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 patients 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 314). 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 315). 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
The 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.
Symptoms 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 patients 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
The 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 peletseperti dalam penampilan sementara yang lain mungkin sempit dan pensilseperti.
Symptoms biasanya dapat dikategorikan sebagai
diare-dominan IBS (IBS-D) atau sembelit-dominan IBS (IBS-C). Pasien dengan IBSD 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 tibatiba.
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.