Polifarmasi

BAB 2

TINJAUAN PUSTAKA

Polifarmasi didefinisikan sebagai penggunaan bersamaan 5 macam atau lebih obat-obatan oleh pasien yang sama. Namun, polifarmasi tidak hanya berkaitan dengan jumlah obat yang dikonsumsi. Secara klinis, kriteria untuk mengidentifikasi polifarmasi meliputi (Terrie, 2004):

  1. Menggunakan obat-obatan tanpa indikasi yang jelas
  2. Menggunakan terapi yang sama untuk penyakit yang sama
  3. Penggunaan bersamaan obat-obatan yang berinteraksi
  4. Penggunaan obat dengan dosis yang tidak tepat
  5. Penggunaan obat-obatan lain untuk mengatasi efek samping obat.

Polifarmasi meningkatkan risiko interaksi antara obat dengan obat atau obat dengan penyakit. Populasi lanjut usia memiliki risiko terbesar karena adanya perubahan fisiologis yang terjadi dengan proses penuaan. Perubahan fisiologis ini, terutama menurunnya fungsi ginjal dan hepar, dapat menyebabkan perubahan proses farmakodinamik dan farmakokinetik obat tersebut (Terrie, 2004).

2.1 Farmakodinamik

Farmakodinamik menggambarkan efek obat terhadap tubuh. Sebagai contoh, Acetylsalycilyc acid (ASA) menghambat fungsi platelet sehingga memperpanjang waktu perdarahan. Oleh karena itu, perdarahan adalah efek farmakodinamik dari ASA.

2.1.1 Efek Samping Obat

Hal utama yang perlu diperhatikan dalam polifarmasi adalah risiko munculnya efek samping obat dan interaksi obat yang serius. Dalam beberapa kasus, memang diperlukan terapi dengan beberapa agen (Terrie, 2004).

Hasil penelitian menunjukkan bahwa lebih dari 75% efek samping obat yang menyebabkan pasien harus dirawat inap berhubungan dengan agen farmakologis dan sebagian karena monitoring yang tidak adekuat, peresepan yang kurang tepat, dan kurangnya edukasi dan kompliansi pasien. Penelitian juga menyatakan bahwa efek samping obat terjadi 6% pada pasien yang mendapat 2 macam obat, meningkat 50% pada pasien yang mengonsumsi 5 macam obat bersamaan, dan 100% ketika lebih dari 8 obat digunakan (Terrie, 2004).

Efek samping obat polifarmasi terutama timbul pada pasien tua. Hal ini dapat menyerupai sindrom geriatrik atau menyebabkan kebingungan, jatuh, inkontinensia, retensi urin, dan malaise. Efek samping ini menyebabkan dokter meresepkan obat lain untuk mengatasinya (Terrie, 2004).

Penelitian tidak dapat menunjukkan bahwa banyaknya penggunaan obat bersifat iatrogenik. Diagnosis klinis berkaitan dengan penyakit cenderung lebih kompleks pada orang tua, sehingga sulit untuk menentukan apakah gejala fisik dan psikis yang timbul merupakan bagian dari proses penuaan normal. Sulit untuk mengetahui apakah gejala yang timbul pada orang tua disebabkan oleh penghentian obat. Penghentian obat menyebabkan banyak gejala, seperti halusinasi dan kejang, yang perlu ditangani dengan obat-obatan baru. Hal ini menyebabkan pemberian polifarmasi. Untuk menghindari efek penghentian obat, semakin lama obat digunakan, semakin lambat penghentian penggunaannya. Dosisnya harus dikurangi setengah atau dua pertiganya. Setelah beberapa minggu atau bulan, perlu dilakukan penurunan dosis menjadi sepertiganya. Penghentian obat harus diturunkan dosisnya perlahan-lahan sampai dosis terkecil obat tersebut dapat ditinggalkan. Obat dengan masa kerja yang panjang, seperti benzodiazepine, memerlukan penghentian yang lama sekitar 6 bulan sampai 1 tahun atau lebih. Karena risiko efek samping obat meningkat dengan banyaknya obat yang dikonsumsi, penting untuk menghentikan terapi yang tidak efektif (Linjakumpu, 2003).

2.1.2 Interaksi Obat

Polifarmasi dan interaksi obat lebih sering terjadi dan lebih serius pada pasien tua. Secara keseluruhan, insiden polifarmasi sekitar 3-5% namun meningkat secara eksponensial dengan banyaknya obat yang dikonsumsi. Interaksi obat sering terjadi pada pasien tua dengan kondisi medis multipel. Interaksi obat menyebabkan kegagalan terapi atau efek samping obat. Inhibisi metabolik dapat meningkatkan kadar obat beberapa kali dengan konsekuensi yang serius (Standridge, et al.,2010).

2.1.2.1 Inhibisi

Obat-obatan saling berinteraksi dan dengan makanan serta ramuan herbal. Interaksi yang signifikan secara klinis terjadi pada obat-obatan yang sering digunakan, seperti warfarin, antibiotik, antidepresan, analgesik, dan HMG-CoA reductase inhibitors). Perubahan absorbsi obat terjadi karena pengikatan obat dalam saluran cerna, misalnya antasida mengganggu penyerapan tetrasiklin, perubahan pH lambung, gangguan flora usus, dan perubahan motilitas saluran cerna. Penurunan keasaman lambung dan melambatnya motilitas saluran cerna merupakan fenomena penuaan yang normal (Standridge, et al.,2010).

2.1.2.2 Potensiasi

Contoh interaksi farmakodinamik yang bersifat potensiasi atau saling menguatkan adalah sebagai berikut. Seorang pasien mengonsumsi ASA yang dibeli sendiri untuk rematiknya dan ginkgo biloba untuk memorinya. Pasien mengalami atrial fibrillation dan diresepi warfarin oleh kardiologisnya untuk mencegah terjadinya stroke. Pada kasus ini, ASA menghambat platelet dan warfarin mempengaruhi faktor pembekuan. Keduanya meningkatkan risiko perdarahan. Ginkgo biloba dosis tinggi juga meningkatkan perdarahan. Interaksi farmakodinamik obat-obatan ini menyebabkan perdarahan pada pasien (Lin, 2003).

2.1.2.3 Akumulasi

Pasien diabetes yang mendapat sulfonylureas, seperti glyburide, beresiko mengalami hipoglikemia ketika mengonsumsi antibiotik sulfonamide, karena obat ini menghambat metabolisme glyburide oleh sistem enzim cytochrome P450 2C9 (CYP 2C9). Toksisitas digoksin dapat timbul pada pasien yang diterapi dengan clarithromycin yang menghambat P-glycoprotein, sehingga meningkatkan renal clearance digoxin. Hiperkalemia banyak terjadi pada pasien yang diterapi dengan angiotensin-converting enzyme (ACE) inhibitors, dan penggunaan bersamaan dengan potassium-sparing diuretics dapat menyebabkan hyperkalemia yang mengancam nyawa (Juurlink, et al., 2003).

Metabolisme obat terutama terjadi di hepar melalui berbagai sistem enzim, seperti cytochrome P450 (CYP450). Suatu obat dapat menjadi inhibitor atau menginduksi jalur tertentu, dan menjadi substrat pada jalur lainnya. Eliminasi obat melalui ekskresi urin dapat dipengaruhi dengan menambahkan obat lainnya, mengubah glomerular filtration rate (GFR), sekresi tubulus, atau pH urin. Diuretik dapat menurunkan GFR sehingga meningkatkan kadar obat dalam serum (Standridge, et al.,2010).

2.2 Farmakokinetik

Linjakumpu, T. 2003. Drug use among the home-dwelling elderly. Oulun yliopisto. University of Oulu. ISBN 951-42-7102-5.

Standrigde JB, Zylstra LG, Miller KE, Ruiz DE, Simpson JD. 2010. Caring for Elderly Individual: Polypharmacy and Drug Interaction.http://www.researchresidency.com/goppert/FP2010/FP_Comprehensive/FP-E_297/section3_polypharmacy.html.

Terrie YC. 2004. Understanding and Managing Polypharmacy in the Elderly. http://www.pharmacytimes.com

Lin, P. 2003. Drug Interaction and Polypharmacy in the Elderly. The Canadian Alzheimer Disease Review, September 2003, p 10-14.

Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. 2003. Drug-Drug Interactions Among Elderly Patients Hospitalized for Drug Toxicity.JAMA. 2003;289(13):1652-1658. doi: 10.1001/jama.289.13.1652

CHAPTER 2

2.1 Pharmacodynamic

When drugs with similar pharmacologic effects are administered concurrently, an additive or synergistic response is usually seen. The two drugs may or may not act on the same receptor to produce such effects. Conversely, drugs with opposing pharmacologic effects may reduce the response to one or both drugs. Pharmacodynamic drug interactions are relatively common in clinical practice, but adverse effects can usually be minimized if one understands the pharmacology of the drugs involved. In this way, the interactions can be anticipated and appropriate countermeasures taken (Rang, et al., 2007).

It was long believed that geriatric patients were much more “sensitive” to the action of many drugs, implying a change in the pharmacodynamic interaction of the drugs with their receptors. It is now recognized that many of these apparent changes result from altered pharmacokinetics or diminished homeostatic responses. Clinical studies have supported the idea that the elderly are more sensitive to some sedative-hypnotics and analgesics. In addition, some data from animal studies suggest actual changes with age in the characteristics or numbers of a few receptors. The most extensive studies show a decrease in responsiveness to α-adrenoceptor agonists (Katzung, 2007).

Certain homeostatic control mechanisms appear to be blunted in the elderly. Since homeostatic responses are often important components of the total response to a drug, these physiologic alterations may change the pattern or intensity of drug response. In the cardiovascular system, the cardiac output increment required by mild or moderate exercise is successfully provided until at least age 75 (in individuals without obvious cardiac disease), but the increase is the result primarily of increased stroke volume in the elderly and not tachycardia, as in young adults. Average blood pressure goes up with age (in most Western countries), but the incidence of symptomatic orthostatic hypotension also increases markedly. It is thus particularly important to check for orthostatic hypotension on every visit. Similarly, the average 2-hour postprandial blood glucose level increases by about 1 mg/dL for each year of age above 50. Temperature regulation is also impaired, and hypothermia is poorly tolerated in the elderly (Katzung, 2007).

2.1.1 Adverse Drug Effects

The positive relationship between number of drugs taken and the incidence of adverse reactions to them has been well documented. In long-term care facilities, in which a high fraction of the population is elderly, the average number of prescriptions per patient varies between 6 and 8. Studies have shown that the percentage of patients with adverse reactions increases from about 10% when a single drug is being taken to nearly 100% when ten drugs are taken. Thus, it may be expected that about half of patients in long-term care facilities will have recognized or unrecognized reactions at some time. The overall incidence of drug reactions in geriatric patients is estimated to be at least twice that in the younger population. Reasons for this high incidence undoubtedly include errors in prescribing on the part of the practitioner and errors in drug usage by the patient (Rang, et al., 2007).

Practitioner errors sometimes occur because the physician does not appreciate the importance of changes in pharmacokinetics with age and age-related diseases. Some errors occur because the practitioner is unaware of incompatible drugs prescribed by other practitioners for the same patient. For example, cimetidine, an H2-blocking drug heavily prescribed (or recommended in its over-the-counter form) to the elderly, causes a much higher incidence of untoward effects (eg, confusion, slurred speech) in the geriatric population than in younger patients. It also inhibits the hepatic metabolism of many drugs, including phenytoin, warfarin, α blockers, and other agents. A patient who has been taking one of the latter agents without untoward effect may develop markedly elevated blood levels and severe toxicity if cimetidine is added to the regimen without adjustment of dosage of the other drugs (Rang, et al., 2007).

Patient errors may result from noncompliance. In addition, they often result from use of nonprescription drugs taken without the knowledge of the physician. Many over-the-counter agents and herbal medications contain “hidden ingredients” with potent pharmacologic effects. For example, many antihistamines have significant sedative effects and are inherently more hazardous in patients with impaired cognitive function. Similarly, their antimuscarinic action may precipitate urinary retention in geriatric men or glaucoma in the patient with a narrow anterior chamber angle. If the patient is also taking a metabolism inhibitor such as cimetidine, the probability of an adverse reaction is greatly increased. A patient taking an herbal medication containing gingko is more likely to experience bleeding while taking low doses of aspirin (Rang, et al., 2007).

2.1.2 Drug Interaction

2.1.2.1 Inhibition

  • β-Adrenoceptor antagonists diminish the effectiveness of β-adrenoceptor agonists such as salbutamol (Rang, et al., 2007).
  • Warfarin competes with vitamin K, preventing hepatic synthesis of various coagulation factors. If vitamin K production in the intestine is inhibited (e.g. by antibiotics), the anticoagulant action of warfarin is increased (Rang, et al., 2007).

2.1.2.2 Potentiation

  • Many diuretics lower plasma K+ concentration, and thereby predispose to digoxin toxicity and to toxicity with type III antidysrhythmic drugs (Rang, et al., 2007).
  • Sildenafil inhibits the isoform of phosphodiesterase (type V) that inactivates cGMP; consequently, it potentiates organic nitrates, which activate guanylate cyclase, and can cause severe hypotension in patients taking these drugs (Rang, et al., 2007).
  • Monoamine oxidase inhibitors increase the amount of noradrenaline (norepinephrine) stored in noradrenergic nerve terminals and interact dangerously with drugs, such as ephedrine or tyramine, that release stored noradrenaline. This can also occur with tyramine-rich foods-particularly fermented cheeses such as Camembert (Rang, et al., 2007).
  • The risk of bleeding, especially from the stomach, caused by warfarin is increased by drugs that cause bleeding by different mechanisms (e.g. aspirin, which inhibits platelet thromboxane A2 biosynthesis and which can damage the stomach) (Rang, et al., 2007).
  • Sulfonamides prevent the synthesis of folic acid by bacteria and other micro-organisms; trimethoprim inhibits its reduction to tetrahydrofolate. Given together, the drugs have a synergistic action of value in treating Pneumocystis carinii (Rang, et al., 2007).
  • Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or indometacin, inhibit biosynthesis of prostaglandins, including renal vasodilator/natriuretic prostaglandins (prostaglandin E2, prostaglandin I2). If administered to patients receiving treatment for hypertension, they cause a variable but sometimes marked increase in blood pressure. If given to patients being treated with diuretics for chronic heart failure, they can cause salt and water retention and hence cardiac decompensation (Rang, et al., 2007).
  • Histamine H1 receptor antagonists, such as promethazine, commonly cause drowsiness as an unwanted effect. This is more troublesome if such drugs are taken with alcohol, and it may lead to accidents at work or on the road (Rang, et al., 2007).

2.1.2.3 Accumulation

The combined use of two or more drugs, each of which has toxic effects on the same organ, can greatly increase the likelihood of organ damage. For example, concurrent administration of two nephrotoxic drugs can produce kidney damage even though the dose of either drug alone may have been insufficient to produce toxicity. Furthermore, some drugs can enhance the organ toxicity of another drug even though the enhancing drug has no intrinsic toxic effect on that organ (Katzung, 2007).

2.2 Pharmacokinetic

Katzung, BG. 2007. Basic and Clinical Pharmacology. 10th ed. San Francisco: McGraw-Hill Medical.

Rang HP, Dale MM, Ritter JM, Flower RJ. 2007. Rang and Dale’s Pharmacology. 6th ed. New York: Churcill Livingstone.

CHAPTER 3

FRAMEWORK AND HYPOTHESIS

3.1 Framework

3.2 Hypothesis

  1. The more medications are used by the patient, the lower MMSE value will be.
  2. The more medications are used by the patient, the lower ADL value will be.
  3. The more medications are used by the patient, the higher GDS value will be.
  4. The more medications are used by the patient, the patient will suffer from spinning sensation, syncope-like sensation, and edematous state.

Polypharmacy and Depression in Elderly Patient who were Admitted in Chronic Ward of Saiful Anwar Hospital

dr. Bernandus Anggaru *, dr. Sri Sunarti, SpPD **, dr. Gadis Nurlaila, SpPD **

Objective: To verify whether depression is associated with greater drug utilization in elderly patients. It was hypothesized by the age-related increase of concurrent disease (polypathology) contribute in polypharmacy. Among these, the perceived need of care could affect the use of drugs and precipitate depression.

Population: 83 patients who was admitted in RSSA during September-October 2011 (Preliminary study)

Main outcome measure: Polypharmacy, ie having more than 6 drugs prescribed at discharge. Depression, ie defined as a 15-item Geriatric Depression Scale (GDS) > 5

Method: Data on drugs that patient had received when patient admitted in hospital were collected. Depression statuses of patients were defined by Geriatric Depression scale more than 5 of 15 items. Logistic regression analysis was performed to investigate the correlation between polypharmacy and depression.

Results: Non polypharmacy patient showed slightly more depressing than polypharmacy patient. However, there is no significant difference of depression status between non polypharmacy and polypharmacy patient ( Mean ± SD of GDS 17.18 ± 7.83 vs 16.08 ± 9.10, p = 0.348 ). GDS>5 suggested depression was found in 90.36% patients and didn’t correlate with polypharmacy (odds ratio 0.367, 95% CI 0.43-3.17, Spearman correlation p = 0.351).

Conclusion: Polypharmacy isn’t associated with depression status in elderly patient who was admitted in RSSA

Keyword: Geriatric, Polypharmacy, Depression, Hospitalized patient

* Resident of Internal Medicine Department

** Internist, Geriatric Department Medical Faculty Brawijaya University
SPSS ANALYSIS

Logistic Regression

Block 0: Beginning Block

Block 1: Method = Enter

Interactive Graph

Kruskal-Wallis Test

Oneway

Crosstabs

 

 

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