[INFO] Interaksi Obat

[Forte]

INTERAKSI OBAT
Created by : Hedi Kasmanto, S.Farm.,Apt.

Untuk thread ini, saya akan mencoba membahas mengenai permasalahan interaksi obat.
Interaksi obat saya anggap cukup penting untuk diperhatikan namun cenderung terlupakan karena banyak terlalu fokus pada penyakit yang kompleks sehingga melupakan obat2 tersebut dapat berinteraksi satu dengan yang lain.

Interaksi obat kerap terjadi akibat penggunaan banyak obat, sehingga membahayakan nyawa pasien itu sendiri.

Interaksi yang kerap terjadi biasanya adalah interaksi farmakodinamik dan interaksi farmakokinetik.
Farmakodinamik dapat diartikan efek obat terhadap tubuh sedangkan farmakokinetik adalah nasib obat dalam tubuh.

Contoh interaksi farmakodinamik adalah interaksi antara 2 atau lebih obat yang mengakibatkan adanya kompetensi dalam pendudukan reseptor sehingga meniadakan salah satu efek dari obat yang digunakan.
Sedangkan contoh dari interaksi farmakokinetik adalah interaksi yang 2 obat atau lebih yang mengakibatkan obat tertentu cepat dibuang dalam tubuh atau lambat dibuang dalam tubuh, akibatnya waktu paruh obat menjadi berbeda dari biasanya.

Akibat dari interaksi obat :
- Efek Sinergis : 1 + 1 = 10
Obat A dan obat B digunakan bersamaan sehingga memberikan efek yang berlipat2
- Efek Antagonis : 1 + 1 = 1
Obat A dan obat B digunakan bersamaan sehingga memberikan efek meniadakan salah satu dari efek obat
- Efek Additif : 1 + 1 = 2
Obat A dan obat B digunakan bersamaan sehingga memberikan efek ganda.

Dalam menyikapi interaksi obat ini, hal2 yang perlu diakali adalah cara pencegahan terjadinya interaksi dengan "memainkan" waktu pemberian obat, misal Obat A diberikan pada jam 8 dan obat B diberikan pada jam 12.
Ada juga teknik2 lain dalam mengakali adalah meningkatkan / menurunkan dosis pemberian obat ketika waktu pemberian obat tidak dapat diubah. Misal dosis obat A karena dapat dinetralkan oleh obat B maka dosis obat A diberikan berlebih

Demikian penjelasan mengenai interaksi obat, jika ada rekan2 sedhamma yang ingin menanyakan resep obat yang diberikan berinteraksi atau tidak, bisa menggunakan thread ini.
 

   

[Forte]

Ini ada sedikit pengetahuan dasar mengenai DDI. Setelah saya baca.. lumayan bagus dan gampang dimengerti.. makanya saya share di sini.
Dalam hal ini dijelaskan interaksi obat yang melibatkan interaksi farmakokinetika dan farmakodinamika.

Untuk calon arahat dan nobby_ta ketika meresepkan obat.. bisa juga memperhatikan hal2 di bawah ini..
Untuk yang lain, ingat2 jika ada dapat obat yang tertulis di bawah ini.. Semoga bermanfaat.

 
Background and Introduction

Finding the most appropriate medication regimen for our patients is a difficult task. Patients often require multiple medications placing them at risk for drug-drug interactions (DDIs), a situation that occurs when 1 of a combination of drugs alters the effect of another drug. Drug-drug interactions may result in decreased therapeutic benefit, adverse effects, or patient harm. The frequency of potential DDIs was estimated to be from 6.2% to 6.7% per year using prescription drug claims data from 2 large health plans.[2] Another study estimated 374,000 plan participants were exposed to clinically important potential DDIs utilizing pharmacy drug claims data for nearly 46 million participants in a pharmacy benefit management organization over a 25-month period.[3] A review of 4 drugs -- warfarin, digoxin, cyclosporine, and simvastatin/ lovastatin -- found that an estimated 1.3-2.7 million insured adults were prescribed a potentially interacting combination.[5] Non-prescription medications, herbal preparations, and complementary medications also contribute to patient polypharmacy and the potential for DDIs.

This activity will provide the clinician with a basic understanding of the most common types of DDIs. In addition, the activity will provide a general overview of DDI mechanisms and strategies to help the clinician identify, prevent, and manage DDIs.

DDIs contribute to patient morbidity and may cause emergency department visits, hospitalizations, and re-admissions.[6,7] Examples of patient morbidity caused by DDIs include gastrointestinal (GI) bleeding, renal dysfunction, electrolyte imbalance, hypertension, hypotension, bradycardia, arrhythmia, drug toxicity, and decreased drug effect.[6-8] Juurlink and colleagues[8] performed 3 population-based, nested case-control studies to evaluate whether elderly patients taking glyburide, digoxin, or an angiotensin-converting enzyme inhibitor (ACEI) who were admitted with drug toxicity had been prescribed an interacting agent within the previous week. They found that patients on glyburide admitted for hypoglycemia were 6 times more likely to have been treated with sulfamethoxazole/ trimethoprim (SMX/TMP). Patients admitted for digoxin toxicity were 12 times more likely to have been started on clarithromycin in the previous week. Patients on ACEIs were 20 times more likely to have been started on a potassium-sparing diuretic in the previous week.

Certain medications have been removed from the market due to patient morbidity and mortality caused as result of DDIs. Development of the dangerous arrhythmia, torsades de pointes (TdP), resulted in death in several instances. Examples from the literature of mortality associated with DDIs include ciprofloxacin in fatal seizures,[9] moclobemide-clomipramine overdose in fatal serotonin syndrome,[10] and fatal outcome from a warfarin and nonsteroidal anti-inflammatory drug (NSAID) interaction.[11] Other examples are fatal interactions between tranylcypromine and imipramine,[12] and also between methotrexate and trimethoprim.[13] Terfenadine, astemizole, and grepafloxacin are examples of drugs taken off the market due to the risk of TdP arrhythmias caused by DDIs.[14] Removal of drugs from the market will eliminate the risk of DDIs in certain situations. Unfortunately, the elimination of all risk is impossible due to, in part, the lack of suitable drug alternatives. Many clinicians have witnessed patient harm caused by DDIs,[15] and many interactions that have caused hospital admission for toxicity could have been avoided. However, in many cases knowledge of DDIs is lacking.[15,16]
DDI Risk Factors to Identify in Practice

Our most complex patients are at highest risk for DDIs. Polypharmacy, narrow therapeutic range of the medication, decreased hepatic and/or renal function of the patient each may increase the risk for DDIs. Each may be identified prior to coadministration. One should consider the potential for DDIs at all steps of the drug-delivery process. In a retrospective review of patients admitted to the emergency department, patients taking 3 or more medications or patients who were 50 years or older taking 2 or more medications had a considerable risk for DDIs.[17] Furthermore, an increasing number of medications administered further increased the risk for adverse effects. Patients taking 2 medications had a 13% risk while patients taking 5 medications had a 38% risk for DDIs. Patients taking 7 or more medications had an 82% risk of developing adverse drug interactions.

Advanced age is an additional risk factor for DDIs. Aparasu and colleagues[4] found that the risk for DDIs increases significantly after 44 years of age and is greatest for patients over 74 years of age. The need for multiple medications often arises with advancing age that may further the risk for DDIs. Almost 25% of the elderly outpatients referred to a diagnostic clinic in The Netherlands for decreased cognition, functional dependence, or both who were taking more than 1 medication were found to have potential adverse effects or decreased drug effect possibly due to a DDI.[4] In general, when multiple medications are prescribed in the elderly population, the risk for DDIs increases exponentially.[18]

Other patient-related risks for DDIs noted below, include very young age, female sex, genetics, decreased organ function, use of a medication having a narrow therapeutic range (eg, warfarin, digoxin, and cyclosporine), major organ impairment, metabolic or endocrine risk conditions (eg, hypothyroidism, hypoproteinemia), and acute medical issues (eg, dehydration).[4,6,17-19]
Patient-Related Risks for Drug-Drug Interactions

    * Acute medical condition (eg, dehydration, infection);

    * Age extremes (ie, the very young and the elderly);

    * Decreased renal/ hepatic function;

    * Female sex;

    * Metabolic or endocrine condition (eg, obesity, hypothyroidism);

    * Multiple medication use;

    * Narrow therapeutic range of medication; and

    * Pharmacogenetics.

Non-patient factors may also affect the risk for DDIs. For example, an increasing number of clinicians or pharmacists involved with the dispensing of medication may increase the risk for DDI. Risk may also increase when computer alerts are too frequent or too infrequent. Pharmacy work flow, and work load also may influence risk of DDIs.[20]

DDIs should be considered at each step of the drug-delivery process. All members of the healthcare team should consider the risk for DDIs when a new medication is prescribed, dispensed, or administered to a patient.


Drug Class Effects and Drug-Drug Interaction Capabilities

Many clinicians have been confronted with the assumption that "all azoles" or "all statins" should be avoided in certain situations. All members of a drug class, however, should not be assumed to have the same DDI capabilities. Such assumptions may ultimately result in providing the patient with a potentially less suitable agent or increasing unnecessary monitoring.[21] For example, erythromycin and clarithromycin may interfere with carbamazepine metabolism and cause increased carbamazepine concentrations. In contrast, azithromycin does not interfere with carbamazepine metabolism.

Alerts in computer software are intended to notify clinicians of potential DDIs, yet such alerts can contribute to the class effect assumption of DDIs.[21] False-positive results may contribute to clinician desensitization of computer alerts, making them prone to over-riding alerts and missing clinically important interactions.[16,21] Clinicians should use alternative DDI resources when confronted with an alert possibly based on a class effect to make clinical decisions on use of the regimen or therapeutic alternatives.[21]

Interpatient Variability Contributes to Drug-Drug Interactions

Patient- and situation-specific factors, such as with patient-specific medication timing, can contribute to DDIs. For example, initiation, discontinuation, or dosage adjustment of thyroid replacement in the patient stabilized on warfarin requires increased INR monitoring due to the potential for altered warfarin effect. When thyroid replacement therapy is added to patients stabilized on warfarin, the warfarin effect may be increased, potentially resulting in overanticoagulation. Conversely, when thyroid medication is discontinued from a patient receiving stable warfarin therapy, the warfarin dosage may need to be gradually adjusted upward to account for a decrease in the anticoagulant effects. Warfarin anticoagulation may be challenging in patients with complex medical states. Patient situations that may influence the anticoagulant effect of warfarin include decreased hepatic function, decreased oral intake, or active infection. Other factors include patient pharmacogenetics, diet, and the narrow therapeutic range of warfarin.[22] DDIs may be particularly difficult to identify in patients with complex medical states and regimens requiring therapeutic adjustment.[23] However, if warfarin is added to the patient already stabilized on thyroid replacement, it is likely that only usual warfarin management will be required.[24]

Patient-specific drug dosing requirements may contribute to DDIs. For example, the ability of fluconazole to inhibit metabolism of certain medications increases with increasing dose.[25] Therefore, the patient requiring single-dose fluconazole is less likely to encounter significant DDIs than the patient requiring daily-dose fluconazole.

Finally, clinicians should consider the possibility that a DDI may occur -- even if statistically rare. As Horn and Hansten[23] explain , a 1 in 1000 incidence of a DDI-induced adverse event requires the observation of 3000 patients on the same regimen to have a 95% likelihood of observing the adverse event.

Gastrointestinal Absorption and Drug-Drug Interactions

When considering potential DDIs caused by interference with gastrointestinal (GI) absorption, in general quinolones should not be coadministered with cations at the same time (eg. iron, calcium, magnesium, aluminum), due to possible chelation in the GI tract. Instead, the drugs should be administered separately by at least 2 hours.[28] Coadministration of proton pump inhibitors should be avoided with ketoconazole because ketoconazole requires an acidic media for absorption.[25] Increased GI motility caused by metoclopramide may decrease absorption of cefprozil by decreasing the cefprozil GI transit time.[29] The interaction between fluoxetine and metoprolol is not due to interference with GI absorption. Fluoxetine may increase the concentration of metoprolol due to decreased metoprolol metabolism.[25]

A DDI such as those described due to interference with the absorption, distribution, metabolism, and elimination resulting in change of drug concentration is termed a pharmacokinetic interaction.[30] In addition to GI absorption interactions as described above, DDIs may also occur due to distribution interactions (eg, alterations in plasma protein binding) elimination interactions (eg, altered renal excretion), and metabolism interactions. Metabolism, particularly via the cytochrome P450 system (CYP) found predominantly in the liver, is the cornerstone of drug biotransformation.[30] Table 1 describes types of pharmacokinetic drug interactions and provides examples of each.

[Forte]

Drug Metabolism Effects

The concentration of a substrate, such as a drug metabolized by the cytochrome P450 enzyme system, may be affected by an inhibitor, such as a drug that reduces the activity of the same enzyme system, or an inducer, for example a drug that increases activity of the same enzyme system.[31] The opening patient case illustrates the consequence of coadministration of simvastatin, a substrate of CYP3A4, with itraconazole, a CYP3A4 inhibitor. Simvastatin is hydrolyzed to an active metabolite, simvastatin acid, and oxidized to inactive metabolites by CYP3A4 during first-pass metabolism in the intestinal wall and liver. CYP3A4 inhibition by itraconazole results in higher concentrations of simvastatin and an elevation of simvastatin acid levels.[28] This accumulation may result in adverse effects, including the development of rhabdomyolysis.

Drug biotransformation occurs by phase I reactions (oxidation, reduction, hydrolysis) and phase II reactions (conjugation). The resulting metabolite is highly polar and more easily eliminated. The cytochrome P-450 (CYP) system of enzymes is located in the endoplasmic reticulum of many cells, typically in the liver, and is primarily responsible for phase I oxidation.[19] The CYP system consists of superfamilies with over 100 types of enzymes, which are named by convention as follows using the example of CYP3A4: CYP (cytochrome P450), 3 (refers to family 3), A (refers to subfamily A), and 4 (designates gene number 4) (Figure 1). However, only a few enzymes (eg, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) are responsible for the majority of drug biotransformation.[25,30] CYP3A4 is the enzyme responsible for the majority of drug biotransformation.[30] Not only are many drugs substrates of CYP 3A4, but drugs may also inhibit or induce this or other CYP enzymes.[25,29]




    Figure 1. Cytochrome P450 nomenclature.[25]

The majority of reported drug interactions may be due to drug metabolism inhibition.[28] The CYP system is subject to genetic polymorphism, making some patients more prone to DDIs than others.[25] Many CYP enzymes are involved in biotransformation and multiple examples of substrates, inhibitors, and inducers are available for reference (Table 2).[26] A more complete listing including genetic references is available for clinicians from Flockhart.[27] Of note, the clinician should also be aware that several medications that may affect the CYP system appreciably are available over-the-counter (eg, omeprazole, cimetidine).





    Figure 2. Drugs metabolized by known P450s

Many references are available to assist the clinician with this complex topic of the cytochrome P450 enzyme system.[19,28,30,32]

Pharmacodynamic Interactions May Cause Drug-Drug Interactions

Pharmacodynamic interactions may occur due to overlapping pharmacologic effects, exemplified by interactions of warfarin - naproxen, amiodarone - levofloxacin, and lisinopril - spironolactone.[30] Bleeding risk may be augmented in the patient taking warfarin, which inhibits vitamin K-dependent clotting factors, and who is also taking NSAIDs, which may inhibit platelet function and/or cause development of gastric erosions. Both amiodarone and levofloxacin may independently cause prolongation of the QTc interval. Coadministration could theoretically lead to the development of the serious and potentially life-threatening arrhythmia, torsades de pointes. Hyperkalemia caused by ACEIs may be augmented by potassium-sparing diuretics. The interaction between rifampin and hormones is not an example of a pharmacodynamic interaction, but of metabolism. Rifampin may increase metabolism of estrogen/progestin medications via CYP induction, causing decreased efficacy.[25]

As illustrated in the discussion above, pharmacodynamic interactions may cause additive effects. However, pharmacodynamic interactions may also cause antagonistic effects. For example, the hypertensive effect of NSAIDs may decrease the antihypertensive effect of ACEIs.[25] Anticholinergic medications, such as oxybutynin, may antagonize the effect of cholinesterase inhibitors, such as donepezil resulting in decreased cognition.[33]

Transporter Protein Interactions Contribute to Drug-Drug Interactions

Drug transporters have emerged as an important contributor to DDIs. P-glycoprotein, PGP, is the drug transporter for which the most DDI information is available. This adenosine triphosphate (ATP)-dependent efflux pump is found in the small intestines, kidney, liver, blood-brain barrier, testes, uterus, and placenta.[19,30] By transporting drugs across cell membranes, PGP reduces drug absorption, promotes drug removal, and decreases drug entry.[30] Like the CYP system, PGP has substrates, inhibitors, and inducers (Table 3).[25,30] In the example given, digoxin is eliminated unchanged by renal and biliary secretion. However, digoxin is a substrate of PGP, and its elimination may be affected by PGP inhibitors or inducers, (Table 3).[30] In addition, drugs may be metabolized by both systems, P450 and PGP, because of common substrates (eg, diltiazem), inhibitors (eg, erythromycin), and inducers (eg, rifampin).[25]



To facilitate the understanding and management of DDIs, drug interaction classifications are often used. The OpeRational ClassificAtion of drug interactions (ORCA)[34] is a system designed by the Drug Interaction Foundation that designates DDIs based on the management of the interaction (Table 4). For purposes of this activity, classes 1-3 will be reviewed.



Drug Combinations to Avoid

The combination of metronidazole and warfarin should usually be avoided because metronidazole (CYP2C9 inhibitor) may inhibit the metabolism of the more active S-isomer of warfarin causing an increased hypoprothrombinemic effect. The combination of repaglinide (CYP3A4 substrate) and diltiazem requires precautionary measures because diltiazem may inhibit the metabolism of repaglinide, causing an increased risk of hypoglycemia. Precautionary measures should be taken if phenobarbital is coadministered with simvastatin because phenobarbital (CYP3A4 inducer) may reduce the efficacy of hydroxymethylglutaryl coenzyme A (HMG-CoA) inhibitors. The combination of nitrates and phosphodiesterase type-5 inhibitors should be avoided due to risk of additive vasodilation causing severe hypotension and possible myocardial infarction.[35] Patient deaths have been reported.[36]

In the example above, the coadministration of nitroglycerin and sildenafil should be avoided because the risk outweighs the benefit.[25] Relatively few drug-drug combinations are those that should always be avoided. In most cases, suitable alternatives and management strategies are available to help minimize the risk of DDIs.

The combination of meperidine, a serotonergic agent, and phenelzine, a monoamine oxidase inhibitor, is an example of a combination that should be avoided due to risk for serotonin syndrome, a potentially serious condition causing symptoms such as mental status changes, agitation, hypertension, or even death.[37] The combination of ergot alkaloids and triptans should be avoided due to risk for excessive vasoconstriction[25] and coronary artery vasoconstriction.[38] However, the combination of simvastatin and amiodarone is an example that should usually be avoided, due to risk for decreased simvastatin (CYP3A4 substrate) metabolism by amiodarone and increased risk for myopathy.[25] In fact, the US Food and Drug Administration (FDA) recently sent out an alert to healthcare professionals warning of the risk for myopathy particularly when simvastatin doses greater than 20 mg are coadministered with amiodarone.[39]

The drug-drug combination that should usually be avoided is used in special situations when the benefit outweighs the risk. If an alternative agent is not available, the clinician should use precautionary measures such as laboratory monitoring and patient education to minimize the potential interaction. In the opening case, the coadministration of itraconazole and simvastatin resulted in rhabdomyolysis. Using this case as an example, many measures could be used to eliminate or minimize this interaction. For example, an HMG-CoA inhibitor other than simvastatin may be considered. Pravastatin (not metabolized via cytochrome P450), fluvastatin, or rosuvastatin (neither metabolized via CYP3A4) are all possibilities in this situation. Similarly, terbinafine (not a CYP3A4 inhibitor) could be considered for the antifungal agent instead of itraconazole. Another strategy is to discontinue simvastatin during the course of itraconazole therapy. Finally, it is imperative that the patient on this combination be educated about the risk for simvastatin and itraconazole coadministration and counseled on signs and symptoms of muscle pain and weakness and dark urine.[25]

Time course of a potential DDI is an important consideration. One may be able to consider the time of DDI onset, time of maximal clinical effect based on pharmacokinetic or pharmacodynamic parameters, when the patient may experience an adverse effect, and when the adverse effect may diminish.[28] Amiodarone may inhibit the metabolism of S-warfarin, resulting in an enhanced hypoprothrombinemic effect. Therefore, the INR should be monitored within 3-4 days after initiation of amiodarone. Warfarin dosing may need to be decreased by 30% to 50%. Patients should be educated about an increased risk of bleeding with this coadministration. Due to the very long half-life of amiodarone, the INR should be monitored for at least 8 weeks after initiation.[25]

In many situations, coadministration of 2 drugs that are known to interact is unavoidable and requires precautionary measures. If alternative agents are unavailable, the clinician should institute precautionary measures to reduce the risk for adverse effects.

[Forte]

Minimizing the Risks for Drug-Drug Interactions

Many reasons explain why prevalence and clinical significance of DDIs are underestimated by clinicians, as noted below.

Factors that contribute to underestimation of DDIs[23]:

    * DDIs may inhibit drug effect;

    * DDIs may mimic normal adverse effects;

    * DDIs may be difficult to identify due to patient factors; and

    * Outpatients may disrupt therapy -- making it difficult for prescribers to manage effectively.

Clinicians should not rely solely on memory, personal experience, or computerized software when assessing risk of drug interactions. Instead, clinicians should use computer software, compendia and other references in addition to their clinical expertise when making an assessment of DDI risk. Knowledge is key for the identification, prevention, and management of DDIs. Education is important for all those involved with medication administration and has been shown to decrease potential DDIs.[40]

Reporting of adverse DDIs to the FDA helps identify potentially harmful interactions. Based on information provided to them by practitioners, the FDA can determine the significance of the DDI and provide education to the healthcare industry. Therefore, the clinician should report adverse events associated with DDIs to the FDA Medwatch program whenever possible. More information is available at www.fda.gov/medwatch.

Juurlink[41] recommends several strategies to minimize the risk of DDIs. First, clinicians should make the study of DDIs a part of continuous professional development using review articles, continuing education, and bookmarked DDI websites if available. DDI review articles and websites available for the clinician are:

    * www.drug-interactions.com (P450-mediated drug interactions);

    * www.arizonacert.org (drug interactions);

    * www.hanstenandhorn.com; and

    * www.qtdrugs.org.

Additionally, technology may help reduce DDIs. For example, computerized physician order entry may reduce the risk for DDIs.[42]

Suggested technological strategies to reduce DDIs include[42]:

    * Electronic information sharing between medical offices and pharmacies;

    * DDI warnings that are patient-specific (ie, tailored to patient age, lab values, etc);

    * Identification and removal of trivial computer alerts from computer software;

    * Addition of timely updates on actual and/or potential DDIs;

    * Removal of inappropriate DDI warnings within an entire class (eg, statins);

    * Access to further DDI information;

    * Suggestion of therapeutic alternative; and

    * Increased difficulty of the override function based on DDI severity.

The patient also plays a part in minimizing the risk of DDIs. Prescribers, pharmacists, and nurses should communicate to the patient any risk of DDIs and reinforce the importance of monitoring for signs and symptoms of DDIs. If necessary, tools (eg, pillbox) should be considered for the patient who might have risk factors for DDIs. Finally, patients should be aware of strategies they can use for DDI risk reduction, such as using a single pharmacy for all medication needs as noted below:[43]

    * Use 1 pharmacy to fill all your prescriptions;

    * Read all drug labels;

    * Learn about the warnings for all your medications;

    * Alert all of your provider about your medications including all prescription drugs, over-the-counter (OTC) drugs, and dietary supplements (including herbals);

    * Keep complete records of all of your medications and carry a list in your wallet or purse. Make sure a family member knows where you keep your medication records;

    * Ask your doctor and pharmacist whether you should avoid any other medications, foods, or beverages when you are prescribed a new medication;

    * Remind your provider about the medications you are taking when you are prescribed a new medication; and

    * Ask your provider or pharmacist about the potential of DDIs before taking any new OTC drug or dietary supplement.


Conclusion

DDIs are preventable medication errors that may cause serious adverse effects. With knowledge and tools, the clinician can anticipate the potential for DDIs and institute preventative or management strategies, and educate the patient. These proactive measures may help reduce the incidence of adverse patient outcomes caused by DDIs.

Assessment: Measuring Educational Impact