©Complications of Pharmacotherapy

Adverse effects of AEDs are frequently dose limiting or can cause a drug to be discontinued. Two types of adverse effects occur with AEDs: serum concentration-related and idiosyncratic (Table 31-3). Concentration-related adverse effects happen with increasing frequency and severity as the dose or serum concentration of a drug is increased. For many AEDs, common concentration-related adverse effects include sedation, ataxia, and diplopia. These adverse effects should be carefully considered and used as one of the AED selection criteria. For example, if a patient has a job that requires mental alertness, it is best to choose an AED that is less likely to cause sedation (e.g., lamotrigine). Idiosyncratic adverse effects are not dose or concentration related and will almost always result in the AED being discontinued. Rash, hepatotoxicity, and hematological toxicities are the most common idiosyncratic reactions seen with AED. Because many of these adverse effects are life threatening or potentially life threatening, the AED should be discontinued immediately when the reaction is observed. Carbamazepine, phenytoin, phenobarbital, valproate, lamotrigine, oxcarbazepine, and felbamate are most likely to cause these types of reactions. Many of these reactions are thought to occur primarily on an immunological basis, which raises the possibility of cross-reactivity. This is especially true for carbamazepine, phenytoin, phenobarbital, and oxcarbazepine, where 15% to 25% of patients who have an idiosyncratic reaction to one drug will have a similar reaction to the other drugs.

©Chronic Adverse Effects

Because AEDs are administered for long periods of time, adverse effects due to prolonged drug exposure are of concern. Some chronic adverse effects associated with AEDs include peripheral neuropathy and cerebellar atrophy. Other chronic adverse effects are extensions of acute adverse effects, for example, weight gain. One chronic adverse effect that is of concern is osteoporosis. 32,33

Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, and valproate have all been shown to decrease bone mineral density, even after only 6 months of treatment. Data on the relationship between other AEDs and osteoporosis are not currently available. Multiple studies have shown the risk of osteoporosis due to chronic AED use to be similar to the risk with chronic use of glucocorticosteroids. Patients taking carbamazepine, oxcarbazepine, phenytoin, phenobarbital, or valproate more than 6 months should take supplemental calcium and vitamin D. Additionally, routine monitoring for osteoporosis should be performed every 2 years, and patients should be instructed on ways to protect themselves from fractures.

©Practical Issues

Comorbid Disease States Patients with epilepsy often have comorbid disease states. Disorders such as chronic headaches and asthma are frequent problems. For patients who also have asthma, care must be taken to identify drug interactions between AEDs and medications used for asthma. These interactions necessitate close monitoring for changes in efficacy or increased toxicity, and dosage changes of other drugs may be necessary when an AED is added or removed. Patients with chronic headaches need special attention in the selection of an AED. Agents known to prevent headache (e.g., valproate and topiramate) may be preferred among several choices, and agents associated with increased headaches (e.g., lamotrigine and felbamate) may be a

secondary or tertiary alternative. Depression is a common problem in patients with epilepsy, with approximately 30% having symptoms of major depression at some point.

Patients with epilepsy should be routinely assessed for signs of depression, and treatment should be initiated if necessary. Certain AEDs may exacerbate depression, for example, levetiracetam and phenytoin. Other AEDs (e.g., lamotrigine, carbamazepine, oxcarbazepine) may be useful in treating depression. Changes in mood can be precipitated by the addition or discontinuation of an AED. If treatment for depression is necessary, caution should be exercised in choosing an agent that does not increase seizure frequency and does not interact with AEDs.

Switching Drugs Changing from one AED to another can be a complex process. If the first drug is stopped too abruptly, breakthrough seizures may occur. 6 Changes in AED regimens should be done in a stepwise fashion, keeping in mind drug interactions that may be present and may necessitate dosage changes in concomitant drugs.Typically the new drug is started at a low initial dose and gradually increased over several weeks. Once the new drug is at a minimally effective dose, the drug to be discontinued is gradually tapered while the dose of the new drug continues to be increased to the target dose. During a transition between drugs, patients should be cautioned about the possibility of increased seizures or adverse reactions.

Stopping Therapy Epilepsy is generally considered to be a lifelong disorder that requires ongoing treatment. However, many patients who are seizure free may desire to discontinue their medications. Patients who become seizure free following surgery for their epilepsy may have medications slowly tapered starting 1 to 2 years after their surgery. Many patients will choose to stay on at least one medication, following successful surgery, to ensure they remain seizure free. 7 Discontinuation of AEDs should be done gradually, only after the patient has been seizure free for 2 to 5 years and with careful consideration of factors predictive of seizure

recurrence.They are

• No seizures for 2 to 5 years

• Normal neurologic examination

• Normal intelligence quotient

• Single type of partial or generalized seizure

• Normal EEG with treatment

Individuals who fulfill all of these criteria have a 61% chance of remaining seizure free after AEDs are discontinued. Additionally, there is a direct relationship between the duration of seizure freedom while taking medications and the chance of being seizure free after medications are withdrawn. Withdrawal of AEDs is done slowly, usually with a tapering dose over at least 1 to 3 months.

©Dosing

Dosing of AEDs is determined by general guidelines and response of the patient. Serum concentrations may be helpful in benchmarking a specific response. Therapeutic ranges that are

often quoted are broad guidelines for dosing but should never replace careful evaluation of the patient’s response. It is not unusual for a patient to be well managed with serum concentrations or doses outside the typical ranges.

©Drug Interactions

AEDs are associated with many different drug interactions. These interactions are primarily in relation to absorption, metabolism, and protein binding. Tube feedings and antacids are known to reduce the absorption of phenytoin and carbamazepine. Phenytoin, carbamazepine, and phenobarbital are potent inducers of various CYP 450 isoenzymes, increasing the clearance of other drugs metabolized through these pathways (Table 31–4). In contrast, valproate is a CYP 450 and UDP-glucuronosyltransferase (UGT) isoenzyme inhibitor and reduces the clearance of some drugs. Phenytoin and valproate are highly protein bound and can be displaced when taken concurrently with other highly protein-bound drugs. For example, when phenytoin and valproate are taken together, there may be increased dose-related adverse effects within several hours of dosing. This can be avoided by staggering doses or giving smaller doses more frequently during the day. Whenever a change in a medication regimen occurs, drug interactions should be considered and appropriate adjustments in dose of AEDs made.

©Special Populations

8 Children and women with epilepsy have unique problems related to the use of AEDs. In children, developmental changes occur rapidly, and metabolic rates are greater than those seen in adults. When treating a child, it is imperative to control seizures as quickly as possible to avoid interference with development of the brain and cognition. AED doses are increased rapidly, and frequent changes in the regimen are made to maximize control of seizures. Due to the rapid metabolic rates seen in children, doses of AEDs are typically higher on a milligram per kilogram basis compared with adults, and serum concentrations are used more extensively to help ensure an adequate trial of a drug has been given.

For women, the treatment of epilepsy poses challenges, including teratogenicity, interactions between AEDs and hormonal contraceptives, and reduced fertility.

Recommendations for managing women of childbearing potential and who are pregnant have been developed (Table 31–5). Several AEDs have been implicated in causing both minor and serious birth defects. Of special concern are neural tube defects (e.g., spina bifida, microcephaly, anencephaly)

associated most commonly with valproate and possibly carbamazepine. Additionally, valproate has been associated with impaired cognitive development in children born to women taking valproate during pregnancy. Use of valproate is not absolutely contraindicated in women who may become pregnant, but it is appropriate to use alternative AEDs, if possible, in women of childbearing potential. All women of childbearing potential who have epilepsy should take 1 to 4 mg daily of supplemental folic acid to reduce the risk of these defects. Many AEDs are excreted in breast milk. However, infants were exposed to higher concentrations of AED in utero, so it is unclear if drugs in breast milk are harmful to the child. Decisions about breast-feeding should be made on an individual basis.

As noted earlier, many of the AEDs induce hepatic microsomal enzyme systems and thus reduce the effectiveness of hormonal contraceptives. Women taking AEDs that may reduce the effectiveness of hormonal contraceptives should be encouraged to also use other forms of birth control.

In contrast to these interactions, hormonal contraceptives induce glucuronidation of lamotrigine and valproate. Oral contraceptives that cycle hormones cause reductions in serum concentrations of lamotrigine or valproate during days of the cycle when hormones are taken; serum concentrations increase during days when hormones are not taken. Due to induction or inhibition of sex hormone metabolism and changes in binding of hormones to sex hormone binding globulin, some AEDs may reduce fertility. For example, valproate has been associated with a drug-induced polycystic ovarian syndrome. Women who experience difficulties with fertility should seek the advice of healthcare professionals with expertise in fertility.

9 Older adults have the highest incidence of newly diagnosed epilepsy and face unique challenges in treatment. The highest incidence of seizures and epilepsy is in individuals older than 65 years. Cerebrovascular disease, tumors, trauma, and neurodegenerative diseases are the primary causes of epilepsy in this age group. Diagnosis of epilepsy in older adults is often difficult. This is due to the subtle symptoms of seizures in the elderly, their often compromised memory, and the fact that many elderly live alone. Carbamazepine, lamotrigine, and gabapentin have been studied in this age group, and all are effective in controlling seizures. Fewer adverse events occur with lamotrigine and gabapentin. Elderly patients are more sensitive to adverse events, so smaller doses tend to be used in this age group.

CLINICAL PRESENTATION AND DIAGNOSIS

Diagnosis

❾The diagnosis of IBS is made by symptom-based criteria and the exclusion of organic disease. IBS is diagnosed by obtaining a careful and thorough history to identify symptoms characteristic of the disorder. It is equally important to distinguish between IBS and conditions having similar symptoms. Patients should be questioned about the character of their stools. This should include questions about frequency, consistency, color, and size. Moreover, because of the functional nature of IBS, a patient may present with symptoms of upper gastrointestinal problems such as gastroesophageal reflux disease (GERD) or with excessive flatulence. Patients should also be questioned about diet to determine whether symptoms seem to occur in relationship to meals or specifically after consumption of certain dietary products.

Barium enema, sigmoidoscopy, or colonoscopy may be indicated in the presence of red flag symptoms (fever, weight loss, bleeding, and anemia, which may be accompanied by persistent severe pain), which often point to a potentially serious non-IBS problem. A barium enema may identify polyps, diverticulosis, tumors, or other abnormalities that might be responsible for the symptoms. In addition, exaggerated haustral contractions may be noted with barium enema. Such contractions impede stool movement and contribute to constipation.

Flexible sigmoidoscopy can be performed to identify obstruction in the rectum and lower colon, whereas colonoscopy can evaluate the entire colon for organic disease.

The diagnostic basis for IBS has long been centered on the presence of symptoms, first defined by the Manning criteria:

(1) abdominal pain relieved by defecation with either (a) looser stools with pain onset, or (b) frequent stools with pain onset;

(2) abdominal distention; (3) mucus in the stool; and (4) sensation of incomplete evacuation. These practical criteria have been used widely. The Rome II criteria (preceded by Rome I) are the most current diagnostic criteria for establishing the presence of IBS.

They presume the absence of a structural or biochemical explanation for the symptoms. These rather stringent criteria can be applied clinically, but not as easily as the older Manning criteria. The Rome II criteria define IBS as occurring when symptoms of abdominal discomfort or pain exist at least 12 weeks (which need not be consecutive) in the preceding 12 months that have two of the

three following features: (1) relieved with defecation; (2) onset associated with a change in the frequency of stool; and/or (3) onset associated with a change in the form of stool. IBS is unlikely if symptom onset occurs in old age, the disorder has a steady but aggressive course, or the patient experiences frequent awakening because of symptoms

Clinical Presentation of Irritable Bowel Syndrome

Symptoms

•Patients report a history of abdominal pain or discomfort that is relieved with defecation. Symptom onset is associated with change in frequency or appearance of stool. Some persons experience hard, dry stools whereas others experience loose or watery stools. Some stools may be small and pellet-like in appearance while others may be narrow and pencil-like.

•❽Symptoms can typically be categorized as either

diarrhea-predominant IBS (IBS-D) or constipation-predominant IBS (IBS-C). Patients with IBS-D usually report more than three loose or watery stools daily. Those with IBS-C usually have fewer than three bowel movements per week; stools are typically hard and lumpy and accompanied by straining.

•While many patients fit into one of these categories, some patients report alternating episodes of diarrhea and constipation.

•Other common symptoms include: (1) feelings of incomplete evacuation; (2) abdominal fullness; (3) bloating; (4) flatulence; (5) passage of clear or white mucus with a stool; and (6) occasional fecal incontinence.

•Periods of normal stools and bowel function are punctuated by episodes of sudden symptoms.

•Symptoms are often exacerbated by stress.

•Left lower quadrant abdominal pain is often brought on or made worse by eating. Passage of stool or flatus may provide some relief.

•IBS-C can often be distinguished from chronic constipation primarily by the presence of abdominal pain and discomfort.

Although pain and discomfort may be present in some patients with chronic constipation, it is an expected feature of IBS.

•Patients with IBS may experience comorbidities outside the gastrointestinal tract such as fibromyalgia, sleep disturbances, headaches, dyspareunia, and temporomandibular joint syndrome.

Signs

•The physical examination is often normal in IBS.

•The patient may appear to be anxious.

•Palpation of the abdomen may reveal left lower quadrant tenderness, which may indicate a tender sigmoid colon.

•Abdominal distention may be present in some cases.

•The following “red flag” or alarm features are notassociated with IBS and may indicate inflammatory bowel disease, cancer, or other disorders: fever, weight loss, bleeding, and anemia, which may be accompanied by persistent severe pain.

Laboratory Tests

•In most cases, laboratory testing reveals no abnormalities in IBS, but certain tests can be used to identify other causes for the patient’s symptoms.

•Complete blood cell count (CBC) may identify anemia, which may suggest blood loss and an organic source for GI symptoms.

•Serum electrolytes and chemistries may indicate metabolic causes of symptoms.

•Thyroid-stimulating hormone (TSH) should be ordered when thyroid dysfunction is suspected. Hypothyroidism may be responsible for constipation and related symptoms.

•Stool testing for ova and parasites may identify Clostridium difficileand amoeba as possible causes of diarrhea rather than IBS.

•Fecal leukocytes can be found in inflammatory diarrhea, especially when due to invasive microorganisms.

•A positive stool guaiac test indicating blood in the gastrointestinal tract does not support a diagnosis of IBS.

•An elevated erythrocyte sedimentation rate (ESR) is consistent with a systemic inflammatory process such as inflammatory bowel disease rather than IBS.

•Testing for lactose deficiency can confirm the presence of lactose intolerance, which may explain the symptoms.

PRESENTASI KLINIS DAN DIAGNOSIS

Diagnosa

❾The diagnosis IBS dibuat dengan kriteria berdasarkan gejala dan mengesampingkan penyakit organik. IBS didiagnosis dengan mendapatkan riwayat secara cermat dan seksama untuk mengidentifikasi gejala karakteristik dari gangguan tersebut. Hal ini sama pentingnya untuk membedakan antara IBS dan kondisi memiliki gejala yang sama. Pasien harus ditanya tentang karakter bangku mereka. Ini harus mencakup pertanyaan tentang frekuensi, konsistensi, warna, dan ukuran. Selain itu, karena sifat fungsional dari IBS, pasien dapat hadir dengan gejala masalah pencernaan bagian atas seperti penyakit gastroesophageal reflux (GERD) atau dengan perut

kembung berlebihan. Pasien juga harus ditanya tentang diet untuk menentukan apakah gejala tampaknya terjadi dalam hubungan dengan makanan atau secara khusus setelah konsumsi produk makanan tertentu.

Barium enema, sigmoidoskopi, atau kolonoskopi dapat diindikasikan dengan adanya gejala merah bendera (demam, penurunan berat badan, perdarahan, dan anemia, yang bisa disertai dengan sakit parah persisten), yang sering menunjuk ke masalah non-IBS berpotensi serius. Sebuah barium enema dapat mengidentifikasi polip, diverticulosis, tumor, atau kelainan lain yang mungkin bertanggung jawab untuk gejala. Selain itu, kontraksi haustral berlebihan dapat dicatat dengan barium enema. Kontraksi tersebut menghambat pergerakan tinja dan berkontribusi untuk sembelit.

Sigmoidoscopy fleksibel dapat dilakukan untuk mengidentifikasi obstruksi pada rektum dan kolon yang lebih rendah, sedangkan colonoscopy dapat mengevaluasi seluruh usus besar untuk penyakit organik.

Dasar diagnostik untuk IBS telah lama berpusat pada adanya gejala, pertama kali didefinisikan oleh kriteria Manning:

(1) sakit perut lega oleh buang air besar dengan baik (a) tinja longgar dengan onset nyeri, atau (b) sering tinja dengan onset nyeri;

(2) distensi abdomen; (3) lendir dalam tinja; dan (4) sensasi evakuasi tidak lengkap. Kriteria praktis ini telah digunakan secara luas. Kriteria Rome II (didahului oleh Roma saya) adalah yang paling kriteria diagnostik saat ini untuk menetapkan keberadaan IBS.

Mereka menganggap tidak adanya penjelasan struktural atau biokimia untuk gejala. Kriteria agak ketat dapat diterapkan secara klinis, tetapi tidak semudah kriteria Manning tua. Kriteria Rome II mendefinisikan IBS sebagai terjadi ketika gejala perut tidak nyaman atau sakit ada setidaknya 12 minggu (yang tidak perlu berurutan) dalam 12 bulan sebelumnya yang memiliki dua dari tiga fitur berikut: (1) lega dengan buang air besar; (2) onset terkait dengan perubahan frekuensi tinja; dan / atau (3) onset terkait dengan perubahan dalam bentuk tinja. IBS tidak mungkin jika onset gejala terjadi pada usia tua, gangguan ini memiliki stabil tapi agresif saja, atau pengalaman pasien sering terbangun karena gejala

Presentasi klinis Irritable Bowel Syndrome

Gejala

• Pasien melaporkan riwayat sakit perut atau ketidaknyamanan yang lega dengan buang air besar. Onset gejala terkait dengan perubahan frekuensi atau penampilan tinja. Beberapa orang mengalami sulit, tinja kering sedangkan yang lain mengalami mencret atau berair. Beberapa tinja mungkin kecil dan pelet-seperti dalam penampilan sementara yang lain mungkin sempit dan pensil-seperti.

• ❽Symptoms biasanya dapat dikategorikan sebagai

diare-dominan IBS (IBS-D) atau sembelit-dominan IBS (IBS-C). Pasien dengan IBS-D biasanya melaporkan lebih dari tiga mencret atau berair harian. Mereka dengan IBS-C biasanya memiliki lebih sedikit dari tiga gerakan usus per minggu; tinja biasanya keras dan kental dan disertai dengan tegang.

• Sementara banyak pasien masuk ke dalam salah satu kategori ini, beberapa pasien melaporkan episode bolak diare dan sembelit.

• termasuk gejala umum lainnya: (1) perasaan evakuasi yang tidak lengkap; (2) kepenuhan perut; (3) kembung; (4) perut kembung; (5) bagian dari lendir atau putih dengan bangku; dan (6) sesekali inkontinensia tinja.

• Periode tinja normal dan fungsi usus yang diselingi oleh episode gejala tiba-tiba.

• Gejala yang sering diperburuk oleh stres.

• Waktu sakit perut kuadran bawah sering dibawa atau diperburuk dengan makan. Bagian dari tinja atau flatus dapat memberikan beberapa bantuan.

• IBS-C seringkali dapat dibedakan dari sembelit kronis terutama dengan adanya nyeri perut dan ketidaknyamanan.

Meskipun rasa sakit dan ketidaknyamanan dapat hadir pada beberapa pasien dengan sembelit kronis, itu adalah fitur yang diharapkan dari IBS.

• Pasien dengan IBS mungkin mengalami komorbiditas luar saluran pencernaan seperti fibromyalgia, gangguan tidur, sakit kepala, dispareunia, dan sindrom sendi temporomandibular.

Tanda

• Pemeriksaan fisik seringkali normal pada IBS.

• Pasien mungkin tampak cemas.

• Palpasi abdomen dapat mengungkapkan meninggalkan nyeri kuadran yang lebih rendah, yang dapat menunjukkan kolon sigmoid lembut.

• Distensi abdomen dapat hadir dalam beberapa kasus.

• Berikut "bendera merah" atau fitur alarm yang notassociated dengan IBS dan dapat mengindikasikan penyakit radang usus, kanker, atau gangguan lain: demam, penurunan berat badan, perdarahan, dan anemia, yang bisa disertai dengan sakit parah persisten.

Tes laboratorium

• Dalam kebanyakan kasus, uji laboratorium menunjukkan ada kelainan pada IBS, namun tes tertentu dapat digunakan untuk mengidentifikasi penyebab lain untuk gejala pasien.

• jumlah sel darah lengkap (CBC) dapat mengidentifikasi anemia, yang mungkin menyarankan kehilangan darah dan sumber organik untuk gejala GI.

• Elektrolit serum dan kimia dapat menunjukkan penyebab metabolik gejala.

• Thyroid-stimulating hormone (TSH) harus dipesan ketika disfungsi tiroid dicurigai. Hypothyroidism mungkin bertanggung jawab untuk sembelit dan gejala terkait.

• pengujian feses untuk ova dan parasit dapat mengidentifikasi Clostridium difficileand amuba sebagai kemungkinan penyebab diare daripada IBS.

• leukosit tinja dapat ditemukan pada diare inflamasi, terutama ketika karena mikroorganisme invasif.

• Tes tinja guaiac positif menunjukkan darah di saluran pencernaan tidak mendukung diagnosis IBS.

• Sebuah tingkat sedimentasi eritrosit (ESR) konsisten dengan proses inflamasi sistemik seperti penyakit radang usus daripada IBS.

• Pengujian untuk defisiensi laktosa dapat mengkonfirmasi kehadiran intoleransi laktosa, yang dapat menjelaskan gejala.