Types of Drug Interactions

Transcription

1 ภญ. อ มพร จ นทรอาภรณ ก ล ภญ.จ นทร พร ก องว ชรพงศ ฝ ายเภส ชกรรม รพ. ศ ร ราช Types of Drug Interactions 1. Pharmacokinetic Absorption Distribution Elimination (metabolism, excretion) 2. Pharmacodynamic 1

2 Pharmacokinetic Interactions Altered Absorption Most interactions involving altered drug absorption occur in the gut. Warfarin is well absorbed, only a few agents have been shown to reduce warfarin's bioavailability. Most of the clinically important warfarin interactions involve formation if a non absorbable complex by either chelation. Cholestyramine, a bile acid sequestrant, can bind with C o esty a e, a b e ac d sequest a t, ca b d t warfarin in the GI tract, resulting in reduced absorption. This interaction can be minimized by spacing the doses (e.g., giving warfarin 2 hours before or 6 hours after cholestyramine). 2

3 Altered Distribution Warfarin is approximately 99% protein-bound (mainly albumin). Highly protein-bound drugs may displace warfarin from its binding sites, resulting in an enhanced anticoagulant effect. This effect appears to be only transient, however, because the increased unbound warfarin is available not only to the site of action but also to sites of elimination. Altered Metabolism Enzyme Induction & Inhibition Warfarin is extensively metabolized by the cyto-chrome P450 enzyme system in the liver. S-warfarin (~5 times more potent than the R-isomer) is metabolized by CYP2C9 isozyme system so it is considered to be most important R-isomer (less active) is metabolized by both the CYP1A2 and CYP3A4 isozyme system. Knowing which isozyme system is affected by other drugs will aid in predicting the severity of the interaction. 3

4 Inhibitors Inducers CYP1A2 and CYP3A4 are the primary isozymes for the metabolism of (R)-warfarin. CYP2C9 is the primary isozyme in the metabolism of (S)-warfarin. 4

5 Mean drug serum level toxic INR therapeutic Enzyme Inhibitor subtherapeutic INR Enzyme Inducer Mean drug blood level response to an enzyme inducer or enzyme inhibitor Pharmacodynamic Interactions 5

6 Clotting factors catabolism of clotting factors: hypermetabolic state t (hyperthyroidism, thyroid replacement) clotting factor synthesis: hepatic dysfunction hepatic blood flow: heart failure clotting factor synthesis: propylthiouracil, estrogens elimination of clotting factors: hypothyroidism Genetic variability Genetic Factors Vitamin K epoxide reductase complex 1 (VKORC1) 6

7 Drug & Food Interactions With Warfarin Drug & Food Interactions With Warfarin by Level of Causation & Direction of Interaction Systematic Overview of Warfarin and Its Drug and Food Interactions. Arch Intern Med. 2005;165:

8 Clinically Significant Interactions With Warfarin by Level of Causation and Drug Group Clinically Significant Interactions With Warfarin by Level of Causation and Drug Group (cont) 8

9 Clinically Significant Interactions With Warfarin by Level of Causation and Drug Group Summary There are many factors that can affect the response to warfarin. The number of drugs reported to interact with warfarin continues to expand. While most reports are of poor quality and present potentially misleading conclusions. Careful monitoring of warfarin therapy (INR) remains the best protection against major harm due to the drug interactions. 9

10 Strategies to Prevent/Manage Drug Interactions 1. Encourage patients to report all prescription (OTC, alternative medicine) 2. Consider whether drug therapy is necessary 3. Screen for potential drug-drug interactions, when adding a new drug to regimen. 4. If drug interaction can not be avoided, adjust doses and/or dosage intervals for affected medication and closely monitor the patient. 5. Carefully monitor other drug therapy when withdrawing a drug that can inhibit or induce hepatic metabolism. 6. Regularly review the need for chronic medications reduce polypharmacy 7. Support the implementation of electronic prescribing and/or the use by patients of one pharmacy with updated drug interaction software. Case Study 10

11 ชายไทยค อาย 48 ป Case 1 CC: มาตรวจตามแพทย น ด HPI: 2 wk PTA ผ ป วยเพ งได ร บการผ าต ด MV repair, ASD closure CASE: MV repair, ASD closure, AF ALL : ปฏ เสธการแพ ยา LAB: INR ว นน 5.66, INR ก อน D/C 2.21 BP 122/68 mmhg P 96/min Case 1 ข อม ลเพ มเต ม ว นท 4-14 ธค 50: ผ าต ด retained blood clot inpericardial cavity and restomotomy with vacuation clot blood repair RA wall ขณะน ก น warfarin(5) 1/2x1 po hs (17.5 mg/wk) สม าเสมอ สมาเสมอ ก นมา กนมา~13 ว น วน ไม ได ก นยา amiodarone ~ 20 ว น เน องจากยาหมด ปฏ เสธอาการของ abnormal bleeding 11

12 ข อม ลเพ มเต ม Case 1 ปฏ เสธอาการของ thromboembolic events ปฏ เสธการใช ยาอ นๆ รวมท งยาล กกลอน ยา สม นไพร ยาหม อ หร ออาหารเสร ม Medications Warfarin(5) ½ x 1 po hs Amiodarone(200) 1x1 po pc (ยาหมด ~ 20 ว น PTA) Furosemide(40) 1x1 po pc Digoxin(0.25) ½ x 1 po pc Enalapril(5) 1 x 1 po pc 12

13 Patient assessment Compliance Too High Dose Food-Drug Interaction Disease-Drug Interaction Drug-Drug Interaction 13

14 Medications Warfarin(5) ½ x 1 po hs Amiodarone(200) 1x1 po pc (ยาหมด ~ 20 ว น PTA) Furosemide(40) 1x1 po pc Digoxin(0.25) ½ x 1 po pc Enalapril(5) 1 x 1 po pc Which drugs? 14

15 Drug-Drug Interaction Warfarin Digoxin Significance Onset Severity Rapid Major Moderate Minor Documentation Established Probable Suspected Possible Unlikely? 1 NO Delayed DATA Drug-Drug Interaction Warfarin Enalapril Significance Onset Severity Documentation Established Rapid Major Probable D l d Moderate Suspected Minor Possible Unlikely? 1 NO DATA Delayed 15

16 Drug-Drug Interaction Warfarin Furosemide Significance 4 Onset Severity Rapid Major Delayed Moderate Minor Documentation Established Probable Suspected Possible Unlikely Drug-Drug Interaction Warfarin Amiodarone Significance 1 Delayed Onset Severity Rapid Major Delayed Moderate Minor Documentation Established Probable Suspected Possible Unlikely 16

17 Pharmacokinetics of Amiodarone Absorption: Bioavailability ~ 50% Distribution: Protein binding 96% Metabolism: Liver hepatic CYP3A-mediated N-deethylation is metabolized to desethylamiodarone by cytochrome P450 3A4 and 2C8. possible enterohepatic recirculation Excretion: Feces, Urine(1%) 17

18 Pharmacokinetics of Amiodarone Cytochrome P450 effect: Inhibits: CYP 1A2 (moderate) CYP 2C9 (moderate) CYP 2C19 (weak) CYP 2D6 (moderate) CYP 3A4 (moderate) R-warfarin S-warfarin R-warfarin Pharmacokinetics of Amiodarone Onset Initial Response: 2days - 6 weeks Peak Response: 1 weeks 5 months Duration Multiple Oral Dose: days Antiarrhythmic effects may persist for 30 to 90 days or longer following discontinuation of the drug, due to its long half-life (40-55 day) 18

19 Drug-Drug Interaction Amiodarone VS Warfarin Onset: Delayed Severity: Moderate Documentation: Excellent Probable Mechanism: decreased warfarin metabolism DRUG-REAX System: Klasco RK (Ed): DRUG-REAX System. Thomson Healthcare, Greenwood Village, Colorado (Edition expires [12/2008]). Management In patients on chronic oral anticoagulant therapy with warfarin, a prophylactic 35 to 65% reduction in the warfarin dosage is recommended at the initiation of therapy with amiodarone. DRUG-REAX System: Klasco RK (Ed): DRUG-REAX System. Thomson Healthcare, Greenwood Village, Colorado (Edition expires [12/2008]). 19

20 Management INR greater than 5 occurred most commonly during the first 12 weeks of concomitant warfarin and amiodarone therapy, intensive monitoring during this period is recommended DRUG-REAX System: Klasco RK (Ed): DRUG-REAX System. Thomson Healthcare, Greenwood Village, Colorado (Edition expires [12/2008]). Management The INR should also be closely monitored with the withdrawal of amiodarone and periodically reassessed during concurrent therapy. DRUG-REAX System: Klasco RK (Ed): DRUG-REAX System. Thomson Healthcare, Greenwood Village, Colorado (Edition expires [12/2008]). 20

21 For patients receiving amiodarone maintenance doses of 400, 300, 200, or 100 mg/d, it is recommended that the daily warfarin dose be reduced by approximately 40%, 35%,30%, or 25%, respectively. Circulation 2002;121:19-23 INR and Dose of Warfarin DATE INR Warfarin Changed regiment warfarin regiment 25/12/ W(5) 1/2x1 po hs (17.5 mg/wk) หย ด warfarin 3 ว น และ ปร บขนาดยาลดลงเป น W(3) 1/2x1 po hs (10.5 mg/wk) 8/1/ W(3) 1/2x1 po hs W(5) 1/4x1 po hs (10.5 mg/wk) (8.75 mg/wk) 5/2/ W(5) 1/4x1 po hs (8.75 mg/wk) W(3) 1/4x1 po hs (5.25 mg/wk) Note 40% จาก TWD เด ม หย ด amiodarone 20 ว น PTA 16.7% จาก TWD เด ม ให amiodarone (200) 1x1 po pc 40% จาก TWD เด ม 21

22 20 INR and Dose of Warfarin 6 total weekly dose of warfarin (TWD D) mg/wk Amiodarone 200 mg/d Off amiodarone 200 mg/d INR TWD INR 0 D/C 2 wk 1 mo 1 mo 1 mo 2 mo 5 mo 2 wk 2 mo TIME 0 INR and Dose of Warfarin DATE INR Warfarin regiment Changed warfarin regiment??? Note 4/3/ W(3) 1/4x11 po hs W(3) 1/4x11 po hs หย ด หยด (5.25 mg/wk) (5.25 mg/wk) amiodarone 1/4/ W(3) 1/4x1 po hs (5.25 mg/wk) 27/5/ W(3) 1/4x1 po hs (5.25 mg/wk) 10/6/ W(3) 1/4x1 จ-ศ และ W(3) 1/4x1 po hs (5.25 mg/wk) W(3) 1/4x1 จ-ศ และ W(3) 1/2x1 ส-อา po hs (6.75 mg/wk) W(3) 1/4x1 จ-ศ และ 30% จาก TWD เด ม W(3) 1/2x1 ส-อา po hs (6.75 mg/wk) W(3) 1/2x1 ส-อา po hs (6.75 mg/wk) 22

23 INR and Dose of Warfarin DATE INR Warfarin regiment Changed warfarin regiment Note 4/3/ W(3) 1/4x11 po hs W(3) 1/4x11 po hs หย ด หยด (5.25 mg/wk) (5.25 mg/wk) amiodarone 1/4/ W(3) 1/4x1 po hs (5.25 mg/wk) 27/5/ W(3) 1/4x1 po hs (5.25 mg/wk) 10/6/ W(3) 1/4x1 จ-ศ และ W(3) 1/4x1 po hs (5.25 mg/wk) W(3) 1/4x1 จ-ศ และ W(3) 1/2x1 ส-อา po hs (6.75 mg/wk) W(3) 1/4x1 จ-ศ และ 30% จาก TWD เด ม เม W(3) 1/2x1 ส-อา po hs (6.75 mg/wk) W(3) 1/2x1 ส-อา po hs (6.75 mg/wk) total weekly dose of warfarin (TWD D) mg/wk INR and Dose of Warfarin Amiodarone 200 mg/d Off amiodarone 200 mg/d INR TWD INR 0 D/C 2 wk 4 wk 1 mo 2 mo 3 mo 5 mo 2 wk 2 mo TIME 0 23

24 Strategies to Prevent/Manage Drug Interactions 1. Encourage patients to report all prescription (OTC, alternative medicine) 2. Consider whether drug therapy is necessary 3. Screen for potential drug-drug interactions, when adding a new drug to regimen. 4. If drug interaction can not be avoided, adjust doses and/or dosage intervals for affected medication and closely monitor the patient. 5. Carefully monitor other drug therapy when withdrawing a drug that can inhibit or induce hepatic metabolism. 6. Regularly review the need for chronic medications reduce polypharmacy 7. Support the implementation of electronic prescribing and/or the use by patients of one pharmacy with updated drug interaction software. ชายไทยค อาย 65 ป Case 2 CC: มาพบแพทย ตามน ด HPI: MVR (St. Jude No 29), AF Old ischemic stroke ~5 yrs PTA LAB: INR 6.40 BP 117/76 mmhg P 86 /min 24

25 Case 2 ข อม ลเพ มเต ม 20-27/4/51: 27/4/51 Admit รพ.ใกลบาน ใกล บ าน ด วยอาการหน าชา ดวยอาการหนาชา ปากเบ ยว พ ดไม ช ด CT brain (20/4/51): Mild aging brain atrophy with old infarctions in both MCA territories ขณะ admit ได ร บยา warfarin ขนาดเด มจากรพ.ศ ร ราช ไม ม การเปล ยนแปลงขนาดยา ได ร บ phenytoin(100) 3x1 po hs จนถ งว นน (30/4/51) ข อม ลเพ มเต ม Case 2 ขณะน ก น warfarin(5) ¾ x 1 po hs (26.25mg/wk) สม าเสมอ ว นน ไม ม หน าชาแล ว แต ย งพ ดไม ช ด ไม ม แขนขาอ อนแรง เหน อยมากข นกว าเด มเล กน อย เด นได ~ เมตร จะ เหน อย สามารถท างานได เล กน อย นอนราบได ไม บวม ปฏ เสธการม เล อดออกผ ดปกต ปฏ เสธการใช ยาสม นไพร ยาหม อ ยาล กกลอน อาหารเสร ม 25

26 Medications Warfarin(5) ¾ x 1 po hs (26.25 mg/wk) Furosemide(40) 1x1 po pc Carvedilol(6.25) 1x2 po pc Senekot 2 tab po hs Lansoprazole(15) 1x1 po ac Phenytoin(100) 3x1 po hs Mianserin(10) 1x3 po hs Cinarizine(25) 1x3 po pc INR and Dose of Warfarin Date INR Warfarin regiment Changed warfarin dose 13/2/ Wafarin(5) 3/4x1 po hs (26.25 ) - 5/3/ Wafarin(5) 3/4x1 po hs (26.25 ) - 30/4/ Wafarin(5) 3/4x1 po hs (26.25 )??? 26

27 Patient assessment Compliance Too High Dose Food-Drug Interaction Disease-Drug Interaction Drug-Drug Interaction 27

28 Which drugs? Medications Warfarin(5) ¾ x 1 po hs (26.25 mg/wk) Furosemide(40) 1x1 po pc Carvedilol(6.25) 1x2 po pc Senekot 2 tab po hs Lansoprazole(15) 1x1 po ac Phenytoin(100) 3x1 po hs Mianserin(10) 1x3 po hs Cinarizine(25) 1x3 po pc 28

29 Drug-Drug Interaction Warfarin Significance Significance? Onset Severity Onset Rapid Severity Major Delayed Moderate Rapid Major? Minor Delayed Moderate Minor Mianserin Documentation Established Documentation Probable Established Suspected NO DATA Probable Possible Suspected Unlikely Possible Unlikely Drug-Drug Interaction Warfarin Significance Significance? Onset Severity Onset Rapid Severity Major Delayed Moderate Rapid Major? Minor Delayed Moderate Minor Cinarizine Documentation Established Documentation Probable Established Suspected NO DATA Probable Possible Suspected Unlikely Possible Unlikely 29

30 Drug-Drug Interaction Warfarin Phenytoin Significance 2 Onset Severity Rapid Major Delayed Moderate Minor Documentation Established Probable Suspected Possible Unlikely Drug-Drug Interaction 30

31 Pharmacokinetics of Phenytoin Absorption: Bioavailability % Distribution: Protein binding 80-95% Metabolism: Dose dependent capacity limited (Michaelis-Menten) Metabolite: 5-(para-hydroxyphenyl)-5-phenylhydantoin yp y) p y y (HPPH), inactive Excretion: Urine Pharmacokinetics of Amiodarone Cytochrome P450 effect: Induces: Strong CYP 2B6 CYP 2B8 CYP 2C9 CYP 2C19 CYP 3A4 S-warfarin R-warfarin 31

32 Drug-Drug Interaction Warfarin Vs. Phenytoin Onset: Delayed Severity: Moderate Documentation: Fair Probable Mechanism: displacement of warfarin from protein binding sites, increased warfarin metabolism DRUG-REAX System: Klasco RK (Ed): DRUG-REAX System. Thomson Healthcare, Greenwood Village, Colorado (Edition expires [12/2008]). Management In patients on anticoagulant therapy with warfarin, the international normalized ratio (INR) should be monitored closely during the two to three week interval following the addition or deletion of phenytoin therapy. DRUG-REAX System: Klasco RK (Ed): DRUG-REAX System. Thomson Healthcare, Greenwood Village, Colorado (Edition expires [12/2008]). 32

33 INR and Dose of Warfarin 30 7 Tota al weekly dose of warfarin (TWD) mg/wk Start Phenytoin 300 mg/d INR TWD INR 0 Baseline 2 mo 2 wk 2 wk 6 wk 0 10 days before TIME next visit Strategies to Prevent/Manage Drug Interactions 1. Encourage patients to report all prescription (OTC, alternative medicine) 2. Consider whether drug therapy is necessary 3. Screen for potential drug-drug interactions, when adding a new drug to regimen. 4. If drug interaction can not be avoided, adjust doses and/or dosage intervals for affected medication and closely monitor the patient. 5. Carefully monitor other drug therapy when withdrawing a drug that can inhibit or induce hepatic metabolism. 6. Regularly review the need for chronic medications reduce polypharmacy 7. Support the implementation of electronic prescribing and/or the use by patients of one pharmacy with updated drug interaction software. 33

34 หญ งไทยค อาย 59 ป Case 3 CC: มาพบแพทย ตามน ด 4/8/2551 PMH: Severe MS, Severe TR S/P MVR with Bjork shilley, De vega Tricuspid annuloplasty (14/5/2530) PI: GERD, Asthma, Osteoporosis SH: ปฏ เสธการร บประทานยาสมนไพร ปฏเสธการรบประทานยาสม นไพร และอาหารเสร มต างๆ และอาหารเสรมตางๆ ALL: ปฏ เสธการแพ ยา LAB: INR 1.16 BP 115/95 mmhg P 61/min ค า INR และขนาดยาท ได ร บต อส ปดาห Date INR Dose TWD(mg/wk) (% changed TWD) 9/5/ Warfarin(5) 3/4x1hs /10/ Warfarin(5) 3/4x1hs /4/ Warfarin(5) 3/4x1hs (baseline) 17/12/ Warfarin(5) 1x1hs 35 (33.33%) 18/2/ Warfarin(3) 2x1 hs 42 (20%) 34

35 ค า INR และขนาดยาท ได ร บต อส ปดาห Date INR Dose TWD(mg/wk) (% changed TWD) 21/4/ Warfarin (5) 1 ½ x1 hs 52.5 (25%) 21/7/ Warfarin (5) 2 สล บ 1 ½ x1 hs (14-19%) 28/7/ Warfarin (5) 2x1 hs 70 ( %) 4/8/ Warfarin (5) 2 ¼ x1 hs (จ-ศ) Warfarin (5) 2 ½ x1 hs (ส-อา) (16%) % จาก baseline Medications (4/8/2551) ยาเด ม 1. Warfarin(5) 2 1/4x1 hs จ-ศ Warfarin(5) 2 1/2 x1 hs ส-อา 2. digoxin (0.25) 1/2x1 pc 3. furosemide (40) 1x1 pc 4. atorvastatin (20)1x1 pc 5. esomaprazole (40) 1x1 ac 6. domperidone 1x3 ac 7. cetirizine 1x1 pc 8. seretide accuhaler 1 puff/day เร ม 10/1/ glakay (menatetrenone) 1x2 pc 10. glucosamine sulfate 1x1 ac 11. calcium carbonate (1) 1x1 pc 12. vitamin B x2pc 35

36 Patient assessment Compliance Too Low Dose Food-Drug Interaction Disease-Drug Interaction Drug-Drug Interaction 36

37 Which drugs? Warfarin(5) digoxin (0.25) Medications (4/8/2551) furosemide (40) atorvastatin (20) esomaprazole (40) domperidone cetirizine seretide accuhaler glakay (menatetrenone) glucosamine sulfate calcium carbonate (1) vitamin B /12/50 10/1/51 18/2/51 INR 4/8/51 37

38 INR and Dose of Warfarin Total weekly dose of warfarin (TW WD) mg/wk /9/ /10/2549 4/9/ /12/ /2/ /4/2551 เร ม GlaKay 10/1/51 21/7/ /7/2551 4/8/ /8/ /8/ /9/ /10/ INR TWD INR Glakay (Menatetrenone 45 mg = VitaminK 2 preparation) Indication: Improvement of decrease in bone mass and relief of pain in patient of osteoporosis Pharmacokinetics : Absorption A) Bioavailability 1) Absolute bioavailability data lacking. B) Effects of Food : enhanced absorption In healthy Japanese subjects, the bioavailability of menatetrenone was greater as the fat content of meals increased; this reached a peak between 35 and 54 g fat content (Uematsu et al, 1996). 38

39 Glakay (Menatetrenone 45 mg = VitaminK 2 preparation) Metabolism A) Metabolism Sites and Kinetics 1) LIVER, extent unknown. a) Based on data for other vitamin K analogs. B) Metabolites 1) Serum concentrations of vitamin K1 have increased significantly during long-term treatment with menatetrenone (Sato et al, 1998b), suggesting in vivo conversion; this requires confirmation. Partial in vivo conversion of vitamin K1 (oral) to menatetrenone has been observed (Sato et al, 1998b). Glakay (Menatetrenone 45 mg = VitaminK 2 preparation) Excretion A) Kidney 1) Other vitamin K compounds are excreted renally. B) Other 1) OTHER EXCRETION a) BILE, extent unknown. 1) Similar to other vitamin K analogs. 39

40 Drug-Drug Interaction Warfarin Vitamin K Significance 2 Delayed Onset Severity Rapid Major Moderate Minor Documentation Established Probable Suspected Possible Unlikely Drug-Drug Interaction Effects : Oral Anticoagulant action is attenuated or reversed, leading to possible thrombus formation Mechanism : VITAMIN K may inhibit the effect of WARFARIN on VITAMIN K- dependent clotting factors. 40

41 Management Avoid or minimize variable consumption of foods or nutritional supplements containing VITAMIN K. Monitor coagulation indices and observe for signs of thrombus formation or bleeding during variable VITAMIN K ingestion. ค า INR และขนาดยาท ได ร บต อส ปดาห Date INR Dose TWD(mg/wk) (% changed TWD) 4/8/ Warfarin (5) 2 ¼ x1 hs (จ-ศ) Warfarin (5) 2 ½ x1 hs (ส-อา) (16%) หย ด Glakay 18/8/ Warfarin (5) 2 ¼ x1 hs ( 3.17%) 25/8/ Warfarin (5) 2x1 hs 70 ( 11%) 22/9/ Warfarin (5) 1 ½ x1 hs 52.5 ( 25%) 13/10/ Warfarin (5) 1 ½ x1 hs 52.5 (-) 41

42 INR and Dose of Warfarin Total weekly dose of warfarin (TW WD) mg/wk /9/ /10/2549 4/9/ /12/ /2/ /4/ /7/ /7/2551 4/8/ /8/ /8/ /9/ /10/2551 เร ม GlaKay 10/1/51 Off GlaKay INR TWD INR Strategies to Prevent/Manage Drug Interactions 1. Encourage patients to report all prescription (OTC, alternative medicine) 2. Consider whether drug therapy is necessary 3. Screen for potential drug-drug interactions, when adding a new drug to regimen. 4. If drug interaction can not be avoided, adjust doses and/or dosage intervals for affected medication and closely monitor the patient. 5. Carefully monitor other drug therapy when withdrawing a drug that can inhibit or induce hepatic metabolism. 6. Regularly review the need for chronic medications reduce polypharmacy 7. Support the implementation of electronic prescribing and/or the use by patients of one pharmacy with updated drug interaction software. 42

43 43