Heart Association, American College of Cardiology, and American Society of Hypertension. (2015). Treatment of hypertension in patients with coronary artery disease: A scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Soc Hypertens. 2015;9(6):453-498. 94. Anderson PO, Sauberan JB. (2016). Modeling drug passage into human milk. (2016). Clin Pharmacol Ther. 2016;100(1):42-52. 95. Elliot WJ, Varon J. (2016). Drugs used for the treatment of hypertensive emergencies. UpToDate. June 6, 2016. Retrieved online

79

nursece4less.com nursece4less.com nursece4less.com nursece4less.com from https://www.uptodate.com/contents/drugs-used-for-the- treatment-of-hypertensive-emergencies#!. 96. August P. (2018). Management of hypertension in pregnant and postpartum women. UpToDate. March 19, 2018. Retrieved online from https://www.uptodate.com/contents/management-of-hypertension-in- pregnant-and-postpartum-women. 97. Gaynor MF, Wright GC, Vondracek S. (2018). Retrospective review of the use of as-needed hydralazine and labetalol for the treatment of acute hypertension in hospitalized medicine patients. Ther Adv Cardiovasc Dis. 2018;12(1):7-15. 98. Khan A, Hafeez S, Nasrullah FD. (2017). Comparison of hydralazine and labetalol to lower severe hypertension in pregnancy. Pak J Med Sci. 2017;33(2):466-470. 99. Sharma KJ, Rodriguez M, Kilpatrick SJ, Greene N, Aghajanian P. (2016). Risks of parenteral antihypertensive therapy for the treatment of severe maternal hypertension are low. Hypertens Pregnancy. 2016;35(1):123-128. 100. Sharma C, Soni A, Gupta A, Verma A, Verma S. (2017). Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial. Am J Obstet Gynecol. 2017;217(6):100. 687.e1-687. doi: 10.1016/j.ajog.2017.08.018. Epub 2017 Sep 1. 101. de Boer YS, Kosinski AS, Urban TJ, et al. (2017). Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol. 2017 Jan;15(1):103-112.e2. doi: 10.1016/j.cgh.2016.05.043. Epub 2016 Jun 14. 102. Stine JG, Northup PG. (2016). Autoimmune-like drug-induced liver injury: a review and update for the clinician. Expert Opin Drug Metab Toxicol. 2016 Jul 21:1-11. [Epub ahead of print] 103. Hassan A, Hammad R, Cucco R, Niranjan S. (2009). Hydralazine- induced cholestatic hepatitis. Am J Ther. 2009;16(4):371-373. 104. Harati H, Rahmani M, Taghizadeh S. (2016). Acute cholestatic liver injury from hydralazine intake. Am J Ther. 2016;23(5): e1211-e1214. 105. Alansari A, Quiel L, Boma N. (2016). A one-two punch: Hydralazine- induced liver injury in a recovering ischemic hepatitis. Am J Ther. 2016;23(4):e1094-e1095. 106. Bartoli E, Massarelli G, Solinas A, Faedda R, Chiandussi L. (1979). Acute hepatitis with bridging necrosis due to hydralazine intake. Report of a case. Arch Intern Med. 1979;139(6):698-699. 107. Mann JFE. (2018). Overview of hypertension in acute and chronic kidney disease. UpToDate. March 3, 2018. Retrieved online from https://www.uptodate.com/contents/overview-of-hypertension-in- acute-and-chronic-kidney-disease#! 108. Mann JFE. (2017). Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults. UpToDate. October 11, 80

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2017. Retrieved online from https://www.uptodate.com/contents/antihypertensive-therapy-and- progression-of-nondiabetic-chronic-kidney-disease-in-adults. 109. Taylor AL, Ziesche S, Yancy C, et al. (2004). Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351(20):2049-2057. 110. Ferdinand KC, Elkayam U, Mancini D, et al. (2014). Use of isosorbide dinitrate and hydralazine in African-Americans with heart failure 9 years after the African-American Heart Failure Trial. Am J Cardiol. 2014;114(1):151-159. 111. Nishimura RA, Otto CM, Bonow RO, et al. (2014). 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):2440-2492. 112. Holman SK, Parris D, Meyers S, Ramirez J. (2017). Acute low-dose hydralazine-induced lupus pneumonitis. Case Rep Pulmonol. 2017;2017:2650142. doi: 10.1155/2017/2650142. Epub 2017 Aug 8. 113. Merola JF. (2017). Drug-induced lupus. UpToDate. January 11, 2017. Retrieved online from https://www.uptodate.com/contents/drug- induced-lupus 114. Handler J. Hydralazine-induced lupus erythematosis. J Clinl Hypertension. 2012;14(2):133–136. 115. National Library of Medicine. TOXNET. LactMed. Hydralazine. Retrieved online from https://toxnet.nlm.nih.gov/cgi- bin/sis/search2/f?./temp/~VzMxcP:1. 116. American Congress of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice. (2017). Committee Opinion No. 692: emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol. 2017;129(4): e90-e95. 117. Lexicomp (2018). Drug information: Minoxidil. UpToDate. Retrieved online from https://www.uptodate.com/contents/minoxidil-systemic- drug- information?search=minoxidil%20adult&source=search_result&selecte dTitle=1~39&usage_type=default&display_rank=1#F8774881. 118. Weber MA, Schiffrin EL, White WB, et al. (2014). Clinical Practice Guidelines for the Management of Hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hyperten (Greenwich). 2014;16(1):14-26 119. Mundt HM, Matenaer M, Lammert A, et al. (2016). Minoxidil for treatment of resistant hypertension in chronic kidney disease--A

81

nursece4less.com nursece4less.com nursece4less.com nursece4less.com retrospective cohort analysis. J Clin Hypertens (Greenwich). 2016;18(11):1162-1167. 120. Cohn JN, McInnes GT, Shepherd AM. (2011). Direct-acting vasodilators. J Clin Hypertens (Greenwich). 2011;13(9):690-692. 121. McComb MN, Chao JY, Ng TM. (2016). Direct vasodilators and sympatholytic agents. J Cardiovasc Pharmacol Ther. 2016;21(1):3–19 122. Martin WB, Spodick DH, Zins GR. (1980). Pericardial disorders occurring during open-label study of 1,869 severely hypertensive patients treated with minoxidil. J Cardiovasc Pharmacol. 1980;2 Suppl 2:S217-S227. 123. Çilingiroğlu M, Akkuş N, Sethi S, Modi KA. (2012). Large pericardial effusion induced by minoxidil. Turk Kardiyol Dern Ars. 2012;40(3):255-258. 124. Martin WB, Spodick DH, Zins GR. (1980). Pericardial disorders occurring during open-label study of 1,869 severely hypertensive patients treated with minoxidil. J Cardiovasc Pharmacol. 1980;2 Suppl 2:S217-S227. 125. Pasala KK, Gujja K, Prabhu H, Vasavada B, Konka S. (2012). Short- term minoxidil use associated with pericardial effusion and cardiac tamponade: an uncommon presentation. Am J Ther. 2012;19(6):e186-e188. 126. Krehlik JM, Hindson DA, Crowley JJ Jr, Knight LL. (1985). Minoxidil- associated pericarditis and fatal cardiac tamponade. West J Med. 1985;143(4):527-529. 127. Sica DA. (2004). Minoxidil: an underused vasodilator for resistant or severe hypertension. J Clin Hypertens (Greenwich). 2004;6(5):283- 287. 128. Chellini PR, Pirmez R, Raso P, Sodré CT. (2015). Generalized hypertrichosis induced by topical minoxidil in an adult woman. Int J Trichology. 2015;7(4):182-183. 129. Rai AK. (2017). Minoxidil-induced hypertrichosis in a child with alopecia areata. Indian Dermatol Online J. 2017;8(2):147-148. 130. Valdivieso A, Valdes G, Spiro TE, Westerman RL. (1985). Minoxidil in breast milk. Ann Intern Med. 1985; 102:135. Letter. 131. National Library of Medicine. TOXNET. LactMed: Minoxidil. Retrieved online from https://toxnet.nlm.nih.gov/cgi-bin/sis/search2. 132. Smorlesi C, Caldarella A, Caramelli L, Di Lollo S, Moroni F. (2003). Topically applied minoxidil may cause fetal malformation: a case report. Birth Defects Res A Clin Mol Teratol. 2003;67(12):997-1001. 133. Smith BA, Ferguson DB. (1992). Acute hydralazine overdose: marked ECG abnormalities in a young adult. Ann Emerg Med. 1992;21(3):326- 330. 134. Isles C, Mackay A, Barton PJ, Mitchell I. (1981). Accidental overdosage of minoxidil in a child. Lancet. 1981;1(8211):97. 82

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 135. Poff SW, Rose SR. (1992). Minoxidil overdose with ECG changes: case report and review. J Emerg Med. 1992;10(1):53-57. 136. Farrell SE, Epstein SK. (1999). Overdose of Rogaine Extra Strength for Men topical minoxidil preparation. J Toxicol Clin Toxicol. 1999;37(6):781-783. 137. MacMillan AR, Warshawski FJ, Steinberg RA. (1993). Minoxidil overdose. Chest. 1993;103(4):1290-1291. 138. McCormick MA, Forman MH, Manoguerra AS. (1998). Severe toxicity from ingestion of a topical minoxidil preparation. Am J Emerg Med. 1989;7(4):419-421. 139. Garrard A, Wood A, Sollee D, Aaronson P. (2011). Refractory hypotension due to Rogaine® (minoxidil) ingestion managed with midodrine. Clin Toxicol (Phila). 2011;49(10):907-909. 140. [No authors listed]. (2015). Topical minoxidil: accidental poisoning in children. Prescrire Int. 2015;24(159):97. 141. IBM Micromedex.® Poisindex. Vasodilators. Retrieved online from https//dhremoteaccess.dhha.org.

83

nursece4less.com nursece4less.com nursece4less.com nursece4less.com