Drug-drug interactions in the elderly

Transcription

1 December 08, 2016 Gerontopsychiatry CME, TAU Drug-drug interactions in the elderly Daniel Kurnik, MD Director of Clinical Pharmacology, Rambam Clinical Associate Professor, Technion

2 Definition DDI: One drug affects the activity (efficacy or toxicity) of another drug to a clinically meaningful degree Main concerns: Enhanced toxicity / reduced efficacy Intentional uses: e.g. Penicillin / probenecid

3 Adverse drug events: Epidemiology Drug errors and adverse drug events are the most common iatrogenic illnesses in the US Drug-related morbidity and mortality: $130 billion/year in US Some adverse drug events are caused by drugdrug interactions

4 Adverse drug events and DDIs DDIs Dose adjustment (disease, age) Dose error Adverse drug event Medication error Administration error Duplicate therapy

5 Adverse Drug Events (ADEs) Responsible for 5-28% of acute geriatric hospital admissions > 90% of ADEs in the elderly are considered predictable, and ~50% are preventable Most errors occur at the ordering and monitoring stages

6 Ageing, DDIs, and adverse effects

7 Ageing and comorbidities 100% 90% 80% 70% 60% 50% 40% 30% 70% 20% 10% 0% 48% yrs 85 yrs % of patients with 5 chronic diseases

8 Older age = more disease = more medications

9 Increasing polypharmacy is associated with NPS wise: Older, wiser, safer, Sept 2013

10 Prescribing Cascade Drug 1 ADE interpreted as new medical condition Drug 2 ADE interpreted as new medical condition Drug 3 Rochon PA, Gurwitz JH. Optimizing drug treatment in elderly people: the prescribing cascase. BMJ 1997;315:1097.

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12 The dogma of aging More Disease Greater impact on functional state More Drugs More DDIs + ADEs

13 DDI epidemiology: Methods (1) 1.Cross-sectional study of medication review - hospitalized patients - nursing home residents - ambulatory patients 2. Case-control studies of patients with ADRs, determining exposure to DDI

14 DDI in elderly: Epidemiology At hospital discharge, 62.5% of patients were prescribed drugs with potential DDIs (38% moderate, 2% severe) 13% of veterans discharged from ER with potential DDI 2 4% of elderly patients in the community take chronic medications with potential major DDIs 3 1 Becker ML. Pharmacoepidemiol Drug Safety 2007;16: Hastings SN. J Am Geriatr Soc Quato DM. JAMA 2008

15 Adverse drug events secondary to DDIs Nested case-control study of patients in Ontario, Canada, aged 66 years, hospitalized for adverse drug event Drug Adverse event resulting in hospitalization Interacting drug Adjusted OR* (95% CI) Glibenclamide (Gluben ) Hypoglycemia Co-trimoxazole (Resprim ) 6.6 ( ) Digoxin Intoxication (serum concentrations) Clarithromycin 11.7 ( ) ACE-inhibitors Hyperkalemia Potassium-sparing diuretics (spironolcatone) 20.3 ( ) Juurlink N. DDIs among elderly pts. Hospitalized for drug toxicity. JAMA 2003;289: *for having used interacting drug prior to ADE

16 Mechanisms of DDIs 1. Pharmacokinetic (PK) interactions - effect on absorption, distribution, metabolism, and elimination (ADME) 2. Pharmacodynamic (PD) interactions - effect on the function of the target organ / system

17 Intermediate steps of drug action Administration Drug effect

18 Pharmacokinetics: What the body does to the drug

19 Plasma concentration Pharmacokinetics ADME Time

20 Intermediate steps of drug action Administration Plasma concentration Pharmacokinetics Pharmacodynamics Concentration at site of action Drug effect

21 Pharmacokinetic DDIs := Delivery of a drug to its target site is affected by another drug One drug alters the rate or extent of absorption, distribution, metabolism or excretion (ADME) of another drug. A change in blood concentration causes a change in the drug s effect.

22 PK-based DDIs: Reduced availability for absorption Change in gastrointestinal ph Ketoconazole needs acidic conditions in gut Drug binding (chelation) in GI tract E.g. tetracycline and calcium Change in gastrointestinal flora Antibiotics with OCs Change in gastrointestinal motility Metoclopramide and digoxin Malabsorption caused by other drugs Orlistat (Xenical) and fat soluble vitamins

23 PK-based DDIs: ph-dependent absorption Dasatinib after famotidine (10 hr) Dasatinib before famotidine (2 hr) 61% AUC reduction Systemic exposure to dasatinib (Sprycel ) and gastric acid-suppression Eley T, J Clin Pharm 2009

24 PK-based DDIs: Intraluminal chelation of Quinolones Ciprofloxacin + Calcium carbonate Ofloxacin + Calcium carbonate Aluminium, magnesium, iron, zinc: Drug-mineral binding, decreased absorption

25 Plasma Levodopa (nmol/ml) Plasma carbidopa (nmol/ml) PK-based DDIs: Intraluminal chelation of L-Dopa Time (min) Time (min) Effect of ferrous sulfate (325 mg) on plasma levodopa and carbidopa concentrations after ingestion of Sinemet (100/25) in patients with Parkinson's disease. Concentrations shown are mean values without (open triangles) and with (closed circles) simultaneous ferrous sulfate administration. Adapted from Campbell NRC et al: Br J Clin Pharmacol 30: , 1990

26 Drug transport in absorption, distribution, and excretion Transporter / Carrier

27 Pharmacokinetics: What the body does to the drug

28 Intestinal drug transporters Uptake transporters, e.g., OATP, MRP2 Efflux transporters, e.g. P-gp (MDR1), BCRP

29 Transporters in biliary drug excretion

30 Drug transporters in renal drug excretion

31 Distribution into target tissues Example: Blood-brain barrier BioImpacts, 2012, 2(1), 5-22

32 P-gp at the BBB

33 Examples: Transporter-based DDIs (1) A 72-yr old patient with atrial fibrillation is treated chronically with digoxin (0.125 mg/d) for rate control, and his serum digoxin concentrations are stable (around 1.0). He then receives clarithromycin (500 mg x2/d) for purulent bronchitis. During his antibiotic treatment, he suffers a syncope. On admission at the ER, he is found to have a 3 rd degree AVblock. His digoxin serum concentrations are 3.6

34 P-glycoprotein (MDR1) distribution

35 P-glycoprotein is a major determinant of drug disposition Location Function Absorption Intestinal epithelium Oral bioavailability Distribution Excretion Capillary endothelium Intestinal + renal tubular epithelium, hepatic biliary membrane Drug penetration into brain, testes / ovaries, fetus Excretion (renal, hepatobiliary, and intestinal)

36 DDIs involving P-gp Digoxin area under the curve (AUC) and peak plasma concentration (c max ) in the presence and absence of a P-gp inhibitor. Fenner, CPT 2008

37 Transporter-based DDIs (2) Mtx with NSAIDs or salicylates: Competition for active secretion via OAT1 and OAT3

38 Therapeutic use of transporter-mediated DDI

39 Metabolic DDIs

40 Drug A Phase 1 metabolism Cytochrome P 450 CYP1A2 CYP3A CYP2C9 CYP2C19 CYP2D6 Phase 2 metabolism Glucuronidation (UDP-glucuronosyltransferases) N-Acetylation (N-acetyltransferases, NATs) Gluthation-conjugation (Gluthatione-S-transferases)

41 Cytochromes P 450 (CYPs) CYP2D6 P4502D6 CYP2C9 P4502C9/10 CYP21A2 P4501A2 P4502A6 CYP2A6 P4502C19 CYP2C19 CYP2E1 P4502E1 CYP3A4/5 P4503A Proportion of drugs metabolized by individual CYPs

42 CYP 450 System Definitions Substrate: Drug is metabolized by the CYP 450 Inducer: Drug increases the synthesis of CYP 450 Inhibitor Drug inhibits the CYP 450 and the metabolism of other substrates. An inhibitor may also be a substrate

43 Drug interaction: Competitive inhibition of drug metabolism Competitive inhibition More Drug drug A Drug B

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45 Enzyme Inhibition Often rapid, reversible and relatively short duration (e.g. erythromycin and cyclosporin) May be prolonged due to long half- life of drug. (e.g. amiodarone and warfarin)

46 Inhibition of metabolic enzymes Inhibition of CYP Lower rate of metabolism Increased substrate serum concentrations Drug toxicity

47 CYP inhibitors 1A2 2B6 2C8 2C9 2C19 2D6 2E1 3A4,5,7 cimetidine fluoroquinolones fluvoxamine 1 ticlopidine thiotepa ticlopidine 2 gemfibrozil montelukast 1 fluconazole 2 amiodarone isoniazid esomeprazole fluoxetine fluvoxamine ketoconazole lansoprazole omeprazole ticlopidine 2 bupropion fluoxetine paroxetine quinidine 1 duloxetine amiodarone cimetidine chlorpheniramine clomipramine doxepin haloperidol methadone mibefradil ritonavir A Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance. A Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance. disulfiram A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). HIV Antivirals: indinavir nelfinavir ritonavir Antibiotics clarithromycin itraconazole ketoconazole nefazodone erythromycin Mixed grapefruit juice verapamil 2 suboxone diltiazem cimetidine amiodarone NOT azithromycin fluvoxamine mibefradil troleandomycin

48 Example: DDI due to metabolic inhibition A 56 yr old patient with COPD and coronary artery disease (S/P MI) suffers from fever (38.0) and COPD exacerbation without signs of pneumonia on chest x-ray. His chronic medications include aspirin, atenolol (100 mg), enalapril (10 mg), Rhabdomyolysis simvastatin (80 mg/d), and inhalers with salbutamol and beclamethasone. You start roxythromycin (150 mg x 2/d for infectious COPD exacerbation. He returns because of muscle pain, small volume of dark urine, and weakness and nausea. On lab: acute renal failure and

49 Example: Warfarin 74-yr-old male patient, with paroxysmal atrial fibrillation (PAF), on chronic warfarin therapy (5 mg/d). For the prevention of recurrent PAF, amiodarone is started. 1 week later:

50 Hemorrhagic stroke On presentation: INR= 7.6

51 Induction of metabolic enzymes (1) Leads to production of more enzyme, usually after 3-4 days of exposure to inducer Most CYPs are inducible (except CYP2D6) Time course of interaction depends on half-life of inducer. Enhanced metabolism of substrate drugs

52 A therapeutic use of metabolic DDI L-Dopa / Carbidopa

53 Induction of metabolic enzymes (2) Induction of CYP Higher rate of metabolism Reduced substrate serum concentrations Therapeutic failure

54 Enzyme Inducers: Examples Rifampicin (short t 1/2, induction within day) Barbiturates (long t 1/2, induction within days) Carbamazepine, phenytoin Amiodarone Tobacco St. John s wort

55 Example A 26-year old patient with bipolar disease has been started on carbamazepine as mood stabilizer. Her other medications include lithium and contraceptive pills. Three months later she is pregnant and files a law suit against you

56 Pharmacodynamic (PD) DDIs

57 Intermediate steps of drug action Administration Plasma concentration Pharmacokinetics Pharmacodynamics Concentration at site of action Drug effect

58 Pharmacodynamics (PD) PD:= Study of effects of drugs on the body and their mechanism of action Drug - receptor interactions Concentration-effect relationship, Mechanism of therapeutic and toxic effects PD: What the drug does to the body

59 Pharmacodynamic DDIs One drug causes a change in patient response to another drug without altering that drug s pharmacokinetics, e.g., because both drugs have similar drug targets or similar therapeutic or adverse effects. Eg increase toxicity of digoxin caused by diuretic induced hypokalaemia Additive effects of alcohol and benzodiazepines Beta-blocker given with beta-agonist

60 PD DDIs: Shared drug target β -adrenergic receptor agonists/antagonists: reduced efficacy (e.g. β 2 -agonists (Ventolin ) and β- blocker) Muscarinic Ach-receptor blockade: additive anticholinergic effects (e.g. antihistamines, phenothiazines, tricyclic antidepressants) Serotonin-reuptake blockade: Serotonergic syndrome (e.g. fluoxetine + amitriptyline)

61 PD DDIs: Shared and thus exaggerated therapeutic effects Antihypertensive drugs (e.g. calcium-channel blockers, ACE-inhibitors, beta-blockers, diuretics) AV-node conduction (beta-blockers + verapamil/diazepam) Coagulation and platelet function inhibitors (Anticoagulants and antiplatelet drugs: e.g. warfarin, dabigatran, rivaroxoban, aspirin, clopidogrel, prasugrel, LMW heparins)

62 PD DDIs: Shared and thus exaggerated adverse effects Additive sedation (e.g. antipsychotics, antiepileptics, antihistamines, opiates, benzodiazepines) Additive electrolyte imbalance (e.g. hypokalemia from furosemide and β 2 -agonists, hyponatremia from SSRIs and furosemide, hyperkalemia from ACE-I and spironolactone) Additive metabolic effects (olanzapine and steroids weight and glucose homeostasis)

63 PD DDIs: other mechanisms Lithium / thiazide diuretics (enhanced Li+-reabsorption because of Na+-excretion) Furosemide/digoxin (furosemide-induced hypokalemia enhances digoxin toxicity)

64 Serotonergic syndrome as DDI Boyer, NEJM 2005

65 Serotonergic syndrome after MAO-I Wimbiscus et al. Cleve Clin J Med 2010

66 Risk factors for DDIs

67 Risk Factors for Drug Interactions High Risk Patients Elderly, young, very sick, multiple disease Multiple drug therapy Renal or liver impairment High Risk Drugs Narrow therapeutic index drugs High-risk PK Recognized enzyme inhibitors / inducers

68 High-risk patients

69 Patient risk factors for PK-DDIs 1. Comorbidities and polypharmacy (source for multiple DDIs!) 2. Decreased renal and/or liver function (decreased hepatic / renal drug elimination) 3. Self-medication (herbal, alternative medicines, illicit drugs)

70 Age as risk factor for DDIs Zisook S, J Clin Psych 1998

71 Older patients have more adverse drug events....mainly because they take more drugs. Gurwitz JH, Ann Int Med 1991

72 High-risk drugs

73 % of population responding Therapeutic index/window Drug dose (mg/kg)

74 Some drugs with a low therapeutic index Lithium Digoxin Theophylline/ Aminophylline Phenytoin Phenobarbitone Cyclosporin Lamotrigine Opiates Tacrolimus Carbamazepine Warfarin Everolimus

75 Low-risk pharmacokinetics Drug M1 Χ M4 M2 M3 M3

76 High-risk pharmacokinetics More Drug M1 Χ M4 M2 M2

77 Drugs often involved in DDIs in the elderly NSAIDs, anticoagulants, cardiovascular drugs Antidepressants, antipsychotics Antiepileptics CNS depressants Anticholinergics Immunosuppressants (after organ transplant) HIV drugs

78 Examples for common DDIs Drug combinations Adverse outcome Predisposing factors ACE-I or ARB with K- sparing diuretic, trimethoprim, betablockers, cyclosporine, NSAIDs, heparin Benzodiazepines/zolpide m Calcium channel blockers (amlodipine, nifedipine) + clarithromycin Sulfonylureas and cotrimoxazole, macrolidse, and quinolones Antipsychotics and metoclopramide Hyperkalemia Falls, fractures Hypotension, acute kidney injury Renal failure Diabetes mellitus age Mechanism PD-DDI Competitive inhibition of CCB metabolism Hypoglycemia Renal failure Competitive inhibition of SH metabolism Extrapyramidal symptoms Additive adverse effects

79 Bryant L. J Prim Health Care 2009

80 High risk-drugs for DDIs Harrison s

81 How to identify and manage a potential DDI

82 Sources: Definitions What constitutes a DDI? - Online databases (Micromedex, LexiComp ) - DDI lists - Books () - Individual literature searches (Pubmed) - FDA / EMA alerts - Drug leaflets, manufacturer information

83 Drug-Drug Interactions (1) Drugs: IBUPROFEN -- METHOTREXATE Severity: Major Documentation: Good Summary: Drug interaction is major Concurrent use of METHOTREXATE and IBUPROFEN may result in an increased risk of methotrexate toxicity (leukopenia, thrombocytopenia, anemia, nephrotoxicity, mucosal ulcerations).

84 DDI evaluation: Clinical significance

85 DDI evaluation: Grading the evidence

86 DDI epidemiology: Methods (2) Grading of evidence 1. How well is the causality of the DDI established, using the hierarchy of evidencebased medicine? Green, Byar, 1984 Anecdotal case reports, case series (no or historical controls) Case-control study (retrospective) Cohort study (prospective) Randomized clinical trial (RCT) Meta-analysis of RCTs Weight of evidence

87 History Comorbidities Concomitant medications Allergies, previous adverse drug responses

88 Managing potential DDIs

89 Summary DDIs are common and largely preventable causes of adverse drug events DDIs are more common for specific high-risk drugs and in high-risk patients When a potential DDI is identified, its management includes risk-benefit assessment, and then, accordingly, change in prescription or careful monitoring

90 Drugs in life

91 Thanks. Questions?