Moher diperbanyak untuk mnahatsrwa a Secnestor ¢ FE EUA 10/21/2015 ‘adwal eles G mole eo1 rey, jam 7 _ Kelas fe wovlar Tabu EJ nam J 10 - Ae ¥ Why worry......Who cares... eter te ene pe em Fenn ne rma Drug drug Interactions Balcones arpiesee aerate etree ‘Abdul Khaiul Rizki Purba, dr, M.Sc., Sp.FK Aaaeoytce Specialist of Clinical Pharmacology ‘mocap Department of Pharmacology & Therapy 3 probe Universitas Airlangga: Risky Drugs Combination Drugs Interactions + The effect of one drug are altered by another drug + The pharmacologic or clinical response to the administration of a drug combination diferent from that anticipated from the known effects of the two agents when given alone + May be harmful: toxicity, reduced efficacy + May be beneficial: synergistic combinations, phermacokinetic boosting, increased ‘convenience, reduced toxicity, cost reduction Factors affecting the occurrence of clinically important ADIs Consequences of ADIs + ges more ly in edety + Gefficacy or T toxicity + 2.Genees: €g in slow acetyatrs penycin + INH > pheno toxic + Clinically important if + 3.used of OTC dns aa, NALD sing (rac Sabir aoe) ae * object drugs have narrow margin of + 4, Pre-existing disease: safety ro ear y * commonly used in combination reams "=" re * consequences: serious or potentially fatal10/21/2015 Examples of drugs that have a narrow therapeutic index + Oral anticoagulant (warfarin) + Anticancer agents (5-fluorouracil) Immunosuppressive agents (cyclosporine) Digitalis glycoside (digoxin) Anticonvulsants (phenytoin) Oral hypoglycemic drugs (glyburide) Aminoglycosides (gentamycin) Antifungals (amphotericin B) Desirable drug interactions + Combination of antituberculosis, + Combination of antihypertensives = Captopril + Furosemide + Combination of antiasthmatics + Combination of anticancer agents + Combination antidiabetics = Metformin + glibenclamid Theophylline + Penicillins + probenecid + Antagonists / antidotes Antagonists/ Antidotes Drug Interactions + Adrenaline >< anaphylactic shocks + Naloxone >< opioid overdose + Atropine >< organophosphate intoxication ZINN Outside Body Pharmacokinet (Cholinesterase inhibitor) (Pharmaceutical) stella Overdose of Paracetamol? Warfarin? Heparin? Alteplase? Pharmacodynamic Incompetabaity Pharmacokinetic (Pharmaceutical interactions) + Direct interactions : physical or chemical + > precipitation, colour change + > drug inactivation + Eg + Phenytoin + § % dextrose > precipitation + Carbenicilin + gentamycin > gentamycin inactivation om cia Soe ing alate concern ante Sat acai by spsstome M0 CrP) Pharmacokinetic interaction Drug A alters the effect of Drug B by changing the plasma concentration of Drug B10/21/2015 What the body does with drugs Drug enter to body L 5 memos (ene a (@)Simaton oa Drug Interactions: pharmacokinetics + Absorption: food, chelation, GI motility, pH, transport + Distribution: transport, protein binding ‘+ Metabolism: Phase | (CYP450), Phase Il (Conjugation) + Elimination: Renal (glomerular ftration); transport Alterations with food + Decreased rate of absorption; not extent (-+ AUC): = Common for many drugs; take without meats + Decreased extent of absorption (| AUC): = indinavir AUC decreased by 77% with high calorie mest take on an empty stomach ~ J abs : peniilin, rifampicin, INH, captopril + Increased extent of absorption (f AUC): ~ kaconazoie (capsules) AUC increaved by 65% with standard meat ~ Tabs of: phenytcin, HOT, mebendazclo Alterations in absorption: food effects Indinavir +1- food Itraconazole caps +/- food Pram Res 1958, 169) 71826 ‘Aatinisc Agent Chater 198, nay Test — Alterations in absorption: chelation + lireversibie binding of ugs Trovafloxacin inthe Gl tact pee: + Tetracycines, quinolone antivotce (eg Ciprofloxacin) + ferous sulfate (Fe+2), antacids (Alr3, Cas2, Mg#2), dairy products (Ca+2) + Usualy separating ‘administration of chelating ‘drugs by 2+ hours decreases Aninirb Agent Chemetar 1987, Interaction effect Sauna 307 ALTERATIONS IN ABSORPTION Complexation/Chelation Example: antacids + tetracycline Impact: tetracycline complexes with divalent cations forming an insoluble complex10/21/2015 Alterations in absorption: GI Motility 1 GI motiliy: cisapride, metoclopramide | motility: narcotics, antidiarrheals, anticholinergic, high calorie meal > delayed gastric emptying se Sadie + Matacore ALTERATIONS IN ABSORPTION Altered GI Transit Example: antichotinergics + acetaminophen Impact: delay in absorption of acetaminophen > Delay the onset of acetaminophen Change in pH of GI fluids + TPH by : antacids/PPI/ H, blockers + ketoconazole, itraconazol (weak bases) > 1 abs (not fluconazol) Impact: dissolution of ketoconazole is decreased, resulting in reduced absorption + Antacids/ H, blockers/PPI + tolbutamide (weak acids) 3 Tabs. Alterations in absorption Pct Sota Antimicrob Agents Chemother 199135:1785-1771 eterna one (mein tines) Drugs Interaction transport protein + Efflux proteins = P-glycoprotein, MRP, MRP2 (transporter) Push out drug from gut back into lumer absorption = Transporter induction may result in J, absorption = Transporter inhibition may result in * absorption = Inhibition may be of clinica significance for drugs that are large molecules, have low bioavailability, dissolve slowly and/or incompletely ting drug ‘Simplified example of P-gp function eed + Pep substrate: digoxin + Pgp inhibitors: Quinidin, verapamil + The combination-> increase F 60-80% * Pap inducers rifampicin + The combination digoxin + rifampicin > decrease digoxin concentration10/21/2015 Drugs Interaction: transport protein v9 Uptake proteins (Organic Anion ‘Transp Prot) “= Tranaport rug across Amen ang er a OATP cubetates * Provan goin, etonsdine, breiponci| = QATP inhibitors “> may su in| absorption and recioed Bomelebity Pee. nav sun, ~ Inthe iletine, OATP functions GePOsiTE of P-gp te. Pap Bhibton IWERERSES nt ‘boorpion We OATP DECREASES hug soso for compounds that ‘Seaubettes of bin proven Changes in gut bacterial flora + Sulfasalazine > sulfapyridine+5-aminosalicylate gut flora + Broad spectrum antibiotics > suppress gut flora > inhibit conversion to the active components (sultapyridine) Interaction in drug distribution + Plasma protein binding displacement + Clinically significant if the object drug has narrow margin of safety protein binding > 85 % volume distribution < 0.15 V kg + Eg: phenylbutazone displaces: warfarin tolbutamide ALTERATIONS IN PLASMA PROTEIN BINDING Example: phenytoin + valproic acid Impact: protein binding of valproic acid is reduced and total Css decreased 2 sites on Albumin (for acid & neutral drugs): * Site | (warfarin site): warfarin, phenylbutazone, phenytoin, valproic acid, tolbutamid, sulfonamid, dan bilirubin. * Site (diazepam site); diazepam, benzodiazepine, most NSAIDs, penicilin Distribution interaction: Body water changes Lita Lithium excretion reduces Lithium plasma level increases Lithium intoxication -> nephrotoxic Drug Metabolism Interactions + Drug metabolism ~ Chemical modification of a xenobiotic = Phase | (functionaization RX) + Cytochrome P50 (CYP): a, CYPSM4, CYPZDE, CYPAAZ et = Phese i (synthetic RX) + Conjugation: Le, gucwoniation (USTIAY et) = Purpose: detoxticaton of foreign compounds ~ Anatomic sites: Liver, Gut, kidney, lang, brain et10/21/2015 Drug Metabolism Interactions CYP 450 Substrates + Drugs may be metabolized by a single isoenzyme ~ Desipramine/CYP206; indinavi/3Ad; midazolam3A, caffene/CYP1A2; omeprazolelCYP2019 + Drugs may be metabolized by multiple isoenzymes ~ Most devas metabolized by more then ane isozyme + imipramine: CYP208, CYPIA2, PSA, CYP2CI CYP 450 Inhibitors + Usually by compettive binding to enzyme site + Mechanistm-based enzyme inactivation ~ Grape juice and intestinal CYPSA content * The ‘usual euspects’ ~ Cimetidine (various) = Omeprazole (various) = Exthromyein,earitremycin (3A) = ketoconazole, Iraconazaie (384) = Fluonetine, paroxetine (CYP208) = Netazadone (CYPSAS) = auinine (C¥ 208) Valproleacis Protease Inhitors: indinavir and roma (CYP 34) = Grapetrut Jice testinal CYP3A4 oni) Sildenafil (Viagra®) + Grapefruit Juice sn Pra 2 aN HH ALTERATIONS IN HEPATIC METABOLISM Inhibition of Metabolism Example: cimetidine + theophylline Impact: cimetidine reduces the clearance of theophylline causing an increase in adverse effects, Example: omeprazole (prodrug) + clopidogrel (prodrug) > CYP 2C19 interaction > recurrence CVevents Interaction with PPI + Metabolized by CYP 2C19 and CYP 344 ‘+ Drugs with the same pathway of metabolism: Warfarin esomeprazole, lansoprazole, omeprazole, and rabeprazole) Diazepam (esomeprazole, omeprazole) ~ Siklosporin (omeprazole and rabeprazole) + Only Omeprazole (prodrug) clopidogrel (prodrug) > CYP 2019 interaction > recurrence CV events Decrease cisulfiram and phenytoin hepatic dearance Note: omeprazole induce CYP1A2 > increase clearance of imipramine, some antipsychotics, theophylline10/21/2015 CYP 450 Induction + The “usual suspects" = Rifampin = Ritebutn = Carbamazepine = Phenobarbital = Phenytoin = Newrapine, efavirenz = St Joha's wert = Tregitazone, piogitezone CYP 450 Induction *+ Results in reduction of plasma concentration of substrate drugs. Risk of therapeutic failure ~ Removal of inducer may lead to toxc concentrations of substrate — Induction may lead to formation of toxic metabolite ALTERATIONS IN HEPATIC METABOLISM Induction of Metabolism Example: phenobarbital + warfarin > CYP 209 Impact: phenobarbital increases the Sean SEs | oenersenten ‘ee + Amiodarone Phenobarbital + Phenytoin Enzyme inducers > metebelis ‘metabolism of warfarin, resulting in reduced + Fenilbutazen [> Decrease plasma digoxin anticoagulation efficacy + Rifampin Table. Representative substrates, inducers and inhibitors of Terfenadine ‘eytochrome P450 (CYP) enzymes + 2% generation Hi antihistamine (1991) Less lipid soluble > minimal CNS side effects, less sedating effect, long acting * Cardiacside effects are serious — inhibition of potassium channels by unmetabolized parent drug causes prolongation of AY interval leading to life threatening arrhythmia (torsades de pointes) Drugs inhibiting terfenadine metabolism: grape fruit, ketoconazole, itraconazole, erythromycin = | somes10/21/2015 epresenatve subetraes, inde and inhibitors of croton PASO (CYP) yes Alteration hepatic blood flow * Lidocaine (high hepatic extraction ratio) + propranolol (decrease HBF) > 1) lidocaine clearance * Lidocaine + (isoproterenol, nifedipine) > lidocaine clearance Alterations in biliary clearance & enterohepatic circulation biliary clearance > Transport + Rosuvastatin, Pravastatin (P-gp substrate) + cyclosporine/verapamil (P-gp inhibitor) > Rhabdomyolisis > myopathy enterohepatic circulation + Broad-spectrum antibiotics (tetracycline, amoxicilin) + oral contraception (estradiol) > estrogen reabsorption + ALTERATIONS IN RENAL CLEARANCE Increase in Renal Blood Flow Example: hydralazine + digoxin Impact: hydralazine increases the renal clearance of digoxin ALTERATIONS IN RENAL CLEARANCE Inhibition of Active Tubular Secretion: Anion transporter Example anion transport: probenecid (uricosuric agent) + penicillin > MRP competition Impact: probenecid prolongs the half-life of penicillin, allowing single dose therapy Drugs interaction in tubular secretion: kation transport protein Ronguchusanel a Br Jin Pamacs 202 62.810/21/2015 ALTERATIONS IN RENAL CLEARANCE Alterations in Tubular Reabsorption Example: antacids + aspirin Impact: antacids reduce the tubular reabsorption of salicylate via an increase in urine pH ‘Overdose appicaton: - Ammonium cherie for overdose of base drugs (¢.6 amphetamine) ~ Sodium bicatbonete -> for overdose of cid drugs (e.9 asin) = Pharmacodynamic Related tothe drug's effects in the body ‘One crug modulates the pharmacologic effect of another ‘additive, synergistc, or antagonistic Pharmacodynamic interaction Drug A alters the effect of Drug B without a ‘change in the concentration of Drug 8 Pharmacodynamic interactions can be extrapolated {forall drugs in a group, because drugs classifications are commonly based on class effect/ pharmacodynamic effects Pharmacodynamic interactions ‘Antidepressants ‘Sympathomimetes Monoamine Oxidase Decongestants Intibors (MAO) Inhibit (pseudoephierine) breakdown of ‘Asthma (salbutamol) Noradtenal Foods rch in tyramine (Beer, Wine, Beans) aera MAOIs enhance effects of these drugs Ipauacaphitne and stb) ‘And enhance the action of tyramine Pharmacodynamic Interactions NSAIDs ‘Antnypertensives Fr intammations {81 Antagonist headache. ft Antagonist Most block Prostaglandin ‘Angiotensin Converting ‘eynthesis, PGE, and PCI; Enzyme (ACE) ‘cause renal arteriolar Innbitors dition Diuretes bp Loss of ability to diate renal arterioles (via PGE, and PG) ‘an lead to hypertensive crisis in people taking anthypertensives Pharmacodynamic Interactions Benzodiazepines cee (and anthistamines, anticonvulsants, barbiturates) CNS depressant (CNS depressant Respiratory depression, typotension, coma Pharmacodynamic interactions Beta 1 blocker Verapamil, Dittazer Inotropic negative cee, ‘Adaltve’ block AV Oo Severe block AV, bradycardia, heart fiure10/21/2015 Pharmacodynamic Interactions Thazige Digoxin Diminich potassium stores Ant-arrhythmia Digenn intoxation a Arthythmias, Anphoterisin > hypokalemia > digitalis toxicity 1 Pharmacodynamic interactions Asthmaties Hypertension fen take a fy ‘Often take B blockers agonist (salbutarno) to (propanol) to reduce induce heart rate force of — Diminished effect of agonist How about patients with Hypertension + Asthmatics + OM? Other pharmacodynamics interactions K sparing diuretic (spironolactone, eplerenone) + ACE inh/ARB -> hyperkalemia Warfarin + aspirin > bleeding Aminoglycosides + furosemide -> ototoxicity & nephrotoxicity Antihistamine + Atropin > muscarinic receptor blockers -> anticholinergic syndrome Evaluation of Specific Drug Interactions + Whatis the time-course of the interaction? — Immediately or over a period of ime + Isita drug class effect? = omeprazole vs, lansoprazole + Is the interaction clinically significant? = Therapeutic index of drugs + Natow o wide? + How should the interaction be managed? ~ Switch to another drug? Change dose? Strategies to Prevent/Manage Drug interactions 4. Encourage patients to report al prescription (OTC and comlemerary ang aerate drugs at ever heath care 2. Consider whether drug therapy is necessary 3. If crug interaction can not be avoided, adjust doses and cnidosage eras for afected medcaton ané onto he patient cosely, 4. Carefuly monitor other drug therapy when witherawing a rug tat ean inhibit or inauee hepate metabelar™ 5, Regularly review the need for chranle medicatione-reduce polypharmacy Success for your study