Antony Q. Pham, PharmD

Dr. Pham is a surgery/transplant clinical pharmacist at Ronald Reagan UCLA Medical Center in Los Angeles, California.

Acid suppression therapy is commonly used for gastrointestinal (GI) prophylaxis in health systems. Over the past 25 years, medications that reduce gastric acid or protect the stomach mucosa have been credited in lowering the risk of stress ulcer-related bleeds from approximately 20% to 30%, to 2% to 14%.

 Available agents include antacids, sucralfate, and misoprostol; the mainstay of acid-suppressive therapy is currently with histamine

RAs) and proton pump inhibitors (PPIs).More recently, concern has grown over the widespread overuse of acid-suppressive agents for stress ulcer prophylaxis in health systems.

Stress ulceration can occur after trauma, surgery, organ failure, sepsis, or thermal injury.

 Causes of stress ulcer lesions appear to be multifactorial.

 Hypersecretion of acid is common in patients following head and thermal injuries.

 In addition, normal protective mechanisms may be altered during stressful events, causing a reduction in mucosal blood flow that can contribute to ulcer formation. Thus, acid suppression therapy can play an important role in the prevention of GI stress ulcers in certain hospitalized patients.

Acid-suppressive agents act either by reducing gastric acid or by protecting the stomach mucosa. Antacids are bases that contain aluminum, magnesium, or calcium that can temporarily neutralize gastric acid. These agents are normally indicated for minor symptoms of heartburn and acid-related indigestion. The major side effects of antacids include diarrhea for magnesium-containing compounds and constipation for aluminum- and calciumcontaining agents.

Sucralfate is a polysaccharide that complexes with aluminum to prevent chemically induced mucosal damage and heal gastric ulcers. Sucralfate does not alter the acid secretion of the stomach; rather, it stimulates the formation of granulation tissue and delivers growth factors to the injured tissue. Aluminum toxicity should be monitored when using sucralfate.

The use of misoprostol has been approved for the prevention of nonsteroidal anti-inflammatory-induced gastric ulcers. Misoprostol is a prostaglandin analog that selectively inhibits acid secretion as well as enhances mucosal defense mechanisms. Its use is contraindicated in women of childbearing potential, as it can lead to spontaneous abortion.

RAs reduce acid secretion by blocking the histamine receptors on parietal cells. Currently 4 H

RAs are available in the United States (Table 1). The primary use of H

RAs is for the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD).

PPIs (Table 2) are more potent acidsuppressing agents and are most commonly used for the treatment of PUD, GERD, and indigestion. These agents provide near-complete blockage of acid secretion by inhibiting the hydrogen-potassium ATPase pump on the parietal cell. All of the PPIs are weak bases that concentrate in the acidic compartments of the parietal cell. PPIs are then activated by the acid and subsequently form a reactive sulfhydryl group. This group binds to the cysteine moiety on the hydrogen-potassium ATPase pump and inactivates the enzyme.

Because PPIs rely on an acidic environment to be activated, the simultaneous use of H

RAs theoretically would decrease their effectiveness.

 Normally all acid-suppressive agents are remarkably safe drugs and usually well-tolerated.

The most current guidelines for the use of acid-suppressive agents in stress ulcer prophylaxis were published by the American Society of Health-System Pharmacists in 1999.

 According to these guidelines, strong evidence supports prophylactic therapy in patients who require mechanical ventilation for >48 hours or in patients with coagulopathy (international normalized ratio >1.5, partial thromboplastin time >2 times normal, or platelet count <50,000). Meta-analyses from randomized controlled trials have shown that patients requiring mechanical ventilation have a 15-fold increased risk of GI bleed, and those with coagulopathy have a 4-fold increased risk of bleeding when compared with other patients.

Prophylaxis is recommended for patients with a history of GI ulcer or previous bleeding within 1 year of admission. In addition, expert opinion from the panel states that prophylaxis is indicated in patients with at least 2 of the following risk factors: sepsis, intensive care unit (ICU) stay of >1 week, occult bleeding lasting ≥6 days, and the use of high-dose corticosteroids (>250 mg/day of hydrocortisone or the equivalent). Prophylaxis is not recommended for general and surgical adult patients in non-ICU settings with <2 of these risk factors. Note that the guidelines assessed stress ulcer prophylaxis with antacids, H

RAs, and sucralfate and did not include PPIs.

Despite these specific guidelines, acid-suppressive agents have been over-used for stress ulcer prophylaxis in non-ICU patients. A review assessing the prevalence of acid-suppressive therapy at the University of Michigan was performed by Pham et al.

 The esearchers found that before admission, 29% of patients were on acid-suppressive therapy. Once admitted to the noncritical care general medicine service, this number increased to 71%. A retrospective chart review of the medical records showed that 69% to 89% of therapy was deemed inappropriate according to established indications.

Nardino et al found similar results in 226 patients admitted to the general medicine unit at the Hospital of Saint Raphael in New Haven, Connecticut.

 The researchers reported that 65% of acid-suppressive therapy was considered inappropriate as determined by consensus review. Of these patients, 55% were discharged on continued therapy.

Zink et al assessed the long-term use of acid-suppressive therapy started inappropriately at William Beaumont Hospital in Detroit, Michigan.

 Of the 324 patients admitted to the general medicine service, 60% received acid suppression without an appropriate indication. The most frequent reason for prescribing therapy was "GI prophylaxis in low-risk patients." Other reasons included pancreatitis and steroid use. About 34% of these patients with inappropriate acid suppression were discharged on the acid-suppressing medication. A follow-up showed that 80% of these patients continued on the medication 3 months after discharge, and 50% of patients were still on acid suppression therapy 6 months postdischarge.

A possible reason behind the inappropriate use of acid-suppressive agents may be the general acceptance that these medications have a low rate of side effects.

 Although this may be true in most cases, there have been reports that altering the acid content in the gut can increase the risk for 

Laheij et al reported that acid suppression could increase the risk of community-acquired pneumonia.

 deficiency and an increased risk of hip fractures have been reported with long-term PPI use.

 The inappropriate use of acidsuppressive agents also has placed an unnecessary burden on health care costs. The estimated cost of a PPI was $102 per month; H

RAs averaged $25 per month for generic forms and $87 per month for a brand name drug.

The economic cost of inappropriate stress ulcer prophylaxis was reviewed by Heidelbaugh and Inadomi.

 Of the 1769 patients reviewed, 22% were prescribed prophylaxis without an appropriate indication, in which more than half (54%) of these patients were discharged with a prescription. The estimated cost of inappropriate acid-suppressive therapy from this cohort was $111,000 per year.

The development of institution-specific guidelines for acid suppression therapy can reduce costs and potential side effects for health systems. Stress ulcer prophylaxis with acid-suppressive agents should be reserved for patients who are in the ICU or who carry ≥2 major risk factors for GI bleed.

Education for providers through inservice training sessions has proven to be beneficial. A study conducted by Liberman and Whelan at the University of Chicago Hospitals showed that a 1-hour educational intervention with the house staff lowered the rate of inappropriate stress ulcer prophylaxis from 59% to 29% after 1 month.

 Health systems with computer order entry also can intervene effectively through pop-up reminders.

 Finally, pharmacy and therapeutics committees can develop a therapeutic interchange protocol among the H

RAs and PPIs. The general clinical equivalence of these agents makes it possible to place only 1 agent from each class on a formulary. This would primarily benefit acquisition costs without compromising drug therapy.

Factors that need to be considered before the addition of an H

RA or PPI to a health-system formulary would include the comparison of pharmacokinetics, pharmacodynamics, available dosage forms and routes of administration, safety, and cost of each agent. In addition, product preparation and administration costs should be taken into account. Most ICU patients cannot take oral medications; thus, an IV formulation of each H

RA and PPI needs to be available on formulary as well. The duration of therapy and the transition from IV to oral or enteral formulations also should be considered by the committee and placed into institutional guidelines.

1. Navab F, Steingrub J. Stress ulcer: is routine prophylaxis necessary? 

2. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. 

3. Cho CH, Koo MWL, Garg GP, Ogle CW. Stress-induced gastric ulceration: its etiology and clinical implications. 

4. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicenter, double-blind, placebo-controlled trial. 

5. Soll AH. Pharmacology of antiulcer medications. www.uptodate.com/patients/content/topic.do?topicKey=~9BBB3xpx_sid9. Accessed April 1, 2008.

6. Wolfe MM. Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders. www.uptodate.com/patients/content/topic.do?topicKey=~x/44UsYRYQJzHr. Accessed April 1, 2008.

7. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. 

8. Pham CQ, Randolph ER, Bostwick TR, Knauf KS. Acid suppressive therapy use on an inpatient internal medicine service. 

9. Nardino FJ, Vender RJ, Herbert PN. Overuse of acid-suppressive therapy in hospitalized patients. 

10. Zink DA, Pohlman M, Barnes M, Cannon ME. Long-term use of acid suppression started inappropriately during hospitalization. 

11. Heidelbaugh JJ, Inadomi JM. Magnitude and economic impact of inappropriate use of stress ulcer prophylaxis in non-ICU hospitalized patients. 

12. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of 

 diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-controlled studies. 

13. Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Sticker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid suppressive drugs. 

14. Heidelbaugh JJ, Goldberg KL, Inadomi JM. Overutilization of proton pump inhibitors: A review of cost-effectiveness and risk. 

15. Liberman JD, Whelan CT. Reducing inappropriate usage of stress ulcer prophylaxis among internal medicine residents. A practice-based educational intervention. 

16. Gardner TB, Robertson DJ. Stress ulcer prophylaxis in non-critically ill patients: less may be more. 

17. Devlin JW. Proton pump inhibitors for acid suppression in the intensive care unit: formulary considerations. 

Articles

Preventing Stress Ulcers with Acid Suppression

Dr. Antony Pham is a pharmacy practice resident at University of California, Los Angeles Medical Center. Dr. David Pham is an assistant professor of pharmacy practice at Western University College of Pharmacy and Health Sciences in Pomona, California.

) affects about 50 million Americans and almost 1 billion people worldwide. People who have normal blood pressure at 55 years of age have a 90% risk of developing high blood pressure in their lifetime. Therefore, it is likely that high blood pressure will affect you or someone closely related to you.

	High blood pressure usually is found by measuring the pressure in the blood vessels during a heartbeat and when the heart is at rest. The reading during a heartbeat is known as 

 pressure. The reading when the heart is at rest is known as 

 pressure. These readings usually are written with the systolic blood pressure number over the diastolic blood pressure number. An example would be 138/93 mm Hg (millimeters of mercury).

	In patients who are older than 50 years of age, controlling systolic blood pressure is more important than controlling diastolic blood pressure, because systolic blood pressure is directly linked to the risk of heart disease. If your systolic blood pressure is more than 140 mm Hg or your diastolic blood pressure is more than 90 mm Hg on 2 separate occasions, your health care provider may diagnose you as having hypertension.

	Lowering your high blood pressure to a specific goal, as set by your health care provider, will reduce your risk of stroke, heart failure, heart attack, kidney failure, and even death. If you are diagnosed with high blood pressure and also have either diabetes or kidney disease, your blood pressure should be less than 130/80 mm Hg. If you are diagnosed with high blood pressure and have other disease states, your blood pressure should be less than 140/90 mm Hg (see the Table).

	To achieve your blood pressure goal, it is recommended that you obtain a blood pressure self-monitoring device. This device will allow you to check your blood pressure in the convenience of your own home at any time of the day. You may bring your monitoring device as well as a log of your blood pressure readings to every health care visit to ensure that your readings are consistent with those of your health care provider.

	To obtain an accurate blood pressure reading, you should sit quietly for at least 5 minutes with your feet uncrossed on the floor and your arm supported at the level of your heart. Make sure that you have an appropriately sized cuff that wraps around at least 80% of your arm. Cuffs that are too big or too small will give incorrect readings.

	Although some digital devices can measure blood pressure on your fingers and your wrist, only those that are used on the upper arm are recommended. When selecting a self-monitoring device, talk to your pharmacist about the differences between each product. If you have trouble reading small numbers, ask for a device that shows larger numbers. Some devices can record your blood pressure readings and give you a printout that you may bring to your health care provider.

	Several healthy lifestyle changes can improve blood pressure in patients with prehypertension (see the Table) and/or hypertension. Patients with high blood pressure are urged to adopt the Dietary Approaches to Stop Hypertension (DASH) plan. This plan encourages patients to eat foods rich in fruits and vegetables, as well as lowfat dairy products. Foods containing a high fiber content and potassium also are suggested. Fish and poultry are recommended, in comparison to red meats. In addition, the DASH plan emphasizes a diet low in saturated and total fat. It is recommended that patients with high blood pressure reduce their daily intake of sodium to less than 2.4 grams. Do not add salt when cooking, and remove all salt from the table.

	Physical activity such as aerobic exercise—for at least 30 minutes a day for most days of the week&mdash;also can reduce blood pressure. This type of exercise includes walking, swimming, jogging, running, and bicycling.

	Healthy weight loss means a 7% to 10% reduction in weight over 1 year. This reduction may be achieved by lowering your total daily intake by 500 calories. A weight loss of 1 to 2 pounds per week is considered healthy. Any greater weight loss is discouraged.

	Men with high blood pressure should limit their alcohol consumption to 2 drinks a day (for example, two 12- ounce beers or 10 ounces of wine). Women should limit their alcohol consumption to 1 drink per day. Lastly, it is recommended that patients with high blood pressure not smoke, because smoking may increase the risk of heart disease.

	Patients are strongly encouraged to adopt these changes, because they can lower blood pressure, enhance the work of blood pressure medicines, and lower the risk for heart problems.

	Medicines can be used in addition to lifestyle changes to lower blood pressure. Several classes of drugs are available to lower blood pressure.

	Many patients with high blood pressure will require 2 or more medications along with lifestyle modifications to achieve blood pressure goals. Follow-up visits with your health care provider, with careful monitoring of your blood pressure, are important to determine the best medicines to control your high blood pressure. Your health care provider will decide which drug or combination is best for you.

	Controlling blood pressure can reduce the risk of stroke, heart failure, heart attack, and kidney failure. Patients with high blood pressure are encouraged to monitor their own blood pressure with a self-monitoring device. Patients should adopt healthy lifestyle changes, and they should discuss medication options with their health care provider.

The Facts About Blood Pressure

Dr. Pham is a Pharmacy PracticeResident at UCLA Medical Center inLos Angeles, California.

Hypertension affects approximately60 million adults in theUnited States and is one of themost common chronic reasons for physicianoffice visits.

 Data from the NationalHealth and Nutrition Examination Surveycensus bureau show that only 34% ofpatients with hypertension have adequateblood-pressure (BP) control

; theresult is that hypertensive emergenciespresent in roughly 27.5% of emergencyroom visits.

 Long-term effects of hypertensionalso are significant risk factorsfor hospitalization.

 is the termused for elevated BP of unknown origin.These elevations have been classifiedinto stages, according to the most recentreport of the Joint National Committeeon Prevention, Detection, Evaluation, andTreatment of High Blood Pressure (JNC7), based on the average of &#8805;2 properlymeasured BP readings on separatehealth care visits (Table).

Improper management of hypertensionis a major risk factor for cardiovasculardisease (CVD), such as left ventricularhypertrophy, angina, myocardialinfarction, and heart failure,

 and canlead to other end-organ damage, such asstroke, retinopathy, chronic kidney disease,and peripheral arterial disease.Benefits of treating hypertension withmedication have been demonstrated innumerous clinical trials.

Thorough patient evaluation for essentialhypertension is key

 and should beginwith a complete history to assess thecourse of BP levels, the extent of organdamage, the presence of other risk factorsfor CVD (eg, obesity, dyslipidemia,diabetes mellitus, cigarette smoking),and other comorbidities. Other evaluationrecommendations include a physicalexamination, observing signs of organdamage; laboratory tests, including urinalysis,blood glucose, hematocrit andlipid panel, serum potassium, creatinine,and calcium; an electrocardiogram, monitoringcardiac activity; and accuratevital-sign assessment, determining BP,heart rate, and respiratory rate.

Treating essential hypertension usuallybegins with lifestyle modifications.

 In thePREMIER trial, sponsored by the NationalHeart, Lung, and Blood Institute, patientsexperienced a lower prevalence ofhypertension and required less use ofantihypertensive medications after 18months of nonpharmacologic therapy.

Health care providers should outline aspecific plan per patient.

A reduced-sodium diet (6 g of saltdaily) has been shown to lower systolicBP (SBP) by about 2 to 8 mm Hg.Weightreduction (maintaining a healthy bodyweight index of 18.5-24.9 kg/m

) canlead to SBP reductions of roughly 5 to 20mm Hg. Patients are encouraged toadopt the eating plan, 

 (DASH diet),which is rich in fruits, vegetables, andlow-fat dairy products, with reduced saturatedand total fat, and can lower SBPby 8 to 14 mm Hg.

Aerobic physical activity at least 30minutes per day, most days of the week,can reduce SBP by 4 to 9 mm Hg. Moderationof alcohol consumption (men &#60;2drinks daily, women &#60;1 drink daily) alsocan slightly reduce SBP. All patients areencouraged to stop smoking.

Pharmacologic treatment of essentialhypertension is usually initiated forpatients who do not achieve their BPgoals (BP &#60;140/90 mm Hg or BP &#60;130/80mm Hg in patients with diabetes orchronic kidney disease) through lifestylemodifications.

 Initial drug choice isbased on the presence or absence ofother compelling factors. Based on outcomesfrom the Antihypertensive andLipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT), the JNC 7guidelines recommend a low-dose thiazidediuretic for patients with uncomplicatedhypertension.

 Results haveshown benefits of diuretics in patientswith heart failure, previous myocardialinfarction (spironolactone), and diabetes,and for stroke prevention.

If BP goals are not reached with a thiazidediuretic, the addition of anangiotensin-converting enzyme (ACE)inhibitor, angiotensin II receptor blocker(ARB), beta-blocker (BB), calcium channelblocker (CCB), or a combination of theseagents should be considered. Patientsinitially diagnosed with stage 2 hypertensionmay need to start with a combinationof the above antihypertensives (usuallydiuretic + ACE inhibitor for synergy).

Although thiazide diuretics are consideredthe initial drug choice for uncomplicatedhypertension, specific compellingindications are used for other antihypertensives.ACE inhibitors are consideredfirst-line options for patients who haveheart failure, previous myocardial infarctions,stroke, diabetes, systolic dysfunction,or chronic kidney disease.

 This isdue to the suggested cardiac and renalprotective effects of inhibiting the reninangiotensin-aldosterone system. ARBsare likely to have similar indications andare usually substituted if patients do nottolerate an ACE inhibitor (eg, cough).

Combination therapy with an ACEinhibitor and an ARB appears to be beneficialin patients with heart failure andchronic renal failure.

 The newly approveddirect renin inhibitor (aliskiren)also may be useful when used alone or incombination with other antihypertensiveagents.

 All medications that block therenin-angiotensin system should be usedwith extreme caution in the 1st trimester(category C) and are contraindicated inthe 2nd and 3rd trimesters (category D)of pregnancy due to fetal injury.

BBs are primarily indicated for essentialhypertension in patients with previousmyocardial infarction, stable heartfailure, and diabetes. BBs also are usefulfor patients with atrial fibrillation, angina,and migraine headaches. Although noabsolute indications for CCBs exist, theycan offer added benefit for patients withatrial fibrillation or angina and may bepreferred in patients with chronic obstructiveairway disease.

The combination of different classes ofantihypertensive medications often isneeded to adequately control BP. A BP&#62;20/10-mm Hg above goal is generally anindication to start an additional medication.

 Diuretics are thought to have a synergisticeffect with ACE inhibitors, ARBs,and BBs by minimizing volume expansion.Combinations can be derived basedon this or other factors (eg, cost, patienttolerability). Some combinations shouldbe used with caution because of possiblepotentiating side effects (ACE inhibitor +ARB can increase serum potassium levels;BB + CCB can potentiate heart block).

Although age and race are not consideredcompelling indications, they can beused to predict response from hypertensivepatients. Young and white patientstend to respond better to ACE inhibitors(and probably ARBs) and BBs.

 Theseresponses may be related to theoreticalelevated baseline plasma renin activitylevels in these patients.

 Elderly andblack patients have been shown torespond better to diuretics and CCBs.

Alpha-blockers (doxazosin, terazosin)are not considered initial treatmentoptions in essential hypertension unlessthe patient has concomitant benign prostatichypertrophy. A central alpha-agonist(clonidine) is used primarily forrefractory hypertension that is not otherwisecontrolled. The transdermal formulationmay be an attractive option forpatients who do not tolerate pills. Directarterial vasodilators (hydralazine, minoxidil)also are considered 2nd- or 3rd-lineagents. Nitrates (isosorbide mononitrateand dinitrate) are usually used in patientswho are resistant to other antihypertensivetherapy; however, a nitrate-free period(12 hours daily) is necessary to avoidtolerance.

With regard to essential hypertensionin a health system, it is strongly recommendedthat each institution considerJNC 7 guidelines when adding medicationclasses to its formulary. Diuretics(thiazide and loop), BBs (specific &#0223;1 withoutintrinsic sympathomimetic activity),ACE inhibitors (short- and long-acting),ARBs, and CCBs (dihydropyridines andnondihydropyridines) are all standardantihypertensive medications thatshould be part of a complete health systemdrug formulary. Agents used forrefractory hypertension (eg, clonidine,hydralazine, nitrates) should be availablefor resistant patients.

Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. 

Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. 

Kitiyakara C, Guzman NJ. Malignant hypertension and hypertensive emergencies. 

Psaty BM, Furberg CD, Kuller LH, et al. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. 

Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. 

Coresh J, Wei L, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Study (1998-1994). 

Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure lowering drugs. 

Wong ND, Thakral G, Franklin SS, et al. Preventing heart disease by controlling hypertension: impact of hypertensive subtype, stage, age, and sex. 

Appel LJ, Champagne CM, Harsha DW, et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. 

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). 

Neutel JM, Black HR, Weber MA. Combination therapy with diuretics: an evolution of understanding. 

Lip GY, Frison L, Grind M. Angiotensin converting enzyme inhibitor and angiotensin receptor blockade use in relation to outcomes in anticoagulated patients with atrial fibrillation. 

Tekturna [package insert]. East Hanover, NJ: 

United States Food and Drug Administration. Center for Drug Evaluation and Research. 

Dickerson JEC, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimization of antihypertensive treatment by crossover rotation of four major classes. 

Blaufox MD, Lee HB, Davis B, et al. Renin predicts the blood pressure response to nonpharmacologic and pharmacologic therapy. 

Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension. 

Lifestyle modifications are usually the first defense against hypertension; however, various pharmacologic options exist.

Chronic Care Focus: Important Considerations for Managing Essential Hypertension

The treatment of seizures with antiepileptic drugs (AEDs) was initiated >150 years ago with the introduction of bromide therapy.

 As different agents became more readily available, physicians started prescribing AEDs for patients based on specific seizure types. Early medications with approved efficacy included phenobarbital, phenytoin, carbamazepine, ethosuximide, primidone, and valproic acid. These AEDs have been shown to be effective for a wide range of seizure types and remain first-line therapy options for all newly diagnosed epilepsy.

Only ~70% of patients achieve seizure control while on these AEDs, however.

 In addition, many of the older AEDs are limited by serious adverse side effects, numerous drug interactions, and challenging pharmacokinetics.

In the past 10 years, the FDA has approved several medications to expand the treatment options for epilepsy.

 Gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and now zonisamide and pregabalin are all widely available options for seizures in the United States. With the introduction of these medications, many health care providers are now seeking updated evidence-based guidelines for the treatment of epilepsy.

Epilepsy and seizure disorders are among the most common neurologic problems in the world. An estimated 3% of the people in the United States will have epilepsy at some point in their lives.

is defined as a sudden, excessive discharge of electrical activity in the brain that causes a change in a person's feelings, perception, or behavior. Epilepsy is a chronic process that causes a person to have 

seizures. Seizures and epilepsy are best understood when classified into 3 categories: partial seizures, generalized seizures, and status epilepticus.

Partial seizures arise from electrical activity in discrete regions of the brain. Hippocampal sclerosis is the most common focal lesion in adults with partial seizures.

 Simple partial seizures can cause motor (eg, progressive jerking, mild paralysis), sensory (eg, hallucinations), autonomic (eg, flushing, sweating), and psychic (eg, fear) symptoms. One's consciousness, however, is intact throughout the attack.

Complex partial seizures are similar to simple partial seizures, but one's consciousness is impaired during the attack. In addition, complex partial seizures are associated with automatisms (eg, lip smacking, chewing, "picking" movements of the hand). Electroencephalography (EEG) shows a burst of repetitive spikes in the right temporal region.

Generalized seizures arise from both cerebral hemispheres, with no detectable focal deficits as found in partial seizures. Within the hemispheres, alterations can be found within neuronal networks or intrinsic neuronal function.

Absence (petit mal) seizures usually occur only in children. They are characterized by 5 to 30 seconds of loss of consciousness, often with eye or muscle fluttering. The children often appear to be staring or daydreaming, then suddenly resume normal activity. Unlike other  seizures, absence seizures are not found to have a postictal or confusion state after the attack. EEG shows 3-Hz spikewave activity over both hemispheres.

Tonic-clonic (grand mal) seizures are the seizures often seen on television. The patient has muscle stiffening throughout the body (in the tonic phase), often causing a fall, followed by rapid and rhythmic muscle jerking in the arms and usually the legs (in the clonic phase). Tongue biting and incontinence often are noted, and recovery from the postictal phase is slow. EEG shows 10-Hz activity, followed by slow waves.

Status epilepticus is a medical emergency when any seizure occurs repeatedly without a return to consciousness between seizures. It often occurs spontaneously or after the sudden withdrawal from antiepileptic medications.

To diagnose any type of seizure, physical examination should be performed, with emphasis on neurologic findings. EEG is used to help confirm diagnosis, to classify seizures, and to locate the site of the seizure. The best time to perform EEG is while the patient is experiencing the actual seizure.

Both the United States and the United Kingdom have recently attempted to develop updated treatment guidelines for epilepsy with the inclusion of modern AEDs. In the United States, the Therapeutic and Technology Assessment Subcommittee and the Quality Standards Subcommittee of the American Academy of Neurology, in collaboration with the American Epilepsy Society, did an extensive literature search to find evidence-based trials of 7 new AEDs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide).

Relevant studies were then reviewed by a panel of experts to evaluate the efficacy, tolerability, and safety of the modern AEDs. The National Institute for Clinical Excellence Committee performed a similar search in the United Kingdom. Only the US results will be reviewed here.

For the treatment of newly diagnosed partial seizures, the current literature suggests that the new AEDs appear similar to older medications in efficacy but better in tolerability (Table 1). There is insufficient evidence, however, directly comparing the old agents with the new agents or the new agents with each other. As a result, for the treatment of partial seizures the guidelines still recommend an older AED or lamotrigine, gabapentin, oxcarbazepine, or topiramate. The actual choice among these agents should be individualized for each specific patient, based on side effects, cost, and tolerability.

were defined as those failing to respond to 3 or more drugs. In these cases, the experts found that all of the new AEDs show efficacy as adjunctive therapy. In addition, the US panel recommended the use of oxcarbazepine, topiramate, and lamotrigine as possible options for monotherapy in refractory partial epilepsy. This recommendation was made despite the relatively limited availability of regulated clinical trials.

Guidelines for newly diagnosed generalized seizures also remain incomplete. The US panel did recommend the inclusion of lamotrigine as an option for newly diagnosed generalized seizures in children. This suggestion was based on class II evidence (on a scale of I to IV, with I being the best rating). Otherwise, an older AED is still the treatment of choice.

For refractory generalized seizures, only topiramate was recommended for treatment in children and adults. Gabapentin was ruled as ineffective for refractory generalized seizures. These recommendations were based on very limited clinical trials, however. A summary of these results is provided in Table 2.

It is important to point out that there were discrepancies between the US and the more conservative UK and Scottish Intercollegiate Network guidelines. These conflicting recommendations can intuitively be explained by possible preferences among the different panelists, as well as the lack of scientific literature available. Future studies should focus on comparing the new AEDs as monoand/or adjunctive therapy in a long-term, randomized clinical trial.

Antiepileptic medications have been in use for more than a century. Older AEDs have proven their efficacy in most newly diagnosed seizures, but they also carry the burden of potential adverse effects and drug interactions.

The recent FDA approval of new AEDs has called for updated evidence-based guidelines. According to the new US guidelines, the treatment of newly diagnosed partial seizures should start with an older AED or lamotrigine, gabapentin, oxcarbazepine, or topiramate. For refractory partial seizures, an older AED or oxcarbazepine, topiramate, or lamotrigine should be used. For newly diagnosed generalized seizures, treatment should be with an older AED or lamotrigine. Finally, the panel recommends either an older AED or topiramate for the treatment of refractory generalized epilepsy.

All new AEDs are indicated as adjunctive therapy for all seizure types. With the limited availability of randomized clinical trials, health care providers should consider these guidelines in addition to safety, tolerability, and cost for each individual patient.

Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE Treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizure and syndromes. 

Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. 

Hitiris N, Brodie MJ. Modern antiepileptic drugs: guidelines and beyond. 

French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I; treatment of new onset epilepsy. 

French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy. 

Annegers JF. The epidemiology of epilepsy. In: Wyllie E, ed. 

The Treatment of Epilepsy: Principles and Practice

. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001:131-138. 

Vincent Pham is an MD candidate at Wayne State University School of Medicine in Detroit, Mich. Dr. Anthony Pham is a pharmacy practice resident at UCLA Medical Center in Los Angeles, Calif. Dr. David Pham is assistant professor of pharmacy practice at Western University of Health Sciences, College of Pharmacy, in Pomona, Calif.