FARMAKOTERAPI I

DEFINISI
 Mual dan muntah adalah keluahan yang terjadi pada
karena gangguan pencernaan
 Penyebabnya sangat variabel, sehingga
penanganannya tergantung penyebabnya
 Mual didefinisikan sebagai kecenderungan untuk
muntah atau sebagai sebuah perasaan dalam
tenggorokan atau epigastric yang mengingatkan
seorang akan terjadi muntah .
 Muntah didefinisikan sebagai ejeksi atau pengusiran
dari isi lambung melalui mulut .
 Mual dan muntah merupakan kondisi yang
berhubungan dan menjadi salah satu kondisi atau
lebih kompleks dari presentasi klinis.
Penyebab
 Mual dan muntah mungkin terkait dengan berbagai
dari presentasi klinis.
 Penyakit yang menyertai misalnya penyakit
kardiovaskular, neurologi atau penyakit metabolik.
 Mual dan muntah dapat terjadi kehamilan, atau dapat
mengikuti prosedur operasi , akibat penggunaan obat-
obatan tertentu.
 CINV: chemotherapy-induced nausea and vomiting
 CTZ: chemoreceptor trigger zone
 NK1: neurokinin1
 NVP: nausea and vomiting of pregnancy
 PONV: postoperative nausea and vomiting
 RINV: radiation-induced nausea and vomiting
 SSRI: selective serotonin reuptake inhibitor
Patofiologi
 Berturut-turut tiga tahapan emesis termasuk mual dan muntah
 Mual berhubungan dengan lambung
 Muntah adalah gerakan otot perut dan dada, pengusiran kuat
dari isi lambung yang disebabkan oleh retroperistalsis gatro
intestinal
 Muntah merupakan koordinasi antara kontraksi otot-otot
perut , pylorus , antrum dan mengangkat lambung , tekanan
sfingter esofagus berkurang , dilatasi esofagus
 Muntah sering terjadi regurgitasi adalah suatu keadaan dalam
esofagus atau isi lambung yang naik ke faring yang disebabkan
oleh karena perbedaan tekanan , misalnya , sfingter esofagus
lebih rendah
 Muntah terjadi akibat impuls aferen ke pusat muntah , inti
sel di medula
 Impuls sensorik yang diterima dari pusat , seperti zona
kemoreseptor yang memicu ( ctz ) , korteks serebral , dan
mendalam afferents dari saluran faring dan
gatstrointestinal .
 Impuls aferen yang terintegrasi dengan pusat muntah ,
yang mengakibatkan eferen impuls ke pusat air liur , pusat
pernapasan,faring, gastrointestinal, dan otot perut, yang
menyebabkan muntah .
 Ctz , yang terletak di pada daerah postrema keempat
ventrikel otak , adalah organ chemosensory emesis dan
berhubungan dengan muntah yang disebabkan secara
kimia .
 Racun dan cairan serebrospinal bloodborne mempunyai
akses untuk ctz . Sehingga sitotoksik sangat mudah
merangsang area korteks serebral daripada afferents
Terapi
Pengobatan mual dan muntah sangat bervariasi,
tergantung pada kondisi yang berkaitan
a. dugaan etiologi dan gejala;
b. frekuensi , durasi , dan tingkat keparahan
c. pemilihan cara pakai
d. penggunaan antiemetik sebelumnya
ANTACIDS

 Patients who are experiencing simple nausea and vomiting may use
various antacids.

 In this setting, single or combination nonprescription antacid products, especially

those containing magnesium hydroxide, aluminum hydroxide, and/or calcium
carbonate, may provide sufficient relief, primarily through gastric acid neutralization.

 Common antacid regimens for the relief of acute or intermittent nausea and vomiting
include one or more 15 to 30 mL doses of single- or multiple-agent products. Potential
adverse effects from antacids are usually related to the presence of magnesium,
aluminum,or calcium salts.

 Specifically, osmotic diarrhea from magnesium and constipation from aluminum or

calcium salts may be of concern to patients, particularly those self-medicating with
high or frequently administered antacid doses. Generally, however, when used
occasionally for acute episodic relief of nausea and vomiting, antacids do not produce
serious toxicities.
H2-RECEPTOR ANTAGONISTS
 Patients may use histamine2-receptor antagonists in low
doses to manage simple nausea and vomiting associated
with heartburn or gastroesophageal reflux.

 Individual dosages of cimetidine 200 mg, famotidine 10

mg, nizatidine 75 mg, or ranitidine 75 mg may be used
for brief periods. Except for potential drug interactions
with cimetidine, these agents cause few side effects when
used for episodic relief.
ANTIHISTAMINE–ANTICHOLINERGIC DRUGS
 Antiemetic drugs from the antihistaminic–anticholinergic
category appear to interrupt various visceral afferent pathways
that stimulate nausea and vomiting and may be appropriate in
the treatment of simple nausea and vomiting.

 Adverse reactions associated with the use of the antihistaminic–

anticholinergic agents primarily include drowsiness, confusion,
blurred vision, dry mouth, and urinary reten-tion, and possibly
tachycardia, particularly in elderly patients.

 Also,as doses are increased or are more frequently administered,

patients with narrow-angle glaucoma, prostatic hyperplasia, or
asthma are at greater risk of complications from the
anticholinergic effects of these drugs.
Phenothiazines
 Phenothiazines have been the most widely prescribed antiemetic
agents and appear to block dopamine receptors, most likely in the CTZ.

 Phenothiazines are marketed in an array of dosage forms, none of which

appears to be more efficacious than another. These agents may be most
practical for long-term treatment and are inexpensive in comparison
with newer drugs. Rectal administration is a reasonable alternative in
patients in whom oral or parenteral administration is not feasible.

 Phenothiazines are most useful in adult patients with simple nausea and
vomiting. Intravenous prochlorperazine provides quicker and more
complete relief with less drowsiness than intravenous promethazine in
adult patients treated in an emergency department for nausea and
vomiting associated with uncomplicated gastritis or gastroenteritis.
There are numerous potential side effects with these medications,
including extrapyramidal reactions, hypersensitivity reactions with
possible liver dysfunction, bone marrow aplasia
BUTYROPHENONES
 Two butyrophenone compounds that have antiemetic activity are haloperidol a
congener droperidol; both block dopaminergic stimulation of the CTZ.

 Although each agent is effective in relieving nausea and vomiting, haloperidol is n

considered first-line therapy for uncomplicated nausea and vomiting but has bee
in palliative care situations

 The current labeling of droperidol recommends that all patients should undergo
lead electrocardiogram prior to administration, followed by cardiac monitoring fo
3 hours after administration because of the possibility of the development of
potentially fatal QT prolongation and/or torsade depointes.

 The clinical use of droperidol has effectively ceased outside of clinical trials in
anesthesia.
CANNABINOIDS
Thirty randomized, controlled trials from 1975 to 1996 were analyzed
to quantify the antiemetic efficacy and adverse effects of cannabis when
given to 1,366 patients who received chemotherapy.
Oral nabilone, oral dronabinol, and intramuscular levonantradol were
compared with conventional antiemetics (prochlorperazine,
metoclopramide, chlorpromazine, thiethylperazine, haloperidol,
domperidone, and alizapride) or placebo.
Across all trials, cannabinoids were slightly more effective than active
comparators and placebo when the chemotherapy regimen was of
moderate emetogenic potential, and patients preferred them. No dose–
response relationships were evident to the authors.
The cannabinoids were also more toxic; side effects included euphoria,
drowsiness, sedation, somnolence, dysphoria, depression,
hallucinations, and paranoia.
The efficacy of cannabinoids as compared to SSRIs has not been studied.
Use of these agents should be considered when other regimens do not
provide desired efficacy.
CORTICOSTEROIDS
 Corticosteroids have demonstrated antiemetic efficacy since the
initial recognition that patients who received prednisone as part
of their Hodgkin disease protocol appeared to develop less
nausea and vomiting than did those patients who were
treated with protocols that excluded this agent.

 Methylprednisolone has also been used as a component of an

antiemetic regimen, but the majority of trials have included
dexamethasone.

 Dexamethasone has been used successfully in the

management of chemotherapy-induced and postoperative
nausea and vomiting, either as a single agent or in combination
with selective serotonin reuptake inhibitors (SSRIs).

 For chemotherapy-induced nausea and vomiting (CINV),

dexamethasone is effective in the prevention of both cisplatin-
induced acute emesis and when used alone or in combination
for the prevention of delayed nausea and vomiting associated
METOCLOPRAMIDE
 Metoclopramide, procainamide’s congener, provides
significant antiemetic effects by blocking the dopaminergic
receptors centrally in the CTZ.

 Metoclopramide increases lower esophageal sphincter

tone, aids gastric emptying, and accelerates transit through
the small bowel, possibly through the release of
acetylcholine.

 Metoclopramide is used for its antiemetic properties in

patients with diabetic gastroparesis and with
dexamethasone for prophylaxis of delayed nausea and
vomiting associated with chemotherapy administration.
SUBSTANCE P/NEUROKININ 1 RECEPTOR ANTAGONISTS

 Substance P is a peptide neurotransmitter in the neurokinin (NK) family whose

preferred receptor is the NK1 receptor.
 The acute phase of CINV is believed to be mediated by both serotonin and
substance P, whereas substance P is believed to be the primary mediator of the
delayed phase.
 Aprepitant is the first substance P/NK1 receptor antagonist in clinical use;
others are in development. The efficacy of aprepitant was demonstrated in
patients receiving highdose cisplatin-based chemotherapy1 and in patients
receiving doxorubicin and cycophosphamide,20 a regimen of moderate emetic
risk.
 The three-drug regimen of aprepitant, dexamethasone, and ondansetron
provided improved protection from vomiting for the 5 days after chemotherapy
administration as compared with the combination of dexamethasone and
ondansetron.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS

 SSRIs block presynaptic serotonin receptors on sensory

vagal fibers in the gut wall, effectively blocking the acute
phase of CINV.

 Theseagents do not completely block the acute phase of

CINV and are less efficacious in preventing the delayed
phase, but they are the standard of care in the management
of chemotherapy-induced, radiationinduced, and
postoperative nausea and vomiting. Issues involved in the
use of dolasetron, granisetron, ondansetron, and
palonosetron are reviewed in detail in the sections that
follow. The most common side effects associated with these
agents are constipation, headache, and asthenia. Safety and
efficacy in children younger than 2 years old have not been
established.
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
 Nausea and vomiting that occurs within 24 hours of
chemotherapy administration is defined as acute,
whereas when it starts more than 24 hours after
chemotherapy administration, it is defined as delayed.

 The primary goal with CINV is to prevent nausea and/or

vomiting.

 Optimal control of acute nausea and vomiting positively

impacts the incidence and control of delayed and
anticipatory nausea and vomiting.
Prophylaxis of PONV
Although the optimal management of PONV is not known,
patients at highest risk of vomiting should receive
prophylactic antiemetics.
Patients at low risk for PONV are unlikely to benefit from
prophylaxis and may potentially experience adverse
reactions from the medications.
Cyclizine, dexamethasone, dolasetron, droperidol,
granisetron, metoclopramide, ondansetron, and tropisetron
are effective as compared with placebo for the prophylaxis of
PONV.
Treatment of PONV
Most patients given a drug to prevent PONV will not benefit from it and 1
to 5 of every 100 patients given PONV prophylaxis may experience a mild
adverse reaction such as headache, sedation, or dry mouth.31 If a patient
develops nausea and/or vomiting despite prophylaxis, treatment options
are limited. Use of the same drug for treatment is ineffective when it was
used for prophylaxis.

SSRIs in doses of dolasetron 12.5 mg, granisetron 0.1 mg, ondansetron 1 mg

or tropisetron 0.5 mg are recommended in patients who experience PONV
despite prophylactic dexamethasone or when no prophylactic agent was
used.29 Treatment doses of SSRIs,when an SSRI was used as prophylaxis,
are not recommended until 6 hours after surgery.

Patients who experience PONV after receiving prophylactic treatment

with a SSRI plus dexamethasone should receive a rescue dose from a
different drug class such as a phenothiazine
or droperidol.
RADIATION-INDUCED NAUSEA AND VOMITING (RINV)
Nausea and vomiting associated with radiation therapy is not well understood. It is
neither as predictable nor as severe as CINV, and many patients receiving radiation
therapy will not experience nausea or vomiting. Risk factors associated with the
development of
RINV include the site of radiation, the dose, dose rate, and area of the body to be
irradiated.
Patients receiving single-exposure, high-dose radiation therapy to the upper
abdomen, or total- or hemibody irradiation, should receive prophylactic
antiemetics for RINV.
Prophylaxis of RINV
Four radiotherapy-induced emesis risk groups have been defined by
the Antiemetic Subcommittee of the Multinational Association of
Supportive Care in Cancer (MASCC) and the ASCO antiemetic
practice guidelines. Both groups recommend preventive therapy
with a SSRI and dexamethasone in patients who are receiving totalbody
irradiation (high emetic risk). The efficacy of oral granisetron 2
mg and ondansetron 8 mg was demonstrated in 34 patients who
underwent hyperfractionated total-body irradiation.
Patients undergoing radiation therapy procedures with moderate to low emetic risk
should receive a SSRI prior to each fraction.
 DISORDERS OF BALANCE
A variety of clinical conditions may be associated with vertigo and
dizziness. The etiology of these complaints may include diseases that
are infectious, postinfectious, demyelinative, vascular, neoplastic,
degenerative, traumatic, toxic, psychogenic, or idiopathic. Symptoms
of imbalance perceived by the patient present a particular clinical
challenge.
Whether associated with a minor or complex disorder,
motion sickness may be associated with nausea and vomiting.Oral regimens of
antihistaminic–anticholinergic agents given one to several times each day may be
effective, especially when the first dose is administered prior to motion.
Scopolamine is commonly used to prevent nausea or vomiting
caused by motion.
The usefulness of scopolamine in preventing motion sickness was enhanced with the
development of the transdermal
system (patch) that increased patient satisfaction and decreased
untoward side effects.
A review of 12 randomized, controlled studies showed that scopolamine provided better
protection from motioninduced sickness than did placebo, but was not superior to
antihistamines
and combinations of scopolamine and ephedrine
ANTIEMETIC USE DURING PREGNANCY
As many as 75% of pregnant women experience nausea and vomiting
to some degree during the first trimester of pregnancy. The severity of the
symptoms varies considerably, from mild nausea to incapacitating nausea
and vomiting.
The etiology of nausea and vomiting of pregnancy (NVP) is not well
understood. For the majority of women, these symptoms are self-limited,
although
approximately 1% to 3% develop hyperemesis gravidarum, a serious
condition marked by severe physical symptoms and/or medical
complications requiring hospitalization. In its most severe state,
hyperemesis gravidarum may result in volume contraction, starvation, and
electrolyte abnormalities.
Initial management of NVP often involves dietary changes and/or lifestyle
modifications.
Nonpharmacologic interventions for NVP include ginger and acupressure,
although efficacy trials for acupressure are lacking. Persistent nausea
and/or vomiting leads to the consideration of drug therapy at a time when
teratogenic potential of each agent must be considered.