Glaucoma Management for Pharmacists

Release Date: April, 2010

Expiration Date: April 30, 2012
Karen K. O’Brien, BS Pharm, PharmD
Pharmacy Sciences Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Alan W. Y. Chock, PharmD
Pharmacy Practice Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Catherine A. Opere, PhD
Pharmacy Sciences Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska

Glaucoma is a chronic disease of the eye characterized by progressive neuropathy of the optic nerve (ON) that can lead to irreversible blindness if untreated or inadequately treated. Primary open-angle glaucoma (POAG), the most common form of this disorder, affects approximately 2.2 million individuals in the United States and is strongly associated with increased intraocular pressure (IOP) and aging.^1-3
As the proportion of elders in the U.S. continues to rise, estimates target greater than 3 million cases of POAG by 2020.³ Because the disease is largely asymptomatic, many persons may be unaware they have POAG until loss of vision occurs. Thus, glaucoma represents an important public health concern. The purpose of this article is to provide an overview of the disease process and treatment strategies, allowing pharmacists to help improve care for their patients with glaucoma.

CLASSIFICATION

Glaucoma is not a single disease, but a group of disorders resulting in optic neuropathy and vision loss. These may be broadly classified as open angle or angle-closure glaucoma (ACG) based on the anatomy of the eye’s anterior chamber, and are further classified as primary or secondary. Primary glaucoma refers to a glaucomatous eye with no pre-existing disease, while secondary glaucoma results from other ocular or systemic disease, trauma, or the effects of some drugs.^2,4 Underlying pathology must be addressed when treating secondary glaucomas.
Primary ACG represents a medical emergency because permanent blindness may quickly develop if it is not promptly treated.⁴ Further discussion will be limited to POAG.

ANATOMY AND PHYSIOLOGY

The eye is broadly divided into the anterior and posterior segments (FIGURE 1). The anterior segment begins at the limbus and consists of the cornea, anterior and posterior chambers (not to be confused with anterior and posterior segments), pupil, iris, lens, zonules, and ciliary body. The posterior segment lies posterior to the anterior segment and consists of the vitreous chamber, retina, choroid, sclera, optic disc, and ON. The trabecular meshwork and Schlemm’s canal are part of the limbus, a transitional structure between the sclera and cornea (FIGURE 2). The uvea is the vascular middle layer of the eye, consisting of the iris and ciliary body in the anterior segment and the choroid in the posterior segment. The anterior segment is further divided into anterior and posterior chambers by the lens-iris diaphragm. The anterior chamber is defined by the iris (forms the floor) and cornea (forms the roof) (FIGURE 2). The trabecular meshwork is positioned at the point where the cornea and iris meet, and forms the apex of the anterior chamber angle of the eye. The trabecular meshwork is a sievelike structure that filters and controls the flow of aqueous humor (AH) from the anterior chamber into Schlemm’s canal, ultimately leading to the bloodstream.
The posterior chamber is bordered laterally by the ciliary processes. The lens surface forms the floor and the posterior surface of the iris forms the roof of the chamber (FIGURE 2).

Aqueous Humor Hydrodynamics

AH functions to maintain the global shape of the eye; supply nourishment to the avascular lens, cornea, and trabecular meshwork; and remove metabolic waste. AH also participates in immunologic responses, contributes to the optical system by providing a transparent refractive medium between lens and cornea, and facilitates some ocular distribution of drugs.⁵ AH is derived from plasma within the capillary network of the ciliary processes (FIGURE 2) and is continually secreted into the posterior chamber at a rate of approximately 2.7 μL per minute in healthy individuals.⁶ The entire chamber content is replaced every 100 minutes to 2 hours.
From the posterior chamber, AH flows through the pupil into the anterior chamber to exit the eye via conventional and unconventional pathways. The conventional pathway accounts for the majority of outflow and refers to AH coursing through the trabecular meshwork and the canal of Schlemm, ultimately draining into the systemic circulation (FIGURE 2).

In unconventional pathways, AH seeps through tissues rather than flowing through the usual channels and vessels. The most common unconventional pathway is the uveoscleral pathway in which AH drains from the base of the ciliary muscle, through tissues in and around the uvea, and eventually into the sclera.⁵
Intraocular Pressure IOP refers to the pressure generated by flow of AH against resistance within ocular structures. IOP, maintained at about 15 mmHg in healthy individuals, is determined by a delicate balance between the rates of AH entering (inflow) and leaving (outflow) the eye. Whereas inflow is dependent upon rate of production of AH, outflow is regulated by resistance to aqueous drainage.⁷ Any condition that alters the equilibrium between inflow and outflow of AH may result in abnormal IOP levels. Resistance to outflow is usually responsible for elevated IOP, but other factors may contribute.⁵

PATHOPHYSIOLOGY AND ETIOLOGY

A basic understanding of the relationship between elevated IOP and visual loss will help the pharmacist appreciate clinical findings and the importance of lowering IOP in glaucoma.
Irrespective of cause, degeneration of retinal ganglion cells (RGCs) is a feature common to all forms of optic neuropathy. RGCs, specialized nerve cells localized within the retina, transmit visual information from retinal photoreceptor cells, via the ON, to the visual cortex in the brain. Axonal fibers projecting from RGCs converge at the optic disc and exit the eye through a meshwork of collagen fibers known as the lamina cribosa (FIGURE 3). In addition to RGC axons, the normal optic disc contains retinal vasculature (central artery and vein) and glial elements that provide support and protection to the neurons. The center of the optic disc does not contain RGC axons and is known as the cup because it appears as a concave indentation on ophthalmic examination (FIGURE 3).

Elevated IOP and RGC Degeneration

As indicated inFIGURE 3, elevation in IOP exerts pressure posteriorly to cause both structural and functional damage to the optic disc. The tough sclera that envelops most of the posterior segment of the eye is relatively immobile, but the gelatinous lamina cribosa is pushed posteriorly with increased IOP. This displacement is thought to cause structural changes in the meshwork of the lamina cribosa. The deformed meshwork is presumed to pinch the nerve fibers and blood vessels present in the ON bundle, resulting in damage to RGC axons and ultimately death to RGCs.⁵ This pathologic process can be seen upon ophthalmic examination as increased optic disc cupping. The diameter of the cup can be compared to that of the entire optic disc (cup-to-disc ratio). The cup-to-disc ratio correlates with extent of ON fiber damage. Disc cupping is important for differential diagnosis of glaucoma from other ocular neuropathies. Functional changes include progressive loss of visual field, short wavelength color sensitivity, spatial resolution, and temporal contrast sensitivity.⁵ Damaged ON fibers cannot be regenerated, and loss of vision is irreversible.

CLINICAL FINDINGS

POAG is a chronic eye disease that is generally progressive. Typically, both eyes are affected, although not necessarily to the same extent. Because symptoms are minimal or absent early in the disease process, a thorough eye examination is essential. In establishing a diagnosis of POAG, the clinician seeks evidence of ON damage. Structural abnormalities in the optic disc or retinal nerve bundle and/or loss of visual field confirm damage. A dilated eye examination is preferred to properly assess the ON. Perimetry testing is used to evaluate the visual field, the full visible range when the eye is fixated straight ahead. In POAG, vision loss usually begins peripherally and moves centrally. Most commonly, structural defects precede vision deficits.¹ Refer to TABLE 1 for other characteristic clinical findings.

Table 1. Characteristic Clinical Findings in POAG Evidence of optic nerve damage (from either or both categories) 1. Optic disc or retinal nerve fiber structural abnormality 2. Visual field abnormality Adult onset Open anterior chamber angles Absence of other reasons for glaucomatous changes Elevated IOP (may or may not be present)

IOP: intraocular pressure; POAG: primary open-angle glaucoma. Source: Reference 1.

Gonioscopy involves examination of the anterior chamber angle through a special contact lens (goniolens), while IOP is measured via tonometry. IOP is often elevated above the normal range (10-21 mmHg), but a significant portion of patients with POAG have normal IOP levels.¹ Conversely, elevated IOP levels do not always indicate POAG. Patients with above-normal IOP but no evidence of ON damage are said to have ocular hypertension. These individuals may or may not receive treatment to lower IOP, based on patient-specific factors. However, they should be monitored closely over time since IOP elevation constitutes a risk for developing POAG. Of note, an IOP measurement only provides a snapshot of the pressure at a given moment in time. Diurnal fluctuation may mask elevated IOP. Tonometric assessment on different days or at varying times of the day may help supply a more accurate measure of IOP.¹
Assessment of the optic disc and visual-field testing are also used to monitor for disease progression and efficacy of therapeutic interventions. While lowering IOP is presumed to decrease disease progression, it is not a surrogate measure of visual function.⁴

RISK FACTORS

IOP is a significant risk factor in the pathogenesis of glaucoma. There is evidence that an increase in IOP is proportional to the prevalence of glaucoma.⁸ Large variation in IOP is an additional risk factor for glaucoma. In nonglaucomatous eyes, IOP varies with circadian rhythm by about 2 to 4 mmHg over a 24-hour period, with peak values observed in the morning hours.⁹ An increase in magnitude of variation above 10 mmHg increases the risk of ON head (optic disc) damage and is considered pathologic.¹⁰
In addition to elevated IOP, increasing age, family history of glaucoma, and African or Hispanic/Latino race are consistently linked to an increased risk of glaucoma.^1-4,11 A meta-analysis of population-based data identified three times the prevalence of POAG in black as compared to white persons. Prevalence in Hispanic/Latino persons was similar to that in white persons except in those over 65 years, in whom significantly higher rates were found.³ Other factors possibly related to POAG include thinner central corneal thickness, diabetes, systemic hypertension, a history of ocular trauma, reduced blood flow to the ON, myopia (nearsightedness), and vasospastic conditions such as Raynaud’s disease or migraines.^1-4

GOALS OF THERAPY

The primary purpose of therapy is to enhance the patient’s quality of life by preserving vision and minimizing adverse therapeutic effects.^1,4 Goals that support therapeutic purpose include stabilizing ON/retinal nerve fiber status and visual fields; controlling IOP; and educating and involving the patient in disease management.¹

TREATMENT STRATEGIES

All current treatment modalities aim to reduce IOP.^1,4 Finding an IOP range that allows for stabilization of visual fields and ON/retinal nerve fiber status is often a process of trial and error. The upper limit of that range is referred to as the target pressure. The clinician assumes pretreatment IOP resulted in optic neuropathy and endeavors to reduce initial IOP target pressure by at least 20%. Once therapy is initiated, IOP measurement and ON assessment guide therapeutic adjustments.¹
Present options for managing glaucoma include pharmacologic therapy and surgical modalities such as laser trabeculoplasty and filtering or cyclodestructive surgery. Each has associated benefits and risks, and patient-specific factors and preferences must be considered when selecting appropriate initial therapy. Therapies may be combined to achieve treatment goals. Topical medications are an effective first approach in many patients, although laser trabeculoplasty may be an acceptable option. In some patients, filtering surgery may be preferred initially.¹

Surgical Management of Glaucoma

Laser Trabeculoplasty: This procedure increases outflow via the conventional pathway. Inflammation is the most common adverse effect. Pharmacologic therapy may be necessary posttreatment, and beneficial effects may dissipate over time, necessitating further treatment.⁴
Filtering Surgery: Trabeculotomy, which creates an alternative pathway for AH drainage, is often performed after medication and laser therapies have failed. Best results are achieved in patients with no prior eye surgeries. Cataracts, corneal problems, intraocular inflammation, growth of scar tissue, and infection are possible adverse effects.¹
Cyclodestructive Surgery: This method for lowering IOP destroys the ciliary body epithelial tissue, resulting in a permanent reduction in AH production. Loss of visual acuity and blindness may occur, so this treatment option is usually reserved for patients with poor visual acuity or those in whom standard medical, laser, or surgical modalities have failed.⁴

CASE STUDY: GLAUCOMA M.M., a 52-year-old African American woman, presents to the clinic today for an ophthalmic exam. Her last exam (5 years ago) indicated a normal IOP (10-21 mmHg). Family History: Mother: cataracts; father: death from myocardial infarction at age 63 Social History: Nonsmoker, nondrinker, married with 2 daughters Allergies: PCN (anaphylaxis) Medications: None Personal Medical History: Unremarkable Vital Signs: BP 112/78, P 70, RR 14, T 36.9°C, HT 168 cm, WT 59.3 kg General: Healthy, ambulatory female Eye Exam: Elevated IOP OU. IOP by tonometry is 25/25 mmHg. Optic disc shows mild cupping, and gonioscopy reveals open angles in the anterior chambers OU. Visual fields are normal, and visual acuity without correction is 20/20 OD and 20/40 OS. No signs of cataract formation are evident. Labs: None Physician’s Assessment: POAG 1. What signs in the visual examination are consistent with diagnosis of POAG?      • Elevated IOP by tonometry—25 mmHg OU.      • Optic disc shows mild cupping.      • Gonioscopy reveals open angles in anterior chambers OU. 2. What are the goals of therapy for this patient?      • Reduce IOP to stop optic nerve damage.      • Preserve vision.      • Maintain patient’s quality of life—select cost-effective pharmacologic treatment with minimal        adverse effects. 3. What available ophthalmic medication would provide appropriate initial treatment of POAG for this patient?      • Since she does not have any other medical problems listed, a selective or nonselective        beta-blocker or a prostaglandin analogue is recommended first line. 4. What counseling should the pharmacist provide to this patient?      • Discuss treatment plan and rationale, so patient understands its importance.      • Discuss adheren/USPExams/compliance with treatment plan. Explain that although glaucoma         may be asymptomatic, it can lead to blindness if inadequately treated.      • Discuss common transient adverse effects—continue medication if possible.      • Discuss possible (serious/frequent) adverse effects—report to eye doctor.      • NLO and closing eye to decrease risk of systemic effects and promote optimal drug effect.      • Appropriate interval between drops if more than one drop per eye is ordered.      • Proper/aseptic technique to use with eye drops—preparation, administration, and storage.      • Shake bottle if it contains a suspension. M.M. was treated with the recommended regimen. Her IOP normalized to 18 mmHg within 3 months, following several dosage adjustments. Two years later her IOP remains normal, and her visual fields and optic nerves are stable.

BP: blood pressure; HT: height; IOP: intraocular pressure; NLO: nasolacrimal occlusion; OD: right eye; OS: left eye; OU: each eye; P: pulse; PCN: penicillin; POAG: primary open-angle glaucoma; RR: retinal reflex; T: temperature; WT: weight.

Pharmacologic Management of Glaucoma

Medications used to manage POAG decrease IOP by two primary mechanisms: decreasing AH production or increasing AH outflow (through either the conventional or unconventional pathways). Glaucoma is a chronic disease—there is no cure, and medical management must be continued throughout a person’s life.
Currently, prostaglandin analogues and beta-blockers are the most frequently used topical medications. Sympathomimetics, topical and oral carbonic anhydrase inhibitors, and cholinergics are used to a lesser degree.^1,4 Adverse effects or inadequate clinical response may necessitate a therapeutic change, while drugs with different mechanisms of action may be used in combination to maximize IOP reduction.
Many minor local adverse effects of POAG medications are transient, and knowledge of this will encourage patients to continue using prescribed medications. If an adverse effect does not subside, the patient should notify his or her eye doctor before discontinuing use of a medication so that another drug can be prescribed. Refer to TABLE 2 for a summary of therapeutic and adverse effects of POAG medications.

Table 2. Pharmacologic Agents for Glaucoma Management in the U.S.
Drug Name	Brand Name	Formulation	Dosage	Notes
Beta-blockers
Betaxolol    hydrochloride	Betoptic Betoptic S	0.25%, 0.5% solution 0.25% suspension	1-2 drops BID 1 drop BID	Clinical effect: decreases production of AH One of the most commonly used medications    for treatment Nonselective: timolol, levobunolol, metipranolol,    carteolol Beta1-selective: betaxolol Contraindications: 1. All beta-blockers: sinus bradycardia,    atrioventricular block (second or third    degree), heart failure, or cardiogenic    shock 2. Nonselective beta-blockers: asthma, COPD
Carteolol	Ocupress	1% solution	1 drop BID
Levobunolol    hydrochloride	Betagan	0.25%, 0.5% solution	1-2 drops    Q day-BID
Metipranolol	Optipranolol	0.3% solution	1 drop BID
Timolol	Betimol, Istalol,    Timoptic Timolol-XE	0.25%,0.5% solution 0.25%,0.5%    gel-forming solution	1 drop    Q day-BID 1 drop Q day
Prostaglandins
Bimatoprost	Lumigan	0.03% solution	1 drop Q day	Clinical effect: increases uveoscleral outflow;    bimatoprost may have additional effect on    outflow at trabecular meshwork One of the most commonly used medications    for treatment Pigmentation of the eye and eyelid as the most    common form of adverse effects, eyelash    effects Avoid in those with active intraocular    inflammation
Latanoprost	Xalatan	0.005% solution	1 drop Q day
Travoprost	Travatan, Travatan Z	0.004% solution	1 drop Q day
Carbonic Anhydrase Inhibitors
Acetazolamide	Diamox Sequels	250-mg, 500-mg tablet/ER capsules	Max: 1 g Q 24 h	Clinical effect: decreases production of AH Topical: used as alternative to monotherapy or    adjunctive therapy Oral: used as adjunctive therapy Caution in those with sulfonamide allergies,    renal insufficiency Avoid using concurrent ophthalmic    and oral CAIs
Brinzolamide	Azopt	1% susp	1 drop TID
Dorzolamide     hydrochloride	Trusopt	2% solution	1 drop TID
Methazolamide	(none in U.S.)	25-mg, 50-mg tablets	50 mg-100 mg BID-TID
Cholinergics
Direct-acting agonists				Clinical effect: increases AH outflow Good efficacy, but not commonly used due to     frequent adverse effects and frequent dosing Excessive miosis may induce angle-closure    glaucoma secondary to pupillary block May produce systemic cholinergic effects
Carbachol	Miostat	0.01% solution	1 mL to anterior chamber of eye
Pilocarpine	Pilopine HS	4% gel	1/2-in ribbon on lower conjunctiva at bedtime
Cholinesterase inhibitor
Echothiophate    iodide	Phospholine Iodide	0.03%, 0.06%, 0.125%, 0.25% solution	1 drop BID
Sympathomimetics
Alpha2-selective adrenergic agonists
Apraclonidine    hydrochloride	Iopidine	0.5%, 1% solution	1-2 drops TID	Clinical effects: increases AH uveoscleral     outflow Apraclonidine efficacy wears off in <1 mo Rate of allergic reactions limits use of     apraclonidine
Brimonidine    tartrate	Alphagan P	0.1%, 0.15%, 0.2% solution	1 drop TID
Nonspecific adrenergic agonists
Dipivefrin    hydrochloride	Propine	0.1% solution	1 drop BID	Clinical effects: increases conventional outflow    (primary); chronic use decreases AH    production (secondary) Epinephrine formulation no longer available in    the U.S. Dipivefrin is a prodrug of epinephrine Limited use due to frequency of adverse effects Monitor for angle-closure glaucoma,    cardiovascular and metabolic effects
Epinephrine	(none in U.S.)	0.5%, 1%, 2% solution	1-2 drops BID
AH: aqueous humor; CAIs: carbonic anhydrase inhibitors; COPD: chronic obstructive pulmonary disease; ER: extended release; Max: maximum. Source: References 27, 28.

Here are some general guidelines for the pharmacist to remember when counseling patients with POAG:
• Systemic adverse effects are rare complications of topical glaucoma medications, but they can be serious. Following instillation of topical medications, nasolacrimal occlusion (NLO) and closing the eyelid for 2 minutes will prevent excess medication from draining into the lacrimal ducts and greatly decrease the risk of systemic effects.⁴ Pharmacists should recommend these techniques to patients using POAG eye drops.
• Instruct patients in aseptic technique to prevent contamination of the container and product, and ultimately the eye. The tip of the medication container must not be allowed to contact the patient’s eye or the hand of whoever dispenses the drops.
• A patient using more than one POAG eye drop (multiple drops of the same medication or different medications) should wait at least 5 minutes between instillation of the drops.⁴
• If different ophthalmic formulations are being used, solutions should always be used before other formulations, such as gels and suspensions, to optimize absorption of each medication.
• Because POAG drugs pass through the placenta, women should inform their health care provider if they are pregnant or are trying to conceive.
Beta-Blockers: Medications in this class lower IOP via decreased production of AH and are considered first-line pharmacologic options.^2,4,12 Nonselective (timolol, levobunolol, metipranolol, carteolol) and selective (betaxolol) forms of beta-blockers are available in the U.S.
Minor, usually transient, ocular adverse affects include blurred vision, irritation, burning, stinging, and tearing. Additional local adverse affects that should be reported to the eye doctor include loss of visual acuity, pain, inflammation, foreign body sensation, and erythema.
Systemic adverse effects are rarely reported for topical beta-blockers, and their occurrence will be minimized by NLO.
Nonselective beta-blockers are contraindicated in patients with asthma or severe chronic obstructive pulmonary disease (COPD) because they can cause bronchospasms, although betaxolol may be used due to its receptor selectivity. Because beta-blockers can both mask the early warning symptoms of hypoglycemia and prolong recovery from low blood sugars, they should be used cautiously in diabetes. All beta-blockers are contraindicated in patients with cardiac diseases such as sinus bradycardia, second- or third-degree atrioventricular block, heart failure, or cardiogenic shock.
Prostaglandin Analogues: Regarded as first-line therapeutic agents, analogues of prostaglandins (bimatoprost, latanoprost, travoprost) bind to prostanoid FP receptors located on the iris, promoting uveoscleral outflow of AH, which subsequently lowers IOP.¹³ Bimatoprost may also significantly affect AH outflow through the trabecular meshwork.
Common, frequently transient, adverse ocular effects include blurred vision or other decreased visual acuity, itching, burning or stinging, dry eyes, and excessive tearing. Patients have reported body aches, rash, upper respiratory infections, cold, and (rarely) flu. Systemic adverse effects are very rare with prostaglandin analogues. Patients with active intraocular inflammation should not be started on ophthalmic prostaglandin analogues because these could worsen their condition. Caution should be used in those with a past history of ocular inflammation.
Darkening of the iris, particularly in patients with hazel eyes, has been reported by persons using ophthalmic prostaglandins. In addition, these medications tend to darken the periorbital tissues to a brownish color. These effects may be permanent. A serendipitous side effect is darkening, thickening, and lengthening of the eyelashes. The FDA has approved Latisse, a form of bimatoprost, for the treatment of hypotrichosis, or inadequate eyelashes.¹⁴
While the American Academy of Ophthalmology and the American Optometric Association have not stated a definitive preference for pharmacologic treatment of glaucoma, it has been argued that prostaglandin analogues are preferable to beta-blockers because of a greater efficacy in lowering IOP and producing fewer systemic effects.^1,2,12,15 However, there are no generic formulations of prostaglandin analogues, so where cost is an important issue, generic beta-blockers will more likely be used.
Carbonic Anhydrase Inhibitors (CAIs): This drug classification is available in both ophthalmic (brinzolamide and dorzolamide) and oral (acetazolamide and methazolamide) formulations. CAIs lower IOP by decreasing production of AH.¹⁶
Topical CAIs are normally well tolerated and are considered second-line therapeutic alternatives. Bitter taste and transient burning, stinging, blurred vision, and foreign body sensation are commonly reported. Corneal inflammation and ophthalmic allergic reactions occur rarely. Systemic adverse effects, including headache, tingling in the extremities, fatigue, liver disease, and kidney stones, are very rare with topical CAIs but are more common with the oral formulations.
While quite effective, oral CAIs are deemed third- or fourth-line agents for POAG because they are not well tolerated; thus, long-term use is uncommon.² They are approved for adjunctive use when maximum topical therapy is inadequate, or for those persons who are intolerant of topicals.² Metabolic acidosis is one of the most common reasons for discontinuing systemic CAIs.
CAIs are sulfonamides, but are structurally different from bacteriostatic sulfonamides. They may be used cautiously in patients with bacteriostatic sulfonamide allergy, but CAIs should be discontinued if reactions suggestive of sulfonamide hypersensitivity emerge.¹⁷ Patients at risk for acidosis, electrolyte imbalance, or kidney or liver dysfunction should avoid systemic CAIs.
Cholinergics: Direct-acting (pilocarpine and carbachol) and indirect-acting (cholinesterase inhibitor, echothiophate iodide) parasympathomimetics exert a miotic effect. As the pupil constricts, channels in the trabecular meshwork open, reducing resistance to outflow of AH.¹ These third- or fourth-line glaucoma medications are rarely used today because of the need for frequent dosing and significant adverse effects such as blurred vision, cataracts, and retinal detachment.^2,12,16 It is important to note that excessive miosis may severely restrict the flow of AH from the posterior to the anterior chamber. Thus, patients should be closely monitored for pupillary block leading to ACG. Systemic cholinergic adverse effects are also possible. Newer, safer drugs have generally eclipsed the need for cholinergics.
Sympathomimetics: The alpha-adrenergic agonists brimonidine and apraclonidine, first-line sympathomimetic agents, are selective to alpha₂-receptors that increase uveoscleral outflow of AH, thereby decreasing IOP.² In addition, brimonidine reduces the production of AH. The efficacy of apraclonidine typically wears off in less than a month, so it is used specifically for short-term adjunctive therapy.
Common ocular adverse effects include burning, stinging, irritation, tearing, and eyelid edema. Mild ocular allergic reactions, such as itching, are common with alpha-adrenergic agonists. More serious allergic reactions may develop over time and should be reported. Dizziness and drowsiness occur rarely, so patients should be cautious when performing hazardous activities that require alertness. These drugs can potentiate the effects of depressants, such as alcohol, barbiturates, and sedatives.
The nonspecific sympathomimetics epinephrine and dipivefrin (a prodrug of epinephrine) increase the outflow of AH through both the trabecular meshwork and uveoscleral route. If used long-term, they also decrease AH production.^12,16 Ophthalmic epinephrine is no longer available in the U.S., and dipivefrin is rarely used because of frequent local adverse effects and significant systemic effects, including elevated blood pressure and irregular heartbeat.¹² It must be used cautiously in the elderly and in persons with hypertension, diabetes, hypothyroidism, and heart disease. Dipivefrin produces mydriasis and may increase IOP by blocking outflow via the conventional pathway. This situation may lead to ACG. Dipivefrin is used primarily as an alternative treatment for those who respond inadequately to other, safer medications.

ADHERENCE TO MEDICAL THERAPY

Poor adherence to therapy is a common problem with chronic diseases. Patients with glaucoma face many challenges as they attempt to lower IOP and preserve their vision through medical therapy regimens. Many studies have attempted to identify obstacles to adherence and define strategies for improving therapeutic outcomes.^18-23 Some of the most common factors associated with poor therapeutic adherence are listed in TABLE 3.

Table 3. Factors Associated With Decreased Adherence
Patient-Specific	Therapy	Provider	Life Circumstances
Dexterity Vision Health literacy Understanding of disease/treatment Concern about vision loss Comorbidities	Doses per day Cost Adverse effects Complexity of regimen	Rapport with patient Patient perception of provider skill	Lack of support system Traveling/vacation Transportation Complicated lifestyle
Source: References 18-23.

Failure to follow recommended therapeutic regimens may lead to continued optic neuropathy and vision loss. Health care professionals diagnose and educate about glaucoma, prescribe and dispense medication, and monitor therapy, but the patient is ultimately responsible for daily ongoing disease management. Home diagnostics allow patients with many chronic diseases to monitor for therapeutic efficacy: blood pressure readings (hypertension), blood glucose levels (diabetes), peak flow measurement (asthma). This valuable feedback allows patients to selfadjust behaviors or recognize the need to contact their health care providers. No day-to-day self-monitoring is available for patients with glaucoma. Moreover, because glaucoma is largely asymptomatic, few cues alert patients to disease progression.
Pharmacists are widely regarded as the most accessible health care providers, and they enjoy the public’s trust and respect. They are ideally positioned to serve as teachers and coaches for patients with glaucoma. Patients must be educated about the disease process and the significance of untreated or inadequately treated glaucoma. Therapeutic regimens must be clearly explained to patients, including the desired effect of therapy, possible side effects, and when to contact a health care provider. Careful counseling, augmented by periodic dialoguing, may help pharmacists identify barriers to adherence and offer solutions to improve outcomes. Pharmacists should assess patients’ understanding by asking questions and offering further explanation or clarification as necessary.²⁰

NEW HORIZONS

Visual function can be preserved by reducing IOP and protecting RGCs from degeneration through pharmacologic and surgical therapies previously described. Unfortunately, in some patients, loss of RGCs progresses in spite of well-controlled IOP. It appears RGC degeneration could also be attributed to vascular insufficiency, axonal transport blockade, diffusion of toxic agents into nerve cells, initiation of apoptosis (programmed cell death), and other causes.²⁴
The concept of neuroprotection, preserving existing RGCs, and rescuing damaged RGCs and their axons has been proposed as superior to treatment modalities aimed at lowering IOP because it would be effective irrespective of disease etiology.²⁵
Several groups of compounds, including the antioxidant alpha-tocopherol, phenytoin, aminoguanidine, and the N-methyl-d-aspartate receptor antagonist memantine, have been proposed as possible candidates for RGC neuroprotection.²⁶ Memantine showed promise in Phase I and II trials but failed to pass Phase III clinical trials.²⁴ The quest for treatment modalities that can stop loss of vision remains a subject of intense investigation.

CONCLUSION

Glaucoma, strongly associated with aging and vision loss, is a serious public health concern in the U.S. because the proportion of elderly persons in the population is rapidly growing. Elevated IOP, along with other as yet unidentified factors, contributes to optic neuropathy and vision loss. All current treatment modalities are aimed at lowering IOP, and adherence to medical therapy is important in preserving vision. Pharmacists may positively impact outcomes by providing education about glaucoma, describing proper use of prescribed medications, identifying barriers to treatment adherence, and developing strategies to help patients overcome obstacles to successful management of glaucoma.

Exploring the Link Between Blood Pressure and Lifestyle

J. Paige High Carson, PharmD, CDE, BCPS
Clinical Pharmacy Specialist, Ambulatory Care
Carolinas Medical Center–NorthEast

US Pharm. 2010;35(2):24-29.

Nearly 72 million people in the United States have hypertension (HTN), and one out of three American adults has HTN. In addition, one-third of people with HTN are unaware they even have high blood pressure (BP), which is why HTN is often referred to as “the silent killer.”¹ Hypertension is defined as a BP >140/90 millimeters of mercury (mmHg). As BP rises, risk increases for heart failure, myocardial infarction, kidney disease, and stroke. For each 20 mmHg increase in systolic blood pressure (SBP) or 10 mmHg increase in diastolic blood pressure (DBP) above 115/75 mmHg, the risk of cardiovascular disease doubles.² A recent study conducted in nondiabetic patients supports treating to a target SBP <130 mmHg versus a target SBP <140 mmHg. The group achieving the lower SBP experienced significantly less development of left ventricular hypertrophy and cardiovascular events than the group treated to the usual SBP goal.³ Current Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) classification and treatment of BP for adults is given in TABLE 1.

Various lifestyle risk factors have been identified that elevate blood pressure and lead to HTN. Many of these risk factors have been well documented in the literature, and according to recent trials or new research awaiting publication, others have recently been postulated to affect BP (TABLE 2). A healthy lifestyle is essential to preventing HTN and managing it successfully. Lifestyle modifications should be incorporated into every treatment regimen for prehypertension and HTN (TABLE 3). Implementation of a healthy lifestyle decreases BP, reduces cardiovascular disease risk, and increases the efficacy of antihypertensive medications.² 

Conventional Risk Factors for Developing Hypertension

Hypertension can develop because of a person’s lifestyle, medication regimen, underlying health conditions, genetic history, or a combination of these factors. Nonmodifiable risk factors include advancing age, race, family history of HTN or premature heart disease, and other concurrent health conditions. Some of these health conditions include adrenal tumors, chronic kidney disease, congenital heart defects, diabetes, thyroid disorders, pheochromocytoma, and pregnancy. Hypertension is more common in African Americans and appears to develop at an earlier age in this race. Medications that may cause HTN include caffeine, chronic steroid therapy, oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, amphetamines and other stimulant drugs, cocaine, decongestants, weight loss drugs, cyclosporine and other immunosuppressants, erythropoietin, and OTC supplements (e.g., ephedra, licorice, ma huang).²

Established Lifestyle Risk Factors for Developing Hypertension

There are many modifiable risk factors for HTN, and the list seems to be growing steadily with ongoing research. Cigarette smoking is the single most common avoidable cause of cardiovascular death in the world.⁴ Data from the CDC show that 21% of adults (18 years of age and older) in the U.S. currently smoke cigarettes.⁵ Those who smoke 15 or more cigarettes per day have a higher incidence of HTN. Smoking immediately raises BP and heart rate transiently through increasing sympathetic nerve activity and myocardial oxygen consumption. Chronically, tobacco chemicals damage the lining of the arterial walls of the heart, resulting in artery stiffness and narrowing that can last for 10 years after smoking cessation. Smoking also increases the progression of renal insufficiency and risk of other cardiovascular complications.^4,6

Obesity is estimated to be the leading cause of preventable illness in the U.S. Greater than two-thirds of HTN prevalence can be attributed to obesity.⁷ The National Heart, Lung, and Blood Institute (NHLBI) defines obesity as having a body mass index (BMI) ³30 kg/m².² Results from the National Health and Nutrition Examination Survey (NHANES, 2005-2006) indicate that 34.3% of the U.S. adult population is obese.⁸ Obesity is most pronounced in the southeast region of the country. Overweight prevalence among children and adolescents also remains high in the U.S., with 10% of U.S. children classified as overweight or obese.^7,8 Abdominal adiposity, in particular, is linked to congestive heart failure, coronary artery disease, diabetes, sleep apnea, and stroke. Being overweight requires that more blood be supplied to oxygenate heart tissues, and as the circulated blood volume increases through the blood vessels, the pressure increases on the artery walls.^6,7

Besides obesity, a lack of physical activity and sedentary lifestyle produce an increase in heart rate. An increased heart rate requires that the heart work harder with each contraction, and it exerts a stronger force on the arteries, thereby raising BP. Physical inactivity has also been linked to more health care office visits, hospitalizations, diabetes, and increased medication burden.^6,9

Multiple dietary factors increase the risk for HTN. It is well known that excessive sodium intake leads to HTN. A diet high in salt causes the body to retain fluid, and increased water movement raises the pressure within the vessel walls.⁶ The majority of the sodium in Western-style diets is derived from processed foods. High-salt diets decrease the effectiveness of antihypertensives in patients with resistant HTN. Resistant HTN is defined as having a BP above one’s goal despite using three or more antihypertensive medications concurrently.¹⁰ A high-salt diet can also increase the need for potassium. Potassium balances the amount of sodium within cells. If not enough potassium is consumed or retained, sodium accumulates in the blood. A diet low in potassium (<40 mEq/day) produces sodium accumulation through decreased sodium excretion, thereby leading to HTN. Potassium deficiency also increases the risk for stroke.^6,11

Excessive alcohol consumption consisting of greater than two drinks per day for men or greater than one drink per day for women leads to sustained BP elevations.² Alcohol interferes with blood flow by moving nutrient-rich blood away from the heart.¹² Alcohol can also reduce the effectiveness of antihypertensives. Binge drinking, or having at least four drinks consecutively, may cause significant and rapid increases in BP.¹³ Debate exists on whether low-to-moderate alcohol consumption raises or lowers BP.

Emerging Risk Factors for Developing Hypertension

A diet high in sugar, fructose in particular, raises BP in men, according to a recent study presented at the American Heart Association’s (AHA) 2009 High Blood Pressure Research Conference.¹⁴ High fructose consumption has also been linked to an increased risk of obesity. Fructose is a dietary sugar that is used in corn syrup and accounts for one-half of the sugar molecules in table sugar. High-fructose corn syrup is often utilized in packaged sweetened products and drinks due to its long shelf life and low cost. In this study, men consuming a high-fructose diet for just 2 weeks experienced an increased incidence of HTN and metabolic syndrome.¹⁴

Vitamin D deficiency (<80 nmol/L) may increase the risk of developing systolic HTN in premenopausal women years later, according to a study conducted in Caucasian women in Michigan.¹⁵ In this study, presented at the AHA’s High Blood Pressure Research Conference, researchers compared BP and vitamin D levels drawn in 1993 to those drawn 15 years later in 2007. Premenopausal women (average age of 38 years) with vitamin D deficiency in 1993 were three times more likely to have HTN in 2007 than those with normal vitamin D levels in 1993.¹⁵

Sleep deprivation raises SBP and DBP and may lead to HTN. In the recent Coronary Artery Risk Development in Young Adults (CARDIA) sleep study, sleep maintenance and sleep duration were measured in a group of adults aged 35 to 45 years and then repeated 5 years later on the same study population.¹⁶ According to this study, shorter sleep duration and poor sleep quality increase BP levels and lead to HTN. Sleep deprivation may produce an increase in heart rate and sympathetic activity, evolving into HTN.¹⁶

A connection has been found between HTN and road traffic noise. An Environmental Health study published in 2009 measured loudness of road noise in decibels at the home address in a large number of adults and their incidence of self-reported HTN. A significant association was found for incidence of HTN and residing near a noisy road. Interestingly, a less prominent effect on BP was noted in the elderly when compared to younger adults. Possible explanations offered by the authors include that noise may be harder to detect in the elderly and may be less of an annoyance in the older population than in younger individuals. The study authors speculate that long-term exposure to noise causes endocrine and a sympathetic stress response on a middle-aged adult’s vascular system, resulting in HTN and an elevated cardiovascular risk profile.¹⁷

A questionnaire completed by deployed American servicemen and servicewomen revealed that those reporting multiple exposures to combat had a significantly higher incidence of HTN than those reporting no combat. The elevation in BP is thought to arise from the high stress situation of combat exposure. Combat stress can result in significant physical and psychosocial stress to those deployed.¹⁸

Lifestyle Modifications for Treatment of Hypertension

Cigarette smoking is a modifiable cardiovascular risk factor that can have profound effects. Smoking cessation can result in immediate improvement in BP and heart rate after just 1 week.¹⁹ A linear relationship has been discovered in improvement in arterial wall stiffness and duration of smoking cessation in ex-smokers. Achievement of a decade of smoking cessation results in remodeling to nonsignificant levels of arterial stiffness.²⁰ In addition to lowering BP, smoking cessation results in an overall cardiovascular risk reduction and reduction in mortality. Rigorous measures should be utilized to assist individuals in achieving smoking cessation.² Smoking cessation should be assessed and discussed at every available opportunity, whether it be inpatient, outpatient, or at the pharmacy. Studies have shown that when patients are told their lung age, they are more likely to quit smoking.²¹ Pharmacists possess an enormous opportunity to assist patients in achieving smoking cessation by teaching patients about the various smoking cessation pharmacotherapy options. An explanation of how to properly use the medications (OTC and prescription), differences between them, and what to expect from the medications can improve adherence and the desired outcome of successful smoking cessation.

Weight reduction can have the most profound effect of all lifestyle modifications on lowering BP, leading to an approximate drop in SBP of 5 to 20 mmHg per 10 kg weight loss. The JNC 7 guidelines recommend weight reduction to maintain a normal body weight defined as a BMI between 18.5 and 24.9 kg/m².² The Surgeon General’s recommendations published by the U.S. Department of Health and Human Services advise determining a person’s BMI and having him or her lose at least 10% of body weight if overweight or obese. It is also recommended to lose weight gradually at a pace of one-half to two pounds per week.²²

Along with weight reduction, regular aerobic physical activity for 30 minutes or more per day most days of the week is recommended and results in an SBP improvement of 4 to 9 mmHg.² It is recommended that children be physically active for 60 minutes most days of the week. The Surgeon General recommends limiting television viewing to below 2 hours per day.²²

The JNC 7 guidelines recommend multiple dietary modifications. The most notable and effective is adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan, which can lower SBP by 8 to 14 mmHg. ² The DASH eating plan is equally efficacious to adding on a single antihypertensive medication. This diet plan includes a significant consumption of fruits and vegetables rich in potassium, which assists in maintaining optimal sodium to potassium ratio. The DASH eating plan is low in saturated fat and consists of low-fat dairy products. Sodium restriction is an important component of the DASH diet and also recommended independently in the JNC 7 guidelines. A reduction in sodium intake to £100 mmol/day (6 g NaCl or 2.4 g sodium) can drop SBP by 2 to 8 mmHg. The DASH diet also provides details on how to check labels for sodium content and how to estimate sodium amounts in foods based on how they are cooked or prepared when eating in restaurants.^2,23 The Surgeon General also recommends selecting sensible portions.²²

Limiting alcohol consumption to two drinks or less for most men and one drink per day or less for women is recommended by the JNC 7 guidelines. The equivalency of two drinks is defined as 24 oz of beer, 1 oz of ethanol (e.g., vodka, gin), 3 oz of 80-proof whiskey, or 10 oz of wine. A decrease in alcohol intake can lower SBP by 2 to 4 mmHg.²

Plausible Lifestyle Modifications for Treatment of Hypertension

Lowering fructose intake through limiting consumption of sweetened products could prevent rises in BP and development of metabolic syndrome. Reducing intake of sweetened drinks or processed foods that contain high-fructose corn syrup and lessening use of regular table sugar will lower intake of fructose.¹⁴

Vitamin D deficiency is widespread among women. It is speculated by some researchers that many women do not receive adequate sun exposure, obtain enough vitamin D in their diet, or supplement with enough vitamin D. The current recommended intake of vitamin D for this population is 400 to 600 IUs per day, though some researchers suggest a higher intake of daily vitamin D. Knowing one’s vitamin D level and obtaining adequate vitamin D through diet and/or supplementation may prevent HTN.¹⁵

A randomized, controlled trial published in 2007 demonstrated that regular consumption of a small amount of dark chocolate has been shown to mildly reduce BP (-2.9 mmHg systolic and -1.9 mmHg diastolic average) in people with stage 1 HTN or prehypertension. The study population did not have other cardiovascular risk factors and were not taking antihypertensive medications. This study compared daily intake (30 kcal, or the equivalent of a Hershey’s Kiss) of dark chocolate and white chocolate for 18 weeks. The group receiving white chocolate had no improvement in BP. It is suspected that the polyphenols in the dark chocolate lower BP.²⁴

A recent study explored the effects of various milk and cheese products on developing HTN in adults aged 55 years and older living in the Netherlands. It was discovered after 6 years that higher dairy intake was associated with lower rates of HTN. The authors concluded that consumption of low-fat dairy products may prevent HTN in older individuals.²⁵ Another study conducted in U.S. women aged 45 years and older showed similar results with intake of low-fat dairy products, but not with supplements of calcium or vitamin D.²⁶

Lastly, various studies have shown that ownership of a dog or cat lowers a person’s BP. Whether this is accomplished through increased exercise or the psychological effects of a human-animal connection is yet to be fully established. Health benefits of pet ownership include BP reductions, a reduction in triglyceride levels, improved exercise habits, decreased feelings of loneliness, and decreased stress levels.^27,28

Conclusion

A person’s way of life can have substantial effects on his or her health, including the risk of developing HTN. Numerous lifestyle risk factors have been implicated in the development of HTN; likewise, several lifestyle modifications effectively lower BP. Alterations in lifestyle are essential to prevention and treatment of HTN and can decrease the need for one or more prescription medications. Lifestyle changes to lower BP can additionally correct obesity, lower cardiovascular risk, decrease insulin resistance, improve drug efficacy, and enhance antihypertensive effect. Greater BP reductions are achieved if two or more lifestyle adjustments are made concurrently. Assisting and motivating patients to make lifestyle changes to lower their BP to goal levels is recommended by the JNC 7 guidelines yet is often underutilized by health care clinicians. It is imperative that pharmacists be knowledgeable in risk factors and treatments for HTN and express interest in having patients reach their BP goals. Studies have proven that involvement of a pharmacist in the treatment of hypertensive patients can result in improved BP control through adoption of lifestyle modifications, proper antihypertensive selection, and better adherence to medications.^2,29

The Treatment and Management of Atrial Fibrillation

Release Date:  February 1, 2010

Expiration Date: February 29, 2012

FACULTY:
Evangelina Berrios-Colon, PharmD, BCPS, CACP
The Brooklyn Hospital Center
Clinical Assistant Professor of Pharmacy Practice,
Long Island University,
Agnes Cha, PharmD
PGY-2 Ambulatory Care Resident,
The Brooklyn Hospital Center, 

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with a prevalence of 0.4% to 1.0% in the general population.¹ Prevalence increases with age, reaching 8% in patients older than 80 years. The average age of patients with AF is 75 years, and the incidence of the condition is relatively equal between men and women. AF is responsible for about one-third of hospital admissions for cardiac-rhythm disturbances. Hospitalizations due to AF have increased by 66% in the past 20 years, owing mostly to more frequent diagnosis resulting from the use of ambulatory monitoring devices, the aging of the population, and the increased prevalence of heart disease.² Since AF is frequently encountered by pharmacists and other health care providers in the ambulatory setting, this article aims to review the basic pathophysiology of AF and various treatment options for the best management of patients with this condition.

Pathophysiology

A normal heartbeat is initiated by the body’s natural pacemaker, the sinoatrial node in the right atrium, which spreads electrical activity across the right and left atria, resulting in a contraction (FIGURE 1). This contraction drives blood into and fills the chambers of the ventricles, which are responsible for pumping blood throughout the body. The electrical signal is slightly delayed by the atrioventricular (AV) node and then spreads rapidly through the bundle of His to the Purkinje fibers, resulting in a ventricular contraction. This normal conduction is termed sinus rhythm. Most of the general population has a resting heart rate (HR) of 60 to 80 beats per minute (bpm).³

AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial electrical conduction, which results in a deterioration of mechanical function.⁴ In AF, disorganized atrial electrical conduction results in rapid atrial bpm (400-600).⁵ This activity results in the loss of an atrial contraction—or atrial kick—sufficient to promote cardiac output. The AV node allows only 1 or 2 out of every 3 atrial beats to pass through to the ventricles, but the resting HR is still 110 bpm to 180 bpm.³ The HR, or pulse, in AF is “irregularly irregular” because of the variable supraventricular impulses that penetrate the AV node.
Although the pathophysiologic mechanisms are not completely understood, it is generally accepted that AF is a result of either multiple reentrant wavelets or a focal triggering mechanism involving automaticity.⁴ These mechanisms may coexist, as they are not mutually exclusive. The multiple-wavelet hypothesis involves multiple atrial reentrant loops, or wavelets, that occur simultaneously in the left and right atria and cause self-perpetuating “daughter wavelets.”^4,5 The perpetuation of wavelets is favored by increased atrial mass, shortened refractory periods, and delayed conduction, collectively promoting sustained AF. The longer the heart is in AF, the less likely it is that the restoration and maintenance of sinus rhythm will be successful, following the notion that “AF begets AF.”^4,5
The second mechanism is triggered by a focal source, and it has been established that the pulmonary veins are a major source of triggers that can initiate AF.⁶ Myocardial muscle fibers extend from the left atrium into the pulmonary veins (1-3 cm), and these muscular sleeves are the source of focal firing. Thus, if AF is caused by this focal source, ablation of that focal trigger may terminate AF (discussion follows). However, in longstanding persistent AF, atrial remodeling occurs, which may enhance the number of triggers and shift them to other locations.
Untreated AF may cause complications, including an increased risk of cerebral thromboembolism, development of heart failure (HF), increased mortality, increased left atrial pressure and volume, shortened diastolic ventricular filling period, AV valvular regurgitation, and irregular and rapid ventricular rate.⁶ In addition, as mentioned earlier, persistent AF can result in electrical and anatomical remodeling of the left atrium, which may enhance the sustainment of AF.

Classification

There are different classifications of AF. The American College of Cardiology/American Heart Association and the European Society of Cardiology (ACC/AHA/ESC) in 2001 established a classification system (revised in 2006) that is widely used.⁴
Paroxysmal AF is defined as recurrent AF (≥2 episodes) that terminates spontaneously within 7 days. Persistent AF is sustained beyond 7 days, or lasts less than 7 days but requires pharmacologic or electrical cardioversion. Long-standing persistent AF is when a patient presents with continuous AF for more than 1 year. Permanent AF is classified as AF in which cardioversion either has failed or has not been attempted because the patient has decided not to pursue restoration of sinus rhythm by any means.⁵

Risk Factors

Various factors predispose patients to AF.⁴ Reversible causes of AF may include alcohol intake (“holiday heart syndrome”), surgery, electrocution, myocardial infarction (MI), myocarditis, pulmonary embolism, and hyperthyroidism. Successful treatment of the underlying condition usually eliminates the AF. Obesity is associated with AF because as body-mass index increases, so does the size of the left atrium, resulting in atrial dilation. Other disease states associated with AF are primarily cardiac conditions: mitral valve disease, HF, coronary artery disease (CAD), hypertension (HTN), left ventricular hypertrophy, and cardiomyopathy.^4,5
However, 30% to 45% of paroxysmal AF cases and 20% to 25% of persistent AF cases occur in young patients without an underlying medical condition, a state known as lone AF.⁴ Lone AF may be a familial arrhythmia, or a causal underlying condition may appear over time.

Diagnosis

Diagnosis of AF requires electrocardiogram (ECG) documentation by at least a single-lead recording during the arrhythmia. Suspected arrhythmias also may be documented by Holter monitor, a small ambulatory ECG device that records 24 hours of continuous electrocardiographic signals. The ECG will display rapid oscillations of varying amplitude, shape, and timing that replace consistent P waves (FIGURE 2).⁴ The resulting ventricular response is an irregularly irregular contraction.

Signs and Symptoms

Classic symptoms of AF are palpitations, chest pain, dyspnea, fatigue, lightheadedness, and syncope—or there may be no symptoms at all. AF may initially present as an embolic complication or exacerbation of HF. Polyuria also may occur as episodes of AF begin or terminate because of the release of atrial natriuretic peptide.
Physical examination may reveal irregular pulse, irregular jugular venous pulsations, variations in intensity of the first heart sound, or absence of the fourth heart sound.⁴ AF may manifest clinically as palpitations, significant hemodynamic or thromboembolic consequences, or an asymptomatic period of unknown duration. Hemodynamic complications involve irregular ventricular response, rapid HR, impaired coronary blood flow, decreased cardiac output, and tachycardia-induced cardiomyopathy.

Management

The ultimate treatment goals for AF are the restoration and maintenance of sinus rhythm and the prevention of thromboembolic complications.⁴ Controlling the ventricular rate in AF without actively attempting to restore sinus rhythm with pharmacologic agents is a safe alternative. In many patients, symptom relief can be obtained by controlling HR. Once adequate rate control is obtained, many patients are unaware of episodes of paroxysmal AF.

Cardioversion

Patients with persistent AF may undergo elective cardioversion to restore sinus rhythm. Typically, cardioversion is not recommended for patients with paroxysmal AF; however, it may be necessary if the AF is responsible for acute HF, hypotension, or worsening angina in a CAD patient. Cardioversion may be performed either pharmacologically or electrically, as direct-current cardioversion (DCC). Both methods are effective; however, there are clear disadvantages that must be considered.
Pharmacologic cardioversion carries the risk of drug-induced torsades de pointes or other serious arrhythmias. More importantly, it is less effective than DCC using biphasic shocks, with respective success rates of 78% for DCC and 59% for pharmacologic cardioversion.^4,7 However, electrical cardioversion requires conscious sedation or anesthesia, which may be disadvantageous. There is no evidence that the risk of thromboembolism or stroke differs between the two methods; thus, recommendations for anticoagulation are identical for pharmacologic and electrical cardioversion.^4,5
Pharmacologic Cardioversion: Pharmacologic cardioversion may be initiated on an inpatient or outpatient basis, but it is most effective when initiated within 7 days of onset. The advantages of antiarrhythmics over placebo are modest after 24 to 48 hours of new onset of AF.⁴ In addition, some agents have a delayed onset of action, and cardioversion may not occur for several days.⁸
Medications with proven efficacy for in-hospital cardioversion of AF of up to 7 days’ duration are the class Ic antiarrhythmics flecainide and propafenone and the class III antiarrhythmics dofetilide, ibutilide, and amiodarone (TABLE 1).^4,5 Quinidine, disopyramide, or procainamide (class Ia antiarrhythmics) may be considered; however, the value of these agents is not well established. In AF that has been present for more than 7 days, the class III antiarrhythmics have proven efficacy. Digoxin and sotalol may be harmful if used for cardioversion and therefore are not recommended.⁴

Table 1. Recommended Effective Dosages in Pharmacologic Cardioversion
Drug	Route	Dosage	Potential Adverse Effects
Amiodarone	po	Inpatient: 1.2-1.8 g/day in divided doses until 10 g total, then 200-400 mg/day Outpatient: 600-800 mg/day until 10 g total, then 200-400 mg/day	Blurred vision, optic neuropathy, hypotension, bradycardia, GI upset, PF, thyroid dysfunction, photosensitivity, constipation, phlebitis (IV), QT prolongation, hepatotoxicity, TDP (rare)
	IV	5-7 mg/kg over 30-60 min, then 1.2-1.8 g/day continuous IV or divided po doses until 10 g total, then 200-400 mg/day
Dofetilide	po	500 mcg bid; must adjust if CrCl <60 mL/min	QT prolongation, TDP
Flecainide	po	200-300 mg	Hypotension, HA, atrial flutter with high ventricular rate, blurred vision
	IVa	1.5-3 mg/kg over 10-20 min
Ibutilide	IV	Patients >60 kg: 1 mg over 10 min; repeat 1 mg when necessary Patients <60 kg: 0.01 mg/kg over 10 min; may repeat same dose only once after 10 min, if necessary	QT prolongation, TDP, hypotension
Propafenone	po	600 mg	Hypotension, HA, atrial flutter with high ventricular rate, blurred vision, bronchospasm
	IVa	1.5-2 mg/kg over 10-20 min
a Available only in Europe. CrCl: creatinine clearance; GI: gastrointestinal; HA: headache; min: minute; PF: pulmonary fibrosis; TDP: torsades de pointes.

The major concern when initiating antiarrhythmics on an outpatient basis is the risk of serious adverse effects. With the exception of amiodarone, most studies of pharmacologic cardioversion have involved inpatients. In paroxysmal AF, the goal of outpatient initiation of antiarrhythmics is to terminate an episode or prevent recurrence. However, in persistent AF, the goal is to achieve cardioversion or to lower the defibrillation threshold to enhance the efficacy of DCC.
Amiodarone may be initiated safely on an outpatient basis, as it has low proarrhythmic potential and causes minimal depression of myocardial function (although a loading dose may be necessary on an inpatient basis for faster restoration in a hemodynamically compromised patient). Amiodarone, with its active metabolite desethylamiodarone, blocks sodium, potassium, and calcium channels. Amiodarone is approved for the treatment of lethal ventricular arrhythmias, but not for the management of AF; nonetheless, it is widely prescribed for the latter condition.⁹
It is recommended that all antiarrhythmics be started at a low dose and titrated up based on patient response. An ECG should be monitored after every dosage change. Specific recommendations state that quinidine, procainamide, disopyramide, and dofetilide should be initiated only on an inpatient basis.⁴
Electrical Cardioversion: DCC consists of delivery of an electrical shock that is synchronized with the R wave of the QRS complex to ensure that electrical stimulation does not occur during the repolarization phase of the cardiac cycle. Patients undergoing DCC should be in a fasting state and under general anesthesia. If a monophasic waveform defibrillator is used, 200 J or 360 J of energy is recommended.¹⁰ Biphasic defibrillators require less energy to convert arrhythmia into sinus rhythm, so it is recommended to start with 200 J.¹¹
Immediate DCC is recommended for patients in AF who are experiencing hemodynamic instability or rapid tachycardia. DCC also is advised in the absence of hemodynamic instability if the symptoms are unacceptable to the patient. Cardioversion has a high rate of efficacy for restoring sinus rhythm; however, recurrent AF is common. If the cardioversion is unsuccessful, additional DCC beyond a second attempt has limited benefit and should be used only in selected symptomatic patients. However, infrequently repeated cardioversions are acceptable for patients who become highly symptomatic during relapses of AF.⁴ Patient preference regarding the use of DCC to help manage their recurrent AF should be considered.
Data have suggested that initiation of antiarrhythmics before DCC can augment immediate success and prevent early recurrence.⁴ Pretreatment with amiodarone, flecainide, ibutilide, propafenone, or sotalol may be used as pharmacologic enhancement while in the hospital. Outpatient initiation of antiarrhythmics may be considered only in patients without heart disease.

Maintenance of Sinus Rhythm

When AF is a chronic disorder, patients most likely will need long-term antiarrhythmic treatment to maintain sinus rhythm, suppress symptoms, and improve exercise tolerance. Most AF patients eventually experience recurrence, except for those with postoperative AF or self-limited AF secondary to transient or acute illness. See TABLE 2 for predisposing factors to recurrent AF.¹²

Table 2. Predictors of Recurrent AFa

Female gender

Heart disease

Hypertension

Age >55 y

AF duration >3 mo

Rheumatic heart disease

Left atrial enlargement

a After 1 DCC in patients with persistent AF over 4 years of follow-up. DCC: direct-current cardioversion. Source: Reference 12.

The decision whether to use a rate-control or rhythm-control strategy depends on patient-specific factors like comorbidities, likelihood of successful cardioversion, and extent of symptoms (FIGURE 3). Selection of the appropriate drug is based first on safety and then tailored to any underlying heart disease. Flecainide, propafenone, and sotalol have been shown to be efficacious for lone AF; beta-blockers also may be an option. Amiodarone and dofetilide are other viable alternatives.⁴

Most clinicians focus initially on maintenance of sinus rhythm and typically choose a rate-control strategy when rhythm control fails. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) was a clinical trial that randomized 4,060 patients at risk for stroke to either rhythm control or rate control and found no between-group difference in mortality.¹³ The researchers concluded that rhythm control offers no survival advantage over rate control and that rate control has potential advantages, such as lower risk of adverse drug effects. A trend toward an increase in AF recurrence and thromboembolic events was noted in the rhythm-control cohort. The ACC/AHA/ESC 2006 guidelines state that rate control is a reasonable option in asymptomatic AF patients.⁴
The Pharmacologic Intervention in Atrial Fibrillation (PIAF) trial studied patients in AF of 7 to 360 days’ duration.¹⁴ Patients were randomized to receive either rhythm control with amiodarone or rate control with diltiazem. Both groups were anticoagulated with warfarin to a target international normalized ratio (INR) of 2.0 to 3.0. After 1 year of follow-up, there was no difference between the groups in symptoms related to AF—specifically, palpitations, dyspnea, and dizziness, as well as quality of life assessed by detailed interviews.
A rate of 60 to 80 bpm while the patient is at rest and a rate of 90 to 100 bpm during exercise are the target goals for adequate rate control.⁴ In most patients, nondihydropyridine calcium channel blockers and beta-blockers (with or without digoxin) are the drugs of choice for rate control. Long-term rhythm control with amiodarone, dronedarone, sotalol, or propafenone may be another option for maintaining sinus rhythm.
Historically, digoxin has been used to restore normal sinus rhythm; however, over the past 10 years it has fallen out of favor because of its slow onset (usually >24-48 hours to obtain HR <100 bpm) and extensive toxicities.¹⁵ Currently, it is used mostly for rate control in patients with HF.
Selection of a rate-control strategy should be based on patient-specific factors like comorbidities and contraindications (TABLE 3).

Table 3. Common Oral Drugs for Rate and Rhythm Control in AF
Drug	Dose	Potential Adverse Effects	Comments
Rate Control
Verapamil	40-160 mg tid or 120-480 mg/day SR	HF, decreased BP	Beneficial in history of hypertrophic cardiomyopathy; may prevent atrial remodeling
Diltiazem	90 mg po qid or 120-360 mg/day SR	Increased digoxin level	Avoid long-term use in HF patients
Metoprolol	12.5-100 mg bid or 25-100 mg ER	Bronchospasm	More efficacious in history of MI or thyrotoxicosis
Carvedilol	3.125 mg bid, up to 25 mg bid	Fatigue, dizziness, headache	Beneficial in HF patients
Digoxin	125-250 mcg/day, up to target level of 1.5-2 mcg/L16	Anorexia, nausea, ventricular arrhythmia; monitor renal function	Used in HF
Rhythm Control
Amiodarone	200 mg/day	Blurred vision, optic neuropathy, hypotension, bradycardia, GI upset, PF, thyroid dysfunction, photosensitivity, constipation, phlebitis (IV), QT prolongation, hepatotoxicity, TDP (rare)	Black box warning: potential fatal pulmonary toxicity
Dronedarone	400 mg bid	Diarrhea, NV, fatigue, weakness	Caution in HF patients
Sotalol	CrCl >60 mL/min: 80 mg bid CrCl 40-60 mL/min: 80 mg/day	Abnormal ECG, chest pain, CHF, edema, HT, lightheadedness, palpitations, prolonged QT interval, syncope	QT >520 msec: may increase to 120 mg/day bid, depending on CrCl QT interval <520 msec: may increase to 160 mg/day bid, depending on CrCl
Propafenone	SR: initial 225 mg bid; increase at 5-day intervals to 325-425 mg bid	Rash, constipation, diarrhea, loss of appetite, NV, taste disturbance, syncope, blurred vision, fatigue	Also available IR
BP: blood pressure; CHF: congestive heart failure; CrCl: creatinine clearance; ECG: electrocardiogram; ER: extended release; GI: gastrointestinal; HF: heart failure; HTN: hypertension; IR: immediate release; MI: myocardial infarction; NV: nausea and vomiting; PF: pulmonary fibrosis; SR: sustained release; TDP: torsades de pointes.

Anticoagulation

Prevention of Thromboembolism After Cardioversion: In patients who require cardioversion for restoration of normal sinus rhythm and have been in AF for more than 48 hours, anticoagulation is needed in order to prevent clot growth, keep new clots from forming, and allow existing clots to become organized and adhere to the atrial wall. Patients with AF are at risk for cardioembolic stroke, mainly owing to formation of a thrombus due to stasis in the left atrial appendage (LAA). For detecting thrombus formation, transesophageal echocardiography (TEE) is more sensitive and specific than transthoracic echocardiography.
A successful cardioversion may stun the LAA and result in increased risk of a thromboembolic event. The risk is the same regardless of type of cardioversion—pharmacologic, electrical, or spontaneous. More than 80% of thromboembolic events occur during the first 3 days after cardioversion. Atrial stunning is at its highest immediately after cardioversion;however, improvement of atrial transport of blood flow may take up to a few weeks. This underscores the importance of anticoagulation in patients undergoing cardioversion.¹⁷
Patients with AF of more than 48 hours’ duration or ofunknownduration should be anticoagulated with warfarin (target INR 2.0-3.0) for at least 3 weeks prior to cardioversion.¹⁷ Even after cardioversion has restored sinus rhythm, anticoagulation should be continued for at least another 4 weeks. If a patient needs immediate cardioversion owing to hemodynamic instability such as angina, MI, shock, or pulmonary edema, low-molecular-weight heparin (LMWH) or IV heparin should be administered (unless contraindicated) by initial IV bolus at 80 U/kg, then continuous infusion at 18 U/kg/h to a goal-activated partial thromboplastin time of 50 to 70 sec.¹⁷ Anticoagulation with warfarin is recommended for at least 4 weeks thereafter.
The American College of Chest Physicians (ACCP) 2008 guidelines on antithrombotic therapy in AF recommend that, in patients who have had AF for less than 48 hours, cardioversion may be performed immediately without prior anticoagulation because it is unlikely that the atrium has had enough time to form a thrombus.¹⁷ However, in consideration of atrial stunning—a consequence of electrical cardioversion that is associated with thrombus formation and embolic stroke—anticoagulation may be continued for an additional 4 weeks.¹⁸
As an alternative to an anticoagulation period before cardioversion, TEE may be performed to rule out a thrombus in the left atrium or LAA. If no thrombus is identified, cardioversion is reasonable, likely with a period of anticoagulation for 4 weeks afterward. In practice, TEE may be performed before cardioversion, even with prior anticoagulation. If a thrombus is found, the patient will have a longer period of anticoagulation.¹⁷ TEE should be repeated to confirm resolution of the clot.
The use of LMWH instead of unfractionated heparin (UFH) in AF patients is based mostly on extrapolation from data concerning venous thromboembolic disease states.¹⁹ Some advantages of LMWH over UFH are longer half-life, predictable clearance, and antithrombotic response. Patients receiving LMWH may self-administer the medication subcutaneously on an outpatient basis.
Long-Term Prevention of Thromboembolism: To prevent stroke in at-risk patients, the ACCP guidelines recommend anticoagulation with warfarin to an INR of 2.0 to 3.0 (target 2.5).¹⁷ At-risk patients are defined as those with prosthetic heart valves, rheumatic valvular disease, history of thromboembolism, HTN, left ventricular dysfunction, or age greater than 75 years.
In all patients who may be placed on oral anticoagulation, a risk evaluation (CHADS₂) must be performed to determine stroke risk. The CHADS₂ score is based on a point system that assigns values to various risk factors (CHF, HTN, age >75 years, diabetes, prior stroke or transient ischemic attack) that predispose patients to thromboembolism.²⁰ A CHADS₂ score of 0 warrants treatment with aspirin, not warfarin; however, if the CHADS₂ score is greater than 1, long-term anticoagulation with warfarin (target INR 2.0-3.0) is warranted to reduce stroke risk. This predictive model was based on data from 1,733 Medicare beneficiaries aged 65 to 95 years with nonvalvular heart disease who were not given warfarin. Higher values were associated with stroke; however, very few patients had a score of 0 or greater than 5. The CHADS₂ score and stroke risk are defined in TABLES 4 and 5.

Table 4. Definition of CHADS2 Score
Risk Criterion	Score
Cardiac failure Hypertension Age >75 y Diabetes Prior Stroke or TIA	1 1 1 1 2
TIA: transient ischemic attack. Source: Reference 20.

Table 5. Stroke Risk According to CHADS2 Score
Score	Adjusted Risk (%/y)
0 1 2 3 4 5 6	1.9 2.8 4.0 5.9 8.5 12.5 18.2
Source: Reference 20.

Aspirin also has been used to prevent stroke in AF. It has been shown to reduce stroke up to 19% in AF patients.²¹ Aspirin reduced rates of noncardioembolic stroke rather than cardioembolic ischemic stroke in AF, showing the greatest benefit in the noncardioembolic population. However, patients with prior stroke benefit substantially from anticoagulation with warfarin rather than aspirin for secondary prevention.
The addition of clopidogrel to aspirin therapy to prevent major vascular events in patients with AF was evaluated in 7,554 patients who were not receiving warfarin.²² It was found that the inclusion of clopidogrel reduced the risk of major vascular events (specifically stroke), but increased the risk of major hemorrhage.
Interruption of anticoagulation may be necessary for surgery or invasive diagnostic procedures. Anticoagulation with warfarin may be interrupted up to 5 days prior to a procedure, and “bridge therapy” with LMWH or IV heparin may be initiated. The ACC/AHA/ESC 2006 guidelines state that, in patients with nonvalvular AF who are interrupting oral anticoagulation, it is appropriate not to overlap with LMWH or IV heparin if anticoagulation is being interrupted for only up to 1 week. However, the ACCP guidelines state that it is appropriate not to overlap with LMWH or IV heparin if anticoagulation is being interrupted for up to 2 weeks.¹⁷ In patients at high risk for stroke, bridge therapy is warranted.

Individualized Pharmacotherapeutic Plan

Pharmacists have numerous opportunities to optimize pharmacotherapy for patients with a history of AF. Ensuring that patients with specific risk factors for cardioembolic stroke are receiving treatment with either an oral anticoagulant or aspirin is vital. Educating patients on their target intensity of anticoagulation, potential drug interactions, dietary restrictions, and self-monitoring of signs and symptoms of bleeding will help prevent adverse sequelae. At every patient encounter, the medication regimen should be reviewed and intervention take place if drug interactions are present. Additionally, patients taking anticoagulants must be assessed regularly for signs and symptoms of bleeding.

Other Treatment Options

Pulmonary Vein Antrum Isolation (PVAI): If a patient continues to have AF that is refractory to antiarrhythmics, PVAI (also known as pulmonary vein ablation) may be considered. PVAI differs from AV nodal ablation, which is used in conjunction with permanent pacemaker implantation to control HR. Over the past decade, catheter ablation of AF has evolved from an experimental method to a commonly performed procedure.⁶
Ablation procedures prevent AF by eliminating the triggering source. They accomplish this by creating circumferential lesions around the pulmonary vein ostium to electrically isolate the focal source of pulmonary veins. PVAI also may alter the tissue located near the atrial–pulmonary vein junction, eliminating the substrate for reentrant circuits that may perpetuate AF. The procedure uses radiofrequency energy delivered by transvenous electrode catheter. The goal of PVAI is to improve a patient’s quality of life, so it is indicated for symptomatic AF that is refractory or intolerant to at least one antiarrhythmic.
Recent randomized clinical trials have demonstrated freedom from recurrent AF in the range of 56% to 86% of patients, and all studies to date have shown improved quality of life.⁵ Similar to cardioversion, restoring sinus rhythm by ablation puts the patient at risk for thromboembolism. In addition, the procedure leaves areas of damaged left atrial endothelium where a thrombus could develop. For these reasons, warfarin is recommended for at least 2 months after AF ablation, with a target INR of 2.0 to 3.0.⁶ Other complications of AF ablation include cardiac tamponade, pulmonary vein stenosis, esophageal injury, atrio-esophageal fistula, phrenic nerve injury, vascular complications, and radiation exposure.⁶
Dronedarone: The FDA approved dronedarone (Multaq) for the treatment of AF and atrial flutter in July 2009, making it the first medication for AF treatment to be approved in 25 years. Dronedarone is a noniodinated derivative of amiodarone without many of the toxicities that are common with amiodarone. Dronedarone’s mechanism of action is similar to that of amiodarone. Dronedarone exerts its action by blocking potassium, sodium, and calcium channels and exhibits antiadrenergic properties. The usual dose of dronedarone for paroxysmal or persistent AF is 400 mg by mouth twice daily with morning and evening meals. Dronedarone has been associated with a 24% reduction in hospitalizations and deaths due to AF and other cardiovascular complications versus placebo.²³ However, higher death rates have occurred in patients with a history of severe HF receiving dronedarone, which resulted in the drug receiving a black box warning. Common side effects of dronedarone include diarrhea, nausea, vomiting, fatigue, and weakness.²⁴

Conclusion

AF will likely affect increasing portions of the population as the baby boomers reach their sixties and seventies. The most significant risk will be stroke. New anticoagulants, novel device therapy, and advanced procedural interventions must be utilized to combat this increase and minimize the risk of cardioembolic complications.