Pendahuluan Interaksi Obat

• Dr. Apt, Diana Laila Ramatillah, M. Farm

• Juleha
• Silvia Hartuti
Definisi

• Interaksi Obat (IO) adalah adanya efek yang ditimbulkan dari reaksi
obat dengan benda lain (obat/herbal/makanan) (sumber :FDA Drugs
Interaction)
Jenis Jenis IO
• Apa beda farmakokinetik dengan farmakodinamik????
Efek yang ditimbulkan dari interaksi Obat
• Penurunan efek

1. Konsentrasi obat dalam plasma menurun

2. Obat lebih banyak berikatan dengan albumin (Obat bebas menjadi
berkurang sehingga efek juga berkurang)
• Peningkatan efek

1. Konsentrasi obat dalam plasma meningkat

2. Obat lebih sedikit berikatan dengan albumin (Obat bebas menjadi
bertambah sehingga efek juga bertambah)
• Toksisitas

• 1. Gangguan pada organ atau system tubuh yang lainnya

• 2. Kerusakan sementara/permanen
TIPE_TIPE INTERAKSI

•- Minor
•-Mayor
Interaksi Obat

• Interaksi Obat Secara farmakokinetik lebih mudah untuk ditebak dibandingkan interaksi obat
secara farmakodinamika
• Interaksi Farmakodinamik terjadi pada saat obat kedua berkompetensi menduduki reseptor
Interaksi Obat

• Ada beberapa contoh interaksi obat yang mengancam jiwa salah satu contohnya adalah aritmia
yang fatal yang diakibatkan dari interaksi antara terfenadine dan ketoconazole
Epidemiologi

• Salah satu efek dari interaksi obat adalah munculnya ADR (adverse drug reactions) yang dikenal
juga dengan reaksi obat yang merugikan
• ADR di US sekitar 4.2-6 % dari seluruh patien yang masuk RS
• Interaksi obat yang terjadi juga tergantung dari jenis pasiennya dan obat yang diterima dari
pasien itu sendiri sebagai contoh pasien HIV / AIDS akan beresiko untuk terjadi interaksi obat
DI Minor

• Minor drug interactions usually have limited clinical consequences and require no change in
therapy. An example of a minor interaction is that which occurs between hydralazine and
furosemide. The pharmacologic effects of furosemide may be enhanced by concomitant
administration of hydralazine, but generally not to a clinically significant degree (9). While minor
drug interactions can generally be disregarded when assessing a medication regimen
DI Moderate

• moderate interactions often require an alteration in dosage or increased monitoring. Combining

rifampin and isoniazid, for instance, leads to an increase in the incidence of hepatotoxicity.
Despite this interaction, the two drugs are still used in combination along with frequent
monitoring of liver enzymes.
DI Severe

• Severe interactions, on the other hand, should generally be avoided whenever possible, as they
result in potentially serious toxicity. For example, ketoconazole causes marked increases in
cisapride exposure, which may lead to the development of QT prolongation and life-threatening
ventricular arrhythmia. It is recommended that these drugs not be used in combination.
• Pharmacodynamic interactions do not involve changes in the concentration
of drug in plasma or at the targeted site of action.
• Pharmacokinetic interactions, on the other hand, occur when one drug
alters the absorption, distribution, metabolism, or elimination of another
drug, thereby changing its concentration in plasma and, consequently, at
the targeted site of action. Clinically significant drug interactions are most
often due to alterations in pharmacokinetics, secondary to modulation of
drug metabolism.
• In some cases a significant interaction may result from a combination of
both pharmacokinetic and pharmacodynamic mechanisms. For instance,
the interaction between cerivastatin and gemfibrozil, which has resulted
in cases of severe rhabdomyolysis, is likely due to the inhibition of
cerivastatin metabolism by gemfibrozil (i.e., pharmacokinetic interaction),
in addition to the propensity of both drugs to cause skeletal muscle
toxicity (i.e., pharmacodynamic interaction)
• Food interactions are typically pharmacokinetic in origin. Most commonly,
food can affect the absorption of drugs. The simplest example of this is
when food delays gastric emptying, slowing down the passage of drug into
the small intestine, the primary site for drug absorption. However, there are
some notable pharmacodynamic drug interactions involving food. One of
the most important examples of a food-drug interaction involves the
anticoagulant warfarin and its interaction with green leafy vegetables,
which contain vitamin K.
Alcohol

The role of alcohol in pharmacokinetic interactions changes depending on whether use is chronic
or acute. Acutely, ethanol competitively inhibits CYP450 enzymes, whereas chronic use leads to
CYP450 induction as the body tries to increase its ability to eliminate ethanol.
Smoking/Environtment

• Cigarette smoking induces CYP450 enzymes

ADR
Definisi

• ADR adalah Reaksi yang sangat berbahaya atau tidak menyenangkan, yang dihasilkan dari
intervensi yang terkait dengan penggunaan produk obat.
Tipe-Tipe ADR

• Reaksi tersebut saat ini dilaporkan dengan menggunakan istilah Reaksi Obat Yang Merugikan (ADR).
• Reaksi obat yang merugikan diklasifikasikan menjadi enam jenis:
terkait dosis (Augmented)
tidak terkait dengan dosis (Bizarre)
terkait dosis dan terkait waktu (Chronic)
terkait waktu (Delayed)
penarikan/ withdrawal (End of use), dan
kegagalan terapi (Failure).
Beberapa obat yang dapat menimbulkan toxicity

• 1. Obat-obat indeks terapi sempit

• 2. Obat-obat yang memperpanjang proses metabolism oleh enzim tertentu di hati
• 3. Obat-obat yang menghambat metabolism di hati dengan menghambat enzim tertentu
• 4. Obat-obat yang mempercepat metabolism di hati dengan menginduksi enzim tertentu
Drug Interactions

1. Quinidine menghambat metabolism dari digoxin, tricyclic

antidepressant dan codein
2. Cimetidine, azole antifungal dan CCB menghambat
metabolism dari quinidine
3. Cimetidine dan Trimetoprine menghambat ekskresi dari
Procainamide
4. Dosis digoxin dan warfarin harus diturunkan setengahnya
kalau digunakan bersama amiodarone
Antiarrhythmic (Michael, 2012)

Class III antiarrhythmic drugs may interact with other drugs

by two major processes: pharmacodynamic and
pharmacokinetic interactions. The pharmacodynamic
interaction occurs when the pharmacological effects of the
object drug are stimulated or inhibited by the precipitant
drug. Pharmacokinetic interactions can result from the
interference of drug absorption, metabolism and/or
elimination of the object drug by the precipitant drug
 Continue,..

• Among the class III antiarrhythmic drugs, amiodarone has been reported to
be involved in a significant number of drug interactions. It is mainly
metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of
CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other
drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane
transporter system, a recently described pharmacokinetic mechanism of
drug interactions.
Continue,…

• Bretylium is not metabolised; it is excreted unchanged in the

urine. Therefore the interactions between bretylium and
other drugs (including other antiarrhythmic drugs) is
primarily through the pharmacodynamic mechanism.
Continue

• Sotalol is primarily excreted unchanged in the urine. The

potential for drug interactions due to hepatic enzyme
induction or inhibition appears to be less likely. However, a
number of drugs (such as digoxin) have been reported to
interact with sotalol pharmacodynamically.
 Antineoplastic Drugs (MTX)
• In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis
of meningeal leukemia and is used in maintenance therapy in combination
with other chemotherapeutic agents. Methotrexate is also indicated in the
treatment of meningeal leukemia.
• Methotrexate is used alone or in combination with other anticancer agents in
the treatment of breast cancer, epidermoid cancers of the head and neck,
advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer,
particularly squamous cell and small cell types. Methotrexate is also used in
combination with other chemotherapeutic agents in the treatment of
advanced stage non-Hodgkin's lymphomas.
Continue

• Methotrexate in high doses followed by leucovorin rescue in

combination with other chemotherapeutic agents is effective
in prolonging relapse-free survival in patients with non-
metastatic osteosarcoma who have undergone surgical
resection or amputation for the primary tumor.
Continue

• Methotrexate is indicated in the management of selected adults with

severe, active rheumatoid arthritis (ACR criteria), or children with active
polyarticular-course juvenile rheumatoid arthritis, who have had an
insufficient therapeutic response to, or are intolerant of, an adequate trial
of first-line therapy including full dose nonsteroidal anti-inflammatory
agents (NSAIDs).
• Aspirin, (NSAIDs), and/or low-dose steroids may be continued, although
the possibility of increased toxicity with concomitant use of NSAIDs
including salicylates has not been fully explored.
• Steroids may be reduced gradually in patients who respond to
methotrexate.
• Combined use of methotrexate with gold, penicillamine,
hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been
studied and may increase the incidence of adverse effects.
Continue

• Nonabsorbable antibiotics can decrease methotrexate

absorption.
• Nephrotoxic drugs can decrease methotrexate renal
clearance.
• Salicylates and probenecid may decrease the plasma protein
binding and renal tubular secretion of methotrexate
(Journal Reumath Supplem)
Digoxin

• The adverse effects of digoxin are potentiated by renal

impairment, which may be pre-existing or due to nephrotoxic
drugs such as nonsteroidal antiinflammatory drugs (NSAIDs),
angiotensin-converting-enzyme (ACE) inhibitors, angiotensin
II receptor antagonists and ciclosporin
• Some coadministered drugs such as macrolides and
cardiovascular drugs (especially amiodarone) can cause
digoxin overdose through pharmacokinetic interactions. The
mechanism most often implicated is inhibition of P-
glycoprotein, of which digoxin is a substrate. (Prescrire, 2010)
Continue

•Drug interactions with digoxin are important

because of this agent's narrow therapeutic index.
Among the drugs that can decrease digoxin
bioavailability are cholestyramine, antacid gels,
kaolin-pectate, certain antimicrobial drugs and
cancer chemotherapeutic agents. In selected
patients, antibiotics may enhance digoxin
bioavailability by eliminating intestinal flora that
metabolize digoxin (Journal of American College of
Cardiology)
Continue

•Antiarrhythmic drugs, such as quinidine and amio-

darone, can markedly increase steady state serum
digoxin levels. Certain calcium channel blocking
drugs, particularly verapamil, have a similar effect.
Potassium-sparing diuretic drugs, such as
spironolactone, can alter digoxin pharmacokinetics
(Journal of American College of Cardiology)
Continue

•Indomethacin may decrease renal excretion

of digoxin in preterm infants. Finally,
rifampin, an antibiotic used in the treatment
of tuberculosis, may lower steady state serum
digoxin levels in patients with severe renal
disease (Journal of American College of
Cardiology)
Pertanyaan

• 1. Seorang pasien 60 tahun diberikan prasugel dan warfarin

dengan dosis lazim. Namun setelah beberapa jam pemakaian
pasien tersebut mengalami pendarahan?
Jelaskan apa yang terjadi?
Cari !!!

Drug Interactions with St John’s Wort (Hypericum perforatum)

Drug Interactions with Grapefruit (Citrus paradisi)
Drug Interactions with Echinacea (Echinacea spp.)
Drug Interactions with Ginkgo (Gingko biloba)
Drug Interactions with Ginseng
Drug Interactions with Garlic (Allium sativum)
Drug Interactions with Saw Palmetto (Serenoa repens)
Drug Interactions with Kava (Piper methysticum)
Drug Interactions with Ginger (Zingiber officinale)
Drug Interactions with Valerian (Valeriana officinalis)
Drug Interactions with Goldenseal (Hydrastis canadensis)
Drug Interactions with Green Tea (Camellia sinensis)
Drug Interactions with Curcumin (Curcuma longa)
Drug Interactions with Black Cohosh (Actaea racemosa)
Drug Interactions with Milk Thistle (Silybum marianum)
Daftar Pustaka

• 1. Koda-kimble
• 2 Drug Interactions
• 3. Medscape
• 4. Drugs Interaction-Overview Elsevier
THANK YOU