1.

Interaksi obat-obatan terjadi ketika satu obat berinteraksi dengan atau mengganggu kerja
obat lain. Sebagai contoh, mengkonsumsi antasid dengan tetrasiklin oral dapat menyebabkan
penurunan efektivitas tetrasiklin tersebut. Antasida secara kimia berinteraksi dengan
tetrasiklin dan mengganggu absorpsinya ke dalam aliran darah, sehingga mengurangi
efektivitas tetrasiklin tersebut. Obat-obat yang diketahui menyebabkan interaksi termasuk
antikoagulan oral, hipoglikemik oral, anti-infeksi, antiaritmia, glikosida jantung, dan alkohol.
Interaksi obat-obatan dapat menghasilkan efek yang aditif, sinergis, atau antagonis.

Reaksi Obat Aditif

Reaksi obat aditif terjadi ketika efek kombinasi dari dua obat yang sama dengan jumlah
masing-masing obat yang diberikan tunggal. Misalnya, mengkonsumsi obat heparin dengan
alkohol akan meningkatkan perdarahan. Persamaan 1 + 1 = 2 kadang-kadang digunakan
untuk menggambarkan efek aditif obat.

Reaksi Obat Sinergis

Sinergisme obat terjadi ketika obat berinteraksi satu sama lain dan menghasilkan efek yang
lebih besar daripada jumlah aksi masing-masingnya. Persamaan 1 + 1 = 3 dapat digunakan
untuk menggambarkan sinergisme. Contoh dari sinergisme obat adalah ketika seseorang
mengkonsumsi baik hipnotik dan alkohol. Ketika alkohol dikonsumsi bersamaan atau sesaat
sebelum atau setelah hipnotik dikonsumsi, aksi hipnotik meningkat. Orang tersebut
mengalami efek obat yang lebih besar daripada jika obat dikonsumsi tunggal. Sesekali,
terjadinya efek obat sinergis serius dan bahkan fatal.

Reaksi Obat Antagonis

Reaksi obat antagonis terjadi ketika satu obat mengganggu dengan aksi lain, menyebabkan
netralisasi atau penurunan efek satu obat. Sebagai contoh, protamine sulfat merupakan
antagonis heparin. Ini berarti bahwa pemberian protamine sulfat sepenuhnya menetralkan
efek heparin dalam tubuh.

Roach, Sally S. 2010. Introductory Clinical Pharmacology.7 th Edition. UnitedStates of

America: Lippincott Williams & Wilkins.
ANTAGONIS
Naproxen interfered with the irreversible inhibitory effect of aspirin on platelet COX-1
activity in vitro and ex vivo. This effect was undetectable during the continuous and regular
administration of an antiinflammatory dose of naproxen (500 mg BID) and low-dose aspirin
because naproxen can mimic the inhibitory effect of aspirin on platelet TXA2 generation.
However, in the real world, naproxen combination with aspirin might undermine the
sustained inhibition of platelet COX-1 necessary for cardioprotection from aspirin.
Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and
function. This pharmacodynamic interaction might undermine the sustained inhibition of
platelet COX-1 that is necessary for aspirin’s cardioprotective effects.

ANTAGONIS
Koopmans et al. (14) carried out an open-label trial of 8 patients to quantify the increase in
blood pressure in subjects treated with the diuretic hydrochlorothiazide 50 mg daily
concomitant to four weeks of ibuprofen 400 mg every 8 hours, diclofenac 25 mg three times
a day, or sulindac 200 mg every 12 hours. A significant rise in systolic blood pressure was
observed in the patients treated with ibuprofen, though the authors concluded that these three
NSAIDs can be used without risk in patients treated with hydrochlorothiazide – provided
careful blood pressure monitorization is carried out on introducing NSAID treatment.
Gurwitz et al. (15) conducted a randomized, double-blind and placebo-controlled clinical trial
of 22 patients over 65 years of age. All the subjects were receiving antihypertensive treatment
with the diuretic hydrochlorothiazide, and were subjected to alternating four-week periods of
treatment with ibuprofen 600 mg every 8 hours or placebo. The authors concluded that in
elderly patients treated with hydrochlorothiazide, ibuprofen induces a significantly greater
increase in blood pressure than placebo, and that ibuprofen may negatively affect high blood
pressure control in elderly individuals. The interaction of ibuprofen with the diuretic
furosemide has been described in two isolated and independent cases involving ibuprofen
doses of 400 mg every 8 hours and 600 mg four times a day, respectively (16,17). In
comparison, the interaction of furosemide with the NSAID indomethacin has been well
documented in different studies (18,19).

ANTAGONIS
Protamine has long been used in conjunction with heparin therapy. At the suggestion of
Professor C. H. Best, in 1937 I undertook a study on the practical use of pro¬ tamine as a
heparin antagonist, after the demonstrations by A. Fischer1 that basic proteins could hinder
the anticoagulant activity of heparin and by Chargaff and Olson2 that protamine was
particularly effective. Our studies demonstrated two uses for this property of protamine. The
first8 was neutralization of the anticoagulant action of heparin in blood samples, both to
demonstrate the presence of heparin in blood and to measure the amount of heparin in the
sample. It was known as protamine titration and has since been widely used by hematologists
and others. Since an excess of protamine shows anticoagulant properties when added to blood
samples, the minimal amount of protamine required to bring the clotting time to a normal
value provides a measure of the amount of heparin present in the blood sample.
The second use of protamine, as demonstrated by Jaques, Charles and Best,4 was to reduce
hypocoagulability due to heparin by its injection into the circulation, known as protamine
neutralization. Protamine is still the chief agent available for neutralizing heparin. Applied to
the titration of the anticoagulant action of heparin in vitro, it provides a useful means of
diagnosis of hemorrhagic states. The amount of heparin present in the circulation is related to
total dosage and the time interval from its administration, but depends markedly on the
absolute concentrations reached in the blood and the hemodynamic and metabolic condition
of the patient. Direct determination in vitro in the operating room of the amount of protamine
required to neutralize the heparin present in the patient's blood can provide an equivalence
figure applicable to the patient. (In addition, it may demonstrate the presence of such
problems as rapid fibrinolysis.) Because of the variability in heparin preparations (probably
related to difficulties of standardization), figures for the heparin equivalent of protamine
preparations are of limited value. Therefore, it is wiser, when a titration on the blood is not
done, to depend on a rule-of-thumb dosage such as not more than 1.0 mg./100 USP units of
heparin. This is to be injected slowly in divided doses, stopping the injection when
hemostasis is achieved. The amount should be reduced in proportion to the time which has
elapsed since the last heparin administration (by about 1 mg./min. for the average patient). In
using protamine to neutralize heparin after extensive and prolonged operations, no simple
rule of protamine-heparin equivalence will suffice to ensure that hemostasis will always be
instantly achieved. When hemostasis is not effected it is essential to appreciate the many
contributing factors and assess their significance for the patient.

SINERGIS
Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor
blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone,
although this additive effect may be abolished with maximal monotherapy dosing. The recent
ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB
combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former
group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria
and disease progression more than monotherapy, but the ONTARGET study showed an
increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-
angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar
efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS
inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2
mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but,
considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are
needed before the use of aliskiren can be recommended in combination with other RAS
inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to
ACE-Is or ARBs, where these are ineffective or poorly tolerated.

SINERGIS
The role of fixed-dose combinations in chronic pain management using tramadol/paracetamol
as an example • Tramadol/Paracetamol may offer distinct advantages in certain patient
populations and for certain types of pain, compared with high doses of NSAIDs or
paracetamol or when NSAIDs or paracetamol are expected to be used for long durations.
However, long-term studies of fixed-dose combinations are required. • Potential advantages
of a fixed-dose tramadol/paracetamol analgesic product include a broader analgesic spectrum,
a complementary pharmacokinetic profile, potentially synergistic analgesic effect, greater
convenience (possibly resulting in better compliance, thus, improved therapy), and an
improved ratio of efficacy to adverse effects.

SINERGIS
The antinociception induced by the intraperitoneal coadministration of combinations of
paracetamol with the nonsteroidal antiinflammatory drugs (NSAIDs) diclofenac, ibuprofen,
ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam was
studied by isobolographic analysis in the acetic acid abdominal constriction test of mice
(writhing test). The effective dose that produced 50% antinociception (ED50) was calculated
from the log dose–response curves of fixed ratio combinations of paracetamol with each
NSAID. By isobolographic analysis, this ED50 was compared to the theoretical additive
ED50 calculated from the ED50 of paracetamol and of each NSAID alone obtained from
ED50 dose–response curves. As shown by isobolographic analysis, all the combinations were
synergistic, the experimental ED50s being significantly smaller than the theoretically
calculated ED50s. The results of this study demonstrate potent interactions between
paracetamol and NSAIDs and validate the clinical use of combinations of these drugs in the
treatment of pain conditions.
In conclusion, the data of the present study demonstrated that paracetamol combined with
NSAIDs produces a supra-additive or synergic analgesic effect. It may be noted that the
doses of paracetamol and NSAIDs are very small and if they are compared with those
referred in the literature, it is possible to suggest that the combinations of paracetamol and
NSAIDs will be effective for the clinical treatment of pain. In addition, it is demonstrated that
the effect of the combinations paracetamol/NSAIDs is superior to that of either component
alone. Therefore, these mixtures are a viable alternative to clinical pain management,
especially because the low doses of the components may be a potential index of lower
incidence of adverse effects.

SINERGIS
It is common practice to use beta-adrenergic stimulants and methyl xanthines in the treatment
of bronchial asthma. The studies of Robison et al. (1971) suggest that the beta-adrenergic
effects of catecholamines are mediated through 3'5' cyclic adenosine monophosphate (cyclic
AMP), the intracellular 'second messenger'. Methyl xanthines inhibit phosphodiesterase, the
enzyme which inactivates cyclic AMP (Butcher and Sutherland, 1962), and it is proposed
(Leading article, 1970) that methyl xanthines and beta-adrenergic agents may produce
bronchodilatation by increasing the level of cyclic AMP in bronchial and bronchiolar smooth
muscle. Drugs which individually act at different points in the metabolic pathway of a
compound in such a way as to increase the amount of that compound may, when used
together, produce an increase greater than the sum of the increases produced 'Present address:
Respiratory Department, Bristol Royal Infirmary 'University Department of Pathology,
Edinburgh by each drug alone, that is, they may interact synergistically (Veldstra, 1956).
There is evidence in vitro for synergy between beta-adrenergic agents and methyl xanthines
(Rall and West, 1963; Lichtenstein and Margolis, 1968; Kaliner et al., 1971). The present
study was designed to establish whether such interaction could be demonstrated in vivo in
man. We studied the effects of inhaled isoprenaline and intravenous aminophylline on the
airways and on heart rate. The level of cyclic AMP in plasma was also measured as it has
been described as a convenient index of effects of drugs on tissue levels of cyclic AMP (Ball
et al., 1972; Karlberg et al., 1974; Wehman et al., 1974).
Our demonstration of the synergistic interaction between a beta-adrenergic stimulant and a
methyl xanthine on the airways of man in vivo supports the concept that cyclic AMP may
participate in the events leading to bronchodilatation and provides a rationale for their
combined use in the treatment of asthma.

ADITIF
Even though none of the observed drug-interactions in this study had statistically significant
association with risk of bleeding many other studies reported NSADs interacting with
warfarin associated with increased risk of serious bleeding [8,21,34-38]. For instance, the
combined use of warfarin and aspirin vs. warfarin alone was 4.5 (95% CI: 1.1–18.1) in a
study by Gasse et al. [8]. Likewise, there were a 13-fold (95% confidence interval, 6.3 to
25.7) increase in the risk of developing hemorrhagic peptic ulcer disease in concurrent users
of oral anticoagulants and NSAIDs in another study [38]. Some antibiotics were also reported
to increase risk of warfarin bleeding. Fischer et al. [39] found ciprofloxacin and
cotrimoxazole associated with increased risk of upper gastrointestinal tract hemorrhage.
Compared with the use of warfarin alone, the use of either cephalosporins (OR 1.157; 95%
CI, 1.043-1.285) or metronidazole (OR 1.578; 95% CI, 1.321-1.886) were associated with
increased risk of hemorrhage, whereas the risk of hemorrhage was not greater with
concomitant use of NSAIDs as reported by Zhang et al. [3]. In this study, the small sample
size as compared to the above studies might have contributed for the lack of statistically
significant association between the type of drug interaction and observed treatment outcomes.
In this study, drug-drug interactions were prevalent. Commonly co-prescribed drugs
interacting with warfarin were antibiotics, anticoagulant, diuretics and NSAIDs. Bleeding
complications were significantly associated with increased INR value. Clinicians should give
attention to potential drug interaction while prescribing drugs in patients with warfarin.
Frequent monitoring of INR value is vital to predict treatment outcome of patients on
warfarin. Patients should also be counseled about drug interactions, sign and symptoms of
warfarin related bleeding complications.

ADITIF
In the companion study to this report, Harris et al.25 have shown that in humans, there is
indeed no synergism between propofol and sevoflurane for immobility and loss of
consciousness. Instead, the two anesthetics were shown to be additive. In this study, we have
also shown that these two general anesthetics are additive in their actions on GABAA
receptors, the most common fast inhibitory neurotransmitter receptor in both the brain and the
spinal cord, sites thought to be critical for loss of consciousness and immobility, respectively.
Propofol and sevoflurane interact in a simple additive manner to produce LOC and
immobility to surgical incision, suggesting a common mechanism or a single site of action.
These clinical observations are consistent with a single site of interaction at the -aminobutyric
acid type A receptor.
This study has shown that propofol and sevoflurane produce sedation (LOC) and immobility
to surgical stimulation (MAC/Cp50INC) that are predictable from their individual potencies
(simple additivity) for each distinct pharmacologic end point. No suggestion of synergistic
action between the two anesthetics was found for either response, suggesting that both drugs
operate through a common mechanism. This study cannot specifically determine whether the
two anesthetics interact at a single site, different drug thresholds at a single site, multiple sites
on the same receptor, or on separate receptors producing these two responses. These results
are also consistent with the companion article demonstrating additivity at the -aminobutyric
acid type A receptor for these two agents in vitro at clinically relevant concentrations.29

ADITIF
Cisatracurium has a similar neuromuscular blocking profile to atracurium but has less
propensity to release histamine. Isobolographic analysis demonstrated synergistic interactions
with respect to the neuromuscular blocking activity of the cisatracurium and mivacurium,
vecuronium or rocuronium combinations but additive interaction between cisatracurium and
atracurium. In the present study, the combination of cisatracurium and atracurium was found
to be additive, probably because their chemical structures are similar.