Artikel Umum: HEPATITIS IMBAS OBAT (HIO) /DRUG

INDUCED LIVER INJURY (DILI)

FAKTA:
- Sebanyak 20-40% gagal hati fulminan disebabkan oleh obat-obatan (i)
- Sekitar 75% reaksi idiosinkrasi karena obat berakhir dengan fatal atau harus menjalani transplantasi hati
(i)
- 50% penderita hepatitis akut merupakan akibat dari reaksi obat terhadap hati (ii)

PENGERTIAN
Apa itu hepatitis imbas obat (HIO) /DRUG INDUCED LIVER INJURY (DILI)?
Hepatitis imbas obat merupakan tipe kerusakan hati akibat obat yang paling sering dijumpai. (ii)
Kerusakan hati akibat obat biasanya didefenisikan sebagai abnormalitas pada uji biokimia hati,
khususnya peningkatan serum alanine amino-transferase (ALT),alkali fosfatase, atau kadar
bilirubin,sampai dengan lebih dari dua kali dari batas normal. (i)
PENYEBAB
Apa saja penyebab HIO?
Banyak obat yang dapat menyebabkan kerusakan hati, beberapa diantaranya yang termasuk yaitu:
Obat analgesik: obat-abatan Non-steroidal anti inflammatory drugs (NSAIDs)

seperti celecoxib,nimesulide, ibuprofen, sulindac, dan diclofenac

Obat antibakterial: obat-

obatan penicillin dan cephalosporin, macrolide, quinolone, sulfonamidedan trimethoprim serta tetracyli
nes
Obat anti-fungal: seperti golongan azole dan terbinafine
Obat antiretroviral
Obat kardiovaskular: seperti angiotensin-converting
enzyme (ACE) inhibitors, amiodarone,hydralazine dan sebagainya.

Central nervous system drug : seperti anticonvulsants (anti kejang)

Obat antidepressant yang memiliki kandungan seperti trycialic
Obat antidiabetik, seperti thiazolidinediones
Obat hypolipidaemics, seperti fibrats, niacin dan sebagainya
Obat anastesi inhalasi yang memiliki kandungan seperti halogen
Produk herbal penurun berat badan (iii)
GEJALA DAN TANDA
Bagaimana gejala dan tanda dari penderita HIO?

Nyeri perut

Urin gelap

Diare

Kelelahan

Demam

Ruam

Sakit kepala
Penyakit kuning
Kehilangan nafsu makan
Mual dan muntah
Tinja bewarna putih atau tanah liat (iii)

TES DAN PENGOBATAN

Bagaimana cara mengetahui HIO?
Pemeriksaan tes darah dapat dilakukan unuk memeriksa fungsi hati. Pada penderita hepatitis imbas obat,
enzim hati akan lebih tinggi dari batas normal. Selain itu, pemeriksaan fisik dapat dilakukan untuk
memeriksa pembesaran hati dan nyeri perut bagian kanan atas. Demam dan ruam dapat menjadi bagian
dari reaksi obat yang mempengaruhi hati. (iv)
Bagaimana pengobatan HIO?
Satu-satunya pengobatan yang dapat dilakukan adalah dengan menghentikan obat penyebab terjadinya
kerusakan hati, diikuti monitoring kondisi klinis dan indikator kerusakan hati secara laboratorium. Lakukan
segera upaya eliminasi obat/metabolit secepatnya misalnya melalui forced
diuresis, dialisis atauplasmaferesis. Jika diketahui, obatnya perlu diberikan antidotnya. (i)
PENCEGAHAN
Apa yang harus dilakukan untuk mencegah terjadinya HIO?
- Jangan mengkonsumsi obat lebih dari dosis yang dianjurkan khususnya yang
mengandungacetaminophen (tylenol).
- Jika memiliki penyakit hati, harus menghindari obat-obat seperti acetaminophen dan fenitoin serta obatobat lain yang diketahui mempunyai efek toksik terhadap hati. (iv)
REFERENSI
(i) Sulaiman, Akbar, Lesmana dan Noer. 2007. Buku Ajar Ilmu Penyakit Hati. Jakarta: Jayabadi
(ii) Feldman, Friedman, dan Brandit .2010. Sleisenger dan Fordtranss. Gastrointestinal and Liver
Disease. Pathophysiology/ Diagnosis/ Manajemen. Ninth Edition. Canada: Saunders Elsevier.
(iii) Dooley, Lok, Burroughs dan Heathcote. 2011. Sherlock Diseases of The Liver and Biliary System.
12th Edition. Singapore: Willey-Blackwell
(iv) Medlineplus. n.d. Drug-induced hepatitis. http://www.nlm.nih.gov/medlineplus/ency/article/000226.htm

BERITA TERKINI
Selamat atas terpilihnya kembali DR. dr. Rino A. Gani, SpPD-KGEH sebagai Ketua Pengurus Besar
Perhimpunan Peneliti Hati Indonesia untuk masa bakti 2013-2016

LOG IN
Username

Password
Remember Me
Log In

Lost Password

LATEST TWEETS
Loading tweets...

STATISTIK WEB

Anda adalah pengunjung ke:

CALENDAR

Sep
6

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

OCTOBER 2014

VIDEO

LINK EKSTERNAL

Drug-induced pulmonary disease is lung disease brought on by a bad reaction to a medicine.

Causes
Many types of lung injury can result from medicines. It is usually impossible to predict who will develop
lung disease from a medicine.
Types of lung problems or diseases that may be caused by medicines include:

Allergic reactions -- asthma, hypersensitivity pneumonitis, or eosinophilic pneumonia

Bleeding into the lung air sacks, called alveoli (alveolar hemorrhage)

Bronchitis

Damage to lung tissue (interstitial fibrosis)

Drugs that cause the immune system to mistakenly attack and destroy healthy body tissue, such
asdrug-induced lupus erythematosus

Granulomatous lung disease -- a type of inflammation in the lungs

Inflammation of the lung air sacks (pneumonitis or infiltration)

Lung vasculitis (inflammation of lung blood vessels)

Lymph node swelling

Mediastinitis

Pulmonary edema

Pleural effusion

Many medicines are known to cause lung disease in some people, including:

Antibiotics, such as nitrofurantoin and sulfa drugs

Heart medicines, such as amiodarone

Chemotherapy drugs such as bleomycin, cyclophosphamide, and methotrexate

Illegal drugs

Symptoms

Bloody sputum
Chest pain

Cough

Fever

Shortness of breath

Wheezing

Note: Symptoms may vary from person to person.

Exams and Tests
The doctor will perform a physical exam and listen to your chest and lungs with a stethoscope. Abnormal
breath sounds may be heard.
Tests that may be done include:

Arterial blood gases

Autoimmune blood tests

Blood chemistry

Bronchoscopy

Complete blood count with blood differential

Chest CT scan

Chest x-ray

Lung biopsy (in rare cases)

Lung function tests

Thoracentesis (if pleural effusion is present)

Treatment
The first step is to stop the medicine that is causing the problem. Other treatments depend on your
specific symptoms. For example, you may need oxygen until the drug-induced lung disease improves.
Anti-inflammatory medicines called steroids are sometimes used to quickly reverse the lung inflammation.
Outlook (Prognosis)
Acute episodes usually go away within 48 to 72 hours after the medicine has been
stopped. Chronic symptoms may take longer to improve.

Some drug-induced lung diseases, such as pulmonary fibrosis, may never go away.
Possible Complications

Diffuse interstitial pulmonary fibrosis

Hypoxemia (low blood oxygen)

Respiratory failure

When to Contact a Medical Professional

Call your health care provider if you develop symptoms of this disorder.
Prevention
Note any past reaction you have had to a medicine, so that you can avoid the medicine in the future.
Wear a medical alert bracelet if you have known drug reactions. Stay away from illegal drugs to prevent
many drug-induced lung diseases.
References
Maldonado F, Limper AH. Drug-induced pulmonary disease. In: Mason RJ, Broaddus VC, Martin TR, et
al., eds.Murray and Nadel's Textbook of Respiratory Medicine. 5th ed. Philadelphia, PA: Elsevier
Saunders; 2010:chap 72.
Update Date: 5/30/2013
Updated by: Denis Hadjiliadis, MD, Assistant Professor of Medicine, Division of Pulmonary, Allergy and
Critical Care, University of Pennsylvania, Philadelphia, PA. Also reviewed by David Zieve, MD, MHA,
Bethanne Black, and the A.D.A.M. Editorial team.
Browse the Encyclopedia

http://www.nlm.nih.gov/medlineplus/ency/article/000104.htm

A 54 year-old man with a chronic cough Chronic cough:

dont forget drug-induced causes
Pages 347-348
*

Andrew RL Medford

Consultant Physician & Honorary Senior Clinical Lecturer in Thoracic Medicine, North Bristol Lung Centre,
Southmead Hospital, Bristol, UK
Received 25 February 2012 Accepted 31 July 2012 Online 30 August 2012

Cite as: Medford ARL. A 54 year-old man with a chronic cough Chronic cough: dont forget drug-induced
causes. Prim Care Respir J 2012;21(3):347-348. DOI: http://dx.doi.org/10.4104/pcrj.2012.00078
* Corresponding author. Andrew RL Medford Tel: +44 (0) 116 250 2766 Fax: +44 (0)116 250 2787
Email: andrewmedford@hotmail.com
2012 Primary Care Respiratory Society UK. All rights reserved.

Clinical scenario
A 54 year-old man consults about a long-standing cough: his wife encouraged him to attend as she was
tired of hearing him cough all the time. He is a bit vague about when it started, but it must be nearly a
year. He has consulted his usual general practitioner about the cough three times. Eight months ago he
presented with a chesty cough associated with a feverish illness and an upper respiratory tract infection; he
was prescribed a course of antibiotics which he thinks might have slightly improved the cough, though it did
not fully resolve. Two subsequent consultations resulted in a further course of antibiotics and a trial of a
salbutamol inhaler, neither of which appear to have made any difference. The clinical notes record that his
chest was clear at each of these consultations. He describes himself as generally well, though he has been
tired recently which he attributes to the long hours he is working. He smoked for about 15 years but quit in
his mid-thirties.
Drugs have the potential to cause a myriad of respiratory syndromes: here we consider specifically druginduced cough. It is important to recognise that cough may be the initial manifestation of more serious
drug-induced pulmonary syndromes such as interstitial lung disease, acute lung injury, pleural disease and
pulmonary vascular disease caused by a number of well-recognised drugs (amiodarone, nitrofurantoin,
methotrexate to name a few) which are not considered here. For more extensive reviews and an online drug
database of pneumotoxicities which can be a useful reference of described toxicities if in doubt, see
www.pneumotox.com.1,2 This short paper will consider the commonly used drugs that may be implicated in
chronic cough.

ACE inhibitors
Angiotensin converting enzyme (ACE) inhibitors cause dry nocturnal cough in about 5-35% of people.
Release of bradykinin, which is normally metabolised by ACE in the lungs, results in a typical tickling,
scratchy or itchy sensation in the throat.3 There is a poor dose- response relationship and it normally occurs
within the first week of treatment but onset can sometimes be delayed for up to six months. In addition,
although most cases subside after four weeks, a significant proportion of cases can take up to three months
to resolve after stopping the drug.4 Although theophylline and cromoglycate have been advocated in the past
to treat this cough, the only effective treatment is stopping the drug. It is more common in women (perhaps
due to the heightened cough reflex in women) and also, interestingly, in Chinese people. 5 Airflow obstruction
is not usually a feature, and the presence of asthma does not change the likelihood of its occurrence. 6 It is a
class effect, and generally recurs if any other ACE inhibitor is reintroduced.

A2R blockers
Angiotensin 2 receptor (A2R) blockers are commonly used as a first substitute when ACE inhibitor cough
appears, though they have a similar side effect profile to ACE inhibitors. However, cough can still occur with
A2R blockers but is typically three to four times less common. 7,8 Cough recurrence rates are also lower with
A2R blockers but they should not be overlooked as a cause of chronic cough.

-blockers
Cough may be the initial manifestation of drug-related airway hyper-responsiveness or bronchoconstriction
that is described with -blockers; associated wheeze and dyspnoea may occur. -blockers (including eye
drops) cause bronchoconstriction via bronchial 2 receptor blockade. A meta-analysis has confirmed no
evidence of long-term decline in lung function in reversible obstructive lung disease with cardio-selective blockers (atenolol, metoprolol, bisoprolol). A short-term decline of 8% in forced expiratory volume in second

(FEV1) was seen, but this was not sustained.9 In addition, long term respiratory symptoms and use of
inhaled -agonists were not increased. Carvedilol has also been shown to be well tolerated (in terms of lung
function indices and aerobic performance) despite being a non-selective -blocker, possibly because of mild
bronchodilation from its -blocking activity.10

NSAIDs
Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac, naproxen, and
indomethacin, can cause bronchoconstriction in 5% of people with asthma by driving cysteinyl leukotriene
production and inhibiting cyclooxygenase-1 (COX-1). Symptoms may occur within 30 minutes to 3 hours of
ingestion and be associated with facial flushing and nasal and upper airway symptoms. Leukotriene
antagonists (as part of asthma therapy) are particularly helpful in treating these symptoms.

Calcium antagonists
Calcium antagonists relax the lower oesophageal sphincter pressure and in dose-dependent fashion impair
oesophageal clearance and cause reflux cough (amongst other symptoms). Reflux cough should be
particularly suspected with cough on phonation, throat clearing, after meals, or cough on rising/stooping; it
may also be the only manifestation of reflux (without dyspeptic symptoms). 11 In studies of reflux-related
symptoms, verapamil and amlodipine were reported as causing more reflux symptoms than diltiazem. 12
Reflux cough may also be aggravated by other drugs including nitrates via similar effects on lower
oesophageal sphincter pressure. Stopping the drug and avoiding other aggravating drugs may be the only
intervention necessary. Resolution of symptoms may take up to 3 months.

Summary
1. Consider the drug history carefully before investigating for other causes of cough; stopping the
relevant drug is the key to treatment
2. ACE inhibitor cough may not arise for 6 months and can take 3 months to subside on stopping the
drug, and A2R blockers can also cause cough (although less commonly)
3. -blockers can be cautiously trialled in mild-moderate reversible obstructive lung disease. Cardioselective -blockers are preferable (atenolol, metoprolol) or combined - and -blockers (carvedilol)
4. Consider occult asthma or bronchial hyper-reactivity with new-onset cough following aspirin or
NSAIDs.
5.

When reflux cough is suspected, dont forget calcium antagonists as a cause and nitrates.

6. Drug-related cough may be the beginning of a more extensive syndrome and many drugs can cause
such syndromes; consult Pneumotox database for quick assistance
Handling editor Hilary Pinnock
Conflicts of interest The author declares that there are no conflicts of interest in relation to this article.

References
1. Medford AR. Drugs and Toxins. In: Maskell N, Millar AB, ed. Oxford Desk Reference Respiratory Medicine. Oxford: Oxford
University Press, 2009. Chapter 16.1, p. 384-9.
2. Foucher P, Camus P, GEPPI (Groupe dEtudes de la Pathologie Pulmonaire latrogene). The drug-induced lung diseases.
Pneumotox online. http://www.pneumotox.com/

3. Irwin RS. Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based
clinical practice guidelines. Chest 2006;129(1 Suppl):1S-23S.http://dx.doi.org/10.1378/chest.129.1_suppl.1S
4. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice
guidelines. Chest 2006;129(1 Suppl):169S-1735S.http://dx.doi.org/10.1378/chest.129.1_suppl.169S
5. Tseng DS, Kwong J, Rezvani F, Coates AO. Angiotensin-converting enzyme-related cough among Chinese-Americans. Am J
Med 2010;123:183.e11-e15.
6. Boulet LP, Milot J, Lampron N, Lacourcire Y. Pulmonary function and airway responsiveness during long-term therapy with
captopril. JAMA 1989;261:413.http://dx.doi.org/10.1001/jama.1989.03420030087036
7. Yusuf S, Teo KK, Pogue J, for the ONTARGET investigators et al. Telmisartan, ramipril, or both in patients at high risk for
vascular events. N Engl J Med 2008;358:1547-59.http://dx.doi.org/10.1056/NEJMoa0801317
8. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med 2008;148:16-29.
9. Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers in patients with reactive airway disease: a metaanalysis. Ann Intern Med 2002;137:715-25.
10. Sirak TE, Jelic S, Le Jemtel TH. Therapeutic update: non-selective beta- and alpha-adrenergic blockade in patients with
coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol 2004;44:497502. http://dx.doi.org/10.1016/j.jacc.2004.03.063
11. Morice AH, McGarvey L, Pavord I et al. BTS guidelines. Recommendations for the management of cough in
adults. Thorax 2006;61:i1-i24. http://dx.doi.org/10.1136/thx.2006.065144
12. Hughes J, Lockhart J, Joyce A. Do calcium antagonists contribute to gastro-oesophageal reflux disease and concomitant
noncardiac chest pain? Br J Clin Pharmacol 2007;64:83-9.http://dx.doi.org/10.1111/j.1365-2125.2007.02851.x

http://pphi-online.org/alpha/?p=806