23/02/15

INTERAKSI OBAT
Valen-na Meta Srikar-ka, S. Farm, MPH, Apt

Drug Interaction De7inition

An interac-on is said to occur when the eects of one drug are
changed by the presence of another drug, herbal medicine,
food, drink or by some environmental chemical agent (Baxter K,
2008)
Drug

Drug

Incidence of Drug Interactions

the reported incidence rates ranged from 2.2 to 70.3%, and
the percentage of pa-ents actually experiencing problems
was less than 11.1% 1
Another review found a 37% incidence of interac-ons among
639 elderly pa-ents 2
Yet another review of 236 geriatric pa-ents found an 88%
incidence of clinically signicant interac-ons, and a 22%
incidence of poten-ally serious and life-threatening
interac-ons 3
An Australian study found that about 10% of hospital
admissions were drug-related, of which 4.4% were due to
drug interac-ons 4
1.
2.
3.
4.

Chemical
Agent

Drink

Food

Herbal
Medicine

Mechanism of Drug Interaction

Pharmacokine-cs Interac-ons

Pharmacodynamic Interac-ons

Absorp-on

Addi-ve/synergis-c

Distribu-on

Anatagonist

Metabolism
Excre-on

Haumschild MJ, Ward ES, Bishop JM, Haumschild MS. Pharmacy-based computer system for monitoring and repor-ng drug interac-ons. Am J Hosp Pharm (1987) 44,
345
Manchon ND, Berco E, Lamarchand P, Chassagne P, Senant J, Bourreille J. Frquence et gravit des interac-on mdicamenteuses dans une popula-on ge: tude
prospec-ve concernant 39 malades. Rev Med Interne (1989) 10, 5215
Lipton HL, Bero LA, Bird JA, McPhee SJ. The impact of clinical pharmacists consulta-ons on physicians geriatric drug prescribing. Med Care (1992) 30, 64658.
Stanton LA, Peterson GM, Rumble RH, Cooper GM, Polack AE. Drug-related admissions to an Australian hospital. J Clin Pharm Ther (1994) 19, 3417.

Drug Absorption Interaction

For drugs that are given long-term, in mul-ple doses (e.g. the
oral an-coagulants) the rate of absorp-on is usually
unimportant, provided the total amount of drug absorbed is
not markedly altered.
On the other hand for drugs that are given as single doses,
intended to be absorbed rapidly (e.g. hypno-cs or analgesics),
where a rapidly achieved high concentra-on is needed, a
reduc-on in the rate of absorp-on may result in failure to
achieve an adequate eect.

1. Effects of changes in GI pH
The passage of drugs through mucous membranes by simple
passive diusion depends upon the extent to which they exist
in the non-ionised lipid-soluble form.
Example: H2 Receptor Antagonist VS Ketoconazole

2. Chelation mechanism
Example: Tetracycline VS Ca, Al, Mg, Fe

3.
Changes in GI motility

Since most drugs are largely absorbed in the upper part of the
small intes-ne, drugs that alter the rate at which the stomach
emp-es can aect absorp-on.
Example: Metoclopramide VS Paracetamol

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Drug Distribution Interactions

Absorp-on drugs are distributed around the body by the
circula-on.
Some drugs are totally dissolved in the plasma water, but many
others are transported with some propor-on of their molecules in
solu-on and the rest bound to plasma proteins (albumins).
One drug may successfully compete with another and displace it
from the sites it is already occupying. The displaced (and now ac-ve)
drug molecules pass into the plasma water where their
concentra-on rises.
For example, a drug that reduces the binding from 99 to 95% would
increase the unbound concentra-on of free and ac-ve drug from 1
to 5% (a vefold increase). This displacement is only likely to raise
the number of free and ac6ve molecules signicantly if the
majority of the drug is within the plasma rather than the 6ssues, so
that only drugs with a low apparent volume of distribu-on (Vd) will
be aected . such as tolbutamide (96% bound, Vd 10 litres), oral
an-coagulants, such as warfarin (99% bound, Vd 9 litres), and
phenytoin (90% bound, Vd 35 litres).
For Example: Warfarin VS Cloral Hydrate

Drug Excretion Interactions

Most drugs are excreted either in the bile or in the urine.
Blood entering the kidneys along the renal arteries is, rst of
all, delivered to the glomeruli of the tubules where molecules
small enough to pass through the pores of the glomerular
membrane (e.g. water, salts, some drugs) are ltered through
into the lumen of the tubules.
Larger molecules, such as plasma proteins, and blood cells are
retained within the blood.
The blood ow then passes to the remaining parts of the
kidney tubules where ac-ve energy-using transport systems
are able to remove drugs and their metabolites from the
blood and secrete them into the tubular ltrate.
The renal tubular cells addi-onally possess ac-ve and passive
transport systems for the reabsorp-on of drugs

Pharmacodynamics Interactions
Addi6ve/synergis6c Interac6ons. If two drugs that have the
same pharmacological eect are given together the eects
can be addi-ve
Addi-ve eects can occur with both the main eects of the
drugs as well as their adverse eects
Example: Methotrexate VS Co-trimoxazole (Bone marrow
megaloblastosis due to folic acid antagonism)
Antagonis6c/opposing Interac6ons. In contrast to addi-ve
interac-ons, there are some pairs of drugs with ac-vi-es that
are opposed to one another.
Example: Coumarin VS dietary vitamin K.

Drug Metabolism Interactions

Enzyme Induc6on. Example: inducers the cytocrome P450:
Carbamazepine, Dexamethasone, Phenobarbital, Phenitoin,
Rifampicin
Example: Rifampicin VS Warfarin
The extent of the enzyme induc-on depends on the drug and its
dosage, but it may take days or even 2 to 3 weeks to develop fully,
and may persist for a similar length of -me when the enzyme
inducer is stopped (delayed in onset and slow to resolve).
Enzyme Inhibi6on. Example of inhibitors the cytocrome P450:
azoles, cime-dine, dil-azem, macrolida
Example: Cime-dine VS Propanolol
The clinical signicance of many enzyme inhibi-on interac-ons
depends on the extent to which the serum levels of the drug rise. If
the serum levels remain within the therapeu-c range the interac-on
may not be clinically important

1. Changes in Urinary pH
Only the non-ionised form is lipid-soluble and able to diuse
back through the lipid membranes of the tubule cells.
Example: Aspirin VS Urine alkalinize/acidier

2.
Changes in Active Renal Tubular Exretion
Drugs that use the same ac-ve transport systems in the renal
tubules can compete with one another for excre-on
Example: Probenecid VS Penisilin

3. Changes in Renal Blood Flow

The ow of blood through the kidney is par-ally controlled by
the produc-on of renal vasodilatory prostaglandins
Example: NSAIDs VS Lithium

Management of Drug Interactions

Obat-obat yang berinteraksi seringkali tetap bisa
digunakan bersamaan
Ada interaksi obat yang menguntungkan

Contoh : probenecid VS penisillin

Sifat laporan / informasi IO
Kedalaman informasi
Waktu penerbitan literature / current literature
Clinical VS statistical significance

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Management of Drug Interactions

terdapat 3 derajat keparahan IO yait: :
Keparahahan MINOR
Bisa terjadi tetapi tidak sigAikan
Keparahan MODERATE
Pasien mungkin mengalami sesuat: yang dapat membuat kondisinya
membur:k karena IO
Jika kedua obat memang har:s dig:nakan bersamaan ?
Keparahan MAYOR
Bila obat dig:nakan bersamaan, maka kemungkinan dapat
mengancam jiwa (life threatening)

Clinical Signi7icance Grading

(Tatro)
Established adalah interaksi obat yang memiliki hasil data klinik yang
memadai dan telah terbuk- terjadi dalam beberapa peneli-an yang
telah dilakukan, baik dari segi efek farmakologis dan interaksi
farmakokine-ka.
Probable adalah interaksi obat yang sangat mungkin terjadi, namun
dalam beberapa uji klinis -dak terbuk-.
Suspected adalah interaksi yang kemungkinan teradi, beberapa
interaksi obat telah memiliki data klinik yang baik dan sebagian
interaksi obat membutuhkan peneli-an lebih lanjut.
Possible adalah interaksi dapat terjadi namun data klinik yang
dimiliki sangat terbatas,
Sedangkan unlikely adalah interaksi obat yang memiliki dokumentasi
pada posibble dan suspected, namun karena memiliki interaksi yang
cukup banyak dan -dak memiliki buk- klinis yang baik sehingga
pada akhirnya dikategorikan sebagai unlikely

Clinical Signi7icance Grading

(Tatro)
Tingkat
Signifikasi
1

Keamanan

Dokumentasi

Major

Moderate

Established, Probable
or Suspected
Established, Probable
or Suspected
Established, Probable
or Suspected
Possible

Minor

Major / Moderate

Minor / Any

Possible/
unlikely

Conclusion
FarSasis sehar:snya siaga terhadap interaksi obat yang
potensial terjadi
Jika kombinasi obat yang potensial menimbulkan
interaksi tidak dapat dihindari : SESUAIKAN DOSIS dan
MONITOR PASIEN
Jika terjadi interaksi obat, kombinasi obat yang potensial
menimbulkan interaksi dapat dihindari dengan
mengganti obat yang dicurigai dengan obat lain yang
tidak menimbulkan interaksi