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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 Herbal

Medicine Food Drink Chemical Agent

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. 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

2. 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

3. 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. 4. Stanton LA, Peterson GM, Rumble RH, Cooper GM, Polack AE. Drug-related admissions to an Australian hospital. J Clin Pharm Ther (1994) 19, 3417.

Mechanism of Drug Interaction Pharmacokine-cs Interac-ons Pharmacodynamic Interac-ons

Absorp-on

Distribu-on

Metabolism

Excre-on

Addi-ve/synergis-c

Anatagonist

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

Example: Tetracycline VS Ca, Al, Mg, Fe

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

2. Chelation mechanism 3. Changes in GI motility

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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 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

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

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

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

The ow of blood through the kidney is par-ally controlled by the produc-on of renal vasodilatory prostaglandins

Example: NSAIDs VS Lithium

2. Changes in Active Renal Tubular Exretion 3. Changes in Renal Blood Flow

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.

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) Tingkat

Signifikasi Keamanan Dokumentasi

1 Major Established, Probable or Suspected

2 Moderate Established, Probable or Suspected

3 Minor Established, Probable or Suspected

4 Major / Moderate Possible

5 Minor / Any Possible/ unlikely

!

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

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