Specific Adverse Drug Reaction

in a Specific Organ or System

Edith Anggina
Jakarta, Maret 2015

Program Pendidikan Dokter Spesialis

Rumah Sakit Cipto Mangunkusumo
Fakultas Kedokteran Universitas Indonesia
Farmakologi Klinik 1
Periode Januari 2015
Subjudul
• Osteoporosis
• Hiperglikemia
• Metallic Taste
• Fibrosis Paru
• Deep Vein Thrombosis
• Rhabdomyolisis
• Osteonecrosis of the Jaw
• Intermittent Porphyria

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 OSTEOPOROSIS
According to the WHO criteria,

Osteoporosis is defined as a Bone Mineral Density that

lies 2.5 standard deviations or more below the average value for
young, healthy adult (a T-score of <-2.5 SD) as measured by dual-
energy X-ray absorptiometry.

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 Osteoporosis
…lanjutan
• Salto M, Marumo K. [Glucocorticoid and Bone. Collagen cross-link
abnormalities in glucocorticoid induced osteoporosis]. Clin Calcium. 2014
Sep;24(9):1351-9.
Bone fragility is one of the side effects of glucocorticoid (GC) use, even at low doses. An
increase in fracture risk due to GC administration occurs immediately after beginning
treatment. A number of GC-mediated effects are responsible for bone fragility.
• Anic B, Mayer M. [Glucocorticoid induced osteoporosis]. Reumatizam.
2014;61(2):105-12.
Secondary osteoporosis most often develops due
to glucocorticoid therapy. Glucocorticoids affect all stages of the bone remodeling cycle,
its formation and resorption. Osteoblasts are primarily affected, decreasing their
activity and enhancing apoptosis. Patients treated with glucocorticoids have
lower bone mineral density and increased fracture risk.

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 Osteoporosis
…lanjutan

• Kaneko K, Kawai S. [Mechanisms and therapeutics of glucocorticoid-

induced osteoporosis]. Nihon Rinsho Meneki Gakkai Kaishi.
2011;34(3):138-48.
Mechanisms of glucocorticoid-induced osteoporosis (GIOP) are categorized into
local and systemic effects. In the local mechanisms, direct inhibitory effect
of glucocorticoid on bone formation is thought to be one of the important
mechanisms of GIOP. In contrast, secondary hyperparathyroidism induced by
negative balance of calcium due to inhibition of absorption and increase of
excretion is an important systemic mechanism of GIOP.

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Farmakologi Klinik 6
 Osteoporosis
Xing-Ming Shi, Norman Chutkan, Mark W. Hamrick and Carlos M. Isales.
[Mechanism of Glucocorticoid-Induced Osteoporosis: An Update].
Xiaoxiao Qian. ISBN 978-953-51-0872-6, Published: November 28, 2012.

• Efek Glukokortikoid pada sel tulang

Gambar 1.
Glukokortikoid berikatan dengan
reseptor glukokortikoid (GR), yang
akan berdampak pada fungsi
mesenchymal stem cell (MSC),
osteoblast (OB), osteoclast (OC), dan
osteosit (Ocyte).
Hal ini akan menurunkan formasi
tulang dan meningkatkan resorpsi
tulang.

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 Osteoporosis
Xing-Ming Shi, Norman Chutkan, Mark W. Hamrick and Carlos M. Isales.
[Mechanism of Glucocorticoid-Induced Osteoporosis: An Update].
Xiaoxiao Qian. ISBN 978-953-51-0872-6, Published: November 28, 2012.
…lanjutan

• Efek Glukokortikoid terhadap MSC sumsum tulang

Gambar 2.
Glukokortikoid menurunkan jumlah
osteoprogenitor pada MSC dengan
mengaktifkan adipogenic differentiation
pathway. Glukokortikoid menginduksi
ekspresi enhancer binding protein (C/EBP)
yang secara langsung mengaktifasi
peroxisome proliferator-activated receptor
gamma (PPARγ), master regulator
adipogenesis, dan mengubah determinasi
MSC ke adipocyte pathway, yang kemudian
menurunkan jumlah sel osteoprogenitor.

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 Osteoporosis
Xing-Ming Shi, Norman Chutkan, Mark W. Hamrick and Carlos M. Isales.
[Mechanism of Glucocorticoid-Induced Osteoporosis: An Update].
Xiaoxiao Qian. ISBN 978-953-51-0872-6, Published: November 28, 2012.
…lanjutan

• Efek Glukokortikoid pada Osteoblast dan Osteosit

Membatasi suplai
GC sel pembangun
tulang (osteoblast)

Apoptosis Osteosit

Osteosit -> Sel mekanosensori yang mendeteksi

dan mengirimkan signal untuk pembentukan
tulang dalam rangka merespon kerusakan.

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 Osteoporosis
Xing-Ming Shi, Norman Chutkan, Mark W. Hamrick and Carlos M. Isales.
[Mechanism of Glucocorticoid-Induced Osteoporosis: An Update].
Xiaoxiao Qian. ISBN 978-953-51-0872-6, Published: November 28, 2012.
…lanjutan

• Efek Glukokortikoid pada Osteoclast

Gangguan
Glukokortikoid
pembentukan
tulang yang slow
progresif
Memodifikasi perilaku Mengganggu
resorpsi osteoclast homeostasis tulang

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 HIPERGLIKEMIA

Hyperglycemia is the medical term for high

blood sugar, which arises due to the body’s
inability to remove glucose from the blood
so that cells can use it for energy.

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 Hiperglikemia
…lanjutan
• Abdur Rehman, PharmD, PhD, Stephen M. Setter, PharmD, DVM, CDE, CGP,
Mays H. Vue, PharmD. [Drug-Induced Glucose Alterations Part 2: Drug-
Induced Hyperglycemia]. Diabetes Spectrum. November 2011;Vol.24(4):
234-238.
It is well known and recognized that glucocorticoid use in people with or without
diabetes results in hyperglycemia.

• Liu XX, Zhu XM, Miao Q, Ye HY, Zhang ZY, Li YM. [Hyperglycemia induced
by glucocorticoids in nondiabetic patients: a meta-analysis]. Ann Nutr
Metab. 2014;65(4):324-32.
Glucocorticoids are associated with a number of side effects including the development
of new-onset hyperglycemia or diabetes.

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 Hiperglikemia
…lanjutan

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 Hiperglikemia
Abdur Rehman, PharmD, PhD, Stephen M. Setter, PharmD, DVM, CDE, CGP, Mays H. Vue, PharmD. [Drug-Induced
Glucose Alterations Part 2: Drug-Induced Hyperglycemia]. Diabetes Spectrum. November 2011;Vol.24(4): 234-238.
…lanjutan

Glukokortikoid
Aktivasi reseptor
phosphoenolpyruvate
carbosykinase pada hati Mengganggu
fungsi sel
Mengganggu Beta
fungsi insulin Pankreas

Glukoneogenesis
Hepatik

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 METALLIC TASTE

Phantogeusia is defined as perception of taste (often

described as metallic or salty) without an external stimulus.

Metallic taste is characterized as a peculiar mouthfeel, which

is similar to that observed when an iron nail or metal foil is placed
in the mouth.

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 Metallic taste
…lanjutan
• I. IJpma, R.J. Renken, G.J. ter Horst, A.K.L. Reyners. [Metallic taste in cancer patients
treated with chemotherapy]. Cancer Treatment Reviews. 2015;41:179–186.
Two studies specifically focused on breast cancer patients, whereas the other studies
investigated heterogeneous cancer populations. All studies investigated taste changes
during chemotherapy in various treatment phases.
• Jae Hee Hong, PhD, Pinar Omur-Ozbek, PhD, Brian T. Stanek, Andrea M. Dietrich, PhD,
Susan E. Duncan, PhD, RD, Yong Woo Lee, PhD, and Glenn Lesser, MD. [Taste and Odor
Abnormalities in Cancer Patients]. The Journal of Supportive Oncology. Maret-April
2009; Vol.7(2).
A metallic and/or bitter taste has been associated with low levels of irradiation and
chemotherapy with cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate, and
cisplatin. Seventy-seven percent of patients treated with cisplatin alone or in
combination with other chemotherapeutic agents reported a metallic taste perception

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 Metallic taste
Jae Hee Hong, PhD, Pinar Omur-Ozbek, PhD, Brian T. Stanek, Andrea M. Dietrich, PhD, Susan E. Duncan, PhD, RD, Yong
Woo Lee, PhD, and Glenn Lesser, MD. [Taste and Odor Abnormalities in Cancer Patients]. The Journal of Supportive
Oncology. Maret-April 2009; Vol.7(2).

Cisplatin

Berasal dari Mucositis

Mengganggu fungsi sel rasa obat itu sendiri (Inflamasi dan ulserasi pada
reseptor pengecap
membrane mukosa)

Masuk ke Berdifusi
Jumlah Interupsi dalam melalui Merusak sel epitel dalam rongga mulut
sel Perubahan
struktur sel koding mulut kapiler
reseptor reseptor melalui
normal ↓ neural sel
cairan reseptor
servikular Lipidperoksidasi sel epitel
indera
dalam pengecap
plasma
Pembentukan Carbonyl Compounds
Penurunan Fungsi
Pengecapan
Persepsi Rasa Pengecapan
Metallic
Taste
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 Metallic Taste
I. IJpma, R.J. Renken, G.J. ter Horst, A.K.L. Reyners. [Metallic taste in cancer patients treated with chemotherapy].
Cancer Treatment Reviews. 2015;41:179–18.
...lanjutan

Cisplatin

Mengandung metal Ambang deteksi

compound platinum metal ↓
Persepsi retronasal

Disekresikan
melalui saliva
Metallic taste Lipid Oksidasi

Kontak langsung dengan

reseptor pengecap Carbonyl

Metallic taste Metallic Taste

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 PULMONARY FIBROSIS

Pulmonary fibrosis develops when the alveoli,

tiny air sacs that transfer oxygen to the blood,
become damaged and inflamed. The body
tries to heal the damage with scars, but these scars collapse
the alveoli and make the lungs less elastic.

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 Pulmonary Fibrosis
…lanjutan
• G. Gumuser, K. Vural, et al. [Assessment of lung toxicity caused by bleomycin and
amiodarone by Tc-99m HMPAO lung scintigraphy in rats]. Ann Nucl
Med;2013(27):592–599.
Amiodarone is a highly effective antidysrhythmic agent though it has numerous
adverse effects, the most critical of which is pulmonary toxicity and consequent
mortality.
• In Sook Kang, Kyung Jin Kim, Yookyung Kim, Seong-Hoon Park. [The diagnostic
utility of chest computed tomography scoring for the assessment of amiodarone-
induced pulmonary toxicity]. Korean J Intern Med; 2014(29):746-753.
Amiodarone is one of the most widely used antiarrhythmic agents; however,
amiodarone-induced pulmonary toxicity (APT) can be irreversible and
sometimes fatal

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 Pulmonary Fibrosis
…lanjutan

• S. George Carruthers MD, et al. Clinical Pharmacology: Basic Principles

in Therapeutic. McGraw-Hill Medical Publishing Division. 2000;4th
edition:1242-3.
Amiodarone is perhaps the most widely used drug that frequently causes
serious pulmonary toxicity, especially since it has been found to be effective at
low dosage for therapy of atrial fibrillation. Pulmonary fibrosis was common
with early amiodarone therapy when high doses (more than 400mg/day) were
used.

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 Pulmonary Fibrosis
Jeanne Elizabeth Black. [Mecanisms of Amiodarone and Desethylamiodarone Cytotoxicity in
Human Lung Cells]. Queen’s University; 2009.
…lanjutan

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 DEEP VEIN THROMBOSIS

DVT is the presence of coagulated blood,

a thrombus, in one of the deep venous conduits
that return blood to the heart.

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 Deep Vein Thrombosis
…lanjutan

• Kiran G. Piparva, Jatin G. Buch. [Deep vein thrombosis in a woman taking

oral combined contraceptive pills]. J Pharmacol Pharmacother; 2011(3):
185–186.
Women taking certain types of oral combined contraceptive pill (OCCP) have higher risk
of developing deep vein thrombosis (DVT).
• Kim JY, Kim YS. [Pulmonary embolism and deep vein thrombosis related to
oral contraceptive use]. Obstet Gynecol Sci. 2013 Jul; 56(4):273-6.
Yasmin, a combined oral contraceptive containing ethinylestradiol 30 µg and
drospirenon 3 mg was launched in the United Kingdom in 2002. We had experienced a
patient, 24-year-old young woman with left inguinal pain on ambulation, and edema of
left leg four months after taking Yasmin. We performed chest pulmonary angiography
computed tomography (CT) and lower extremity venogram CT. She was diagnosed to PE
in both lower lobes and DVT below the level of left external iliac vein, and treated by
low molecular weight heparin and warfarin.

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 Deep Vein Thrombosis
…lanjutan

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 Deep Vein Thrombosis
Svetlana N. Tchaikovski, Jan Rosing.[Mechanisms of Estrogen-Induced Venous Thromboembolism].
Thrombosis Research.2010:126;5–11.
…lanjutan

Meningkatkan kadar
fibrinogen,
prothrombin, F.VII, VIII,
X
Estrogen
Aktivasi factor II
Menurunkan kadar F.V menjadi IIa ->
Menurun

Ketidakseimbangan
sistem koagulasi
dan antikoagulasi

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 RHABDOMYOLISIS

Rhabdomyolysis is a syndrome caused by injury to skeletal

muscle and involves leakage of large quantities of potentially toxic

intracellular contents into plasma.

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 Rhabdomyolysis
…lanjutan

• Kazuho Sakamoto, Junko Kimura. [Mechanism of Statin-Induced

Rhabdomyolysis]. J Pharmacol Sci. 2013; 123:289 – 294.
Statins, a group of drugs used for the treatment of hypercholesterolemia, have
adverse effects on skeletal muscle. The symptoms of these effects range from
slight myalgia to severe rhabdomyolysis.

• Antons KA, Williams CD, Baker SK, Phillips PS. [Clinical perspectives of statin-
induced rhabdomyolysis]. Am. J. Med. May 2006; 119(5):400-9.
New findings suggest that exercise, Asian race, and perioperative status also
may increase the risk of statin muscle toxicity.

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 Rhabdomyolisis
M. John Chapman, Alain Carrie. [Mechanisms of Statin-Induced Myopathy A Role for the Ubiquitin–
Proteasome Pathway?]. Arteriosclerosis, Thrombosis, and Vascular Biology.2005;25:2441-2444.
…lanjutan

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 OSTEONECROSIS OF JAW
• American Association of Oral and Maxillofacial Surgeons, 2009:

Patients may be considered to have bisphosphonate related osteonecrosis of

the jaw (BRONJ) if all of the following characteristics are present:

1. Current or previous treatment with antiresorptive or antiangiogenic

agents;
2. Exposed bone or bone that can be probed through an intraoral or
extraoral fistula(e) in the maxillofacial region that has persisted for more
than eight weeks;
3. No history of radiation therapy to the jaws or obvious metastatic
disease to the jaws.

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 Osteonecrosis of Jaw
…lanjutan

• Silverman SL, Landesberg R. [Osteonecrosis of the jaw and the role of

bisphosphonates: a critical review]. Am. J. Med. 2009; 122(2):33-45.
Osteonecrosis of the jaw (ONJ), a condition characterized by necrotic exposed
bone in the maxillofacial region, has been reported in patients with cancer
receiving bisphosphonate therapy, and rarely in patients with postmenopausal
osteoporosis or Paget disease of bone receiving such therapy.
• Michèle Tubiana-Hulin et al. [Physiopathology and management of osteonecrosis
of the jaws related to bisphosphonate therapy for malignant bone lesions. A
French expert panel analysis]. Oncology Hematology. 2009;71(1):12-21.
Bisphosphonates (BP) are the current standard of care for preventing malignant
skeletal related-events. Recent reports have documented the relationship
between osteonecrosis of the jaws (ONJ) and the use of BPs.

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 Osteonecrosis of the Jaw
Salvatore L. Ruggiero, DMD, MD, et al. Medication-Related Osteonecrosis of the Jaw—
2014 Update. American Association of Oral and Maxillofacial Surgeons. 2014

1. Menghambat fungsi dan

Inhibisi resorpsi diferensiasi osteoclast
dan remodeling
osteoclast 2. Meningkatkan apoptosis
osteoclast

Menghambat
Osteonecrosis diferensiasi,
of the jaw Inhibisi pertumbuhan, dan Nekrosis
migrasi sel endotel
angiogenesis untuk membentuk avaskular
pembuluh darah
baru
Inflamasi/
Infeksi

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 Osteonecrosis of the Jaw
Lars Rasmusson, Jahan Abtahi. [Bisphosphonate Associated Osteonecrosis of the Jaw: An Update on
Pathophysiology, Risk Factors, and Treatment]. Hindawi Publishing Corporation International Journal of
Dentistry.2014.
…lanjutan

Non-nitrogen: Masuk ke dalam Mengubah fungsi Apoptosis

Clodronate Osteoclast Mitokondria Osteoclast

Bisfosfonat
Menghambat Daya tahan dan
Nitrogen:
Farnesilpirofosfat dan aktifitas osteoclast
Zoledronate terganggu
Geranylgeranylpyrofosfat

Menghambat
resorpsi
tulang
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 Osteonecrosis of the Jaw
Vijay Kumar, Raman Kant Sinha. Evolution and Etiopathogenesis of Bisphosphonates Induced Osteonecrosis of the
Jaw. North American Journal of Medical Sciences. 2013. Vol 5(4).

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 Osteonecrosis of the Jaw
Vijay Kumar, Raman Kant Sinha. Evolution and Etiopathogenesis of Bisphosphonates Induced
Osteonecrosis of the Jaw. North American Journal of Medical Sciences. 2013. Vol 5(4).
…lanjutan

Tulang mandibularis dan Periodontium mengandung

maksilaris mempunyai 2 Remodelling melibatkan fibroblast gingiva dan sel
komponen penting: osteoblast dan resorpsi ligament periodontal yang
1. Alveolar melibatkan osteoclast memiliki peran dalam
2. Periodontium osteoclastogenesis

Remodelling
alveolar: 10- Vaskularisasi
20 kali lebih lebih banyak
cepat daripada
os iliaca
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 INTERMITTENT PORPHYRIA
Acute intermittent porphyria (AIP) is a rare
hereditary disease in which the blood pigment
hemoglobin is abnormally metabolized. Porphyrins are
excreted in the urine, which becomes dark; other
symptoms include mental disturbances and extreme
sensitivity of the skin to light.
.

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 Intermittent Porphyria
…lanjutan

• Stig Thunell, Erik Pomp, Atle Brun. Guide to drug porphyrogenicity

prediction and drug prescription in the acute porphyrias. Br J Clin
Pharmacol. 2007; 64(5): 668–679.
A few substances, repeatedly recognized as extremely porphyrogenic, are
potent batch-inducers of a multitude of hepatic microsomal enzymes including
CYP isoenzymes and uridinediphosphate glucuronosyl transferases (UGTs). Since
they act on more than one system they have been termed multifunctional
inducers. The drugs best studied in this category are the classical antiepileptic
drugs phenobarbital, phenytoin, carbamazepine and primidone

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 Intermittent Porphyria
…lanjutan
• Mahagna Antonio Abed, Vissio Elena. Acute
Intermittent Porphyria. flipper e nuvola. 2014.
Drugs like barbiturates, phenytoin, and griseofulvin induce
acute attack because they stimulate Cytochrome P450
synthesis that consumes heme.

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 Intermittent Porphyria
Joseph R. Bloomer, MD; Brendan M. McGuire, MD, MS. The Diagnosis and
Management of Acute Porphyrias. Medscape Oncology. 2008.
…lanjutan

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 Intermittent Porphyria
Joseph R. Bloomer, MD; Brendan M. McGuire, MD, MS. The Diagnosis and
Management of Acute Porphyrias. Medscape Oncology. 2008.
…lanjutan

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 Intermittent Porphyria
…lanjutan

Fenobarbital
Terjadi akumulasi ALA Peningkatan ekskresi
menginduksi sitokrom
dan PBG urin dari ALA dan PBG
P450 (CYP)

Menginduksi secara
Defisiensi
langsung Acute Intermittent
porphobilinogen
amynolevulinate acid Porphyria
deaminase (PBGD)
synthetase (ALAS1)

Produksi ALA dan

Tidak terjadi negative
porphobilinogen
feed-back control
(PBG) meningkat

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TERIMA KASIH

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