1. Dr. DATTEN BANGUN MSc,SpFK Bagian Farmakologi dan Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara DRUG INTERACTIONS

2. CONCEPT : Drug interactions involve changes in the duration or intensity of a drug’s action caused by the presence of another drug.

3. Outcomes of drug interactions 1)Loss of therapeutic effect 2)Toxicity 3)Unexpected increase in pharmacological activity 4)Beneficial effects e.g additive & potentiation (intended) or antagonism (unintended). 5) Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture

4. Drug interaction :  desirable  undesirable =  adverse drug interaction.

5. Clinical impact of adverse drug interactions. Boston collaborative drug surveillance program (1972) -drug interactions were determined to account for 7% of in-hospital drug reactions. Out patient ? -Less, because they are exposed to fewer drugs.

6. Mechanism of A.D.I. 1.Pharmacokinetic factors  ADME 2.Pharmacodynamic factors  additive effects  opposing effects 3. Pharmaceutical Interactions

7. Pharmaceutical Interactions Interactions that occur prior to systemic administration. For example incompatibility between two drugs mixed in an IV fluid. These interactions can be physical (e.g. with a visible precipitate) or chemical with no visible sign of a problem

8. Mechanisms of drug interactions Pharmacokinetics Pharmacodynamics Pharmacokinetics : =involve the effect of a drug on another from the point of view that includes absorption,distribution, metabolism and excretion. Pharmacodynamics : =are related to the pharmacological activity of the interacting drugs e.g synergism.antagonism, altered cellular transport, effect on the receptor site.

9. Pharmacokinetic mechanism This interaction happens at the level of : - drug absorbtion - drug distribution - drug metabolism - drug excretion Drug absorbtion: - Chemical interaction==  drugs can react physically or chemically before they are administered or in the case of oral preparation,before they are absorbed. ----  pharmaceutical interaction

10. General Rule: Drugs should not be mixed before parenteral administration unless they have been demonstrated by rigorous testing to be chemically compatible. Chemical interactions are very unlikely to occur once drugs reach the sytemic circulation,because the concentration in the plasma are low How about orally administered drugs? = tetracycline and divalent cations = cholestyramine and colestipol

11. Pharmacokinetic interactions 1) Altered GIT absorption. Altered pH, Altered bacterial flora, formation of drug chelates or complexes, drug induced mucosal damage and altered GIT motility. a)Altered pH; The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does.

12. Ex1., antiacids Decrease the pH Decrease the tablet dissolution of Ketoconazole (acidic) Ex2., H2 antagonists pH Therefore, these drugs must be separated by at least 2h in the time of administration of both.

13. b) Altered intestinal bacterial flora ; EX., In 10% 0f patients receive digoxin…..40% or more of the administered dose is metabolized by the intestinal flora Antibiotics kill a large number of the normal flora of the intestine Increase digoxin conc. and increase its toxicity

14. c) Complexation or chelation; EX1., Tetracycline interacts with iron preparations or Milk (Ca 2+ ) Unabsorpable complex Ex2., Antacid (aluminum or magnesium) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation

15. d) Drug-induced mucosal damage. Antineoplastic agents e.g., cyclophosphamide vincristine procarbazine Inhibit absorption of several drugs eg., digoxin e) Altered motility Metoclopramide (antiemitic) Increase absorption of cyclosporine due to the increase of stomach empting time Increase the toxicity of cyclosporine

16. Interactions affecting oral bioavailability Merubah gastric emptying time akan merubah kecepatan absorbsi,TIDAK merubah bio- availability. Cara terbaik utk mempercepat absorbsi ialah dg minum obat wkt perut kosong dg kira2 200 ml air. Faktor yg memperlambat GETime: -makanan,berbaring,olahraga berat, -obat2 spt:anticholinergic;antasida, narkotik.

17. Obat-obat yg mempercepat gastric emptying time (GETime) - metoclopramide -cisapride -domperidone NOTE: =bila obat dirusak oleh asam lambung,maka bila *GETime melambat===  bioavailability berkurang. *bila GETime jadi cepat,mengganggu pe- cahnya enteric-coated tablet

18. Pharmacokinetic mechanism Chemical interactions -in the parenteral administration =may significantly decrease the activity of one or both drugs General Rule :never mix the drugs unless you are sure that they are compatible ORAL ADMINISTRATION: -Tetracycline and divalent cation -Cholestyramine and Colestipol can bind - anionic drugs.

19. Interactions affecting oral bioavailability -Affecting gastric emptying -Affecting drug absorbtion -Affecting presystemic elimination (first – pass effect) Grape juice : -Inhibit CYP3A4 in the intestinal wall  felodipine, cyclosporine bioavailability increase. Food-drug interactions Contoh lain: -tyramin & MAO-I yang non-selective

20. Displaced protein binding It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity. Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and warfarin (99%) Drugs that displace these agents are Aspirin Sulfonamides phenylbutazone Interaction on distribution

21. Protein-binding Interaction Drugs ==  circulation==  distributed throughout the body,dependent upon: -ionic composition -lipid solubility -protein-binding characteristic * in the plasma---- to albumin -----to alfa-acid glycoprotein * to tissue proteins Only free drug can exert pharmacologic effect Drug with stronger affinity will displace the weaker one -----  produce higher free drug conc.-----  can lead to toxic effect if this drug has narrow therapeutic index.

22. = Protein binding interactions - Sulfonamide + bilirubin - NSAID + oral antidiabetes Sulfonamida akan menggeser bilirubin dari ikatan Protein==  bilirubin jadi bebas. Bila ini terjadi pd new-born baby=  menembus sawar-obat===  kern-icterus===  JANGAN BERI Sulfa pada ibu hamil. NSAIDs akan menggeser oral antidiabetic dari protein plasma===  free-drug meningkat====  hypoglikemia. JADI: perhatikan dosering obatnya.

23. Interaction due to altered biotransformation Drugs ===  * enzyme –inducer ===  * enzyme –inhibitor Enzyme-induction: -akan berakibat metabolisme obat jadi lebih cepat shg kadarnya dalam darah akan turun mis: -rifampisin------- cyclosporin,prednison -fenobarbital----- oral contraceptive -fenitoin---------- methadone withdrawal -isoniazid--------- acetaminophen-induced hepatotoxicity meningkat.

24. CYP450 Nomenclature CYP2D6 Family Sub-Family Individual Gene

26. CYP 450 System Definitions Substrate: Drug is metabolised by the enzyme system Inducer: Drug that will increase the synthesis of CYP450 enzymes Inhibitor Drug that will decrease the metabolism of a substrate

27. Enzyme Induction Leads to production of more enzyme, usually after 3-4 days of exposure to inducer Most CYPs are inducible but not CYP2D6 Time course of interaction depends on half-life of inducer.

28. Enzyme Induction Rifampicin has short half-life and induction apparent with 24 hours Phenobarbitone has longer half life so time to complete induction takes longer

29. Enzyme Inducers Examples Rifampicin Phenobarbitone Carbamazepine Cigarette smoke

30. Enzyme Inhibition Often rapid, reversible and relatively short acting. E.g. erythromycin and cyclosporin NB erythromycin is a substrate and an inhibitor of CYP 3A4 May be prolonged due to long half- life of drug. E.g. amiodarone and S-Warfarin NB amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP

31. Enzyme characteristics % drugs metabolised by enzyme 3A4 60% 2D6 25% 1A2 15% 2C9 Small no. but significant interactions 2C19 Small no. but significant interactions 2E1 ?

32. Enzyme Inhibition Menghambat metabolisme obat===  kadar dalam darah akan meningkat AKIBATNYA? -tergantung jenis obat dan jalur metabolismenya Contoh: INH menghambat metabolisme acetaminophen dan juga carbamazepine a.acetaminophen=  reaksi konjugasi yg dihambat---  hanya 15% perlambatan clearance b.Carbamazepine=  reaksi oxidative dihambat-----  increase steady-state serum conc.

34. EX1., Enzyme induction A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g., Carbamazepine (antiepileptic drug ) increases its own metabolism Phenytoin increases hepatic metabolism of theophylline Leading to decrease its level Reduces its action and Vice versa N.B enzyme induction involves protein synthesis.Therefore, it needs time up to 3 weeks to reach a maximal effect

35. First-pass metabolism: Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor. EX., Rifampin lowers serum con. of verapamil level by increase its first pass. Also, Rifampin induces the hepatic metabolism of verapamil

36. TIPS Apakah obat yang bersifat enzyme inducer atau inhibitor tak boleh diberi bersama obat yg diinduksi atau diinhibisi? BOLEH,ASAL DOSIS DIATUR. HOW?? Bila obat A penginduksi,obat B yg diinduksi,maka dosis obat B dinaikkan dan stlh penginduksi distop, maka dosis obat B diturunkan kembali Bila obat A inhibitor,obat B yg diinhibisi,maka dosis obat B diturunkan dan setelah obat penginhibit distop,maka dosis obat B dinaikkan kembali

37. Excretion 1. By alteration pH of the urine Contoh: = pengeluaran obat basa dg mengasamkan urine = pengeluaran obat bersifat asam dg membasakan urine 2.Dengan mengganggu proses renal clearance: mis: -renal clearance Lithium is decreased by thiazide and loop diuretic----  because of the narrow margin of safety-----  toxic effect -probenecid mengurangi clearance penisilin---  memperpanjang effeknya (menguntungkan)

38. Renal excretion: Active tubular secretion; It occurs in the proximal tubules (a portion of renal tubules). The drug combines with a specific protein to pass through the proximal tubules. When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug.This will reduce such a drug excretion increasing its con. and hence its toxicity. EX., Probenecid ….. Decreases tubular secretion of methotrexate.

39. * Passive tubular reabsorption; Excretion and reabsorption of drugs occur in the tubules By passive diffusion which is regulated by concentration and lipid solubility. N.B., Ionized drugs are reabsorbed lower than non-ionized ones Ex1., Sod.bicarb. Increases lithium clearance and decreases its action Ex2., Antacids Increases salicylates clearance and decreases its action

40. Pharmacodynamic interaction = Receptor interaction: * adrenergic blocking drug vs adrenergic agonist * antiparkinson levodopa vs dopamine-blocking drug,haloperidol * antihistamin,phenothiazine,TCA,share the mus- rinic blocking effect of atropin * aminoglycoside in patient after muscle relaxant or in myasthenic patient-----  paralysis or apnea

41. Pharmacodynamic interactions; It means alteration of the drug action without change in its serum concentration by pharmacokinetic factors. EX., Propranolol + verapamil Synergistic or additive effect Synergism means =1+1=3 Additive means= 1+1=2 Potentiation means= 1+0=2 Antagonism means 1+1=0 or 0.5 Effect at the receptor site Antiadrenegic anticholinergic On the other hand

43. * Risk factors: 1)High risk patients ; these are the groups of patients that should be treated with caution due to a specific health condition e.g., = pregnant women, =malignant cases, = diabetic patients, = patients with liver or kidney disorders, = asthmatic patients and cardiac disorders. = Elderly, young, very sick, multiple disease = Multiple drug therapy

44. Risk Factors for Drug Interactions 2)High Risk Drugs –Narrow therapeutic index drugs –Recognised enzyme inhibitors or inducers Narrow therapeutic index e.g., - corticosteroid -rifampin, - oral contraceptives, - quindine, - lidoquine

45. Onset of drug interaction It may be seconds up to weeks for example in case of enzyme induction, it needs weeks for protein synthesis, while enzyme inhibition occurs rapidly. The onset of action of a drug may be affected by the half lives of the drugs e.g., cimetidine inhibits metabolism of theophylline. Cimetidine has a long half- life, while, theophylline has a short one. When cimetidine is administered to a patient regimen for Theophylline, interaction takes place in one day.

46. * Prevention of drug interaction 1)Monitoring therapy and making adjustments 2)Monitoring blood level of some drugs with narrow therapeutic index e.g., digoxin, anticancer agents…etc 3)Monitoring some parameters that may help to characterize the early events of interaction or toxicity e.g., with warfarin administration, it is recommended to monitor the prothrombin time to detect any change in the drug activity. 4)Increase the interest of case report studies to report different possibilities of drug interaction Use drugs as minimal as possible!!!