Pharmacokinetic and Pharmacodynamic Drug Interactions in Palliative Care Kathryn Walker, Pharm.D., BCPS, CPE Assistant Professor University of Maryland School of Pharmacy
Disclosure • Nothing to disclose
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Learning Objectives • Differentiate between pharmacokinetic and pharmacodynamic drug properties • Define a drug interaction • List 3 drug-drug interactions that are common in long term care facilities
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Are Palliative Care Patients at Risk for Drug Interactions (DI)? • General population: 3-20% depending on severity of illness and number of medications • Risk Factors: – Live alone – 3 or more medications – Elderly and/or memory problems – Many doctors and pharmacies involved – Adherence Bruera E, Bernard SA. JCO. 2000; 18:1780-1799.
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Illustrating the Challenge • Average 5.6 (1-16) medications per patient (n=106) • 60% noncompliant (n=111 terminally ill palliative care patients) • 33% took less medications than prescribed (commonly analgesics) • 16% took additional medication (e.g., OTC vitamins/analgesics) • 11% both
• 90% had two or more prescribers Zeppetella G. Palliat Med. 1999; 13:469-475.
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Illustrating the Challenge • Survey of 405 cancer patients • 25% at risk for potential drug interactions • 87% noncancer medications (e.g., warfarin, HTN corticosteroids, anticonvulsants) • Severity – 9% considered major interactions – 77% considered moderate interactions
Riechelmann RP, et al. J Natl Cancer Inst. 2007; 99: 592-600.
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Challenges in Palliative Care • Difficult to distinguish between “True” drug interactions vs. disease progression or adverse effect
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Pharmaco-Stuff • Pharmacokinetic – Absorption, distribution, metabolism, excretion
• Pharmacodynamic – The action of the drug once it reaches its target (receptor) in the body
• Pharmaceutical – Relating to the preparation of the drug, including its inactive components, form, solvent, etc.
Defining a Drug Interaction • “A measurable modification (in magnitude or duration) of the action of one drug by prior or concomitant administration of another substance.” – Drug-drug (Rx, OTC, herbal) – Drug-food, drug-alcohol – Drug-lab, drug-disease, drug-chemical
Wright 1992. Drug Interactions. In: Melmon and Morrelli’s Clinical Pharmacology 1992
Drug metabolism in the liver • Metabolism is characterized by two phases of enzymatic reactions which make the drug more water soluble to facilitate elimination from the body – Phase I (biotransformation) • Oxidation, hydroxylation, reduction, hydrolysis • Chemical modification to add a functional group
– Phase II (conjugation) • Functional group used to attach a conjugate • Acetylation, glucuronidation, sulfation, methylation
Phase I Drug Oxidation
www.fda.gov/cder/drug/drugReactions/
Cytochrome P450 System • A very large and diverse superfamily of hemecontaining proteins – Founds in mammals, birds, fish, insects, worms, sea squirts, sea urchins, plants, fungi, slime molds, bacteria and archaea
• The cytochrome P450 system – Drug-metabolizing enzymes – Enzymes that are used to make cholesterol, steroids, and other lipids (prostacyclins, thromboxane A2)
Cytochrome P450 Oxidase (CYP2C9)
http://en.wikipedia.org/wiki/Image:CytP450Oxidase-1OG2.png
Cytochrome P450 Nomenclature (e.g. CYP2D6) CYP = cytochrome P450 (root) 2 = genetic family D = genetic sub-family 6 = specific gene – All CYP isoenzymes in the same family have at least 40% structural similarity – All member in the same subfamily have at least 60% structural similarity • NOTE that this nomenclature is genetically based: it has NO functional implication • • • •
www.fda.gov/cder/drug/drugReactions/
Major CYP450 Enzymes • More than 90% of human drug metabolism is due to six CYP isoenzymes • 1A2 • 2C9 • 2C19 • 2D6 • 2E1 • 3A4
Importance of CYP450s Relative Importance of P450s in Drug Metabolism CYP2E1
Relative Quantities of P450s in Liver
CYP1A2
?
CYP1A2
CYP2C CYP2C CYP3A CYP2D6
CYP2E1 CYP3A
Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414. www.fda.gov/cder/drug/drugReactions/
CYP2D6
Consequences of drug metabolism • • • • • •
Inactive products Active metabolites Similar to parent drug More active than parent New action Toxic metabolites
www.fda.gov/cder/drug/drugReactions/
Alteration in drug metabolism • May alter consequences of drug metabolism • Altered activity may be due to – Interacting drugs that increase or decrease inherent enzyme activity – Inter-individual capability of metabolic enzymes – Other patient factors
What is a substrate? • Substrate – a compound that is metabolized by a given enzyme – Fluoxetine (substrate) is metabolized by CYP2D6 and CYP3A4 • More than one enzyme can metabolite a single agent • If one enzyme system is shut down (or otherwise altered) the other can still metabolize fluoxetine
What is an inhibitor? • Inhibitor – a compound that “slows down” the metabolism of a substrate by a given enzyme – Fluoxetine (inhibitor) slows down the metabolism of desipramine (substrate) by CYP2D6 – Causes desipramine levels to rise – Can have adverse clinical consequences • Arrhythmias • Possibly fatal
http://apotential.wordpress.com/2011/08/22/how-to-memorize-cyp450/
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What is an inducer? • Inducer – a compound that “speeds up” the metabolism of a substrate by a given enzyme – Carbamazepine (inducer) speeds up the metabolism of clozapine (substrate) by both CYP1A2 and CYP3A4. – Clozapine plasma levels will fall – If carbamazepine is discontinued, clozapine levels will rise
• Potent inducers of multiple CYP450 enzymes: – Rifampin, barbiturates, carbamazepine, griseofulvin, primidone, phenytoin – Roy’s Black Car Goes Putt Putt
http://apotential.wordpress.com/2011/08/22/how-to-memorize-cyp450/
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Effects of inducers and inhibitors Toxic
Concentration of Drug X
Therapeutic
A
B
Subtherapeutic
Drug Y
Drug Z
A – an inducer (Drug Y) was added to drug regimen (Drug X) B – an inhibitor (Drug Z) was added to drug regimen (Drug X)
www.drug-interactions.com
Methadone: bad kitty • Primarily metabolized by N-demethylation to an inactive metabolite: – 2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidene (EDDP)
• Metabolized by – CYP3A4, CYP2B6, and CYP2C19 – To a lesser extent CYP2C9 and CYP2D6 Weschules, et al. Pain Medicine. 2008;9:315-44.
Methadone Inhibitors • • • • • • • • • •
Amiodarone (Cordarone) Cimetidine (Tagamet) Ciprofloxacin (Cipro) Erythromycin (EES) Clarithromycin (Biaxin) Fluconazole (Diflucan) Fluoxetine (Prozac) Paroxetine (Paxil) Ketoconazole (Nizoral) Ritonavir (Norvir)
• Results in INCREASED methadone serum concentrations • Reduce calculated methadone dose by approximately 25%
Methadone Inducers • Carbamazepine (Tegretol) • Phenobarbital (Luminal) • Phenytoin (Dilantin) • Primidone (Mysoline) • Rifampin (Rifadin) • METHADONE (autoinduces)
• Results in REDUCED methadone serum concentrations • Encourage use of breakthrough opioid as needed
Polymorphic distribution for CYP2D6
Number of Subjects
• Polymorphic = a trait that has differential expression in >1% of the population
PM
EM Increasing Metabolic Capacity
www.fda.gov/cder/drug/drugReactions/
URM
Metabolizer status in racial/ethnic groups Enzyme
Phenotype
Frequencies
CYP1A2
PM
Caucasians 12%
CYP2C9
PM
Caucasians 2-6%
CYP2C19
PM
Caucasians 2-6% Chinese 15-17% Japanese 18-23%
CYP2D6
PM
Caucasians 3-10% Chinese/Japanese/ AA < 2%
UR
Ethiopians 20% Hispanics 7% Scandinavians 1.5%
Pain Medicine 2004;5(1):81-93
PM â&#x20AC;&#x201C; poor metabolizer UR â&#x20AC;&#x201C; ultra-rapid metabolizer
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Top Ten DI in LTC Drug Interaction
Description
Warfarin ↔ NSAIDs
Bleeding risk
Warfarin ↔ Sulfa drugs
Bleeding risk
Warfarin ↔ Macrolides
Bleeding risk
Warfarin ↔ Quinolones
Bleeding risk
Warfarin ↔ Phenytoin
Bleeding risk
ACE Inhibitors ↔ Potassium Supplements Increased K levels ACE Inhibitors ↔ Spironolactone
Increased K levels
Digoxin↔ Amiodarone
Digoxin toxicity
Digoxin↔ Verapamil
Digoxin toxicity
Theophylline↔ Quinolones
Theophylline toxicity
http://www.amda.com/tools/clinical/m3/topten.cfm
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Drug interactions in palliative care • Mostly involve warfarin and anticonvulsants • Higher risk groups – Older – More comorbidity – Increasing number of meds – CNS tumors
Riechelmann, et al. J Pain Symptom Manage. 2008;35:535-43.
Examples in palliative care • Codeine (CYP2D6) – Poor metabolizers are unable to convert codeine to morphine (no pain relief)
• Hydrocodone, oxycodone (CYP2D6) – Structurally similar to codeine and as such their metabolism could be under genetic control leading to variability of clinical response (side effects, efficacy, and dependence) Bernard. Hematol Oncol Clin N Am 2002;16:641-55.
Examples in palliative care • Phenytoin (CYP1A2, CYP2C9, CYP2C19) – Phenytoin toxicity for poor metabolizers; low levels of drug for ultra-rapid metabolizers at therapeutic doses
• Diazepam (CYP2C19, CYP3A4) – Unacceptable prolonged sedation in poor metabolizers, unconsciousness noted more in Asian populations Bernard. Hematol Oncol Clin N Am 2002;16:641-55.
Examples in palliative care • Venlafaxine (CYP2D6) – Metabolism slower in those lacking a functional CYP2D6 gene
• Nortriptyline (CYP2D6, CYP1A2) – Ultra-rapid metabolizers require up to 500 mg/day to reach therapeutic dose
Bernard. Hematol Oncol Clin N Am 2002;16:641-55.
Warfarin • Several hundred interacting drugs, foods, herbs, and supplements, and the list continues to expand • Potentiation (high INR): acetaminophen, amiodarone, ciprofloxacin, fenofibrate, fish oil, sertraline, metronidazole, fluconazole, traimethoprim/sulfamethoxazole • Induce (low INR): vitamin K foods, avocado, sucralfate, all inducers Holbrook et al. Arch Intern Med 2005;165:1095-1106.
Mnemonic and mechanisms of Interaction for the FAB-4 Significant Warfarin Drug Interactions Medication F
A B
Mechanism of Drug Interaction
Clinical Outcome
Patient Education
Elevated INR
Inform patient of drug interaction and management approach.
Fluconazole (Diflucan)
• Inhibition of CYP2C9 • Decreased vitamin K production
Amiodarone (Cordarone)
• Inhibition of CYP2C9
Increased risk of bleeding
Bactrim (TMP/SMX)
• Inhibition of CYP2C9 • Decreased vitamin K production
Consider alternative agents when appropriate
Four Flagyl (metronidazole)
• Inhibition of warfarin metabolism • Decreased vitamin K production
The Consultant Pharmacist March 2009; Vol 24, No 3
Stress importance of follow-up and frequent INR monitoring. Review sxs bleeding and actions to take 41
Food-drug interactions • Grapefruit juice – a selective inhibitor of intestinal metabolism – Inhibits CYP3A enzymes in intestinal cells (minimal effect on hepatic CYP3A enzymes) – Felodipine increased from 14.2% with water to 25.3% after grapefruit juice – One glass of juice / day x 3 days doubled serum concentrations of lovastatin – Three glasses / day: 15-fold increase in lovastatin and simvastatin serum concentrations Kiani J, Imam SZ. Nutr J. 2007;6:33.
Drug Interactions • Pharmacodynamics – The study of the action and effects of medications on physiologic function
• Pharmacodynamic drug interactions can be: – Additive (two or more analgesics) – Synergistic – Antagonistic (dexamethasone and glyburide)
Pharmacodynamic Drug Interactions in Palliative Care • • • • • •
Anticholinergic effects Constipation Lowered seizure threshold Serotonin syndrome CNS depression QTc prolongation
Antimuscarinic Pharmacologic Effects: Peripheral • • • •
Dry eyes Urinary retention Dry mouth Constipation
• Heat intolerance • Tachycardia • Decreased sweating
Carnahan et al. J Clin Pharmacol 2006;46:1481-1486
Antimuscarinic Pharmacologic Effects: Central • • • •
Forgetfulness • Dizziness Agitation / confusion • Drowsiness Delirium • Falls Paranoia
Carnahan et al. J Clin Pharmacol 2006;46:1481-1486
Evoking Antimuscarinic Effects Overactive bladder • Oxybutynin (Ditropan) • Toleradine (Detrol) • Trospium (Sanctura) • Solifenacin (Vesicare) • Darifenacin (Enablex) Anticholinergic / • Trihexyphenidyl (Artane) Antiparkinson’s • Benztropine (Cogentin) • Amantadine (Symmetrel) Antivertigo / • Meclizine (Antivert) antiemetic • Scopolamine (TransDerm Scop)
Evoking Antimuscarinic Effects Gastrointestinal / Antispasmodics Antisecretory / Drying Agents Bronchospasm
• Diphenoxylate (Lomotil) • Dicyclomine (Bentyl) • Hyoscyamine (Levsin) • Atropine (ophthalmic given PO) • Ipratroptium (Atrovent) • Tiotroptium (Spiriva)
Antimuscarinic Adverse Effects Sedating Antihistamines
• Diphenhydramine (Benadryl) • Hydroxyzine (Vistaril)
Tricyclic Antidepressants
• Amitriptyline (Elavil) • Nortriptyline (Pamelor) • Desipramine (Norpramin) • Doxepin (Sinequan) • Chlorpromazine (Thorazine) • Olanzapine (Zyprexa) • Clozapine (Clozaril) • Thioridazine (Mellaril)
Antipsychotic Agents
Antimuscarinic Adverse Effects Phenothiazines
• Prochlorperazine (Compazine) • Promethazine (Phenergan)
Antiarrhythmic Agents
• Disopyramide (Norpace)
Muscle relaxants
• Cyclobenzaprine (Flexeril) • Orphenadrine (Norflex)
Constipation • 40% of all ADR affect the GI tract • Drug-induced constipation occurs at therapeutics doses of drugs and is dose-related • Medications most likely to cause constipation include: – – – – – –
Antispasmodics (11.6%) Antihistamines (9.2%) Antidepressants (8.2%) Diuretics (5.6%) Aluminum antacids (3.0%) Opioids (2.6%) Talley NJ et al. Amer J Gastroenterology 2003;98:1107-1111.
Drug-Induced Constipation Therapeutic Category
Examples
Analgesics
Opioids (morphine), NSAIDs (ibuprofen)
Anticholinergics
TCA, antipsychotics (haloperidol), antiparkinsonian agents (benztropine), antihistamines (H1; diphenhydramine), antispasmodics (dicyclomine)
Cation-containing agents
Aluminum (antacids, sucralfate), calcium (antacids, supplements), bismuth, iron supplements, lithium
Chemotherapy
Vinca alkaloids (vincristine), alkylating agents (cyclophosphamide)
Antihypertensives
CCB (verapamil, nifedipine), diuretics (furosemide), centrally-acting (clonidine), antiarrhythmics (amiodarone), beta blockers (atenolol)
Bile acid sequestrants
Colestyramine, colestipol
5HT3-receptor antagonists
Ondansetron
Laxatives
Chronic abuse Branch RL, Butt TF. Drug-induced constipation. Adverse Drug Reaction Bulletin 2009;257.
Drug-Induced Constipation Therapeutic Category
Examples
Excess fiber
Dietary or prescribed
Other antidepressants
Monoamine amine oxidase inhibitors
Other antiparkinsonian agents
Dopamine agonists
Other antispasmodics
Peppermint oil
Anticonvulsants
Carbamazepine
Miscellaneous
Barium sulphate, octreotide, polystyrene resins, oral contraceptives Vitamin C tablets, 131I thyroid ablation, erythropoietin, baclofen Pamidronate, alendronic acid, PPI and H2 antagonists
Branch RL, Butt TF. Drug-induced constipation. Adverse Drug Reaction Bulletin 2009;257.
DDIs in Palliative Care • Retrospective chart review of 200 consecutive PC unit inpatient • 631 potential DI in 151 patients (75%) • Median number of meds: 14 (2-25) • Common DI meds: scopolamine, neuroleptics, metoclopramide, antihistamines, non-steroidal anti-inflammatory drugs, (levo-) methadone, amitriptyline, carbamazepine and diuretics
• No documentation of clinical relevance in high risk for severe DI patients (n=8) Gaertner J, et al. Palliat Med. 2011; July 7.
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Top Offenders 300
Red Flag Score
250 200 150 100 50 0
Red Flag Score: # DDIs class 1-4 per pt. exposed55
Risky Business • Check Interactions in advance: – Micromedex – Lexi-Comp
• Look at the data • Assess your patient • Make a good decision
Assessing DI • Consider potential risk • Assess clinical signs/symptoms • Compare onset to timeframe of new meds or medication changes
I Found A DI… now what?! • drug interaction does not automatically negate the usefulness of the drug combination • dose may be changed • timing of administration may be altered
• And you may have beneficial results for required drug regimen
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Questions?
Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Medicine 2008;9(3):315-344. Bernard SA and Bruera E. Drug interactions in palliative care. Journal of Clinical Oncology 2000;18(8):1780-99. Kapur BM, Hutson JR, Chibber T, Luk A, Selby P. Methadone: A review of drug-drug and pathophysiological interactions. Critical Reviews in Clinical Laboratory Sciences 2011;48(4):171-195.