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 tetrasik tetrasiklin lin dan mengga menggangg nggu u absorp absorpsiny sinyaa ke dalam dalam aliran aliran darah, darah, sehingg sehinggaa mengur mengurang angii 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.
eaksi Obat Aditif eaksi obat aditif terjadi ketika efek kombinasi dari dua obat yang sama dengan jumlah masing-masing obat yang diberikan tunggal. !isalnya, mengkonsumsi obat heparin dengan alkohol akan meningkatkan perdarahan. "ersamaan 1 # 1 $ % kadang-kadang digunakan untuk menggambarkan efek aditif obat.
eaksi Obat Sinergis Sinergisme obat terjadi ketika obat berinteraksi satu sama lain dan menghasilkan efek yang lebih besar daripada jumlah aksi masing-masingnya. "ersamaan 1 # 1 $ & dapat digunakan untuk untuk menggambar menggambarkan kan sinergisme. sinergisme. 'ontoh 'ontoh dari sinergisme sinergisme obat adalah ketika seseorang mengkonsumsi baik hipnotik dan alkohol. (etika alkohol dikonsumsi bersamaan atau sesaat sebel sebelum um atau atau setela setelah h hipn hipnot otik ik diko dikons nsum umsi, si, aksi aksi hipn hipnot otik ik meni mening ngka kat. t. Oran Orang g terse tersebu butt mengala mengalami mi efek obat obat yang yang lebih lebih besar besar daripa daripada da jika jika obat obat dikons dikonsum umsi si tungga tunggal. l. Seseka Sesekali, li, terjadinya efek obat sinergis serius dan bahkan fatal.
eaksi Obat Antagonis eaksi obat antagonis terjadi ketika satu obat mengganggu dengan aksi lain, menyebabkan netrali netralisasi sasi atau atau penuru penurunan nan efek efek satu satu obat. obat. Sebaga Sebagaii contoh contoh,, protam protamine ine sulfat sulfat merupa merupakan kan antagonis heparin. Ini berarti bah)a pemberian protamine sulfat sepenuhnya menetralkan efek heparin dalam tubuh.
oach, oach, Sally S. %*1*. %*1*. Introductory Introductory 'linical 'linical "harmacology "harmacology.+ .+ th dition. dition. nitedState nitedStatess of America /ippincott 0illiams 0ilkins.
A23A4O2IS 2apro5en interfered )ith the irreversible inhibitory effect of aspirin on platelet 'O6-1 activity in vitro and e5 vivo. 3his effect )as undetectable during the continuous and regular administration of an antiinflammatory dose of napro5en 78** mg 9I:; and lo)-dose aspirin because napro5en can mimic the inhibitory effect of aspirin on platelet 36A% generation.
A23A4O2IS (oopmans et al. 71>; carried out an open-label trial of ? patients to @uantify the increase in blood pressure in subjects treated )ith the diuretic hydrochlorothiaide 8* mg daily concomitant to four )eeks of ibuprofen >** mg every ? hours, diclofenac %8 mg three times a day, or sulindac %** mg every 1% hours. A significant rise in systolic blood pressure )as observed in the patients treated )ith ibuprofen, though the authors concluded that these three 2SAI:s can be used )ithout risk in patients treated )ith hydrochlorothiaide B provided careful careful blood blood pressu pressure re monito monitoria riatio tion n is carried carried out on introd introduci ucing ng 2SAI: 2SAI: treatme treatment. nt. 4ur)it et al. 718; conducted a randomied, double-blind and placebo-controlled clinical trial of %% patients over C8 years of age. All the subjects )ere receiving antihypertensive treatment )ith the diuretic hydrochlorothiaide, and )ere subjected to alternating four-)eek periods of treatment )ith ibuprofen C** mg every ? hours or placebo. 3he authors concluded that in elderly patients treated )ith hydrochlorothiaide, ibuprofen induces a significantly greater increase in blood pressure than placebo, and that ibuprofen may negatively affect high blood pressure control in elderly individuals. 3he interaction of ibuprofen )ith the diuretic furosemide has been described in t)o isolated and independent cases involving ibuprofen doses of >** mg every ? hours and C** mg four times a day, respectively 71C,1+;. In comparison, the interaction of furosemide )ith the 2SAI: indomethacin has been )ell documented in different studies 71?,1D;.
A23A4O2IS "rotamine has long been used in conjunction )ith heparin therapy. At the suggestion of "rofessor '. <. 9est, in 1D&+ I undertook a study on the practical use of proE tamine as a
heparin heparin antagonist antagonist,, after the demonstratio demonstrations ns by A. Fischer1 that basic proteins proteins could hinder hinder the antico anticoagu agulan lantt activity activity of heparin heparin and by 'harg 'hargaff aff and Olson% Olson% that that protam protamine ine )as particularly effective. Our studies demonstrated t)o uses for this property of protamine. 3he first? )as neutraliation 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 )as kno)n as protamine titration and has since been )idely used by hematologists and others. Since an e5cess of protamine sho)s anticoagulant properties )hen added to blood samples, the minimal amount of protamine re@uired to bring the clotting time to a normal value provides a measure of the amount of heparin present in the blood sample. 3he second use of protamine, as demonstrated by Ga@ues, 'harles and 9est,> )as to reduce hypocoagulability due to heparin by its injection into the circulation, kno)n as protamine neutraliation. "rotamine is still the chief agent available for neutraliing heparin. Applied to the titration of the anticoagulant action of heparin in vitro, it provides a useful means of diagnosis of hemorrhagic states. 3he 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. :irect determination in vitro in the operating room of the amount of protamine re@uired to neutralie the heparin present in the patientHs blood can provide an e@uivalence figure figure applica applicable ble to the patient patient.. 7In additi addition, on, it may demonstra demonstrate te the presen presence ce of such such problems as rapid fibrinolysis.; 9ecause of the variability in heparin preparations 7probably related to difficulties of standardiation;, figures for the heparin e@uivalent of protamine preparations are of limited value. 3herefore, it is )iser, )hen a titration on the blood is not done, to depend on a rule-of-thumb dosage such as not more than 1.* mg.1** S" units of hepa heparin rin.. 3his 3his is to be inje injecte cted d slo) slo)ly ly in divi divide ded d dose doses, s, stopp stoppin ing g the the injec injecti tion on )hen )hen hemostasis is achieved. 3he amount should be reduced in proportion to the time )hich has elapsed since the last heparin administration 7by about 1 mg.min. for the average patient;. In using protamine to neutralie heparin after e5tensive and prolonged operations, no simple rule of protamine-heparin e@uivalence )ill suffice to ensure that hemostasis )ill al)ays be instantly achieved. 0hen hemostasis is not effected it is essential to appreciate the many contributing factors and assess their significance for the patient.
SI24IS 'ombining an angiotensin-converting enyme inhibitor 7A'-I; and angiotensin II receptor blocker 7A9; lo)ers blood pressure 79"; by >& mm
although this additive effect may be abolished )ith ma5imal monotherapy dosing. 3he recent O23 O23A43 43 study study sho) sho)ed ed no redu reduct ctio ion n in prim primary ary outc outcom omes es )hen )hen an A'-I '-I-A -A9 9 combination )as compared to an A'-I alone, despite %.>1.> mm
% mm
SI24IS 3he role of fi5ed-dose combinations in chronic pain management using tramadolparacetamol as an e5ampl e5amplee J 3rama 3ramadol dol"a "arace racetam tamol ol may offer offer distin distinct ct advant advantage agess in certain certain patient patient populations and for certain types of pain, compared )ith high doses of 2SAI:s or paracetamol or )hen 2SAI:s or paracetamol are e5pected to be used for long durations.
SI24IS 3he antino antinocice cicepti ption on induce induced d by the intrape intraperit ritone oneal al coadmi coadminist nistrat ration ion of combin combinati ations ons of paracetamol )ith the nonsteroidal antiinflammatory drugs 72SAI:s; diclofenac, ibuprofen, ketoprofen, ketoprofen, melo5icam, melo5icam, metamiol, metamiol, napro5en, napro5en, nimesulide, pareco5ib and piro5icam piro5icam )as studied by isobolographic analysis in the acetic acid abdominal constriction test of mice 7)rithing test;. 3he effective dose that produced 8*K antinociception 7:8*; )as calculated from the log doseBresponse curves of fi5ed ratio combinations of paracetamol )ith each 2SAI:. 9y isobolographic analysis, this :8* )as compared to the theoretical additive
:8* calculated from the :8* of paracetamol and of each 2SAI: alone obtained from :8* doseBresponse curves. As sho)n by isobolographic analysis, all the combinations )ere synerg synergist istic, ic, the e5perim e5periment ental al :8*s :8*s being being signif significan icantly tly smaller smaller than than the theoret theoretical ically ly calcu calculat lated ed :8* :8*s. s. 3he 3he resu result ltss of this this study study demo demons nstra trate te pote potent nt inter interact actio ions ns bet) bet)ee een n paracetamol and 2SAI:s and validate the clinical c linical use of combinations of these drugs in the treatment of pain conditions. In conclusion, the data of the present study demonstrated that paracetamol combined )ith 2SAI:s produces a supra-additive or synergic analgesic effect. It may be noted noted that the doses of paracetamol and 2SAI:s are very small and if they are compared )ith those referred in the literature, it is possible to suggest that the combinations of paracetamol and 2SAI:s )ill be effective for the clinical treatment tr eatment of pain. In addition, it is demonstrated that the effect of the combin combinati ations ons paracet paracetamo amol2 l2SAI SAI:s :s is superio superiorr to that that of either either compon component ent alone. alone. 3herefore, these mi5tures are a viable alternative to clinical pain management, especially because the lo) doses of the components may be a potential inde5 of lo)er incidence of adverse effects.
SI24IS It is common practice to use beta-adrenergic stimulants and methyl 5anthines in the treatment of bronchial asthma. 3he studies of obison et al. 71D+1; suggest that the beta-adrenergic effects of catecholamines are mediated through &H8H cyclic adenosine monophosphate 7cyclic A!";, the intracellular Hsecond messengerH. !ethyl 5anthines inhibit phosphodiesterase, the enyme )hich inactivates cyclic A!" 79utcher and Sutherland, 1DC%;, and it is proposed 7/eadi 7/eading ng article, article, 1D+*; 1D+*; that methy methyll 5anthi 5anthines nes and beta-ad beta-adrene renergi rgicc agents agents may produc producee bronchodilatation by increasing the level of cyclic A!" in bronchial and bronchiolar smooth muscle. :rugs )hich individually act at different points in the metabolic path)ay of a compound in such a )ay as to increase the amount of that compound may, )hen used together, produce an increase greater than the sum of the increases produced H"resent address espir espirato atory ry :epart :epartmen ment, t, 9risto 9ristoll oyal oyal Infirm Infirmary ary Hnive Hniversit rsity y :epartm :epartment ent of "athol "athology ogy,, dinburgh by each drug alone, that is, they may interact synergistically 7Leldstra, 1D8C;. 3here is evidence in vitro for synergy bet)een beta-adrenergic agents and methyl 5anthines 7all and 0est, 1DC&M /ichtenstein and !argolis, 1DC?M (aliner et al., 1D+1;. 3he present study )as designed to establish )hether such interaction could be demonstrated in vivo in man. 0e studied the effects of inhaled isoprenaline and intravenous aminophylline on the air)ays and on heart rate. 3he level of cyclic A!" in plasma )as also measured as it has
been described as a convenient inde5 of effects of drugs on tissue levels le vels of cyclic c yclic A!" 79all et al., 1D+%M (arlberg et al., 1D+>M 0ehman 0ehman et al., 1D+>;. Our demonstration of the synergistic interaction bet)een a beta-adrenergic stimulant and a methyl 5anthine on the air)ays of man in vivo supports the concept that cyclic A!" may participate in the events leading to bronchodilatation and provides a rationale for their combined use in the treatment of asthma.
A:I3IF ven though none of the observed drug-interactions in this study had statistically significant associat association ion )ith )ith risk of bleedi bleeding ng many many other other studie studiess report reported ed 2SA:s 2SA:s interac interactin ting g )ith )ith )arfarin associated )ith increased risk of serious bleeding N?,%1,&>-&?. For instance, the combined use of )arfarin and aspirin vs. )arfarin alone )as >.8 7D8K 'I 1.1B1?.1; in a study by 4asse et al. N?. /ike)ise, there )ere a 1&-fold 7D8K confidence interval, C.& to %8.+; increase in the risk of developing hemorrhagic peptic ulcer disease in concurrent users of oral anticoagulants and 2SAI:s in another study N&?. Some antibiotics )ere also reported to incr increa ease se risk risk of )arf )arfar arin in blee bleedi ding ng.. Fisc Fische herr et al. al. N&D N&D foun found d cipr ciprof oflo lo5a 5aci cin n and and cotrimo5aol cotrimo5aolee associated associated )ith increased risk of upper gastrointestina gastrointestinall tract hemorrhage. hemorrhage. 'ompared )ith the use of )arfarin alone, the use of either cephalosporins 7O 1.18+M D8K 'I, 1.*>&-1.%?8; or metronidaole 7O 1.8+?M D8K 'I, 1.&%1-1.??C; )ere associated )ith incre increase ased d risk risk of hemo hemorrh rrhag age, e, )here )hereas as the the risk risk of hemor hemorrh rhag agee )as )as not not grea greater ter )ith )ith concomitant use of 2SAI:s as reported by Phang et al. N&. In this study, the small sample sie as compared to the above studies might have contributed for the lack of statistically significant association bet)een the type of drug interaction and observed treatment outcomes. In this this study study,, drug-d drug-drug rug interac interactio tions ns )ere )ere preval prevalent. ent. 'ommon 'ommonly ly co-pre co-prescri scribed bed drugs drugs interacting )ith )arfarin )ere antibiotics, anticoagulant, diuretics and 2SAI:s. 9leeding complications )ere significantly associated )ith increased I2 value. 'linicians should give attention to potential drug interaction )hile prescribing drugs in patients )ith )arfarin. Fre@ue Fre@uent nt monito monitoring ring of I2 value is vital vital to predic predictt treatmen treatmentt outcom outcomee of patien patients ts on )arfarin. "atients should also be counseled about drug interactions, sign and symptoms of )arfarin related bleeding complications.
A:I3IF In the companion study to this report,
consciousness. Instead, the t)o anesthetics )ere sho)n to be additive. In this study, )e have also sho)n that these t)o general anesthetics are additive in their actions on 4A9AA 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. "rop "ropof ofol ol and and sevo sevoflu fluran ranee inte interac ractt in a simp simple le addi additi tive ve mann manner er to prod produc ucee /O' /O' and and immobility immobility to surgical surgical incision, suggesting suggesting a common common mechanism mechanism or a single single site of action. action. 3hese clinical observations are consistent )ith a single site of interaction at the -aminobutyric acid type t ype A receptor. 3his study has sho)n that propofol and sevoflurane produce sedation 7/O'; and immobility to surgical stimulation 7!A''p8*I2'; that are predictable from their individual potencies 7simple additivity; for each distinct pharmacologic end point. 2o suggestion of synergistic action bet)een the t)o anesthetics )as found for either response, suggesting that both drugs operate through a common mechanism. 3his study cannot specifically determine )hether the t)o anesthetics interact at a single site, different drug thresholds at a single site, multiple sites on the same receptor, or on separate separate receptors receptors producing producing these t)o responses. 3hese results are also consistent )ith the companion article demonstratin demonstrating g additivity additivity at the -aminobutyric -aminobutyric acid type A receptor for these t)o agents in vitro at clinically relevant concentrations.%D
A:I3IF 'isatra 'isatracur curium ium has a similar similar neurom neuromuscu uscular lar blocki blocking ng profile profile to atracu atracurium rium but has less propensity to release histamine. Isobolographic analysis demonstrated s ynergistic interactions )ith respect to the neuromuscular blocking activity of the cisatracurium and mivacurium, vecuronium or rocuronium combinations but additive interaction bet)een cisatracurium and atracurium. In the present study, the combination of cisatracurium and atracurium )as found to be additive, probably because their chemical structures are similar.
