Dawn S. Knudsen, PharmD

Dr. Knudsen is an assistant professor of pharmacy practice at Midwestern University College of Pharmacy&#8212;Glendale, Glendale, Arizona.

In 2004, Surgeon General Richard H.Carmona estimated that sleep disorderscost the United States $15 billionin health care expenses and $50 billion inproductivity losses each year.

 Productivitylosses usually stem from excessivedaytime sleepiness, which is a symptomassociated with all sleep disorders.

Although insomnia is the most well-knownsleep disorder and has the mostpharmacotherapy options, the sleep-disordercategory actually contains 4 disorders&#8212;including narcolepsy (daytimesleep attacks), sleep apnea (breathinginterruptions during sleep), restless legssyndrome (RLS; a tingling or prickly sensationin the legs), and insomnia (difficultyfalling or staying asleep).

Of the 4 sleep disorders, insomniaaffects the largest number of patients&#8212;an estimated 10% to 20% of the US population&#8212;and 47% of elderly patientsexperience chronic insomnia.

 In 2007,insomnia patients incur annual costsbetween $92.5 billion and $107.5 billion.

Although these numbers are staggering,so is the plethora of treatment options.

Medication classes available for insomniatreatment include: benzodiazepine(BZD) hypnotics, non-BZD hypnotics, amelatonin receptor agonist, and OTC antihistamines.Pharmacotherapy shouldinclude "use of the lowest effective dose,use of intermittent dosing (2-4 timesweekly), short-term medication prescribing(regular use for not more than 3-4weeks), and gradual medication discontinuationto reduce rebound insomnia."

BZDs improve insomnia by "reducingREM sleep, decreasing sleep latency, anddecreasing nocturnal awakenings."

 Theyare initially very effective in inducing andprolonging sleep and are relatively inexpensive;however, many problems areassociated with them.

BZDs are associated with reboundinsomnia that can occur within 1 or 2weeks of use, hangover effects, tolerance(which can develop rapidly onrepeated administration), and addictionpotential.

 Whereas short-acting BZDsare preferred, both short-acting (eg,temazepam) and long-acting (eg,diazepam) agents have the potential tocause these problems.

Non-BZD hypnotics, like zolpidem(Ambien), zaleplon (Sonata), eszopiclone(Lunesta), changed the landscape ofinsomnia treatments. Ancoli-Israel andcolleagues described the benefits ofzaleplon in older adults during short- andlong-term treatment as having "no pharmacologictolerance developed duringtreatment and no rebound insomnia orwithdrawal symptoms after medicationdiscontinuation."

As much as these agents have positiveaspects, adverse effects became apparentduring postmarketing monitoring.

In December 2006, the FDA askedmanufacturers of products approved forthe treatment of sleep disorders torevise their product labeling to includewarnings about potential adverse eventssuch as "anaphylaxis (severe allergicreaction) and angioedema (severe facialswelling), which can occur as early as thefirst time the product is taken," as well as"complex sleep-related behaviors, whichmay include sleep driving, making phonecalls, and preparing and eating food(while asleep)."

 Complex sleep-relatedbehaviors have received a great deal ofpress.

 At this time, the exact mechanismis not clear, nor is the commonality ofthese types of events in patients treatedwith these agents.

Ramelteon (Rozerem), a melatoninreceptor agonist, was included in thelabel revisions. Griffiths and colleaguesreported that, compared with 19 otheragents including non-BZDs, BZDs, anddiphenhydramine, ramelteon producedno detectable subjective effects thataffect likelihood of abuse at up to 20times the recommended therapeuticdose.

Sleep apnea causes repetitive episodesof upper airway occlusion during sleep.Although the mechanism of action of thiscondition does not seem to fall into thecategory of sleep disorder, it is the resultof excessive daytime sleepiness thatallows its inclusion. These repetitiveepisodes cause oxygen desaturation andsleep disruption.

Surgery, dental appliances, and continuouspositive airway pressure are thepreferred treatments. Antidepressants,protriptyline, or fluoxetine may be usedin combination with nonpharmacotherapytreatments to decrease excessivedaytime sleepiness because of their suppressionof rapid eye movement (REM)sleep.

RLS has a complicated history and hasonly recently received FDA-approvedtreatments. The condition occurs mostfrequently in middle-aged and olderadults, is worsened by stress, and itscause remains unidentified.

 It can be difficultfor patients and physicians to communicatesymptoms and come to a positivediagnosis. RLS is described in verypatient-specific, subjective terms, whichcan include "burning," "creeping," "crawling,""aching," "tingling," and/or "tugging."Many people with RLS have difficultyexplaining the odd sensations they feel,even when talking to their doctors.

RLS has 2 FDA-approved treatmentoptions: pramipexole (Mirapex) and ropinirole(Requip). Other agents, such as sedatives(eg, diazepam, temazepam) and narcotics(eg, hydrocodone, propoxyphene),have been used in the past, but thesehave adverse effects that may outweighthe possible benefits they provide.

The pathophysiology of RLS is for themost part unknown; neuropharmacologicevidence proposes primary dopaminergicsystem involvement. Although theprecise mechanisms of action ofpramipexole and ropinirole for RLS areunknown, both agents are dopamineagonists,

 so their effectiveness in RLSis understandable. Both agents also areused for Parkinson's disease because oftheir dopamine agonist properties, butthe doses used for RLS are much lowerthan those used for Parkinson's disease.These agents should be administered 1to 2 hours before symptoms occur.

Pramipexole's adverse events seem tobe dose-related (>3 mg/day): posturalhypotension, nausea, constipation, somnolence,and amnesia. The incidence ofsomnolence reported with pramipexoleat a dose of 1.5 mg/day is comparablewith placebo, which is higher than themaximum dose recommended of 0.5 mgfor RLS.

Ropinirole's prescribing informationincludes a warning that "patients treatedhave reported falling asleep whileengaged in activities of daily living,including the operation of motor vehicles,which sometimes resulted in accidents.Although many of these patientsreported somnolence while on ropinirole,some perceived that they had nowarning signs, such as excessive drowsiness,and believed that they were alertimmediately prior to the event."

 Theprescribing information further statesthat "some of these events have beenreported as late as 1 year after initiationof treatment." These events seem tooccur at higher doses than are used forRLS, however.

Narcolepsy affects only a very smallpercentage of the population&#8212;about 1 inevery 2000 Americans, totaling about135,000 individuals.

 Few treatment optionsexist for narcolepsy, and no cure exists.

Pharmacotherapy for narcolepsy canbe split into 2 categories: nonamphetaminesand amphetamines. The nonamphetaminemedication includes modafinil(Provigil). Amphetamine medicationsinclude methylphenidate (Ritalin) anddextroamphetamine.

Modafinil is the medication of choicefor initial treatment. Compared withother medication options, modafinil hasless rebound hypersomnia, tolerance islimited, and it does not affect blood pressure.The main side effect of modafinil isheadache.

Although nonamphetamine treatmentsare preferred for first-line treatment, donot carry controlled-substance status,and have decreased risk of abuse, theamphetamine medication class is still anoption. If tolerance develops duringamphetamine treatment, switching drugsis more appropriate, compared withincreasing the dose of current treatment.LexiComp reports that little cross-toleranceexists in this treatment category.

Auxiliary symptoms, such as cataplexy,hypnagogic hallucinations, and sleepparalysis also have treatment options,which may include antidepressantsbecause of their suppression of REMsleep.

With all 4 sleep disorders, the maingoals of therapy are to balance the needto prevent excessive daytime sleepiness,improve the quantity and quality ofpatient sleep, and avoid adverse effectsof pharmacotherapy.

Traynor K. Insomnia sufferers need better care, experts say. 

www.nlm.nih.gov/medlineplus/sleepdisorders.html

Navarro R, Mitrzyk BM, Bramley TJ. Chronic insomnia treatment and Medicare Part D: Implications for Managed Care Organizations. 

Reeder CE, Franklin M, Bramley TJ. Current Landscape of Insomnia in Managed Care. 

Mirapex [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2007. 

Kamel NS, Gammack JK. Insomnia in the Elderly: Cause, Approach, and Treatment. 

Ancoli-Israel S, Richardson GS, Mangano RM. Long-term use of sedative hypnotics in older patients with insomnia. 

Articles

Various pharmacologic agents are available for sleep disorders, which affect a large portion of the US population.

Sleep Disorders: Treatment Options for a Tiring Problem

Dr. Knudsen is an assistant professorof pharmacy practice at MidwesternUniversity College of Pharmacy&#8212;Glendale, Glendale, Arizona.

Every day the general public isbombarded with commercialsadvertising products or medicationsfor weight loss, as well as direct-to-consumer advertisements cataloginglong lists of side effects that includeweight gain.

Data from 2 National Health and NutritionExamination surveys by theCenters for Disease Control andPrevention's National Center for HealthStatistics show that, among adults aged20 to 74 years, the prevalence of obesityincreased from 15% (in the 1976-1980survey) to 32.9% (in the 2003-2004survey).

Pharmacists often encounter patientsattributing recent or long-term weightgain to their medication(s) or patientswanting to know if a new medicationwill cause weight gain. Sifting througheach medication can be a dauntingtask&#8212;one that is equaled by determiningif weight gain is caused by medication,lifestyle, or just plain edema.

When the source of the problem isedema associated with heart failure,and it is treated with diuretics, potassiumreplacement may be needed; as aresult, patients may increase dietaryconsumption of potassium-rich food,which can lead to weight gain.

 Patientsshould be encouraged to keep a weightdiary and report sudden weight increasesto their physician. This can preventthem from developing a largebuildup of fluid weight and further cardiacproblems before seeking medicaltreatment. Patients also should beadvised that prescription potassium replacementshould suffice during diuretictreatment; consuming potassiumand calorie-rich foods is unnecessary.

Medications associated with weightgain include antipsychotics, antidepressants,and anticonvulsants. For patientstaking antipsychotics, for example,medication-induced weight gainhas been cited as a contributor todecreased quality of life and nonadherenceto their drug regimen.

Of the 2 antipsychotic medicationclasses, the use of certain atypicalantipsychotics has produced evidencesupporting the risk of weight gain. Thisweight gain may have a relationshipwith the documented risk of developingdiabetes during atypical antipsychotictreatment. The risk of weightgain mirrors the risk of developing diabetesfor these agents. Atypical antipsychoticsinclude aripiprazole (Abilify),clozapine (Clozaril), olanzapine (Zyprexa),paliperidone (Invega), quetiapine (Seroquel),risperidone (Risperdal), andziprasidone (Geodon). Aripiprazole andziprasidone are associated with theleast amount of weight gain and arelisted as weight-neutral in some medicalliterature.

Patients experiencing atypicalantipsychotic-induced weight gain canuse calorie reduction and dietary educationprograms, as well as pharmacologictreatment.

 Orlistat 60 mg (alli),orlistat 120 mg (Xenical), and sibutramine(Meridia) are available agents,but, currently, little literature existsregarding how they affect atypicalantipsychotic-induced weight gain.

Another option is switching between antipsychoticagents.

 Switching between antipsychotics, however, is notas easy as switching between statins. The risks and benefitsmust be seriously considered, and patients must be monitoredclosely during and after the transition period. Patientscan respond to antipsychotics differently depending on theagent, and little guidance is available for equivalent dosingbetween the agents. An American Diabetes Association consensustask force recommends changing agents if a patientgains more than 5% of baseline body weight after treatmentinitiation.

Although more medical literature exists regarding weightgain and antipsychotic medications, antidepressants also areassociated with weight gain. Tricyclic antidepressants (TCAs)are known for their anticholinergic side effects; however,weight gain can be an unfortunate side effect as well. TCAsblock histamine and serotonin receptors and peripheralalpha receptors. The blocking of these 3 receptors leads toincreased carbohydrate cravings, decreased physical activity,and increased appetite. TCAs also cause decreased basalmetabolic rates.

 The combination of these effects can lead toweight gain.

Mirtazapine (Remeron), an alpha-2 antagonist antidepressant,joins TCAs on the list of medications commonly causingweight gain. Of the several classes of antidepressants,selective serotonin reuptake inhibitors (SSRIs), including fluoxetine,citalopram, sertraline, paroxetine, fluvoxamine, andescitalopram,

 have a low association with weight gainbecause they do not have the receptor blockade like TCAs;therefore, if weight becomes an issue, switching a patient toan SSRI for depression treatment maybe a good choice.

 When switching apatient between antidepressants, however,proper titration and patient counselingare very important.

Anticonvulsants, such as carbamazepine,gabapentin, lamotrigine,lithium, and valproic acid, can produceweight gain. Approximately one fifth ofpatients gain &#8805;22 lb while on lithiumtreatment. This could be due to fluidretention or decreased metabolic ratefrom hypothyroidism, both commonwith lithium.

 Frequent and close monitoringof these parameters can helpavoid weight gain.

Increased appetite and weight gainoccur in approximately 50% of patientson long-term valproate therapy.

Weight gain may be related to changesin metabolic rates and not to excessivefood intake; excessive weight gain mayresult in obesity-induced hyperinsulinemiaand insulin resistance.

 Carbamazepinecauses weight gain less frequentlythan valproate.

Among the other most common pharmacotherapiesassociated with weightgain are diabetic medications, such asinsulin and thiazolidinediones. An average3% to 9% increase in weight can bea consequence of insulin therapy.

Weight gain is predominantly from increasedtruncal fat and tends to be relatedto daily dose and plasma insulin levels.Less weight gain, when comparedwith more traditional insulin strategies,is achieved when patientsare converted to insulin byusing a bedtime injection ofan intermediate- or long-actinginsulin and using oralagents primarily for controlduring the day.

Thiazolidinediones (rosiglitazoneand pioglitazone)can cause weight gainthrough both fluid retention and fataccumulation.

 Thiazolidinedionesstimulate appetite and fat-cell differentiation.A weight gain of 3.3 to 8.8 lb isnot unusual and seems to be doserelated.

 In addition, these agents carrya black-box warning regarding theincreased risk of new or worsening congestiveheart failure.

 The prescribinginformation states, "observe patientscarefully for signs and symptoms ofheart failure including excessive, rapidweight gain, dyspnea, and/or edema."

Appropriate medical nutrition therapyand healthy lifestyle education arecritical to minimize weight gain associatedwith insulin therapy.

Weight gain during smoking cessationhas been a deterrent to patientswishing to quit or being successful intheir attempts.

 Patientshoping to find a medicationthat assists with smokingcessation and causes weightloss or be weight-neutral willbe disappointed to learn thatsustained-release bupropion(Zyban) and nicotine-replacementtherapies&#8212;in particularnicotine gum&#8212;havebeen shown to delay, but not prevent,weight gain.

 Pharmacists must educatepatients about lifestyle modificationsand choices during smoking cessationto decrease the risk of weightgain.

Women taking oral contraceptives(OCs) have thought that these productscan be the cause of weight gain. Manyof the newer OCs advertise their abilityto prevent weight gain. Drospirenone(Angeliq) has antimineralocorticoid orantialdosterone activities, which mayresult in less weight gain, when comparedwith OCs containing levonorgestrel.

 A 2003 review of the datadid not find evidence supporting acausal association between combinationOCs or combination skin patchesand weight gain.

Pharmacists should expect questionsfrom patients experiencing weightgain while taking a particular medicationand counsel them on the possiblecontributing factors, including lifestyleand edema, in addition to potentialside effects of the medication itself.

Centers for Disease Control and Prevention. Overweight and Obesity. 

www.cdc.gov/nccdphp/dnpa/obesity/index.htm

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds.  

Pharmacotherapy: A Pathophysiologic Approach

Nasrallah, HA.  Pharmacoeconomic implications of adverse effects during antipsychotic drug therapy.  

Guthrie, SK. Clinical issues associated with maintenance treatment of patients with schizophrenia. 

American Diabetes Association. Consensus development conference on antipsychotic drugs and obesity and diabetes. 

Tom WC et al.  Drugs Associated with Weight Gain. Pharmacist's Letter. March  2007. 

Stoneking, K.  Initiating basal insulin therapy in patients with type 2 diabetes mellitus.  

Young, D.  Experts: Rosiglitazone needs stronger warnings. Panel backs diabetes drug. 

us.gsk.com/products/assets/us_avandia.pdf

Garwood CL, Potts LA. Emerging pharmacotherapies for smoking cessation. 

Gallo MF, Grimes DA, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight. 

Pharmacists often see patients attributing weight gain to their medications or wanting to know if a new drug might lead to it.

Side Effect Solutions: How to Avoid Medication-induced Weight Gain

Dr. Knudsen is a clinical pharmacistat Arizona Medical Clinic Ltd inPeoria, Ariz.

Alzheimer's disease (AD) is aprogressive and degenerativeneurologic disorder that ischaracterized by a slow but suredecline in cognition and behavior. AD isthe most common cause of dementiaamong people aged 65 and older, andscientists estimate that 4.5 millionpeople in the United States currentlyhave the disease.

 This disease not onlyaffects the individual suffering from itsmind-altering effects, but also affectsthe family, friends, and caregivers ofthe patient.

The disease is a mystery to the medicalcommunity; diagnosis is by exclusionand is not confirmed until deathwith an autopsy. Just as the disease isan enigma for health care providers, itcan be frustrating to family members,friends, and caregivers of the patient.For that reason, it is important to providecounseling to the patient, the family,and caregivers. As the medicationexperts in the community, pharmacistsmust educate patients and caregiversto ensure that they have realisticexpectations and understand the limitationsof AD medications.

The Alzheimer's Disease AssessmentScale-Cognition (ADAS-cog) and theMini-Mental State Examination (MMSE)are 2 tools to evaluate the status andprogression of AD. The ADAS-cog istime-consuming, whereas the MMSE iseasier to administer in clinical practice.

 MMSE scores range from 0 to 30(from severe to mild disease; Table 1).

MMSE scores naturally decrease 2 to 4points per year if AD is untreated.

Pharmacists need to emphasize thatAD medications slow the progressionof the disease, but patients should notbe expected to return to baseline functioning.A change in medicationsshould take place only if the decline inthe MMSE score is equal to or greaterthan normal disease progression afterthe patient has used a specific treatmentfor 1 year.

For a disease that affects so manypeople and has no cure, only 4 medicationsin 2 drug classes are available toslow the progression (Table 2). Acetylcholinesterase(AChE) inhibitors arethe mainstay of AD therapy. There are 4agents in the class, but only 3 are commonlyprescribed: donepezil (Aricept),galantamine (Razadyne, Razadyne ER),and rivastigmine (Exelon). Tacrine(Cognex) was approved in 1993 but israrely used because of its severe sideeffects and the risk of hepatotoxicity.

Donepezil has an easy titrationschedule and can be increased from 5mg to 10 mg once daily (maximumdose) in 4 to 6 weeks.

 Unlike the otheragents in this class, the side effects areusually mild and include headache,nausea, diarrhea, anorexia, and fatigue.

Donepezil also comes in an orally disintegratingtablet for easier administration.

Rivastigmine has a time-consumingtitration schedule and is dosed twiceper day. The capsules should not beopened and mixed with food or a beverage. If administration is a problem, anoral solution and a patch are available.Patients and caregivers should be educatedon the proper administration anddisposal of the Exelon Patch. WhenExelon Oral Solution is combined withcold fruit juice or soda, the mixture isstable at room temperature for up to 4hours.

 If the patient stops the medicationfor more than several days, treatmentshould be reinitiated with thelowest daily dose and titrated back upto the previous dose.

 It is important tolet the caregiver know about the titrationrequirements to avoid intolerablegastrointestinal (GI) adverse effects.

Galantamine has a complicated titrationschedule and must be given withmeals. Tablets are dosed at 4 mg twicedaily, titrated monthly to 12 mg twicedaily. Extended-release tablets are availablefor once-daily dosing, and an oralsolution is available if administration is aproblem. Caregivers should be instructedin the correct procedure for administeringthe Razadyne Oral Solution andshould be shown the instruction sheetthat comes with the product. If therapyhas been interrupted for several days orlonger, the medicine should be restartedat the lowest dose and escalated tothe current dose.

Memantine is the only agent availablein the 

-methyl-D-aspartate antagonistclass. It is approved for moderate-to-severe disease. It can be used asmonotherapy or combination therapywith an AChE inhibitor. It can be titratedfrom 5 mg daily every 7 days untilthe goal dose of 10 mg twice daily isreached.

As with any disease for which themedical community cannot provide acure, people often go beyond allopathictreatment options (Table 3). Herbaland dietary supplements such as ginkgobiloba, coenzyme Q

, orvitamin E are used as alternativesor adjuncts topharmacotherapy. Ginkgobiloba may have a bleedingrisk if used concomitantlywith other bleeding-riskmedications (eg, nonsteroidalanti-inflammatorydrugs [NSAIDs], warfarin)and may increase theadverse effects of AChEinhibitors.

 may increasebleeding risk and should be used withcaution with antidiabetic, psychiatric,and cardiovascular drugs. CoenzymeQ

 has potential adverse effects similarto those with the AChE inhibitors.

Vitamin E at more than 400 IU/dayhas been studied, and, although it hasnot shown clinically significant resultsin large studies for AD, it was associatedwith an increase in all-cause mortalityin a large meta-analysis and thusshould be avoided.

 Epidemiologicstudies have suggested that NSAIDsmay have a benefit, but the risks ofbleeding events and GI adverse effectsoutweigh the possible benefit.

Patients wanting more informationregarding these products can reviewthe ongoing clinical trials at theNational Institutes of Health ClinicalTrials Web site, 

,but this information is not targeted tothe lay public. If a pharmacist directssomeone to this site, it is important tostress that the patient should discussthe findings with a pharmacist oranother qualified health care providerbefore making any changes to his orher therapy.

Pharmacists are in a great positionto discuss these products with patients.Many of the electronic resourcesavailable to pharmacists&#8212;such as Lexi-Comp, Micromedex, andClinical Pharmacology&#8212;have scientificinformation available regarding dietarysupplements or natural products.Pharmacists need to educate patientsthat, with any product that falls underthe FDA's definition of 

(vitamin, mineral, herb, botanical,amino acid, enzyme, organtissue, metabolite, etc),there is a lack of standardizationand a lack of safetyinformation about the potentialfor adverse effectsand medication interactions.

Also, pharmacists are inan excellent place to helpthe caregivers of ADpatients. This disease isoften difficult for the caregiver,especially when the patient hasepisodes of depression, paranoia,sleep disturbances, and aggression.Spousal or caregiver abuse can occur.Being aware of these types of issuescan allow the pharmacist to providesupport and encouragement. Lettingthe caregiver know about supportgroups and the availability of treatmentfor these additional conditions thatoften accompany AD can increase thequality of life for the caregiver and inturn the quality of life for the patient.

Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. 

DiPiro JT, Talbert RL, Yee GC, Matzke GR. 

. 6th ed. New York, NY: McGraw-Hill; 2005: 1163-1167.

Galasko D. An integrated approach to the management of Alzheimer's disease: assessing cognition function and behavior. 

Aricept  prescribing information. Available at: 

Exelon prescribing information. Available at: 

www.pharma.us.novartis.com/product/pi/pdf/exelon.pdf

Razadyne ER prescribing information. Available at: 

Namenda prescribing information. Available at: 

Lexi-Comp online. Ginkgo biloba. Available at: 

Lexi-Comp online. Coenzyme Q10. Available at: 

Pharmacists must educate patients and caregivers to ensure that they have realistic expectations and understand the limitations of AD medications.

Complexities of AD Require Extensive Counseling

Prostate conditions can affect men's quality of life and the ability to enjoy social situations. The prostate is located in front of the rectum and just below the bladder surrounding the urethra. There are 3 main conditions that affect the prostate: prostatitis (inflammation of the prostate), prostate cancer, and benign prostate hyperplasia (BPH).

Up to 25% of all office visits by young and middle-aged men for complaints involving the genital and urinary systems may be due to prostatitis.

 There are 4 types of prostatitis, and treatment is dependent on the underlying cause for each. Only acute bacterial prostatitis and asymptomatic inflammatory prostatitis require antibiotics.

Prostate cancer is a disease for which the average man over the age of 50 should be tested every year. In 2003, prostate cancer was responsible for 29,554 deaths in the United States.

 Prostate-specific antigen (PSA) is a laboratory value that can be obtained by a simple blood draw to screen for prostate cancer. Most doctors consider PSA values below 4.0 ng/mL to be normal.

 An abnormal PSA value indicates the need for further assessment, because a clinician cannot distinguish between BPH and prostate cancer on the basis of PSA level alone.

The prevalence of BPH is age-dependent; 75% of men will develop symptoms by age 70 and 90% by age 80.

 The prostate undergoes 2 growth spurts throughout the life span of most men. The first growth spurt is during puberty, and the second begins at age 40 and continues until around age 70. The benign enlargement of the prostate causes hesitancy and difficulty in initiating urination, interruption of flow, weak urine stream, sensation of incomplete emptying, nocturia, frequency, and urgency.

The American Urological Association (AUA) Symptom Index

 provides an objective assessment of subjective symptoms. The patient rates the "bothersomeness" of 7 categories of symptoms on a scale of 1 to 5. The higher the AUA score is, the more severe the condition is (Table 1).

BPH symptoms can be exacerbated by other medications, both prescription and OTC. It is important to educate patients about the impact that OTC and prescription medications?by exacerbating BPH symptoms and severity?can have on BPH symptom control. Commonly used OTC cold medications containing pseudoephedrine or phenylephrine can compromise bladder emptying. Diuretics, in large doses, can cause increased urination, which can compound the symptoms that BPH patients experience. Also, medications with considerable anticholinergic adverse effects?such as antihistamines, tricyclic antidepressants, and antispasmodics?can cause urinary retention when combined with BPH pathophysiology.

Only 2 classes of medications can provide treatment and symptom relief for BPH: a-1-adrenergic antagonists and 5-a-reductase inhibitors (Table 2). Watchful waiting and surgery also are viable options in some BPH cases, depending on the patient and the physician.

Five a-1-adrenergic antagonists are available in the United States: prazosin (Minipress; Pfizer), terazosin (Hytrin; Abbott Laboratories), doxazosin (Cardura; Pfizer), alfuzosin (UroXatral; sanofi-aventis), and tamsulosin (Flomax; Boehringer Ingelheim). Only 4 of these agents are long-acting a-1-antagonists: terazosin, doxazosin, alfuzosin, and tamsulosin.

This class of drugs has evolved through several generations. The first generation had many serious adverse effects and is no longer used. The second generation, which includes prazosin, terazosin, doxazosin, and alfuzosin, improves voiding symptoms and produces less tachycardia and cardiac arrhythmia. Prazosin is short-acting, is dosed multiple times per day, and is no longer recommended by the AUA.

a-1-adrenergic antagonist agents relax smooth muscle in the prostate and bladder neck, thereby increasing urinary flow rates and reducing postvoid residual urine volume, but they have no effect on decreasing prostate volume or PSA levels. They require 2 to 4 weeks to reach peak effect on BPH symptoms.

Side effects of these medications include orthostatic hypotension and dizziness. Ensuring that the medication is dosed at bedtime and titrated up over several weeks can minimize these side effects. There are fast and slow titration schedules. Younger patients may be able to handle a faster titration. Elderly patients may be physiologically more vulnerable to the hypotensive effects and already may be taking medications that affect blood pressure, and thus they may require a slower titration schedule. If the medication is discontinued for a period of time, retitration may be required.

Alfuzosin is dosed once per day, does not require titration up, and may cause less significant reductions in blood pressure due to its uroselectivity, compared with the other second-generation agents.

Tamsulosin is the only available third-generation agent. It produces a low incidence of hypotension because of its high affinity for prostate-specific a-adrenergic receptors only. Tamsulosin does not require bedtime dosing or titration schedules, unlike the other agents. This drug is a good choice for patients who cannot tolerate hypotension or are taking multiple medications that have hypotensive adverse effects.

Two 5-a-reductase inhibitors are approved in the United States: finasteride (Proscar; Merck) and dutasteride (Avodart; GlaxoSmithKline). These agents work to reduce the size of the prostate, slow disease progression, and decrease the need for surgery. They are especially ideal for patients with prostates that are at least 50 g. Unlike the comparatively quick symptom relief of the a-1-adrenergic antagonists, treatment for 6 to 12 months generally is needed before prostate size is sufficiently reduced to improve symptoms with the 5-a-reductase inhibitors. Once treatment is discontinued, prostate size and symptoms return to baseline. 5-a-reductase inhibitors also decrease PSA levels by ~50%. Therefore, interpreting PSA levels while the patient is using these agents requires adjustment.

Sexual dysfunction is a serious adverse effect of 5-a-reductase inhibitor treatment. This dysfunction can include impotence, decreased libido, ejaculation disturbances, and decreased volume of ejaculate. Ejaculation dysfunction incidence seems to double during combination BPH therapy.

 These adverse sexual effects are reversible and uncommon after the first year of therapy.

 Tamsulosin and alfuzosin also can cause patients to have low rates of erectile dysfunction.

5-a-Reductase inhibitors can be absorbed through the skin. Women who are pregnant or may be pregnant should not handle these agents because of the possibility of absorption and the potential risk of a fetal anomaly. According to Avodart prescribing information, if contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

Because the 2 classes of medications for BPH work through different mechanisms of action, it is logical to consider using combination therapy. This therapy seems to be ideal for patients with severe symptoms and enlarged prostates of >40 g. The disadvantages of combination therapy include the increased cost and the increased incidence of adverse effects from the 2 agents. Past studies of <12 months of combination therapy did not find superiority over a-1-adrenergic antagonist monotherapy.

 In a study of 5 years in duration, combination therapy demonstrated superiority in relief and prevention of BPH symptoms.

http://kidney.niddk.nih.gov/kudiseases/pubs/prostatitis

www.cancer.gov/templates/doc.aspx?viewid=4D0E8A1A-5770-4A6F-BAAC- DED5595D97DF.

4. Eure GR, et al. Benign prostatic hyperplasia disease management guide. Montvale, NJ: Thomson PDR; 2005. 

5. Barry MJ, et al. The American Urological Association Symptom Index for benign prostatic hyperplasia. 

6. Lee M. Alfuzosin hydrochloride for the treatment of benign prostatic hyperplasia. 

http://online.lexi.com/crlsql/servlet/crlonline

8. Avodart prescribing information. Available at: 

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9. McConnell JD, et al. The long term effects of medical therapy on the progression of BPH: results from the MTOPS trial. 

Dr. Knudsen is a clinical pharmacist at Arizona Medical Clinic, Peoria, Ariz.